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关键词： Gynostemma pentaphyllum   Amino acid metabolism   Protein regeneration   Biomarkers   PXR-IL-6-SERCA1a  

摘要： Background: Gynostemma pentaphyllum (GYP) is a traditional Chinese medicine (TCM) used for strengthening and injure recovery, previous research has revealed that a 50% ethanol extract of GYP markedly influences strained skeletal muscle regeneration. Further research has clarified that GYP took such effect via recovery of liver and spleen, whose function and morphology also damaged when muscle is strained. However, the mechanism and biological basis of GYP's regeneration effect still needs deeper investigation. Objective: To elucidate the mechanism and biomarkers of GYP regulating the recovery of skeletal muscle proteins, as well as discovery of related targets involved in such process. Methods: A rat blunt skeletal muscle strain model was established for pharmacodynamic evaluation, with administration of GYP extract or reference drug;the serum and tissue (liver, spleen) samples were collection for subsequent investigation of target expression and metabolomics;Serum metabolomics research was carried out to screen differential metabolites related to the skeletal muscle regeneration;Subsequently, the metabolomic results were combined with network pharmacology and results of target expression to clarify the signaling pathway;Then, guided by this, the differential metabolites related to the targets/pathways in organs such as the liver and spleen were determined by UPLC-MS;Eventually, biomarkers characterizing the promotion of protein regeneration in strained skeletal muscle by GYP were found. Results: The serum metabolomic analysis successfully identified 20 differential metabolites associated with its efficacy, and further screened out metabolites like l-tryptophan, DL-glutamic acid, tyrosine, arachidonic acid as significant biomarkers that related to PXR-IL-6-SERCA1a pathway;As the regulatory mechanism of GYP indicated, those markers are recognized as key indicators of the process of strained muscle regeneration, as well as GYP's therapeutic effect. Conclusion: By rest

关键词： HPV16 E6   Pgp3   Daxx   Apoptosis   MDM2   p53  

摘要： Background and aims: As a common pathogen of sexually transmitted diseases, Chlamydia trachomatis (C. trachomatis) may be a cofactor in the progression of cervical cancer induced by persistent HPV infection, but its molecular mechanism is unclear. The aim of this study is to explore whether HPV16 E6 and C. trachomatis Pgp3 proteins inhibit apoptosis through the Daxx-mediated MDM2-p53 pathway, in order to reveal the potential mechanism of their synergistic effects. Methods: The HeLa cell model was used to analyze the effects of HPV16 E6 and Pgp3 proteins on Daxx expression and the MDM2-p53 pathway, combined with interfering with Daxx, TNF-alpha-induced apoptosis assay and Nutlin3a treatment to validate the function of key molecules. Results: HPV16 E6 and C. trachomatis Pgp3 proteins can upregulate the expression of Daxx proteins individually or synergistically, and the inhibitory on TNF-alpha-induced apoptosis may be superimposed. Interference with Daxx partially reversed the apoptosis inhibition of HPV16 E6 and Pgp3, suggesting that it may act by promoting MDM2 phosphorylation and p53 degradation. Moreover, Nutlin-3a treatment can attenuate the apoptosis inhibitory of HPV16 E6 and Pgp3, further supporting the involvement of MDM2-p53 pathway. Conclusions: This study suggests that HPV16 E6 and C. trachomatis Pgp3 proteins can inhibit TNF-alpha-induced apoptosis through Daxx-mediated MDM2-p53 pathway, which may provide a mechanistic foundation for the study of HPV16 and C. trachomatis co-infection on cervical cancer progression.

关键词： Cell lines   CRISPR-Cas9   Haplotype-resolved assembly   MHC   Targeted sequencing  

摘要： The major histocompatibility complex (MHC) region plays a crucial role in immune function and is implicated in various diseases and cancer immunoediting. However, its high polymorphism poses challenges for accurate genetic profiling using conventional reference genomes. Here, we present high-quality, haplotype-resolved assemblies of the MHC region in five widely used tumor cell lines: A 549, HeLa, HepG2, K562, and U2OS. Numerous oncologi cal studies extensively employ these cell lines, ranging from basic molecular research to drug discovery and personalized medicine approaches. By integrating CRISPR-based targeted enrichment with 10 x Genomics linked-read and PacBio HiFi long-read sequencing, we constructed MHC haplotypes for each cell line, providing a valuable resource for the research community. Using these assembled haplotypes as references, we characterize the aneuploidy of the MHC region in these cell lines, offering insights into the genetic landscape of this critical immunological locus. Our work addresses the urgent need for accurate MHC profiling in these widely used cell line models, enabling more precise interpretation of existing and future genomic and epigenomic data. This resource is expected to significantly enhance our understanding

关键词： Uterine cervix   Neuroendocrine tumor   Large cell neuroendocrine carcinoma   Small cell neuroendocrine carcinoma   Tumor microenvironment   Human leukocyte antigen   Programmed cell death ligand 1  

摘要： Neuroendocrine neoplasms (NENs) of the uterine cervix are highly malignant tumors associated with a poor prognosis. Human papillomavirus test-based uterine cervical cancer screening methods can detect early-stage uterine cervical NENs, so therapeutic strategies for the earliest stages are urgently needed. This study aimed to investigate and evaluate the prognostic significance of intratumoral and stromal immune cell densities, as well as human leukocyte antigen (HLA) and programmed cell death ligand 1 (PD-L1) expression in stage I uterine cervical NENs. Sixteen NENs were identified, including 8 large cell neuroendocrine carcinomas (LCNECs), 4 small cell neuroendocrine carcinomas (SCNECs), 3 neuroendocrine tumors (NETs), and 1 LCNEC with an SCNEC component. Only 3 cases were pure NENs, while 13 cases included a component of adenocarcinoma or squamous cell carcinoma. Eight of the 16 patients experienced postoperative recurrence. The recurrence-free group exhibited significantly higher densities of intratumoral CD3- and CD8-positive cells compared to the recurrence group (median densities: 136 vs. 48 cells/mm2, P = 0.0281 and 91 vs. 27 cells/mm2, P = 0.0359, respectively). No significant differences in clinicopathological characteristics, other immune cell densities, or expression of HLA class I, HLA-DR, or PD-L1 were observed between groups. HLA-DR expression was nearly absent in uterine cervical NENs, whereas adjacent non-NEN components displayed varying degrees of HLA-DR expression. PD-L1 expression was observed in 25 % of cases, with CD3- and CD8-positive T-cell-rich stroma. The observed modifications to tumor microenvironments could offer clues to future treatments for uterine cervical NEN. (240/250 words)

关键词： Deguelin   Inflammation   IL-1 beta   Chondrocytes   NF-kappa B  

摘要： Osteoarthritis (OA), a prevalent age-related degenerative joint disorder, is characterized by progressive articular cartilage degradation accompanied by subchondral bone remodeling, synovitis, and reactive osteophytosis. Discovering natural medicines capable of inhibiting inflammatory response of chondrocytes and cartilage degeneration is necessary for OA treatment. Emerging investigations have systematically demonstrated deguelin's multimodal anti-inflammatory efficacy mechanistically across multiple pathological contexts. However, its effect on chondrocytes remains unknown. Through a dual-level investigation combining in vitro mechanistic analysis and in vivo disease modeling, this study delineates deguelin's chondroprotective mechanisms in primary murine chondrocytes, while demonstrating potent disease-modifying effects in surgically induced OA pathogenesis. Deguelin demonstrated significant anti-inflammatory activity in IL-1 beta-activated chondrocytes. It diminished cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) mRNA and protein levels, and it prevented extracellular matrix (ECM) catabolism by reducing matrix metalloproteinases (MMPs) expression. Mechanistically, deguelin exerted anti-inflammatory effects through targeted suppression of NF-kappa B pathway activation, as confirmed by immunofluorescence and western blot analyses. Consistent with the in vitro findings, deguelin treatment protected against articular cartilage erosion and subchondral bone loss in OA murine model in vivo, suggesting its potential as an effective agent for treating OA.

关键词： Th9   IL-9   Rheumatoid arthritis  

摘要： Early studies on T helper (Th) 9 cells and their specific cytokine IL-9 mainly focused on the field of allergic diseases. In addition to pathological studies, IL-9 can also affect the normal development and various functions of T cells and B cells. In recent years, a series of studies have found that IL-9 may play a pathogenic role in a range of autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). Specifically, Th9 cells and IL-9 show abnormally high expression in peripheral blood, synovial fluid, and synovial tissue of patients with RA. Based on this, therapeutic strategies targeting IL-9, such as monoclonal antibodies, have become potential treatments for RA. However, research on Th9 and IL-9 in RA has only been conducted for less than two decades, and many issues are worth further exploration. This article reviews the molecular mechanisms underlying the pathogenic effects of Th9 and IL-9 in RA, summarizes the potential reasons for inducing abnormally high expression of Th9 and IL-9 in RA, and discusses future research directions. The existing evidence shows that Th9-derived IL-9 is a potential biomarker or therapeutic target in RA. We hope that this current review can play a bridging role and provide new ideas for the study of Th9 and IL-9 in RA.

关键词： Angiopoietin-Like Protein   Diabetes Complications   Diabetes Mellitus   Growth Differentiation Factor 15   Inflammation  

摘要： OBJECTIVES:To investigate serum levels of growth differentiation factor 15 (GDF-15), inflammatory biomarkers, and betatrophin in individuals with diabetes mellitus, both with and without complications. METHODS:A cross-sectional analysis was conducted involving patients with diabetes. Participants were categorized into 3 groups: Group 1 (30 healthy individuals without diabetes), Group 2 (30 diabetic patients without complications), and Group 3 (30 diabetic patients with complications). Blood samples were collected to assess standard biochemical parameters, as well as plasma concentrations of betatrophin, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and GDF-15. All serum biomarkers were quantified using enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS:Median GDF-15 concentrations were 486.96 pg/mL (range: 172.2-1272.0) in the control group, 843.9 pg/mL (range: 458.3-1393.3) in diabetics without complications, and 1794.3 pg/mL (range: 741.6-4449.5) in those with complications. The GDF-15 levels were significantly elevated in diabetic patients compared to healthy controls (<0.001), and markedly higher in patients with complications than those without (<0.001). Additionally, TNF-α, IL-6, and betatrophin levels were significantly increased in diabetic individuals relative to the control group (all <0.001). CONCLUSION:Serum GDF-15 levels are elevated in diabetic patients compared to non-diabetic controls and are further increased in those with complications. These findings suggest that GDF-15 may serve as a potential biomarker for diabetes severity and complication risk.

关键词： cytokine   hepatocellular carcinoma   immune checkpoint   biomarker  

摘要： Hepatocellular carcinoma (HCC) is predominantly diagnosed at advanced stages due to a lack of reliable biomarkers for early detection. Consequently, identifying predictive biomarkers for HCC development in patients with chronic liver diseases holds significant potential for improving early diagnosis and clinical outcomes of this aggressive malignancy. Serum levels of immune checkpoint proteins and cytokines were quantified by ELISA in patients with chronic hepatitis B, liver cirrhosis, and HCC, with healthy subjects serving as controls. Cytokine profiles were compared between patients with HCC and without HCC using one-way ANOVA and multivariate logistic regression. The diagnostic performance of interferon (IFN)-gamma, interleukin (IL)-22, and alpha-fetoprotein (AFP) was evaluated by receiver operating characteristic (ROC) curve analysis. The serum levels of programmed cell death protein 1 and programmed death-ligand 1 progressively increased with advancing stages of liver disease. IFN-gamma emerged as a protective factor against HCC [odds ratio (OR)=0.991;95% CI, 0.984-0.997], while IL-22 was identified as a risk factor (OR=1.020, 95% CI, 1.004-1.036). The combined evaluation of IFN-gamma and IL-22 demonstrated superior diagnostic accuracy [area under the curve (AUC)=0.863;95% CI, 0.755-0.971] compared with AFP alone (AUC=0.644;95% CI, 0.483-0.804). The combination of IFN-gamma and IL-22 exhibited enhanced diagnostic performance compared with AFP alone in predicting and detecting early-stage HCC, suggesting its potential utility as a novel biomarker panel for HCC screening.

关键词： HLA‐DQA1*03:63   next‐generation sequencing   novel allele  

摘要： HLA-DQA1*03:63 differs from HLA-DQA1*03:02:01:01 by a single nucleotide substitution at position 722 G>A.