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The microbiome in our digestive system plays a crucial role in maintaining a healthy balance and preventing diseases. Any imbalance in the microbiome, called dysbiosis, can increase the risk of sepsis and lead to a poor response to infection in the body. This review provides an overview of this topic's extent, range, and nature by clarifying the gaps in current knowledge and planning for future works. Our research involved identifying clinical trials that administered biotics to adult patients with sepsis. We thoroughly reviewed the studies to determine if any harm was caused to the microbiome during sepsis treatment. In addition, we explored other literature to gain insights into the relationship between the microbiome and sepsis. Our findings indicate that biotic products have been used in treating septic patients in only three studies. The studies varied in terms of conditions, assessed outcomes, populations, and products administered. To ensure the patient's well-being and avoid complications, treatment strategies for sepsis should prioritize maintaining a balanced microbiome and avoiding dysbiosis. Maintaining a healthy microbiome is not just about taking probiotic supplements. A deeper understanding of complex concepts like organ interaction and epigenetic modification can help understand the connection between the microbiome and sepsis, which could lead to new avenues of research. However, this is still a difficult task, and further clinical trials are needed to explore this area.
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This article reviews research progress on gastric cancer and tumor-associated macrophages (TAMs). Firstly, the definition, classification and pathogenesis of gastric cancer are introduced, followed by an overview of the definition, origin, differentiation, and function of TAMs. Then, the role of TAMs in the development of gastric cancer is discussed, including their interaction with the tumor microenvironment (TME), and mechanisms which affect gastric cancer development and progression. In terms of tumor treatment, this article summarizes the role of TAMs as targets for the treatment of gastric cancer, including research progress on gastric cancer treatment, immunotherapy and targeted therapy. Finally, this article proposes future research directions, including in-depth study of the regulatory mechanisms of TAMs, exploring the heterogeneity of TAMs, investigating the diagnostic and predictive value of TAMs, and developing and optimizing treatment strategies targeting TAMs.
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The gut microbiota (GM) plays a significant role in regulating the immune system, digestion, and estrogen levels. However, the extent of its impact on pregnancy and abortion remains unclear. Recent studies have demonstrated the importance of the gut-brain axis in digestion and psychological communication between the brain and gut tract. That suggests that GM may also play a role in fertility, as it can influence the brain and immune system. Herein, we aim to determine the evidential relationship between the gut microbiome and fertility in females. Moreover, we also discuss the potential mechanisms by which the GM can affect pregnancy and abortion.
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Metabolic syndrome (MetS) is a multifactorial disorder characterized by insulin resistance, dyslipidemia, central obesity, and hypertension, leading to an increased risk of cardiovascular diseases and type-2 diabetes. Although conventional drugs have been used to treat MetS and its associated complications, they are often linked with undesirable side effects. Consequently, there is a growing interest in herbal remedies as potential alternatives. Among these remedies is Withania somnifera, commonly known as Ashwagandha, a revered medicinal herb in traditional Chinese medicine and Ayurveda due to its numerous health-promoting properties. Withanolides, such as withaferin-A and withanolid-D, are the primary active compounds in W. somnifera and suggested to play a pivotal role in managing MetS. Moreover, Ashwagandha exhibits hypotensive, anti-obesity, anti-diabetic, and anti-hyperlipidemic properties, influencing multiple molecular and cellular pathways associated with MetS. W. somnifera has been demonstrated its potential to considerably reduce atherosclerotic plaque formation, as well as lower levels of very low-density lipoprotein (VLDL), triglycerides (TG), and low-density lipoproteins (LDL). This comprehensive review provides valuable insights into the latest research findings on the preventive potential of W. somnifera against MetS. Furthermore, recent studies on Ashwagandha highlight the need for additional clinical trials to evaluate its optimal dosage, safety profile, efficacy, and precise mechanisms of action.
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Background: Non-alcoholic fatty liver disease (NAFLD) is among the most common liver diseases. Epigenetic factors are involved in the development of NAFLD. However, studies have shown inconsistent results. This study aims to review the association between DNA methylation and NAFLD.
Methods: A systematic search was conducted in the Medline database (PubMed), Web of Science, Scopus, and Google scholar until the end of October 2021. All observational studies including cross-sectional, case-control, cohort and English-language human studies that assessed the effects of DNA methylation on NAFLD were included.
Results: Among 787 studies, 12 articles were included in the systematic review. Most studies showed that lower levels of DNA methylation in specific genes lead to NAFLD promotion. Among all the NAFLD-associated genes which were identified in the included studies, transforming acidic coiled-coil 2 (TACC2), STE20 Related Adaptor Beta (STRADB), Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1) and Hepatocyte Nuclear Factor 1 Beta (HNF1B), appear more frequently compared to other genes.
Conclusion: Results indicated a negative correlation between methylation status and NAFLD development. The role of DNA methylation can be considered as a risk factor for NAFLD.
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Objectives: Several clinical trials have been conducted to investigate the safety and efficacy of pembrolizumab-containing therapy for esophageal cancer (EC) and gastroesophageal junction cancer (GEJC), but the outcomes vary greatly among studies and the optimal choice has not been identified. This study aimed to evaluate the efficacy and safety of pembrolizumab in the treatment of EC/GEJC by meta-analysis.
Methods: PubMed, Embase, Web of Science and Cochrane library databases were searched to identify eligible studies (including single-arm studies or randomized controlled studies) of pembrolizumab for treating EC and GEJC updated to December 13, 2022. Primary outcomes including overall survival (OS), objective response rate (ORR), disease control rate (DCR) and treatment related adverse events (TRAEs) were pooled using random-effect or fixed-effect models by considering of the heterogeneity. Meta-analysis was implemented using Stata statistical software.
Results: A total of 8 clinical trials involving 1165 patients were enrolled. The pooled median OS time was 7.69 months (95% confidence interval (CI): 5.60, 9.79) for patients treated with pembrolizumab. The pooled rates of objective response, disease control and total TRAEs were 21.3% (95% CI: 9.9%, 35.3%), 48.9% (95% CI: 33.3%, 64.6%) and 78.5% (95% CI: 61.1%, 91.8%), respectively. Subgroup analysis indicated that pembrolizumab-based combination therapy tended to improve OS (8.74 vs. 7.14 months), ORR (39.1% vs. 12.8%) and DCR (66.7% vs. 37.6%) compared to pembrolizumab monotherapy, but there was no statistical significance (all p > 0.05). Notably, pembrolizumab monotherapy significantly decreased the rate of total TRAEs than combination therapy (67.1% vs. 90.1%, p = 0.033), mainly reflected on fatigue (18.0% vs. 45.6%), white blood cell decreased (0.7% vs. 30.4%), anorexia (8.8% vs. 36.5%), nausea (6.4% vs. 35.6%) and diarrhea (5.2% vs. 14.8%).
Conclusion: Pembrolizumab was effective on clinical outcomes in the treatment of EC/GEJC, and individualized pembrolizumab is recommended on a clinical basis.
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Background: Bone is a dielectric material. Thus, improving the dielectric properties of bioceramics has become an important issue in recent years. In this study, we aimed to investigate the effects of europium (Eu) and ruthenium (Ru) doping on the structural, morphological, and dielectric properties of strontium apatites (SrAp). For this, pure, Eu- and Ru-doped SrAp nanoparticles were synthesized by the hydrothermal method.
Methods: Hydrothermal synthesis was carried out at 200 °C for 3 h. The structural and morphological properties of the synthesized SrAp nanoparticles were investigated by field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), and energy-dispersive X-ray spectroscopy (EDX) analyses. The dielectric properties of the synthesized nanoparticles were investigated.
Results: Eu and Ru additives reduced the XRD peak intensities and broadened the peaks. The characteristic XRD peaks of SrAp were affected by Eu and Ru doping. Doping of Ru and Eu co-doped with Ru shifted the planes below the 2θ values. The synthesized particles are in the nanoscale range and in the form of nanorods. The lengths of the nanorods were shortened and expanded by the addition of Eu and Ru. The closest value to 1.67, which is the stoichiometric ratio of Sr/P, was obtained for the sample that had Eu and Ru co-doped (1.47). The Eu and Ru addition affected the electrical properties of the synthesized nanoparticles. Superior dielectric constants, dielectric losses, and alternative current (AC) conductivities were obtained compared with those for Eu- and Ru-doped pure SrAp samples.
Conclusions: The results showed that the dielectric properties of SrAp nanoparticles improved; thus, more studies should be performed. The nanoparticles produced in this study can likely be used as biomaterials in biosensors, biomedical applications, and orthopedic and dental applications.
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Background: The corpuscles of Stannius (CS) are endocrine glands that regulate homeostasis of minerals, including calcium and phosphate, in bony fish. The hormone secreted by the CS, known as stanniocalcin, has been found in humans and bony fish. In mammals, stanniocalcin expressed in osteoblasts and has been reported to regulate osteoblastic differentiation. However, the details regarding its effect on osteoclasts remain uninvestigated. Therefore, in this study, we aimed to evaluate the effects of stanniocalcin on bone metabolism, including osteoclasts.
Methods: Stanniocalcin is composed of approximately 250 amino acids, including several cysteines and glycans. Artificially synthesizing this hormone is difficult. In the present study, we used the CS extract to evaluate the effects of stanniocalcin on bone metabolism. Moreover, we established an in vitro bioassay system utilizing goldfish scales as a coexistence model of osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells) in the calcified bone matrix. Using the goldfish scales, we examined the effects of CS extract treatment on the mRNA expressions of osteoclast- and osteoblast-related genes. Furthermore, to assess the inhibitory action of osteoclasts, we examined the receptor activator for NF-κB ligand (Rankl), osteoclastogenesis-promoting factor, osteoprotegerin (Opg), osteoclastogenesis inhibition factor, involved in the osteoblast–osteoclast interaction.
Results: The expression of osteoblastic markers, such as alkaline phosphatase and collagen type I alpha 1 (Col1a1), significantly increased 6 h post-treatment with the CS extract. At 18 h post-incubation, Col1a1 and osteocalcin mRNA expressions in the treated scales also significantly upregulated. Conversely, at 6 and 18 h post-incubation, the mRNA expression of osteoclastic markers, cathepsin K, tartrate-resistant acid phosphatase, and matrix metalloproteinase-9, significantly decreased. Further, at 6 h post-incubation, Rankl/Opg expression significantly decreased on adding the CS extract.
Conclusions: The CS extract was found to inhibit the osteoclastic activity by modulating Rankl/Opg expression. Thus, stanniocalcin inhibits the osteoclastic activity but promotes osteoblastic activity and bone formation.
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Background: Sphingosine kinase 1 (SphK1) is a crucial oncogenic lipid kinase responsible for regulating the sphingolipid balance. It plays a key role in apoptosis, cell growth, proliferation, inflammation, migration, signal transduction, metabolism, and cancer progression. Overexpression of SphK1 is observed in cancer, making it a potential target for cancer treatment and other diseases. Our study aimed to identify novel fungal bioactives with possible anti-SphK1 activity using in-silico approaches.
Methods: The bioactives' absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties were determined, and molecular docking was conducted with the target protein. Protein-protein interactions, gene enrichment analysis, and comprehensive topological properties of selected protein were also assessed. Furthermore, we evaluated the molecular dynamics simulation (MDs) of the top-docked protein-ligand complex.
Results: All the compounds selected for the present study met the criteria for drug-like characteristics and adhered to Lipinski's rule of five (RO5). The Molecular binding results showed that Cytochalasin H was the most significant molecule, displaying a binding affinity of –11.1 kcal/mol. The search tool for the retrieval of interacting genes/proteins (STRING) database provided insights into the protein-protein network interactions. This study's enrichment analysis indicated that the differentially expressed genes were significantly enriched in sphingolipid metabolism, followed closely by the vascular endothelial growth factor (VEGF) signaling pathway. Computed atlas of surface topography of proteins (CASTp) analysis revealed the topographic properties of SphK1 protein, with the top pocket having an area accessible surface (AS) of 7119.22 Å2 and volume accessible surface (AS) of 7762.45 Å3. The MDs analysis showed increased root mean square deviation (RMSD) and radius of gyration (Rg) values, indicating significant conformational alterations during the simulation period.
Conclusions: This study suggests that cytochalasin H may be repurposed as a potential SphK1 inhibitor. These findings could be clinically relevant for the development of therapeutic drugs.
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Background: Cardiovascular disease (CAD) are the leading cause of human death, resulting in high morbidity, disability, and mortality. (-)-Epicatechin [(-)-EPI], a traditional Chinese medicine, has been used for treating CAD. This study aims to investigate the role of (-)-EPI in myocardial fibrosis (MF).
Methods: We established an acute myocardial infarction (AMI) model mouse. The mice were fed with (-)-EPI and/or SRI-011381 hydrochloride (TGF-β1 agonist, HY-100347A) for 10 days. Hematoxylin and eosin (H&E) staining, Masson staining, and Western blot were used to confirm the effects of (-)-EPI alone or in combination with HY-100347A on the pathological injury, MF, and transforming growth factor-β (TGF-β) pathway in AMI model mice. In vitro experiments were conducted to verify whether (-)-EPI could affect the proliferation, apoptosis, and collagen deposition through the TGF-β1 pathway in myocardial fibroblasts under hypoxia.
Results: In the AMI model mice, (-)-EPI was found to attenuate pathological injury and MF, and suppress the TGF-β pathway. However, these inhibitory effects mediated by (-)-EPI could be reversed by the administration of the TGF-β1 pathway activator (HY-100347A). Moreover, myocardial fibroblasts were successfully extracted and certified. (-)-EPI inhibited apoptosis and collagen deposition in hypoxic myocardial fibroblasts by suppressing the TGF-β1 pathway (p < 0.05, p < 0.01, p < 0.001).
Conclusions: Collectively, (-)-EPI has the potential to improve pathological injury and MF in AMI patients by suppressing the TGF-β1 pathway. This discovery provides new insights into the treatment of AMI.
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Objective: The differences in the expression levels of differentially-expressed proteins (DEPs) in serum specimens from non-small cell lung cancer (NSCLC) patients presenting with radiation pneumonia (RP) and non-pneumonia at 0, 3, and 6 weeks after radiotherapy were compared by a quantitative proteomics approach. This study aims to identify reliable biomarkers for predicting RP.
Methods: Twenty-eight patients who were pathologically diagnosed as locally advanced NSCLC and received radiotherapy for the first time from October 2017 to July 2018 were recruited. Serum samples were collected before radiotherapy and 3 and 6 weeks after radiotherapy. Three patients with grade ≥2 RP were assigned into the experimental group (RP group). Three patients with the same sex, pathological type, age, and clinical stage were selected from the remaining 25 patients without RP, and allocated into the control group (C group). DEPs were identified using tandem mass tags (TMT) labeling and liquid chromatography-mass spectrometry, functional annotation, functional enrichment, and protein-protein interaction (PPI) network analyses.
Results: 812 quantifiable proteins were identified by mass spectrometry of peptides. Bioinformatics analysis revealed that these proteins were mainly involved in binding, biological regulation, metabolic processes, signaling transduction processes, and pertussis in the Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway. Using 1.2 times as the threshold for differential expression change and p < 0.05 as the significance threshold, the expression levels of recombinant zyxin (ZYX) and recombinant fetuin B (FETUB) were up-regulated before radiotherapy and 3 weeks after radiotherapy (both p < 0.05). Recombinant Cystatin A (CSTA) and calmodulin-like 5 (CALML5) expression levels were down-regulated before radiotherapy and 6 weeks after radiotherapy (both p < 0.05). Nicotinamide nucleotide transhydrogenase (NNT) expression level was significantly down-regulated before radiotherapy and 3 and 6 weeks after radiotherapy, with ratios of 0.296, 0.314 and 0.238, respectively (all p < 0.05). The expression levels of NNT, haptoglobin-related protein (HPR), and pregnancy zone protein (PZP) were significantly down-regulated before radiotherapy, with ratios of 0.296, 0.377 and 0.376, respectively (all p < 0.05). PPI network constructed by STRING database found that fetuin B (FETUB) interacted with PZP among these DEPs, and PZP was associated with the pathophysiological pathways of RP, such as transforming growth factor-β (TGF-β), interleukin-1β (IL-1β), IL-6, tumor necrosis factor (TNF) and inflammatory response-related pathways.
Conclusions: Quantitative proteomics analysis identifies the differences in the expression levels of DEPs between NSCLC patients presenting with or without RP throughout radiotherapy. Based on proteomics analysis and PPI network, FETUB and PZP are optimal candidate proteins for RP, which provides evidence for verifying the potential predictive biomarkers of RP.
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Background: As a common and aggressive cancer, gastric cancer is a severe threat to human health. This experiment investigated the function of p21-activated kinase 6 (PAK6) in gastric cancer, in order to explore its possibility as tumor marker and prognostic indicator for gastric cancer.
Methods: Sixty pairs of gastric cancer tissues and adjacent normal tissues were collected from patients with gastric cancer in the Third Affiliated Hospital of Shandong First Medical University (Affiliated Hospital of Shandong Academy of Medical Sciences). Western blot, real time quantitative PCR (RT-qPCR) and immunohistochemical tests were carried out to validate the level of PAK6 in gastric cancer tissues and adjacent normal tissues. The effect of PAK6 on the proliferative activity, migration, invasion, apoptosis and epithelial-mesenchymal transition (EMT) of gastric cancer cells was examined by cell counting kit‑8 (CCK-8), scratch, Transwell, flow cytometry (FCM) and western blot assays. The correlation between PAK6 and miR-200b-3p was detected by a dual-luciferase reporter gene assay.
Results: PAK6 was overexpressed in gastric cancer tissues, and had a negative correlation with overall survival in patients with gastric cancer. Next, we successfully knocked down PAK6 in AGS and MKN45 cells. PAK6 silencing significantly reduced the proliferation, invasive and migratory abilities, EMT process, and accelerated the apoptosis. Furthermore, miR-200b-3p was confirmed to be a targeted miRNA for PAK6.
Conclusions: We found that PAK6 played a promoting role in gastric cancer, and might serve as a new oncogenic indicator of gastric cancer to guide clinical practice.
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Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer. At present, stem cell therapy has gradually attracted attention in LUAD treatment. Therefore, this study was designed to explore the effects and mechanisms of lung-resident mesenchymal stem cells (LR-MSCs) on LUAD.
Methods: Xenograft tumor models of LUAD mice were established and randomly divided into four groups, namely human umbilical cord mesenchymal stem cells (hUCMSCs), LR-MSCs and gemcitabine (GEM) treatment groups as well as the normal saline (NS) group. The tumor growth volume was recorded every 3 days, and after 21 days, the nude mice were sacrificed. Subsequently, pathological changes of the tumor, lung, and liver tissues were observed by hematoxylin and eosin (H&E) staining; protein expressions of vascular endothelial growth factor (VEGF), B-cell lymphoma-2 (BCL-2), and matrix metalloproteinase-9 (MMP-9) were examined by immunohistochemistry.
Results: Xenograft tumor models of LUAD mice were successfully established. Compare with the NS group, the treatment groups had smaller volume and size of xenograft tumors. Besides, the results of H&E staining showed slighter pathological changes of tumor tissues in the treatment groups than those in the NS group. Therefore, MSCs may inhibit the growth of subcutaneous xenograft tumors. Furthermore, the protein expression levels of VEGF and BCL-2 in tumor tissues of each treatment group were significantly lower than those in the NS group. Notably, the MMP-9 protein of the LR-MSCs and GEM treatment groups were significantly lower than that of the NS group and hUCMSCs group. The inhibition of tumor growth by MSCs may be related to its functions that controlled angiogenesis in tumors and promoted rapid apoptosis of tumor cells. Additionally, no metastases and liver injury were observed in the liver tissues of nude mice.
Conclusion: LR-MSCs can inhibit the growth of subcutaneous xenograft tumors in LUAD nude mice by down-regulating the expressions of VEGF and BCL-2 proteins, Moreover, the effect of LR-MSCs is comparable to that of hUCMSCs.
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Backgrounds: Laryngeal cancer manifests as a malignant tumor, often leading to unfavorable prognosis for patients. There is a pressing need for potential biomarkers and therapeutic targets for laryngeal cancer. Our study delved into the role of tripartite motif-containing 27 (TRIM27) in laryngeal cancer cells and studied the effect of interleukin-6 (IL-6) coupled with janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway on the pathogenesis of laryngeal cancer.
Methods: Initially, using the quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), we investigated the expression levels of TRIM27 in both normal epithelial cells (NP69) and laryngeal cancer cells (Hep2). Subsequently, the effects of TRIM27 on IL-6 inflammatory factors and JAK-STAT pathway-associated proteins were measured using enzyme-linked immunosorbent assay (ELISA) and western blot, respectively. Finally, the mechanism of TRIM27 on the growth and metastasis of Hep2 cells was assessed through cell counting kit 8 (CCK8), flow cytometry, and transwell assays.
Results: Compared to the normal epithelial cell NP69, TRIM27 levels in the laryngeal cancer cell Hep2 were markedly increased (p < 0.001). TRIM27 overexpression has increased IL-6 levels, activated the JAK-STAT pathway, and increased p-JAK2 and p-STAT3 protein levels. Conversely, silencing TRIM27 inhibited the proliferation and metastasis of Hep2 cells by blocking the JAK-STAT pathway, especially when compared to overexpressing TRIM27 (OE-TRIM27) (p < 0.001).
Conclusions: This study demonstrates that silencing TRIM27 can effectively inhibit the progression of laryngeal cancer cells through the deactivation of the IL-6/JAK-STAT pathway, indicating that TRIM27 may be a promising target for laryngeal cancer treatment.
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Background: Achyranthes bidentata Blume (Abb) is a renowned medicinal herb in traditional Chinese medicine. The molecular mechanism associated with the anti-diabetic potential of Abb is yet to be determined. In this study, we elucidated the in vivo and in vitro anti-diabetic potential of the methanolic leaf extract of Abb (Abb-ME) in alloxan-induced diabetic mice and HepG2 cells.
Methods: Qualitative and quantitative phytochemical analysis was performed to identify the metabolites in the Abb-ME. Diabetes mellitus (DM) was induced in mice using alloxan monohydrate (150 mg/kg). Diabetic parameters (blood glucose, body weight, lipid profile, hematological indices, histopathological changes) were observed post Abb-ME administration. The in vitro study included glucose uptake assay and quantitative reverse transcription-PCR (qRT-PCR) analysis of glucose transporters 2 (GLUT2) gene expression in HepG2 cells.
Results: Qualitative and quantitative phytochemical analysis revealed the presence of alkaloids, flavonoids (44.89 ± 3.9 mg/g extract), carbohydrates, proteins, phenols (60.3 ± 1.2 mg/g extract), and steroids. The results showed that the Abb-ME treatment group (500 mg/kg) exhibited significant (p < 0.05) reductions in blood glucose levels compared to the diabetic control and Glibenclamide group. Other diabetic parameters, such as body weights and lipid profiles, were significantly improved (p < 0.05) in the Abb-ME treated group (500 mg/kg) compared to the diabetic control mice. The altered hematological indices, including packed cell volume (PCV), hemoglobin (Hb), Red Blood Cell (RBC), mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), Total White Blood Cell (TWBC), and White Blood Cell (WBC) differentials, observed in the diabetic control group were normalized after Abb-ME administration. These findings revealed that Abb-ME treatment effectively resolved several aberrant hematological indices associated with diabetes. Histopathological analysis of mice pancreas confirmed increased acini cell density, β-cell counts, and clear border formations between the endocrine and exocrine regions following Abb-ME treatment. In vitro studies showed significant (p < 0.05) glucose uptake (169.6%, 100 μg/mL) in HepG2 cells following Abb-ME treatment compared to the control (100%). GLUT2 gene expression was increased (1.28-fold) following Abb-ME treatment relative to the control.
Conclusions: Our data suggest that Abb-ME possesses antidiabetic potential, providing a basis for further studies and applications.
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Background: Myelination defects in the medial prefrontal cortex (mPFC) have been linked to depression-like behaviors in mice. Gastrodin (GAS) has been identified as a pro-myelinating drug and has demonstrated anti-depressant potential in depression models. This study aimed to evaluate the roles and possible mechanisms of GAS in regulating depressive behaviors and myelination in a chronic restraint stress (CRS) mouse model.
Methods: A CRS protocol was implemented to induce depression-like behaviors in mice. Myelination in the mPFC of CRS mice was assessed by analyzing the expression of myelin proteins and examining the ultrastructure of the myelin sheath. GAS and clemastine fumarate (CF) were administered to CRS mice to investigate their effects on depression-like behaviors and myelin restoration. Additionally, the activities of Notch and β-catenin pathways were assessed using western blot analysis.
Results: CRS resulted in depression-like behaviors in 75% of stressed mice (labeled as ‘De’ mice), accompanied by hypomyelination in the mPFC. Treatments with GAS and CF in the ‘De’ mice ameliorated depression-like behaviors and restored myelination in the mPFC. GAS treatment in the ‘De’ mice suppressed the activity of the Notch and β-catenin pathways, while CF treatment in the ‘De’ mice only inhibited the β-catenin pathway.
Conclusions: GAS restored myelination in the mPFC, alleviating depression-like behaviors in CRS-induced ‘De’ mice. These effects may be attributed to the inhibition of the Notch and β-catenin pathway activity by GAS.
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Background: A boosted protease inhibitor (PI) plus two nucleoside reverse-transcriptase inhibitors (NRTIs) or a boosted PI plus an integrase inhibitor is recommended as second-line antiretroviral therapy (ART) alternatives. Our study aimed to evaluate the efficacy and safety of raltegravir (RAL)-based and lopinavir-boosted ritonavir (LPV/r)-based regimens as second-line options in the Chinese population.
Methods: A multicenter, open-label, prospective, randomized controlled cohort study was performed at 18 research sites in China. Human immunodeficiency virus (HIV)-infected adults with a plasma viral load >400 copies/mL after at least 1 year of first-line ART were enrolled. Participants were randomized in a 2:1 ratio to receive oral RAL plus tenofovir disoproxil fumarate (TDF) plus LPV/r (RAL group) and lamivudine (3TC) plus TDF plus LPV/r (LPV/r group) for 48 weeks. The primary endpoint was a plasma viral load <400 copies/mL at the 48th week, which was measured by reverse transcription polymerase chain reaction (RT-PCR). Other important indicators, such as cluster of differentiation 4 (CD4) cell count and HIV-1 DNA, were measured by flow cytometry and quantitative PCR, respectively.
Results: A total of 175 patients were randomized to either the RAL group (n = 119) or the LPV/r group (n = 56). High levels of drug resistance to both TDF and 3TC were observed in both groups (41.4% vs. 39.5%, p = 0.84). At the 48th week, the viral load <400 copies/mL was achieved in 100 (94.3%) out of 106 patients in the RAL group and 47 (92.2%) out of 59 patients in the LPV/r group (p = 0.60). There was non-significant difference between the two groups in the percentage of patients with cluster of CD4 cell counts >200 cells/μL (85.0% vs. 76.5%, p = 0.19). Likewise, the non-significant decrease in HIV-1 DNA was observed in the two groups at the 48th week. Faster viral suppression and CD4 cell recovery were observed in the RAL group.
Conclusions: The LPV/r-based regimen as a second-line ART demonstrated a similar effective long-term virologic suppression rate compared to the RAL-based regimen. A regimen of NRTIs plus PI remains the most effective and cost-effective second-line option in developing regions.
Clinical Trial Registration: NCT01844310; Registered May 1, 2013. Available at:
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Background: N6-methyladenosine (m6A) modification regulates gene stability, leading to the progression of lung adenocarcinoma (LUAD). However, the regulatory mechanism of the RNA-binding motif protein 15 (RBM15), an m6A methyltransferase that regulates SCL-interrupting locus protein (STIL) stability, has not yet been elucidated. This study aimed to determine the function and mechanism of action of RBM15 in LUAD.
Materials and Methods: Bioinformatics analysis predicted the expression and correlation of RBM15 and STIL in LUAD. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the levels of RBM15 and STIL in clinical samples from patients with LUAD. Then, in vitro and in vivo experiments were performed to confirm the effects of RBM15 and STIL on the progression of LUAD. Finally, Methylated RNA Immunoprecipitation, mRNA stability, qRT-PCR, and western blotting were performed to identify the correlation between RBM15 and STIL in LUAD cells.
Results: RBM15 was confirmed to be upregulated in LUAD, and its knockdown inhibited LUAD malignancy by decreasing proliferation, migration, and invasion. In vivo experiments confirmed that RBM15 knockdown inhibited tumor growth. RBM15 knockdown reduces STIL stability via m6A modification. Additionally, STIL overexpression contributed to the malignancy of LUAD cells; however, RBM15 knockdown partly relieved this effect.
Conclusion: RBM15 knockdown suppresses LUAD progression by reducing STIL stability. This may provide novel biomarkers for the diagnosis and therapy of LUAD.
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Background: Although limited work has been done on investigating the effects of Histone deacetylases (HDACs) on osteoclast formation and function, HDACs have been shown to regulate gene expression and may work as a critical regulator of osteoclast differentiation, especially class II and IV HDACs which function as inhibitors. The study aims to investigate whether HDAC4 has an effect on the compressive force (CF)-induced osteoclast differentiation in human periodontal ligament cells (PDLCs) and its role in regulating the mitogen-activated protein kinase/beta-catenin (MAPK/β-catenin) signaling pathway.
Methods: The PDLCs were isolated from normal premolar extracted for orthodontic purposes. The expression of HDAC4 during osteoclast differentiation was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot. Then, the characteristic changes of PDLCs were evaluated utilizing tartrate-resistant acid phosphatase (TRAP) staining, cell counting kit-8 (CCK-8), and colony-forming units-fibroblast (CFU-F) procedures. Then, the CF group was transfected and divided into four groups: CF cells transfected with small interference RNA (Si-RNA) against HDAC4 (Si-HDAC4) and the corresponding scramble Si-RNA as negative control (CF cells transfected with scramble small interfering (Si)-RNA, Si-NC), cells transfected with lentiviral vectors encoding HDAC4 overexpression-RNA (CF cells transfected with lentiviral vectors encoding HDAC4 overexpression-RNA, OE-HDAC4) and the corresponding blank vectors as negative control (CF cells transfected with blank lentiviral vectors, OE-NC). The expression of MAPK/β-catenin pathway-related proteins in these groups was detected, and the regulation of HDAC4 on the MAPK/β-catenin pathway was verified by adding pathway activator isomycin or cells transfected with Si-β-catenin.
Results: It was observed that the expression of HDAC4 decreased in PDLCs after CF. Inhibition of HDAC4 promoted osteoclast differentiation in PDLCs. The study also revealed that due to the inhibition of HDAC4, the relative expression of p-p38/p38 in PDLCs was significantly down-regulated (p < 0.001). However, using the MAPK pathway activator, the osteoclast differentiation expression level returned to or above the normal levels (p < 0.05). Additionally, we investigated that the inhibition of HDAC4 significantly upregulated the relative expression level of β-catenin (p < 0.001). Moreover, after transfecting the cells with Si-β-catenin, the progress of osteoclast differentiation was restored to or above the normal level.
Conclusion: It is concluded that suppressing HDAC4 expression could promote osteoclast differentiation in human PDLCs. HDAC4 also plays an important role in regulating the MAPK/β-Catenin signaling pathway. At present, there are a few applications of orthodontic tooth movement (OTM) treatment using PDLCs, this study could aid the clinical applications of PDLCs for OTM treatment.
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Background: Osteocellular necrosis due to prolonged or heavy glucocorticoid application plays an essential role in the steroid-induced necrosis of the femoral head (SONFH). Promoting osteoblast proliferation and osteogenic differentiation is an effective therapeutic strategy for SONFH. Panax Notoginseng Saponins (PNS) can increase osteoblasts' proliferative activity and alleviate glucocorticoid's inhibitory effect on the proliferation of MC3T3-E1 cells. As a nanoscale natural drug carrier, exosomes have unique advantages in improving drug efficacy and reducing side effects. This study aimed to test whether PNS could promote osteogenic differentiation of MC3T3-E1 cells via osteoclast-derived exosomes in a hormonal environment.
Methods: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was utilized to screen the non-toxic concentrations of PNS action on RAW264.7 cells. In addition, the non-toxic concentration of dexamethasone (Dex) acting on RAW264.7 with MC3T3-E1 cells was screened using cell counting kit-8 (CCK-8) assay. RAW264.7 cells were induced to differentiate into osteoblasts by receptor activator for nuclear factor kappa-B ligand (RANKL) reagent and identified by tartrate resistant acid phosphatase (TRAP) staining. Model group exosomes (OC-Exos) and PNS intervention group exosomes (PNS+OC-Exos) in the Dex environment were obtained using ultra-high-speed centrifugation. MC3T3-E1 cells were sorted into blank control (NS) group, OC-Exos group, and PNS+OC-Exos group and added with phosphate buffered saline (PBS) solution, OC-Exos, and PNS+OC-Exos for intervention, respectively. In addition, the exosomes of the OC-Exos group and PNS+OC-Exos group were labeled by PKH67 dye. Subsequently, osteogenic changes were evaluated by alkaline phosphatase (ALP) staining and alizarin red S (ARS) staining. Finally, the expression levels of osteogenic markers such as ALP, osteocalcin (OCN), runt-related transcription factor2 (Runx2), and collagen type I alpha 1 (COL1A1) were determined in the three groups of MC3T3-E1 cells utilizing real time-polymerase chain reaction (RT-PCR) assay and Western blot assay.
Results: TRAP staining highlighted that RAW264.7 was successfully induced to osteoclasts by RANKL, while PNS inhibited its differentiation. OC-Exos and PNS+OC-Exos were successfully extracted. In addition, PKH67 fluorescence staining confirmed the uptake of exosomes by MC3T3-E1 cells in both groups. The number of ALP activity and calcified nodules in MC3T3-E1 cells elevated in the PNS+OC-Exos group compared to the OC-Exos group. Gene and protein expression levels in the PNS+OC-Exos group significantly higher in ALP, OCN, Runx2 and COL1A1 than in the OC-Exos group (p < 0.05).
Conclusion: PNS inhibited RANKL-induced differentiation of RAW264.7 cells to osteoblasts in a Dex environment. Furthermore, PNS reversed the inhibition of osteogenic differentiation of MC3T3-E1 cells by OC-Exos.
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Background: Testis-specific protein Y-encoded-like 2 (TSPYL2) has been identified as a tumor suppressor on the X chromosome whose hypomethylation is regarded as a biomarker of uterine leiomyomas. Its methylation status in prostate cancer (PCa) remains unclear. The purpose of this study was to investigate the methylation status of TSPYL2 in PCa and its role in the migration and proliferation of PCa cells.
Methods: Following the required transfection with short hairpin RNA-methyltransferase-like 3 (shRNA-METTL3) and TSPYL2 overexpression plasmid, both quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot assays were adopted to measure the expressions of METTL3 and TSPYL2. The content of N6-methyladenosine (m6A) was measured through RNA immunoprecipitation (RIP). Whether TSPYL2 RNA was methylated in PCa cells was validated by RIP-qPCR. The level of TSPYL2 RNA methylation was determined through Methylated (Me) RIP-qPCR. Scratch and colony formation assays were separately adopted to evaluate migration and proliferation, respectively.
Results: TSPYL2 expression was down-regulated (p < 0.001) while METTL3 expression was up-regulated (p < 0.001) in PCa cells (LNCaP and PC3). The expression level of TSPYL2 was down-regulated in prostate adenocarcinoma (PRAD) tumor samples (p < 0.05). m6A content was high in LNCaP and PC3 cells (p < 0.01). TSPYL2 possessed METTL3-related methylation in PCa cells. METTL3 positively regulated TSPYL2 methylation in PCa cells. Both shRNA-METTL3 and TSPYL2 overexpressions decreased the migratory and proliferative abilities of LNCaP and PC3 cells (p < 0.001).
Conclusions: TSPYL2-mediated RNA hypomethylation suppresses migration and proliferation of PCa cells.
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Objective: To explore the effect of nuclear factor kappa-B (NF-κB) on vascular injury in patients with obstructive sleep apnea hypopnea syndrome (OSAHS).
Methods: 51 OSAHS patients were enrolled in this study. According to apnea hypopnea index, patients were divided in three groups: Mild (10 cases), moderate (14 cases) and severe OSAHS (27 cases) groups. OSAHS patients who were treated with Continuous Positive Airway Pressure (CPAP) were considered as treatment group (25 cases).
Results: The flow-mediated dilation (FMD) level of OSAHS group significantly decreased compared to the control group (p < 0.05), but carotid arterial intima-media thickness (CIMT) level was significantly higher in OSAHS group compared to the control group (p < 0.05). Moreover, FMD level in the moderate and severe OSAHS groups were lower compared to the control and mild OSAHS groups (p < 0.05). The CIMT level was positively related to the obstruction degree (p < 0.05). Furthermore, NF-κB p65 protein level in the moderate and severe OSAHS groups were higher compared to the control and mild OSAHS groups (p < 0.05). After CPAP treatment, FMD level significantly increased, and CIMT level and NF-κB p65 protein level were lower in the OSAHS group (p < 0.05).
Conclusions: NF-κB might be involved in the vascular endothelial injury induced by chronic intermittent hypoxia in patients with OSAHS.
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Background: Intracerebral hemorrhage (ICH) is a prevalent cerebrovascular disorder in clinical practice. Secondary brain injury (SBI) is observed in the perihematomal tissue following ICH. A traditional Chinese herb astragalus membranaceus (AM) has been reported to treat cerebrovascular disease. The study aimed to explore the function and mechanism of cycloastragenol (CAG), a hydrolysis product of astragaloside IV isolated from AM, on ICH.
Methods: Male Sprague-Dawley rats weighing 300 ± 20 g were randomly assigned to the sham group, ICH group, CAG-low group (CAG-L), CAG-medium group (CAG-M), and CAG-high group (CAG-H). Rats were used to establish an ICH model by intrastriatal injection of collagenase type IV. Different concentrations of CAG (2.5, 5, and 10 mg/kg) were intraperitoneally injected at 1 h and 6 h after immunohistochemistry (IHC) induction. Rats were necropsied on the 3 days after ICH induction. Neurobehavioral assessments (daily), blood-brain barrier (BBB) permeability, brain water content (BWC), immunofluorescence staining, and western blot were performed. HT22 cells were treated with different concentrations of CAG (1, 10, and 20 μM). Cell proliferation was assessed using the Cell Counting Kit-8 (CCK-8), while cell apoptosis was evaluated via flow cytometry.
Results: CAG improves ICH-induced neurological deficits and neuronal apoptosis in a dose-dependent manner. CAG also decreases BBB permeability and BWC during continuous testing. Enzyme-linked immunosorbent assay (ELISA) of brain tissues from the peri-hematoma area shows CAG dose-dependently inhibited oxidative stress and inflammation of ICH rats. These functional improvements are correlated with reductions in inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α, and reactive oxygen species (ROS) levels as well as microglial deactivation. Mechanistically, CAG dose-dependently inhibits the p38 mitogen-activated protein kinase (MAPK)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling in neurons and astrocytes. In vitro, hemin induces apoptosis and inhibits proliferation of HT22 cells. In addition, CAG inhibits hemin-induced apoptosis and promotes proliferation of HT22 cells.
Conclusions: Taken together, these data indicate that CAG may provide therapeutic benefits for ICH patients.
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Background: Abnormal Choline (Cho) metabolism is a hallmark of breast cancer (BC). Since the key role of choline transporter-like protein 4 (CTL4) in Cho transport and acetylcholine (ACh) biosynthesis has been reported, this study aimed to investigate additional role and mechanisms of CTL4 in BC.
Methods: CTL4 expressions in BC and cAMP-responsive element (CRE)-binding protein-1 (CREB1)-binding motif were analyzed by bioinformatic analysis. After BC cells were transfected with short hairpin RNA against CTL4 (shCTL4) or CREB1-specific small interfering RNA (siCREB1), the CTL4 and CREB1 expressions in BC cells were measured by quantitative real-time polymerase chain reaction (qRT-PCR), and the levels of markers relevant to Cho metabolism were also studied. The binding of CREB1 to the CTL4 promoter was verified by chromatin immunoprecipitation assay. After BC cells were transfected with CTL4 overexpression plasmid or siCREB1, BC cell viability, proliferation, invasion, and migration were assessed by cell counting kit-8, 5ʹ-ethynyl-2ʹ-deoxyuridine (EdU) and Transwell assays. Furthermore, CTL4 protein expression and ACh content in BC cells were determined by western blot assay and high-performance liquid chromatography (HPLC) with enzyme-coupled electrochemical assay.
Results: CTL4 was highly expressed in BC and its knockdown diminished cell viability, restrained proliferation, migratory and invasion capabilities, reduced ACh content, and down-regulated the level of markers relevant to Cho metabolism in BC cells (p < 0.01). CREB1 could bind to the CTL4 promoter in BC cells. CREB1 silencing decreased the viability, proliferation, migration, invasiveness, ACh content, and the expression levels of CTL4 and Cho metabolism-relevant markers in BC cells (p < 0.001). Moreover, these aforementioned effects were reversed by CTL4 overexpression (p < 0.001).
Conclusions: Inhibition of CREB1-CTL4 cascade attenuated aberrant Cho metabolism, thus restraining the malignant progression of BC cells.
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Background: Salvianolic acid A (SAA) is a biologically active compound that has anti-oxidative and anti-inflammatory pharmacological effects. There are limited studies on its pharmacological properties and role in cardiac remodeling. Therefore, this study aims to investigate the role and underlying mechanisms of SAA in cardiac remodeling in a mouse model.
Methods: A mouse model of cardiac remodeling was constructed through intraperitoneal injection of isoproterenol (ISO). Two weeks after administration, the hearts of the treated and control groups were removed for determination of the heart weight (HW), body weight (BW), and lung weight (LW) to determine HW/BW and LW/BW ratios. We performed hematoxylin-eosin (HE) analysis, Masson staining and Western blotting to observe changes in each group. Doppler Echocardiography was utilized to acquire M-mode images to measure the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS). In addition, to further assess and validate the activation of the Phosphatase and tensin homolog (PTEN) signaling pathway in mice with cardiac remodeling treated with SAA, we employed VO-Ohpic as an additional experimental approach.
Results: This study showed that treatment with SAA in mice significantly mitigated cardiac dysfunction, while ameliorating pathological alterations associated with cardiac hypertrophy and fibrosis in the context of cardiac remodeling. In addition, SAA could improve antioxidant levels and depress inflammation in myocardial remodeling. Furthermore, SAA achieves this by promoting the PTEN signaling pathway.
Conclusion: SAA exhibits potential in improving cardiac remodeling and dysfunction, potentially through its modulation of oxidative stress via the Nuclear factor kappa-B pathway mediated by PTEN (PTEN/NF-κB) pathway. These results provide a theoretical foundation for future clinical investigations on the therapeutic effects of SAA in myocardial remodeling.
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Background: Sepsis has been the main cause of mortality in patients in the world. The present study aimed to identify and validate the key genes involved in the development of sepsis.
Methods: Gene expression profiles obtained from GSE35590 were used to screen the differentially expressed genes (DEGs) after endotoxin stimulation. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were carried out to analyze the function of hub genes. The G protein-coupled receptor 84 (GPR84) with the greatest fold change was used as the target gene. The upregulation of GPR84 was validated in THP1, RAW264.7 cells and cecal ligation and puncture (CLP) animal model. Moreover, the predictive ability of GPR84 was evaluated by the area under curve (AUC) in two sepsis datasets.
Results: In total, 267 genes were differentially expressed at three time points. Especially, GPR84 had 39.8, 28.7 and 15.8 folds changes at three time points. The GO and KEGG analysis indicated that GPR84 was mainly correlated with the neutrophil degranulation, immune response-regulating signaling pathway, and immune response-activating signal transduction. Then, the upregulation of GPR84 was validated in the whole blood, THP-1 cells and RAW264.7 cells under lipopolysaccharides (LPS) stimulation. Meanwhile, we also validated the overexpression of GPR84 in sepsis animals and patients. The results indicated that GPR84 may be utilized to predict the risk of sepsis with the AUC of 0.765 (0.649–0.858) in GSE9960 and 0.759 (0.666–0.837) in GSE74224.
Conclusions: This study concluded that upregulated GPR84 may be a target gene for the development of sepsis, and GPR84 could be used to predict the incidence of sepsis.
Clinical Trial Registration: Chinese clinical trial registry: ChiCTR2200064742.
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Background: As a main micronutrient, Vitamin C is crucial for preserving the body's homeostasis and regular metabolic functions. The goal of this study is to evaluate the impact of Vitamin C on diabetes-induced changes in the lipid content, conformation/structure and dynamics of testicular tissue using Fourier Transform Infrared (FTIR) microspectroscopic technique.
Methods: Male Wistar rats were classified into 4 as: control, diabetic, low (15 mg/kg/day) and high (100 mg/kg/day) Vitamin C-treated groups. The animals in the diabetic and treated groups were first given Streptozotocin (STZ). Diabetic animals were chosen according to their blood glucose levels (values equal to or higher than 300 mg/dL). Vitamin C therapy was started 7 days after STZ treatment and continued for 5 weeks, after which the testis tissues were removed and used for FTIR microspectroscopy studies. The spectral parameters that were evaluated included relative saturated and unsaturated lipid contents, unsaturation indices, lipid orders/disorders and membrane fluidity values.
Results: There was a significant reduction in saturation levels, lipid acyl chain length, lipid dynamics (p < 0.001 for all of the mentioned parameters), in addition to an increase in unsaturation levels (p < 0.001) as a result of lipid peroxidation and higher lipid order (p < 0.01) in diabetic tissues, compared to the control rat group. Those variations were significantly recovered by an increase in saturated lipid amount, lipid acyl chain length and dynamics (p < 0.01) with a decrease in unsaturated lipid content (p < 0.001) and lipid order (p < 0.01) in the testis of the low dosage of Vitamin C therapy group compared to the diabetic group. Those parameters were taken to close values to the control group by the low dosage of Vitamin C therapy. Even though high dosage of Vitamin C was also successful in enabling recovery from most of the effects of diabetes on the tissue (p < 0.05 for lipid order, p < 0.01 for saturation and p < 0.001 for unsaturation index), it could not overcome the diabetic effects on the membrane dynamics of the testis tissue.
Conclusions: Low dosages of Vitamin C can repair the diabetes-induced damage efficiently and protect the cells and the biomembranes against the damage originating from lipid peroxidation in the tissues.
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Background: Endometriosis affects 5%–10% of fertile women globally. Microarray analysis predicted that Delta-like non-canonical Notch ligand 1 (DLK1) is differentially expressed in normal endometrium tissues (NET) and ectopic endometrial tissues (EET). Insulin-like growth factor 2 (IGF-2) is closely associated with endometriosis. This study aimed to clarify whether the DLK1/IGF-2 axis is involved in the pathogenesis of endometriosis.
Methods: DLK1 and IGF-2 expression in endometrial tissues and endometrial stromal cells were measured by quantitative real-time polymerase chain reaction, western blotting, and immunohistochemical assays. After knockdown DLK1 in ectopic endometrial stromal cells (EESCs), cellular behaviors were evaluated using cell counting kit-8, transwell assay, wound healing assay, and western blotting. The interaction between DLK1 and IGF-2 was verified using luciferase reporter assay and RNA-binding protein immunoprecipitation. Finally, an endometriosis mouse model was generated to evaluate the effect of DLK1 on lesion.
Results: DLK1 was highly expressed in EET and EESCs. DLK1 silencing inhibited EESC viability, migration, and adhesion. Moreover, IGF-2, which can interact with and is positively regulated by DLK1, was highly expressed in EET and EESCs. IGF-2 overexpression abrogated the biological function of EESCs induced by DLK1 depletion. In addition, DLK1 knockdown suppressed endometrial lesion size and weight and attenuated histopathology.
Conclusions: Silencing the DLK1/IGF-2 axis attenuates endometriosis progression by inhibiting EESC viability, migration, and adhesion. These results indicated that the DLK1/IGF-2 axis may be a therapeutic target for the treatment of endometriosis.
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Background: Breast cancer is a prevalent malignancy in women worldwide. Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 are critical for repair of DNA damage. In this study, we aimed to investigate whether PARP inhibitors can increase the sensitivity of breast cancer cells to DNA damage-based chemotherapy and radiotherapy and its related mechanisms.
Methods: Quantitative-polymerase chain reaction (Q-PCR) was carried out to measure long non-coding RNA (lncRNA) in non-homologous end joining (NHEJ) pathway 1 (LINP1) expression in a breast cancer cell line and tumor tissue specimens collected from 23 patients with breast cancer. siRNAs for LINP1 and PARP were transfected to knockdown their expressions. The cell counting kit-8 (CCK-8) was used to measure cell survival. A wound-healing assay was used to assess the cell migration ability. Western blotting was used to measure the expression of DNA damage marker phosphorylated histone H2AX (γ-H2AX). Flow cytometry assay was used to measure the repair ability of non-homologous end joining (NHEJ) pathway in breast cancer cells.
Results: The expression of the lncRNA LINP1 was significantly increased in both breast cancer tissues and Michigan Cancer Foundation-7 (MCF-7) cells (p < 0.01). Its expression was significantly reduced after treatment with a PARP inhibitor Olaparib (p < 0.01). After ultraviolet C (UV-C) irradiation, the expression of the DNA damage marker γ-H2AX was significantly increased in Olaparib-treated cancer cell, and the cell survival rate was significantly reduced (p < 0.01). However, cells treated with Olaparib and transfected with LINP1 plasmid effectively rescued their sensitivity to DNA damage and survival rate after irradiation.
Conclusions: The PARP inhibitor Olaparib increases the sensitivity of breast cancer cells to DNA damage by reversely regulating the expression of LINP1.
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Background: Silver sulfadiazine is effective in the treatment of sepsis in patients with burns, and its clinical value lies in studying the mechanism of its cellular immune activity.
Methods: This study included 70 patients with sepsis following burn injury, with 35 patients treated with zinc sulfadiazine and 35 patients treated with silver sulfadiazine in our hospital. The inflammation status and treatment outcomes were compared in these two groups of patients.
Results: The effective rate of treatment in the zinc sulfadiazine group was 80.00%, while the silver sulfadiazine group had a significantly higher effective rate of 94.29% (p < 0.05). The decrease in various inflammatory factors was greater in the silver sulfadiazine group than the zinc sulfadiazine group (p < 0.05). Patients in the silver sulfadiazine group also showed better improvement in vital signs (p < 0.05). The silver sulfadiazine group had a higher bacterial clearance rate, higher anti-infection efficiency, shorter duration of antibiotic use, and shorter hospital stay than the zinc sulfadiazine group (p < 0.05). The 14-day mortality rate was 5.7%, and the 28-day mortality rate was 8.6% in the silver sulfadiazine group. By contrast, the 14-day mortality rate was 8.6%, and the 28-day mortality rate was 14.3% in the zinc sulfadiazine group. The 14-day and 28-day mortality rates were significantly lower in the silver sulfadiazine group than in the zinc sulfadiazine group (p < 0.05).
Conclusion: Silver sulfadiazine treatment significantly improves the patients' quality of life, inhibits inflammatory reactions, and has a higher treatment Efficacy and positive clinical value. Therefore, silver sulfadiazine can be promoted to treat patients with burns and sepsis.
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Background: Diabetic nephropathy (DN) is one of the complications of diabetes, and may lead to abnormal renal functions. Although many studies confirmed that proteins serve as essential factors in DN progression, the function of Fos-like antigen 2 (FOSL2) in DN has not been properly investigated. The purpose of this study is to explore the regulatory role of FOSL2 in DN progression.
Methods: The rats were divided into four groups such as Sham, DN, DN+Adeno-associated virus (AAV)-Scramble, and DN+AAV-shFOSL2 groups. The cells were divided into the control, high glucose (HG), HG+negative control (si-NC), and HG+si-FOSL2 groups. The levels of fasting blood glucose (FBG) and oral glucose tolerance (OGTT) were measured through the glucometer. The levels of glycosylated hemoglobin (HbA1c), serum creatinine (Scr), and blood urea nitrogen (BUN) were measured through the automatic biochemistry analyzer. The damage of renal tissues was evaluated through hematoxylin-eosin (HE) staining. The cell apoptosis was measured through TdT-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry. The mRNA expression was examined through Real-time quantitative polymerase chain reaction (RT-qPCR). The protein levels were determined through enzyme linked immuno sorbent assay (ELISA) and western blot. The cell viability was detected through cell counting kit-8 (CCK-8) assay.
Results: In this experiment, the animal model (rats induced by Streptozocin (STZ)) and cell model (Human renal glomerular endothelial cells (HRGEC) induced by HG) were built at first. FOSL2 improved the protein expression and knockdown of FOSL2 improved DN progression by reducing FBG, OGTT, HbA1c, 24 hours (h) urine protein (UP), Scr, and BUN levels (p < 0.001). In addition, FOSL2 suppression improved renal injury and inhibited cell apoptosis in DN rats (p < 0.001). Down-regulation of FOSL2 also reduced the inflammation and oxidative stress in DN rats (p < 0.001). In vitro experiments, FOSL2 inhibition enhanced cell viability (p < 0.001) and retarded cell apoptosis (p < 0.05), as well as reduced the inflammation (p < 0.05) and oxidative stress (p < 0.05) in HRGEC cells induced by HG. It was also identified that FOSL2 inhibition suppressed the activation of nuclear factor kappa-B (NF-κB) pathway in DN (p < 0.001).
Conclusions: The findings in this study revealed that FOSL2 aggravated renal injury in DN by activating NF-κB signaling pathway. This discovery might offer a promising biomarker for DN treatment.
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Background: The incidence of acute myocardial infarction is increasing annually. The primary percutaneous coronary intervention (PCI) is an effective method for treating acute myocardial infarction. However, the no-reflow phenomenon (NRP) during or after PCI can significantly weaken the efficacy of PCI. Therefore, this study aimed to develop and evaluate a predictive nomogram for slow-flow/no-reflow phenomenon (SFP/NRP) in patients with ST-segment elevation myocardial infarction (STEMI).
Method: A retrospective observational study was conducted in Heping Hospital and Heji Hospital, affiliated with Changzhi Medical College. A credible random split-sample method was used to divide data into training and validation datasets (split ratio = 0.7:0.3). The outcome variable was SFP/NRP. Least absolute shrinkage and selection operator (LASSO) logistic regression was applied to select predictors and develop the nomogram. The platelet/lymphocyte ratio (PLR), CHA2DS2-VASc score, and HAKTT score are selected as predictors. The discrimination of the nomogram was assessed using the receiver operating characteristic (ROC) curve, and the calibration curve was used to evaluate the accuracy of the prediction. The clinical usefulness of the nomogram was evaluated with decision curve analysis (DCA).
Result: The patients (n = 311) with STEMI who underwent emergency PCI from July 2021 to September 2022, were retrospectively analyzed. The incidence of SFP/NRP was found to be 32.5%. The PLR (Odds Ratio (OR): 1.006, 95% Confidence Interval (CI): 1.003–1.010, p = 0.001), CHA2DAS2-VASc score (OR: 1.388, 95% CI: 1.146–1.682, p = 0.001), and HAKTT score (OR: 1.170, 95% CI: 1.100–1.246, p < 0.001) were identified as predictors and developed a nomogram. The nomogram showed good discrimination in both the training (area under the ROC curve (AUC): 0.78, 95% CI: 0.73–0.85) and validation (AUC: 0.70, 95% CI: 0.55–0.84) datasets as well as calibrated in both datasets (all p > 0.05). Moreover, DCA demonstrated that the nomogram is clinically useful.
Conclusions: This study proposed an effective nomogram comprising PLR, CHA2DS2-VASc score, and HAKTT score with potential application in facilitating the individualized prediction for SFP/NRP in STEMI patients.
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Background: Ferroptosis has garnered increasing attention; however, relevant researches are insufficient.
Methods: We incorporated two microarray datasets from Gene Expression Omnibus (GEO) and utilized the FerrDb website to identify ferroptosis genes. Differential expression analysis of ferroptosis-related genes and functional enrichment analysis were performed using R software. Machine learning technique was employed to screen for core genes and evaluate their correlation with immune cells, ultimately identifying core genes with diagnostic value. In vivo and in vitro experiments were conducted to confirm the relationship between the core gene and ulcerative colitis (UC) ferroptosis. We conducted a UC mouse model using 3% dextran sodium sulfate (DSS) free drinking water method. We detected the expression of Fatty Acid Biding Protein-4 (Fabp4), glutathione peroxidase 4 (Gpx4), ferritin heavy chain (Fth), protein kinase B (PKB, also named as Akt), Phosphatidylinositide 3-kinases (Pi3k), and interleukin-1β (IL-1β) in the mouse colon through quantitative real-time PCR (qPCR) and western blot (WB) analysis. Additionally, we performed an in vitro experiment using the THP-1 cell line. The cells were pretreated with Ferrostatin-1 (Fer-1) and FABP4 inhibitor (BMS 3094033) for 1 hour, followed by the addition of Erastin. We then measured the intracellular expression of FABP4, GPX4, FTH, AKT, PI3K, and IL-1β using qPCR and immunofluorescence.
Results: FABP4 is a crucial gene in ulcerative colitis (UC). It is associated with the infiltration of immune cells like macrophages, dendritic cells, and neutrophils, as well as Phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway. In vivo experiments have demonstrated that the expressions of Fabp4, Fth, Pi3k, Akt, and Il-1β were elevated in the colon of UC mice, while the Gpx4 was reduced. In vitro experiments found that after adding FABP4 inhibitors, the expressions of FTH, PI3K, AKT, and IL-1β decreased, while GPX4 increased.
Conclusions: FABP4 has been identified as a pivotal gene in the ferroptosis process in UC. It is suggested that FABP4 regulates the PI3K/AKT signaling pathway, thereby playing a crucial role in UC's ferroptosis development.
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Background: Hirschsprung associated enterocolitis (HAEC) is a common complication of Hirschsprung's disease (HD), with high morbidity and mortality. Short-chain fatty acids (SCFAs) have been shown to play a role in maintaining intestinal integrity, and regulating the immune system, inflammatory response, and lipid metabolism. This study explored the SCFAs in HD and HAEC and their possible underlying mechanism.
Methods: Ednrb-/- (Targeted-null mouse) mice were selectively bred and fed until 2-weeks old and 3-weeks old as HD model and HAEC model mice, respectively; the mouse genotypes were identified by polymerase chain reaction (PCR). Hematoxylin-eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), immunofluorescence, and immunohistochemistry were used to assess histopathological damage, interleukin (IL)-6 levels, intestinal barrier dysfunction (ZO-1, E-cadherin and occludin), and apoptosis (Bax and caspase-3). The level of G-protein-coupled receptor 43 in colon tissue was measured by Western blotting. The content of SCFAs in the feces of the mice was evaluated by gas chromatography-mass spectrometer (GC-MS).
Results: Integrated colon tissue with clear structure was observed in the “2-week-old” and “3-week-old” control groups. In HD mice, intermuscular layer tissue was hypertrophic with suspected hypertrophic plexus structures. In HAEC mice, disordered intestinal gland structure was observed, with hypertrophic intermuscular layer. The serum level of interleukin-6 (IL-6) in HAEC mice was much higher than that of controls (p < 0.01). ZO-1 and E-cadherin were mainly expressed in Galeati's glands. ZO-1 (p < 0.01) and E-cadherin (p < 0.05) were significantly lower in HD and HEAC mice than in corresponding controls. Bax and caspase-3 levels were extremely low in HD and HEAC mice, with a reduced occludin level (p < 0.01). Moreover, remarkedly down-regulated G-protein-coupled receptor 43 (GPCR43) protein levels were observed in HD and HEAC mice (p < 0.01). Furthermore, n-propylacetate and propanoic acid were markedly lower in HD mice compared with those in controls.
Conclusion: SCFAs might play a protective role in colon tissue structure by regulating occludin to enhance the barrier function of intestinal epithelium.
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Background: This study investigated the role of tRNA methyltransferase 10C (TRMT10C) and the mechanism of N1-methyladenosine (m1A) methylation modification in lung cancer (LC).
Methods: Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to measure high mobility group nucleosomal binding domain 2 (HMGN2) expression in LC cells. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, flow cytometry and tube formation assay were utilized to assess the cell viability, angiogenesis, and apoptosis, respectively. m1A-qRT-PCR was engineered to elucidate the impacts of m1A methylation related genes (TRMT10C, alkB homolog 1 (ALKBH1), and ALKBH3) upon the m1A methylation of HMGN2 in LC cells. StarBase, along with Kaplan-Meier Plotter, was used to test TRMT10C expression in LC and find out its correlation with the survival of LC patients. Cell function assays were operated again to identify the role of TRMT10C in LC cells.
Results: There was a low expression of HMGN2 in LC cells, but TRMT10C expression was increased in LC. Kaplan-Meier Plotter website showed that high expression of TRMT10C was coupled with the low survival of LC patients (logrank p = 1.2 × 10-8). After that, the m1A methylation of HMGN2 was induced in LC cells and enhanced by TRMT10C overexpression. In addition, TRMT10C overexpression increased the cell viability and angiogenesis rate while suppressing apoptosis and HMGN2 expression. Its effects were counteracted by overexpressed HMGN2.
Conclusion: TRMT10C augments the malignant phenotype of LC by increasing m1A methylation modification of HMGN2.
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Background: Hepatoblastoma (HB) is a common tumor in children, but there are few effective drugs against this tumor. Jolkinolide B (JB) has been found to inhibit tumorigenesis by inducing apoptosis in diverse cancer types. However, the effect of JB has not yet been reported in HB. The aim of this work was therefore to study the effect of JB on HB cells and the possible mechanism of action.
Methods: The proliferative capacity of HB cells was determined with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and 5-Ethynyl-2′-deoxyuridine (EdU) assays. Transwell assay was employed to evaluate cell migration, while cell apoptosis was assessed by flow cytometry. The formation of autophagosomes was evaluated by calculating the number of green fluorescent protein-tagged LC3 (GFP-LC3) puncta. In addition, Western blot analysis was used to quantify the levels of cleaved-caspase-3, B-cell lymphoma-2 (Bcl-2)-Associated X (Bax), Bcl-2, sequestosome 1 (p62), microtubule associated protein 1 light chain 3 (LC3), phosphorylated protein kinase B (p-AKT) and p-mechanistic target of rapamycin kinase (mTOR).
Results: JB treatment of HB cells decreased their viability and suppressed migration (p < 0.01). The administration of JB also increased apoptosis and autophagy in HB cells (p < 0.01). Interestingly, JB-induced apoptosis relied on the occurrence of autophagy. At the molecular level, JB decreased activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which further induced autophagy-mediated apoptosis (p < 0.01).
Conclusion: JB inhibited the proliferation and migration of HB cells, and induced autophagy-dependent apoptosis at least partly by modulating PI3K/AKT/mTOR cascade signaling. These findings indicate that JB could be a potent compound for treating patients with HB.
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Background: Anemia is a common complication of chronic kidney disease (CKD). Hemoglobin variability is a well-documented parameter representing hemoglobin control. However, there is still lack of evidence about whether risk factors related to hemoglobin (Hb) level simultaneously affect Hb variability. This study aimed to evaluate the association of serum phosphorus with hemoglobin level and its longitudinal variation in patients with chronic kidney disease.
Methods: Data were obtained from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE), which was a nationwide multicenter prospective cohort study. The association of phosphorus with hemoglobin level was evaluated in 3227 patients. Longitudinal variation of hemoglobin level was evaluated in 753 patients. Linear regression models and logistic regression models were used to assess the association of phosphorus with hemoglobin level, anemia prevalence, and longitudinal variation of hemoglobin over 2 years.
Results: Serum phosphorus was negatively associated with hemoglobin level. While 1 mmol/L increase in serum phosphorus was associated with 11.72 g/dL decrease in hemoglobin (95% Confidence interval 14.42 to 9.02 g/dL). Each 0.1 mmol/L increase in phosphorous was associated with 14% increase in prevalence of anemia (odds ratio (OR): 1.14, 95% CI: 1.12 to 1.16). In the longitudinal analysis, serum phosphorus was independently associated with the residual standard deviation and absolute range of hemoglobin.
Conclusion: Serum phosphorus level was independently associated with baseline hemoglobin level, the prevalence of anemia and longitudinal variation of hemoglobin in Chinese patients with chronic kidney disease (CKD).
Clinical Trial Registration: NCT03041987, available at:
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Background: Intermittent fasting (IF) has a broad spectrum of benefits for obesity and related metabolic disorders. However, serum metabolic signatures from IF remain relatively unexplored, and it remains uncertain whether different IF approaches exert similar effects on metabolism. This study was designed to examine the effects of three distinct IF approaches time-restricted feeding (TRF), alternate-day fasting (ADF), and intermittent fasting 5:2 (IF 5:2)-on the serum metabolomics of obesity mice.
Methods: Male C57BL/6 mice were placed on either a normal-fat diet (NFD) or a high-fat diet (HFD) for 10 weeks. The HFD-fed mice were subsequently subjected to dietary intervention using ADF, TRF, and IF 5:2 for another 10 weeks. Parameters such as body weight, serum lipid levels, homeostasis model assessment of insulin resistance (HOMA-IR), and glucose tolerance were assessed in each group. Hepatic lipid accumulation and pathological changes were examined using Oil Red O staining and hematoxylin and eosin (H&E) staining. Quantitative real-time PCR (qRT-PCR) was used to analyze the expression of inflammatory factors. The impact of IF on serum metabolites was investigated through non-targeted metabolomics based on UHPLC-HRMS/MS.
Results: ADF, TRF, and IF 5:2 led to a significant reduction in body weight (p < 0.01), HOMA-IR (p < 0.01), and serum lipids level (p < 0.05) while also improving glucose tolerance in obese mice. All three IF approaches reduced hepatic lipid accumulation and decreased inflammation levels in adipose tissues of obese mice. Serum metabolomics analysis revealed 209 differential metabolites affected by IF. Pathway enrichment analysis identified 8 relevant pathways involved in IF.
Conclusions: ADF, TRF, and IF 5:2 diets could attenuate obesity, hyperglycemia, insulin resistance, and inflammation induced by HFD. Furthermore, IF improved the serum metabolic patterns in obese mice.
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Background: It has previously been shown that protease-activated receptor 2 (PAR2) could be involved in regulating the visceral hypersensitivity process. It has also been shown that PAR2 expression in the intestinal tissue of a visceral hypersensitivity rat model was increased and that the activation of intestinal PAR2 significantly increased the intestinal sensitivity of rats. Based on that, the research reported here aimed to explore the role and mechanism of PAR2 on the colonic motility regulating progress in an irritable bowel syndrome (IBS) rat model via Nesfatin-1.
Methods: Neonatal two days old male Sprague Dawley PAR2+/+ and PAR2-/- rats were randomized into control and IBS model groups. IBS syndrome model rats were made via the method of mother-infant separation and acetic acid enema. After successful verification, rats were divided into control, PAR2+/+IBS, PAR2-/-IBS, PAR2-/-IBS with central intervention, and PAR2-/-IBS with peripheral intervention groups. The colonic motility indexes and the colonic tissues mammalian target of rapamycin (mTOR) expression of rats were collected and the statistical differences of various groups were determined.
Results: (1) The abdominal withdraw reflex (AWR) scores of PAR2+/+IBS model group (WM group) and PAR2-/- IBS model group (KM group) were higher than control group (C group), and the WM group score was the highest (p < 0.05). The colonic histological staining of the WM and KM groups all excluded organic pathological changes. PAR2+/+ and PAR2-/-IBS models were successfully established. (2) The amplitude and frequency of the colonic fast wave in the KM+ Nesfatin-1 central intervention group (KM+NCI group) were higher than in the WM, KM, and KM+Nesfatin-1 peripheral intervention groups (KM+NPI groups) (p < 0.05). The KM group was the lowest. The amplitude and frequency of colonic slow wave in the KM+NCI group were higher than in the WM, KM and KM+Nesfatin-1 peripheral intervention groups (KM+NPI groups, p < 0.05). The KM group was the lowest. (3) Colonic mTOR expression in the KM+NCI group was higher than in the WM, KM and KM+NPI groups (p < 0.05). The highest colonic mTOR expression was in the KM+NCI group, the lowest expression was in the KM group.
Conclusions: The PAR2 gene knockout affected the Nesfatin-1 central and peripheral pathways of regulating IBS colonic motility and mTOR expression. It was speculated that Nesfatin-1 might regulate IBS colonic motility through the PAR2/mTOR signaling pathway with Nesfatin-1 central intervention method and Nesfatin-1 peripheral intervention method.
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Background: Plumbago zeylanica L. (P. zeylanica L.), an ethnomedicinal plant species, is known for its diverse therapeutic benefits, such as anti-malarial, anti-inflammatory, anti-microbial, memory enhancing, and wound-healing properties. This study aimed to investigate the antioxidant, genoprotective, and cytotoxic activities of different root fractions of P. zeylanica L., namely PzMH (hexane fraction), PzMC (chloroform fraction), PzME (ethyl acetate fraction) and PzMM (methanol fraction).
Methods: The present study involved the investigation of the free radical scavenging potential of all the fractions. Antioxidant activity was assessed through superoxide radical scavenging, nitric oxide radical scavenging, and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) assays. Genoprotective efficacy was determined using the alkaline comet assay to evaluate the protective effects against DNA damage induced by hydrogen peroxide (H2O2) in human blood lymphocytes. Additionally, cytotoxicity was investigated against three different cancer cell lines: MCF-7, MDA-MD231 (breast cancer cell lines), and A498 (kidney carcinoma cell line) to examine the suppression of cell proliferation.
Results: Among all the fractions, PzME exhibited the highest antioxidant activity with IC50 values of 80.94 μg/mL, 79.63 μg/mL, and 98.3 μg/mL in superoxide radical scavenging, nitric oxide radical scavenging, and DPPH assays, respectively. In terms of genoprotective effects, the PzME fraction demonstrated the highest protection against H2O2-induced DNA damage in human blood lymphocytes, reducing the percentage tail DNA content from 29.6% to 7.34% at the highest tested concentration (400 μg/mL). Additionally, the PzME fraction showed potent cytotoxicity against MCF-7 cells, followed by MDA-MB-231 and A498 cells, with 50% growth inhibition at concentrations of 147.95 μg/mL, 225.37 μg/mL, and 226.13 μg/mL, respectively. Phytochemical screening revealed the highest total phenolic, total flavonoid, and total tannin contents in the PzME fraction. GC-MS analysis of the PzME fraction identified trans-cinnamic acid, 2,4-Di-tert-butylphenol, and 2-Methoxy-4-vinylphenol as potential compounds responsible for the observed genoprotective and cytotoxic activities.
Conclusions: The study highlights the antioxidant, genoprotective, and cytotoxic properties of PzME fraction from Plumbago zeylanica L. root. The fraction exhibited robust antioxidant potential and protected human blood lymphocytes from DNA damage. Additionally, it exhibited notable cytotoxic effects against breast cancer and kidney carcinoma cell lines.
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Background: Myeloid-derived suppressor cell (MDSC)-mediated immunosuppression is an important factor involved in tumor metastasis and survival of lung cancer (LC) patients, resulting in a poor prognosis. We aimed to unravel the underlying mechanism behind this process.
Methods: Bioinformatics analysis was performed to predict the expression of C-X-C motif chemokine ligand 13 (CXCL13) and to investigate the characteristic of RAD21 cohesin complex component (RAD21) in lung adenocarcinoma (LUAD). After identification of RAD21 expression and peripheral blood-derived MDSCs in LC patients, the role of RAD21 in the recruitment of LC cells to MDSCs was explored using different approaches such as cell transfection, cell counting kit-8 (CCK-8) assay, enzyme-linked immunosorbent assay (ELISA), cell co-cultivation, CXCL13 neutralization, flow cytometry, quantitative real-time reverse transcription polymerase chain reaction, and western blot.
Results: It was observed that CXCL13 and RAD21 were overexpressed in LUAD or LC tissues (p < 0.001), and the RAD21 was positively linked to poor overall survival of the patients. Furthermore, LC patients had a high proportion of MDSCs in peripheral blood mononuclear cells (PBMCs) (p < 0.001). Additionally, we found that RAD21 overexpression promoted the expansion of MDSCs (p < 0.001), and enhanced the secretion of CXCL13 in LC cells, as well as C-X-C motif chemokine receptor 5 (CXCR5) in LC cell-cocultured PBMCs (p < 0.001). However, CXCL13 neutralization in LC cells reversed the effect of RAD21 overexpression on MDSC recruitment and CXCR5 secretion (p < 0.001).
Conclusion: RAD21 overexpression can lead to MDSC-induced immunosuppression in LC by stimulating the CXCL13-CXCR5 pathway.
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Background: Cell division cycle protein 45 (CDC45) has been proven to regulate the occurrence and progression of various types of tumors. Therefore, a study was designed to investigate the impact of CDC45 on hepatocellular carcinoma (HCC) and to provide new insights into the novel therapeutic options.
Methods: The CDC45 expression level in HCC patients and the overall survival rate of HCC patients with different CDC45 expression levels were analyzed using the starBase and Gene Expression Profiling Interactive Analysis (GEPIA) databases. The HCC cells were transfected with CDC45 overexpression plasmid or siRNA and phosphofructokinase liver type (PFKL) overexpression plasmid, followed by treatment with U0126, an inhibitor of extracellular regulated kinase 1/2 (ERK1/2). The levels of cleaved Caspase-3, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (Bax), and ERK1/2 proteins were measured through quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The pyruvate and lactate production, and glucose consumption in HCC cells were determined using their corresponding kits. Additionally, HCC cells were assessed for their viability, number of clones formation, and apoptosis rate using cell function assays.
Results: It was found that HCC patients with high CDC45 expression had a shorter survival time. Furthermore, CDC45 overexpression in HCC cells promotes viability, proliferation, and ERK1/2 phosphorylation level while inhibiting the apoptosis (p < 0.05). However, CDC45 silencing has opposite effect and reduces the impacts of PFKL overexpression on HCC cell proliferation and apoptosis (p < 0.001). Moreover, CDC45 overexpression promotes pyruvate and lactate production, and glucose consumption (p < 0.001). However, the U0126 treatment neutralizes the impacts of CDC45 overexpression on cell glycolysis, proliferation, and apoptosis (p < 0.001).
Conclusions: It is suggested that CDC45 promotes HCC cell proliferation and glycolysis through ERK1/2 signaling pathway.
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Background: Oral squamous cell carcinoma (OSCC) is a major oral malignancy. The molecular mechanism of OSCC growth and metastasis is an urgent issue. COOH-terminal binding protein 2 (CTBP2) is involved in the occurrence and development of various tumors, but its role in OSCC is poorly defined. This study aims to investigate CTBP2 expression and its biological function in OSCC cells.
Methods: CTBP2 mRNA expression in OSCC cells was detected by real-time quantitative polymerase chain reaction (RT-qPCR). CTBP2 expression in OSCC cells was downregulated using siRNA interference technology. The effects of CTBP2 downregulation on OSCC cell proliferation were detected by cell counting kit-8 (CCK-8) and clone formation assay. The migration and invasion were detected through scratch healing and Transwell assays, respectively. Western blot was used to detect CTBP2, epithelial-mesenchymal transition (EMT)-related protein, rho associated coiled-coil containing protein kinase 1 (ROCK1) and its downstream molecules expression in OSCC cells.
Results: CTBP2 expression was upregulated in OSCC cell lines (p < 0.01, p < 0.001). CTBP2 silencing inhibited OSCC cells proliferation ability, migration rate, and invasion number (p < 0.05, p < 0.01, p < 0.001). Western blot results showed that CTBP2 silencing promoted E-cadherin expression and inhibited N-cadherin and Vimentin expression (p < 0.05, p < 0.01). CTBP2 downregulation decreased protein levels of ROCK1 and its downstream molecules in OSCC cells (p < 0.05, p < 0.01, p < 0.001).
Conclusions: Silencing CTBP2 could inhibit malignant behavior of OSCC cells, which may play a role by inhibiting the EMT process and ROCK1 signaling.
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Objective: Glioma is a primary central malignant tumor, but its curative effects and postoperative prognosis are still not ideal. Tankyrase1 (TNKS1) has been reported to promote the progression of glioma. This study aimed to assess the potential molecular mechanisms by which TNKS1 regulates the metabolism and proliferation of glioma.
Methods: U87 and U251 cells with TNKS1 knockdown were established upon transfection using shRNA-TNKS1. Cell viability was detected by the Cell Counting Kit-8 (CCK-8) assay, the glucose and lactic acid levels were measured using a biochemical detection kit. While reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) levels were detected through flow cytometry. The Western blot assay was applied to check the expression levels of Akt, phosphorylated Akt (p-Akt), and glucose transporter type 1 (GLUT1). Besides, TNKS1-knockdown U87 and U251 cells were implanted to establish a nude mice xenograft model, followed by tumor growth monitoring. The apoptosis was evaluated using the Terminal-deoxynucleoitidyl transferase Mediated Nick End Labeling (TUNEL) assay and the immunohistochemical assay was applied to check the expression levels of peroxisome-proliferator-activated receptor γ coactivator (PGC)-1α, Akt, p-Akt, and GLUT1.
Results: After knocking down TNKS1 in both U251 and U87 cells, the cell viability was significantly suppressed. The content of glucose, lactic acid, and PGC-1α was significantly downregulated, and the production of ROS was enhanced while the MMP level was reduced. Moreover, the Akt, p-Akt, and GLUT1 expressions were notably inhibited. The tumor growth was inhibited, and apoptosis was greatly induced in U87 and U251 xenograft tumor tissues, accompanied by the downregulation of PGC-1α, Akt, p-Akt, and GLUT1 in tumor tissues.
Conclusions: Knockdown of TNKS1 could inhibit the metabolism and proliferation of glioma by mediating the PGC-1α.
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Background: Ginsenoside Rc has been known for its promising protective effects against myocardial injury, including inflammation, apoptosis, oxidative stress, and related pathways. However, the underlying molecular mechanisms behind these effects still need to be explored. The purpose of this study was to explore the therapeutic effect of Ginsenoside Rc on acute myocardial infarction (MI) and the molecular mechanism behind it.
Methods: MI mouse model and oxygen-glucose deprivation (OGD) cardiomyocyte injury model were established and Ginsenoside Rc was treated. Troponin I3 (TNNI3)/C-reactive protein (CRP) expression was altered by plasmid transfection or lentiviral vector injection. Myocardial histopathological changes were evaluated by hematoxylin-eosin (HE) staining and terminal deoxynucleotidyl transferase-mediated dNTP nick end labeling (TUNEL) staining. The changes in inflammatory cytokines in cells and tissues were evaluated by enzyme-linked immunosorbent assay (ELISA). Commercial kits were used for the assessment of creatine kinase-MB (CK-MB) and lactic dehydrogenase (LDH). Western blot was used to analyze cleaved caspase-3 protein expression in cells and tissues. The apoptosis rate of cardiomyocytes was measured by flow cytometry. The interaction between TNNI3 and CRP was detected by co-immunoprecipitation (CO-IP) assay.
Results: TNNI3/CRP expression was abnormally high in MI, and Ginsenoside Rc decreased their relative expression (p < 0.05). Ginsenoside Rc administration reduced inflammation and apoptosis in MI mice and OGD-injured cardiomyocytes (p < 0.05). Ginsenoside Rc administration or TNNI3 knockdown improved the myocardial tissue injury in MI mice (p < 0.05). The therapeutic effect of Ginsenoside Rc on myocardial injury in MI mice was weakened by overexpressing TNNI3 (p < 0.05). Similarly, its therapeutic effect on OGD cardiomyocyte injury was also weakened by enhancing TNNI3 and CRP (p < 0.05). TNNI3 and CRP also interacted in cardiomyocytes.
Conclusions: Ginsenoside Rc improves MI-induced cardiomyocyte apoptosis and inflammation by inhibiting the TNNI3/CRP axis. The study shows that Ginsenoside Rc can serve as a potential drug for the future treatment of MI.
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Background: Retinoblastoma (RB) is a common childhood malignancy and can be fatal if left untreated. However, extensive work is needed to acquire a better understanding of the disease mechanism and identify novel therapeutic options. Therefore, we investigated whether the p53/high mobility group box 1 (HMGB1) complex is involved in regulating autophagy and apoptosis in retinoblastoma cells.
Methods: The human RB cell line Y79 was maintained in Roswell Park Memorial Institute (RPMI)-1640 medium supplemented with 20% fetal bovine serum (FBS) and 1% penicillin-streptomycin. The immunoprecipitation approach was used to verify the formation of p53/HMGB1 complex. We induced starvation using Hank's balanced salt solution (HBSS), inhibited p53 with pifithrin-α (PFT-α), inhibited HMGB1 using ethyl pyruvate (EP), inhibited light chain 3 (LC3)-II degradation using bafilomycin A1, induced apoptosis using Adriamycin (ADM) and limited autophagy using 3-methyladenine (3-MA). To determine the effect of altering p53 and high mobility group box 1 (HMB1) on autophagy and apoptosis, different approaches, including RT-qPCR, Western Blot, flow cytometry, and enzyme-linked immunosorbent assay (ELISA), were used.
Results: The study revealed that p53 binds with HMGB1 to form a complex in the nuclear region. Furthermore, starvation increased the formation of the p53/HMGB1 complex. Moreover, a decrease in p53 resulted in increased autophagy, while a decrease in HMGB1 led to decreased autophagy. Additionally, a decrease in p53 reduced apoptosis and B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) expression, while increasing B-cell lymphoma-2 (Bcl-2) expression. We also found that this effect could be reversed by decreased HMGB1, which caused more apoptosis. Finally, we observed that a decrease in autophagy induced more apoptosis.
Conclusion: The p53/HMGB1 complex is crucial in regulating autophagy and apoptosis in RB cells. HMGB1 promotes autophagy and limits apoptosis, whereas p53 induces apoptosis and limits autophagy. A decreased level of autophagy can induce apoptosis, suggesting that p53 and HMGB1 may be potential therapeutic targets for treating RB.
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Background: Bladder cancer is the most ordinary malignant tumor of the urinary tract globally. As a transcription factor, pleomorphic adenoma gene like-2 (PLAGL2) is overexpressed in many malignancies, including bladder urothelial carcinoma. This study aimed to explore the effects of PLAGL2 on the malignant progression of bladder cancer and the molecular mechanism related to the downstream gene Olfactomedin 4 (OLFM4).
Methods: Western blot was applied for the estimation of PLAGL2 and OLFM4 expression in bladder cancer cells. After PLAGL2 or OLFM4 silencing, cell viability and cell proliferative capability were evaluated utilizing cell counting kit-8 (CCK-8) and 5-ethynyl-2′-deoxyuridine (EDU) staining. Cell apoptosis and stemness were tested by Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) staining and tumor sphere formation assay. JASPAR database predicated that PLAGL2 could bind to OLFM4 promoter region, which was confirmed by luciferase reporter assay and Chromatin immunoprecipitation (ChIP) assay. Subsequently, the rescue experiments were conducted by OLFM4 overexpression or signal transducer and activator of transcription 3 (STAT3) activator treatment in PLAGL2-silenced bladder cancer cells.
Results: Highly expressed PLAGL2 (p < 0.01 or p < 0.001) and OLFM4 (p < 0.01 or p < 0.001) were observed in bladder cancer cells. PLAGL2 or OLFM4 silencing suppressed the proliferation, promoted the apoptosis and alleviated stemness of bladder cancer cells (p < 0.001). Additionally, PLAGL2 could transcriptionally activate OLFM4 and regulate OLFM4 expression to affect STAT3 activation (p < 0.001). Rescue experiments suggested that OLFM4 overexpression or STAT3 activator restored the impacts of PLAGL2 interference on cell proliferative capability and cell apoptotic level in bladder cancer (p < 0.01 or p < 0.001).
Conclusion: Collectively, this study demonstrated that PLAGL2 drives the advancement of bladder cancer via modulating the transcriptional activation of OLFM4 to regulate STAT3 signaling. This finding might provide a new sight for the mechanism underlying bladder cancer and reveal PLAGL2/OLFM4 as candidate targets for bladder cancer therapy.
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Background: The treatment of lung cancer continues to encounter substantial challenges, necessitating ongoing exploration of effective drugs and targets. This study aims to investigate the regulatory mechanism behind the combined application of the three-step analgesic morphine and the active ingredient Glabrene found in the Tianchan capsule, within the context of non-small cell lung cancer (NSCLC).
Methods: A549 cells were treated with morphine (10 μM) and morphine combined with Glabrene (3.5 μM) for 48 h. Cell proliferation was detected using 5-ethynyl-2′-deoxyuridine (EdU) staining. Alterations in cell invasion capacity were evaluated using the Transwell® assay. The expression levels of fibroblast growth factor receptor 3 (FGFR3), Vimentin, and E-cadherin were measured using quantitative polymerase chain reaction (qPCR). Subsequently, A549 cells were implanted into the left axillary region of nude mice. The mice were treated with morphine (1.5 mg/kg) or Glabrene (0.5 mg/kg) or morphine combined with Glabrene (0.5 mg/kg). Tumor mass changes were evaluated after 4 weeks. Finally, network pharmacology and molecular docking analysis were used to explore the relationship between Glabrene and FGFR3.
Results: In this study, the results indicate that the combination of morphine and Glabrene effectively inhibits tumor growth in the NSCLC mouse model and reduces cancer cell proliferation and invasion (p < 0.05). Network pharmacology and molecular docking analysis identified Glabrene, the active ingredient found in the Tianchan capsule, as well as its target gene, FGFR3. Bioinformatics analysis revealed a compelling association between FGFR3 and numerous immune pathway marker genes. Moreover, FGFR3 exhibited a significant correlation with the immune infiltration scores (p < 0.05). qPCR testing showed that the expression levels of FGFR3 and Vimentin in the morphine + Glabrene group and the Glabrene group were significantly lower than those in the control group and the morphine group (p < 0.05).
Conclusions: The combination of morphine and Glabrene or Glabrene alone can significantly inhibit tumor growth and reduce cancer cell proliferation and invasion in the NSCLC mouse model. Glabrene exhibits a strong affinity for FGFR3, which is significantly associated with immune pathways and immune infiltration.
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Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by motor nervous system dysfunction and non-motor symptoms. Constipation is a common non-motor symptom affecting approximately 50%–70% of ALS patients. However, the underlying pathophysiological mechanism remains poorly understood. Notably, intestinal structure and function abnormalities have been observed in multiple neurodegenerative disorders. Thus, this study aimed to investigate potential pathological alterations contributing to intestinal dysmotility of ALS.
Methods: In this study, we utilized mutant superoxide dismutase 1G93A (SOD1G93A) transgenic mice models of ALS to elucidate the possible pathophysiological mechanisms of constipation in ALS. We examined alterations in structures related to intestinal movement, including enteric neurons, enteric glial cells, muscularis macrophages (MMs), interstitial fibroblast-like cells, MMs- bone morphogenetic protein-2 (BMP2) - bone morphogenetic protein receptor (BMPR) pathway, and the autonomic nervous system, including the vagal, thoracolumbar spinal cord and lumbosacral spinal cord, using immunofluorescence and western blot analyses.
Results: SOD1G93A mice exhibited a significant delay in bowel movement compared to wild-type mice at 90 days of age (p = 0.013) and 120 days of age (p < 0.001). Histopathological analyses revealed substantial alterations in the intestinal structure of SOD1G93A mice, including a reduction in cholinergic neurons (p = 0.002) and an upregulation of glial fibrillary acidic protein in the myenteric ganglion. Additionally, the number of MMs was reduced (p = 0.003) and the MMs-BMP2-BMPR pathway was abnormal.
Conclusions: In SOD1G93A mice, pathological alterations in the structural components responsible for intestinal movement may contribute to delayed bowel movement frequently observed in SOD1G93A mice and in individuals with ALS who experience increased constipation. Furthermore, this study provides novel insights into the potential involvement of the gut-brain axis in ALS.
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Background: Trimetlylamine N-oxide (TMAO) is an important factor in the development of atherosclerosis. Research suggests that grape seed proanthocyanidin extract (GSPE) modulates gut microbiota and alleviates obesity. Therefore, we speculate that GSPE may alleviate atherosclerosis by regulating TMAO production. This study aims to explore the effect of GSPE on the TMAO content and atherosclerosis.
Methods: A high fat diet mice model was established for performing this study. Low-dose/high-dose GSPE (GSPE-L/GSPE-H) and Atorvastatin (Ato) were used to treat the mice for 6 weeks. The body weight, fat, blood glucose, and blood lipid of the mice were recorded and compared. The plaques and pathological changes of mouse aorta were observed by Oil Red O, Hematoxylin-Eosin and Masson staining. Serum and caecal contents of mice were collected, where TMAO level was assessed by enzyme-linked immunosorbent assay (ELISA) and gut microbial content was determined by quantitative real-time polymerase chain reaction (qRT-PCR).
Results: GSPE-H down-regulated blood glucose and blood lipid levels, and reduced aortic plaque generation and atherosclerotic damage in model mice (p < 0.05). More importantly, it reduced the TMAO content in the serum of model mice and regulated the gut microbial content (p < 0.05). The therapeutic effect of GSPE-H was similar to that of Ato.
Conclusions: GSPE-H alleviates atherosclerosis by reducing production of TMAO.
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Background: The present study was conceived to compare the chemical composition and the related antimicrobial activity of essential oils (EOs) obtained from nine commonly used Moroccan lavender species, namely L. mairei, L. multifida, L. tenuisecta, L. maroccana, L. latifolia, L. pedunculata subsp. atlantica, L. stoechas, L. angustifolia and L. dentata. It aimed to classify these widely used Moroccan lavenders, based on their chemical profiles and antimicrobial effectiveness against some human pathogenic microorganisms.
Methods: Plant aerial parts were steam-distilled and the obtained EOs were initially analyzed using gas chromatography/mass spectrometry (GC/MS), then investigated for their antimicrobial activity against six bacteria and four candida strains, using disc diffusion and broth microdilution methods.
Results: The chemical analyses showed that all the EOs investigated were classified as oxygenated monoterpene-rich oils (61.78%–92.46%). Hierarchical cluster analysis (HCA) based on the EO chemical compositions enabled the classification of these Moroccan lavender species into four distinct chemical groups: a carvacrol group (Group I), comprising the species L. tenuisecta, L. maroccana and L. mairei, a carvacrol/camphor group (Group II), represented by the species L. multifida, a camphor group (Group III), composed of L. dentata, L. stoechas, L. pedunculata subsp. atlantica, L. latifolia, and a camphor/endo-borneol/1,8 cineole group, represented by L. angustifolia (Group IV). The highest antimicrobial activity was observed for oils obtained from L. tenuisecta, L. maroccana and L. mairei (carvacrol group), with inhibitory zone diameters ranging from 10.30 ± 0.16 to 35.34 ± 0.85 mm, and minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC) ranging from 0.039 mg/mL to 5 mg/mL. L. multifida EO (carvacrol/camphor group) showed potent activity, while the lavender EOs from groups III and IV demonstrated the weakest activity.
Conclusions: These results support the potential use of some native Moroccan lavenders, particularly those characterized by carvacrol and/or carvacrol/camphor rich oils, as promising sources of natural antimicrobials to combat some human infectious diseases.
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Background: With aging, body functions of the elderly decline. Among the more prominent organs in decline is the skeleton, especially osteoporosis. The most serious consequence of osteoporosis is hip fracture with minimal trauma. Total hip arthroplasty is frequently used to repair hip fracture. The choice of anesthesia during an operation is extremely important, because it directly affects the postoperative recovery of the patients. In recent years, it has been found that combined spinal-epidural block anesthesia can blend the advantages of spinal and epidural block anesthesia, resulting in a better outcome for the patient. The objective of this study was to investigate the outcome of combined spinal-epidural block anesthesia on the stress response, inflammatory factors and immune function in elderly patients after total hip arthroplasty used to treat hip fracture.
Methods: 116 elderly patients who underwent total hip arthroplasty after hip fracture were enrolled. Participants were assigned to a Control group (N = 58), which accepted epidural block anesthesia, and an Observation group (N = 58), which accepted combined spinal-epidural anesthesia. The blood levels of stress response [cortisol (Cor), epinephrine (E), adrenocorticotropin hormone (ACTH)], inflammatory factors [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10)] and immune function [CD3+, CD4+, CD8+ and CD4+/CD8+ ratio] were compared before and at 24 hours and 72 hours after the operation.
Results: Significant differences occurred in plasma concentrations of Cor, E and ACTH at 24 h after operation. The protein levels of serum TNF-α, IL-6 and IL-10 increased less in the Observation group than in the Control group (p < 0.05). Furthermore, CD3+, CD4+ and the ratio of CD4+/CD8+ were higher and CD8+ was lower (p < 0.05) in the Observation group than in the Control group. There were significantly fewer perioperative adverse reactions in the Observation group than in the Control group (p < 0.05).
Conclusions: The effect of combined spinal-epidural block anesthesia for total hip arthroplasty in elderly patients with recent hip fracture is significant. Patients using combined spinal-epidural block anesthesia showed a reduced stress and inflammatory reaction which occurs after surgery, with faster recovery of immune function, and fewer adverse reactions, than did patients with epidural block anesthesia.
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Background: Slow transit constipation (STC) is a chronic gastrointestinal dysfunction that significantly impairs the quality of life for many individuals. This study aims to explore the role and mechanism of Benzoylmesaconine (BAC) in the treatment of STC.
Methods: Rats were treated with loperamide (Lop) hydrochloride for 7 days to build the STC model. After that, they were given BAC concentrated solution and 0.2 g/L Mosapride via intragastric treatment. The rats' body weight was monitored, and their intestinal propulsion rate was determined using the intestinal charcoal powder propulsion assay. Pathological symptoms were assessed by hematoxylin-eosin (HE) staining. Additionally, the concentrations of 5-hydroxytryptamine (5-HT) in both serum and colon tissues were detected by enzyme-linked immunosorbent assay (ELISA). The expression levels of 5-HT receptor 3 (5-HT3R), 5-HT receptor 4 (5-HT4R) and Chlorogenic acid (CgA) were evaluated using immunohistochemistry (IHC) and immunofluorescence (IF), respectively. Moreover, the gut microbiota profiles of fecal samples were analyzed through 16S rRNA analysis.
Results: BAC treatment improved the intestinal propulsion rate and pathological symptoms induced by Lop. In rats treated with Lop, the concentrations of 5-HT in both serum and colon tissues, and the expression levels of 5-HT3R, 5-HT4R (p < 0.05), and CgA were decreased. However, these levels were restored with the BAC and mosapride treatments. Additionally, BAC improved the decrease of intestinal microflora caused by Lop and changed the fecal microbial composition caused by Lop.
Conclusions: BAC alleviated the symptoms of STC and improved the composition of intestinal microflora associated with STC. These findings suggest that BAC could be a potential treatment for functional bowel disease.
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Background: Zuojin Pill is a widely recognized Traditional Chinese Medicine (TCM) prescription used to treat chronic atrophic gastritis (CAG). However, its mechanisms of action are not fully understood.
Objectives: This study utilized a combination of network pharmacology and molecular docking to investigate the pharmacological mechanism of Zuojin Pill in the treatment of CAG.
Methods: To identify the pharmacologically active ingredients of the Zuojin Pill and predict potential targets, we used the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. We obtained CAG-related targets from the Online Mendelian Inheritance in Man (OMIM) database and Genecards database. A protein-protein interaction network was established in the STRING database to explore the interactions between Zuojin Pill potential targets and CAG-related targets. Topological parameters were then calculated to identify key targets (main targets in the protein-protein interaction (PPI) network) of the Zuojin Pill for CAG treatment. The network of active ingredients and targets of Zuojin Pill in CAG treatment was visualized using Cytoscape. Additionally, Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the key targets were conducted using Database for Annotation, Visualization and Integrated Discovery (DAVID). Finally, molecular docking was performed to verify the binding of active compounds with the core targets.
Results: A total of 29 active ingredients corresponding to 32 key targets were identified. GO and KEGG enrichment analysis indicated that the targets of Zuojin Pill in CAG treatment primarily involve various biological processes associated with inflammation and apoptosis, as well as related pathways such as mitogen-activated protein kinases (MAPK), tumour necrosis factor (TNF) , PI3K-AKT, and others. The molecular docking results showed that isorhamnetin, quercetin, rutaecarpine, and sitosterol exhibited strong binding affinities for TNF, MAPK1, and RAC-alpha serine/threonine-protein kinase (AKT1). Among them, the binding energy between AKT1 and sitosterol was the lowest (–7 kcal/mol), indicating that it was the most stable receptor-ligand pair.
Conclusions: This study used network pharmacology and molecular docking to investigate the pharmacological mechanism of Zuojin Pill in treating various pathological factors of CAG, including inflammatory reactions and apoptosis. The process involved the use of diverse factors and a “multi-pathways and multi-targets” approach. The findings of this study provide a novel perspective and theoretical basis for the clinical treatment of CAG.
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Backgrounds: Protein biosynthesis takes place in the ribosome. Some antibiotic and antitumor molecules show more reactivity and affinity with ribosome proteins. These observations encourage the search for protein synthesis inhibitors of targets in the fight against infectious diseases and cancer. This study assessed the utilization of Lepidium sativum (LS) seeds germination in rapidly screening new anticancer candidates for drugs.
Methods: Antineoplastic prescribed in the clinic was used at different concentrations in the medium of LS seed germination, and the rootlet length was measured after 72 hours.
Results: The results showed that antineoplastics inhibitors of protein synthesis inhibit the germination of seed rootlets whatever their origin: chemicals (R2 = 0.99), antibiotics (R2 = 0.87), or extracts of medicinal plants (R2 = 0.93). The half maximal inhibitory concentration (IC50) obtained was close to that of cancer cell lines.
Conclusion: To our knowledge. This is the first demonstration that utilization of seed germination of LS might be used for the rapid screening of new antineoplastics candidates.
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Background: Focal segmental glomerulosclerosis is the leading cause of kidney disease worldwide. The potential effect of quercetin on glomerulosclerosis was identified using quantification-based proteomic analysis.
Methods: Glomerulosclerosis was induced using adriamycin in rats treated with quercetin for 8 weeks starting on the day of adriamycin injection. Next, significant differentially expressed proteins (DEPs) were identified through label-free quantification-based proteomic analysis of renal samples. Functional analysis was performed to evaluate the effects of quercetin on glomerulosclerosis.
Results: In this study, 26,431 peptides and 5272 proteins were identified using quantification-based proteomic analysis. Clusters of Orthologous Groups analysis identified general function prediction as the only key initiation factor in the glomerulosclerosis process. Gene Ontology analysis showed that these DEPs were parsed into six major components: cell, cell part, cellular process, binding organelle, single-organism process, and metabolic process. Kyoto Encyclopedia of Genes and Genomes analysis revealed 803 DEPs involved in metabolic pathways. Notably, DEPs were distributed in the PI3K-Akt signaling pathway at a proportion of 3.08%. We showed that quercetin substantially contributes to the protection against glomerulosclerosis through the extracellular region. Quercetin can also inhibit the progression of glomerulosclerosis through the PI3K/Akt pathway.
Conclusions: These results suggest a novel therapeutic approach for glomerulosclerosis.
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Background: Antimicrobial resistance (AMR) has become an emerging public health issue in recent years, particularly in uropathogenic bacteria such as Escherichia coli, Citrobacter freundii, Pseudomonas aeruginosa, Enterobacter aerogenes, and Morganella morganii. These pathogenic bacteria are a leading cause of morbidity and mortality among hemodialysis patients. This study investigated the molecular characterization and phylogenetic analysis of antibiotic-resistance genes in uropathogenic bacteria recovered from hemodialysis patients.
Methods: A total of 2360 urine samples were taken from hemodialysis patients with Urinary Tract Infections (UTIs), who attended Khyber Teaching Hospital in Peshawar, Pakistan from January 2019 to December 2021. The samples were cultured and the isolates were confirmed through biochemical analysis. The antibiotic-resistant genes were amplified using PCR followed by the Sanger sequencing. Finally, phylogenetic trees were generated using Molecular Evolutionary Genetic Analysis (MEGA)-7 software.
Results: Among a total of 509 (21.6%) uropathogenic isolates, Escherichia coli, Citrobacter freundii, Morganella morganii, Enterobacter aerogenes and Pseudomonas aeruginosa were reported as 54%, 17.5%, 11.78%, 10.6% and 6.0%, respectively. The genetic analysis revealed that bla-CTXM was the most prevalent gene then, bla-SHV and bla-VIM among uropathogenic bacteria. Most of the isolates were resistant to Ciprofloxacin, Ampicillin, Cefotaxime, Ceftazidime, Amoxicillin, Cefepime, Aztreonam, Doxycycline and Trimethoprim. Minimum inhibitory concentrations (MICs) ranged from 64 to >256 ug/mL. Point mutations were observed in the sequence of the bla-VIM gene at positions 240 (C-T), 295 (G-A), and 293 (A-G). The phylogenetic tree predicated that the bla-CTXM gene is 99% closely related to Escherichia coli, Citrobacter, and Enterococci strains, whereas the bla-TEM gene is 99% similar to Escherichia coli strain and Enterobacter species.
Conclusions: Antibiotics such as Tigecycline, Meropenem, Fosfomycin, Nitrofurantoin and Amikacin may be promising treatment options against MDR ESBL-producing uropathogenic bacteria. These drugs may be the first-line option against uropathogenic bacteria resistant to Cephalosporins, Ciprofloxacin, and Gentamycin from this region.
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Background: Chronic obstructive pulmonary disease (COPD) and mild cognitive impairment (MCI) are two conditions that are closely associated with worse progression and prognosis. However, the potential common pathogenetic mechanisms and genetic modulators that link these two conditions remain elusive. This study aimed to investigate the shared differentially expressed genes (DEGs) to reveal the co-genetic features and molecular mechanisms between COPD and MCI.
Methods: Overlapping DEGs were identified from the COPD dataset (GSE148004) and the MCI dataset (GSE63060). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted based on the overlapping genes to annotate the biological signaling pathways. Then, a protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape software to screen out the key subnetworks and hub genes. Finally, the hub genes were validated in external datasets (GSE11784, GSE106986, and GSE63061) to enhance the reliability and efficacy of the results.
Results: In total, 26 overlapping DEGs in COPD and MCI, as well as crucial pathways such as adenosine triphosphate (ATP) synthesis coupled electron transport, respiratory electron transport chain, and oxidative phosphorylation were obtained. Through the constructed PPI network, 12 hub genes were identified, including ATP5C1, ATP5J, ATP5O, cytochrome c oxidase subunit 7C (COX7C), histidine triad nucleotide binding protein 1 (HINT1), NADH:ubiquinone oxidoreductase subunit A1 (NDUFA1), NDUFB2, NDUFA4, NDUFS4, NDUFS5, translocase of outer mitochondrial membrane 7 (TOMM7), and ubiquinol-cytochrome c reductase complex III subunit VII (UQCRQ), along with their enriched biological pathways, oxidative phosphorylation, and ATP metabolic process. The validation of hub genes in external datasets showed that ATP5C1, COX7C, NDUFA1, and NDUFS5 might be the pivotal therapeutic targets.
Conclusions: To uncover the underlying mechanisms between COPD and MCI, this study identified the hub genes and corresponding regulatory mitochondrial pathways, which might provide promising insights and novel strategies for further research.
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Background: Since cells in myocardial tissue do not only express a single marker, several different stem cell markers may be colocalized on the same type of cell simultaneously. Therefore, using only one stem cell marker protein to classify myocardial cell populations may not be accurate. There are few reports on the co-expression of various marker proteins in the heart. Therefore, to investigate the co-expression between different stem-cell or embryonic markers in myocardial tissue, we selected three typical molecular markers, namely stem cell antigen-1 (Sca-1), an embryonic transcription factor (Nanog) and Insulin gene enhancer protein-1 (Islet-1).
Methods: We obtained the hearts of newborn, 1-week-old, 3-week-old, and 5-week-old mice, and separated the cells using density gradient centrifugation. The expression of Sca-1, Nanog, and Islet-1 in cardiac cells of different age groups was detected by immunofluorescence staining, myocardial differentiation potential identification, and Western blotting. Immunofluorescence analysis was used to co-express Sca-1, Nanog, and Islet-1. Single cell RNA sequencing was used to analyze cardiac tissue cell type and stem cell gene localization.
Results: The results showed that Sca-1+ and Islet-1+ cells had a stronger potential to express cardiac troponin T (cTnT) than Nanog+ cells (p < 0.05). Western blotting results showed that with the increase in age, the expression of Sca-1 first increased and then decreased, while the expression of Nanog steadily increased (p < 0.05). The expression of Islet-1 did not change significantly (p > 0.05). Immunofluorescence results showed that the co-expression rates of Sca-1 and Islet-1 increased from birth to the 3rd week, and then gradually decreased (p < 0.05). The co-expression rate of Sca-1 and Nanog continued to increase from birth, and showed a downward trend at the 5th week (p < 0.05). The co-expression rate of Islet-1 and Nanog gradually increased from 1 week after birth (p < 0.05). Single-cell RNA sequencing analysis identified eight major cell populations, including cardiomyocytes. Further analysis showed that Sca-1 positive cells had the highest proportion and were mainly concentrated in fibroblasts and endothelial cells.
Conclusion: Sca-1, Nanog, and Islet-1 positive cells vary dynamically at different stages of cardiac development. Therefore, a single stem cell marker cannot be used to classify cardiac stem cell subpopulations.
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Background: The ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates urgent solutions. Despite extensive clinical investigations and trials, no approved treatment has been found. To address this critical need, we designed a study to create and validate a subunit vaccine against SARS-CoV-2 based on cytotoxic T-lymphocyte (CTL) epitopes, using various immunoinformatics tools to gain essential insights into the associated immune responses.
Methods: We focused on the spike region of SARS-CoV-2, vital for its survival and virulence, to identify potential antigenic CTL epitopes. Our predictions suggested that these epitopes could significantly stimulate cell-mediated immunity. We selected a sequence comprising three antigenic and nontoxic CTL epitopes to enhance the safety and immunogenicity of the final vaccine. We predicted the three-dimensional (3D) structure of the vaccine and conducted docking studies with human major histocompatibility complex 1 (MHC-1) and toll-like receptor-3 (TLR-3) receptors. Molecular dynamics (MD) simulations were performed to confirm the stability of the vaccine binding with these receptors. Additionally, in-silico Polymerase Chain Reaction (PCR) and cloning were conducted to evaluate the amplification and protein expression of the final vaccine.
Results: Molecular docking studies showed strong binding between the vaccine construct and the human leukocyte antigen (HLA)-A heavy alpha chain of MHC-1 and the C-terminal domain of TLR-3 receptors. MD simulations in an explicit system further confirmed the robust and stable binding of CTL epitopes with MHC-1 and TLR-3 receptors. Using computational cloning based on SnapGene, excellent protein expression was achieved in the pET-28b(+) plasmid.
Conclusions: The findings of this study strongly support the manufacturing and in vitro and in vivo investigations of this vaccine to evaluate its effectiveness as a therapy for COVID-19.
