课程文献中心 更多>>

关键词： MC-LR   Apoptosis   TNF-R1   RIPK1   HEK293  

摘要： In recent years, the outbreak of cyanobacterial blooms has become increasingly frequent. Microcystin-LR (MC-LR), a metabolite of cyanobacteria, poses a significant threat to the ecosystem and human health. Several studies have demonstrated that MC-LR might induce renal cell apoptosis, as a consequence of tissue damage. However, the molecular mechanisms underlying MC-LR-initiated renal injury remain to be determined. This investigation aimed to determine the role of apoptosis in MC-LR-induced kidney damage and its potential underlying mechanisms using the human embryonic kidney (HEK293) cell line. The results of TUNEL and immunofluorescence assays indicated that MC-LR induced increased apoptosis in HEK293 cells. Compared to control, the mRNA expression levels of RIPK1, caspase-8, and TNF-alpha were elevated following incubation with MC-LR, while the mRNA expression level of Bcl-2/Bax was decreased. The protein levels of RIPK1, TNF-R1, and caspase-8 were elevated in the MC-LR-treated HEK293 cells. Data demonstrated that MC-LR induced renal cell apoptosis through activation of the TNF-R1/RIPK1 pathway, providing new insights into understanding the toxic mechanisms attributed to MC-LR.

摘要： In recent years, circRNAs have garnered increasing attention for their role in cervical cancer. However, the functions of many newly identified circRNAs remain unclear and require further exploration. In this study, we investigated the expression and oncogenic potential of the novel circRNA circSTX6 in cervical cancer. Our findings revealed that circSTX6 is highly expressed in cervical cancer (CC) and is significantly associated with poor patient prognosis, promoting cell survival, proliferation, invasion, and migration. Mechanistically, circSTX6 enhances the stability of the transcription factor SPI1 by binding to it, thereby upregulating IL6 transcription and activating the JAK2/STAT3 signaling pathway. Additionally, METTL3-mediated N6-methyladenosine (m6A) modification stabilizes circSTX6 through recognition by YTHDC1, forming a positive feedback regulatory loop among METTL3, circSTX6, and SPI1. These findings not only deepen our understanding of the biological mechanisms underlying CC but also highlight circSTX6 as a potential target for molecular therapies.

摘要： The regulatory molecule Human Leukocyte Antigen F (HLA-F) has been implicated in trophoblast proliferation during pregnancy, and reduced levels of this antigen have been identified in trophoblast cells of patients with preeclampsia. This study aimed to analyze the effect and mechanism of HLA-F on the proliferation of trophoblast and the underlying mechanism of reduced HLA-F involved in preeclampsia. q-PCR, Western blot (WB), and Immunohistochemistry (IHC) were used to detect the expression of HLA-F and Pyruvate Kinase Muscle isoform 2 (PKM2) in placenta tissues. Jar cells were transfected with overexpression lentivirus, specific siRNA, and shRNA to regulate corresponding genes. Immunofluorescence was used to analyze the expression and distribution of HLA-F and PKM2. Extracellular and intracellular lactate, pyruvate, and enzymatic activity of PKM2 were measured using the corresponding assay kits. Cell proliferation was measured by CCK8, MTT, colony formation assay, and Mini patient-derived xenograft (Mini-PDX). Chromatin Immunoprecipitation and deep sequencing (ChIP-seq) and 4-dimensional label-free quantitative proteomics (4D-LFQP-LA) were used to analyze the HLA-F-binding DNA sequences and the differential lactylation proteins in HLA-F-overexpression Jar and its control. The expression of HLA-F is reduced in extravillous trophoblast and villous cytotrophoblast from patients with preeclampsia. Over-expression of HLA-F promoted proliferation while under-expression inhibited it. Further experiments demonstrated that over-expression of HLA-F promoted expression of the PKM2 protein and its enzymatic activity, resulting in enhanced glycolysis in Jar cells. Specifically, we determined that HLA-F regulated the expression of PKM2 by binding the promoter of PKM, and promoted PKM2 enzyme activity by down-regulating the lactylation of residue K305. Moreover, silencing PKM2 with siRNA reduced HLA-F–mediated glycolysis and proliferation in HLA-F–overexpressing Jar cells. Finally

摘要： In this study, we aim to explore the roles of IL-16 in sarcopenia based on older orthopedic patients and animal research. This clinical research in this study was an observational investigation and included all the older patients with orthopedic trauma admitted to our department between January 2021 and January 2022. Patients were identified with sarcopenia if they have both low hand grip strength (HGS) and low appendicular skeletal muscle mass (ASM). Propensity score matching (PSM) was performed to reduce the bias caused by the co-factors and levels of IL-16 between normal patients and patients with sarcopenia were compared. In animal research, mice were treated with IL-16 to identify the effects of IL-16 on muscle function and muscle mass. Then the sarcopenia models were established and the anti-IL-16 was performed to identify the potential therapeutical effect of targeting IL-16. 421 individuals were included in the clinical study, and 77 were identified as sarcopenia. In the matched populations, the serum levels of IL-16 of individuals with low HGS, ASM, and sarcopenia were significantly higher than normal individuals (all p < 0.001). The mice treated with IL-16 showed significantly impaired muscle function and physical performance and loss of muscle mass. Using anti-IL-16 antibodies may rescue the sarcopenia traits caused by botulinum toxin type A. Individuals with high levels of IL-16 may have a significantly high risk of sarcopenia. IL-16 impairs muscle function and physical performance and leads to muscle atrophy in mice, and these effects could be reduced by targeting IL-16.

摘要： IL-17 (interleukin-17) is a common proinflammatory cytokine and can be adopted as an important biomarker for several diseases; it is thus very necessary to design an effective method for monitoring IL-17. Herein, by preparing silver nanoparticles/graphdiyne (Ag/GDY) with simple electroless deposition as the sensing platform and methylene blue/UiO-66-NH2 MOFs (MB/MOFs) as the signaling-amplifier, a highly efficient sandwich-like electrochemical immunosensing (SLEI) platform was designed for IL-17 detection. The superior electrical property, easy preparation, large surface area, and high stability of Ag/GDY make it a desirable substrate to immobilize primary antibody of IL-17. Meanwhile, the unique structure of UiO-66-NH2 is beneficial to immobilize MB probe and secondary antibody. By optimizing experimental conditions, the MB current obtained at the as-designed SLEI platform increases along with IL-17 increase, and the related linearity is 1.0 pg mL−1–1.0 ng mL−1 coupled with a low detection limit of 0.3 pg mL−1. It is expected that the SLEI platform based on Ag/GDY and MB/MOFs shows some potential application for IL-17 detection.

关键词： HLA infertility   HLA   IVF   Unexplained infertility   HLA similarity  

摘要： Objective: To examine whether the rate of HLA similarity among 609 primarily infertile couples is higher than would be expected by chance. Design: Clinical Trial. Subjects: 609 primary infertile couples (mean age women: 34.35 years, men: 37.59 years) were recruited before undergoing IVF or ICSI therapy. Couples with former pregnancies, tubal factor, azoospermia or donor therapies were excluded. Intervention: For each of the partners, exons encoding the corresponding antigen recognition sites of HLA-A,-B,-C,-DRB1,-DQB1, and-DPB1 were sequenced by using next-generation sequencing. HLA similarity between partners was determined based on the probability of homozygous offspring and the observed probability of heterozygous offspring in the sample of primary infertile couples was comparted to the probability for random pairing using bootstrapping. Main outcome measures: HLA similarity of infertile couples compared to randomly assigned couples. Results: In each of the loci, infertile pairs shared more alleles than expected by chance. This result was significant for all HLA class 2 loci (-DRB1,-DQB1,-DPB1), as well as for the HLA class I locus-C, while HLA-A and-B showed a nonsignificant trend towards higher similarity. Conclusion: These data suggest that HLA similarity between couples relates to primary infertility.

关键词： Stromal cell-derived factor 1   Ferroptosis   Chondrocyte   Osteoarthritis   Interleukin 6   Hypoxia-inducible factor 1 alpha  

摘要： Background: Osteoarthritis (OA) is a common joint disease with an incompletely understood pathogenesis. SDF-1, a key factor in cartilage matrix degradation, is involved in OA cartilage degeneration, yet its mechanism, especially regarding ferroptosis, remains unclear. This study focuses on elucidating the role of SDF-1-induced chondrocyte ferroptosis and the IL6/HIF-1 alpha signalling axis in OA. Methods: A rabbit OA model was created via SDF-1 induction. Knee cartilage tissues were sequenced and analyzed bioinformatically to identify key genes, and explore critical pathways. Clinical tissue samples were utilized to validate their clinical relevance. Furthermore, cell and rabbit models were constructed through gene interference and pathway blocking. The expression of related genes and proteins was detected by QPCR, ELISA, Western blot, and immunofluorescence. Additionally, OA and ferroptosis indicators such as cell viability, immunohistochemistry, ROS, lipid ROS, Fe2+, MDA, and mitochondrial morphology were evaluated to uncover the molecular mechanism by which SDF-1 regulates the IL6/HIF-1 alpha signalling axis to mediate chondrocyte ferroptosis. Results: Bioinformatics revealed that ferroptosis was significantly activated in SDF-1-induced OA, with IL6 and HIF-1 pathways implicated. In vitro and in vivo, SDF-1 increased the expression and secretion of MMP13 but decreased COL2A1 and ACAN in chondrocytes, leading to OA-like changes. It also suppressed the expression levels of SLC7A11 and GPX4, upregulated the gene and protein levels of ACSL4, promoted the accumulation of MDA, Fe2+, and ROS, and caused mitochondrial morphological changes. These ferroptosis manifestations could be alleviated by the ferroptosis inhibitor Fer-1. IL6 was an important mediator of SDF-1-induced ferroptosis, and knocking down IL6 also inhibited chondrocyte ferroptosis changes. Overexpressing IL6 (oeIL6) and using PX478 to inhibit the HIF-1 signalling pathway showed that PX478 could significan

关键词： Inflammatory bowel disease   Phellodendrine   IL-17 signaling pathway   Intestinal mucosal barrier   Inflammation  

摘要： Background: Phellodendrine (PHE) has anti-inflammatory and antioxidant effects. However, the function of PHE in treating inflammatory bowel disease (IBD) has not been fully elucidated. The aim of this study was to investigate the effects and mechanisms of PHE on IBD with in vivo and in vitro assays. Materials and Methods: Bioinformatics was used to identify hub genes associated with IBD pathogenesis. Virtual screening was applied to predicting the natrual compounds targeting hub genes. A mouse model with colitis was established by oral administration of 3 % dextran sulfate (DSS), and the mice were treated with normal saline or PHE (30 mg/kg/day or 80 mg/kg/day). On day 14, the mice were sacrificed and their colons were collected for measurement and histological analysis. The pathological change and inflammation of the tissues in different groups also were evaluated. In addition, the intestinal epithelial Caco-2 cell line was treated with lipopolysaccharide (LPS) to establish an in vitro intestinal inflammation model. CCK-8 assay and flow cytometry were used to detect the effects of PHE (10 mu M or 40 mu M) on cell viability and apoptosis. Western blot was used to the investigate the regulatory effects of PHE on the expression levels of zonula occludens 1 (ZO-1), occludin, claudin1, collagen type I alpha 1 (COL1A1), vascular cell adhesion molecule 1 (VCAM1), interleukin-17 A (IL-17 A), phosphorylated AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). Results: COL1A1 and VCAM1 were identified as therapeutic targets in IBD. PHE was identified as a natural drug simultaneously targeting COL1A1 and VCAM1. PHE treatment alleviates the weight loss and symptoms of mice induced by acute colitis. PHE treatment reduced myeloperoxidase (MPO) activity and pro-inflammatory cytokine levels in colonic tissues, and inhibited expression levels of COL1A1, VCAM1 and IL-17 A, and promoted expression levels of ZO-1, occludin and claudin-1. In vitro, PHE treatmen

关键词： Allergic rhinitis   The aryl hydrocarbon receptor   M2 macrophage  

摘要： Background: Epidemiological evidence suggests that environmental pollutants precipitate the occurrence of allergic rhinitis (AR). The aryl hydrocarbon receptor (AhR), a receptor or sensor for various contaminants, is closely related to immunomodulation and the polarization of M2 macrophages. However, the mechanisms involving AhR and M2 macrophages in AR remain unclear. Methods: Bioinformatics analysis of GEO datasets (GSE180697 and GSE180697) assessed AhR and IL4I1 expression levels, which were then verified in the nasal mucosa, monocytes and serum of patients with AR using western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Primary human mononuclear cells were isolated from peripheral blood using a magnetic separation technique, and THP-1 cell lines with IL4I1 overexpression or downexpression were established through lentiviral constructs. M2 macrophages were induced with the cytokines CSF, IL4 and IL13 and then treated with the AhR agonist FICZ or inhibitor CH223191. The polarization of M2 macrophages was measured by flow cytometry and western blotting. Furthermore, primary nasal epithelial cells and macrophages were co-cultured to assess the epithelial-mesenchymal transition (EMT) in epithelial cells. The AR murine model was established using ovalbumin (OVA). Inflammation within the nasal mucosa and lung tissue was examined after CH223191 or IL4I1 treatment. Results: Nuclear translocation of AhR and upregulation of IL4I1 was observed in peripheral mononuclear cells and nasal mucosal tissue of patients with AR. Through the activation of AhR, IL4I1 promoted M2 macrophage polarization. Furthermore, modulation of the IL4I1/AhR axis regulated the migratory impact of OVA on T-M2 cells. The IL4I1/AhR axis was involved in the regulation of M2 macrophage-associated EMT and contributed to the expression of IL-33 and STAT6 phosphorylation in epithelial cells. In AR mice, increased A

关键词： Colitis   Hif-1α   IL-4   Succinate   Type 2 immunity  

摘要： Inflammatory bowel disease (IBD) remains a pressing global health challenge, necessitating novel therapeutic strategies. Succinate, a metabolite known for its role in type 2 immunity and tuft cell activation in the small intestine, presents its potential in IBD management. However, its impact on colonic inflammation has not been explored. Here, we demonstrate that succinate administration induces a type 2 immune response, significantly alleviating dextran sulfate sodium (DSS)-induced colonic inflammation. Succinate enhances antibacterial capacity, reduces intestinal permeability, and reshapes the colonic cytokine milieu. Mechanistically, succinate promotes myeloid cell expansion in peripheral blood, mesenteric lymph nodes, and the colonic lamina propria. The protective effects of succinate were abolished in Ccr2^−/− mice, confirming the role of monocyte recruitment, but persisted in Rag1^−/− mice, indicating independence from adaptive immunity. Adoptive transfer of monocytes from succinate-treated donors mitigated intestinal inflammation in recipient mice. Transcriptomic analysis revealed heightened expression of Il1b and Il6, and higher lactate production in monocytes upon lipopolysaccharide (LPS) stimulation, highlighting a reprogrammed pro-inflammatory trained immunity phenotype. Finally, we identify the IL-4Rα/Hif-1α axis is critical for succinate-mediated protection. These findings reveal the ability of succinate to reprogram monocytes into protective intestinal macrophages via induction of type 2 response, restoring homeostasis through enhanced barrier function and immune modulation. Our study positions thus uncover succinate as a promising therapeutic candidate for IBD. © 2025 Elsevier B.V.