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关键词： biologic therapy   dual biologic therapy   dupilumab   atopic dermatitis   psoriasis   psoriatic arthritis   inflammatory bowel disease   rheumatoid arthritis   TNF-alpha inhibitors  

关键词： Thyroid hormone receptor alpha 1   Female reproduction   Resistance to thyroid hormone   KLF9   Spatial transcriptomics   Endometrial metaplasia   Infertility  

摘要： Thyroid hormone receptors (TRs) mediate the genomic actions of thyroid hormone. Mutations of THRA gene cause a human disease known as resistance to thyroid hormone (RTH alpha). We created a mouse model expressing a dominant negative mutated TR alpha 1 (Thra1PV/+ mice) that exhibits growth retardation, bone abnormalities, constipation, and anemia, as found in RTH alpha patients. In addition, female Thra1PV/+ mice exhibit decreased fertility. In the present study, we aimed to characterize the molecular events leading to infertility. Histologically, there was progressive uterine atrophy in Thra1PV/+ mutant mice, characterized by squamous metaplasia of the endometrial mucosa and endometrial fibrosis. RNA-seq analysis of laser-captured micro-dissected endometrium and spatial transcriptomics revealed a key role for Kr & uuml;ppel-like factor (Klf9), a directly-regulated TR target gene, in normal endometrial differentiation. Klf9 was suppressed in the endometrium of mice harboring mutated TR alpha 1 and pathway analysis revealed that deficient Klf9 signaling was associated with squamous differentiation, consistent with the endometrial metaplasia observed histologically. Further, we showed that this metaplastic endometrial mucosa was the source of ectopic IL-33, which was associated with increased T-cell infiltrates, destruction of glands, and endometrial fibrosis. Our studies provide new insights to understand uterine epithelial morphogenesis and how thyroid dysfunction could lead to female infertility.

关键词： Diabetic mice   Mudan granules   TMT proteomics   FBN2   TNF-alpha  

摘要： Ethnopharmacological relevance: Mudan granules (MuD), a time-honored traditional Chinese patent medicine (TCPM), are widely utilized in the clinical treatment of diabetic peripheral neuropathy (DPN). In the field of biomedical diagnostics, both diabetic retinopathy (DR) and DPN are recognized as critical microvascular complications associated with diabetes. According to the principles of traditional Chinese medicine (TCM), these conditions are primarily attributed to a deficiency in Qi and the obstruction of collaterals. Despite this, the protective effects of MuD on DR and the underlying mechanisms remain to be comprehensively elucidated. Aims of the study: The purpose of this study was to investigate the effect of MuD on DR and to further explore the promising therapeutic targets. Methods: A diabetic mouse model was established by administering 60 mg/kg of streptozotocin (STZ) via intraperitoneal injection for five consecutive days. The therapeutic efficacy of MuD was evaluated using a comprehensive approach, which included electroretinogram (ERG) analysis, histopathological examination, and assessment of serum biochemical markers. Then, the pharmacodynamic mechanisms of MuD were systematically analyzed using Tandem Mass Tags-based proteomics. Meanwhile, the candidate compounds of MuD were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) and molecular docking was applied to estimate the affinity of the active ingredient to their potential key targets. In addition, the functional mechanisms identified through bioinformatics analysis were confirmed by molecular biological methods. Results: We demonstrated that MuD provided significant protection to retinal function and effectively mitigated the reduction in retinal thickness observed in the animal model. Through proteomic analysis, we identified a substantial regulation by MuD of 70 biomarkers associated with diabetic retinal damage. These proteins were n

关键词： CD8(+) T cells   Tc17 cells   colon   inflammation   immunity  

摘要： Colon-resident CD8(+) T cells actively contribute to gut homeostasis and the pathogenesis of inflammatory bowel disease. However, their heterogeneity in generating IL-17-expressing CD8(+) T cells, i.e. Tc17 cells, has not been thoroughly revealed. This study aims to characterize the abilities of mouse colonic intraepithelial (IE) and lamina propria (LP) CD8(+) T cell subsets to differentiate into Tc17 cells. Using flow cytometry, we found that normal TCR beta(+)CD4(-)CD8 alpha alpha(+) cells (CD8 alpha alpha T cells) and TCR beta(+)CD4(-)CD8 alpha beta T cells, (CD8 alpha beta T cells), either IE or LP, expressed abundant granzymes and IFN-gamma but minute IL-17A. Under the in vitro Tc17-inducing condition, IE CD8 alpha alpha T cells showed the weakest Tc17 differentiation ability and LP CD8 alpha beta T cells exhibited the strongest Tc17 differentiation ability, whereas IE CD8 alpha beta T cells and LP CD8 alpha alpha T cells demonstrated moderate Tc17 differentiation abilities. The expression of IL-6 receptor, TGF-beta receptor, TCR signaling indicators, CD161, and IL-23 receptor was low in IE CD8 alpha alpha T cells, median in IE CD8 alpha beta T cells and LP CD8 alpha alpha T cells, but high in LP CD8 alpha beta T cells. IE CD8 alpha alpha T cells weakly induced the expression of chemokines, cytokines, and host defense mediators in colonic epithelial cells while LP CD8 alpha beta T cells showed a robust up-regulatory effect. Furthermore, these colonic CD8(+) T cell subsets also exhibited different abilities to generate Tc17 cells in inflamed colons. Collectively, LP CD8 alpha beta T cells have the strongest Tc17 differentiation ability and might play a more significant role than the other subsets in Tc17-mediated immunity or inflammation in the colon.

关键词： Liver transplantation   Gut microbiota   Cytokine   IL-10   IL-17   Nosocomial infection  

摘要： BackgroundLiver transplantation (LT) is a critical intervention for individuals with end-stage liver disease;yet, post-transplant problems, especially infections, graft rejection, and chronic liver disease, are often linked to systemic inflammation. Cytokines, small signaling molecules, significantly influence immune responses during and post-liver transplantation. Nonetheless, the intricate relationships among cytokines, immune responses, and the gut microbiota, especially gut dysbiosis, are still inadequately comprehended. Thus, this study aims to identify the gut microbiota (GM) and determine their relationship to cytokines (IL-17 and IL-10) in LT patients, due to their importance in enhancing the recovery *** research included 31 liver transplant (LT) patients from the Gastroenterology Surgical Center at Mansoura University, resulting in the collection of 174 stool and blood samples from all participants. Fourteen bacterial species have been identified in samples collected at three intervals: one week before, one week post, and two weeks post LT. A change in gut microbiota composition was noted, characterized by a rise in potentially pathogenic bacteria such as Enterococci and Enterobacteriaceae (including Escherichia coli and Klebsiella) and a reduction in beneficial bacteria such as Bacteroidetes and Firmicutes. The examination of patient demographic and clinical data revealed no significant correlations between sex, age, or diagnostic categories and gut microbiota composition. The findings of the Multivariate Analysis of Variance (MANOVA) indicated a substantial effect of gut microbiota composition on cytokine levels (IL-10 and IL-17), with all tests producing p-values of 0.001. The assessment of cytokine levels indicated fluctuating variations at several time points following surgery. IL-10 levels in the GM groups exhibited a statistically significant elevation during the second week post-surgery (p = 0.036), suggesting a potential recovery-relate

关键词： C. mannii seed oil   cyclophosphamide   Liver and kidney toxicity   Prophylactic efficacy  

摘要： This study aimed to determine whether C. mannii seed oil (CMSO) could shield rats from cyclophosphamide-induced hepatorenal toxicity. The focus was on its antioxidant and anti-inflammatory properties. We randomly assigned thirty-six (36) male Wistar rats into six groups of six rats each. Groups A and B served as normal and negative controls, respectively. Group C, the standard control, was administered 300 mg/kg body weight (bw) of Omega 3 oil for 27 days, followed by 100 mg/kg bw of cyclophosphamide on day 28. Group D, E, and F received 5, 2.5, and 1.5 ml/kg b.w. of CMSO for 27 days, then 100 ml/kg b.w. of cyclophosphamide on day 28. We measured the body weights of the experimental rats every week. Rats of all groups were sacrificed on day 30 and collected blood for biochemical analysis using standard methods. The phytochemical constituents were determined by the spectrophotometric method. The phytochemical study of CMSO indicated the relative composition of constituents(mg/100g) as phenols (30 %), tannins (20 %), flavonoids (18 %), terpenoids (15 %), glycosides (10 %), alkaloids (5 %), and HCN (2 %) in Cucumeropsis mannii seed oil. When cyclophosphamide was given to Wistar albino rats, it greatly decreased the activities of catalase (CAT) and superoxide dismutase (SOD), but it increased the activities of iNOS and the levels of MDA and IL-1β. Cyclophosphamide increased ALT (52.3 U/L), AST (48.7 U/L), ALP (46.5 U/L), total bilirubin (1.4 mg/dL), conjugated bilirubin (0.8 mg/dL), creatinine (0.8 mg/dL), urea (45.6 mg/dL), and BUN (15.7 mg/dL), with a reduction in the albumin (4.8 g/dL) level. Cyclophosphamide administration also caused hepatocellular necrosis, inflammatory leukocyte infiltration, tubular necrosis, and proteinaceous deposits in Bowman's space in the kidney. However, combining CMSO and Omega 3 oils significantly restored the altered histology architecture, antioxidant, inflammatory markers, and liver and kidney function parameters to levels comparable

摘要： Oncolytic viruses (OVs) emerge as a promising cancer immunotherapy. However, the temporal impact on tumor cells and the tumor microenvironment, and the nature of anti-tumor immunity post-therapy remain largely unclear. Here we report that CD4+ T cells are required for durable tumor control in syngeneic murine models of glioblastoma multiforme after treatment with an oncolytic herpes simplex virus (oHSV) engineered to express IL-12. The upregulated MHCII on residual tumor cells facilitates programmed polyfunctional CD4+ T cells for tumor control and for recall responses. Mechanistically, the proper ratio of Bcl-6 to T-bet in CD4+ T cells navigates their enhanced anti-tumor capacity, and a reciprocal IL6ra-Bcl-6 regulatory axis in a memory CD4+ T-cell subset, which requires MHCII signals from reprogrammed tumor cells, tumor-infiltrating and resident myeloid cells, is necessary for the prolonged response. These findings uncover an OV-induced tumor/myeloid-CD4+ T-cell partnership, leading to long-term anti-tumor immune memory, and improved OV therapeutic efficacy.

关键词： angiogenesis   ERK1/2   gastric cancer   Interleukin-1 ss   reactive oxygen species   triptolide   Interleukin-8  

摘要： Triptolide, the major component of Chinese herbal medicine Tripterygium wilfordii Hook F, possesses potent anticancer and anti-inflammatory effects. IL-8, a proinflammatory cytokine, is associated with cancer cell proliferation and angiogenesis. Here, we found that Triptolide has an inhibitory effect on IL-1 beta-induced IL-8 expression in human gastric cancer cells, via the suppression of reactive oxygen species (ROS) production, AP-1, and NF-kappa B activation, which in turn affects human endothelial cell angiogenetic activity in tumor microenvironments. Human gastric AGS cells were treated with IL-1 beta (10 ng/mL) and Triptolide (0-20 nM), and the ROS generation, ERK, AP-1, and NF-kappa B signaling were all investigated. These results demonstrate that Triptolide inhibits the IL-1 beta-induced IL-8 expression in gastric cancer cells by inhibiting ROS production and angiogenesis, via the dose-dependent attenuation of ERK, AP-1, and NF-kappa B activation. In this study, we showed that Triptolid inhibits ROS/ERK-mediated AP-1 and ROS-mediated NF-kappa B axes potentially leading to an improved treatment outcome for gastric cancer and its associated tumor microenvironment.

关键词： Melastoma dodecandrum   Isovitexin   TNF-alpha   Cell membrane chromatography   Key component  

摘要： Ethnopharmacological relevance: Melastoma dodecandrum (MD), a traditional ethnomedicine, has been widely used for the treatment of fractures, osteoarthritis, and osteoporosis due to its remarkable anti-inflammatory activity. However, the specific active components responsible for its therapeutic effects on orthopedic conditions remain unidentified. Aim of the study: This study aimed to screen and identify key active components in MD using a combination of cell membrane chromatography and mass spectrometry, followed by cellular validation. Materials and methods: A TNF-alpha-induced osteoblast injury model and an osteoblast membrane chromatography screening system were established to select and identify chemical components of MD that directly act on osteoblasts. The protective effects of MD on osteoblasts were assessed by evaluating cell viability, alkaline phosphatase (ALP) activity, cell mineralization and the expression of osteogenesis-related proteins OCN, RUNX2, and the TNF-alpha receptor protein TNFR1. Validation of the activity of individual components was also conducted. Results: MD significantly improved the viability of osteoblasts under TNF-alpha-induced injury, enhanced ALP activity, stimulated the expression of OCN and RUNX2 proteins, and decreased the expression of TNFR1. Cell membrane chromatography screening identified 32 chemical components, including 21 flavonoids, 6 organic acids, 2 phenylpropanoids, 2 terpenes, and 1 nucleotide. Molecular docking revealed that isovitexin could bind to the specific receptor TNFR1 on the cell membrane. Furthermore, cellular validation demonstrated that isovitexin significantly protected osteoblasts. Conclusions: MD and its pharmacologically active component, isovitexin, exhibit protective effects against TNF alpha-induced inflammatory injury in osteoblasts, laying a solid foundation for future drug development.