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Contemporary asthma management requires a proactive and personalized approach, integrating precise diagnosis with individualized treatment strategies. The incorporation of biological therapies for severe asthma into standard clinical practice underscores the importance of specific patient selection, outcome prediction, and continuous monitoring of these costly and prolonged treatments. Biomarkers, functioning as crucial indicators, have significantly impacted asthma by facilitating disease identification, predicting severity and prognosis, and assessing treatment effectiveness. This comprehensive review aims to thoroughly explore the diverse biomarkers associated with asthma, elucidating their roles in disease identification, severity prediction, and treatment response assessment. By delving into the intricate molecular and genetic aspects of asthma susceptibility, the review seeks to provide a nuanced understanding of the factors that influence the onset and severity of asthma. The review covers a spectrum of molecular factors that influence the susceptibility and severity of asthma. It explores the roles of specific biomarkers such as galectin-3, periostin, fractional exhaled nitric oxide, and eosinophils in airway remodeling and inflammation. Genetic factors like filaggrin mutations and chitinase-3-like protein 1 (CHI3L1 or YKL-40) variations are also examined. The review delves into proteomics, revealing unique plasma protein signatures linked to severe asthma and chronic obstructive pulmonary disease. It thoroughly examines the impact of the microbiome on asthma development, persistence, and severity, considering gut and lung microbial dysbiosis. Additionally, it highlights the potential of probiotics in managing allergic respiratory diseases and investigates the preventative effects of early exposure to pets in childhood. This review is a valuable resource for clinicians, researchers, and healthcare professionals in this field. It highlights the crucial role of biomarkers in asthma and offers a comprehensive understanding of genetics, proteomics, and the microbiome, enriching our comprehension of asthma management and preventive measures.
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The human gut has 12 distinct phyla, among which Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes make up ˃90%. Depressed individuals are a significant phylum and are differentiated from healthy individuals by their firmicutes. The microbiome is a key component of the pathological basis of major depressive illness as a result of disruption of the microbiota-gut-brain (MGB) axis. The fact is that there is bidirectional communication inside the brain, stomach, and brain-gut, wherein the brain highlights a systemic disease characterized by both brain and peripheral dysfunction. According to the microbiota hypothesis, MGB axis dysfunction is a significant contributor to the pathogenic underpinnings of major depressive disorder (MDD). The etiology of MDD is complicated and includes an imbalance of neurotransmitters, an impaired hypothalamic-pituitary-adrenal (HPA) axis, inflammation, and the MGB axis. According to research, having an aberrant microbiome or a disjointed MGB axis may directly cause psychiatric diseases such as MDD. Hence, resolving these issues may help with depression symptoms. Probiotics may therefore have therapeutic benefits for psychiatric symptoms by fostering healthy and balanced gut flora. The probiotic Bifidobacterium longum NCC3001 has been shown to reduce depression scores. In this review, the unknown mysteries and myths of probiotics are unlocked with special attention given to MDD or depression.
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Autism spectrum disorder (ASD) is a composite neurodevelopmental disorder characterized by a broad range of symptoms and varying severity. Although the exact cause of ASD remains unknown, new research has identified modifiable risk factors that may contribute to the pathophysiology of the disease. A combination of environmental and genetic variables influences the risk of ASD. Recent studies suggest that prenatal exposure to environmental pollutants, such as air pollution and certain pesticides, may increase the incidence of ASD. Additionally, maternal health during pregnancy, including obesity and gestational diabetes, has been identified as a modifiable risk factor. Furthermore, ongoing investigations explore probiotics and dietary modifications as potential means to alter these risk factors. There is also increasing attention given to the role of immunological dysregulation and inflammation in ASD. Studies have linked pregnant women with autoimmune diseases or infections to a higher incidence of ASD. Potential preventative interventions being explored include immunomodulatory methods. In summary, recent studies have identified modifiable risk factors contributing to the pathophysiology of ASD, offering the potential for early intervention and prevention. Reducing the prevalence of ASD may require a multimodal strategy addressing immune system regulation, maternal health, and environmental exposures. Further investigation is needed to translate these discoveries into practical therapeutic approaches.
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Mushrooms emerge as fascinating organisms within the vast expense of the natural world. They have been rapidly expanding in demand due to their popularity among consumers for their delightful taste, distinctive odor, and nutritional value. They are regarded as functional foods, that confer nutritional benefits and enhance health. Macrofungi exhibit a diverse array of bioactive compounds, categorized as secondary metabolites. Mushrooms are the richest source of proteins, polysaccharides, polysaccharide-protein complexes, phenolic compounds, sterols, triterpenes, triterpenoids, and vitamins. Mushroom extracts have great medicinal uses for human well-being as they possess numerous properties such as anticancer, antimicrobial, antidiabetic, antioxidant, antiobesity, antilipidemic, antiaging, immunomodulatory, hepatoprotective, and neuroprotective properties. This review highlights the nutraceutical and therapeutic potential of various macrofungi. Furthermore, it serves as a valuable resource for researchers, enabling them to access existing knowledge on the ethnopharmacological activities of bioactive compounds extracted from macrofungi and other useful compounds that could be the source for the discovering novel drugs with better pharmaceutical and therapeutic properties.
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Diabetes mellitus is a multifaceted metabolic disease with consequences for global health. It is characterized by insulin resistance and irregularities in insulin secretion. The global prevalence of diabetes necessitates a nuanced understanding beyond traditional classifications, emphasizing the dynamic nature of this health threat. Recent strides in genetics have led to the development of personalized treatments, while the emergence of type 3 diabetes underscores the need for refined classifications, standardized definitions, and improved screening methods. The fusion of neuropharmacology with diabetes care signals a transformative shift, with a focus on cognitive function and neuronal survival alongside glycaemic control. Repurposing antidiabetic medications for neurodegenerative diseases introduces a promising frontier at the intersection of diabetes and neurological research. Investigating the molecular and metabolic pathways that underlie diabetic problems reveals complex processes, including the generation of diacylglycerol, modified redox states, the polyol pathway, and advanced glycation end-product synthesis. Strategies targeting these pathways unveil novel therapeutic strategies to mitigate vascular dysfunction and oxidative stress. Antidiabetic drugs, including metformin, thiazolidinediones, and glucagon-like peptide-1 receptor-targeting compounds, show promise for neuroprotection, extending beyond glycaemic control to enhance insulin signaling and protect against degeneration. Molecular targets such as peroxisome proliferator-activated receptors (PPARs), protein tyrosine phosphatase 1B (PTP-1B), and glycogen synthase kinase-3 (GSK-3) offer potential avenues for reshaping diabetes management, presenting both challenges and opportunities in the pursuit of precision medicine. In envisioning the future, the concept of type 3 diabetes will become a focal point, leading to dedicated exploration for accurate diagnostics and targeted treatments. This paper serves as a catalyst for sustained exploration, interdisciplinary collaboration, and an unwavering commitment to pioneering the future of diabetes care, aiming to illuminate the present while shaping a future met with precision, empathy, and innovative solutions.
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Melatonin is a tryptophan-derived hormone recognized for its diverse physiological benefits such as circadian rhythm regulation and sleep modulation. Its antioxidant properties have implications for cancer prevention, immune enhancement, neuroprotection, and cardiovascular health. In contrast, phytomelatonin, a plant-derived counterpart discovered in 1995, shares similar antioxidant capabilities but follows distinct synthesis pathways. Phytomelatonin shows promise in managing sleep disorders and reducing oxidative stress, aligning with the growing interest in plant-based solutions. This review highlights melatonin's physiological roles and explores the potential of phytomelatonin as a nutraceutical for preventive and therapeutic interventions. Moreover, this review identifies research gaps to direct future investigations and refine the understanding of melatonin and phytomelatonin. Phytomelatonin, as a safer alternative to synthetic melatonin, holds therapeutic promise and warrants further research to elucidate its efficacy, bioavailability, and optimal usage. This review underscores the nuanced interplay between melatonin and phytomelatonin, offering insights into natural supplementation and therapeutics aligned with evolving preferences for effective healthcare practices.
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Background: Existing evidence suggests that obesity has an impact on the onset and development of rheumatoid arthritis (RA) and may also affect the response of patients to different treatments. However, findings from previous studies are controversial. This study aims to obtain evidence-based medical information on the influence of obesity on the response rate of biological agents in patients with RA through a systematic review and meta-analysis.
Methods: A search was performed on Pubmed, Medline, Web of Science, Scopus, and Cochrane Library from their inception to June 2023. Studies that met the inclusion criteria were enrolled. A meta-analysis was used to evaluate remission, response, good European League Against Rheumatism (EULAR) response, moderate EULAR response, retention rate, and clinical disease activity index (CDAI). Subgroup analysis was carried out to identify sources of heterogeneity and sensitivity analysis was performed.
Results: A total of 15 articles met the inclusion criteria and four biological disease-modifying antirheumatic drugs (bDMARDs) were included. The meta-analysis showed that the odds of reaching good EULAR response or achieving CDAI were lower in obese than in non-obese patients treated with bDMARDs. Subgroup analysis revealed significant differences between the two groups. Remission, good EULAR response and retention rate were lower in the obese group than in non-obese patients treated with tumor necrosis factor inhibitors (TNFi). However, there was no significant difference between patients receiving abatacept and tocilizumab treatment. Sensitivity analysis and publication bias confirmed that the results were highly reliable and stable.
Conclusions: Obesity affects the clinical response rate of RA patients receiving TNF inhibitors (TNFi), but it does not have an adverse effect on abatacept and tocilizumab. This suggests that when choosing biological agents for RA patients, the impact of obesity should be considered. Further research is needed to validate these findings.
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Background: In the last decade, the wide spread of the multidrug resistant yeast C. albicans has challenged the development of new approaches to treatment. Among various options, the use of natural and synthetic terpenes as antifungals or enhancers of conventional drugs has been offered in many works. Here we show the effect of the recently synthesized compound isobornane sulfide named KS1 on C. albicans and discuss its potential mechanism of action.
Methods: To characterize the impact of the compound on the yeast minimum inhibitory concentration (MIC) determination on clinical isolates, quantitative PCR with reverse transcriptase (qRT-PCR) of efflux genes expression, cytotoxicity determination on eukaryotic cells, bright-field and fluorescent microscopy with KS1 conjugate with BODIPY fluorophore have been used. The in silico prediction of KS1 properties has been performed using the ADMET server, and molecular docking was used for the modeling of KS1 interaction with putative targets.
Results: While exhibiting moderate antifungal activity as compared to fluconazole and terbinafine, KS1 has a synergy with both antifungals on resistant clinical isolates while not stimulating the expression of the CDR1 and MDR1 efflux genes. Moreover, KS1 represses hypha formation by C. albicans, reducing the number of germ tubes more than twice compared to the control. It readily penetrates the cell, as shown by confocal microscopy using the created KS1-BODIPY fluorophore conjugate, apparently thereby facilitating the penetration of antifungals into the cell. As judged by the ADMET server, KS1 falls into the category of drug-like compounds and neither inhibits the isoforms of cytochrome P450 nor manifests mutagenicity or carcinogenicity that fits with in vitro data. The molecular docking showed that KS1 has a high affinity for the transcription activator transcription activator (Tec1) protein of C. albicans, responsible for invasion and hypha formation, which fits with the in vitro data.
Conclusions: These findings suggest KS1 as promising both a solely antifungal and an enhancer of conventional antimycotics blocking fungal virulence.
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Purpose: This study aimed to assess the efficacy of endoscopic treatment alone compared to the combination of carvedilol with endoscopic treatment in preventing rebleeding of esophagogastric varices of varying severity in patients with hepatic cirrhosis.
Methods: The study included 867 patients with hepatic cirrhosis and esophagogastric varices, who were admitted to Nanjing Drum Tower Hospital between July 2018 and December 2022. A 180-day follow-up period was implemented to evaluate the association between the combined use of carvedilol and endoscopy and clinical outcomes, focusing on esophagogastric variceal rebleeding and all-cause mortality. Propensity score matching (PSM) was performed on initially enrolled patients meeting the inclusion criteria (n = 232), resulting in the selection of 105 patients each in the endoscopy group and the combined carvedilol and endoscopy group. Subgroup analyses based on the severity of esophagogastric varices were conducted to compare the efficacy of the two treatment modalities.
Results: After PSM, the endoscopy group and the combined carvedilol and endoscopy group exhibited a significant difference in rebleeding rates (29.52% vs. 14.29%, p = 0.006) and no significant difference in all-cause mortality (6.67% vs. 1.90%, p = 0.085). Multivariate Cox regression analysis revealed that the severity of esophagogastric varices was an independent risk factor influencing rebleeding (χ2 = 3.993, p = 0.046, hazard ratios (HR) = 2.85, 95% confidence intervals (CI): 1.02–7.95), while carvedilol emerged as an independent protective factor against rebleeding (χ2 = 6.222, p = 0.013, HR = 0.46, 95% CI: 0.25–0.85). Subgroup analysis based on the severity of esophagogastric varices showed that among patients with severe esophagogastric varices, the endoscopy group and the combined carvedilol and endoscopy group exhibited significant differences in rebleeding rates (34.12% vs. 16.25%, p = 0.009) and no significant differences in all-cause mortality (7.06% vs. 1.25%, p = 0.063). Among patients with non-severe esophagogastric varices, the endoscopy group and the combined carvedilol and endoscopy group showed no significant differences in rebleeding rates (10.00% vs. 8.00%, p = 0.684) and all-cause mortality (5.00% vs. 4.00%, p = 0.860).
Conclusion: Combining carvedilol with endoscopy is more effective than endoscopy alone in preventing rebleeding from esophagogastric varices, though it does not impact patient survival. In patients with non-severe esophagogastric varices, the incorporation of carvedilol alongside endoscopy does not yield significant benefits in rebleeding or survival compared to endoscopy alone. Conversely, for patients with severe esophagogastric varices, the combined use of carvedilol and endoscopy demonstrates greater efficacy in preventing rebleeding than endoscopy alone, yet it does not influence all-cause mortality.
Clinical Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-17012836.
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Background: Vascular dementia (VaD) is a kind of cerebrovascular diseases characterized by decreased cognitive function. No effective treatments have been approved for the treatment of VaD. Accumulative evidence reveals that pyroptosis plays a key role in mediating VaD. Therefore, this study aimed to identify pyroptosis-linked hub genes by using bioinformatics analysis and construct a regulatory network among transcription factors (TFs), microRNAs (miRNAs), and mRNAs for VaD.
Methods: Differentially expressed genes (DEGs) in the frontal cortex between VaD and control samples were identified. Several analyses were performed, including functional enrichment, protein-protein interaction (PPI), miRNA-target gene interaction, transcription factor-microRNA (TF-miRNA) interaction, and drug-hub gene interaction. The goal was to obtain pyroptosis-related hub genes and create a TF-miRNA-mRNA regulatory network for VaD.
Results: We identified 27 DEGs related to pyroptosis, nine of which were considered as pyroptosis-related hub genes. These hub genes were nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), TLR2, CASP1, heat shock protein 90 kDa alpha family class A member 1 (HSP90AA1), VEGFA, AIM2, LY96, CEBPB, and BTK. In our TF-miRNA-mRNA regulatory network, two hub genes (vascular endothelial growth factor-A (VEGFA) and heat shock protein 90 kDa alpha family class A member 1 (HSP90AA1)), four miRNAs (miR-1304-3p, miR-1293, miR-191-5p, and miR-5193), and five TFs (Early Growth Response Protein 1 (EGR1), runt-related transcription factor-1 (RUNX1), SPI1, PHD finger protein 8 (PHF8), and CCAAT/enhancer binding protein beta (CEBPB)) were identified as potential biomarkers for VaD. The expression levels of these key target genes, miRNAs, and TFs were verified using an oxygen-glucose deprivation (OGD)-induced SH-SY5Y cell model. The drug-target gene interaction analysis revealed that three drugs (tanespimycin, bevacizumab, and aflibercept) targeting HSP90AA1 and VEGFA could be potential drugs for VaD treatment.
Conclusions: This study built a pyroptosis-related regulatory network among TFs, miRNAs, and target genes for VaD. The results of this study might assist with clarifying the new molecular mechanisms of VaD. Additionally, HSP90AA1 and VEGFA were identified as potential biomarkers or therapeutic targets for VaD treatment.
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Background: The prognosis of patients with cerebral hemorrhage is strongly linked to systemic inflammatory responses. This study aimed to investigate the correlation between the systemic immune inflammation index (SII) and adverse outcomes in patients diagnosed with aneurysmal subarachnoid hemorrhage (aSAH).
Method: Between February 2020 and September 2022, we conducted a retrospective cohort analysis involving 102 aSAH patients who visited our hospital. We collected baseline and clinical data to assess the relationship between SII and prognosis. Patients were categorized into either the good or poor prognosis group based on the modified Rankin Scale (mRS) score three months post-discharge. Comparative analysis of baseline and clinical data at admission and three months post-discharge was conducted between the two groups.
Result: The study included 51 patients in the good prognosis group and 51 patients in the poor prognosis group. Statistically significant differences were observed between the groups in terms of age, the number of patients undergoing craniotomy clipping surgery, the number of patients receiving endovascular embolization treatment, main grade of Fisher at admission, and postoperative complications (p < 0.05). The Area Under Curve (AUC) for predicting adverse outcomes in aSAH using SII was 0.812 (95% confidence interval (CI): 0.730–0.894, p < 0.001), with a sensitivity of 0.863, specificity of 0.627, and an optimal cut-off value of 2214.5. Furthermore, the odds ratio (OR) of SII as an independent influencing factor was 10.586 (95% CI: 3.977–28.177, p < 0.001).
Conclusion: The prognosis of aSAH patients at three months post-discharge is associated with their SII at admission. An elevated SII indicates a higher incidence of adverse outcomes in aSAH patients.
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Background: Numerous reports have suggested a correlation between the occurrence of heart failure (HF) and the methylation status of specific key genes in myocardial cells. This study aimed to elucidate the mechanistic role and functional impact of the methylation of pentenyl diphosphate synthase subunit 2 (PDSS2) methylation in HF, offering insights for novel therapeutic approaches in HF management.
Methods: The HF rat model was established via surgical intervention to explore the in vivo exacerbation of HF by PDSS2 methylation. Cardiac ultrasound and morphological assessments were used to evaluate HF in rat hearts. Hematoxylin-eosin (HE) staining was used to assess cardiac injury. The levels of PDSS2 methylation and expression were quantified, and the underlying mechanisms of PDSS2 in HF pathogenesis were explored.
Results: Our findings revealed a significant reduction in PDSS2 levels in the heart tissue of HF rats (p < 0.05), concurrent with a notable increase in PDSS2 methylation (p < 0.05). Decreased PDSS2 methylation led to the upregulation of nuclear factor-kappaB (NF-κB) expression (p < 0.05) and chemokine (C-X-C motif) ligand 14 (CXCL14) levels (p < 0.05), consequently attenuating myocardial tissue damage in HF rats. However, silencing CXCL14 or administering the NF-κB inhibitor BAY 11-7082 reversed the protective effects of 5-Aza-2′-deoxycytidine (5-Aza) (p < 0.05), thus increasing myocardial tissue damage in HF rats.
Conclusion: PDSS2 methylation is a significant contributor to cardiac dysfunction and the progression to heart failure, underscoring its potential importance in the therapeutic landscape of HF.
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Background: In dental avulsion, delayed replantation usually has an uncertain prognosis. After tooth replantation, complex inflammatory responses promote a return to periodontal tissue homeostasis. Various types of cytokines are produced in the inflammatory microenvironment, and these cytokines determine the periodontal tissue response. This study aims to conduct in-depth research on developing a novel root canal medicament, which employed methylcellulose hydrogel as a carrier system and was loaded with clindamycin, acetazolamide and triamcinolone, to determine its triple action of antibacterial, anti-inflammatory and anti-resorptive capabilities in delaying tooth replantation and to preliminarily explore its potential mechanisms of action.
Methods: The release concentration of the paste from human extracted root apices was determined using UV-spectrophotometry. The cytotoxicity of corresponding drug concentrations on HPDLFs (human periodontal ligament fibroblasts) was assessed on days 1, 3, 5, and 7 using the CCK-8 (cell counting kit-8) assay. The antibacterial activity against Fusobacterium nucleatum (F. nucleatum) was measured using the agar diffusion method. The gene and protein expression of inflammatory factors (IL-1β (interleukin-1β), IL-6 (interleukin-6), TNF-α (tumor necrosis factor-α) and bone metabolism molecules (RANK (Receptor Activator of Nuclear Factor-κB), RANKL (Receptor Activator of Nuclear Factor-κB Ligand), OPG (Osteoprotegerin)) in HPDLFs stimulated with Escherichia coli (E. coli) lipopolysaccharide were determined by ELISA (enzyme-linked immunosorbent assay) and RT-qPCR (real-time quantitative polymerase chain reaction), respectively. Furthermore, the rat delayed replantation tooth models were established and the resorption of incisors was analyzed by micro-CT (micro-computed tomography) after 60 days. The degree of root inflammation and resorption was evaluated by hematoxylin-eosin (HE) staining, and the expression of RANKL/OPG was assessed by immunohistochemical staining.
Results: The novel paste showed sustained slow release in root canals for 60 days. In vitro, the experiments demonstrated good cell compatibility and antibacterial activity (p < 0.01). The paste suppressed the expression of IL-1β, IL-6 and TNF-α, and down-regulated the RNA and protein levels of RANKL and OPG in HPDLFs stimulated by E. coli (p < 0.05). In vivo experiments revealed that the novel paste down-regulated the expression of RANKL and OPG, effectively preventing inflammatory root resorption in rat delayed replantation teeth (p < 0.05).
Conclusion: The novel paste can inhibit inflammatory root resorption by modulating the RANKL/RANK/OPG signaling pathway and has the potential to be used as an intracanal medicament for root canal treatment in delayed replantation teeth.
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Background: Migraine is known as a persistent neurological condition marked by recurring bouts of head pain and diverse neurological manifestations. Emodin exhibits a wide range of pharmacological activities, particularly its neuroprotective effects on neurodegenerative diseases. Emodin is capable to alleviate nitroglycerin (NTG)-induced migraine in rats. Furthermore, it has been witnessed that transient receptor potential vanilloid-4 (TRPV4)/p38 signaling pathway is involved in the development of migraine pathogenesis.
Methods: Rats subjected to repetitive NTG administration were considered a model replicating clinical manifestations of migraine. Three different Emodin dosage groups (high, medium, and low) and control group were used to observe the effects of different doses on the behavior and other related indicators of migraine rats.
Results: The results showed that high and medium doses of Emodin significantly delayed the appearance time of redness and scratching in the ears of rats, shortened their disappearance time, and increased the mechanical pain threshold of rats, indicating that Emodin can remarkably improve the behavior of migraine rats and increase their mechanical pain threshold. At the same time, high and medium doses of Emodin significantly increased the content of peripheral blood 5-hydroxytryptamine (5-HT) in migraine rats, indicating that Emodin can treat migraine headaches by increasing the peripheral blood 5-HT content. In addition, high and medium doses of Emodin can reduce the expression of TRPV4 protein and p38 mRNA in the trigeminal ganglion of migraine rats, indicating that Emodin can negatively regulate the expression and gene transcription of TRPV4/p38 signaling pathway-related proteins. Therefore, it inhibits neuroinflammation, reduces pain-induced sensitization, and exerts a therapeutic effect on migraine.
Conclusions: Our findings demonstrate that Emodin is capable to mitigate headaches, which are associated symptoms in migraine-afflicted rats. This effect is likely attributed to the elevation of peripheral blood 5-HT content and the suppression of expression and gene transcription related to the TRPV4/p38 signaling pathway.
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Background: Coixol (COI) is derived from C. lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf and has been shown with protective effects on rheumatoid arthritis (RA). However, the detailed mechanisms of COI on RA remain unknown. The current study aimed to assess the therapeutic effect and possible mechanism of COI on RA.
Methods: A collagen-induced arthritis (CIA) rat model was established, and COI was administered to CIA rats orally. The therapeutic effects of COI on RA were assessed based on arthritis score and paw volume, pathological staining and the levels of inflammatory factors. Then, the effects of COI on M1 macrophages (Mφ) polarization were evaluated through measuring the levels of M1Mφ-related factors, detecting the proportion of M1Mφ in spleen and synovium. Furthermore, the inhibitory effect of COI on M1Mφ polarization was verified in vitro and the changes in toll-like receptor 4 (TLR4)/nuclear factor-kappaB (NF-κB) pathway in M1Mφ after COI treatment was evaluated through detecting the related levels of proteins and genes. Additionally, the inhibitory effect of COI on NF-κB p65 activation in M1Mφ was assessed through detecting the nucleus transition of NF-κB p65 and the NF-κB transcriptional activity.
Results: COI decreased arthritis score and paw volume, improved the pathological changes, and reduced the levels of inflammatory factors in CIA rats (p < 0.01). Besides, COI treatment reduced the proportion of M1Mφ in the spleen and synovium (p < 0.01). In vitro studies suggested that COI decreased the proportion of M1Mφ and reduced the production of pro-inflammatory cytokines (p < 0.05, p < 0.01, respectively). Besides, COI treatment lowered the protein levels of TLR4/NF-κB pathway-related factors and downregulated the gene expression of downstream cytokines (p < 0.05, p < 0.01, respectively). Furthermore, COI treatment inhibited the nucleus transition of NF-κB p65 and diminished the transcriptional activity of NF-κB (p < 0.05).
Conclusions: COI exhibits a significant therapeutic effect on RA. The anti-inflammatory mechanism of COI on RA is associated with inhibiting TLR4/NF-κB-mediated M1Mφ polarization.
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Background: Renal fibrosis is a common pathological alteration in chronic kidney disease (CKD), in which prominin 1 (PROM1) serves as a hub signature, as confirmed by a weighted gene co-expression network analysis. This study aims to investigate the precise function and mechanism of PROM1 in renal fibrosis.
Methods: The in vivo and in vitro models of renal fibrosis were established by inducing overexpression of PROM1 in unilateral ureteric obstruction (UUO) mice and transforming growth factor-β (TGF-β)-treated HK-2 cells (renal tubular epithelial cells). Mammalian target of rapamycin complex 1 (mTORC1) activator MHY1485 was used in rescue experiments in vitro. Expressions of PROM1 and proteins relevant to fibrosis, the mTORC1 pathway, and glycolysis in animal and cell models were determined using western blot. Kidney fibrosis and injury, as well as 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) location were observed following tissue staining. Lactate content and extracellular acidification rate (ECAR) were measured to assess cellular glycolysis level.
Results: PROM1 was lowly expressed in kidneys and its overexpression improved kidney fibrosis of UUO mice. PROM1 overexpression rescued TGF-β-induced fibroid transformation, lactate accumulation, and ECAR increase in HK-2 cells. PROM1 overexpression reversed upregulation of fibronectin (FN), type I collagen (COL-I), plasminogen activator inhibitor-1 (PAI-1), mTOR, Raptor, Rictor, phosphorylated S6 ribosomal protein (p-S6), hexokinase 2 (HK2), and PFKFB3 in kidneys of UUO mice and TGF-β-treated HK-2 cells. MHY1485 generated opposite effects on TGF-β-treated HK-2 cells, and weakened the effects of PROM1 overexpression on suppression of the mTORC1 pathway and glycolysis.
Conclusion: PROM1 upregulation in renal tubular epithelial cells regulates PFKFB3-driven glycolysis through the mTORC1 pathway to improve renal fibrosis. Our results suggest that PROM1 is a promising therapeutic target for CKD prevention and treatment.
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Background: The long non-coding RNAs (lncRNAs) have been found crucial in the pathogenesis of cardiovascular diseases, including myocardial infarction (MI). Therefore, we aimed to investigate the role of lncRNA smooth muscle and endothelial cell-enriched migration/differentiation-associated lncRNA (SENCR) in MI.
Methods: An in vitro model of MI was established by treating human cardiomyocytes (HCM) with hypoxia conditions. The quantitative real-time polymerase chain reaction (RT-qPCR) and western blot analysis were used to assess the expression of genes both at RNA and protein levels. However, Cell Counting Kit-8 (CCK-8) and flow cytometry analysis were employed for the assessment of HCM viability and apoptosis. Furthermore, RNA-binding protein immunoprecipitation (RIP), RNA pull-down, and luciferase reporter assays were conducted to explore the regulatory relationship between SENCR and related molecules.
Results: The expression levels of SENCR were found to be progressively reduced in HCM under hypoxia treatment (p < 0.01). Furthermore, overexpression of SENCR stimulated HCM viability and reduced apoptosis rate during hypoxia conditions (p < 0.01). Moreover, SENCR was found to function as a competing endogenous RNA (ceRNA) to sequester miR-206, consequently modulating SMAD family member 4 (SMAD4) expression (p < 0.01).
Conclusions: LncRNA SENCR ameliorated hypoxia-induced MI by targeting the miR-206/SMAD4 axis. The findings of this research might offer novel insight for improving the treatment of MI.
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Background: Burn injuries lead to hemolysis and inflammation, simultaneously releasing reactive oxygen species (ROS) and toxic extracellular components such as hemoglobin, heme, and iron. Although the body naturally counteracts this toxicity by increasing the production of plasma scavenger proteins such as haptoglobin (Hp), hemopexin (Hpx), and transferrin (Tf), this protective response takes several hours to reach its peak. In the case of more severe burns, these plasma proteins may be depleted. Iron also serves as a nutrient for growing pathogens, potentially leading to subsequent infection.
Methods: We tested the effect of a human plasma protein cocktail consisting of Hp, Hpx, and Tf on hydrogen peroxide (H2O2)-induced ROS injury in vitro and a burn injury mouse model of full-thickness wounds using different delivery routes of the protein cocktail. In addition, the antibacterial properties of the protein cocktail were assessed against Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus).
Results: Metabolic activity of human fibroblasts decreased significantly after 1000 μM of H2O2 treatment for 24 hours, while the protein cocktail significantly reversed this effect in a dose-dependent manner. In the burn injury animal model, after 3 days, wound expansion and iron deposition were significantly reduced via daily treatment with the protein cocktail. This further led to better and more complete wound healing in these mice. Histologically, burn wounds were not entirely closed in the control group, unlike protein cocktail-treated wounds. Therefore, wound width was significantly larger in the control group. In bacterial zone inhibition assays against P. aeruginosa and S. aureus, the protein cocktail had minimal effect on bacterial inhibition when used alone; however, the protein cocktail, when used in conjunction with minimum doses of gentamicin, inhibited bacterial growth significantly.
Conclusions: Using the scavenger plasma protein cocktail may reduce ROS injury, wound expansion, and bacterial growth in both in vitro and in vivo burn injury models. This approach could be potentially used in infected bacterial burn injury animal models and sets the stage for future application in burn injury patients for wound management and promotion of healing.
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Objective: Endometrial cancer (EC), a prevalent malignancy in women's reproductive system, commonly occurs in uterine tissue. Due to its persistently high incidence despite considerable medical advancements, there is a need for the identification of novel diagnostic and treatment biomarkers. This study aims to investigate the potential of IQ motif-containing GTPase-activating protein 3 (IQGAP3) as a biomarker for early diagnosis of endometrial cancer and explore its significance in cervical cancer.
Methods: This study utilized CaSki and Hela cell lines and employed siRNA/shRNA and scrambled control antisense for transfection experiments. However, the expression level of the gene was assessed using qPCR (Quantitative Polymerase Chain Reaction). Additionally, the involvement of IQGAP3 in the cell cycle pathway was elucidated through pathway analysis.
Results: Tumor Immune Estimation Resource (TIMER) 2.0 data analysis showed that IQGAP3 exhibited significant overexpression in cancer groups (*p < 0.05), with elevated levels in EC samples compared to normal tissues (***p < 0.001). Furthermore, IQGAP3 showed significantly close association with survival prognosis (p < 0.05). Additionally, we observed that the knockdown of IQGAP3 inhibited cell proliferation in endometrial cancer cells.
Conclusion: This study provides valuable insights into the role of IQGAP3 in cancer diagnosis and treatment. The findings suggest that IQGAP3 holds potential as a promising biomarker for endometrial cancer diagnosis and as a therapeutic target for its treatment.
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Objective: Sevoflurane is an inhalation anesthetic that exhibits a crucial role in cell growth, invasion, and apoptosis across various tumor types. Nevertheless, the underlying molecular mechanism remains largely unknown. Therefore, this study aimed to investigate sevoflurane's effects on colorectal cancer (CRC) progression and its underlying mechanisms.
Materials and Methods: The SW480 and LOVO cells were divided into two groups: a control group (cells without treatment) and a sevoflurane group (cells treated with 4% sevoflurane for 6 hours). Cell viability, proliferation, and clone formation ability were determined through 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), 5-Ethynyl-2′-deoxyuridine (EdU), and clone formation assays, respectively. Moreover, metastasis in these cells was determined using transwell and wound healing assays. Furthermore, flow cytometry was utilized to assess cell apoptosis rate. Additionally, Western blot assay was employed to determine the p38/mitogen-activated protein kinases (MAPK) pathway.
Results: Sevoflurane hindered CRC cell proliferation, clone formation, and metastasis while promoting apoptosis. Mechanically, sevoflurane restrained the p38/MAPK pathway in CRC cells. However, p38/MAPK agonist dehydrocorydaline (DHC) restored the inhibitory effect of sevoflurane on the cell function.
Conclusion: These results uncover an antitumor activity of sevoflurane on the invasion and migration of CRC through the p38/MAPK pathway, offering a novel mechanism for studying surgery-mediated CRC treatment.
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Background: Dental fluorosis is a condition resulting from excessive fluoride intake during tooth development, leading to abnormalities in enamel formation. This study aimed to investigate the impacts of transmembrane protein 16A (TMEM16A) on ameloblast proliferation, apoptosis, and the expression levels of associated genes in a dental fluorosis cell model under high-calcium conditions.
Methods: Ameloblasts were isolated from two C57BL/6 male mice and treated with NaF (3.2 mmol/L) for 24 hours to establish the dental fluorosis cell model. Subsequently, ameloblasts were cultured in Dulbecco's modified eagle medium (DMEM) with varying calcium concentrations such as 2.0, 3.0, or 4.0 mmol/L, along with 10% fetal bovine serum, for 48 h, representing low, medium, and high calcium treatment groups, respectively. Control and NaF model groups were also included. Immunohistochemistry was used to identify the specific marker ameloblastin (AMBN) for ameloblasts. Cell proliferation was assessed using 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, apoptosis was examined using TUNEL assay, and intracellular Ca2+ concentration was measured using fluorescent probes. Moreover, the impacts on the expression of apoptosis-related genes (Bcl2 associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), nuclear factor kappaB (NF-κB), nuclear factor kappa-Bp65 (NF-κBp65)), bone morphogenetic protein-2 (BMP-2), and TMEM16A were evaluated using quantitative real time polymerase chain reaction (qRT-PCR) and Western blot analysis. Additionally, the effects of the TMEM16A inhibitor T16Ainh-A01 on cell apoptosis and gene expression were investigated.
Results: Compared to the NaF model group, calcium treatment significantly increased AMBN in ameloblasts, promoted cell proliferation (p < 0.01), reduced intracellular Ca2+ concentration (p < 0.01), and inhibited cell apoptosis. Moreover, calcium treatment substantially elevated the expression levels of B-cell lymphoma-2 (Bcl-2) and BMP-2 (p < 0.05), while suppressing the expression levels of Bcl2 associated X protein (Bax), nuclear factor kappa-Bp65 (NF-κBp65), and TMEM16A, with the highest efficacy observed in the high-calcium group (p < 0.05). Co-treatment with the TMEM16A inhibitor T16Ainh-A01 and high-dose calcium further enhanced cell proliferation (p < 0.01), reduced Ca2+ concentration (p < 0.05), and inhibited cell apoptosis. Additionally, T16Ainh-A01 significantly increased the expression levels of Bcl-2 and BMP-2, while suppressing Bax and NF-κBp65 expression (p < 0.05).
Conclusion: Elevated levels of calcium and inhibition of TMEM16A expression can inhibit the apoptosis of ameloblasts caused by fluorosis by regulating the NF-κBp65 signaling pathway and apoptosis-related genes, potentially alleviating fluorosis-induced tooth damage. These findings offer a novel strategy for the prognosis and treatment of dental fluorosis.
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Background: A high-calorie diet (HCD) is a significant pathogenic factor contributing to obesity and can induce dysbiosis in the intestinal flora. Fecal microbiota transplantation (FMT) has been recognized for potentially restoring intestinal microecology. However, precise mechanisms underlying its therapeutic effects remain largely elusive. This study aimed to investigate the impact of FMT on the gut microbiota-short-chain fatty acids (SCFAs)-G protein-coupled receptor 43 (GPR43)-interleukin-18 (IL-18) pathway in HCD-induced rats. The findings provide insights and evidence for preventing and treating pediatric diseases caused by HCD.
Methods: Forty specific pathogen-free (SPF)-grade Sprague-Dawley (SD) rats were randomly allocated into six groups: normal control 1 (NC1), normal control 2 (NC2), normal control 3 (NC3), high-calorie diets model (M), fecal microbe transplantation treatment (FMTT), and Medilac-Vita (MV) groups. Antibiotic intervention simulated the state of antibiotic-treated rats, and a specialized diet was used to replicate the HCD model. Based on group assignments, rats received a normal diet bacterial solution, normal saline enema, or MV. Clinical characteristics and colonic morphology were observed, while changes in gut microbiota, SCFAs, GPR43, and IL-18 were assessed using 16SrDNA, gas chromatography-mass spectrometry (GC-MS), hematoxylin-eosin (HE), immunohistochemistry (IHC), and enzyme-linked immunosorbent assay (ELISA), respectively.
Results: FMT effectively restored the gut microbiota of antibiotic-induced rats. In the HCD-induced rats, FMTT significantly alleviated the pathological state and increased alpha indices and beta distances (p < 0.05). Furthermore, significant alterations in the relative abundances of gut bacterial genera associated with SCFAs production were observed. FMTT increased SCFA content in feces, especially acetic acid (p < 0.05). Notably, downstream pathways related to SCFAs, such as GPR43-IL-18, were modulated by FMT in HCD-induced rats (p < 0.05). Recognizing the crucial role of gut microbiota in SCFAs metabolism, a co-occurrence network among the Lactobacillaceae and SCFAs-GPR43-IL-18 was constructed.
Conclusion: The Lactobacillaceae-acetic acid-GPR43-IL-18 pathway emerges as a potential biological basis for the pathological state of HCD-induced rats. FMT exhibits corrective properties by influencing this pathway.
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Background: Iodine plays a key role in various functions of the central nervous system, and both iodine deficiency and excess are harmful to health. This study aimed to explore the potential metabolites and pathways involved in the effects of excess maternal iodine or iodine deficiency on offspring.
Methods: All female rats were randomly grouped into severe iodine deficiency (SID), mild iodine deficiency (MID), normal iodine (NI), mild iodine excess (MIE), and severe iodine excess (SIE), and the corresponding model was constructed based on the water iodine intervention. After successful conception, the same feeding conditions were maintained for the pregnant rats. On the 21st day of pregnancy, serum samples of the offspring were collected for liquid chromatography-tandem mass spectrometry and bioinformatics analyses.
Results: With the increase in the iodine intervention dose, the median urinary iodine of rats, as well as their free thyroxine levels and positive rate of thyroglobulin antibody, were also elevated (p < 0.05), suggesting that the model was successfully constructed. By analyzing the serum metabolites of offspring, 173, 186, 66, and 92 differential metabolites, such as L-glutamic acid and deoxycytidine, were found to be significantly altered in the severe iodine deficiency SID vs. the normal iodine, the mild iodine deficiency vs. the normal iodine, the mild iodine excess vs. the normal iodine, and the severe iodine excess vs. the normal iodine groups, respectively. Pathway enrichment analysis revealed that ATP-binding cassette (ABC) transporters were the most commonly enriched metabolic pathways.
Conclusion: These findings suggest that maternal iodine deficiency or excess may affect the development of offspring by regulating metabolites such as L-glutamic acid and deoxycytidine via the ABC transporter pathway.
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Background: The accumulating evidence suggests that immunogenic cell death (ICD) proves to be an effective therapeutic strategy for various tumors. This study aims to establish a model for the predictive evaluation of melanoma and investigate the potential clinical applications of ICD.
Methods: The mRNA profile data of melanoma samples, sourced from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, were employed to examine the expression patterns of genes associated with ICD in melanoma. Practical enhancement methods were applied to investigate the biological function of differentially expressed ICD-related genes. Multiple immune estimation approaches were employed to assess the infiltration of the immune landscape of samples in various clusters, aiming to explore the interaction between ICD and the immune system. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate the expression levels of key genes.
Results: Through unsupervised clustering analysis, melanoma patients were categorized into two distinct clusters based on the expression patterns of ICD-related genes. The overall survival rate was significantly higher in the group with elevated expression. The proportion of macrophages in the high-expression group was considerably greater. Additionally, ICD played a positive role in triggering anti-tumor immunity. Lastly, eight important candidate genes were identified to construct the prognostic model for melanoma patients. The qRT-PCR confirmed the increased level of BAX in melanoma cells, while decreased levels of ATG5, CASP8, CD8A, CXCR3, EIF2AK3, IFNG, and PIK3CA were observed.
Conclusions: This research illustrates the potential role of ICDs in the prognosis and treatment of melanoma. The development of a prognostic model based on this information could offer a reliable prognostic prediction for melanoma patients, aiding in the individualization of patient treatment.
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Background: The typical symptoms of asthma, including airway hyperresponsiveness (AHR) and airway remodeling, induce mechanical stress. Despite its crucial role in tissue development and pathophysiology, the role of mechanical stress in the development of asthma and its impact on the induction of AHR remain unclear. In this study, we aimed to investigate the potential contribution of mechanical stress to asthma by using a mouse model.
Methods: Healthy mice were challenged with methacholine (METH) and compared with an allergic airway inflammation model induced by ovalbumin (OVA). Different approaches, including immunofluorescence, immunohistochemical staining, Western blot analysis, and histopathology were employed to detect pathological changes in the lung tissue of the experimental mice. Transcriptome analysis was conducted to identify the genetic changes in AHR-related genes within the lung tissue of mice following METH treatment.
Results: METH treatment did not promote allergic phenotypes, but induced asthma-like changes in gene expression profiles. Affected genes were enriched in the immune response and inflammation-related genes, including genes involved in granulocyte migration and inflammatory reactions. Importantly, mechanical force perception ability was significantly enhanced in the OVA-induced allergic airway inflammation mouse lung, evidenced by increased expression of mechanoreceptor proteins.
Conclusions: Short-term bronchial constriction without inflammation may not lead to tissue remodeling. However, genes involved in asthma development remain active.
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Background: Diabetic nephropathy (DN), a severe complication of diabetes, is one of the primary causes of chronic kidney disease (CKD) in China. Epigallocatechin gallate (EGCG), a natural compound found in tea leaves, exhibits both preventive and therapeutic properties against several diseases, including cancer, obesity, diabetes, and cardiovascular diseases. Therefore, this study aimed to investigate the protective effects of EGCG on renal tissue apoptosis induced by endoplasmic reticulum stress in rats with type 2 diabetes mellitus (T2DM).
Methods: The kidney tissues of Wistar rats were collected and analyzed following treatment with Streptozotocin (STZ) and EGCG. Moreover, fasting blood glucose (FBG), fasting insulin (FINS), urea nitrogen (UREA), and creatinine (CREA) were assessed using corresponding enzyme-linked immunosorbent assay (ELISA) kits. Similarly, the apoptosis index (AI) was examined utilizing terminal deoxynucleotidyl transferase-mediated dUTP Nick end labeling (TUNEL). Furthermore, the expression levels of C/EBP homologous protein (CHOP) and phosphorylated c-Jun N-terminal kinase (p-JNK) were determined in each group of rats by immunohistochemistry and Western blot analysis. Additionally, the mRNA transcription levels of CHOP and JNK were assessed using real-time fluorescent quantitative polymerase chain reaction (RT-qPCR).
Results: Compared to the normal control group (NOR), the levels of FBG, FINS, UREA, CREA, and apoptosis index (AI) were elevated (p < 0.0001) in the diabetic model control group (MOR). Furthermore, the mean optical density values of CHOP and p-JNK, the mRNA and protein expression levels of CHOP, the protein expression levels of p-JNK, and the mRNA expression levels of JNK were significantly increased in the experimental group (p < 0.0001). Additionally, compared to the MOR group, the levels of FBG, FINS, UREA, CREA, and AI were significantly alleviated in both the EGCG low-dose group (EGCG1) and EGCG high-dose group (EGCG2) (p < 0.0001). Similarly, the average optical density values of CHOP and p-JNK, the mRNA and protein expression levels of CHOP, the protein expression level of p-JNK, and the mRNA expression level of JNK were significantly decreased (p < 0.01).
Conclusions: These findings indicate that EGCG reduces renal injury and cell apoptosis in diabetic rats by inhibiting the expression of endoplasmic reticulum stress-related proteins, such as CHOP and JNK.
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Background: Capsaicin is known for its therapeutic benefits, including anti-inflammatory, antioxidant, and cholesterol-lowering effects. However, its clinical application is limited by poor bioavailability, primarily due to its low solubility in water.
Objective: To evaluate the efficacy of our newly optimized capsaicin-loaded chitosan nanocapsules (CAP@CS) in mitigating cardiotoxicity induced by type 2 diabetes mellitus (T2DM) and a high-fat diet in male Sprague Dawley rats.
Methods: Nanocapsules containing capsaicin and chitosan were synthesized using the micro-emulsion technique and characterized using dynamic light scattering (DLS) and transmission electron microscopy (TEM), were administered to sixty male rats, which assigned to five groups: control, diabetic, diabetic with rosuvastatin, diabetic with capsaicin (CAP), and diabetic with CAP@CS. The inflammatory markers and biochemical indicators associated with myocardial damage, tissue oxidative stress, and inflammation were assessed.
Results: DLS analysis revealed an average size of ~260 nm and a zeta potential of ~+18 mV. TEM images depicted circular and uniform nanocapsules. The diabetic + CAP@CS group showed more significant reductions in blood glucose and lipid levels compared to other diabetic groups, and markedly increased the concentrations of the antioxidant enzymes superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), reduced glutathione, and upregulated nuclear factor erythroid 2-related factor 2 (NRF-2), and heme oxygenase-1 (HO-1) expressions more significantly than the diabetic + CAP group. CAP@CS upregulated nitric oxide concentrations and its bioregulator, inducible nitric oxide synthase (iNOS), demonstrating enhanced cardioprotection. The formula exhibited a more pronounced anti-inflammatory impact, as demonstrated by the tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) assessment. Histological investigations employing hematoxylin and eosin stain, Masson trichrome (MTC), and immunohistochemical analysis of α-smooth actin and desmin revealed the notable superiority of the new formula (CAP@CS) over capsaicin (CAP) in mitigating the myocardial damage mediated by diabetes. This efficacy was substantiated by assessments of myocardial protein content, malondialdehyde (MDA), heat shock protein 70 (HSP70) determination, alanine transaminase (ALT), aspartate transaminase (AST), and troponin levels.
Conclusion: CAP@CS nanocapsules present a promising therapeutic strategy, improving for cardioprotection in T2DM, offering potential benefits such as improved efficacy, bioavailability, and reduced side effects.
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Background: There is an urgent need for reliable biomarkers for early detection and effective therapeutic targeting of hepatocellular carcinoma (HCC). This investigation aimed to elucidate neurexophilin 4 (NXPH4) expression in HCC and explore its impact on the biological functions of HCC cells.
Methods: This research employed publicly available transcriptomic data from The Cancer Genome Atlas (TCGA) database to evaluate the expression profiles of the NXPH family members in HCC. We collected 70 HCC tissue samples and assessed NXPH4 expression levels using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot analysis, and immunohistochemistry. Furthermore, HCC cell lines with overexpressed and knocked down NXPH4 were established. Methyl thiazolyl tetrazolium (MTT) assay and colony formation analysis were conducted to assess the proliferation and colony formation capabilities of the HCC cells. Additionally, scratch assays and transwell experiments were employed to elucidate the migration and invasion capabilities of these cells.
Results: NXPH4 showed significant differential expression in HCC compared to adjacent non-cancerous tissues (p < 0.001), which was associated with overall patient survival (p < 0.001). Moreover, the knockdown of NXPH4 (shNXPH4-1 and shNXPH4-2) significantly suppressed the proliferation and clonogenicity of HepG2 HCC cells (p < 0.01). Conversely, transfection with an overexpression vector (Ov-NXPH4) substantially elevated the proliferation and clonogenicity of Hub-7 cells (p < 0.01). Furthermore, knockdown of NXPH4 (shNXPH4-1 and shNXPH4-2) significantly suppressed the migration and invasion of HepG2 cells (p < 0.01), while its overexpression vector (Ov-NXPH4) significantly promoted these capabilities (p < 0.01).
Conclusion: Elevated expression of NXPH4 in HCC regulates crucial biological processes, such as proliferation, migration, and invasion, suggesting its potential role as a biomarker for the progression of hepatocellular carcinoma.
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Background: Cervical cancer (CC) is the fourth most prevalent cancer among women worldwide, imposing a significant burden. While radiotherapy is a cornerstone in CC treatment, radioresistance remains a challenge, necessitating the exploration of mechanisms and novel targets for overcoming this challenge. Opsin 3 (OPN3) has been implicated in cancer treatment resistance, and the glucose-6-phosphate dehydrogenase (G6PD)-mediated glucose metabolism, along with oxidative stress, has been associated with radioresistance. This study aimed to explore the impact of OPN3 knockdown on the radioresistance of CC cells and the involvement of G6PD and oxidative stress in the underlying mechanisms.
Methods: The HeLa cell line, a representative of CC, was utilized in this study. OPN3 knockdown was established through cell transfection. The subsequent effects on HeLa cell viability and apoptosis under ionizing radiation (IR) were assessed using cell counting kit-8 (CCK-8) assay, colony forming assay, terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay, and western blot analysis to detect apoptosis-related proteins. Additionally, proteins associated with oxidative stress, DNA damage, and G6PD protein levels and activity were measured using enzyme-linked immunosorbent assay (ELISA) and western blot. Acquired radioresistant HeLa cells (RR-HeLa) were generated using IR. OPN3 knockdown was performed in RR-HeLa cells, and subsequent effects were assessed as described for HeLa cells. Reactive oxygen species (ROS) scavenger and G6PD inhibitor were employed to investigate the role of OPN3 in regulating oxidative stress and G6PD during radioresistance. Furthermore, in the G6PD degradation, autophagy inhibitor and proteasome pathway inhibitor were used to confirm the regulatory role of OPN3 on G6PD through autophagy.
Results: OPN3 was upregulated in RR-HeLa cells (p < 0.001). OPN3 knockdown decreased the proliferation (p < 0.001), DNA damage (p < 0.001), and oxidative stress (p < 0.001) while reducing cell apoptosis (p < 0.001), glucose metabolism (p < 0.001), G6PD protein levels (p < 0.001), and activity (p < 0.001) in HeLa and RR-HeLa cells following IR treatment. OPN3 overexpression in HeLa cells increased proliferation post-IR treatment. The post-IR cell proliferation reduction induced by OPN3 knockdown was reversed by ROS inhibitor and G6PD overexpression (p < 0.001), while further decreased by G6PD inhibitor (p < 0.001). The OPN3 knockdown-induced decrease in G6PD was unchanged by the proteasome pathway inhibitor (p > 0.05) but was reversed by the autophagy inhibitor (p < 0.001), thereby reversing the post-IR cell proliferation (p < 0.001).
Conclusion: OPN3 knockdown renders HeLa cells more radiosensitive and mitigates radioresistance by promoting the autophagic degradation of G6PD and exacerbating oxidative stress within the cells.
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Background: Psoriasis is a prevalent immune-mediated chronic inflammatory skin disorder, and the persistent challenge associated with its high recurrence rates remains. This study aimed to investigate the involvement of lysine-specific histone demethylase 1A (KDM1A) in psoriasis pathogenesis.
Methods: An imiquimod-induced psoriasis-like dermatitis mouse model was generated and KDM1A knockdown was conducted using lentivirus. Skin appearance was scored and pathological changes were observed. Oxidative stress, lipid peroxidation, inflammatory response, iron accumulation, and ferroptosis-related proteins in the skin were assessed. Afterward, human HaCaT keratinocytes were treated with proinflammatory cytokines to mimic psoriatic conditions and ferroptosis-related proteins were determined. The ferroptosis inducer erastin was used to treat HaCaT keratinocytes, and its influences on oxidative stress and inflammation were assessed.
Results: Imiquimod increased the levels of KDM1A, and KDM1A knockdown ameliorated skin psoriatic lesions in mice and reduced inflammatory infiltration. Oxidative stress, lipid peroxidation, iron accumulation, and iron transport-related proteins in skin were also reduced. In HaCaT keratinocytes, KDM1A knockdown similarly mitigated lipid peroxidation and reduced iron transport-related proteins. Importantly, erastin disrupted the inhibition of oxidative stress and inflammation in keratinocytes induced by KDM1A knockdown.
Conclusion: This study highlights the significance of KDM1A in psoriasis pathogenesis and suggests that its regulation of ferroptosis may play a critical role in disease development.
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Background: Androgen has been regarded as the strongest stimulator of sebum formation and sebocyte proliferation in individuals with acne. However, the underlying mechanisms remain to be elucidated. Recent studies suggest that autophagy is involved in lipid degradation and the regulation of cell proliferation. This study aims to explore the effects of testosterone on autophagy and its potential contribution to lipid accumulation and sebocyte proliferation.
Methods: Human SZ95 sebocytes were cultured with linoleic acid (LA) to induce sebum production. This study examined the role of testosterone in acne development by measuring autophagy, lipid accumulation, and cell proliferation. To determine whether testosterone's effects on acne depend on autophagy, the autophagy inducer rapamycin and the inhibitor 3-methyladenine (3-MA) were used in combination with LA.
Results: The results indicated that treatment with testosterone decreased the levels of LC-3II (p < 0.01) and Beclin 1 (p < 0.01) while increasing p62 level (p < 0.05) in SZ95 cells. Additionally, testosterone treatment induced lipid accumulation, as demonstrated by Oil Red O staining (p < 0.01), and increased Triglyceride (TG) content (p < 0.01) in SZ95 cells. Moreover, testosterone treatment increased cell viability in SZ95 cells according to the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay (p < 0.01) and increased the count of Ki67 positive cells in immunofluorescent staining (p < 0.01). Co-treatment with rapamycin reversed the effects of testosterone on autophagy (p < 0.05 or p < 0.01), lipid accumulation (p < 0.01), and sebocyte proliferation (p < 0.01). In contrast, treatment with 3-MA mimicked all the aforementioned effects of testosterone (p < 0.05 or p < 0.01). Furthermore, immunoblot analysis revealed that treatment with testosterone enhanced the phosphorylation of v-akt murine thymoma viral oncogene homolog (AKT) (p < 0.01) and the mammalian target of rapamycin (mTOR) (p < 0.05), which were counteracted by rapamycin (p < 0.05 or p < 0.01) but mimicked by 3-MA (p < 0.05).
Conclusions: These findings suggest that testosterone may facilitate acne progression by activating mTOR and subsequently inhibiting autophagy.
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Background: Ischemic stroke is the leading cause of permanent disability, affecting approximately 14 million people annually. Therefore, this study aimed to elucidate the role and underlying mechanism of p53/cysteinyl aspartate specific proteinase 1 (CASP1) in ischemic stroke.
Methods: The raw data regarding ischemic stroke were acquired from the GSE97537 data set of Gene Expression Omnibus (GEO). Moreover, a mouse model of cerebral ischemia was established. Neurons and microglia cells were used for in vitro experiments. Quantitative polymerase chain reaction (qPCR) and western blot analysis were used to assess the expression levels of target genes.
Results: We observed that ubiquitinconjugating enzyme E2H (UBE2H) expression was downregulated following ischemic stroke. The expression of UBE2H was found to promote pyroptosis of microglia cells. Furthermore, a negative correlation was observed between CASP1 and UBE2H. The inhibition of CASP1 significantly reduced pyroptosis, while the inhibition of UBE2H increased CASP1 activity in microglia. Additionally, we observed a close association between elevated CASP1 expression and poorer survival in ischemic stroke.
Conclusions: In summary, this study indicates that UBE2H inhibits microglial apoptosis following ischemic stroke by mediating the ubiquitination of p53/CASP1.
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Background: Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance, culminating in right ventricular failure and heightened mortality. Utilizing bioinformatics can aid in unraveling the underlying mechanisms of various diseases. Our study aimed to elucidate the novel pathogenic role of periostin (POSTN) in PAH through bioinformatics method.
Methods: Gene expression microarray datasets and single-cell RNA sequencing (scRNA-seq) data were retrieved from the Gene Expression Omnibus. Differential expression analysis and identification of key hub genes were performed to identify crucial pathogenic genes in PAH. Functional enrichment and Gene Set Enrichment Analysis were employed to elucidate the pertinent biological functions of these key genes. A comprehensive array of bioinformatics techniques, including locus analysis, transcription factor regulation analysis, and cell interaction analysis, were further utilized to conduct an in-depth analysis of the scRNA-seq dataset. The analyses aimed to explore the association between POSTN, smooth muscle cells, and macrophages, unveiling the clinical correlation and potential pathogenic mechanisms of POSTN and PAH. Additionally, this association was validated in animal models.
Results: POSTN expression was significantly elevated in PAH (p < 0.0001), and was closely associated with fibroblast infiltration (p < 0.0001). In the scRNA-seq dataset, POSTN expression was observed in fibroblasts and smooth muscle cells (SMCs), with POSTN as the most differentially expressed gene between the SMCs of PAH and donors. POSTN-positive (POSTN+) SMCs were notably enriched in the microenvironment of PAH. Activation of hypoxia-inducible factor 1-alpha in POSTN+ SMCs potentially facilitated PAH progression. Furthermore, cell-cell interactions between POSTN+ SMCs and regulator of G protein signaling-2 (RGS2+) macrophages may participate in forming an inflammatory microenvironment.
Conclusions: Our study corroborated the correlation between POSTN and PAH through bioinformatics methods. It unveils that POSTN+ SMCs and RGS2+ macrophages form a mutually supportive and functionally significant interaction network, possibly playing a pivotal role in remodeling the extracellular matrix and promoting an inflammatory environment in PAH. These findings offer novel insights into PAH pathogenesis.
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Background: Azathioprine (AZA) is a purine-derived drug used for immunosuppression. The molecular mechanisms by which AZA protects cardiomyocytes remain unclear. This experiment will further elaborate, on the basis of the previous study, the mechanism of AZA's protection against hypoxia-induced cardiomyocyte injury in high glucose conditions.
Methods: We utilized a high glucose (HG) and hypoxia/reoxygenation (H/R) cell model and a diabetic Sprague-Dawley (SD) rat ischaemia/reperfusion (I/R) model to detect cellular calcium ions, mitochondrial membrane potential, and reactive oxygen species (ROS) levels using Fluo-4 AM, MitoTracker Red, and ROS Assay Kit. Malondialdehyde (MDA), superoxide dismutase (SOD) and pro-inflammatory cytokines (interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α) levels were measured using the appropriate kits. Cellular energy metabolism was analyzed by oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). The expression of Voltage-dependent anion channel 1 (VDAC1), Nucleotide-binding oligomerization domain-like receptor protein 3 (NALP3), Nuclear factor-kappa B p65 (NF-κB p65), ATP synthase subunit alpha (ATP5A1), ATP synthase subunit beta (ATP5B), B-cell lymphoma 2 (Bcl-2), Caspase-3 and Bcl-2 associated X protein (Bax) was detected.
Results: It was shown in the HG+H/R cell model that AZA up-regulated the levels of calcium ions (p < 0.05) and mitochondrial membrane potential (p < 0.05). AZA reduced ROS accumulation (p < 0.01) and oxidative stress marker MDA levels (p < 0.01), improved cellular energy metabolism, and increased expression of the antioxidant defense enzyme SOD (p < 0.05). AZA treatment inhibited VDAC1, NALP3, and NF-κB activation, upregulated ATP synthase (ATP5A1, ATP5B), and Bcl-2 expression, as well as inhibited apoptosis by downregulating Bax and Caspase3 expression in HG+H/R cells and I/R rat cardiomyocytes (p < 0.001). We constructed a VDAC1 siRNA cell model, and knockdown of VDAC1 significantly promoted the expression of ATP synthases (ATP5A1, ATP5B) under HG+H/R conditions (p < 0.001).
Conclusion: Our data reveal the molecular mechanisms by which AZA protects cardiomyocytes from injury induced by HG+H/R and I/R in diabetic rats. We demonstrate that AZA ameliorates mitochondrial dysfunction, oxidative stress, inflammation, and apoptosis by modulating VDAC1 and ATP synthase expression. Our findings suggest that AZA may be a potential therapeutic agent for mitigating myocardial ischemic injury in diabetes.
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Background: DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) can promote the development of oral squamous cell carcinoma (OSCC), while glutathione peroxidase 3 (GPX3) can inhibit it. In this study, we aimed to investigate the underlying mechanism by which DNMT3B and GPX3 influence OSCC.
Methods: Bioinformatics was used to analyze the expression patterns of DNMT3B and GPX3 in head and neck squamous cell carcinoma (HNSC), as well as the methylation sites in the promoter region of GPX3. Additionally, various cellular assays were conducted to assess the proliferation, migration, invasion, and apoptosis of OSCC cells including colony formation, Transwell®, and flow cytometry analyses. The levels of DNMT3B, GPX3, and factors related to the Jun N-terminal kinase (JNK)/c-JUN axis were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. The methylation of the GPX3 promoter and the interaction between DNMT3B and the GPX3 promoter were evaluated through quantitative methylation-specific PCR and chromatin immunoprecipitation-PCR assays.
Results: The analysis revealed elevated expression of DNMT3B and reduced expression of GPX3 in HNSC. Additionally, methylation sites were identified in the promoter region of the GPX3 gene. Further investigation demonstrated that silencing DNMT3B suppressed the proliferation, migration, and invasion of OSCC cells while promoting apoptosis. This was accompanied by an increase in GPX3 level and dephosphorylation of the JNK and c-JUN signaling pathways. DNMT3B was found to directly bind to the promoter of the GPX3 gene. Overexpression of GPX3 inhibited the proliferation, migration, and invasion of OSCC cells and promoted apoptosis. It also suppressed the JNK/c-JUN pathway. Conversely, silencing GPX3 had the opposite effects and counteracted the effects of DNMT3B silencing.
Conclusions: After inhibiting DNMT3B, the expression of GPX3 is upregulated, which may suppress the progression of OSCC.
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Background: In recent years, agents with anti-cancer, immunomodulatory and immunostimulatory potential have gained great importance. In this study, the cytotoxic and anti-prolifative activity of a new 10-[4-(4-chlorobutoxy)butyl]-10H-phenothiazine (OZF2) phenothiazine derivative against a colon cancer cell line as well as its antiinflammatory effects on lipopolysaccharide (LPS)-activated macrophage cell line (RAW 264.7) were examined.
Methodology: An N-substituted phenothiazine derivative named 10-[4-(4-chlorobutoxy)butyl]-10H-phenothiazine (OZF2) was synthesized and its molecular structure was confirmed by 1H Nuclear Magnetic Resonance (NMR) and 13C NMR. The molecule contains electronegative oxygen and chlorine atoms in the long alkyl chain attached to the nitrogen atom in the phenothiazine ring. The anti-cancer activity of the OZF2 phenothiazine derivative was evaluated with the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) test on the colon cancer cell line. The anti-inflammatory activity of OZF2 was tested by measuring the levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) released from macrophage cells in the presence and absence of LPS and/or OFZ2 using enzyme-linked immunosorbent assay (ELISA). Quantitative real time polymerase chain reaction (q-RT-PCR) analysis was performed to evaluate expression levels of these cytokines also in presence and absence of LPS and/or OFZ2.
Results: OFZ2 had anti-proliferative activity on the colon cancer cell line and anti-inflammatory activity on the mammalian macrophages at subtoxic concentrations. It did not stimulate IL-6 and TNF-α cytokines in the absence of LPS in ELISA. But when stimulated with LPS, a significant decrease in the production level of the IL-6 cytokines was observed, while the TNF-α production was not affected. No change in the gene expression of TNF-α was observed, whereas IL-6 gene expression significantly decreased in the presence of OZF2.
Conclusions: The anti-proliferative activity of OZF2 against colon cancer cells makes of it a potential drug candidate for colon cancer research and treatment. It also has the potential to be an anti-inflammatory drug agent that can suppress the production of IL-6-based autoimmune and inflammatory diseases.
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Background: Ezrin exhibits aberrant expression across diverse cancer types and significantly contributes to cancer initiation and advancement. However, the precise mechanism by which Ezrin regulates M1/M2 macrophage polarization in prostate cancer (PCa) remains unclear. This study aimed to elucidate the role and mechanism of Ezrin in regulating M1/M2 macrophage polarization in PCa.
Methods: Initially, Ezrin levels were evaluated in transfected cells using real-time quantitative PCR (RT-qPCR), followed by Western blotting (WB) to evaluate Ezrin expression levels in PCa PC-3 cells overexpressing Ezrin and treated with the Mitogen-Activated Protein Kinase (MAPK) and nuclear factor kappa B (NF-κB) pathway inhibitors PD0325901 and BAY11-7082. Colony formation and Transwell assays were used to assess cell proliferation, migration, and invasion abilities. Additionally, its effects on levels of epithelial-mesenchymal transition (EMT)-associated markers (E-cadherin, ZO-1, Vimentin, Snail Slug, β-Catenin) and pathway-associated proteins were examined. Subsequently, transfected PC-3 cells were co-cultured with macrophages, and the expression of Cluster of Differentiation 206 (CD206) and CD86 in macrophages was assessed using flow cytometry and RT-qPCR. The expressions of M1/M2 markers (tumor necrosis factor (TNF)-α, interleukin (IL)-6, inducible nitric oxide synthase (iNOS), IL-10, Arg1) in macrophages were also detected by RT-qPCR. Finally, the impact of PD0325901 and BAY11-7082 on macrophage polarization after Ezrin overexpression was investigated.
Results: Ezrin expression decreased in the si-Ezrin group and increased in the oe-Ezrin group compared to the control group (p < 0.05). Overexpression of Ezrin heightened Ezrin expression, increased proliferative, migratory, and invasive potential of PC-3 cells, enhanced EMT transition ability, and upregulated pathway-related proteins compared to the control group (p < 0.05). However, expression of Ezrin decreased in the oe-Ezrin+PD0325901 group and oe-Ezrin+BAY11-7082 group compared to Ezrin overexpression alone, inhibiting the growth and migration capabilities of PC-3 cells, reducing the expression of EMT markers, and suppressing the activation of the MAPK/NF-κB pathway (p < 0.05). Compared to the control group, cells in the si-Ezrin group exhibited an increase in CD86, TNF-α, IL-6, and iNOS, meanwhile, those in the oe-Ezrin group displayed a rise in CD206, IL-10, and Arg1 (p < 0.05). Moreover, the addition of pathway inhibitors PD0325901 and BAY11-7082 resulted in reduced CD206, IL-10, and Arg1 expression, while enhancing CD86, TNF-α, IL-6, and iNOS expression compared to the oe-Ezrin group (p < 0.05).
Conclusion: Ezrin facilitates the proliferation and metastasis of PCa cells by activating the MAPK/NF-κB pathway. Additionally, Ezrin induces M2 polarization of macrophages, exacerbating the progression of PCa.
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Background: Atherosclerosis is a chronic inflammatory disease that leads to ischemic cerebrovascular and cardiovascular diseases. Curcumin, known for its anti-inflammatory properties, may influence the development of atherosclerosis. This study aims to elucidate the effects of curcumin and its mechanisms on atherosclerosis progression.
Methods: The proliferative ability, the angiogenesis capacity, and cell migration rate were assessed using cell counting kit-8 (CCK-8), 5-ethynyl-29-deoxyuridine (EdU), tube formation assays, and wound healing, respectively. Furthermore, the protein expression levels of proliferating cell nuclear antigen (PCNA), glycogen synthase kinase 3β (GSK3β), p-GSK3β, β-catenin, and c-myc were determined utilizing western blot analysis.
Results: Oxidized low-density lipoprotein (ox-LDL) significantly triggered cell damage by inhibiting cell proliferation, reducing the migration rate, and angiogenesis capacity in human umbilical vein endothelial cells (HUVECs) (p < 0.05). Curcumin treatment significantly alleviated ox-LDL-induced HUVECs injury (p < 0.05), as evidenced by elevating the proliferative ability (p < 0.05), cell migration (p < 0.05), and angiogenesis (p < 0.05). Moreover, the Wnt/β-catenin pathway was substantially boosted following ox-LDL treatment (p < 0.05), which was suppressed by curcumin (p < 0.05). Additionally, SKL2001 significantly increased the levels of β-catenin and c-myc (p < 0.05). The inhibitory effects of curcumin treatment on the Wnt/β-catenin signaling pathway were reduced by SKL2001 (p < 0.05). Furthermore, the promoting effects of curcumin on ox-LDL-induced cell damage were hampered following SKL2001 treatment in HUVECs (p < 0.05).
Conclusion: Curcumin elevated cell proliferation, migration, and angiogenesis of HUVECs to inhibit the development of atherosclerosis through inactivating the Wnt/β-catenin pathway.
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Background: Regulatory T cells (Treg) effectively impact allergic rhinitis (AR), the underpinning mechanism of which still warrants investigation. The predominant mite allergen, Dermatophagoides pteronyssinus 1 (Der p1), is the primary inducing factor for AR. Therefore, our study aims to explore whether Der p1 can induce AR by regulating Treg.
Methods: The AR mouse model was established by exposure to Dermatophagoides pteronyssinus 1 (Der p1). The behaviors and pathological alterations in the nasal mucosa tissues of mice were assessed, and biochemical indexes of mouse serum were examined. Determination concerning the functions of nasal mucosal epithelial barrier as well as the expressions of epithelial-mesenchymal transition (EMT)/inflammation-related factors was achieved using Western blot, fluorescein isothiocyanate-dextran (FD4) assay, and enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to determine the proportion of Treg in peripheral blood mononuclear cells (PBMCs). Furthermore, the conditioned medium of PBMCs treated with Der p1 (CM-Der p1) or nuclear factor-kappaB (NF-κB) inhibitors (CM-Der p1-NI) was used to culture nasal mucosal epithelial cells (NMECs), and then the vitality, barrier function, and EMT in NMECs were tested.
Results: Der p1 increased the frequency of rubbing and sneezing in mice, allergy-related biochemical indexes in serum, and interleukin (IL)-4, IL-6, and IL-10 levels in PBMCs (p < 0.001). Moreover, Der p1 increased the proportion of eosinophil infiltration in the nasal mucosa, impaired epithelial barrier function, EMT, NF-κB activation, and Treg differentiation (p < 0.01). However, these effects of Der p1 were reversed by NF-κB inhibitors (p < 0.05). Interestingly, NMECs cultured in CM-Der p1-NI showed higher viability, less IL-10 secretion, repaired barrier function, and inhibited EMT compared to the NMECs cultured in CM-Der p1 (p < 0.05).
Conclusions: Der p1 may stimulate IL-10 secretion through NF-κB pathway-mediated Treg differentiation, thereby inducing EMT in NMECs to impair epithelial barrier function.
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Background: Endothelial progenitor cells (EPCs) migrate to ischemic or injured sites to participate in angiogenesis, whereas periosteum-derived stem cells (PDSCs) can differentiate in multiple directions. This study aimed to investigate the roles and mechanisms of EPCs in promoting the osteogenic differentiation of PDSCs.
Methods: Alizarin red and alkaline phosphatase staining was conducted after 3, 7, and 14 days of co-culture to evaluate the osteogenic differentiation of PDSCs. Subsequently, exosomes were isolated from EPCs. Following 7 and 14 days of treatment with PDSCs, scanning electron microscope and alizarin red staining were performed. EPCs with methyltransferase-like 3 (METTL3) knockdown and PDSCs overexpressing serum and glucocorticoid-induced kinase 1 (SGK1) were constructed to further explore the underlying mechanism.
Results: As the co-culture time increased, the alkaline phosphatase and calcification levels gradually increased in the co-cultured group. EPC-derived exosomes also elevated alkaline phosphatase and calcification levels of PDSCs, and significantly upregulated osteopontin (OPN), osteoprotegerin (OPG), and runt-related transcription factor 2 (RUNX2) expression (p < 0.05). Both immunofluorescent staining and western blot revealed that treatment with the EPC-derived exosomes significantly enhanced the expression levels of METTL3 and SGK1 were significantly enhanced in PDSCs compared with those in control cells (p < 0.05). Exosomes were successfully isolated from EPCs with METTL3 knockdown; these exosomes significantly downregulated the expression levels of OPN, OPG, and RUNX2 (p < 0.05). SGK1 expression was significantly upregulated by EPC-derived exosomes in PDSCs overexpressing METTL3 (p < 0.05) and markedly downregulated in PDSCs treated with EPC-derived exosomes with METTL3 knockdown (p < 0.05).
Conclusions: EPC-derived exosomes carrying METTL3 may promote the osteogenic differentiation of PDSCs by regulating SGK1.
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Background: Acute severe craniocerebral injury (ASBI) is a leading cause of morbidity and mortality following trauma. Emodin has demonstrated a range of pharmacological effects, including anti-inflammatory and antioxidant properties. This study sought to investigate the effect of emodin on ASBI in rats and to elucidate its potential mechanisms.
Methods: Thirty sprague-dawley (SD) rats were randomly assigned into five subgroups: the sham subgroup, the model subgroup, the low-dose emodin subgroup, the middle-dose subgroup, and the high-dose subgroup. Initially, we recorded the grip traction time and neurobehavioral scoring in each subgroup. Moreover, pathological injury in brain tissue was observed using hematoxylin-eosin (H&E) staining. Immunohistochemical staining was utilized to evaluate the levels of positive glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba1). Furthermore, the levels of cytokines were assessed using biochemical assays. The levels of reactive oxygen species (ROS) in the brain tissue were determined using a 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. Additionally, the mRNA levels of inducible nitric oxide synthase (iNOS) and p38 mitogen-activated protein kinase (p38 MAPK) were evaluated employing quantitative real-time polymerase chain reaction (qRT-PCR). Heat shock proteins 70 (HSP70), B cell lymphoma-2 (Bcl-2), Bcl-2 associated X-protein (Bax), NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3), caspase-1, iNOS, phosphorylated-p38 MAPK (p-p38 MAPK), p38 MAPK levels in the brain tissue were examined utilizing Western blot analysis.
Results: Emodin treatment significantly improved the neurobehavioral and pathological damage of brain tissue in ASBI rats. HSP70, Bcl-2, glutathione (GSH), and superoxide dismutase (SOD) levels were substantially elevated in the brain tissue of the emodin subgroup. Conversely, emodin treatment reduced the levels of Bax, NLRP3, caspase-1, malondialdehyde (MDA), nitric oxide (NO), and ROS. Furthermore, serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interferon-γ (IFN-γ), and IL-6 were significantly reduced in the emodin subgroup compared to the model subgroup (p < 0.05). Additionally, iNOS mRNA and protein levels were reduced in the brain tissue of the emodin subgroup compared to the model subgroup (p < 0.05). Similarly, the p-p38 MAPK protein concentrations were also alleviated in the brain tissue of the emodin subgroup compared to the model subgroup (p < 0.05).
Conclusion: Emodin enhances motor function recovery, mitigates apoptosis and neuroinflammation, and reduces oxidative stress in ASBI rats, potentially through the p38 MAPK signaling pathway.
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Background: Aortic Dissection (AD) is the most common aortic emergency, and its exact etiology is still not fully understood. With advancements in molecular biology, a more profound understanding of the causes of AD will result in more significant breakthroughs in prevention and treatment. This work aimed to explore the role of genome-wide Deoxyribonucleic acid (DNA) methylation in exploring the pathogenesis and outcome mechanism of AD from the perspective of molecular biology.
Methods: Aortic tissue was collected from 8 AD patients and 8 non-AD volunteers to analyze DNA methylation characteristics in AD patients through the whole genome DNA methylation method. Based on bioinformatics, epigenetic characteristics during AD were studied. Finally, the accuracy of the chip results was verified by pyrosequencing.
Results: A total of 1563 sites were counted. Compared with the normal group, there were 942 methylation upregulated sites and 621 downregulated sites in the AD group. Differential methylation sites detected by the chip were distributed in Transmission Start Site (TSS) 1500, 5′ Untranslated Region (UTR), Genebody, 3′UTR, Cytosine, Phosphoric acid, and Guanine (CpG) island, and off-island CpG sites, mainly located in Genebody. After Gene Ontology (GO) enhancement analysis and pathway analysis of biological pathways, it was found that some methylated genes were closely related to cell differentiation, growth, maturation, aging, and death, affecting AD development.
Conclusion: Whole genome DNA methylation plays a positive role in exploring the pathogenesis and outcome mechanism of AD from molecular biology. This helps explore new diagnostic markers and intervention targets for AD and improve the clinical diagnosis and treatment of AD in the future.
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Background: Postoperative nausea and vomiting (PONV) is a common side effect after thyroidectomy, which can affect the recovery of patients who underwent thyroid surgery. It has been reported that cerebral oxygen metabolism may affect the occurrence of postoperative adverse reactions. Therefore, this study aimed to investigate the relationship between cerebral oxygen metabolism and PONV incidence in patients after thyroidectomy.
Methods: This study retrospectively analyzed the clinical data of 100 female patients who underwent thyroid surgery in a tertiary hospital between May 2022 and September 2023. The study participants were categorized into two groups: the Mannitol group (n = 50), patients who received an intravenous infusion of 0.5 g/kg mannitol at a rate of 150 drops/minute before the operation, and the Control group (n = 50), patients who intravenously received the equivalent volume of normal saline. All participants received the same anesthesia induction and maintenance treatment. During the surgery, we recorded their heart rate (HR), mean arterial pressure (MAP), urine volume, cerebral oxygen metabolism index (cerebral oxygen extraction ratio (CERO2) and difference in arteriovenous oxygen (Da-jvO2)) at each time point, including T0, 5 minutes after entering into the operating room; T1, 5 minutes after tracheal intubation; T2, immediately after cervical hyperextension; T3, immediately after the operation; T4, 50 minutes after the operation; T5, immediately at the operation stopped. Moreover, the incidence of PONV was assessed within 48 hours post-surgery.
Results: There were no statistical differences in HR and MAP between the two groups at each time point (p > 0.05). Compared to the Control group, urine output in the Mannitol group showed no significant changes at T0, T1, T2, and T3 (p > 0.05) but significantly increased at T4 and T5 time points (p < 0.05). Da-jvO2 and CERO2 in T1, T2, T3, T4 and T5 time points were significantly reduced compared to T0 (p < 0.05). Compared to T2 and T3, Da-jvO2 and CERO2 at T4 and T5 were significantly reduced in the Mannitol group (p < 0.05), but they showed no substantial changes in the Control group (p > 0.05). Furthermore, Da-jvO2 and CERO2 were significantly decreased at T4 and T5 time points in the Mannitol group compared to the Control group (p < 0.05). Additionally, PONV incidence was significantly lower (26.0%) in the Mannitol group compared to the Control group (50.0%) within 48 hours post-surgery (p < 0.05). The severity of PONV in the Control group was substantially higher than in the Mannitol group.
Conclusion: The preoperative intravenous infusion of mannitol can affect cerebral oxygen metabolism, thereby reducing the incidence and severity of PONV in patients who underwent thyroid surgery.
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Background: Deubiquitinases (DUBs) are essential components of the ubiquitin-proteasome system (UPS) that regulates cancer-related processes. Effective inhibitors of 19S proteasome-associated DUBs, including ubiquitin carboxy-terminal hydrolase L5 (UCHL5), ubiquitin-specific protease 14 (USP14), and gold-(triphenylphosphine (PPh3))-platinum (AuPT), suppress cell growth in several human tumor cell lines. The aim of this study was to determine the effect of AuPT and its mechanism of action on prostate cancer (PCa) progression.
Methods: The malignant PCa phenotype and apoptotic cell death were evaluated in vitro. The antitumor activity of AuPT was verified using nude xenografts. Furthermore, the protein levels in the UPS and the phosphorylation of p65 were determined by overexpression plasmid transfection using Western blotting.
Results: The viability, invasion, and migration abilities of PCa cells decreased and the cell apoptosis rate increased with AuPT treatment in a time-dependent manner (p < 0.05, p < 0.01). The tumor weight and volume were effectively suppressed in nude mice (p < 0.01). DUB protein expression levels and p65 phosphorylation were downregulated and restored after overexpression of USP14 or UCHL5 (p < 0.05, p < 0.01, p < 0.001).
Conclusions: We found that AuPT induced PCa cell apoptosis and inhibited the activation of nuclear factor-κB (NF-κB) signaling by disturbing UPS functioning. AuPT treatment may enable specific targeted therapy against NF-κB-activated PCa.
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Background: Color Doppler ultrasound, mammography and serum tumor marker examination are commonly used tests for diagnosing breast cancer, while the value of individual test is limited. This study explored the clinical significance of these tests in combination, including color Doppler ultrasound, mammography, serum tumor markers, Carbohydrate antigen 153 (CA153), Carcinoembryonic antigen (CEA), and Carbohydrate antigen 125 (CA125) for the diagnosis of breast cancer.
Methods: A retrospective analysis of 80 patients diagnosed with breast cancer and 50 patients with benign breast lesions was performed. These study participants underwent color Doppler ultrasound and mammography, and their serum levels of tumor markers CA153, CEA, and CA125 were assessed using electrochemiluminescence immunoassay.
Results: Color Doppler ultrasound revealed irregular morphology, unclear boundaries, burr sign, posterior echo attenuation, tiny calcifications, aspect ratio ≥1, and proportions of blood flow grades II to III in the breast cancer group. The maximum blood flow velocity (Vmax), Resistance index (RI), and Pulse index (PI) of blood flow were significantly higher in the breast cancer group compared to those in the benign control group (p < 0.01). Mammography revealed that irregular morphology, unclear boundaries, lobulation signs, and spiculated changes in the tumor, and the proportions of tiny calcifications, granular calcifications, or cast-shaped calcifications were significantly greater in the breast cancer group compared to the benign control group (p < 0.01). Furthermore, serum CA153, CEA, and CA125 levels were significantly elevated in the breast cancer group compared to the benign control group (p < 0.01). Moreover, the levels of high clinical stage, poor differentiation, distant metastasis, and the levels of Estrogen Receptor (ER)/Progesterone Receptor (PR) negative and human epidermal growth factor receptor 2 (HER2) positive group were significantly greater compared to the benign control group (p < 0.01). Additionally, the sensitivity, accuracy and each individual examination of color Doppler ultrasound and mammography in combination with serum CA153, CEA, and CA125 in diagnosing breast cancer were significantly improved (p < 0.01), which were 95.00% and 92.31%, respectively.
Conclusion: The combination of ultrasound, mammography, and serum tumor markers CA153, CEA, and CA125 shows promise as a diagnostic approach for breast cancer. While individual tests have limited clinical significance, their combined use can substantially improve diagnostic sensitivity and accuracy, thereby reducing the likelihood of misdiagnosis.
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Background: Intracerebral hemorrhage (ICH) stands as a crucial cerebrovascular pathology, wherein subsequent neuroinflammatory reactions augment neuronal detriment. Microglia, the principal immune effectors within the central nervous system, significantly influence the inflammatory cascade following ICH. Interleukin (IL)-10 is an anti-inflammatory cytokine that functions via the IL-10 receptor (IL-10R). It has been demonstrated to facilitate M2 polarization of microglial cells, thereby aiding in the resolution of inflammation and the repair of neural tissue. However, the specific mechanism of IL-10R in regulating microglial polarization remains unclear. Therefore, this study aimed to elucidate the role of IL-10R in facilitating microglia differentiation into the M2 phenotype, specifically focusing on its modulation of the toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) signaling pathway.
Methods: We established a mouse model of intracerebral hemorrhage (ICH) to investigate the impact of neural stem cell (NSC) transplantation. IL-10R knockdown was achieved through cell transfection. The expression levels of inducible nitric oxide synthase (iNOS) and the mannose receptor (CD206) were evaluated using Western blot analysis to assess microglial polarization. Furthermore, we quantified inflammation levels by assessing the expressions of IL-10R, IL-1β, and tumor necrosis factor-alpha (TNF-α) using enzyme-linked immunosorbent assay (ELISA). Assessment of motor function was conducted using the modified neurological severity score (mNSS) and the rotarod performance test. Neuronal injury and mortality were determined by measuring brain water content, conducting Nissl staining, and performing the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Additionally, Western blot analysis was employed to evaluate the activity of the toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB) pathway, with its activation being suppressed by the specific inhibitor Resatorvid (TAK-242).
Results: We found that NSC transplantation significantly decreased microglial M1 polarization, inflammatory response, brain water content, neuronal cell damage, and apoptosis while increasing microglial M2 polarization and mice motor function following ICH. Inhibition of IL-10R reversed the effect of NSC transplantation, indicating its crucial role in NSCs-mediated neuroprotection. Furthermore, the activity of the TLR4/NF-κB inflammatory pathway was enhanced after ICH, which was suppressed by NSCs. Following NSC treatment, the IL-10R inhibition activated the TLR4/NF-κB pathway, which was reversed by TLR4/NF-κB pathway inhibitor TAK-242. Additionally, IL-10R inhibition counteracted the effect of NSC transplantation, which was disrupted when the TLR4/NF-κB pathway was inhibited.
Conclusion: This study suggests that IL-10R plays a crucial role in NSC transplantation for treating ICH. Inhibiting the TLR4/NF-κB pathway facilitates M2 polarization of microglial cells, leading to a decrease in neuroinflammatory response. This finding provides a new molecular target for treating ICH and other neuroinflammatory diseases. It emphasizes the potential therapeutic value of NSC transplantation in conjunction with the modulation of IL-10R signaling.
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Background: Mammary gland carcinoma is a solid tumor with a hypoxic core due to oxygen deficiency. Factor inhibiting hypoxia-inducible factor-1α (FIH-1) is an oxygen sensor that becomes inactive in a hypoxic environment, making it unable to regulate rapidly proliferating cancer cells. Thus, we hypothesize that the chemical activation of FIH-1 could be a novel mechanism for regulating mammary gland carcinoma. In this study, 6-(5,11-dioxoisoindolo [2,1-a] quinazolin-6(5H,6aH,11H)-yl)-N-(1H-imidazol-2-yl) hexanamide (BBAP-9) was investigated for its anticancer potential.
Methods: A library of 67,609 drug-like molecules was virtually screened against FIH-1 based on Lipinski's rule from the ZINC database. BBAP-9 was selected as a potent FIH-1 activator through docking study, absorption, distribution, metabolism, excretion and toxicity (ADMET) profile, and in vitro 2-oxoglutarate dependent FIH-1 activation assay. Further, its in vitro cytotoxicity and apoptotic activity were scrutinized against MCF-7 cells using acridine orange/ethidium bromide (AO/EB) and 5,5,6,6′-tetrachloro- 1,1′,3,3′-tetraethylbenzimi-dazoylcarbocyanine iodide (JC-1) stainings and its in vivo activity against 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary gland carcinoma in Wistar rats by performing various parameters such as hemodynamic, carmine-alum staining, histology, scanning electron microscopy, and biochemical analysis.
Results: Our results demonstrated that BBAP-9 showed a good docking score (–8.162) and a suitable ADMET profile. BBAP-9 activated FIH-1 when scrutinized through a 2-oxoglutarate dependent assay (p < 0.05). BBAP-9 exhibited significant cytotoxicity with half-maximal inhibitory concentration (IC50) of 16.9 ± 0.85 μM (p < 0.05) and induced apoptotic changes in MCF-7 cells, as revealed by AO/EB (p < 0.05) and JC-1 stainings (p < 0.05). Once scrutinized against DMBA-induced mammary gland carcinoma, BBAP-9 restored autonomic dysfunction (p < 0.05), tissue vascularization, morphological architecture, membrane ruffles, and oxidative stress markers [thiobarbituric acid reactive substances (TBARs), protein carbonyl (PC), glutathione (GSH), super oxide dismutase (SOD), and catalase)] toward normal control (p < 0.05).
Conclusions: Overall, the current study's findings demonstrate that BBAP-9 has significant cytotoxicity and apoptotic activity against MCF-7 cells. Moreover, BBAP-9 has chemotherapeutic efficacy on DMBA-induced mammary gland carcinoma, which can be attributed to its propensity to enhance antioxidant profiles and inhibit cellular proliferation, improve surface architecture, soothing membrane ruffles, and decrease lactate effects. Thus, we postulated that BBAP-9 may be a novel FIH-1 activator in mammary gland carcinoma.
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Background: Malignant tumor cells can directly affect the biological behavior of the cells through the interaction with the surrounding microenvironment. This study aimed to investigate the effects of adipose-derived stem cell microenvironment (ADSCM) on the growth of colon cancer (CC) and the expression of malignant surface markers and abnormal pathways in the cells.
Method: Adipose-derived stem cells (ADSCs) were extracted using collagenase digestion, followed by culture and identification. A three-dimensional stem cell microenvironment was established and co-cultured with CC cell lines. Furthermore, clonogenic assays were conducted to assess cell proliferation. Annexin V staining was employed to detect cell apoptosis and an invasion assay was performed to study cell migration capabilities. Moreover, immunohistochemistry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were employed to assess the expression levels of surface markers in CC cells, and WB analysis was used to determine the levels of signaling pathway proteins. A CC model was established by subcutaneous injection of ADSCs and CC cells into Balb/c mice. Additionally, western blot (WB) was performed to investigate changes in inflammatory factors within tumor tissues.
Result: After introducing CC cell lines into the ADSCM, a significant decrease in cell proliferation and invasion capability was observed, accompanied by a substantial increase in apoptosis rate. Furthermore, CC cells grown within the microenvironment exhibited reduced malignant phenotypic features, and the expression levels of common cancer signaling pathways were also diminished. Additionally, there was a decrease in the content of inflammatory factors within CC tissues.
Conclusion: ADSCM can inhibit the growth of colon cancer, reduce the malignant markers and abnormal pathways in cancer cells and hinder the progression of CC.
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Background: The resveratrol (RES) exhibits inhibitory effects against lung cancer through various targets. However, the exact underlying mechanism remains unclear. This study aims to investigate the effect of RES on the growth and metastasis of lung cancer and its impact on polarization of tumor-associated neutrophils (TANs) and epithelial-mesenchymal transition (EMT).
Method: The A549 lung cancer cell line was treated with varying concentrations (0, 5, 10, 20, 40, and 60 μM) of RES. The impact of RES on cellular proliferation was assessed using Cell Counting Kit-8 (CCK-8) assay, and the optimal dosage was selected for subsequent analysis. Furthermore, the effects of RES treatment on the apoptosis, invasion, and migration of the cells, along with its impact on the EMT process, were examined. Neutrophils were isolated from the blood of the health individuals and were co-cultured with A549 cells to investigate the TANs polarization. Additionally, we established a nude mouse model of the subcutaneous tumor. The lung cancer growth, tumor tissue pathology, and tumor cell metastasis were evaluated.
Results: We observed that RES effectively suppressed A549 cell growth in a concentration-dependent manner within the dosage range of 10–40 μM (p < 0.001). Furthermore, RES promoted A549 cell apoptosis while limiting invasion and migration (p < 0.001). Moreover, RES was observed to regulate the EMT pathway in A549 cells, thereby limiting its progression (p < 0.01). Notably, RES restricted lung cancer by inducing TANs to polarize toward type N1 while impeding type N2 polarization (p < 0.001). In the nude mouse model, RES demonstrated the above-mentioned effects and considerably reduced lung cancer growth, improved tumor tissue pathology, and limited tumor growth (p < 0.01), as well as reduced the expression of Matrix Metalloproteinase-2 (MMP2) and MMP9 (p < 0.05).
Conclusion: Overall, RES effectively reduces lung cancer growth and tumor cell metastasis by boosting N1 polarization of TAN, suppressing N2 polarization, and reducing EMT.
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Background: Cerebral ischemia-reperfusion injury (CIRI) is a common neurological disorder involving pathways such as cell apoptosis and inflammation. N-acetylcysteine (NAC), an antioxidant and anti-inflammatory agent, is widely studied for various diseases. However, its specific mechanism in CIRI remains unclear. Therefore, this study aims to explore the mechanism of action of NAC in CIRI.
Methods: In this study, we utilized a Middle Cerebral Artery Occlusion (MCAO) mouse model to investigate the effects of N-acetylcysteine (NAC) on cerebral ischemia-reperfusion injury (CIRI). The experimental mice were divided into two groups: the Model group and the NAC treatment group. The NAC was administered after the induction of MCAO. The therapeutic outcomes were assessed through behavioral tests and neuropathological examinations. Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) was used to measure the levels of inflammatory factors, specifically tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Western blot analysis was employed to assess the expression of apolipoprotein E (APOE) following CIRI. The infarct volume post-CIRI was determined using pathological sections and image analysis. Additionally, the impact of NAC on the c-Jun N-terminal Kinase/Cysteine-aspartic Acid Protease-3 (JNK/Caspase-3) signaling pathway in neuronal cells was examined through immunofluorescence and western blot analysis.
Results: NAC treatment improved motor and cognitive functions (p < 0.05), reduced neuronal damage, and increased survival rates (p < 0.05). NAC treatment also led to a decrease in inflammatory factors, including TNF-α, IL-1β, and IL-6 after MCAO (p < 0.01). Furthermore, NAC significantly decreased the expression of APOE (p < 0.01), which contributed to neuroprotection. The administration of NAC also reduced the infarct volume induced by MCAO (p < 0.01) and inhibited cell apoptosis (p < 0.05). Hematoxylin and eosin (HE) staining demonstrated that NAC treatment resulted in reduced structural damage in the hippocampal CA1 region. Immunofluorescence and western blot analyses showed that NAC suppressed the expression of JNK, p-c-Jun, Caspase-3, and Caspase-9 in the oxygen-glucose deprivation (OGD) neuronal cell model (p < 0.01).
Conclusions: The findings of this study suggest that NAC alleviates CIRI by inhibiting the JNK and Caspase-3 signaling pathways. This reveals the potential mechanism of NAC in the treatment of CIRI and provides a theoretical basis for its clinical application.
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Background: Breast-cancer susceptibility gene 1 (BRCA1) associated RING domain 1 (BARD1) expression is upregulated in colorectal cancer (CRC), and its mutation forms are also related to clinical prognosis of the cancer. The primary focus of this study is to delineate the mechanism of BARD1 underlying the development and progression of CRC.
Methods: BARD1 expression pattern in CRC was uncovered by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) with the aid of bioinformatics means. Following transfection of small interfering RNA targeting BARD1 (siBARD1) and short hairpin RNA against slit guidance ligand 3 (SLIT3; shSLIT3), CRC cell viability, proliferation, apoptosis, migration, and invasion were measured by cell counting kit-8 assay, colony formation assay, flow cytometry, wound healing assay, and Transwell assay. To verify how BARD1 impacts SLIT3 degradation, CRC cells were treated with cycloheximide (CHX) for different periods of time (0, 2, 4, 6, 8 h). After administration of siBARD1-transfected CRC cells or blank treatment into Balb/c nude mice, the tumor volume and weight of the animals were determined, followed by quantification of cyclin D3 (immunohistochemistry) and corresponding genes/proteins (qRT-PCR and western blotting).
Results: BARD1 expression was upregulated in CRC cells (p < 0.001). SiBARD1 reduced cell viability, proliferation, migration and invasion; increased apoptosis; upregulated E-cadherin level; and downregulated N-cadherin, Snail, and cyclin D3 levels in CRC cells (p < 0.05). In contrast, shSLIT3 presented an opposite effect on these indexes in CRC cells (p < 0.05). SiBARD1 suppressed the degradation of SLIT3, hampered tumor growth, reduced cyclin D3 expression, and promoted SLIT3 expression in vivo (p < 0.001). Additionally, shSLIT3 was found to reverse the effects of siBARD1, and vice versa (p < 0.05).
Conclusion: BARD1 deletion stifled the progression of CRC in vitro and in vivo by upregulating SLIT3 expression and inhibiting cyclin D3 expression, corroborating BARD1 as a potential biomarker in CRC carcinogenesis.
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Background: Non-small cell lung cancer (NSCLC) is the most commonly occurring type of lung cancer. Previous studies have shown reduced expression of long noncoding RNA (lncRNA) RAMP2 antisense RNA1 (RAMP2-AS1) in NSCLC; however, the mechanism of RAMP2-AS1 in NSCLC is not clear.
Methods: Cell Counting Kit-8 was used to assess cell viability. Cell apoptosis was detected using flow cytometry. Western blot assay was used to examine protein levels. N6-methyladenosine (m6A)-RNA immunoprecipitation and Fluorescence in situ hybridization assays were used to detect the m6A modification and cellular location of RAMP2-AS1, respectively. Glycolysis level was examined by commercial kits.
Results: RAMP2-AS1 and large tumor suppressor 2 (LATS2) were downregulated in NSCLC tissues. Knockdown of fat mass and obesity-associated protein (FTO) elevated the m6A modification RAMP2-AS1. Overexpression of RAMP2-AS1 inhibited proliferation, glycolysis (indicated by high levels of glycolysis-related proteins, glucose consumption, lactate production, adenosine triphosphate content, and extracellular acidification rate) and induced cell apoptosis through Hippo signaling. RAMP2-AS1 transcriptionally activated LATS2 by binding with Krüppel-like factor 9 (KLF9). Downregulation of LATS2 reversed the suppressive impact of RAMP2-AS1 on cell glycolysis.
Conclusion: FTO-mediated m6A demethylation of RAMP2-AS1 increased glycolysis by reducing the impact of KLF9 on LATS2 transcriptional activity. This study provides insights for developing novel therapeutic strategies for NSCLC.
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Background: The postoperative healing of rotator cuff tear (RCT) often presents challenges. Poly (lactic-co-glycolic acid)/tricalcium phosphate (PLGA/TCP) scaffold is a composite biomaterial for repairing bone defect. This study aimed to investigate the impact of tendon stem cells (TDSCs)/PLGA/TCP composite scaffold on a rabbit model of RCT.
Methods: After induction using osteogenic, adipogenic and chondrogenic medium, TDSCs differentiation was achieved. The multi-directional differentiation of TDSCs was confirmed through colony formation and staining with alizarin red, oil red, and toluidine blue. Quantitative real-time polymerase chain reaction was utilized to assess the expressions of stemness, osteogenesis, and tendon-related genes. TDSCs were cultured in PLGA/TCP scaffold, and their attachment, markers, and viability were evaluated using immunofluorescence and cell counting kit-8 assay. The rabbit RCT model was made. The morphology and tensile strength of tendon-bone healing were assessed by hematoxylin-eosin, masson, dil staining and tendon stretch assay. Quantification of β-catenin protein was realized by western blot.
Results: The obtained TDSCs were identified as having the ability of multi-directional differentiation and stemness. CD73, CD90, and CD105 were positive and CD45 was negative in TDSCs. The multi-directional differentiation ability of TDSCs was improved on PLGA/TCP scaffold. The TDSC/PLGA/TCP composite scaffold promoted tendon-bone healing, fibrocartilage mineralization and formation, the expressions of osteogenic and tendon-related genes. Furthermore, it significantly promoted β-catenin expression, the invasive number of TDSCs, the ultimate load and stiffness of healing tendon.
Conclusions: The loading of TDSCs further optimized the role of PLGA/TCP scaffold in promoting rotator cuff tendon-bone surface healing, which was closely related to the expression of β-catenin protein.
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Background: Hepatic ischemia-reperfusion (I/R) injury, an inexorable event after liver surgery, is associated with circulating platelet activation and aggregation. Phosphodiesterase 5 inhibitor (PDE5i) is a promising option for treating organ I/R injury. Therefore, this study investigated the underlying mechanism of PDE5i in hepatic I/R injury.
Methods: Rats received tadalafil pre-treatment (a PDE5i; 5 mg/kg/day) and underwent hepatic I/R modeling. The impact of tadalafil against liver injury was assessed by measuring the nitric oxide (NO) content as well as the levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), followed by histological analysis and TdT-mediated dUTP nick end labeling (TUNEL) assay. The liver sinusoid endothelial cells (LSECs) isolated from normal rats were pre-treated with tadalafil (100 nM) and co-cultured with platelets obtained from hepatic I/R rats. Additionally, cell viability, lactate dehydrogenase (LDH) activity, and degree of pyroptosis were evaluated using Western blot analysis in in vitro experimental settings.
Results: Tadalafil protected rats against hepatic I/R by reducing serum levels of AST and ALT and attenuating liver tissue damage, cell apoptosis, and NO content (p < 0.01). Tadalafil inhibited the secretion of NO by platelets in hepatic I/R-induced rats (p < 0.001). Furthermore, it enhanced cellular viability and decreased LDH activity and pyroptosis of LSECs in platelets derived from hepatic I/R rats (p < 0.01). Additionally, tadalafil suppressed LSEC pyroptosis in hepatic I/R rat-derived platelets by down-regulating the expression levels of nucleotide-binding oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), C-caspase 1, N-terminal fragment of gasdermin D (GSDMD-N), interleukin (IL)-1β, and IL-18. Furthermore, tadalafil treatment decreased phosphorylation levels of vasodilator-stimulated phosphoprotein (VASP) and nuclear factor kappa-B (NF-κB) inhibitor alpha (IKB-α) (p < 0.001).
Conclusion: Tadalafil attenuates LSEC dysfunction in rat hepatic I/R injury by reducing the levels of platelet-secreted NO and suppressing LSEC pyroptosis. These observations indicate the dual role of tadalafil in modulating platelet function and directly protecting LSECs, offering novel insights into the underlying mechanistic pathway.
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Background: Gamboge, a desiccating resin secreted by the gamboge tree, has shown potential anti-tumor effects. However, its impact and the underlying mechanisms against lung cancer are not well understood. This study explores the molecular mechanisms through which epigambogic acid A, a principal component of gamboge, inhibits the proliferation of non-small cell lung cancer (NSCLC) cells.
Methods: Normal lung epithelial cells BEAS-2B and human NSCLC cells were exposed to various concentrations of epigambogic acid A for 48 and 72 hours (h). Cell viability was assessed using a Cell Counting Kit-8 (CCK-8) assay, while colony formation ability was determined through a colony formation assay. Transwell invasion and migration assays were used to evaluate the cells' migratory and invasive capacities. Apoptotic processes were analyzed through flow cytometry, and expressions of associated biomarkers were investigated using Western blot. The Illumina HiSeq XTEN platform facilitated sequencing, while quantitative Real-time Polymerase chain reaction (qRT-PCR) quantified the expression of collagen type III alpha 1 chain (COL3A1) and disrupted in renal cancer 1 (DIRC1).
Results: Epigambogic acid A significantly inhibited NSCLC cell growth, with a 99.94% inhibition rate. It also reduced cell colony formation and suppressed the migratory and invasive abilities of NSCLC cells, and promoted apoptosis (p < 0.05). Transcriptome sequencing and analysis revealed that epigambogic acid A significantly decreased oncogene levels, including DIRC1 and COL3A1. Furthermore, DIRC1 was found to enhance colony formation and proliferation of NSCLC cells (p < 0.05).
Conclusions: This study demonstrates that epigambogic acid A effectively suppresses tumor growth in NSCLC by downregulating DIRC1 expression. These findings suggest that epigambogic acid A is a potential therapeutic target for NSCLC treatment.
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Background: 7,8-dihydroxyflavone (DHF) is a potent agonist of tropomyosin-related kinase B (TrkB), which binds to TrkB and causes TrkB phosphorylation, reducing cell apoptosis improves the stability of the nervous system. It has been shown to play a therapeutic role in various animal disease models, such as ischemic stroke, traumatic brain injury, and Alzheimer's disease. To investigate the protective effect of 7,8-dihydroxyflavone (7,8-DHF) on neuronal cells, we explore the improvement effect of 7,8-DHF on intracerebral hemorrhage (ICH) by activating the TrkB signaling pathway, and study the related mechanism.
Methods: Venous blood samples were collected from patients with ICH before and after treatment and normal people in a fasted state, and mRNA expression levels of brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), phosphatidylinositol 3 kinases (PI3K), protein kinase B (AKT), mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (Erk), and other genes were determined by real-time quantitative PCR (RT-qPCR). An animal model of C57BL/6J mice with ICH was established by injecting collagenase and heparin into the cerebral striatum, with normal C57BL/6J mice as controls. Both groups were injected intraperitoneally or intravenously with DHF or normal saline once a day for two weeks before euthanasia. The neuronal and glial cells of the cerebral cortex striatum were collected from the mice, from which the apoptosis of neuronal and glial cells was detected by ELISA, and mRNA expression of BDNF, TrkB, PI3K, AKT, MAPK, and Erk genes were detected by qPCR.
Results: The RNA expression (BDNF, TrkB, PI3K, AKT, MAPK, and Erk) in the ICH treat group was significantly higher than in the ICH group, without significant difference in RNA (BDNF, TrkB, PI3K, AKT, MAPK, Erk) between ICH treat group and Normal group. Compared with the ICH group, the apoptosis of neuronal and glial cells of ICH mice significantly decreased. At the same time, the expression levels of BDNF, TrkB, PI3K, AKT, MAPK, and Erk were significantly increased. DHF promotes the expression of cellular neurotrophic factor-related genes and proteins in ICH mice and neuronal cell models.
Conclusion: 7,8-DHF can inhibit the apoptosis of neuronal and glial cells, promote their proliferation, increase mRNA expression levels of neurotrophin and its receptors, and activate neurotrophic factor receptors. 7,8-DHF has the potential to protect neuronal cells and possibly improve ICH.
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Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by the significant involvement of both environmental and immunological factors. The pathophysiology of ASD has been linked to dysregulation of the antioxidant network and production of oxidants in immune cells. Previous studies have demonstrated disequilibrium in different enzymatic antioxidants in the plasma, red blood cells, and leukocytes of individuals with ASD; however, there has been no investigation thus far into the evaluation of these antioxidants in peripheral platelets in both individuals with ASD and typically developing control (TDC) children.
Methods: Given this context, we investigated the levels and functions of key enzymatic antioxidants in peripheral platelets of TDC (n = 23)/ASD (n = 26) individuals, including superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and thioredoxin reductase (TRxR) through flow cytometric and enzymatic activity analyses. Further, levels of oxidative stress were evaluated by analysis of inducible nitric oxide synthase (iNOS) and nitrotyrosine formation in the platelets of both groups.
Results: Our findings reveal a marked reduction in SOD1 (p < 0.0001) and TRxR1 (p < 0.01) expression in the platelets of ASD individuals, as evidenced by diminished SOD1+ and TRxR1+ immunostaining in CD42+ cells. SOD (p < 0.01) and TRxR (p < 0.01) activity were also significantly lower in ASD participants compared to the TDC group. In contrast, when comparing individuals with ASD to TDC group, GPx/GR activity/expression in platelets is either decreased or unaffected. A notable increase in iNOS (p < 0.0001) coupled with reduced SOD/TRxR activity in ASD platelets correlated with a significant rise in nitrotyrosine expression (p < 0.001), indicative of oxidant damage.
Conclusions: Our findings demonstrate, for the first time, that ASD individuals have a disrupted enzymatic antioxidant system and heightened oxidative stress in their peripheral platelets. This imbalance in enzymatic antioxidants may significantly impact the development of ASD and its associated comorbidities.
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Background: Ovarian cancer is frequently associated with chemoresistance, which is the major cause of treatment failure. In this study, we utilized relative expression ordering (REO) of gene pairs to develop a novel model to predict chemotherapy response and prognosis in ovarian cancer. Moreover, we attempted to explore the mechanisms underlying ovarian cancer chemoresistance.
Methods: Datasets were downloaded from publicly available databases, and differentially expressed gene pairs were filtered using Wilcoxon signed-rank test, Cox proportional hazards regression and Fisher's test to develop the model. Subsequently, the efficacy was validated by Kaplan–Meier analysis in training and validation sets. Comprehensive investigations were performed to investigate pathway variation, immune infiltration, and single-cell analysis. Next, gene expression was measured in chemoresistant ovarian cancer cells and their parent cells, and risk scores were calculated. Finally, a series of experiments were conducted to evaluate the regulatory impacts on chemosensitivity of lysyl oxidase-like 4 (LOXL4), one of the upregulated genes in chemoresistant cells.
Results: The developed model, comprising 19 genes for predicting chemoresistance and prognosis, demonstrated robust performance in training and five validation sets. Chemoresistant samples identified by this model exhibited enrichment of genes in four pathways and downregulation of genes in one pathway. Besides, chemoresistant samples displayed a lower abundance of various immune cell types, indicating immune suppression within the tumor microenvironment. Single-cell analysis indicated heterogeneity within samples, revealing cell populations that may survive after chemotherapy. Chemoresistant ovarian cells exhibited higher risk scores compared to their parent cells, and LOXL4 was found to modulate cisplatin sensitivity in ovarian cancer cells.
Conclusions: This study presents a novel prognostic model and provides possible therapeutic targets for further research in ovarian cancer.
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Objective: Coronary heart disease (CHD), emerging as a common chronic disease, is threatening the lives of middle-aged and older people in China, with a gradual increase in morbidity and mortality. However, the metabolic mechanism of CHD remains unclear, necessitating a comprehensive elucidation. Therefore, this study aimed to examine the underlying regulatory mechanism of epicardial lipid metabolism in CHD.
Methods: This study collected epicardial adipose tissue samples (n = 40), including 20 patients with CHD and 20 non-CHD. 3T3L1 was induced to differentiate into mature adipocytes in vitro and subsequently treated with different concentrations of oxidized low-density lipoprotein (ox-LDL), glucose, and lipopolysaccharide (LPS). The contents of glycerol and triglyceride were determined using corresponding kits. Moreover, the concentrations of cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) were assessed utilizing ELISA. Furthermore, western blotting analysis and qRT-PCR were employed to determine protein and mRNA expression levels. Additionally, immunofluorescence analysis was utilized to assess the expression of lipid droplet coating protein perilipin A. The morphology and count of lipid droplets were observed using a confocal microscope.
Results: Compared to the non-CHD group, the level of triglyceride and perilipin A increased significantly, while the content of glycerol, PKA, cAMP, adipose triglyceride lipase (ATGL), and hormone-sensitive lipase (HSL) decreased in the CHD group. Furthermore, high ox-LDL and glucose significantly decreased small lipid droplets, glycerol, ATGL, and HSL while substantially increasing large lipid droplets, triglyceride, cAMP, PKA, and perilipin A in 3T3L1 cells. Additionally, high LPS concentration significantly increased small lipid droplets, glycerol, cAMP, PKA, ATGL, and HSL, and decreased large lipid droplets, triglyceride, and perilipin A.
Conclusions: In summary, high ox-LDL and glucose levels regulate the lipolysis of 3T3L1 adipocytes by regulating the cAMP-PKA and perilipin A-ATGL-HSL pathways. However, high LPS can promote the hydrolysis of 3T3L1 adipocytes.
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Background: Triple-negative breast cancer (TNBC) stands out as the most aggressive form of breast cancer due to its significant propensity for metastasis. Exploring the molecular mechanisms of TNBC metastasis is essential to develop TNBC therapeutic strategies. Mex-3 RNA Binding Family Member A (MEX3A) has been recognized to promote TNBC proliferation. However, its role in TNBC metastasis hasn't been investigated.
Methods: We investigated MEX3A levels in breast cancer cells, normal mammary tissues, and breast cancer tissues using Western blot analysis. Moreover, immunohistochemistry (IHC) analysis was used to determine MEX3A levels in TNBC tissues. Cell migration and invasion assays and lung metastasis assay were performed to investigate the role of MEX3A in TNBC metastasis in vitro and in vivo. Additionally, Co-immunoprecipitation was used to determine the interacting proteins of MEX3A.
Results: MEX3A was upregulated in TNBC tissues compared to the normal mammary tissues, especially in TNBC tissues. Patients with high MEX3A expression exhibited shorter overall survival, distant metastasis-free-, relapse-free-, and post-progression survival time than those with low MEX3A expression (p < 0.05). MEX3A knockdown inhibited TNBC cell migration and invasion in vitro (p < 0.05). MEX3A overexpression promoted TNBC metastasis in vivo (p < 0.05). Mechanistically, MEX3A could interact with Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1), resulting in activation of Ras GTPase (Ras-GTP), AKT Serine/Threonine Kinase (AKT), and Extracellular signal-regulated kinase (ERK) pathways, thereby promoting TNBC metastasis. Additionally, Ras pathway inhibitor MCP110 reversed the effect of MEX3A overexpression on TNBC cell migration and invasion.
Conclusion: MEX3A is upregulated in TNBC tissues and can serve as an independent prognostic factor for TNBC patients. MEX3A promotes TNBC cell migration, invasion, and metastasis by interacting with NTRK1, resulting in the activation of Ras, AKT, and ERK pathways. These findings offer a potential therapeutic target for patients with TNBC.
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Backgrounds: Diabetic nephropathy (DN) is a microvascular disease affecting the glomeruli and renal tubules, resulting from diabetes mellitus. Our present experiment was designed to assess the potential therapeutic of Polygala fallax Hemsl (PFH) on DN in diabetic rats.
Methods: As a model of DN, Sprague-Dawley (SD) rats were fed a high-sugar, high-fat diet with streptozotocin (STZ) intraperitoneally injected. The rats that exhibited successful modeling were randomly allocated into different groups, including the model group, as well as PFH low (2 g/kg), medium (4 g/kg), and high (8 g/kg) dose groups. Additionally, there was a positive drug group treated with Losartan Possaium (LP) at a dosage of 16 mg/kg. The general condition of rats was observed, and biochemical tests were conducted. Histopathological changes in renal tissue were assessed using staining techniques such as Hematoxylin-eosin (H&E), periodic acid-Schiff (PAS), and Masson staining. Immunofluorescence (IF), immunohistochemistry (IHC), and Western blot analyses were utilized to assess protein expression levels in renal tissue.
Results: Intragastric administration of PFH for 4 weeks in diabetic rats dose-dependently decreased renal weight/body weight (p < 0.05 or p < 0.01), insulin resistance (p < 0.05 or p < 0.01), total cholesterol (TC; p > 0.05 or p < 0.01), triglyceride (TG; p < 0.05 or p < 0.01), serum albumin (ALB; p < 0.01), creatinine (CREA; p < 0.05 or p < 0.01), carbamide (UREA; p < 0.01), alanine aminotransferase (ALT; p < 0.01), aspartate aminotransferase (AST; p < 0.05 or p < 0.01) levels. PFH significantly inhibited podocyte damage, basement membrane thickening, renal tubular epithelial cell swelling, and inflammatory cell infiltration. Moreover, PFH dose-dependently promoted mitochondrial membrane potential (MMP; p < 0.05 or p < 0.01) and inhibited reactive oxygen species (ROS; p < 0.01) generation, podocyte apoptosis (p < 0.01), mitochondrial fragmentation, and dysfunction in vivo. Besides, the high-dose PFH treatment group had a similar improvement effect on podocyte mitochondrial damage andapoptosis as the positive drug control group. Mechanistically, PFH could stabilize mitochondrial morphology in podocytes via activation of AMP-activated protein kinase (AMPK)/silent information regulator sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α signaling.
Conclusion: Thus, PFH mitigated mitochondrial dysfunction and oxidative damage in renal podocytes of DN rats, thereby safeguarding renal function. This protective mechanism is believed to involve the mobilisation of the AMPK/SIRT1/PGC-1α axis.
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Background: Cerebral ischemia-reperfusion injury (CIRI) is a common severe complication following cerebrovascular diseases and poses significant challenges to human health and life. Aripiprazole, due to its unique pharmacological effects, is recognized to exert a protective effect against Ischemia/Reperfusion (I/R) injury. Therefore, this study aimed to explore the protective effect of Aripiprazole on CIRI by inhibiting the p38 mitogen-activated protein kinase (MAPK) signaling pathway and its impact on the function of cerebral blood flow autoregulation.
Methods: We successfully developed the CIRI rat model and divided rats into different groups: the Sham group, the I/R+DMSO group, the I/R+Aripiprazole low-dose group (1 mg/kg), and the high-dose group (3 mg/kg). The neuroprotective effect of Aripiprazole, its impact on the p38 MAPK signaling pathway, cell apoptosis, inflammatory response, oxidative stress response, and improvement of cerebral blood flow autoregulation function were evaluated using Triphenyltetrazolium Chloride (TTC) staining, western blot, terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) staining, and Enzyme-Linked Immunosorbent Assay (ELISA).
Results: Compared to the I/R+DMSO group, the I/R+Aripiprazole group exhibited a significant reduction in the volume of cerebral infarction, brain edema, neurological function injury scores, and the number of TUNEL-positive cells in brain tissue (p < 0.05, p < 0.01, and p < 0.001), indicating a significant neuroprotective effect of Aripiprazole. Western blot results revealed that Aripiprazole significantly inhibited the activation of the p38 MAPK signaling pathway induced by I/R (p < 0.05, p < 0.01, and p < 0.001). Additionally, Aripiprazole significantly reduced the expressions of pro-inflammatory cytokines (interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), IL-6), decreased malondialdehyde (MDA) levels, and elevated the levels of superoxide dismutase (SOD) and glutathione (GSH) (p < 0.05, p < 0.01, and p < 0.001).
Conclusion: Aripiprazole effectively protects rats from CIRI by inhibiting the p38 MAPK signaling pathway, reducing cell apoptosis, suppressing inflammation and oxidative stress response, and improving cerebral blood flow autoregulation function. These findings provide an experimental basis for applying Aripiprazole in treating CIRI and lay the foundation for future clinical research.
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Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating condition caused by a putative mechanism associated with the activation of the mammalian target of rapamycin (mTOR). The current study aims to unravel the signaling pathway leading to CTEPH on the basis of mTOR activation.
Methods: In vivo CTEPH models were established from rats exposed to repeated autologous thromboembolization. The rats were subjected to right ventricular pressure (RVP) and mean pulmonary artery pressure (mPAP) measurement as well as histopathological examination. To establish CTEPH cellular models for in vitro experiments, pulmonary artery endothelial cells were isolated from CTEPH rats and identified via immunofluorescence/flow cytometry. AZD8055, an mammalian target of rapamycin complex 1 (mTORC1) inhibitor, was used to treat both in vivo and in vitro models. Activating transcription factor 4 (ATF4) was overexpressed in in vitro models. Viability and apoptosis were detected using cell counting kit-8 assay and flow cytometry. Expression of mTOR, ATF4 and monocyte chemoattractant protein-1 (MCP-1) in pulmonary artery tissues/cells was measured by means of immunohistochemistry, Western blotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and enzyme-linked immunosorbent assay (ELISA). The interaction between ATF4 and MCP-1 was predicted with bioinformatics approach and validated using Chromatin immunoprecipitation (ChIP) assay.
Results: CTEPH rats exhibited elevated mPAP, activated mTORC1-ATF4-MCP-1 pathway, increased area/total area of pulmonary artery, and enhanced apoptosis and thromboembolism in the pulmonary artery tissues, which were all reversed by AZD8055 treatment. In in vitro models, ATF4 overexpression decreased cell viability, enhanced apoptosis and upregulated MCP-1 level, while AZD8055 exerted an opposite effect, normalizing these changes and suppressing the mTORC1-ATF4-MCP-1 pathway. ATF4 could bind to MCP-1 promoter region.
Conclusion: The mTORC1-ATF4-MCP-1 pathway induces endothelial dysfunction and pulmonary artery thromboembolism to promote the development of CTEPH in rats.
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Background: Melanoma is the deadliest form of skin malignant tumor, with NFE2 like bZIP transcription factor 2 (NRF2) and glutathione peroxidase 2 (GPX2) implicated in its progression. In this report, we explored the interplay of NRF2 and GPX2 in melanoma using both in vitro and in vivo approaches.
Methods: B16 cells were transfected with NRF2 overexpression plasmid and/or small interfering RNA against GPX2 (Si-GPX2) plasmid and treated with erastin to induce ferroptosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine transfection efficiency. To investigate immune escape, B16 cells were co-cultured with CD8+ T cells, and mice bearing subcutaneous xenograft tumor were established and injected with programmed cell death 1 (PD-1) or CD274 molecule (PD-L1) antibody. Cell viability, colony formation, and expressions of GPX2 and PD-L1 were analyzed by Cell Counting Kit-8, colony formation, and western blot assays. Levels of ferrous iron (Fe2+), malondialdehyde (MDA), lipid peroxidation, and reactive oxygen species (ROS) were measured. CD8+ T cell apoptosis and infiltration were determined by flow cytometry and immunohistochemistry.
Results: NRF2 overexpression increased viability, colony formation, and GPX2/PD-L1 expression (p < 0.05), but reduced levels of Fe2+, MDA, lipid peroxidation, and ROS in erastin-treated B16 cells, while GPX2 knockdown decreased colony formation and PD-L1 expression, but increased levels of Fe2+ and lipid peroxidation (p < 0.01). Following co-culture, CD8+ T cell apoptosis was promoted by NRF2 overexpression, but inhibited by GPX2 knockdown (p < 0.01). GPX2 knockdown reversed the effects of NRF2 overexpression on the above indices (p < 0.01). In mice with subcutaneous xenograft tumor, NRF2 overexpression decreased CD8+ T cell infiltration, which was restored by blocking PD-1 and PD-L1 (p < 0.01).
Conclusion: NRF2 upregulates GPX2 to inhibit ferroptosis and enhance immune escape of melanoma, unveiling a previously unknown therapeutic target to improve the efficacy of melanoma immunotherapy.
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Background: Burn healing consists of four stages, homeostasis, inflammation, proliferation, and remodeling. Burn treatment aims to avoid infection, enhance tissue recovery, and prevent scarring. Recently, regenerative therapy shifted from using fat that contains mesenchymal stem cells to using various types of cells isolated from fat tissue called Stromal Vascular Fraction (SVF). It can be isolated either enzymatically, using collagenase, or mechanically, using emulsification of fat and filtration of cells. Previous research showed that both enzymatical and mechanical isolation of SVF can enhance neovascularization, re-epithelization and reduce inflammation. However, the mechanism behind its therapeutic effect needs to be explored. This study aims to investigate the role of mechanical isolation of SVF on the re-epithelization stage of deep-partial thickness burn in Wistar rats.
Methods: Eighteen Wistar rats were used in this experiment. Three rats were used for fat isolation. After burn induction, fifteen rats were grouped randomly as follows: the control group (5 rats) received intradermal injection of 1 mL saline, Silver Sulfadiazine (SSD) Cream group (5 rats) was treated with the cream, and the SVF group (5 rats) received intradermal injection of (1 × 106 cells/mL). All rats were euthanized at day 32 post-treatment. Morphological and histological examination for re-epithelization, measuring epithelial thickness and Ki-67 immunostaining was compared between all groups.
Results: Wound contraction and re-epithelization were completed in all experimental groups. However, the epithelial thickness of the epidermis was higher in the SVF group than in the SSD group (p = 0.034). Ki-67 staining was higher in the SVF group than in the SSD group (p = 0.025).
Conclusion: Mechanically-isolated SVF showed a positive effect on re-epithelization by increasing cell proliferation via the activation of Ki-67 thus increasing the epidermis thickness in a regulated way.
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Background: The development of several human diseases has been linked to microRNA-342-5p (miR-342-5p). However, its specific function in the inflammatory reactions associated with sepsis-triggered acute kidney injury (AKI) remains unexplored. This study aims to delve into the role of miR-342-5p in the progression of sepsis-induced AKI.
Methods: To understand the underlying mechanism of miR-342-5p in sepsis, we established sepsis models through induction with lipopolysaccharide (LPS). The cell proliferation and apoptosis were assessed using the 5-ethynyl-2′-deoxyuridine (EdU) method and flow cytometry, respectively. Bioinformatics analysis was employed to predict the downstream binding target of miR-342-5p, and their interaction was confirmed through a dual-luciferase reporter gene assay. The rescue tests were conducted to further explore the action pathway of miR-342-5p.
Results: The administration of LPS significantly decreased the HK2 cell proliferation (p < 0.05), and increased cell apoptosis. Additionally, there was a notable downregulation in miR-342-5p expression accompanied by an elevated level of inflammatory factor (p < 0.05). Furthermore, the overexpression of miR-342-5p effectively attenuated the LPS-induced inflammatory response in HK2 cells (p < 0.05). Profilin-1 (PFN1) emerged as a pivotal player in sepsis pathogenesis, serving as a critical downstream target of miR-342-5p. Interestingly, rescue experiments demonstrated that the stimulatory effects of miR-342-5p mimics were counteracted by the overexpression of PFN1 in sepsis.
Conclusions: MiR-342-5p alleviates inflammatory responses in sepsis by targeting PFN1.
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Background: Dental caries, a prevalent oral disease, has long been a focal point of research in dentistry concerning its prevention and treatment. While hydroxyapatite (HAP) repair coatings and sodium fluoride solutions are commonly employed for combating dental caries, but their effectiveness and underlying mechanisms are not fully understood. This study aims to investigate the preventive impact of hydroxyapatite repair coatings on oral infectious caries in rats.
Methods: To create an oral infectious caries model, a total of 35 Wistar rats were selected. After the selection process, 30 rats successfully were established as the model. These rats were randomly divided into three distinct groups for treatment purposes. The first group was the physiological saline group, where the surface of teeth was gently wiped with cotton soaked in physiological saline. The second group was the sodium fluoride group, in which the surface of the teeth was wiped with cotton soaked in sodium fluoride solution. The third group was the experimental group, where the surface of the teeth, previously corroded by acid, was treated with HAP paste. The treatment was performed once a week for a total of four weeks. To evaluate the effectiveness of each treatment, the colony count and Keyes score were recorded. Furthermore, the morphology of the tooth surface for each group was closely observed using an electron microscope.
Results: Based on the experimental results, the experimental group showed significant improvement after four weeks of treatment. The colony count revealed a significant decrease in the number of Streptococcus mutans in the experimental group (p < 0.05). Additionally, the Keyes score demonstrated that the experimental group had significantly lower scores in the enamel (E)-level and slight dentinal (Ds)-level on the smooth surface of caries compared to both the sodium fluoride group and the saline group, with statistical significance (p < 0.05). At the moderate dentin (Dm)-level, the experimental group's scores were significantly lower than those of the control group (p < 0.05). The electron microscopy results showed that the experimental group exhibited a marked enhancement in the surface structure of the teeth. Specifically, the experimental group displayed shallow demineralization areas and a reduced number of cavities compared to the sodium fluoride group and the physiological saline group. Furthermore, the experimental group showed a superior ability to inhibit dental caries, indicating its potential as a promising solution for dental health.
Conclusions: The application of HAP repair coatings has demonstrated a substantial reduction in the population of Streptococcus mutans within the oral cavity of rats, with no significant difference in the degree of damage on smooth and cracked surfaces of caries compared to the sodium fluoride group. Electron microscopy observations showed that HAP repair coatings can protect the surface of enamel from acid erosion and abrasion. These results suggest the promising potential of HAP restorative coatings in the prevention of dental caries and provide novel directions for future clinical practice.
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Background: Chronic obstructive pulmonary disease (COPD) is a respiratory illness, with cellular senescence recognized as an essential mechanism driving this chronic lung disease. Salidroside (Sal), a natural compound, is recognized for its anti-aging impacts. Therefore, this study aims to investigate the role and the underlying mechanism of Sal on airway epithelial cell senescence.
Methods: In vitro experiments were performed by treating BEAS-2B cells with cigarette smoke extract (CSE), AG490 (Janus kinase 2 (JAK2) inhibitor), or Sal (40 μM, 80 μM, 160 μM). Moreover, senescence-associated β-galactosidase (SA-β-gal) staining and the manifestation of senescence-related genes were used to assess cellular senescence. The mRNA levels of cyclin-dependent kinase inhibitor 2a (p16) and cyclin-dependent kinase inhibitor 1a (p21) were evaluated. Furthermore, Western blot analysis was employed to determine the expression levels of p16, p21, Janus kinase 2 (JAK2), phosphorylated-JAK2 (p-JAK2), signal transducer and activator of transcription 3 (STAT3), and phosphorylated-STAT3 (p-STAT3). Additionally, the cytokine levels associated with the senescence-associated secretory phenotype (SASP) were evaluated utilizing corresponding enzyme-linked immunosorbent assay kits.
Results: In vitro, cellular experiments demonstrated that Human bronchial epithelial cells underwent senescence in response to CSE, as evidenced by elevated expression of p16 (p < 0.05) and p21 (p < 0.05), and promotion of senescence-associated secretory phenotype (SASP), as well as up-regulation of JAK2/STAT3 signaling pathway activity. AG490 treatment significantly ameliorated CSE-induced cellular senescence, resulting in down-regulation of the JKA2/STAT3 signaling pathway, alleviation of the senescence molecules p16 (p < 0.05), p21 (p < 0.05), p-JKA2 (p < 0.01) and p-STAT3 (p < 0.05). The inhibitor decreased the secretion of SASP cytokines, and decreased the activity of SA-β-gal. Additionally, Sal reduced p16 (p < 0.01) and p21 (p < 0.05) expression, potentially reversed CSE-induced cellular senescence, and inhibited the JAK2/STAT3 signaling pathway, as well as decreased SASP secretion and SA-β-gal activity.
Conclusion: Sal reduces CSE-induced BEAS-2B cellular senescence by inhibiting the JAK2/STAT3 signaling pathway, providing a novel strategy for COPD treatment.
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Background: Prostate cancer is the most common and solid malignancy among male tumors worldwide. Converting tumor-associated macrophages (TAMs) into anti-tumor M1 macrophages holds a promising potential for cancer treatment. Therefore, this study investigated whether M1 macrophage-derived exosomes affect prostate cancer progression by inducing TAM reprogramming into M1-like macrophages.
Methods: LPS-induced RAW264.7 cells were polarized into M1-type macrophages. Exosomes isolated from the M1 macrophages (M1-exos) were observed using transmission electron microscopy (TEM), tracked by nanoparticle tracking analysis (NTA), and identified through western blot analysis. After this, M1-exos were co-cultured with human prostate cancer (PC-3) cells and interleukin-4 (IL-4)-induced M2-like macrophages. The effects of M1-exos on prostate cancer progression and TAM polarization were evaluated using cell counting kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), flow cytometry, Transwell, and wound healing assays. Furthermore, to analyze the impact of M1-exos on prostate cancer progression by inducing TAM polarization, in vivo xenograft tumor models were constructed, followed by H&E staining, immunohistochemistry, and TdT-mediated dUTP nick end labeling (TUNEL) assays.
Results: We successfully polarized immature M0 macrophages into an M1 phenotype using RAW264.7 cells and obtained M1-exos from these cells. Moreover, findings from both in vivo and in vitro experiments unveiled that M1-exos inhibited the proliferation (p < 0.05), invasion (p < 0.05), and migration of prostate cancer cells (p < 0.05). Additionally, M1-exos promoted apoptosis (p < 0.05) and induced the polarization of TAM into M1-type macrophages.
Conclusion: M1-exos induced the polarization of TAM into the M1 phenotype with anti-tumor potential, thereby suppressing prostate cancer growth and metastasis. Therefore, M1-exos hold promising potential for treating prostate cancer.
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Background: Gastric cancer (GC) ranks as the fourth most prevalent cancer globally, with heterogeneous prognosis and high mortality rates. Numerous studies have highlighted the close association between the occurrence and progression of gastric cancer and the N7-methylguanosine (m7G) mechanism. This study aims to determine the clinical significance of m7G-related genes (m7Gs) in gastric cancer prognosis and investigate their potential connection with the tumor immune microenvironment (TIME).
Methods: Gastric cancer data was obtained from the Cancer Genome Atlas (TCGA) library to generate the m7G pattern prognosis-related genes (m7G-PRGs) matrix. Two distinct m7G typings were initially identified, followed by unsupervised clustering based on m7G-related cluster C1 and C2 (m7G-C1/2) integrated differentially expressed genes (DEGs) to acquire a scoring system. The m7G-related prognostic model (m7G-RPM) was then constructed, with key prognostic genes experimentally validated through Western blot analysis. Subsequently, gastric cancer patients were stratified into high/low-scoring subgroups using the calculated median m7G_score, facilitating the investigation of prognosis-related mechanisms. Furthermore, biological signaling pathways were systematically enriched, a nomogram was developed, and TIME in gastric cancer was assessed.
Results: Alterations in m7Gs are associated with a poor prognosis, with the primary outcome being hypermethylation in cancer, which regulates immune signaling and promotes cellular infiltration. Two distinct m7G clusters were identified, revealing m7Gs' bidirectional regulatory role in clinicopathological features and the TIME. A nomogram containing seven variable genes improved the clinical applicability of m7G-RPM, with increased solute carrier family 39 member 4 (SLC39A4) and matrix metallopeptidase 7 (MMP7) expression observed in gastric cancer cells. The m7G_score was significantly associated with microsatellite instability (MSI), tumor mutation burden (TMB), chemotherapeutic drug sensitivity, and cancer stem cell (CSC) index.
Conclusion: A comprehensive analysis of m7G s in gastric cancer confirmed their potential role in genetic alterations, TIME, clinical traits, and prognosis, especially in tumor-infiltrating immune cells (TIICs). We constructed a novel prognostic model based on m7Gs and performed preliminary validation of the screened genes. These findings present innovative perspectives for assessing the prognosis of gastric cancer and guiding individualized immunotherapy strategies for patients.
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Background: Angiopoietin-2 (Ang-2), a significant chemokine influencing monocyte chemotactic migration, was investigated under conditions of intermittent hypoxia and in obstructive sleep apnea (OSA) patients. This study aimed to elucidate the chemotactic impact of Ang-2 on monocytes during intermittent hypoxic conditions and to assess changes in the circadian concentration of Ang-2 in individuals with OSA.
Methods: The OSA dataset GSE135917 was downloaded, and the Gene Set Enrichment Analysis (GSEA) method was employed to investigate the association between Ang-2 expression and potential signaling pathways in OSA. Monocytic THP-1 cells were utilized to examine the modulation of Ang-2 under intermittent hypoxia. Subsequently, the chemotactic motility of THP-1 cells was evaluated using a Transwell migration assay, and the number of migrating cells was quantified through flow cytometry. Monocyte RNA was isolated from peripheral venous blood obtained from 60 adult OSA patients and 60 healthy controls to conduct an Ang-2 mRNA expression study.
Results: Bioinformatic analysis indicated that pathways significantly associated with high Ang-2 expression were predominantly enriched in extracellular regulated protein kinases (ERKs), phosphatidylinositol 3 kinase/serine-threonine kinase (PI3K/AKT), and nuclear factor kappa-B (NF-κB) signaling pathways. Experimental results demonstrated that intermittent hypoxia actively enhanced the expression of Ang-2 in monocytic THP-1 cells and facilitated the migration of THP-1 cells. Evidence suggested intermittent hypoxia induced the upregulation of Ang-2 expression via PI3K, ERKs, and NF-κB pathways. Additionally, Ang-2 expression in peripheral blood mononuclear cells was elevated in OSA patients, correlating with disease severity. Furthermore, Ang-2 mRNA expression in the OSA group was higher than in the control group.
Conclusion: Ang-2 levels are elevated in OSA patients and are correlated with disease severity. Increased monocytic expression of Ang-2 is closely associated with intermittent hypoxia induced by OSA.
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Background: Hepatocellular carcinoma (HCC) poses a significant challenge in oncology due to its high mortality rates and limited treatment options resulting from its aggressive nature and often late-stage diagnosis.
Objective: This study aimed to systematically identify a potent anti-HCC agent to address the challenges.
Materials and Methods: Initiating with a molecular docking analysis, a comprehensive virtual screening of various compounds was conducted to identify the most promising anti-HCC agent. Berberine (BBR), an isoquinoline alkaloid derived from Hydrastis canadensis and Coptis chinensis, emerged as the most potent candidate, showcasing diverse anti-cancer mechanisms. The BBR, historically recognized for managing bacterial diarrhea, faces challenges in clinical application against HCC due to limitations in solubility and bioavailability. To overcome these constraints, this study employed a protein-based nanoparticulate drug delivery system, leveraging bovine serum albumin nanoparticle (BSA NP) advantages. The synthesis of BSA NPs encapsulating BBR was meticulously executed, yielding BBR-BSA NPs.
Results: Subsequent in vitro investigations unequivocally demonstrated the heightened cytotoxicity of BBR when encapsulated within BSA NPs, showcasing superior efficacy compared to free BBR. These nanoformulations exhibited pronounced induction of apoptosis in hepatoma cells, highlighting their enhanced therapeutic potential.
Conclusions: In conclusion, this comprehensive approach not only reveals the promise of BBR-BSA NPs in combatting human hepatoma but also represents a significant advancement by addressing limitations associated with conventional BBR formulations, offering improved solubility and bioavailability in the context of HCC therapy.
