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关键词： Colon Carcinogenesis   Cytotoxicity   Inflammation   Antioxidants   Xenobiotic Enzymes   Oxidative Stress  

摘要： Colon cancer ranks third in terms of prevalence and is the second leading cause of cancer-associated deaths globally. Colon cancer exhibits more prevalence among males than in females. The aim of this work is to develop a carcinogen-induced rat model of colon cancer and investigate the anti-tumor effects of muscone. Colon cancer was initiated in rats by administering 1,2-dimethylhydrazine and treated with low and high concentrations of muscone before and during the anti-tumor challenge. After the completion of treatments, the body weight changes and the occurrences of colonic polyps were analyzed, and data were tabulated. The biomarkers of oxidative stress in the colon and liver tissues were assessed using assay kits. The levels of inflammatory biomarkers and xenobiotic enzymes were examined using assay kits. The in vitro assays were conducted on human colon cancer cells 116. The treatment of muscone substantially enhanced bodyweight gain and reduced the formation of colon polyps. The treatment with muscone resulted in a reduction of inflammatory biomarkers and oxidative stress markers, as well as an improvement in the antioxidant levels in both the liver and colon tissues of rats with 1,2-dimethylhydrazine-induced colon cancer. The treatment with muscone significantly reduced the phase I enzymes and elevated the phase II enzyme in the 1,2-dimethylhydrazine-induced rats. It can be concluded that muscone has the capacity to be a chemotherapeutic agent for treating colon cancer.

关键词： alpha 7nAChR   Interleukin 22   Liver injury   Regeneration   Vagus nerve  

摘要： Background: Acute liver injury is a common pathological feature of various clinical diseases, and prolonged liver damage can lead to fibrosis and even liver failure. Studies have reported that the vagus nerve can repair liver injury through the regulation of the cholinergic anti-inflammatory pathway. However, there is limited research on the regulation of interleukin-22 and its role in liver injury. This study aimed to investigate the regulatory effect of vagus nerve receptor alpha 7nAChR on interleukin-22 and whether this regulatory axis can protect against liver injury. Methods: Rats and the human liver cell line L-02 were treated with carbon tetrachloride to simulate acute liver injury. The experimental groups were divided as follows: control group, model group, model + PNU282987 group, model + MLA group, and MLA group. After the intervention, blood samples, liver tissues, and cells were collected to assess liver function (AST, ALT), inflammation (TNF-alpha, IL-6,), alpha 7nAChR and interleukin-22 concentrations, apoptosis levels (Bax, BCL-2), and proliferation markers (Ki-67, PCNA) using quantitative real time PCR, Western blot, immunohistochemistry and ELISA. Results: The results indicated that carbon tetrachloride intervention led to compensatory increases in interleukin22 while inhibition of alpha 7nAChR decreased interleukin-22 concentrations and exacerbated the injury marked by high levels of AST, ALT and TNF-alpha,IL-6. Exogenous administration of a vagus nerve agonist alleviated liver injury and was accompanied by an increase in interleukin-22 levels. In rescue experiments, simultaneous inhibition of vagus nerve receptors and administration of exogenous interleukin-22 reduced liver injury and significantly enhanced liver regeneration. Conversely, activation of vagus nerve receptors while inhibiting interleukin-22 aggravated liver injury. Conclusion: This study confirms that vagus nerve receptor alpha 7nAChR can promote liver regeneration and protect again

关键词： Inflammatory bowel disease   Interleukin-34   Escherichia coli Nissle1917   Genetically engineered bacteria   Intestinal mucosal barrier   Tight junction protein  

摘要： Background: The intestinal mucosa of ulcerative colitis patients expresses high levels of interleukin 34, and mice lacking IL-34 have more severe DSS-induced experimental colitis. There are no studies on the effects of directly upregulating intestinal IL-34 on experimental colitis in mice. Methods: The bacteria EcN/CSF-1 and EcN/IL-34, which express CSF-1 and IL-34, respectively, were genetically engineered from Escherichia coli Nissle 1917 (EcN). Colitis mice received daily gavage of sterile PBS buffer, empty plasmid E. coli (EcN/WT), EcN/CSF-1, or EcN/IL-34. Each group of mice was assessed for body mass, clinical signs, DAI, intestinal mucosal permeability, pathological, and immunohistological changes. In vitro, NCM460 cells were treated with CSF-1 or IL-34 recombinant proteins in the presence of signaling pathway inhibitors to evaluate tight junction protein expression. Additionally, intestinal mucosal epithelial cells isolated from active UC patients were analyzed for IL-34 and tight junction protein levels. Results: DSS-induced colitis mice are protected by EcN/IL-34 gavage. Pathological results showed that EcN/IL-34 group colonic histological injury was significantly improved and tight junction protein ZO-1 and Occludin expression increased. In NCM460 cells, IL-34 also increased tight junction protein expression. More importantly, expression of IL-34 was positively correlated with the level of tight junction protein expression in epithelial cells of UC patients. Conclusion: EcN/IL-34 can directly act on damaged intestinal mucosa, up-regulate IL-34 expression, and promote tight junction protein expression in intestinal mucosal epithelial cells to alleviate experimental colitis in mice. IL- 34 may be a potential therapeutic target for ulcerative colitis, and genetically engineered bacteria carrying the cytokine may offer new ideas for treating UC.

关键词： HLA   HLA-A*03:01:130   novel allele   sequencing-based typing  

摘要： HLA-A*03:01:130 differs from HLA-A*03:01:01:01 by one nucleotide substitution in codon 266 in exon 4.

关键词： Endometriosis   Adenomyosis   Frozen embryo transfer   TNF-alpha inhibitor  

摘要： Problem: Endometriosis and adenomyosis have common pathogenesis and close relationship, with multi-factors involved in related infertility and IVF failure. They lead to anatomical changes, ovarian reserve reduction, endocrine abnormalities, altered endometrial receptivity and immunological dysfunction. Collective evidence indicate that abnormal function of immune cells and secretion of cytokines are closely related to reproductive outcomes among the women. Some studies showed that increased secretion of tumor necrosis factor alpha (TNF alpha) led a key role in pro-inflammatory response in women with endometriosis/***-a is embrryotoxic and receptivity impairing. Therefore, immunotherapy is a targeted therapeutic strategy apart from routine treatment. TNF-alpha inhibitors such as etanercept and adalimumab were shown to reduce the embryotoxic and antiinflammatory effects to increase IVF pregnancy rates in recurrent implantation failure or endometrioma patient. However, there's no evidence about the use of adalimumab for patients with endometriosis and/or adenomyosis undergoing Frozen embryo transfer(FET). Method of study: A retrospective analysis of 141 women with endometriosis and/or adenomyosis undergoing FET from January 2021 to Jun 2023 was *** were 20-42 years old, with or without previous implantation failure. Endometriosis was diagnosed by laparoscopy during their infertility workup and adenomyosis was confirmed by vaginal ultrasound screening. GnRH agonist and hormone replacement treatment (HRT) or HRT were taken for endometrium preparation according to doctor's evaluation and preference. Before and after embryo transfer, 84 women were treated with Adalimumab and 57 patients were untreated. Implantation rate, clinical pregnancy rate, ongoing pregnancy rate and live birth rate were compared between the two groups. Results: The demographics and baseline characteristics between the two groups were comparable. Stage of embryo transferred and

关键词： Chick   Eimeria necatrix   Matrine   Tuft cell-intestinal stem cell-goblet loop   IL-13/JAK2/STAT3 signaling  

摘要： As sensors in the gut, tuft cells integrate a complex array of luminal signals to regulate the differentiation fate of intestinal stem cells (ISCs), which trigger a loop of tuft cell-ISC-goblet cell after parasitic infection. As a plantderived alkaloid, Matrine plays a prominent role for standardizing ISC functions in Eimeria necatrix (EN)exposed chicks. In this study, we investigated the modulation effects of Matrine on the specific intestinal epithelial cell loop in EN-exposed chicks in vivo and intestinal organoids (IOs) ex vivo. The results showed that EN infection resulted in swelling and hemorrhage of the jejunum, accompanied by the increase in levels of sIgA and inflammatory cytokines (IL-6, IL-1 beta, and TNF-alpha). And these inflammatory symptoms were effectively relieved by Matrine intervention. Concurrently, Matrine resisted the EN-induced increase in tuft cell numbers and levels of crucial pro-inflammatory factors (IL-25 and IL-13), while also reversing the differentiation of secretory cell progenitors into goblet cells. Importantly, Matrine impeded the upregulation of the inflammatory signaling pathway JAK2/STAT3 in EN-infected chicks and IOs. Conversely, exogenous supplementation of IL-13 or activation of STAT3 via Colivelin eliminated the standardization of the tuft cell-ISC-goblet cell loop by Matrine. Overall, our findings suggested that Matrine intercepted the tuft cell-ISC-goblet cell loop by reinstating IL-13/ JAK2/STAT3 signaling after EN infection.

关键词： Breast cancer   HLA-A   HLA-B/C   ESR1   prognosticator   survival  

摘要： Background/Aim: The loss of breast cancer cell differentiation during metastatic progression leads to a down- regulation of class 1 human leukocyte antigen (HLA) expression, which in turn hinders cytotoxic T lymphocytes from effectively preventing tumor cell proliferation. Consequently, one would expect that decreased HLA expression would correlate with decreased 5-year survival. However, estrogen receptor alpha (ESR1) is known to be positively associated with overall survival. The study aimed to determine the expression levels of HLA-A, HLA-B/C, and ESR1 and to assess their influence on distant disease-free survival (DDFS). Materials and Methods: This retrospective subgroup analysis of the initial prospective, single-center, double-blind cohort study included a total of 34 patients who underwent a new treatment line for metastatic breast cancer (MBC). The MBC cells were examined using RTqPCR. Results: The acquired data and the subsequent survival and ROC analyses indicated a positive association of reduced expression of HLA-A and HLA-B/C with DDFS. A statistically significant association of ESR1 with DDFS could not be shown. Conclusion: A potential positive association between reduced expression of HLA-A and HLA-B/C and DDFS is observed. This contrasts with the generally observed association between HLA expression loss and poor prognosis, as reported in previous protein-based studies. In metastatic settings, reduced expression of particular HLA subsets, measured at the mRNA level, might have a protective effect against disease progression.

关键词： chronic GN   clinical trial   EGF   glomerulopathy   nephrotic syndrome  

摘要： Background FSGS and treatment-resistant minimal change disease (TR-MCD) are heterogeneous disorders with subgroups defined by distinct underlying mechanisms of glomerular and tubulointerstitial injury. A noninvasive urinary biomarker profile has been generated to identify patients with intrakidney TNF activation and to predict response to anti-TNF treatment. We conducted this proof-of-concept, multicenter, open-label clinical trial to test the hypothesis that in patients with FSGS or TR-MCD and evidence of intrarenal TNF activation based on their biomarker profile, short-term treatment with adalimumab would reverse the elevated urinary excretion of monocyte chemoattractant protein-1 (MCP-1) and tissue inhibitor of metalloproteinases 1. Methods Patients with FSGS or TR-MCD, eGFR >30 ml/min per 1.73 m(2), urine protein:creatinine ratio >= 1.5 g/g, and age 6-80 years were eligible for this trial. Adalimumab, 20-40 mg, was administered through subcutaneous injection every 2 weeks for five doses. Participants were evaluated at weeks 0 (baseline), 2, 8, and 10. Excretion of urinary monocyte chemoattractant protein-1, urinary tissue inhibitor of metalloproteinases 1, urinary excretion of EGF, and plasma monocyte chemoattractant protein-1 were measured at each visit. Results Seven participants were enrolled, with median baseline urine protein:creatinine ratio 12.1 mg/mg (interquartile range [IQR], 2.2-18.6), serum albumin 2.4 g/dl (IQR, 2.0-2.8), and eGFR 57 ml/min per 1.73 m(2) (IQR, 44-96). On the basis of self-report, they received all prescribed doses of adalimumab. The patients with the most favorable response on the basis of changes in urinary biomarkers had the best preserved kidney parenchyma based on urinary excretion of EGF. Conclusions Precision medicine trials are feasible in rare glomerular disorders. In this pilot study, adalimumab resulted in a heterogenous response of the candidate mechanistic-predictive biomarkers of TNF-mediated inflammation in patients wi