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Silybin represents the most bioactive compound of Silymarin, a flavonoid derived from Silybum marianum species. As a medicinal plant extract, Silybin possesses protective and regenerative action with respect to hepatic parenchyma. Due to its anti-oxidant, anti-inflammatory and anti-fibrotic effects, Silybin has been proposed as an extremely attractive molecule in the prevention and treatment of different hepatic diseases related to steatosis, such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). However, the full comprehension of the molecular mechanisms by which Silybin acts as hepato-protector is still far from being complete. Silybin-mediated properties usually involve modulation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor family (PPARs) pathways, which can affect NAD+-dependent protein lysine deacetylase Sirtuin (SIRT) family members either directly or indirectly. Starting from a detailed overview of its liver-related features, as well as the underlying molecular mechanisms, this review aimed at collecting evidence that correlates Silybin-mediated outcomes with SIRT pathways. With particular reference to SIRT1 and SIRT2, a theoretical map is designed in an effort to highlight shared molecular interactions. Finally, future perspectives concerning the integration of Silybin and Sirtuin pathways in fatty liver diseases are discussed, along with the major limits for its current therapeutic usage.
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Introduction: Natural products offer diverse therapeutic effects in chronic disorders, of which cancer is a major one. Natural products act as modulators of the receptor pathway, thus being protective and reducing the impact of many coexisting medical problems. The present review evaluates the therapeutic efficacy of natural products in the context of cancer therapy.
Methods: A detailed and thorough survey of the research and review papers published in the concerned domain was extensively studied and considered with the help of suitable keywords in all prominent databases.
Results: The increasing popularity of natural products as anticancer agents can be attributed to their distinctive chemical composition and capacity to target a wide range of cancer pathways. This in-depth review examines the classifications, mechanisms of action, preclinical and clinical investigations, and prospects of natural product combination cancer therapy. Phytochemicals from plants, marine organisms and fungi induce apoptosis, reduce cell proliferation, and regulate signalling pathways to fight cancer. Preclinical studies demonstrated cytotoxic effects and molecular targets, whereas clinical trials showed cancer shrinkage and improved survival. Natural treatments enhance orthodox therapy and reduce pharmaceutical resistance. Clinical usage requires safety and formulation uniformity.
Conclusion: Future research on natural phytochemicals, novel compounds, and delivery systems for immunotherapy and personalized treatment is warranted. More research and validation are required to optimize cancer treatment using natural products.
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The enormousness of Invasive fungal infections (IFIs) are coming much more into notice lately. The clinical manifestations vary and can range from colonization in allergic broncho-pulmonary disease to active infection in local aetiological agents. The increase of immunosuppressive agents in association with solid organ transplants, chemotherapy and improved life-saving medical techniques necessitating indwelling catheters led to a substantial increase in the occurrence of serious invasive fungal infections. Azole antifungals helped by adding to therapeutic options in treatment of IFIs works by inhibiting 14α-lanosterol demethylase, a key enzyme in ergosterol biosynthesis, resulting in depletion of ergosterol and accumulation of toxic 14α-methylated sterols in membranes of susceptible fungus. Azoles are classified into two: the triazoles (fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole) and the imidazoles (ketoconazole). Despite wide spectrum activity, these drugs show toxic effects like hepatitis and inhibition of steroid hormone synthesis, prolonged corrected for heart rate (QTc) intervals, Suppressive effects on spatial learning and memory in long-term treatments and treatment with higher concentrations. Many clinical cases have reported visual impairment, photopsia and photophobia along with many other symptoms. Drug interactions of azoles are numerous and show effects like seizures, neuropathy and serotonin toxicity. The review gives an overview of mechanism, spectrum of activity and toxic effects of azole drugs observed in clinical cases as well as animal studies.
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Background: Krabbe disease is due to a deficiency of lysosomal enzyme galactosylceramidase, which leads to destruction of the myelin sheath around nerves in the brain and spinal cord. In addition, Krabbe disease is associated with neuroinflammation in which harmful amounts of lipids are produced. To assess the importance of the regulation of lipid metabolism in the pathogenesis and intervention options in Krabbe disease, the aim of this study was to identify a set of specific biomarkers in a mouse model of the disease and to analyze the correlation between each biomarker.
Methods: In this study, fatty acid mediators were investigated in twitcher mice, a natural model of Krabbe disease, and the genotype was determined. Mass spectrometry was used to quantify F₂-isoprostanes and immune techniques were used to investigate F₂-isoprostanes, resolvin D1 (RvD1), peroxisome proliferator-activated receptor gamma, apelin, and the apelin receptor in the brains of heterozygous and affected homozygous mice and in wild-type control mice.
Results: The results of molecular analysis showed that there was a reduction in peroxisome proliferator-activated receptor gamma in the brains of both heterozygous and affected homozygous mice (p < 0.001). In addition, in the brains of mice with Krabbe disease RvD1 levels were decreased (p < 0.001), oxidation of arachidonic acid was increased (p < 0.001) and low levels of apelin (p < 0.001) were associated with an increase in apelin receptor (p < 0.05). RvD1 and apelin levels were associated with disease severity (r = –0.638, p < 0.001 and r = –0.725, p < 0.001, respectively).
Conclusion: Our results indicate that mutation of the galactosylceramidase gene is associated with altered homeostasis of fatty acid oxidative metabolism. These homeostatic alterations reflect the disease phenotype. Our findings highlight a relevant aspect of fatty acid metabolism in the Krabbe disease brain and support the view that fatty acid metabolism is an active player in the pathogenesis of this still incurable disease.
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Background: Growing evidence supports the pivotal role of berberine in non-small-cell lung cancer (NSCLC) and its ability to confer cisplatin resistance in NSCLC. This study aimed to investigate the impact of berberine on NSCLC cells.
Methods: A549 and H1299 cells were selected as the subjects of this study, and cisplatin-resistant cell lines were established. Cell counting kit 8 (CCK-8) was utilized to assess cell vitality, while cell apoptosis was quantified through the TUNEL (TdT-mediated dUTP nick-end labeling) test. The influence of berberine on cell proliferation was examined using a colony formation test and EdU (5-ethynyl-2′-deoxyuridine). Western blotting was employed to identify the effects of cisplatin and berberine on the expression levels of the phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway.
Results: The results indicate that 40 μm berberine significantly decreased the activity of NSCLC cells, without significantly affecting the activity of normal cells (Human Normal Lung Epithelial Cells, BEAS-2B). Berberine reduced the growth of A549 and H1299 cells and accelerated cell apoptosis. Furthermore, experimental data revealed that berberine could attenuate the resistance of NSCLC cells to cisplatin. Cisplatin-resistant cell lines of A549 and H1299 were established, showing that 15 μm cisplatin had no noticeable impact on the proliferation and apoptosis rates of drug-resistant cell lines. However, co-treatment with berberine and 15 μm cisplatin significantly reduced the proliferation of the drug-resistant cell lines and increased apoptosis rates. Western blot results indicated that drug-resistant cells treated with cisplatin had lower phosphorylation levels of PI3K and AKT than the control group. However, a substantial decrease in PI3K and AKT phosphorylation levels was observed when drug-resistant cells were co-treated with berberine.
Conclusion: Berberine effectively suppressed the proliferation of NSCLC cells and, when combined with cisplatin, induced apoptosis in these cells.
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Background: Cancer is the second leading cause of death world-wide, surpassed only by heart diseases. Diabetes Mellitus is the most globally recorded disease, and a significant number of patients receive diagnoses for both cancer and diabetes. Diabetic patients are prone to developing liver and pancreatic cancer. The objective of this study to identify spirooxindoles scaffold with a broad spectrum of biological targets, particularly those associated with cancer and diabetes.
Methods: New spirooxindole-pyrrolidines analogs were designed, synthesized and isolated through a [3 + 2] cycloaddition reaction (32CA) protocol. Following separation and purification via column chromatography, the target spirooxindole-pyrrolidines analogs underwent screening for anticancer activity against breast cancer cells (MDA-MB-231) and liver carcinoma (HepG2) cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Additionally, molecular docking and investigation of Absorption, Distribution, Metabolism, and Excretion (ADME) pharmacokinetics were conducted for the studied compounds.
Results: The compound 8e demonstrated the highest activity against triple-negative breast cancer and liver cancer, with Half maximal inhibitory concentration (IC50) values of 4.1 and 8 μM, respectively. The inhibition potential of α-Amylase ranged from 25.25% to 62.96%. Notably, within this series, compound 8c exhibited the highest activity, showing an inhibition rate of 62.96%. To gain insights into the binding mode of these compounds within the enzyme's active site, a molecular docking study was conducted. The results of the docking study identified compound 8c as the most potent within the series, with docking scores of –8.91. Furthermore, a molecular dynamic simulation (MDS) was carried out for the most active compound. The analysis revealed that compound 8c remained highly stable throughout the 50 ns simulation.
Conclusions: A new class of spirooxindole analogs has been identified as small molecule inhibitors with potential applications in diabetes and cancer. These compounds exhibit promising characteristics, warranting further in-depth investigations.
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Background: Ligustilide (LIG) has been found to inhibit osteoclastogenesis and promote osteogenesis. However, its impact on osteoporosis remains inadequately understood. This study, therefore, aims to investigate the anti-osteoporotic mechanism of LIG.
Methods: Bilateral ovariectomy (OVX) was performed on female rats to simulate estrogen deficiency-induced osteoporosis. Subsequently, LIG was administered in vivo experiments to investigate its effects on osteoporosis in OVX-treated rats. Following the administration of LIG or estradiol (E2), used as a positive control, femoral and lumbar vertebrae specimens were collected for histological analysis, micro-computed tomography, and Western blot. Blood and urine samples were taken for biochemical analysis and enzyme-linked immunosorbent assay. Isolated bone marrow mesenchymal stem cells (BMSCs) were used to explore the effects of LIG on cell activity, osteogenic differentiation, prostaglandin-endoperoxide synthase 2 (PTGS2) expression, and the bone morphogenetic protein (BMP)/contraction of Sma and Mad (Smad) pathway. These cells were transfected with PTGS2 short hairpin RNA (shRNA) and then treated with LIG at different concentrations, followed by alkaline phosphatase (ALP) staining, Alizarin Red S staining, and Western blot.
Results: LIG significantly increased serum estrogen levels and uterine weight in OVX-treated rats (p < 0.01) and improved bone morphology, including trabeculae in the femurs and the fourth lumbar vertebrae, with no significant change in body weight. LIG elevated bone mineral density (BMD), trabecular number (Tb.N), and trabecular bone volume/tissue volume (BV/TV) while decreasing trabecular spacing (Tb.Sp) levels (p < 0.05, p < 0.01, and p < 0.001). However, it had an insignificant effect on trabecular thickness (Tb.Th) levels. LIG enhanced serum calcium, phosphorus, ALP, and osteoprotegerin (OPG) levels, while reducing urinary calcium and phosphorus levels, as well as levels of bone resorption indicators (tartrate-resistant acid phosphatase-5b (TRAP-5b) and C-terminal telopeptide of type I collagen (CTX-I)) in the serum of OVX-treated rats (p < 0.05, p < 0.01, and p < 0.001). LIG augmented PTGS2, bone morphogenetic protein 2 (BMP2), and Smad4 expressions in bone tissues of OVX-treated rats (p < 0.01 and p < 0.001). In BMSCs, LIG dose-dependently promoted cell viability, ALP positivity, mineralization, and up-regulated the osteoblast markers (collagen type I alpha 1 (Col1A1), RUNT-related transcription factor 2 (RUNX2)), PTGS2, BMP2, and Smad4 levels (p < 0.05, p < 0.01, and p < 0.001). Conversely, PTGS2 silencing reversed the promoting role of LIG in osteogenesis of BMSCs by inhibiting the BMP/Smad pathway (p < 0.01 and p < 0.001).
Conclusion: LIG ameliorates osteoporosis in OVX-treated rats and promotes osteogenesis in BMSCs by targeting PTGS2 to regulate the BMP/Smad pathway.
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Background: In Turkey, Astragalus species are highly appreciated for their traditional therapeutic values. This research was devised to investigate the chemical composition, antioxidant, and enzyme inhibition activities of the aerial components of Astragalus (A.) angustifolius subsp. pungens, A. prusianus, and A. zederbaueri.
Methods: Four extracts namely; ethyl acetate (EtOAc), methanol (MeOH), 70% MeOH, and aqueous extracts, were meticulously prepared. The chemical composition was examined utilizing spectrophotometric and High performance liquid chromatography-mass spectrometry (HPLC-MS)/MS techniques. The antioxidant activity was assessed by investigating the extracts' capability to scavenge radicals, reduce ions, and chelate ferrous ions. The enzyme inhibition properties were evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase (Tyr), α-glucosidase, and α-amylase enzymes.
Results: The findings revealed that the greatest total phenolic (28.33 mg gallic acid equivalent/g) and flavonoid (66.59 mg rutin equivalent/g) contents were achieved with the MeOH extract of A. angustifolius. The chemical profiles of the three species were marked by the presence of flavonol glycosides containing kaempferol, rhamnetin, isorhamnetin, and quercetin structural motifs. MeOH extract of A. angustifolius exerted the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (48.73 mg trolox equivalent (TE)/g), Cu++ (150.10 mg TE/g) and Fe+++ (84.78 mg TE/g) reducing capacity. The three polar extracts (67.18–69.64 mg TE/g) of this species in addition to the aqueous extract (69.46 mg TE/g) of A. zederbaueri displayed the best 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity. 70% MeOH extract of A. prusianus had the highest metal chelating power (25.61 mg ethylenediaminetetraacetate equivalent (EDTAE)/g). MeOH extracts (2.37–2.50 mg galatamine equivalent (GALAE)/g) of the three species revealed the highest AChE inhibition activity while EtOAc extract (2.01 mg GALAE/g) of A. zederbaueri had the highest BChE inhibition activity. The highest anti-Tyr (50.40 mg kojic acid equivalent/g) activity was recorded from the EtOAc extract of A. zederbaueri.
Conclusion: Thus, the three species of the studied Astragalus may represent a promising natural source of pyhtopharmaceutical agents for various pharmaceutical and nutritional uses.
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Background: Hepatic fibrosis (HF) is a prevalent precursor to cirrhosis in various chronic liver diseases, underscoring the need for comprehensive investigations into its etiology, prevention, and management. Pyroptosis, an emerging form of cellular death, is prevalent in liver diseases. Recent research suggests that ten-eleven-translocation protein 3 (TET3), an enzyme responsible for DNA demethylation, plays a vital role in regulating HF, although the precise mechanism remains unclear. This experimental study aimed to investigate the impact of the TET3-mediated pyroptotic pathway on HF in mice and elucidate the underlying regulatory mechanisms.
Methods: HF was induced in mice through intraperitoneal injection of carbon tetrachloride (CCl4), while lipopolysaccharide (LPS) induced pyroptosis in murine hepatocytes. Protein expression was detected using the Western blotting technique, and pathological alterations were evaluated through hematoxylin and eosin (H&E) and Masson staining. Immunofluorescence and dot blotting assessed the expression of 5-hydroxymethylcytosine (5-hmC), while transmission electron microscope measured hepatocyte ultrastructure. The relationship between TET3 and NLR family pyrin domain containing 3 (NLRP3), Caspase-1, and gasdermin D (GSDMD) was evaluated using chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR).
Results: The expression of pyroptotic proteins showed a positive correlation with the extent of HF (p < 0.05), while the expression of TET3 and 5-hmC exhibited a negative correlation (p < 0.05). TET3 overexpression successfully prevented HF, upregulated 5-hmC expression, and attenuated pyroptosis (p < 0.05). TET3 administration significantly increased LPS-induced pyroptosis in hepatocytes of mice (p < 0.05). Finally, TET3 was shown to target NLRP3, Caspase-1, and GSDMD genes (p < 0.01).
Conclusions: By reversing the classical pathway of pyroptosis, TET3 can potentially improve HF progression in mice by targeting NLRP3, Caspase-1, and GSDMD.
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Background: Sepsis characterized by an uncontrolled inflammatory response is a common clinical syndrome which can cause organ dysfunction, shock, and often death. Importantly, no specific treatment for sepsis exists. Little is known about the therapeutic effects of stem cells from human exfoliated deciduous teeth (SHEDs) on sepsis. The study aims to investigate immunomodulatory and protective effects of SHEDs against sepsis.
Methods: Polymicrobial sepsis was induced in mice via cecal ligation and puncture (CLP). SHEDs or normal saline was intravenously injected 30 min after CLP. Seventy-five adult male C57BL/6 mice were randomized into three groups (n = 25/group): (1) Sham-CLP; (2) CLP; (3) CLP+SHED. Mice (20/group) were monitored for 96 h post-CLP for survival. Five mice/group were euthanized at 24 h post-CLP; blood and tissues (lung, liver, kidney, spleen, and intestine) were harvested for pathophysiological study. A cytometric bead array assay was employed to assess plasma concentrations of cytokines [interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocytechemoattractant protein-1 (MCP-1), IL-10], and an automatic biochemical analyzer was used to assess liver and kidney function. Hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining were performed to evaluate organ injuries. Immunofluorescence staining and E. coli colony-forming units (CFUs) counts of the spleen were also employed.
Results: Kaplan-Meier survival analysis revealed a significantly lower survival rate in CLP than in Sham-CLP mice, and a significantly better survival rate in CLP+SHED mice than in CLP mice (p = 0.021). At 24 h post-CLP, serum IL-6, MCP-1, TNF-α, and IL-10 were significantly lower in the CLP+SHED group than in the CLP group (all p < 0.05). When compared to CLP mice, CLP+SHED mice had altered distribution of cluster of differentiation 3+ (CD3+) T cells and CD11c+ dendrocytes in the spleen, decreased the number of TUNEL+ cells in the kidneys and lungs, and altered TUNEL+ cell distribution in the intestine and spleen. Compared to CLP mice, TUNEL+ cells in kidney, lung and spleen of CLP-SHEDs group were attenuated although without significance (p = 0.079, 0.045 and 0.075 respectively). However, the distribution of TUNEL+ cells in intestine were altered in CLP+SHED mice when compared to CLP mice. The E. coli clearance in spleen was improved (p = 0.075) in the CLP+SHED mice when compared to CLP group.
Conclusions: SHEDs treatment 30 min after sepsis induction improves survival in mice with CLP-related sepsis. It has potential to be a new therapeutic option for sepsis.
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Background: The adverse effects of synthetic drugs have led to a rising interest in natural alternatives globally. In Pakistan, rural areas heavily rely on plant-based treatments for 80% of healthcare needs. Fernandoa adenophylla (F. adenophylla), a woody plant native to South Asia, possesses antimicrobial properties and has been traditionally used for various ailments. This research aims to formulate a syrup from F. adenophylla hydromethanolic leaf extracts, leveraging its antioxidant properties. The study follows United States Pharmacopeia guidelines to assess the potential anti-emetic properties of the syrup as an alternative to synthetic drugs, with a specific focus on emesis in female Albino Mice.
Methods: By the United States Pharmacopeia (USP) guidelines, we meticulously prepared a simple syrup and a decoction. The syrup was formulated by blending the decoction and simple syrup in a 1:5 ratio supplemented with 0.2% Methyl Paraben and rose oil. Antibacterial activity was assessed using urine samples, and antibiotic susceptibility was determined with ten antibiotics. The syrup's antibacterial and antifungal properties were evaluated through well diffusion assays. The insecticidal activity was tested on Tenebrio molitor and Dermetes ladies insects. Antioxidant activity was determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, and antiemetic effects were investigated in Albino female mice with castor oil-induced emesis. Statistical analysis was performed using statistical package for social sciences (SPSS) (p < 0.05).
Results: Our findings revealed noteworthy antibacterial activity, with the highest inhibition observed against V. cholera (32 mm). Additionally, the syrup demonstrated substantial antifungal activity, particularly against Rhizopus spp. (21 mm). Impressively, the syrup exhibited robust insecticidal properties, causing mortality rates of 80% in Tenebrio molitor and 70% in Dermetes ladarius.
Conclusion: The investigation of F. adenophylla leaf extract revealed the presence of potential antimicrobial compounds, which hold promise for treating various microbial infections. Phytochemical screening unveiled the presence of essential bioactive constituents such as terpenoids, flavonoids, saponins, glycosides, tannins, and reducing sugars in the F. adenophylla leaf extract. Moreover, the study suggests that the plant-based syrup derived from F. adenophylla may possess valuable antioxidant properties, making it a candidate for exploration in the realm of therapies targeting oxidative stress-related health conditions.
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Background: The tertiary lymphoid structures (TLSs) play a crucial role in the prognosis and response to skin cutaneous melanoma (SKCM) immunotherapy. Nevertheless, the molecular mechanisms underlying this connection remain unclear. Therefore, this study aimed to investigate the molecular subtypes of SKCM based on TLSs and to develop a scoring model using advanced bioinformatic approaches.
Methods: The Cancer Genome Atlas (TCGA) data were retrieved from University Of Cingifornia Sisha Cruz Xena (UCSC-Xena), and the SKCM series matrix file GSE19234 was obtained from Gene Expression Omnibus (GEO). Using R 4.1.1 and the Sva package, the sample data were integrated to eliminate batch effects. Univariate Cox regression and Kaplan-Meier analysis were employed for the identification of prognosis-related tertiary lymphoid structure-related genes (TRGs). Based on TRGs expression, SKCM patients were categorized into different subtypes. Furthermore, unsupervised learning-cluster analysis was used to evaluate their clinical features, prognosis, and gene expression. Similarly, pathway enrichment and immune infiltration differences were assessed using Molecular Signatures Database (Msigdb), gene set variation analysis (GSVA), and single-sample gene set enrichment analysis (ssGSEA). Subsequently, subtypes were verified using limma, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Additionally, a scoring model was developed to analyze immune infiltration and the relationship between clinical features and drug sensitivity in SKCM.
Results: Analysis of TCGA-SKCM revealed that over 80% of the SKCM patients exhibited TRG mutations, with missense mutation being predominant. Moreover, the Kaplan-Meier (K-M) survival analysis revealed that all TRGs acted as protective factors in SKCM, leading to prolonged survival among patients with elevated TRG expression. TRG expression clustered SKCM patients into three subtypes: Cluster A, Cluster B, and Cluster C. The K-M survival analysis revealed that patients in Cluster B exhibited the best prognosis and longest survival time as well as the highest TRG expression followed by Cluster A. Using 23 prognostic-related differentially expressed genes (DEGs), a scoring model was developed indicating worse prognosis and lower immune infiltration with higher scores. Lower scores correlated with longer survival, lower recurrence/metastasis, higher immune checkpoint expression, and better immunotherapy outcomes. Higher scores correlated with lower chemokine expression and reduced sensitivity to immune checkpoint inhibitors.
Conclusions: We established a new classification of SKCM based on TLSs. The constructed scoring model could evaluate the immune infiltration, prognosis, and response of immunotherapy in SKCM, thereby assisting clinical treatment.
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Background: Ketotifen is a leukotriene receptor antagonist that exerts anti-inflammatory effects primarily by antagonizing leukotriene B4 receptors. While the effect of ketotifen on sepsis-induced cardiac dysfunction remains to be further explored and its underlying mechanisms remain unclear. Hence, this study aimed to investigate the role and mechanisms of ketotifen in sepsis-induced cardiac dysfunction.
Methods: Rats were divided into five groups (n = 5 each group): control group, sepsis group, sepsis + low-dose ketotifen (1 mg/kg) group, sepsis + high-dose ketotifen (10 mg/kg) group and Healthy control group (HC group). Sepsis was induced by intraperitoneal injection of Lipopolysaccharide (LPS) at a dosage of 5 mg/kg and controls received Phosphoric acid buffer solution (PBS) injections instead. Ketotifen was intraperitoneally injected immediately before sepsis induction at doses of 1 or 10 mg/kg. The serum levels of inflammatory cytokines were determined and myocardial tissues were harvested.
Results: Compared to sepsis model group, ketotifen administration significantly alleviated sepsis-induced cardiac dysfunction, manifested as reduced serum levels of interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 17 (IL-17), tumor necrosis factor α (TNF-α), receptor for advanced glycation end products (RAGE) and soluble receptor for advanced glycation end products (sRAGE) (p < 0.05), increased left ventricular fractional (LVFS) (%) and left ventricular ejection fraction (LVEF) (%) detected by echocardiography (p < 0.05), improved myocardial structure shown by electron microscopy and reduced expression of transient receptor potential ankyrin 1 (TRPA1) in myocardial tissues of septic rats (p < 0.05). By western blotting, our results showed that the expressions of programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), V-domain Ig suppressor of T cell activation (VISTA) as well as Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) were remarkably elevated in sepsis model group (p < 0.05), and administration of ketotifen significantly downregulate the expressions of them.
Conclusion: Ketotifen exerted beneficial effects against cardiac dysfunction induced by sepsis in rats. The cardioprotective effect of ketotifen was possibly attributed to inhibiting PD-1/PD-L1 pathway in myocardial tissues of septic rats.
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Background: Acorus calamus is a perennial herbaceous plant indigenous to wetlands in Asia and Europe. It is also known by the common names Sweet Flag and Calamus. Traditional medicine and perfumery have long utilized its unusual sword-shaped leaves and scented rhizomes. In addition to being treasured for its possible therapeutic benefits, it is a cultural emblem in many communities. The current study investigates the composition of phytoconstituents of Acorus calamus essential oil (ACEO), assesses its drug-likeness properties, performs molecular docking studies with interleukin (IL)-1β, and evaluates its antioxidant and anti-inflammatory activities.
Methods: Gas Chromatography-Mass Spectrometry (GC-MS) was used for the analysis of phytoconstituents present in the ACEO. In silico studies were carried out to determine the pharmacokinetics, toxicity, drug-likeliness and interaction of ACEO phytoconstituents with IL-1β. In vitro assays, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and protein denaturation inhibition, were done to investigate the potential antioxidant and anti-inflammatory activities of the bioactive molecules present in ACEO, respectively.
Results: GC-MS analysis revealed the presence of 20 secondary metabolites with (Z)-Asarone as the major component (91.44%). In silico analysis showed the drug-likeness of (Z)-Asarone, isoshyobunone, and γ-Asarone. Molecular docking revealed strong binding affinities of these compounds with IL-1β. In vitro experiments demonstrated ACEO's significant (p < 0.01) antioxidant activity at the concentrations 6 and 12 μg/mL with an IC50 value of 6.68 μg/mL, comparable to the standard (ascorbic acid, IC50 = 3.69 μg/mL). ACEO also exhibited significant (p < 0.05) protein denaturation inhibition compared to diclofenac sodium (IC50 = 365.43 μg/mL vs. 446.20 μg/mL).
Conclusion: Acorus calamus essential oil primarily composed of (Z)-Asarone, possesses potential antioxidant and anti-inflammatory properties. These findings suggest its therapeutic potential in addressing oxidative stress-related conditions and inflammation-associated diseases, warranting further investigation and development as a natural remedy.
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Background: Primary membranous nephropathy (PMN) is the leading cause of nephrotic syndromes in adults. However, biopsy is a commonly used approach in diagnosing as well as assessing renal disease progression. This study aimed to screen potential PMN biomarkers using proteomic methods on peripheral blood mononuclear cells (PBMCs) and to provide an important reference value for the scientific diagnosis of PMN.
Methods: Peripheral blood samples were obtained from both PMN patients and healthy controls. Total RNA was extracted and subsequently reverse-transcribed into cDNA. Meanwhile, by combining proteomics analysis with Liquid Chromatography with tandem mass spectrometry (LC-MS/MS) technique, candidate biomarkers for PMN were screened employing bioinformatics analysis of PBMCs. Furthermore, the expression levels of differentially expressed proteins in both PMN patients and normal controls were assessed using quantitative real-time polymerase chain reaction (qRT-PCR).
Results: A total of 81 differential expressed proteins (DEPs), of which 29 were up-regulated and 52 were down-regulated, were isolated and screened. Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment of DEPs was observed for fatty acid metabolism. Furthermore, four candidate PMN biomarkers were identified, including H2A clustered histone 20 (H2AC20), H2B clustered histone 21 (H2BC21), splicing factor 3a subunit 1 (SF3A1), and serine and arginine rich splicing factor 1 (SRSF1). The mRNA expression levels of these genes were assessed using the qRT-PCR analysis and were found consistent with LC-MS/MS data. Moreover, the mRNA expression levels of H2AC20, H2BC21, SF3A1, and SRSF1 were significantly reduced in PMN patients compared to the healthy controls.
Conclusion: In summary, H2AC20, H2BC21, SF3A1, and SRSF1 are the candidate PMN biomarkers using proteomic methods based on PBMCs. More importantly, these findings suggest a potential link between fatty acid metabolic pathways and PMN. Finally, this study provides a scientific reference for the diagnosis of PMN.
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Background: Testicular damage is considered one of the detrimental consequences linked to the use of the chemotherapeutic compound cyclophosphamide (CP). The present in vivo study examined the possible protective effects of apigenin (AP) against CP-induced testicular damage in mice.
Methods: Mice received AP (20 and 40 mg/kg/day) for 15 days, followed by a single dose of CP (150 mg/kg) at day 16. At the end of the study, the blood, tissue, and mouse epididymal sperm samples were collected. Sperm cell counts, viability, motility, and serum levels of testosterone were estimated. Oxidative stress markers, antioxidants, inflammatory, and apoptotic signaling proteins were evaluated by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry in the testicular tissue. Moreover, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) levels were estimated in the testes.
Results: The findings showed that the CP-intoxicated mice had significantly low sperm count, viability, motility, and testosterone levels. Remarkably, the administration of 20 or 40 mg AP significantly attenuated testosterone levels and sperm measurements (p < 0.05). Likewise, treatment of CP-injected animals with AP counteracted the CP-induced histopathological changes in testes. In addition, AP administration significantly (p < 0.05) diminished the CP-induced testicular damage by boosting antioxidants such as glutathione, superoxide dismutase, and catalase, suppressing the pro-inflammatory cytokines tumor necrosis factor alpha, interleukin-1beta, interleukin-6 and nuclear factor-kappa B, and decreasing apoptosis as measured by B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X (BAX), and caspase-3 levels in the testes. This was accompanied by increased Nrf2/HO-1 expression in the testicular tissue of CP-treated mice.
Conclusions: AP may be a strong preventive compound against CP-induced testicular oxidative damage, inflammation, and apoptosis, possibly by stimulating Nrf2/HO-1 signaling pathway.
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Background: Osteoblasts play a pivotal role during fracture healing. Piezo-Type Mechanosensitive Ion Channel Component 1 (Piezo1) is crucial in regulating bone homeostasis. Hence, the objective of this investigation was to explore the molecular mechanisms associated with Piezo1 in the fracture healing process and to clarify its influence on the physiological activities of osteoblasts.
Methods: At the outset, the MC3T3-E1 cells were categorized into three sets: the control group, the Yoda1-treated group, and the Grammostola spatulata Mechanotoxin 4 (GsMTx4)-treated group. Subsequently, the cells underwent transfection with Scramble siRNA (Sc siRNA), Piezo1-specific siRNA, pcMV-FLAG Expression (pcMV-FLAG) vector, or pcMV-FLAG-Piezo1. The quantification of gene and protein expression levels was carried out utilizing quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Following that, the effects of manipulating Piezo1 expression, along with the use of the Piezo1 agonist (Yoda1) and inhibitor (GsMTx4), on cell proliferation, adhesion, and migration were assessed through the Cell Counting Kit-8 (CCK-8) assay, cell adhesion assay, scratch assay, and Transwell assay. Ultimately, the influence of Yoda1 and GsMTx4 on the Piezo1/Phosphoinositide 3-kinase (PI3K)/Protein kinase B (AKT)/Mammalian target of rapamycin (mTOR)/Cyclin D1 signaling pathway was examined utilizing Western blot analysis.
Results: The overexpression of Piezo1 and the presence of Yoda1 significantly enhanced the viability, adhesion, and metastatic capabilities of MC3T3-E1 osteoblasts (p < 0.01 and p < 0.001). Conversely, Piezo1 knockdown and the application of GsMTx4 significantly suppressed the viability, adhesion, and metastasis of MC3T3-E1 cells (p < 0.01 and p < 0.001). Moreover, Yoda1 induced an elevation in the protein levels of Piezo1, Cyclin D1, p-PI3K, p-AKT, and p-mTOR (p < 0.01 and p < 0.001). In contrast, GsMTx4 resulted in a marked decrease in their expression levels (p < 0.05 and p < 0.01).
Conclusion: Piezo1 modulates the migration and adhesion of osteoblasts during the bone healing process, acting as a mediator in the signal transduction through the PI3K/AKT/mTOR/Cyclin D1 pathway.
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Background: The chronic progression of ankylosing spondylitis is accompanied by inflammatory bone erosion, vertebral bone loss, and abnormal bone overgrowth. It is known that targeting osteogenic differentiation of fibroblasts can prevent new bone formation, representing an effective approach to alleviating the burden caused by ankylosing spondylitis. The upregulation of ankylosis progressive homolog (ANKH) has been found to inhibit ankylosing spondylitis ligament-derived fibroblast ossification. This study was designed to decipher the mechanism behind this effect mediated by ANKH.
Methods: The interplay between ANKH and estrogen receptor 1 (ESR1) gene was assessed by bioinformatics/chromatin-immunoprecipitation/dual-luciferase reporter assay. Ankylosing spondylitis-derived fibroblasts were isolated from human ankylosing spondylitis ligaments, where ESR1 expression was assessed with Western blotting. Co-immunoprecipitation assay was utilized to investigate the affinity between ESR1 and small ubiquitin-like modifier 1 (SUMO1). After inducing ESR1 overexpression and SUMO1 knockdown, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Alizarin red staining were performed to evaluate the viability and mineralization of fibroblasts. Real-time quantitative polymerase chain reaction and Western blotting were carried out to determine the gene and protein expression of ANKH, ESR1, SUMO1, osteogenesis-related markers, and Wnt/β-catenin pathway-related markers.
Results: ESR1 overexpression upregulated ANKH and p-β-catenin/β-catenin levels, decreased the viability, inhibited the mineralization, and downregulated the expression levels of osteogenesis-related genes, c-Myc and β-catenin in ankylosing spondylitis-derived fibroblasts. It was found that SUMO1 could bind to ESR1, and the SUMO1 knockdown downregulated ESR1 level, exerting effects contrary to those after ESR1 overexpression. This finding indicates that the effects of SUMO1 knockdown and ESR1 overexpression on ankylosing spondylitis-derived fibroblasts are opposite to each other.
Conclusions: In sum, the SUMO1/ESR1 pathway upregulates ANKH level to inhibit ankylosing spondylitis-associated fibroblast ossification.
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Background: Titanium dioxide nanoparticles (TiO2 NPs) are widely used in medicine and industry. In this study, the protective effects of fat-soluble vitamins A (1000 IU/kg) and E (100 IU/kg) on oxidative stress caused by TiO2 NPs (300 mg/kg body weight (BW) in the testes of rats were studied.
Methods: A total of 36 male Wistar rats were randomly divided into six groups of six rats. Two control groups were treated with bi-distilled water and olive oil, respectively. The intoxicated group received 300 mg/kg TiO2 NPs. The three remaining groups were given vitamins E (100 IU/kg) + TiO2 NPs (300 mg/kg), vitamins A (100 IU/kg) + TiO2 NPs (300 mg/kg), and a mixture of vitamins E (100 IU/kg) and vitamins A (100 IU/kg) + TiO2 NPs (300 mg/kg), correspondingly. The treatments were carried out for two weeks, although vitamins were given to animals one week earlier than TiO2. At the end of treatment, the testicular tissue of rats was studied for total antioxidant capacity (TAC); catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities by related kits; total oxidant status (TOS) and lipid peroxidation index, malondialdehyde (MDA) through manual methods; Furthermore, gene expression levels of SOD, GPx, Nuclear factor kappa B (NF-κB) and tumor necrosis factor alpha (TNF-α) were evaluated by real-time polymerase chain reaction (RT-PCR) and protein assay of TNF-α was conducted using enzyme-linked immunosorbent assay (ELISA) kit.
Results: TiO2 NPs stimulated oxidative stress via the marked reduced antioxidant (p < 0.05), increased oxidant status p < 0.05, and elevated inflammatory mediators in testicular tissue (p < 0.05) compared to the control groups. Interestingly, treatment with the vitamins significantly attenuated the oxidative stress induced through TiO2 NPs (p < 0.05). The combination of vitamins A and E on reducing oxidative stress and inflammation had a more significant effect than the vitamins alone.
Conclusion: Vitamins A and E, as effective agents, have antioxidant and anti-inflammatory properties on the toxicity of TiO2 NPs in testes.
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Background: Neointimal hyperplasia (NIH)-induced vein graft remodeling poses a challenge for coronary artery bypass grafting surgery. Despite the crucial influence of hemodynamic conditions on vein graft remodeling, the specific mediators orchestrating cellular processes and morphological changes during this process remain unclear. A comprehensive understanding of flow-mediated NIH is essential for developing preventive strategies.
Methods: Sprague-Dawley (SD) rats were utilized to establish a vein transplantation model, manipulating flow states by ligating the distal carotid branch. Graft tissues exposed to high-flow and low-flow conditions were assessed at control, Day 7, Day 14, and Day 28 time points to evaluate the neointimal area and cell phenotypes using histological staining. Immunofluorescence staining was employed to examine LIM and cysteine-rich domains 1 (Lmcd1) gene expression under different flow conditions. Additionally, changes in NIH were observed in SD rats through adeno-associated viral gene transfer of Lmcd1 short hairpin RNA (shRNA).
Results: The model demonstrated an immediate decrease in mean flow rates of vein grafts over the 28-day period following ligation of the carotid artery branch (p < 0.0001). This significantly increased the intimal area, which progressively rose until day 28 (p < 0.05). Low-flow arterial hemodynamic conditions markedly downregulated the expression of characteristic mature muscle markers and significantly upregulated cell proliferation, Lmcd1, and phosphoinositide 3-kinase (PI3K) pathway. Gene transfer of Lmcd1 shRNA inhibited PI3K pathway activation, promoted the adoption of a mature phenotype by neointimal cells, and reduced neointimal area in low-flow vein grafts compared to controls (p < 0.01).
Conclusions: Distinct vein graft remodeling patterns arise from flow environment alterations. The observed increase in NIH in low-flow grafts is associated with differentially expressed Lmcd1, which regulates the PI3K pathway, influencing the phenotypic modulation of cells within the neointima. Perturbations in Lmcd1 activity regulate the PI3K pathway and contribute to maladaptive vascular remodeling under reduced blood flow conditions.
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Background: Sirtuin3 (SIRT3), a pivotal mitochondrial regulatory enzyme, protects cellular components in the central nervous system against oxidative and metabolic stress. However, its influence on cognitive functions, especially within the hippocampal neurons and the cognitive disruptions induced by sepsis, remains elusive. This study aimed to elucidate the direct impact of SIRT3 on neuronal health and its involvement in cognitive deficits following sepsis.
Methods: Behavioral changes were evaluated using fear conditioning protocols in wild-type (WT) and SIRT3 deficient (Sirt3-/-) mouse models. SIRT3 expression levels were quantified in septic mice following intraperitoneal lipopolysaccharide (LPS) administration (LPS, 10 mg/kg). In cellular experiments, HT22 neuronal cells were exposed to LPS (1 μg/mL) or conditioned media from LPS-stimulated BV2 microglial cells (Mi-sup). Western blot analysis was employed to assess the presence of synapse-related and mitochondrial apoptosis-associated proteins. Oxidative stress and mitochondrial membrane potential (MMP) were respectively performed with reactive oxygen species (ROS) staining and 5,5′,6,6′-tetrachloro1,1′,3,3′-tetraethylbenzimid azolocarbocyanine iodide (JC-1) staining. Mitochondrial p66Shc and c-Jun N-terminal kinase (JNK) phosphorylation levels were evaluated through western blotting and immunofluorescence assays.
Results: Contextual and cued freezing durations were significantly shorter in Sirt3-/- mice than in wild-type counterparts (p < 0.05 and p < 0.01, respectively). Sirt3-/- mice exhibited a reduction in postsynaptic density protein 95 (PSD95) (p < 0.05) and an increase in brain-derived neurotrophic factor precursor (pro-BDNF) (p < 0.001). Sepsis led to a marked decrease in SIRT3 expression (p < 0.001) in mice. In cellular studies, the elevation of SIRT3 significantly increased PSD95 (p < 0.01), reduced pro-BDNF (p < 0.05), and enhanced the B-cell lymphoma 2/Bcl-2-associated X protein (Bcl-2/Bax) ratio (p < 0.05) while decreased cytochrome C release (p < 0.05) in Mi-sup-treated HT22 cells. Additionally, SIRT3 elevation reduced ROS production (p < 0.05) and enhanced MMP (p < 0.05). Mi-sup exposure was associated with elevated p-p66Shc/p66Shc and p-JNK/JNK ratio (p < 0.05 and p < 0.01). The activation of JNK/p66Shc was mitigated by either SIRT3 overexpression or the application of a JNK inhibitor (p < 0.01).
Conclusion: SIRT3 deficiency contributes to cognitive impairment. SIRT3 expression was reduced in the hippocampus of septic mice, resulting in similar cognitive deficits. Mechanistically, the neuronal JNK/p66Shc activation contributed to SIRT3 deficiency-mediated synaptic dysfunction and mitochondrial apoptosis in response to microglia activation-induced inflammation and oxidative stress. Our findings provide new insights into the role of SIRT3 in cognitive function and its potential clinical significance in sepsis-induced cognitive impairment.
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Background: Multiple myeloma (MM) is characterized by destructive osteolytic lesions, hypercalcemia, renal insufficiency, and anemia. However, bortezomib (Btz) has been recognized as a cornerstone treatment for various types of MM. Therefore, this study explored the effect of erastin on the efficacy of Btz and evaluated the synergistic effects of erastin in combination with Btz on MM cells.
Methods: Glutathione (GSH) level was evaluated in MM cell lines to determine its effects on redox balance and cell growth. Furthermore, Solute Carrier Family 7 Member 11 (SLC7A11) was inhibited in MM cells using small-interfering RNA (siRNA) and erastin to determine its effect of redox balance on cell proliferation. Moreover, western blot analysis, flow cytometry, and ferroptosis-related verification experiments were employed to assess the changes that occur after treatment in the cell cycle, the expression of DNA damage repair marker protein, and ferroptosis. Additionally, the synergistic zero interaction potency (ZIP) scores and combination indexes (CIs) of these two drugs were calculated using different concentrations of Btz and erastin, and MM cell proliferation was compared when treated with single and combined drugs.
Results: It was observed that increased GSH levels (p < 0.05) disrupted the redox equilibrium and promoted MM cell proliferation. Moreover, activation of siSLC7A11 induced the Ataxia Telangiectasia and Rad3-related Checkpoint Kinase 1 (ATR-CHK1) DNA repair pathway, resulting in a decrease in GSH levels (p < 0.05), a rise in intracellular reactive oxygen species (ROS) levels, alterations in intracellular redox equilibrium, and the induction of ferroptosis. Additionally, the ATR-CHK1 DNA repair pathway resulted in cell cycle S-phase arrest and effectively reduced MM cell growth. However, inhibiting SLC7A11 (p < 0.05) led to higher MM cell response to Btz. Moreover, the combination of erastin and Btz significantly increased cytotoxicity in MM cells (p < 0.05).
Conclusion: Erastin increases the level of reactive oxygen species (ROS) in MM cells by inhibiting SLC7A11, which activates the ATR-CHK1 DNA damage repair pathway and causes MM cells to ferroptosis. Furthermore, erastin synergistically increases the cytotoxicity of Btz in multiple myeloma.
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Background: Primary liver cancer (PLC) is the sixth most common malignant tumor in the world. Hepatocellular carcinoma is the most common form (85–90%) of PLC. We aimed to explore the construction of a new type of Glypican-3 (GPC3) antibody and determining its value in the diagnosis and immunotherapy/targeted therapy of hepatocellular carcinoma.
Methods: Patients with or with hepatic benign tumors were recruited. Preoperative peripheral blood and postoperative paraffin samples of patients with HCC and peripheral blood samples of patients with benign liver tumors were collected. The expression of GPC3 protein was measured by immunohistochemical assay and enzyme-linked immunosorbent assay (ELISA). The Laser scanning confocal technique was used to observe the phenomenon of endocytosis induced by antibodies and the localization of endocytosis bodies. The viral plasmid targeting GPC3 chimeric antigen receptor (CAR-GPC3) was constructed using BMK antibody and the gene sequences of # 5m and # 49m scFv. The antibody-radionuclide conjugate 131I-anti-GPC3 Conjugate (131I-aGPC3) was prepared by labeling # 49GPC3-mAb with 131I. A mouse model of subcutaneous xenograft tumor was established using 7721 cells without GPC3 and Hep3b cells with high expression of GPC3. The targeting effect of 131I-aGPC3 on tumors in mice was observed by single photon emission computed tomography (SPECT).
Results: GPC3 protein was mainly expressed in the tumor cell membrane and cytoplasm. The antibody content in the peripheral blood of patients with positive expression of GPC3 protein was significantly higher than in patients with negative GPC3 protein and benign tumors (p < 0.01). The radiation signals were gradually enriched in the tissue of GPC3-positive tumors. 72 hours after injection, the background signal in vivo gradually disappeared, whereas the radiation signal in the tumor site concentrated significantly concentrated and could last longer. In addition, 131I-aGPC3 was gradually enriched in the tumor site of the Hep3b transplanted tumor model. The radiation signal was significantly enhanced, while in the 7721 transplanted tumors, the antibody was metabolically cleared, and there was no obvious radiation signal.
Conclusion: CAR-GPC3-T, constructed with new antibody sequences of # 5GPC3-mAb and # 49GPC3-mAb, kills HCC tumor cells in vitro.
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Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a growing incidence and mortality despite novel therapeutic strategies. Its aggressiveness and difficulty in treatment suggest the need for a better understanding of associated molecular mechanisms that could be targeted for treatment. The complement signalling pathway may play diverse roles in PDAC by eliciting an immune response, inducing inflammatory responses, and elevating pathways linked to chemoresistance. However, their role in the progression of PDAC is not fully understood. This study aimed to identify potential immune response-related targets in a group of patients.
Methods: Thirty tissue samples (tumours and corresponding normal tissues) were obtained from 15 PDAC patients, 34 plasma samples from 25 PDAC patients, six patients with chronic pancreatitis, and three healthy control participants. Targeted pathway-specific polymerase chain reaction (PCR) analysis was conducted to determine the gene expression profiles of immune-response-related genes. The circulating levels of complement proteins C3 and C5 were further investigated. Pharmacological inhibition of the complement pathway in MIA PaCa-2 pancreatic cancer cell lines was performed, and the effect was assessed by cell proliferation, cell migration, and cell cycle assays. Finally, Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) was performed to identify potential molecular mechanisms during inhibition.
Results: The results identified C3 as overly expressed in early PDAC compared to later stages in plasma (p = 0.047). Pharmacological inhibition of the complement pathway led to increased cell growth (p < 0.0001), proliferation (p = 0.001) and migration (p = 0.002) in vitro. Proteomic analysis implicated several proteins, such as the mitochondrial and histone proteins, that could play a role in inducing this phenotype.
Conclusion: Complement C3 and C5 are elevated in PDAC samples compared to healthy ones. Furthermore, the inhibition of the complement pathway was shown in vitro to result in a more aggressive phenotype by stimulating cellular growth, proliferation, and migration, indicating the involvement of complement C3 and C5 in tumour progression. This study helps to delineate further the role of the complement pathway in PDAC progression.
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Background: Dry eye is an ocular complication of diabetes mellitus. Due to its complex pathogenesis, treatment still needs to be studied.
Objectives: This study aimed to explore the role of signal transducer and activator of transcription 3 (STAT3) in diabetes mellitus-related dry eye.
Methods: High-fat and high-carbohydrate diet and streptozotocin were used to establish a diabetes mellitus-related dry eye rat model. All rats were divided into four groups (n = 6 in each group), including control group, diabetes mellitus-related dry eye group (model group), vehicle group, and STAT3 inhibitor group (S3I-201 group). Tear production was assessed using phenol red cotton threads. A CochetBonnet esthesiometer was used to evaluate corneal sensitivity. Periodic acid-schiff (PAS) and in situ terminal deoxynucleotidyl transferase (TUNEL) staining were conducted to measure the number of goblet cells and apoptotic cells in conjunctivae. Enzyme-linked immunosorbent assay (ELISA) was employed to determine the levels of tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-17A (IL-17A), and Interleukin-1β (IL-1β) in the conjunctival tissues. Western blot was applied for assessing the expression of nuclear factor-κB (NF-κB)/STAT3 pathway related proteins.
Results: S3I-201 increased tear production, corneal sensitivity, the number of goblet cells, and decreased cell apoptosis in diabetes mellitus-related dry eye rats (p < 0.05). Moreover, diabetes mellitus-related dry eye has the potential to induce inflammation by upregulating the levels of TNF-α, IL-6, IL-17A, and IL-1β (p < 0.05), which were significantly reduced after S3I-201 treatment (p < 0.05). In addition, diabetes mellitus-related dry eye induced activation of NF-κB pathway and increased the ratio of p-STAT3/STAT3, both of which were reversed by S3I-201 treatment (p < 0.05).
Conclusions: Inhibition of STAT3 alleviated diabetes mellitus-related dry eye in rats by regulating the inflammation.
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Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening drug reactions of uncertain pathogenesis. Ferroptosis is an emerging, iron-dependent mode of regulated cell death. However, the correlation between SJS/TEN and ferroptosis has not been elucidated. The purpose of this study is to investigate the relationship between SJS/TEN and ferroptosis.
Methods: Proteomic profiling of plasma proteins and imbalance of iron homeostasis of SJS/TEN patients are accompanied with high level of High Mobility Group Box 1 (HMGB1). Glutathione peroxidase 4 (GPX4) and system xc- (xCT) levels were detected by quantitative Polymerase Chain Reaction (qPCR) and Western blot. The morphology of cells was also observed by an electron microscope.
Results: The increased serum iron in SJS/TEN patients and mitochondrial morphological alteration further suggested a link between ferroptosis and SJS/TEN. Compared with healthy control, the expressions of xCT, glutathione (GSH), and GPX4 were decreased in SJS/TEN patients, p < 0.05. Additionally, the results of validation experiment in vitro with blister fluids from SJS/TEN patients were also consistent. The expression levels of xCT (p < 0.05) and GPX4 (p < 0.001) were reduced after treatment with erastin and blister fluids, while this phenomenon was reversed by pretreatment with Ferrostatin-1 (Fer-1). Most importantly, we found that the serum concentration of ferritin showed a positive clinical correlation with the severity of drug eruption and the high scoring of severity-of-illness score for TEN (SCORTEN).
Conclusions: The overall results show that ferroptosis is involved in the development of SJS/TEN and can be used as a potential target for therapeutic treatment.
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Background: Colorectal cancer (CRC) is a type of malignant gastrointestinal cancer with a poor prognosis. Cold-inducible RNA binding protein (CIRBP) is a novel proto-oncogene that promotes the development of certain malignancies. Nevertheless, the relevance of CIRBP in CRC and the molecular processes behind it are still unknown. This study aimed to explore the molecular mechanism and biological function of CIRBP in CRC.
Methods: In this study, CIRBP protein expression in CRC samples and control samples was analyzed by Immunohistochemistry (IHC) analysis. The relationship of CIRBP expression and disease-free survival (DFS) and overall survival (OS) was assessed in CRC patients. Immunofluorescence (IF) assay, western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to analyze the expression or connection of CIRBP and Src associated in mitosis of 68 kDa (sarcoma-associated in mitosis of 68 kDa (SAM68)). CRC proliferation was investigated by cell-counting-kit-8 (CCK8) assay, colony formation assay, flow cytometric analysis, and animal studies. Migration and invasion were investigated by transwell assay. RNA sequencing and Common-immunoprecipitation (Co-IP) with protein mass spectrometry were used to investigate the underlying pathways of CIRBP in CRC.
Results: The findings demonstrated that CIRBP was abundant in CRC tissues, and that individuals with significant CIRBP expression had a poor prognosis. In vitro and in vivo, CIRBP/SAM68 knockdown or overexpression reduced or accelerated CRC proliferation, invasion and migration, respectively. Moreover, overexpression of SAM68 rescued the influence of CIRBP silencing on the malignant phenotype. Mechanistically, CIRBP directly bound to and increased the expression of SAM68. This mediated the excessive activation of the p38 signaling pathway. Overall, this study showed that CIRBP was an upregulated CRC-related oncogene.
Conclusion: Higher CIRBP expression may be related to decreased prognostic factors for overall survival (OS) and disease-free survival (DFS). CIRBP was found to enhance CRC development via the SAM68/p38 signal transduction pathway.
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Background: Platelet-rich plasma (PRP) is extensively used in both basic research and clinical applications of tissue repair and regeneration. PRP has a variety of different growth factors and particularly plays a crucial role in promoting osteogenic differentiation (OD) of bone marrow stromal stem cells (BMSCs). However, the underlying mechanisms behind this phenomenon remain unrevealed. Therefore, we aimed to investigate the underlying molecular events behind the role of PRP in promoting the osteogenic differentiation of BMSCs.
Methods: BMSCs were isolated from mice and exposed to different concentrations of PRP at different time intervals. Cell proliferation was evaluated using the Cell Counting Kit-8 (CCK-8), and the OD of BMSCs was assessed by measuring calcium deposition, alkaline phosphatase (ALP) activity, and osteocalcin content. The expression of osteogenic genes at the mRNA level was analyzed using real-time quantitative PCR (RT-qPCR), and western blot was used to detect the expression of osteogenic proteins.
Results: PRP significantly improved the proliferation of BMSCs, calcium deposition, ALP activity, and osteocalcin content in a concentration-dependent manner. Furthermore, PRP significantly increased the expression of ALP, Runx2, Osterix (OSX), osteocalcin (OCN), Osteopontin (OPN), and Bone morphogenetic protein 2 (BMP2) at the mRNA level, and Runx2, BMP2, and OCN at the protein level. Moreover, the findings revealed that PRP significantly increased the Osteoprotegerin (OPG)/Receptor activator of nuclear factor-κb ligand (RANKL) gene ratio in BMSCs in a concentration-dependent manner. Interestingly, PRP-promoted osteogenic differentiation in BMSCs could be reversed by OPG knockdown or RANKL overexpression, as evidenced by altering calcium deposition, ALP activity, and osteocalcin content.
Conclusion: PRP improves the osteogenic differentiation of BMSCs by increasing the OPG/RANKL ratio.
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Background: Colorectal cancer (CRC), a malignant tumor, shows the highest incidence and mortality rates in China and worldwide. Inositol-3-phosphate synthase 1 (ISYNA1) is the core enzyme involved in inositol biosynthesis. However, the effect of ISYNA1 on human cancer development, particularly CRC, has been poorly studied. Our study aimed to explore the precise molecular targets related to the diagnosis and treatment of CRC.
Methods: We evaluated ISYNA1 expression and gene control networks in CRC applying sequencing data. We measured ISYNA1 mRNA and protein degrees in CRC cell lines applying quantitative real-time polymerase chain response and immunofluorescence imaging. While knocking down ISYNA1 expression in HCT116 and SW480 cell lines by small interfering RNA (siRNA) transfection, we verified this by cell viability, colony formation, and migration assays.
Results: Evaluation on the cancer genome atlas (TCGA) database demonstrated the overexpression of ISYNA1 in CRC, and survival discussion demonstrated that patients with great ISYNA1 expression had a lower prognosis (p < 0.05). According to univariate and multivariate Cox regression models, ISYNA1 is an independent prognostic element for CRC. ISYNA1 affects tumor progression via multiple cancer-related signaling pathways. Real-time quantitative polymerase chain reaction (RT-qPCR) results demonstrated that HCT116 and SW480 cells displayed greatly higher ISYNA1 expression than DLD1 and HT29 cells (p < 0.05). ISYNA1 expression in HCT116 and SW480 cell lines was knocked down. Compared to the control group, ISYNA1-down-regulated CRC cell lines demonstrated significantly reduced proliferation, colony formation, and migration (p < 0.05).
Conclusions: In conclusion, ISYNA1 may be a novel prognostic biomarker for CRC, laying the basis for further studies the effect of ISYNA1 on CRC occurrence and development.
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Background: Ischemia-reperfusion (I/R) injury is a key challenge in the treatment of ischemic cerebrovascular diseases. This study aimed to explore whether phosphorylated C-terminal domain (CTD) interacting factor 1 (Pcif1) could attenuate mouse I/R injury and its downstream mechanisms.
Methods: An I/R injury cellular model was induced by treating mouse cortical neurons with oxygen-glucose deprivation and reoxygenation (OGD/R). Mouse cortical neurons were normally cultured (control group cells), and all were subjected to OGD/R after transfection. These were categorized into various groups, including OGD/R group (OGD/R model cells), OGD/R+siRNA negative control (siNC) group (cells were transfected with siNC and then underwent OGD/R treatment), OGD/R+siPcif1-1/2/3 group (OGD/R cells were transfected with siPcif1-1/2/3 before OGD/R treatment), siNC+shNC group (siNC and shNC were transfected into cells), siNC+3-phosphoinositide-dependent protein kinase 1 (Pdpk1) short hairpin RNA (shPdpk1) group (siNC and shPdpk1 were transfected into cells), siPcif1+shNC group (cells were transfected with siPcif1 and shNC), and siPcif1+shPdpk1 group (cells were transfected with siPcif1 and shPdpk1). Pcif1 and Pdpk1 expressions were detected by quantitative real-time PCR. The effects of silenced Pcif1 on cell viability, lactate dehydrogenase (LDH) release rate, malondialdehyde (MDA) level, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) concentrations, apoptosis, and V-akt murine thymoma viral oncogene homolog (Akt) related proteins were evaluated by cell counting kit-8 assay, LDH activity assay kit, MDA assay kit, enzyme-linked immunosorbent assay (ELISA), flow cytometry, and western blot, respectively. The targeting relationship between Pcif1 and Pdpk1 was analyzed by m6A-RNA immunoprecipitation qPCR. The loss-of-function assays were used to evaluate the function of Pdpk1 knockdown on OGD/R-treated cells.
Results: Pcif1 expression was elevated but Pdpk1 expression was reduced in mouse cortical neurons following OGD/R treatment (p < 0.001). Pcif1 silencing reversed the effects of OGD/R treatment on inhibiting cell viability, and on promoting LDH release, MDA level, TNF-α, and IL-6 contents and apoptosis rate (p < 0.001). Pcif1 knockdown also facilitated B-cell chronic lymphocytic leukemia/lymphoma-2 (Bcl-2) expression and Akt signaling pathway activation, and suppressed Bcl-2-associated X protein (Bax) expression (p < 0.05). Pdpk1 was validated as a downstream target of Pcif1, and its knockdown offset the above effects induced by silencing Pcif1 on OGD/R-treated cells (p < 0.05).
Conclusions: Pcif1 knockdown alleviates OGD/R-induced neuronal injury in mice by inhibiting Pdpk1 mRNA translation to activate Akt signaling pathway.
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Background: Renal toxicity is a significant concern in various clinical settings, yet its examination with a focus on particular parameters remains limited. A variety of factors including medications, chemicals, environmental toxins, and medical conditions can contribute to renal toxicity. Cisplatin (CP) is a widely used chemotherapeutic agent for the treatment of various cancers. However, one of its significant side effects is nephrotoxicity, which can lead to acute kidney injury. The purpose of this research was to investigate the potential protective effects of hibiscetin against CP-induced nephrotoxicity in rats.
Methods: The study employed a simple randomization method, involving four groups of six rats each. The groups were designated as follows: the normal control group, the CP injected group, the CP + hibiscetin group (10 mg/kg), and the hibiscetin-treated group (10 mg/kg) for 25 days. Various biochemical parameters were measured, including kidney function markers [blood urea nitrogen (BUN), serum albumin, creatinine, creatinine clearance], tubular damage biomarkers [N-Acetyl-b-D-glucosaminidase (NAG)], antioxidant levels [superoxide dismutase (SOD), glutathione transferase (GST), catalase (CAT), and malondialdehyde (MDA)], anti-inflammatory markers [interleukins-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukins-33 (IL-33), interleukins-6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2)], and apoptotic markers (Caspase-3 and p53). The assessment was performed using serum and urine samples. Antioxidants, inflammatory markers, and apoptotic markers were measured using kidney tissue homogenate.
Results: The findings of the study show that the administration of hibiscetin significantly reduced the biochemical, enzymatic, and inflammatory alterations induced by CP in rats. This protective effect was evident in the modulation of various biomarkers, including IL-1β, IL-6, IL-33, TNF-α, iNOS, COX-2, p53, and Caspase-3 (Casp-3). Notably, hibiscetin exhibited statistically significant effects in counteracting CP-induced nephrotoxicity (p < 0.05).
Conclusions: The current study suggests that hibiscetin may be effective in nephroprotection in rats induced with CP.
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Background: The repulsive guidance molecule-a (RGMa) is associated with neuronal death after stroke. The nuclear factor kappa-B (NF-κB) inhibitor-interacting Ras-like protein 2 (NKIRAS2) is involved in regulating the NF-κB signaling pathway. Nonetheless, the effects of RGMa and NKIRAS2 on the progression of ischemic stroke are still unknown. Therefore, this study aims to explore the mechanism of action of RGMa and NKIRAS2 on ischemic stroke through in vivo and in vitro experiments.
Methods: Highly aggressively proliferating immortalized (HAPI) microglia were stimulated with lipopolysaccharide (LPS) and oxygen-glucose deprivation/reperfusion (OGD/R) induced primary rat neurons. Small interfering RNA (siRNA)-RGMa and siRNA-NKIRAS2 were transfected to observe the effects of RGMa and NKIRAS2 on neuronal cell damage in vitro. Additionally, a rat model of middle cerebral artery occlusion and reperfusion (MCAO/R) was constructed and injected with short hairpin RNA (shRNA)-RGMa and sh-NKIRAS2 after reperfusion. Hematoxylin-eosin (H&E) staining was used to detect pathological changes in brain tissue, 2, 3, 5-triphenyltetrazolium chloride staining was used to evaluate cerebral infarction, and enzyme-linked immunosorbent assay was used to detect the level of inflammatory factors. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to detect mRNA and protein levels, flow cytometry was used to detect apoptosis, and immunofluorescence was used to identify primary rat neurons. Finally, a cell counting kit-8 (CCK-8) reagent was used to determine primary rat neuron cell viability.
Results: Cell experiments showed that siRNA-RGMa decreased the expression level of NF-κB pathway-related proteins and the secretion of inflammatory factors in HAPI microglia (p < 0.05). After OGD/R treatment, the conditioned medium supplemented with LPS and siRNA-RGMa stimulated HAPI microglia, significantly improving the activity of neuronal cells and inhibiting the apoptosis level and inflammatory response of neuronal cells (p < 0.05). These effects were eliminated by siRNA-NKIRAS2 (p < 0.05). The animal experiments showed that adenovirus (Ad)-sh-RGMa alleviated the damage of nerve function in MCAO/R rats, significantly improving neuronal injury, cerebral infarction size, inhibiting the secretion of inflammatory cytokines, microglia p65 nuclear ectopic, apoptosis gene and protein levels in brain tissue (p < 0.05). These effects can be reversed by Ad-sh-NKIRAS2 (p < 0.05).
Conclusions: The development of ischemic stroke could be alleviated by silencing RGMa and elevating NKIRAS2, indicating that both RGMa and NKIRAS2 could be potential therapeutic targets for ischemic stroke.
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Background: Enhancer of zeste homolog 2 (EZH2) acts as an essential epigenetic modifier that has been reported to be changed in glioblastoma (GBM). This study aims to explore the molecular mechanism of EZH2 in GBM.
Methods: In this current study, we first analyzed the expression of EZH2 in glioma and GBM cell lines by The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Rembrandt databases, and western blotting. Then, we constructed EZH2-silencing lentiviral vectors (LV-EZH2-siRNA) to transfect glioma cells and to establish a subcutaneous tumor model. Different concentrations of EZH2 inhibitors (GSK126) and autophagy inhibitor (autophinib) were selected to investigate their effects on GBM cell apoptosis. We examined the relationship between mammalian target of rapamycin (mTOR) or EZH2 and microRNA (miR)-101 to explore potential molecular mechanisms. An intracranial homograft model was established to investigate the therapeutic effect of GSK126 on GBM.
Results: EZH2 knockdown and GSK126 could diminish the invasion, migration, and proliferation of GBM cells. The autophagy level and apoptosis rate were elevated in GBM cells treated with the GSK126 (p < 0.05). Additionally, GSK126 modulated the expression of miR-101 via Trimethylation of histone H3 lysine 27 (H3K27me3) modification in the miR-101 promoter region and regulated the protein expression of mTOR, a target of miR-101. GSK126 could inhibit the growth of GBM in vivo.
Conclusions: EZH2 affects the autophagy and apoptosis of GBM cells via mTOR signaling through the feedback loop of EZH2/miR-101, hence providing a promising target for developing new therapeutic intervention strategies for GBM.
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Background: Human immunodeficiency virus (HIV) infection leads to acquired immunodeficiency syndrome (AIDS), posing a significant public health concern and affecting the quality of life. Furthermore, this infection can disrupt the intestinal mucosal barrier and increase the number of harmful bacteria, resulting in an intestinal inflammatory response and immune dysfunction. This study aimed to investigate the changes in inflammatory factors and gut microbiota in HIV-positive individuals and to explore the correlation between the gut microbiota and inflammatory factors, or T lymphocytes.
Methods: Blood samples of 34 patients with HIV/AIDS were collected. Enzyme-linked linked immunosorbent assay (ELISA) was used to detect cytokine levels, and flow cytometry was used to detect the number of clusters of differentiation 4 (CD4) and CD8 T lymphocytes. The Spearman method was used to explore the correlation between the intestinal microbiota of HIV-infected individuals and T lymphocytes or cytokines.
Results: At the family level, the number of Enterobacteriaceae bacteria was negatively correlated with CD4 T cell count (p = 0.04), while Micrococcaceae were positively correlated with CD4 T cell number (p = 0.04). Furthermore, Bifidobacteriaceae and Caulobacteraceae were positively correlated with CD8 T cells (p = 0.00 and 0.01), whereas Bacillaceae was negatively correlated with CD4/CD8 (p = 0.04). Additionally, Veillonellaceae showed a significant positive correlation with interleukin-6 (IL-6) (p = 0.04), while Carnobacteriaceae exhibited a significant negative correlation with IL-6 (p = 0.01). Micrococcaceae showed a significant positive correlation with IL-17 (p = 0.04), whereas Veillonellaceae displayed a significant positive correlation with lipopolysaccharide (LPS) (p = 0.01). Conversely, Carnobacteriaceae showed a significant negative correlation with LPS (p = 0.01), and Bacillaceae showed a significant negative correlation with IL-10 (p = 0.04).
Conclusion: These findings revealed a strong correlation between the intestinal microbiota of HIV-infected individuals and their immune status and might affect their inflammatory response, indicating that targeting intestinal microbiota might be a promising approach in treating HIV patients.
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Background: In recent years, the incidence of thyroid cancer (TC) has gradually increased. Investigating the underlying molecular mechanism of occurrence and development of TC holds significant potential in early diagnosis and treatment. The expression of endothelial cell-specific molecule 1 (ESM1) in TC tissue and its role in the development of TC are still unknown. Therefore, this study investigated ESM1 expression and its clinical significance in TC.
Methods: Initially, ESM1 expression was comparatively analyzed between TC tissues and normal tissues using the Gene Expression Profiling Interactive Analysis (GEPIA) database. TC and adjacent tissues (≥3 cm from cancer tissue after thyroidectomy) were collected from 51 TC patients. ESM1 expression in tissues was assessed using real-time quantitative polymerase chain reaction (RT-qPCR), western blot analysis, and immunohistochemical (IHC) staining. The correlation between ESM1 expression and clinical data of TC patients was examined using the chi-square test. Risk factors for the prognosis of patients with TC were analyzed using Cox regression analysis. TC cell lines were transfected with ESM1 small hairpin RNA (shRNA) or its negative control employing a Lipofectamine™ 2000 kit to inhibit ESM1 expression. After ESM1 was inhibited, malignant behaviors of cells were evaluated using cell counting kit-8 (CCK-8), clone formation, wound healing, and Transwell assays to assess the effect of ESM1 on TC progression.
Results: The expression levels of ESM1 were significantly increased in TC tissues (p < 0.05, p < 0.01, p < 0.001, p < 0.0001). Moreover, the ESM1 expression was correlated with lymph node metastasis, cancer stage, and tumor size. After silencing ESM1, the proliferation, migration and invasion abilities of TC cells were significantly reduced (p < 0.05, p < 0.01, p < 0.001). ESM1 expression was identified as an independent prognostic factor of TC patients through Cox regression analysis.
Conclusions: ESM1 promotes the development of TC and is one of the independent factors of TC prognosis. The detection of ESM1 expression may have important clinical value in the evaluation of TC, and become a new target for TC.
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Background: With the advancement of artificial intelligence, machine learning (ML) has brought new opportunities in osteoporosis diagnosis and prevention. Therefore, this study aimed to explore the correlation between blood-related biochemical indicators and bone mineral density (BMD) values, and to construct an osteoporosis risk prediction model using ML algorithms.
Methods: In this study, biochemical markers-related data were obtained from 3892 participants, and subsequently the study subjects were categorized into three groups: the normal bone density group, the low bone density group, and the osteoporosis group. Furthermore, various algorithms, such as Random Forest (RF), eXtreme Gradient Boosting (XGBoost), Logistic Regression (LR), Decision Tree (DT), Neural Network (NN), Gradient Boosting Decision Tree (GBDT), Support Vector Machine (SVM), and Naïve Bayes (NB), were used to construct predictive models on the training dataset. Moreover, the model's performance was assessed in the test dataset using the receiver operating characteristic (ROC) curve and Area Under the ROC Curve (AUC), as well as the precision-recall (PR) curve AUC. Additionally, variable importance plots as well as SHapley Additive exPlanations (SHAP) plots were generated to determine contributing factors in the optimal model.
Results: Among these models, the RF model exhibited the most effective performance, with a prAUC of 0.866. Various factors such as parathyroid hormone (PTH), total procollagen type I N-terminal propeptide (T-PINP), Age, beta-collagen special sequence (β-CTX), 1,25-hydroxyvitamin vitamin D3 (1,25 (OH)2VD3), N-terminal middle segment osteocalcin (N-MID), Weight, Height, phosphorus, body mass index (BMI), and coronary artery disease (CAD) significantly contributed to the model's predictive outcomes, particularly within the RF model's predictions, where they displayed a substantial impact.
Conclusion: The predictive models established using eight algorithms, including RF, XGBoost, LR, DT, NN, GBDT, SVM, and NB, demonstrated excellent performance. However, among these models, the RF model particularly demonstrated the best predictive efficacy.
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Background: Otitis media (OM) is a prevalent pervasive illness among the pediatric population. Research on sirtuin 1 (SIRT1), a deacetylase sensitive to nicotinamide adenine dinucleotide (NAD(+)), has increasingly identified its pivotal role in various inflammatory conditions. Our study aims to elucidate the role of SIRT1 in inflammatory injury in OM and its potential action mechanism.
Methods: Human middle ear epithelial cells (HMEECs) were stimulated with lipopolysaccharide (LPS) to establish in vitro models of OM. Western blot was used to assess SIRT1 expression. Following the addition of SIRT1 activator SRT1720, with or without the autophagy inhibitor 3-Methyladenine (3-MA), the Cell Counting Kit-8 (CCK-8) assay was used to evaluate cell viability. Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay was used to assess cell apoptotic levels. Enzyme-linked immunosorbent assay (ELISA) was used to estimate inflammatory levels and dichloro-dihydro-fluorescein diacetate (DCFH-DA) staining was used to estimate reactive oxygen species (ROS) activity. Western blot was used to analyze the content of apoptosis-, inflammatory response-, autophagy-, and nuclear factor-kappaB (NF-κB) signaling-associated proteins.
Results: SIRT1 expression was attenuated in LPS-treated HMEECs (p < 0.05). SRT1720 pretreatment significantly enhanced cell viability (p < 0.05), attenuated apoptosis (p < 0.05), suppressed the inflammatory response (p < 0.05), and reduced ROS production (p < 0.05). Additionally, it inhibited NF-κB signaling (p < 0.05) while inducing autophagy (p < 0.05) in HMEECs exposed to LPS in a concentration-dependent manner. Furthermore, 3-Methyladenine (3-MA) partially counteracted the suppressive effects of SRT1720 in LPS-induced viability loss, apoptosis (p < 0.05), inflammatory response (p < 0.05), NF-κB signaling activation (p < 0.05), and ROS generation (p < 0.05) in HMEECs.
Conclusions: In summary, the activation of SIRT1 may mitigate the inflammatory response in LPS-induced HMEECs through the modulation of apoptosis, inflammatory signaling, and autophagic processes.
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Background: Phosphatidylethanolamine (PE) is a vital component of cell membranes, and alterations in its content serve as an indicator of cancer metastasis risk. Phosphoethanolamine cytidine transferase-2 (PCYT2), an enzyme responsible for PE synthesis, is pivotal in promoting tumor cell proliferation and invasion. Inhibiting PCYT2 expression has the potential to reduce the occurrence of ovarian cancer metastasis and thereby improve the management of ovarian cancer.
Methods: Ovarian cancer primarily manifests in the perimenopausal period, coinciding with significant changes in lipid metabolism. To elucidate this relationship, we conducted non-targeted lipid metabolomics analyses on primary and matched metastatic tissues from ten patients with epithelial ovarian cancer. Lipid metabolism in vivo is intricately linked to the synthesis of lipid metabolic enzymes, which are governed by genetic regulation. To study the relationship between lipid metabolism and gene expression, we performed transcriptomic analyses on primary and matched metastatic tissues from eight patients with epithelial ovarian cancer. To validate the robustness of our findings, we performed PCR and Western-blot analyses on tissues from 20 patients with epithelial ovarian cancer.
Results: Our results reveals elevated PCYT2 expression in metastatic ovarian cancer tissues and abnormal phospholipid metabolism. Correlation analyses reveals a strong positive correlation between PCYT2 and phospholipid metabolism. Notably, PCYT2 expression is significantly higher in metastatic tissues compared to primary tissues (p < 0.001). Additionally, our study identifies decreased expression of phosphatase and tensin homolog (PTEN) and yes-associated protein (YAP1), coupled with elevated protein kinase B (AKT) and mammalian target of rapamycin (mTOR) expression in metastatic tissues (p < 0.05). Notably, we observed disparities in the expression of PCYT2 proteins, with higher PCYT2-β expression in metastatic lesions (p < 0.001). Moreover, a specific mRNA transcribed by ENST00000572995 exhibits high expression in metastatic lesions.
Conclusions: Based on our findings, we propose that PCYT2-β may play a significant role in driving the metastasis of epithelial ovarian cancer.
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Background: The mechanisms underlying the uric acid-lowering effect of chlorogenic acid (CGA) remain unclear. In this study, the therapeutic effects of CGA on rats were investigated using a 5/6 nephrectomy and hyperuricemia model and the related mechanisms were explored.
Methods: The rat model with 5/6 nephrectomy and hyperuricemia was established. A total of 40 Sprague–Dawley rats were categorized into five groups, namely, control group, M group (no treatment), FT group (treatment with febuxostat), and LT group (treatment with CGA). Moreover, rats with 5/6 nephrectomy were categorized as the chronic kidney disease (CKD) group (n = 8). Blood biochemical indices; changes in renal and bone histomorphology; plasma metabolomics and changes in the metabolic spectrum; expression levels of toll-like receptor 4 (TLR4), intercellular adhesion molecule-1 (ICAM-1), fibronectin (FN1), and Beclin-1 (BECN1) in kidneys; expression levels of TLR4, ICAM-1, BECN1, and microtubule-associated proteins 1A/1B light chain 3B (LC3B) in the kidney tissue; and expression levels of matrix GLA protein (MGP) and TLR4 in the femur were evaluated.
Results: Compared with the CKD group, serum levels of uric acid, creatinine, urea nitrogen, urinary protein, tartrate-resistant acid phosphatase (TRACP-5B), and β-CrossLaps (β-CTX); renal mRNA levels of ICAM-1 and FN1; and renal expression level of ICAM-1 were increased. However, the levels of 25-hydroxy vitamin D, blood calcium, and osteocalcin; renal mRNA levels of Beclin-1 and TLR4; and renal expression levels of LC3B, Beclin-1, and TLR4 were reduced in the M group. These changes were significantly alleviated using febuxostat or CGA (p < 0.05). In total, 903 metabolites were identified in the four groups in both positive and negative ion modes, and differential metabolites were mainly enriched in protein digestion and absorption, central carbon metabolism in carcinomas, ATP-binding cassette transporters, pyrimidine metabolism, mineral absorption, and amino acid biosynthesis. In the M group, febuxostat or CGA improved the renal and bone pathological changes and femoral expression levels of MGP and TLR4.
Conclusions: This study is the first to show improvement in renal tubulointerstitial fibrosis and osteoporosis using CGA, which may be associated with autophagy activation regulated by TLR4. Untargeted metabolomics analysis revealed differential serum metabolites and metabolic pathways, thus providing a basis for using CGA to treat hyperuricemia in CKD.
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Background: Antioxidants derived from medicinal plants have the capacity to protect the liver from oxidative stress and exposure to chemicals. The current study is aimed at assessing the potential benefits of a plant-based treatment involving Swertia chirality (S. chirayita).
Methods: Gas Chromatography-Mass Spectrometry (GC-MS) analysis was conducted to identify the chemical constituents of the experimental plants. The 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was performed to assess the cytotoxic activity of medicinal herbs on the HepG2 cell line. The antiproliferative activity of Swertia chirayita and the anticancer standard drug cisplatin was determined using Annexin V staining on a flow cytometer. The effectiveness of S. chirayita extracts as a hepatoprotectant was further evaluated in a Carbon tetrachloride (CCl4)-induced rat model, while antioxidant activity was measured through Superoxide Dismutase (SOD), glutathione peroxidase (GPx), and Catalase (CAT) assays. An in silico study was carried out to assess the efficacy of ethanol extract of S. chirayita (ESC) and hexane extract of S. chirayita (HSC) on Transforming growth factor-beta (TGF-β) and Matrix metalloproteinase-8 (MMP-8) inflammatory markers.
Results: The ESC extract exhibited the highest concentration of bioactive phytocompounds and displayed remarkable scavenging capabilities against 2,2-Diphenyl-1-picrylhydrazyl (DPPH), Nitric Oxide (NO), superoxide anion (O2-), and the reducing power assay compared to the HSC extract. The antimicrobial effects of the herbal extracts yielded superior results against bacterial pathogens. Additionally, the ESC extract demonstrated more potent cytotoxic and apoptotic activities against HepG2 cancer cells than the HSC extract and cisplatin, with fewer adverse effects on normal HEK-293 cells. Statistically significant differences (p < 0.05) were observed in various parameters. To further validate these results, liver function enzyme assays, stress indicators, and inflammatory biomarkers were employed. Histopathological examination of the liver revealed the protective effects of S. chirayita extracts and cisplatin, effectively mitigating and reversing hepatotoxicity. Furthermore, molecular docking, coupled with absorption, distribution, metabolism, excretion and toxicity (ADMET) profiling, identified the top five phytocompounds with anti-inflammatory potential against TGF-β and MMP-8 proteins, making them suitable targets for combating liver disease.
Conclusions: S. chirayita extracts exhibit potent hepatoprotective activity attributed to the presence of significant phytocompounds. Their efficacy suggests their potential utilization as robust therapeutic agents in the pharmaceutical industry, validating the effectiveness of their ethnopharmacological properties.
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Background and Aims: A high-fat diet can induce hepatic steatosis, hyperlipidemia, obesity, diabetes, and other lipid metabolism disorders through the regulation of lipid metabolism signaling pathways in the liver. The objective of this study was to investigate the influence of dietary fiber on the composition of the intestinal microbiota to improve lipid metabolism.
Materials and Methods: Male Sprague Dawley (SD) rats were divided into four groups: a Control group (ZC), a high-fat diet group (HF), a fiber diet group (GQ), and a combination of high-fat and fiber diet group (GZGQ). Following four weeks of feeding with experimental diets, the rats were euthanized, and the blood sample was collected from the abdominal aorta. Plasma levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were assessed. Furthermore, total DNA was extracted from a 100 mg stool sample. The 16S ribosomal RNA gene sequencing and quadrupole time-of-flight mass spectrometry coupled with high-performance liquid chromatography to detect the structure and metabolites of rat intestinal gut flora. Linear discriminant analysis effect size was used to determine the major communities or species across various experimental groups.
Results: Using high-throughput 16S rRNA gene sequencing, 8, 6, 2, and 5 unique bacteria were observed in the ZC, GQ, HF, and GZGQ group, respectively. Compared to the Control group, the proportion of thick-walled phyla decreased in the GQ and GZGQ groups and increased in the HF group. The relative abundance of Bacteroidales S24-7 group, Bacteroides, and Ruminococcus gnavus group was significantly higher in the GQ and GZGQ groups (p < 0.05), whereas the relative abundance of some bacteria was elevated in the HF group. Moreover, it was found that the atorvastatin-induced metabolites were elevated in the HF group. Furthermore, choline content was significantly increased in the GZGQ group, and levocarnitine content was significantly lower in both the GQ and GZGQ groups. Additionally, dietary fiber reduced the levels of TC, TG, and LDL-C in high-fat rats.
Conclusions: These findings indicate that through the gut microbiota, dietary fiber regulates dyslipidemia, increases choline and L-carnitine, and reduces the risk of diseases associated with a high-fat diet.
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Background: The stemness capacity of cancer cells has an important role in the initiation and development of pancreatic ductal adenocarcinoma (PDAC). An important regulator of cancer cell stemness is the Wnt/β-catenin signaling pathway. To further deepen the understanding of the pathogenesis of PDAC, the aim of this study was to investigate the regulatory mechanisms of cancer cell stemness.
Methods: Genetic screening was performed to identify candidate proteins that might regulate cell stemness in PDAC. Subsequently, Western blot analysis and quantitative polymerase chain reaction (qPCR) assays were used to evaluate the expression of GATA Binding Protein 6 (GATA6) in PDAC cell lines. Stable cell lines expressing GATA6 were also established. Cell counting kit-8 (CCK8) assay, colony formation assay, and gemcitabine resistance assay were used to investigate the effect of GATA6 on the malignant behavior of PDAC cells. Experimental knockdown and overexpression groups were also studied. Western blot and qPCR assays were used to detect alterations in cancer stem cell characteristics after changing the GATA6 protein expression level in PDAC cells. Changes in the knockdown and overexpression groups were compared with controls. Dual-luciferase reporter assays and chromatin immunoprecipitation assays were also used to investigate the molecular mechanisms in this biological model.
Results: Using a small range for overexpression screening, GATA6 overexpression was found to significantly reduce the stemness of PDAC cells. Furthermore, stably expressing cell lines were used to show that the malignant biological behavior of PDAC cells was significantly reduced following the overexpression of GATA6, and vice versa for the knockdown of GATA6 (p < 0.05). Western blot and qPCR assays showed that elevated GATA6 protein expression inhibited the stemness of PDAC cells through the Wnt/β-catenin signaling pathway (p < 0.01). Further experiments showed that GATA6 exerts its biological effects by binding to the β-catenin promoter region to inhibit its transcription.
Conclusion: GATA6 can inhibit the stemness properties of PDAC cells via the Wnt/β-catenin signaling pathway.
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Background: Long noncoding RNA plasmacytoma variant translocation 1 (lncRNA PVT1) is upregulated and manifested in various cancer types. LncRNA PVT1 plays a vital role in regulating proliferation, invasion, migration, and autophagy which could promote malignant progression. However, its mechanism of clinical significance for colon cancer remains unclear.
Methods: The biological behaviors of lncRNA PVT1 were explored in the present study. HCT116 cells were transfected with PVT1 siRNA (si-PVT1) or PVT1 plasmid (oe-PVT1) to establish a PVT1 deletion and overexpression model. The levels of lncRNA PVT1 were assessed in transfected colon cancer cells using qRT-PCR. Furthermore, the cell viability, scratch, and transwell assays were performed to evaluate cell proliferation, migration, and invasion at different levels of lncRNA PVT1. However, their autophagy effects were assessed by employing Immunofluorescence assay and western blot (WB). Similarly, the rate of inflammatory infiltration was determined using the enzyme-linked immunosorbent assay (ELISA) experiment. Additionally, hematoxylin and eosin (HE) staining were utilized for indicating the metastatic tumor nodules in vivo.
Results: The HCT116 cells exhibited significantly higher levels of the lncRNA PVT1 compared to the normal colonic epithelial cells. Compared to the deleted cells and untreated cells, lncRNA PVT1-overexpressing cells exhibited increased cell viability and migratory capability (p < 0.05). Suppressing PVT1 expression significantly reduced PVT1 mRNA levels post-transfection, leading to a significant decrease in cell proliferation ability (p < 0.05). Consistent with the proliferation experiment, the same trend was observed in the cell migration and invasion assays. Moreover, autophagy-associated genes, including microtubule-associated protein 1 light chain 3 (LC3), beclin-1, and Autophagy Related 3 (Atg3) were significantly upregulated in the PVT1 overexpressed cells, while decreased in the siRNA-treated cells (p < 0.05). Furthermore, there were fewer small tumor nodules observed in the lncRNA PVT1 siRNA transfected mice. While the elevated presence of lncRNA PVT1 was correlated with significantly metastatic tumor nodules and much obvious inflammatory infiltration (p < 0.05). Additionally, the levels of the tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and colony stimulating factor 1 (CSF1) were remarkably elevated in the PVT1 overexpressed mice, while exhibiting a substantial reduction in the PVT1 inhibited mice (p < 0.05).
Conclusion: This study unveiled the potential of lncRNA PVT1 as a target for therapeutic interventions in the management of colorectal cancer.
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Background: Dementia is caused by cognitive decline that interferes with daily living. It is often considered a syndrome rather than a single disease. The causes of dementia are diverse, including brain degeneration and cerebrovascular disease, but the pathogenic mechanisms remain unclear. Alzheimer's disease (AD) and vascular dementia (VaD) are the most common forms of dementia. As dementia cases continue to rise worldwide, investigating dementia has become increasingly important. Early-stage AD and VaD may cause amnestic mild cognitive impairment (MCI). Therefore, elucidating the relationship among AD, VaD, and MCI is crucial. This study aimed to analyze the correlations among AD, VaD, and MCI, and differences in these three diseases using bioinformatics methods on gene expression omnibus (GEO) databases, to provide information.
Methods: Gene set enrichment (GSE) 18309 and GSE122063 were utilized to identify differentially expressed mRNAs among AD, VaD, and MCI. The gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on these mRNAs.
Results: The main functions of the identified mRNAs were revealed, with phosphatidylinositide 3 kinases-protein kinase B (PI3K-Akt) signaling and hypoxia-inducible factor-1 (HIF-1) signaling showing the highest frequency.
Conclusion: Bioinformatics analyses of public databases provide insights into the relationship and differences among AD, VaD, and MCI based on differential mRNA expression and pathway enrichment, laying the foundation for future mechanistic studies. The identified pathways such as PI3K-Akt and HIF-1 signaling represent promising targets for further investigation and therapeutic development.
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Background: Syphilis, an infectious disease caused by Treponema pallidum, poses a severe threat to the central nervous system (CNS). Despite the well-established affinity of the spirochete for the CNS, the specific regulatory mechanisms of Treponema pallidum on chemokine receptors in human brain microvascular endothelial cells (HBMEC) remain unclear. Therefore, our study aims to investigate the impact of Treponema pallidum on the expression of chemokine receptors in HBMEC, focusing on the chemokines Chemokine (C-X-C motif) Ligand 7 (CXCL7) and Chemokine (C-X-C motif) Ligand 13 (CXCL13).
Methods: The serum samples from 60 neurosyphilis patients and 60 healthy controls were retrospectively analyzed. The HBMEC cells were exposed to active and inactivated Treponema pallidum and the expressions of chemokines (CXCL7 and CXCL13), both at gene and protein levels, were assessed using quantitative PCR (qPCR) and Western blot analysis. Additionally, Transwell migration assays were employed to investigate the impact on HL-60 cell chemotaxis.
Results: Neurosyphilis patients exhibited elevated serum levels of CXCL7 and CXCL13 compared to controls. Exposure of HBMEC to active Treponema pallidum significantly increased the expression of CXCL7 and CXCL13 both at mRNA and protein levels. Moreover, active Treponema pallidum enhanced the chemotactic ability of HBMEC for HL-60 cells, while inactivated Treponema pallidum did not show any effect. Cell Counting Kit-8 (CCK8) assays revealed a significant decrease in HBMEC cell viability upon exposure to Treponema pallidum.
Conclusion: Active Treponema pallidum upregulates CXCL7 and CXCL13 expression in HBMEC, promoting chemotaxis and enhancing the migratory potential of HL-60 cells. This suggests a potential role for these interactions in the pathogenesis of neurosyphilis. Future studies should consider more complex blood-brain barrier (BBB) models and assess the activation and phagocytic capabilities of migrated cells.
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Background: Chronic cerebral hypoperfusion (CCH) induces mild cognitive impairment and contributes to the progression of vascular dementia and Alzheimer's disease. Hydrogen has demonstrated protective effects against various neurological disorders. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, plays a significant role in this context. This study aimed to investigate the impact of saturated hydrogen-rich saline (HRS) on cognitive deficits and explore potential mechanisms following CCH.
Methods: CCH was induced in rats via two-vessel occlusion, and the animals were subsequently treated with saturated HRS. Cognitive function was assessed using the Morris water maze. The neuronal morphology and number in the hippocampus were evaluated through hematoxylin and eosin (H&E) staining, Nissl staining, and immunofluorescence of neuronal nuclear protein (NeuN) and microtubule-associated protein 2 (MAP2). Neuronal ultrastructure was observed under a transmission electron microscope. Lipid peroxide biomarkers were measured to estimate lipid peroxide injury. Iron accumulation was detected using Perls Prussian Blue (PPB) staining. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to determine iron metabolism and ferroptosis-associated factors. Mechanism validation involved the administration of Ferrostatin-1, Erastin, and RAS-selective lethal 3 (RSL3), inhibitors of ferroptosis, cystine/glutamate antiporter (System Xc-) and glutathione peroxidase 4 (GPX4), respectively.
Results: HRS reduced cell death in the hippocampal region of CCH rats, restored the ruptured outer mitochondrial membrane of neurons, and increased levels of superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px), GPX4, and solute carrier family 7 member 11 (SLC7A11), while decreasing Malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE). Additionally, iron deposition was reduced in HRS-treated CCH rats. HRS inhibited ferroptosis, as evidenced by upregulation of ferritin light chain (FTL) and ferritin heavy chain (FTH1), and down-regulation of transcription factor (TF), transferrin receptor 1 (TFR1), solute carrier family 11 member 2 (DMT1), Iron responsive element binding protein 2 (IREB2), and prostaglandin-endoperoxide synthase 2 (PTGS2). The inhibition of ferroptosis induced by HRS was mimicked by Ferrostatin-1. Erastin or RSL3 simulated CCH-induced neuronal injury and ferroptosis, which were alleviated by HRS.
Conclusion: HRS improved cognitive impairment by suppressing ferroptosis in hippocampal neurons through the System Xc-/GSH/GPX4 pathway following CCH, suggesting its potential as a novel therapeutic agent for CCH treatment.
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Background: Cholangiocarcinoma (CCA) is a type of cancer that originates from the biliary system. It typically has a subtle onset and high degree of malignancy, often leading to a terminal stage diagnosis, which limits the possibility of surgical intervention. Recent advancements in mitochondrial transfer therapy have enabled more precise treatment of CCA. This study aimed to investigate the effects and potential mechanisms of normal mitochondrial transplantation on the proliferation and energy metabolism of cholangiocarcinoma cells.
Methods: The human cholangiocarcinoma cell line HuCCT1 was randomly divided into 5 groups: control (Con) group, mitochondrial transplantation 1 h (Mito-1 h) group, mitochondrial transplantation 6 h (Mito-6 h) group, mitochondrial transplantation 12 h (Mito-12 h) group, and mitochondrial transplantation 24 h (Mito-24 h) group. HuCCT1 cells received 143B wild-type mitochondrial fusion cells (143BρW)-derived mitochondria for different periods. Cell proliferation was detected using the Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was assessed using immunofluorescence and flow cytometry. Glycolytic activity was measured using commercial kits. RNA-seq was employed to analyze the differentially expressed genes (DEGs) in HuCCT1 cells following mitochondrial transplantation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were employed for further interpretation of the data. Protein expression levels were evaluated using western blot.
Results: Normal mitochondria were successfully extracted from 143Bρw. Mitochondrial transplantation inhibited proliferation and promoted apoptosis of HuCCT1 cells. Western blot analysis suggested that mitochondrial transplantation significantly enhanced the expression of the mitochondrial apoptosis pathway, including Cytochrome C (Cyto-C), apoptosis-inducing factor (AIF), phosphorylated p53 (p-p53) and cleaved-Caspase-9. Moreover, mitochondrial transplantation enhanced the glucose uptake of HuCCT1 cells. Meanwhile, the levels of lactate acid, adenosine triphosphate (ATP), and Nicotinamide adenine dinucleotide phosphate (NADPH) were decreased by mitochondrial transplantation. Finally, RNA-seq results show that mitochondrial transplantation resulted in 60 significantly differentially expressed genes in HuCCT1 cells. Bioinformatics analysis indicated that the pentose phosphate pathway, Notch signaling pathway, Voltage-gated potassium channel complex, and insulin signaling are potential pathways for mitochondrial transplantation to inhibit CCA progression.
Conclusions: Mitochondrial transplantation has the potential to impede cholangiocarcinoma cell proliferation by modulating energy metabolism, thus presenting a promising therapeutic strategy for this malignancy.
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Background: Ankylosing spondylitis (AS) is a common inflammatory arthritis. The complex etiology of AS involves genetic, environmental, and immunological factors. However, prior research has associated blood metabolites with the onset and progression of AS. Therefore, in this study, a Mendelian randomization (MR) approach was utilized to assess the causal effects of blood metabolites on AS.
Methods: The exposure factor data were retrieved from the Metabolite Genome-Wide Association Study (mGWAS) Summary data (IEU OpenGWAS project:
Results: Out of 486 blood metabolites were investigated using MR and GWAS data from the FinnGen consortium, ten known metabolites exhibited significant causal associations with AS. Moreover, metabolites identified as risk factors for AS included 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), butyrylcarnitine, tryptophan, N-acetylornithine, gamma-tocopherol, glycylvaline, taurodeoxycholate, hydroxyisovaleroyl carnitine, bilirubin, and aspartylphenylalanine. Conversely, taurodeoxycholate, hydroxyisovaleroyl carnitine, bilirubin, and aspartylphenylalanine were identified as protective factors for AS. Furthermore, Metabolic pathway analysis found that arginine biosynthesis, porphyrin and chlorophyll metabolism, tryptophan metabolism, and aminoacyl-tRNA biosynthesis were significantly linked to the development of AS.
Conclusions: This study confirmed a causal relationship between blood metabolites and AS, and identified several metabolites of potential clinical and biological significance. These findings offer new insights for advancing diagnostic approaches and improving treatment options.
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Background: One of the most popular drinks in the world is caffeine, which is known to produce anxiety symptoms that are clinical in nature. There are numerous classes of anxiolytics in the market. Still, there is always a need to find safe substitutes for medications because of their poor effectiveness and long-term side effects. This study aimed to investigate the anxiolytic effects of Manilkara zapota (MZ) leaf extract on caffeine-induced anxiety in mice.
Methods: The study was conducted on albino mice, in which anxiety disease was induced with a caffeine dose of 25 mg/kg by intraperitoneal (i.p) route. The animals were pretreated with different drugs for 14 days and caffeine was administered during the last 7 days of the treatment. The mice were randomly divided into 6 groups with 6 animals each, including control, caffeine (used for inducing anxiety), diazepam (1 mg/kg by oral route, as reference standard), and three doses of MZ (150, 300, and 450 mg/kg orally). Various behavioral, biochemical, and histopathological parameters were evaluated in caffeine-induced anxiety.
Results: MZ leaf extract demonstrated a significant increase in behavioral activity. In light/dark exploration (LDE), the extract significantly increased (p < 0.01) the duration spent in the light chamber and the number of switches from light to dark, which was otherwise diminished by caffeine. Similarly, in the open field test (OFT), the extract shows a significant increase (p < 0.001) in the number of rearing and the squares crossed. In the force swim test (FST), the extract showed an increase in the immobility time compared to the inducer. Compared to the caffeine-treated group, there was a significant increase (p < 0.01) in the levels of catalase, glutathione, and serotonin in the extract-treated groups. The histopathological changes showed a considerable decrease in the caffeine-induced damage in the brain and showed normal morphology in the hippocampus (dentate gyrus) region.
Conclusion: In the present study, data suggested that MZ extract exhibited anxiolytic-like activity. The observed activity could be linked to enhanced antioxidant status that was responsible for restoring the serotonin level and preventing structural damage in the brain. More research might provide a cost-effective alternative source for treating anxiety disorders.
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Background: DNA ligase 1 (LIG1) can regulate ubiquitin like with PHD and ring finger domains 1 (UHRF1) to the replication site, thereby maintaining DNA methylation, a biological behavior associated with the occurrence of colorectal cancer (CRC). On this basis, this study is engineered to explore whether LIG1 could affect the development of CRC by regulating UHRF1 to promote maternally expressed 3 (MEG3) methylation.
Methods: The expressions of LIG1, UHRF1, and MEG3 in CRC were analyzed using bioinformatics and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Co-Immunoprecipitation (Co-IP), Western blot, and Chromatin Immunoprecipitation (ChIP) were used to determine the interaction between UHRF1 and MEG3. Methylation of the MEG3 promoter was determined by Quantitative Methylation-Specific PCR (qMSP). The effects of LIG1 and UHRF1 on CRC cell viability, migration, invasion, and epithelial-mesenchymal transformation (EMT) were studied by loss- and gain-of-function and rescue experiments.
Results: LIG1 and UHRF1 levels were up-regulated while MEG3 level was down-regulated in CRC. Overexpression of LIG1 or UHRF1 promoted the migration, invasion, and EMT of CRC cells, while shLIG1 or shUHRF1 had the opposite effect. LIG1 regulated UHRF1 to suppress MEG3 expression and promote MEG3 methylation. There existed negative interactions between shUHRF1 and overexpression of LIG1 and between shLIG1 and overexpression of UHRF1 in the regulation of CRC cells.
Conclusion: LIG1 promotes CRC development by regulating UHRF1 to increase MEG3 methylation.
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Background: The aldehyde dehydrogenase 1 family member A3 (ALDH1A3)-mammalian target of rapamycin (mTOR) axis has been proven to be a therapeutic target for some tumors. We aimed to investigate the effect of ALDH1A3-mTOR axis on neurological dysfunction after deep hypothermic circulatory arrest (DHCA).
Methods: Cardiopulmonary bypass (CPB) models were constructed using Sprague-Dawley (SD) rats, subjected to treatment with normal temperature circulatory arrest (NTCA) or DHCA, or pretreated with rapamycin, and their heart rate and breathing were monitored. The pathological damage of brain tissue was evaluated by hematoxylin and eosin staining. The expression of caveolin-1 (Cav-1) and nuclear factor-kappa B (NF-κB) was detected by quantitative real-time polymerase chain reaction. Oxygen glucose deprivation (OGD) cortical neurons model was employed, followed by treatment with hypothermia, MHY1485, or plasmid transfection as required. The effect of ALDH1A3-mTOR axis on OGD-induced neuronal activity and apoptosis in hypothermia state was detected by cell counting kit-8 (CCK-8) and flow cytometry. Mitochondrial membrane potential (MMP), reactive oxygen species (ROS) level, and mTOR-70 kDa ribosomal protein S6 kinase (P70S6K) activation were determined by 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) probe, and western blot.
Results: Deep hypothermia reduced the heart rate and breathing of CPB rats. CPB aggravated tissue damage, reduced Cav-1 expression and MMP level, but increased ROS level and promoted NF-κB, ALDH1A3 expression and mTOR-P70S6K phosphorylation. Deep hypothermia slightly weakened the nerve damage induced by CPB. Rapamycin had shown a protective effect on the DHCA rat model. In the hypothermia state, silencing ALDH1A3 in vitro increased the cell viability and MMP inhibited by OGD, and reversed the apoptosis, ROS levels, ALDH1A3 expression, and activation of mTOR-P70S6K pathway.
Conclusions: Silencing ALDH1A3 protects DHCA rats from nerve damage by inhibiting the mTOR-P70S6K pathway.
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Background: Graves' disease (GD) is the most common cause of hyperthyroidism, and is a part of extensive autoimmune thyroid disease, involving both innate and adaptive immunity. However, connections between these immune components are complex and need to be fully understood. The purpose of this study was to determine the clinical characteristics of the subtypes of leukocytes associated with Graves' disease (GD) at different pathological stages.
Methods: In this study, 2290 patients were enrolled and divided into 3 groups: graves disease (1586 patients), subacute thyroiditis (SAT, 443 subjects), and subacute thyroiditis hypothyroidism (261 patients) groups. The collected data included the clinical symptoms and hormonal results. Related data from 167 healthy individuals served as normal control parameters. Two correlation analyses were performed for categorical variables and some valid factors using logistic regression analysis (LRA).
Results: Compared to the patients in SAT group, higher counts and percentage of lymphocytes (p < 0.001) were detected in GD group, coupled with the lower counts and percentage of neutrophils (p < 0.001). Compared to the patients with hypothyroidism, lymphocyte counts (p < 0.001), monocyte counts (p < 0.001), and their percentage (p < 0.001) were higher in GD group, while the counts (p < 0.001) and percent of neutrophils (p = 0.009) and eosinophils were lower (p < 0.001). LRA revealed that in GD group, total thyroxine (TT4) was positively correlated with lymphocyte count (p = 0.021) and its percentage (p = 0.019), and negatively correlated with neutrophil count (p = 0.026) and its percentage (p = 0.006). Moreover, in the hypothyroid group, TT4 was positively correlated with eosinophil count (p = 0.017) and its percentage (p = 0.015), and negatively correlated with lymphocyte count (p = 0.018) and its percentage (p = 0.027).
Conclusions: Circulating leukocyte parameters are related to thyroid function, and there is an interaction between thyroid hormones and immune responses in GD patients. Clinical manipulation of immune functions could be applied as potential therapeutic strategy to modulate thyroid hormone levels.
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Background: Curcumin is an active ingredient isolated from the turmeric with anti-tumor activity. Cancer-associated fibroblasts (CAFs) can promote the development of chemical resistance in tumor cells. The present study aimed to explore the effect and molecular mechanism of curcumin on the chemosensitivity of breast cancer (BC).
Methods: BC cell lines (MCF-7 and MDA-231) and paclitaxel (PTX)-resistant cell lines (MCF-7/PTX and MDA-231/PTX) were initially subjected to treatment with either curcumin or PTX. The cell proliferation and apoptosis rates were subsequently evaluated using Cell Counting Kit-8 (CCK-8) and flow cytometry. Western blotting was employed to evaluate the protein expression of fibroblast growth factor 2 (FGF2) and specific receptor-FGF receptor 2 (FGFR2). Because of the involvement of certain factors secreted by CAFs in chemotherapy resistance, the BC cells were exposed to a conditioned medium derived from CAFs (CAFs-CM). Subsequently, the changes in PTX resistance were monitored following interventions with both CAFs-CM and curcumin.
Results: Curcumin blocked the proliferation (p < 0.01) and promoted apoptosis in BC cells (p < 0.01). Moreover, it reduced the proliferation (p < 0.01) and augmented the apoptosis (p < 0.01) in MCF-7/PTX and MDA-231/PTX cells after PTX intervention by inhibiting the expression of FGF2 and FGFR2. CAFs-CM enhanced PTX resistance in BC cells, while the phenomenon was reversed by curcumin. Moreover, CAFs-CM induced an increase in FGF2 and FGFR2 protein expression in BC cells (p < 0.01), and this effect was eliminated after curcumin treatment (p < 0.01).
Conclusions: Curcumin increases BC cell sensitivity to PTX by inhibiting the secretion of FGF2/FGFR2 from CAFs.
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Background: Colorectal cancer (CRC) is the third most common cancer worldwide. However, CRC treatment with radiotherapy often results in the development of radiation resistance. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis of histone H3K27 acetylation (H3K27ac) revealed that enhancers play important roles in CRC. This study investigated the relationship between an active CRC enhancer and kallikrein-related peptidase 6 (KLK6) and its effect on CRC radiation resistance.
Methods: Enhancer-driven genes in CRC were obtained from public H3K27ac ChIP-seq data and intersected with highly expressed genes in radioresistant CRC. The clinical roles of KLK6 in CRC and radiation resistance were analyzed using the standardized mean difference (SMD) model, summary receiver operating characteristic (SROC) curves, and Kaplan–Meier curves. The biological mechanisms of KLK6 were also explored using multiple computational biology algorithms and software such as R, STATA and SPSS.
Results: The analysis of 58 H3K27ac ChIP-seq datasets revealed a total of 13,703 enhancer-regulated CRC genes. KLK6 was enhancer-driven and notably up-regulated in CRC tissues compared with non-CRC controls, exhibiting an SMD value of 1.03 (95% CI (confidence interval) = 0.68–1.38). Moreover, in radiation-resistance CRC, KLK6 expression was increased, exhibiting an SMD value of 0.29 (95% CI = 0.11–0.46) and an area under the curve (AUC) value of 0.74 (95% CI = 0.70–0.78). Additionally, KLK6 was associated with the immune microenvironment and was enriched in the ribosomal pathway of radioresistant CRC.
Conclusions: The enhancer-regulated gene KLK6 is involved in radiation resistance in CRC patients.
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Background: Acute kidney injury (AKI) following acute myocardial infarction (AMI) is a specific type of cardio-renal syndrome (CRS) with a complex pathogenesis that has not been fully understood. This study aimed to explore the possible risk factors, and predict cardiovascular outcomes, AKI, and long-term renal function deterioration after AMI to provide guidance for improving cardiac and renal prognosis in type 1 CRS.
Methods: A total of 723 patients who were admitted for AMI were enrolled and were grouped based on in-hospital death, major adverse cardiovascular events (MACEs) within 1 year, AKI, and long-term decline in renal function defined as estimated glomerular filtration rate (eGFR) decline of at least 25% or development of end-stage renal disease within 1 year of discharge in sequence, respectively. The influence of common cardiovascular risk factors as well as cardiac and renal indicators on these outcomes was investigated. The prediction models of AKI after AMI were established and compared.
Results: For patients with AMI, AKI was found to be an independent risk factor for in-hospital death [Odds ratio (OR) = 4.28, 95% confidence interval (CI): 1.745–10.501, p = 0.001], MACEs within 1 year (OR = 2.249, 95% CI: 1.37–3.692, p = 0.001), and long-term renal impairment (OR = 5.292, 95% CI: 2.422–11.567, p < 0.001). Fasting blood glucose (FBG) (OR = 1.146, 95% CI: 1.038–1.264, p = 0.007), cystatin C (OR = 3.900, 95% CI: 1.805–8.430, p = 0.001), and left ventricular ejection fraction (LVEF) (OR = 0.977, 95% CI: 0.956–0.999, p = 0.041) were identified as independent risk factors for AKI after AMI. A prediction model that combines FBG, LVEF, cystatin C, hypertension, and N-terminal pro-brain natriuretic peptide (NT-proBNP) [ln(p/1-p) = 0.082 × FBG – 0.026 × LVEF + 0.743 × cystatin C + 0.698 × HBP + 0.001 × NT-proBNP – 2.414, the area under the ROC curve (AUC) = 0.800, 95% CI: 0.754–0.847] was relatively effective in predicting AKI after AMI, with sensitivity and specificity of 0.779 and 0.722, respectively.
Conclusions: AKI is an independent risk factor for in-hospital death, major cardiovascular adverse events, and long-term decline in renal function in AMI patients. A prediction model consisting of FBG, LVEF, cystatin C, hypertension, and NT-proBNP could be useful in predicting AKI after AMI.
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Background: Silicosis is a severe occupational disease induced by silica inhalation. It is characterized by chronic persistent pulmonary inflammation and progressive widespread interstitial lung fibrosis with worldwide prevalence. The purpose of this study was to elucidate whether fluorofenidone (AKF-PD), a newly developed anti-fibrotic chemical, can prevent pulmonary fibrosis and inflammation induced by silica.
Methods: Male C57BL/6J mice were used to develop a silicosis model and randomly divided into three groups: the control group (abbreviated as Control), the silica-treated group (abbreviated as Silica), and the silica plus AKF-PD treated group (abbreviated as AKF-PD). Pathological changes in the tissue of the lungs were examined using Hematoxylin and eosin (HE) and Masson's trichrome staining methods. Western blot analysis was used to assess the expression levels of α-smooth muscle actin (α-SMA), fibronectin, caspase-1, pro-caspase-1, and pro-interleukin (IL)-1β in lung tissues. Moreover, the levels of inflammatory cytokines were determined using their corresponding Enzyme-linked Immunosorbent Assay (ELISA) kits. Before the stimulation with 100 μg/mL nano-silica, the THP-1 cells were pre-treated with either AKF-PD (400 μg/mL) or serum-free RPMI-1640 medium. Additionally, we evaluated the proteins involved in the assembly of the NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes in the cell and the production of inflammatory cytokines in the cell medium. Moreover, we assessed the expression levels of phosphorylated NLRP3, phosphorylated apoptosis-associated speck-like protein containing with CARD domain (ASC), and the proteins involved in the assembly of the NLRP3 inflammasomes in the lung tissues mice.
Results: We observed that AKF-PD treatment significantly reduced alveolitis (p < 0.001), lung fibrosis (p < 0.01), and collagen III distribution (p < 0.0001) in the silica-induced silicosis model mice. AKF-PD decreased the expression levels of fibronectin (p < 0.05), α-smooth muscle actin (p < 0.05), interleukin-1β and transforming growth factor-β (p < 0.05), as well as the levels of interleukin-6 and tumor necrosis factor-α (p < 0.01) compared to the silica group. The AKF-PD treatment significantly reduced the silica-induced elevated levels of caspase-1 in lung tissues (p < 0.05), but did not reduce the expression of pro-caspase-1 and pro-IL-1β. However, AKF-PD treatment attenuated the expression levels of interleukin-1β, interleukin-6, tumor necrosis factor-α, and caspase-1 (p < 0.05) in silica-treated THP-1 cells, whereas did not reduce the expression of pro-IL-1β and pro-caspase-1 in these cells. Additionally, it was observed that AKF-PD treatment did not reduce the silica-induced elevated expressions of NLRP3 and ASC. However, it reduced the expression levels of phosphorylated NLRP3 (p-NLRP3) (p < 0.05), and phosphorylated ASC induced by silica (p < 0.05). Moreover, a similar trend in the data was observed in mouse lung tissue homogenates analysis.
Conclusions: In summary, AKF-PD exhibits anti-inflammatory and anti-fibrotic effects in silicosis, reducing pulmonary inflammation and fibrosis while decreasing the release of IL-1β and the activation of NLRP3 inflammasome. These findings suggest AKF-PD as a potential therapy for silicosis-induced fibrosis.
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Background: Bladder cancer (BLCA) is a common malignancy with rising incidence worldwide. The deoxythymidylate kinase (DTYMK) plays a crucial role in the progression of cancers. However, its precise function and significance in the diagnosis of BLCA are yet to be properly explored. This study aimed to elucidate the correlation between DTYMK and BLCA.
Methods: The Cancer Genome Atlas Program (TCGA) database was utilized to verify the DTYMK expression. The expression levels of DTYMK in bladder tissues were assessed using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis, and immunohistochemistry. Moreover, the relationship between DTYMK and the prognosis of bladder cancer was analyzed using the KM-plotter and Ualcan databases. DTYMK was knocked down in bladder cancer cells by transfecting with a lentivirus vector to investigate the role of DTYMK both in vitro and in vivo. Additional analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and GeneMania online tools to explore the underlying mechanisms in the progression of bladder cancer.
Results: DTYMK expression was significantly increased in bladder cancer tissues compared to the paracancerous tissues (p < 0.01) and found associated with the degree of differentiation (p < 0.05), lymph node metastasis (p < 0.01), tumor node metastasis (TNM) stage (p < 0.01), and poor prognosis in bladder cancer patients. Functional studies demonstrated that down-regulation of DTYMK inhibited cell proliferation and migration in vitro and suppressed xenograft tumor formation in vivo (p < 0.01). GO and KEGG results associated DTYMK with certain physiological events, such as neuroactive ligand-receptor interaction and retinol metabolism. Additionally, 20 genes exhibited a synergistic effect and 10 genes showed interaction with DTYMK in bladder cancer.
Conclusions: DTYMK expression was significantly increased in bladder cancer cells. The elevated expression was associated with the degree of differentiation, lymph node metastasis, tumor node metastasis (TNM) stage, and poor prognosis in bladder cancer patients. These findings suggest its potential as a novel predictive biomarker. These findings offer evidence for the potential use of DTYMK as a targeted therapy for bladder cancer.
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Background: The aim of this study was to utilize a pharmacokinetic/pharmacodynamic (PK/PD) model for evaluating the in vitro antibacterial effectiveness of biapenem when used in combination with amikacin, fosfomycin, and sulbactam against Pseudomonas aeruginosa (PAE). The single drug (combined) inhibitory concentrations of these four antibiotics against eight common bacteria were detected, and PK/PD model was established for evaluation.
Methods: Twenty-one strains of PAE were isolated from sputum samples of the patients and the cultures were maintained on Mueller-Hinton (M-H) agar and M-H broth media. The sensitivity of bacteria to these antibacterial drugs was tested using K-B susceptibility disk method both as a single drug sensitivity test or combination therapy sensitivity test. Furthermore, minimum inhibitory concentration (MIC) was determined for each drug as well in combination. Moreover, the PK/PD model was developed by using probability of target attainment (PTA) and cumulative fraction of response (CFR) values.
Results: Single drug sensitivity test showed that, out of the total PAE strains, 7 strains (33.33%) were resistant to biapenem, 5 strains (23.81%) were resistant to amikacin, 3 strains (14.29%) were resistant to fosfomycin, and 9 strains (42.86%) were resistant to sulbactam. Furthermore, the combined drug sensitivity test revealed that 3 PAE strains exhibited synergistic effect when biapenem was combined with amikacin, with a synergistic rate of 19.04%, 12 strains showed synergistic effect when biapenem was combined with fosfomycin, with a synergistic rate of 57.14%, and 11 strains showed synergistic effect when biapenem was combined with sulbactam, with a synergistic rate of 52.38%. Moreover, it was found that, except Acinetobacter baumannii, the MIC50, t > MIC50 of all strains exceeded 50%, However, the MIC90, t > MIC90 for PAE, Acinetobacter baumannii, and Serratia was equal to 0%.
Conclusions: In summary, the combination of biapenem and sulbactam was recommended for the treatment of multidrug-resistant-induced infections to effectively control infections and improve therapeutic outcomes.
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Background: Acute kidney injury (AKI) often leads to impaired filtration and excretion of waste products. It is characterized by mitochondrial dysfunction, elevated inflammatory response, and oxidative stress. However, angiopoietin-like 4 (ANGPTL4) plays a significant role in angiogenesis and lipid metabolism, thereby regulating inflammation and protecting cells from injuries. Therefore, this study explored whether ANGPTL4 played roles in protecting against AKI as well as the underlying mechanisms.
Methods: The lipopolysaccharide (LPS) was used for stimulating the human renal cortex proximal tubule epithelial HK-2 cells to establish the model of AKI. The changes of ANGPTL4 in LPS-treated HK-2 cells were detected by western blot. Subsequently, small interference (si)RNA/plasmid transfection technology was used to decrease or increase the ANGPTL4 expression. The transfection efficiency was verified using real-time reverse transcriptase-polymerase chain reaction (RT-qPCR). Moreover, the impact of ANGPTL4 on LPS-induced cytotoxicity was determined by measuring cell viability and apoptosis rate using cell counting kit-8 (CCK-8) assay and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay, respectively. Additionally, the levels of LPS-induced cytokines tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) along with changes in cellular reactive oxygen species (ROS) levels were investigated. Finally, the effect of ANGPTL4 on mitochondrial dysfunction and oxidative stress was assessed using mitochondrial function assay kit and ROS detection kit.
Results: The level of ANGPTL4 in HK-2 cells decreased after LPS treatment (p < 0.05). Moreover, ANGPTL4 overexpression alleviated LPS-induced cytotoxicity and cell apoptosis (p < 0.01), inhibited the production of LPS-induced cytokines (p < 0.01), and reduced the cellular ROS levels (p < 0.05). Concurrently, ANGPTL4 overexpression improved LPS-induced mitochondrial dysfunction (p < 0.05).
Conclusion: In summary, ANGPTL4 can improve mitochondrial dysfunction in LPS-induced AKI and reduce inflammation and oxidative stress. This study offers a new direction for understanding and treating AKI, providing evidence for using ANGTL4 as a novel therapeutic strategy with potential clinical applications.
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Background: Ischemic stroke (IS) continues to be the foremost cause of mortality and disability worldwide. Ginkgolide B (GB), an originally natural terpene lactone, is widely employed in the treatment of cerebrovascular disease. Nevertheless, a comprehensive understanding of the precise role and underlying mechanisms of GB in white matter injury after IS necessitates further elucidation. The objective of the present study was to assess the impact of GB on white matter injury and to analyze alterations in the types and gene expression of neuroglial cells using single-cell RNA sequencing (scRNA-seq).
Methods: Ninety-four male C57BL/6 mice were categorized into four groups: (1) Sham control (n = 21); (2) middle cerebral artery occlusion (MCAO) mice receiving PBS vehicle (MCAO+PBS) group (n = 29); (3) MCAO mice subjected to a 1-week-long GB treatment (MCAO+GB1w) group (n = 13); (4) MCAO mice undergoing a 2-week-long GB treatment (MCAO+GB2w) group (n = 31). GB or PBS was administered to the mice following ischemic cerebral injury induced by middle cerebral artery occlusion (MCAO). Neurobehavioral state was assessed using foot fault (FF) and rotarod (RR) tests. White matter injury and microglial cell subtypes were determined through immunofluorescence. ScRNA-seq was employed to illustrate the crucial biological processes and gene expressions influenced by GB in white matter injury after MCAO.
Results: Our findings indicated a significant prolongation in the latency to fall during RR test and a decrease in the FF rate for both forelimb and hindlimb in the MCAO+GB2w group compared to the MCAO+PBS group. The demyelinating damage to white matter in the MCAO+GB2w group was notably milder than that in the MCAO+PBS group (p < 0.05), as evidenced by a significantly increased MBP/SMI-32 ratio. Immunofluorescence analysis revealed an elevated proportion of M2 microglial cells and a decreased level of M1 microglial cells in the MCAO+GB2w group compared to the MCAO+PBS group on the 14th day, 21st day, and 28th day (p < 0.05). ScRNA-seq findings demonstrated that GB provides protection against ischemia/reperfusion (I/R)-induced white matter injury by upregulating critical processes such as myelin sheath reproduction and oligodendrocyte maturation. Gene Ontology (GO) enrichment and analysis of differentially expressed genes (DEGs) revealed a significant upregulation of proteolipid protein 1 (PLP1), alphaB-Crystallin (CRYAB), ß-tubulin 4A (TUBB4A), constitutive androstane receptor 2 (CAR2), and ATPase Na+/K+ transporting subunit beta 2 (ATP1B2) in the myelin sheath pathway of microglial cells. Similarly, echinoderm microtubule-associated protein-like 1 (EML1), Heat shock proteins 72 (HSPA1A), signal peptide peptidase-like 2b (SPPL2B), and alpha 1A (TUBA1A) were significantly upregulated in oligodendrocytes (p < 0.05). Cell trajectory analysis indicated that oligodendrocytes underwent induction towards more mature subclusters following GB administration.
Conclusions: GB has the potential to alleviate white matter injury and neurobehavioral dysfunction following MCAO by increasing the proportion of M2 microglial cells, decreasing M1 microglial cells, and promoting oligodendrocyte maturation to enhance myelination.
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Background: Depression is a prominent psychiatric condition that needs efficient management through various therapeutic approaches. The genus Jasminum has a diverse array of attractive shrubs that are classified under the Oleaceae family and distributed throughout India. Jasmine plants have been extensively employed in the fragrance business to produce fragrances, oils, and lotions. Moreover, these substances have been conventionally employed in managing wounds, cancer, inflammation, urolithiasis, cardiac disease, stress, rheumatism, and other medical conditions. The present study assessed the possible antidepressant properties of two plant species, namely Jasminum multiflorum (J. multiflorum) Andrews and Jasminum mesnyi (J. mesnyi) Hance, members of the Oleaceae family.
Methods: The stems of J. multiflorum and J. mesnyi were subjected to successive extraction methods involving petroleum ether, chloroform, ethanol, and water. The initial inquiries into the quality of the medicine led to the assessment of the antidepressant properties of each subsequent extract. This evaluation was conducted on Swiss albino mice using the Force swim test and Tail suspension test, with four different doses administered orally (150, 300, 450, and 600 mg/kg body weight). The present study evaluated and assessed two distinct extracts, namely the ethanolic extract and the aqueous extract, obtained from each plant. The objective was to investigate and analyse their potential antidepressant action. This was accomplished by utilising two specific tests conducted on mice: the 5-hydroxy tryptamine-induced head twitches test and the tetrabenazine antagonism test. The potential antidepressant effects of each species' most active ethanolic extract were evaluated using the chronic unpredicted mild stress method. Following the chronic unpredictable mild stress test, biochemical parameters (including Malondialdehyde, Superoxide dismutase, Catalase, and Reduced glutathione) were assessed in both species.
Results: The findings from the inquiry indicate that the administration of an ethanolic extract derived from J. mesnyi and J. multiflorum demonstrates a positive effect on the modified behaviour observed in mice. Specifically, it (p < 0.05, p < 0.01, p < 0.001) reduces head twitching in the 5-hydroxy tryptamine-produced Head twitch test and alleviates symptoms of ptosis and catalepsy in depressed mice through tetrabenazine antagonism. The group treated with the ethanolic extract of J. mesnyi and J. multiflorum exhibited (p < 0.01, p < 0.001) decrease in immobility time compared to the negative control group. Furthermore, the administration of an ethanolic extract derived from J. mesnyi has been shown to improve (p < 0.01, p < 0.001) the disrupted oxidative stress levels in the brain tissue of mice suffering from depression generated by persistent unpredicted mild stress.
Conclusion: The study's findings indicate that the administration of ethanolic extract derived from J. mesnyi and J. multiflorum positively affects the behavioral alterations and neurochemical balance in a mouse model of depression generated by prolonged unpredicted mild stress. This effect is achieved through the reduction of oxidative stress.
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Background: Cerebral ischemic stroke (CIS) results from insufficient blood supply to the brain, leading to disabilities and even death. Currently, available CIS treatment primarily focuses on promoting angiogenesis. The tumor necrosis factor receptor-associated factor 7 (TRAF7) plays a pivotal role in various biological processes and has been associated with neuronal damage. However, its role in CIS remains uncertain. Therefore, this study aimed to investigate the role of TRAF7 in angiogenesis during CIS.
Methods: A middle cerebral-arterial occlusion (MCAO) mice model with knocked-down TRAF7 was established to investigate its effects on neurological deficits, brain water content, and infarct volume. CD31/ki67 dual-immunofluorescent (IF) staining was performed to assess the impact of TRAF7 on angiogenesis in vivo. Furthermore, an Oxygen and Glucose Deprivation and Reoxygenation (OGD/R) cell model was constructed to mimic ischemia and explore the influence of the TRAF7/Krupple-like family of transcription factor 4 (KLF4) axis on cell migration and tube formation.
Results: TRAF7 protein expression was found to be elevated in both the in vivo and in vitro ischemic models. Its silencing improved neurological function, reduced cerebral water content and infarct volume, and enhanced angiogenesis after CIS in vivo. Furthermore, its silencing promoted bEnd3 cell migration and tube formation following OGD/R injury. Moreover, it was observed that TRAF7 regulated expression levels of KLF4 and vascular endothelial growth factor (VEGF) in both in vivo and in vitro settings. Mechanistically, it was found that TRAF7 mediated bEnd3 cell migration and angiogenesis post-OGD/R injury by modulating KLF4 expression.
Conclusions: Our findings indicate that TRAF7 knockdown confers vascular protection against CIS, offering a novel perspective for CIS treatment.
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Backgrounds: The incidence of spinal cord injury (SCI) is progressively increasing. The persistent SCI often leads to paralysis, emphasizing the need for timely and effective treatment. In this study, we analyzed the effect of resveratrol (Res) in ameliorating SCI and its effect on astrocytes, aiming to provide new clinical insights for treating SCI in the future.
Methods: Sprague-Dawley (SD) rats (n = 25) were divided into sham (sham operation), SCI (SCI modeling), Res (SCI modeling+intraperitoneal Res injection), adenosine triphosphate (ATP; SCI modeling+intraperitoneal injection of exogenous ATP), and Res+ATP (SCI modeling+intraperitoneal injection of Res and ATP) groups. Inflammation, oxidative stress, and apoptosis were assessed in the spinal cord tissue obtained from each group. Astrocytes were purchased, and an SCI model was induced through hypoxia/reoxygenation to observe the effect of Res on cell viability. Moreover, the expression levels of the Phosphatidylinositol3-kinase (PI3K)/Protein kinase B (AKT) pathway were determined in rats and cells.
Results: The SCI group exhibited severe pathological injury, intensified tissue inflammatory and oxidative stress responses, and increased apoptosis rate (p < 0.05). Moreover, pathological injuries were alleviated in Res and ATP groups (p < 0.05), with no significant inter-group difference (p > 0.05). The Res+ATP group showed better SCI repair effects than the Res and ATP groups (p < 0.05). Furthermore, in cell-based experiments, cell activation was lower in the SCI group than in the sham group (p < 0.05). The improving capability was higher in the Res and ATP groups than in the SCI group (p < 0.05). The Res+ATP group exhibited astrocyte activation and axonal regeneration ability second only to the sham group (p < 0.05). Moreover, the PI3K/AKT pathway was inhibited in both rats and cells in the SCI group, while p-PI3K/PI3K and p-AKT/AKT levels were increased in Res, ATP, and Res+ATP groups (p < 0.05).
Conclusion: Res can repair the pathological injury in SCI by activating the PI3K/AKT axis, and promote astrocyte activation and axonal regeneration.
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Background: Analyses of immune cell subsets and immune indices are becoming increasingly important. By interacting molecular probe and immunohistochemistry (IHC) analysis with laser ablation, imaging mass cytometry (IMC) offers high-dimensional in situ measurements in tissue slides with a spatial resolution of 1 μm. One of the most significant challenges is to implement stringent quality control strategies during the application of IMC to facilitate reproducible data analysis. We have developed a comprehensive protocol for clinical and experimental use by comparing IMC to standard clinical immunohistochemical approaches.
Methods: We discussed the multi-step experimental processing procedures of IMC, including specimen preparation, panel design, antibody selection, lanthanide metal labelling, and data pre-processing workflows by IHC and fluorescent multiplex immunohistochemistry (mIHC) analysis. Based on IMC, we developed a standard operation and a well-established agreement for 29 breast cancer (BC) patients to identify a structured tumor immune microenvironment.
Results: Metal labelling has no effect on the specificity of the antibodies' target (p > 0.05). The 3 μm-thick formalin-fixed and paraffin-embedded (FFPE) and fresh-frozen slides exhibited the least blur (p < 0.01) and the lowest nonspecific adsorption of antibodies (p < 0.01). A detailed analysis of human breast cancer tissues revealed a wide range of differences in the composition and frequency of immune cells within the tumor microenvironment.
Conclusions: This study presents optimized proposals on procedures for IMC analysis and a standardized quality control strategy.
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Background: The fluorouracil folinate and irinotecan (FOLFIRI) regimen, comprising fluorouracil, calcium folinate, and irinotecan, is the primary chemotherapy drug for managing colorectal cancer (CRC) liver metastasis. However, the emergence of chemotherapy resistance limits the therapeutic efficacy of this regimen. This study aimed to use bioinformatics analysis to elucidate factors linked to FOLFIRI regimen resistance in CRC liver metastasis, focusing on genes and pathways, and providing a theoretical framework for enhancing chemotherapy resistance in affected patients.
Methods: Initially, the gene expression profiles of GSE3964 were investigated using the Gene Expression Omnibus (GEO) database, revealing differentially expressed genes (DEGs) in FOLFIRI regimen-sensitive and resistant tissues. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for Gene Ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway evaluation. The STRING tool facilitated the construction of a protein-protein interactions (PPI) network, and Molecular Complex Detection (MCODE) plugins identified pivotal genes. Survival analysis was conducted using the Cancer Genome Atlas (TCGA) database to generate Kaplan-Meier (K-M) survival curves. Additionally, miRNAs associated with resistance were predicted using the miRWalk database.
Results: Data analysis unveiled 135 DEGs comprising 87 upregulated and 48 downregulated genes. GO analysis highlighted the association of these genes with structural components of the extracellular matrix, imparting stress resistance and receptor activator activity. The PPI network identified 17 key genes and two high-scoring clusters. KEGG pathways analysis revealed DEGs predominantly linked to cell division, DNA replication, progesterone-mediated maturation of the oocyte, hypoxia inducible factor-1 (HIF-1) signaling pathway, and FoxO signaling pathway. K-M survival curves demonstrated a more favorable prognosis in individuals with elevated ASF1 anti-silencing function 1 homolog B (ASF1B), GINS complex subunit 2 (GINS2), minichromosome maintenance complex component 2 (MCM2), polo-like kinase 1 (PLK1), and TTK Protein Kinase (TTK), while elevated TIMP metallopeptidase inhibitor 1 (TIMP1) expression indicated a poorer prognosis. Four miRNAs related to resistance were identified using miRWalk prediction: hsa-miR-4284, hsa-miR-6795-5p, hsa-miR-3945, and hsa-miR-4433a-3p.
Conclusion: Bioinformatics analysis has elucidated crucial genes and signaling pathways in FOLFIRI regimen resistance. This study enhances our understanding of the underlying mechanisms contributing to resistance in CRC liver metastases and establishes a robust foundation for future clinical research on diagnostic and treatment strategies.
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Background: Diabetic vascular complications are mainly caused by endothelial dysfunction, which is influenced by inflammation and epigenetic modifications. In this study, we aimed to investigate the role of fat-, mass- and obesity-associated (FTO) protein, an N6-methyladenosine (m6A) demethylase, in diabetes-induced retinal vascular endothelial dysfunction.
Methods: Human retinal vascular endothelial cells (RECs) were treated with high glucose (HG). The effect of HG on RECs was examined by various methods. The cell proliferation and apoptosis rate were determined using cell counting kit-8 (CCK-8) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) methods. The oxidative stress represented by the levels of Fe2+, malondialdehyde (MDA), and reduced glutathione (GSH) was assessed using commercially available kits. Moreover, the levels of m6A methylation and FTO protein, and the levels of ferroptosis-related proteins were evaluated using corresponding kits and Western blot analysis, respectively. The cell transfection method was used to regulate FTO in RECs and to determine the consequent effect on HG-treated RECs. Additionally, the levels of reactive oxygen species (ROS), MDA, 4-hydroxynonenal (4-HNE), and the structural changes in mitochondria were observed using Transmission electron microscopy. Furthermore, Erastin was used to induce ferroptosis in RECs with FTO knockdown and the consequent effects on ferroptosis, m6A methylation, oxidative stress, proliferation and apoptosis of HG-treated RECs were evaluated.
Results: HG treatment decreased proliferation (p < 0.01) and m6A methylation (p < 0.01), while increased apoptosis (p < 0.01), oxidative stress (p < 0.01), and ferroptosis (p < 0.01) in RECs. Furthermore, these HG-induced changes were ameliorated by FTO (p < 0.01). Additionally, it was found that the protective effect of FTO knockdown was disrupted by ferroptosis inducer (p < 0.01).
Conclusion: This study revealed the pathological role of FTO-dependent RNA demethylation in the retinal endothelial homeostasis induced by diabetes. Our findings suggest that FTO mediates diabetes-induced vascular endothelial changes by regulating ferroptosis. This finding could provide a new strategy for intervening in FTO and its related inflammatory pathways to treat diabetic vascular complications.
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Background: The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) serves as a key mediator of apoptosis and inflammation. However, the role of TRAIL and its receptors in ionizing radiation (IR)-induced skin injury remains unclear. Soluble death receptor 5-Fc (sDR5-Fc), a synthetic TRAIL blocking agent, is comprised of the small, unstable, and short half-life endogenous human soluble death receptor 5 (sDR5) molecule along with the Fc portion of human immunoglobulin 1 (IgG 1). This compound has demonstrated efficacy in treating various diseases induced by TRAIL. The primary objective of this study was to investigate whether the TRAIL signaling pathway is implicated in the development of radiation-induced skin injury and to assess whether sDR5-Fc could alleviate such damage.
Methods: The expression of TRAIL and its receptors in IR-induced human cells and C57 mouse skin was investigated through the application of immunohistochemistry (IHC) and flow cytometry (FCM). FCM and the Cell Counting Kit-8 (CCK-8) assay were employed to assess the apoptotic and proliferative effects of TRAIL on human keratinocyte (HaCat) cells. The potential alleviation of IR-induced skin damage in HaCat and human foreskin fibroblast-1 (HFF-1) cells, as well as in C57 mice, by sDR5-Fc, was examined using Western Blot (WB), flow cytometry (FCM), terminal deoxynucleotidyl transferase-mediated dUTP Nick-End Labeling (TUNEL) assay, and hematoxylin-eosin (H&E) staining.
Results: The expression of TRAIL and TRAIL-R2 in the skin tissues of mice was upregulated after exposure to 30 gamma rays (Gy). Following IR, the expression of secreted TRAIL (sTRAIL), as well as TRAIL-R1 and TRAIL-R2 on the surface of HaCat cells, significantly increased. The addition of TRAIL induced apoptosis and dose-dependently inhibited the proliferation of HaCat cells. IR induced apoptosis in HaCat cells in a manner dependent on both time and dose, directly and through the bypass effect. This inhibited cell proliferation and stimulated interleukin-6 (IL-6) secretion from HaCat cells, which could be partially prevented by sDR5-Fc treatment. Furthermore, sDR5-Fc alleviated radiation-induced skin injury in mice, resulting in a significantly lower skin injury score, a thinner epidermis, more hair follicles, and fewer collagen fibers.
Conclusions: We have demonstrated that TRAIL signaling plays a role in the pathogenesis of radiation-induced skin injury. This injury is alleviated both in vivo and in vitro through the use of sDR5-Fc, a TRAIL blocker.
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Background: Interstitial Cystitis (IC), also known as bladder pain syndrome (BPS), is a chronic urinary system disorder characterized by pelvic pain and urinary discomfort. The specific mechanisms underlying IC/BPS are yet to be fully understood. This study aimed to explore the role of the hydrogen sulfide (H2S)/cystathionine β-synthase (CBS)/cystathionine γ-lyase (CSE) signaling pathway in the IC/BPS model and its impact on urinary function mechanisms.
Method: Sprague-Dawley (SD) rats (n = 100) were randomly assigned into four groups: a control group (CG), a model group (MG), an inhibition group (IG), and an activation group (AG), with 25 rats in each group. The MG group was treated with acetylcholine to establish a bladder pain model (BPM), while the CG group received an equivalent quantity of saline treatment. Furthermore, the IG group was treated with H2S/CBS/CSE signaling pathway (SPW) inhibitors, while the AG group was intraperitoneally administered with H2S/CBS/CSE SPW activators. All rats were consistently fed, and their voiding behavior was observed, subsequently, their voiding function was evaluated after one day. Furthermore, rats were euthanized three days after treatments, and bladder tissue was surgically excised. Additionally, the levels of inflammatory factors and the activities of related pathway enzymes were assessed in the bladder tissues.
Results: Compared to the CG group, both the MG and IG groups exhibited a significant increase in Interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6) levels, as well as in bladder pressure (p < 0.01). However, urinary flow rate (UFR) and the activity of ion-channels (Na+, K+, and Na+/Ca2+) related enzymes were significantly decreased (p < 0.01) in these groups. In the AG, the bladder tissue had lower levels of IL-1β, TNF-α, IL-6, and bladder pressure compared to the CG group (p < 0.05), while UFR and the activity of ion-channels (Na+, K+, and Na+/Ca2+) related enzymes were significantly higher compared to the CG group (p < 0.05).
Conclusion: The H2S/CBS/CSE SPW alleviated bladder pain and improved voiding function in rats by reducing the levels of inflammatory factors, attenuating inflammatory responses, and regulating bladder contraction and relaxation.
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Background: Circular RNAs (circRNAs) are known to act as key regulators in a variety of malignancies. However, the role of circRNAs in gastric cancer remains largely unknown. This research aimed to explore the key biological function, clinical relevance, and expression of the circular RNA ACTN4 (circACTN4) in gastric cancer.
Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine circACTN4 expression in gastric cancer cell lines and tissue samples. The effects of circACTN4 depletion or overexpression on the angiogenesis, migration, invasion, colony formation, and proliferation of gastric cancer cells were assessed by cell counting kit-8 (CCK-8), clonogenic assay, Transwell assay, and angiogenesis analyses. Western blot assay determined whether low or high levels of circACTN4 mRNA affected the expression of invasion- and angiogenesis-related proteins. Utilizing a tumorigenicity experiment in nude mice, the effect of circACTN4 inhibition on the ability of gastric cancer to proliferate in vivo was investigated. The effect of circACTN4 knockdown on the expression of the protein implicated in angiogenesis, migration, and proliferation in tumor-bearing tissues was investigated using immunohistochemistry.
Results: Compared with para-carcinoma tissue and normal gastric epithelial cells, circACTN4 was upregulated in gastric cancer tissues (p < 0.01) and cell lines. CircACTN4 knockdown decreased gastric cancer cells proliferation (p < 0.01), migration (p < 0.05), and angiogenesis (p < 0.01), whereas circACTN4 overexpression had the opposite effect. The western blot showed that inhibiting circACTN4 substantially increased E-cadherin expression (p < 0.05) but decreased the expressions of Vimentin, N-cadherin, and Vascular Endothelial Growth Factor A (VEGFA) (p < 0.05). Knocking down circACTN4 in BALB/c mice significantly inhibited gastric cancer cell proliferation (p < 0.01), promoted E-cadherin expression, and suppressed Ki-67 (nuclear protein-67) and VEGFA expressions.
Conclusions: In conclusion, the current research showed that circACTN4 functions as a tumor-promoting gene and is overexpressed in gastric cancer tissues and cells. Experiments conducted in vitro and in vivo showed that circACTN4 knockdown can greatly reduce angiogenesis, invasion, and proliferation of gastric cancer. Therefore, circACTN4 may be a molecular target in the treatment of gastric cancer.
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Background: Hereditary spastic paraplegias (HSPs) are a heterogeneous and rare group of neurodegenerative disorders characterized by gradually progressing spasticity and weakness in the lower limbs. Various genes are associated with both the pure and the complex types of hereditary spastic paraplegia (HSP).
Methods: In this study, next-generation sequencing was employed to explore the case of a male proband suffering from HSP who has been unable to stand or walk since childhood due to an abnormal gait. A thorough examination was conducted, and the sequence data from both the proband and his parents were analyzed. Adhering to the guidelines set by the American College of Medical Genetics and Genomics (ACMG), these data were processed using the Online Mendelian Inheritance in Man (OMIM) database, as well as other resources such as The Human Phenotype Ontology (HPO), Chinese Human Phenotype Ontology (CHPO), and Orphanet.
Results: The cause of HSP in the proband was identified as a novel Exon 11 mutation detected at c.1131A>C (p.Asp444Ala). This mutation was determined to be a pathogenic gene and de novo, with no family history of the disorder.
Conclusions: This study aimed to uncover a novel genetic basis for HSP and advocate for Spastin (SPAST) testing among patients with the disorder. This research contributes to the understanding and expansion of the phenotype spectrum of SPAST-related diseases.
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Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation, pain, stiffness, and swelling in the affected joints typically with a symmetrical pattern on both sides of the body, which becomes more drastic and can also affect other organs and systems in the body. Thus, regular monitoring, follow-up of the disease, and exploring new metal-based therapy with minimum or no side effects are important challenges for managing the disease effectively.
Methods: Complexes with the common formula [M(L)(OAc)] (M = Cu (II) or Zn (II)) and HL = 2-(-3-hydroxy-2-naphthoyl)-3,4,4a,5,10,10a-hexahydro-1H-5,10-benzeno-benzo [g] phthalazine-1,4-dione) were synthesized through a reaction between phthalazinedione derivative (HL) and Cu (II) and Zn (II) acetates. For synthesis and description of the HL, various elemental analyses, UV-Vis, infera red (IR), 1H-NMR, 13C-NMR, conductance, thermal gravimetric analysis (TGA), and magnetic moments were accurately performed. Additionally, the analgesic and anti-inflammatory activities of phthaline metal compounds were identified using adjuvant arthritis model comprising of forty-eight Sprague-Dawley rats (200–250 g). In that model, the rats were categorized into two main groups: control group (received sodium carboxymethyl cellulose (SCMC) solvent, n = 6) and arthertis group (n = 42). In arthertic group, the rats had been inoculated by the reagent of collagen-adjuvant arthritis into the left paw pad. After 45 days, the arthertic rats were further divided into seven different groups (n = 6 each): arthritic control, piroxicam-treated, zinc acetate-treated, copper acetate-treated, HL, copper complex-, and zinc complex-treated groups. Then for all treated and non-treated rats, paw edema, pain and pressure tolerance measurements, and mobilization tolerance (pain scoring) were identified as measures of improvement in the disease activity following the respective piroxicam as standard and metal compounds.
Results: Phthalazine Copper (II) and Zinc (II) complexes showed anti-inflammatory action against rheumatoid arthritis as predicted by an equation with a regression correlation (R2 = 0.95) calculated using quantitative structure activity relationship (QSAR) analysis. The anti-inflammatory activity of synthesized phthalazine metal complexes was supported by the application of docking analysis and in vivo model of collagen adjuvant arthritis in rats, respectively. The results of docking showed that phthalate-zinedine derivatives in keto form structure have a MolDock Score of –130.726 Kcal/mol and a MolDock Rerank Score of –96.2 Kcal/mol, respectively. These suggest that phthalazinedione derivatives in keto form are strong and anchored with a cyclooxygenase-2 active site, which consequently decreases the inflammatory pathways associated with the progression of rheumatoid arthritis (RH). RH rats treated with piroxicam reported significant (p = 0.001) anti-inflammatory activity with an improved bor RI and analgic effects measured by both increase in pain tolerance and decrease in pain score compared to RH- non-treated rats. In addition to that, significant (p = 0.01) analgesic and anti-inflammatory effects of the ligand (HL) and its copper and zinc complexes than piroxicam RH treated rats and non-treated RH rats, respectively, were reported when the complexes were applied to in vivo rat models with collagen adjuvant arthritis.
Conclusions: Phthalazinedione derivative (HL), Cu (II), and Zn (II) acetates combined to treat rheumatoid arthritis (RH) show a good docking with inflammatory enzyme cyclooxygenase-2 (COX-2), with improved anti-inflammatory activities against RH as measured by docking and in vivo rat model of collagen adjuvant arthritis. In addition, the newly synthesized phthalazine metal complexes disclosed a significant anti-inflammatory and analgesic effect sequenced as [Zn(L)(OAc)] > HL > [Cu(L)(OAc)].
