Genes & Diseases
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2025
·
IF 9.4
Hui Gan,Mi Zhang,Yuhao Duan,Palahati Ailiyaer,Qi He,Junyi Tan,Yong Li,Xuan Zhai,Jing Zhao
Microglial activation triggers the inflammatory cascade and exacerbates brain injury following ischemic stroke. Middle cerebral artery occlusion (MCAO) modeling increased the expression of nuclear factor of activated T cells 5 (NFAT5) in microglia. However, the role of microglial NFAT5 in ischemic stroke remains unclear. Here, our findings indicated that microglial NFAT5 knockdown reduced the expression of pro-inflammatory factors, microglial activation, and neutrophil infiltration, ultimately ameliorating cerebral infarction and neurological deficits in mice following MCAO. Additionally, we treated hippocampal neuronal cells (HT22) with a conditioned culture medium from a microglia cell line (BV2) to simulate microglia-induced neuronal injury in vitro . We observed that NFAT5 knockdown attenuated the expression of pro-inflammatory factors in BV2 cells and reduced apoptosis in HT22 cells. Previously, our published work reported that the NOD-like receptor pyrin domain-containing 6 (NLRP6) inflammasome contributed to inflammatory injury after MCAO. In this study, we discovered that NFAT5 promoted the transcriptional activity of the Nlrp6 promoter through its −1527 bp to −1518 bp element. Notably, our results also demonstrated that NFAT5 regulated the stability of NLRP6 mRNA via the 5'UTR of Nlrp6 . Thus, our findings reveal the pivotal role and partial mechanism of microglial NFAT5 in neuroinflammation following ischemic stroke.
研究领域:
神经科学
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免疫学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Neuroscience
·
2021
·
IF 4.677
Wang Rui,Hong Ming,Huang Jingyi,Zhou Na,Zhang Yao,Xu Siyuan,Liu Jiaye,Yuan Junjie,Zhang Lusiqi,Huang Linyuan,Huang Ping,Tan Bo,Cao Hong-ying
Aim: This research aimed to investigate the neurotoxicity of low-dose cyclophosphamide (CYP) on the urinary bladder of rats by in vivo and in vitro studies.Methods: To establish CYP-induced cystitis rat model, rats were treated with three intraperitoneal injections of CYP (25 mg/kg) in a week. During treatment, the up-down method was used to assess the mechanical withdrawal threshold. On day 8, urodynamic test and bladder smooth muscle contractility study, including the contraction of bladder strips to electrical field stimulation (EFS, 2–64 Hz), carbachol (CCh, 10–8–10–5 M) and KCl (120 mM), were performed to evaluate the function of bladder function. Body weight and bladder weight were also recorded. Morphometric analysis using an optical microscope and transmission electron microscope was performed to observe the changes of microstructure and submicrostructure of the bladder. The major pelvic neurons were isolated and treated with acrolein (the main CYP metabolite) to assess apoptosis in vitro. RT-PCR assays were used to quantify the mRNA expression levels of Nlrp6, Asc, Casp11 and Casp1 in bladder tissues and primary neurons.Results: After CYP injections, the body weights decreased, but the bladder weights increased in the model group. The mechanical withdrawal threshold of the cystitis model remained at a low level. The morphometric analysis suggested bladder inflammation and neuroinflammation in the bladder of the cystitis rat model. Urodynamic test revealed that, the amplitude, the pressure baseline, the peak pressure and pressure threshold of model rats significantly increased after CYP treatment. The muscle strips of model rats exhibited significantly higher contractility caused by EFS and CCh than the controls. Apoptotic cells appeared at the highest concentration group (100 μM acrolein) after 6 h of acrolein incubation in apoptosis assay of primary neurons. The mRNA expression levels of Nlrp6 and Casp11 were significantly increased in the cystitis rat model and in the acrolein-treated neurons.Conclusions: Low-dose CYP treatment was confirmed to induce nerve injury, which leading to bladder pain and overactive bladder in female rats, and the up-regulation of Nlrp6 and Casp11 may contribute to these pathological changes.
研究领域:
药理学
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神经科学
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泌尿学
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DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2026
·Vol. 22
·期 3
·1162
·
IF 10
Hong Ding,Wen-Xuan Wang,Qiong-Dan Liang,Chuan-Feng Tang,Tang-Di Xu,Zi-An Miao,Bang-Xing Han,Ling-Dong Kong
Mitochondria-mediated apoptosis is the key determinant of glomerular podocyte injury. NOD-like receptor family pyrin domain proteins (NLRPs) are aberrant in clinical kidney diseases, but the role in podocyte mitochondrial dysfunction is unclear. Here, we first observed only NLRP6 expression change in nephrotic syndrome patients with proteinuria. Next, we found that mouse glomerular podocyte NLRP6 expression was increased in high fructose-induced proteinuria with mitochondria-mediated apoptosis. Importantly, Nlrp6 deficiency ameliorated these disturbances in mice. NLRP6 downregulation inhibited podocyte mitochondrial outer membrane permeabilization (MOMP)-associated apoptosis via suppressing B-cell lymphoma 2-related ovarian killer (BOK) under high fructose stimulation. However, high NLRP6 expression blocked the binding of Tripartite motif-containing protein 7 (TRIM7) with Bok mRNA 3' untranslated region, decreased mRNA decay, and thereby downregulated antioxidant protein family with sequence similarity 213, member A (FAM213A), resulting in mitochondria-mediated apoptosis in high fructose-exposed podocytes. A nephroprotective agent gastrodin was found to decrease NLRP6 and relieve mitochondria-mediated apoptosis caused by high fructose, possibly through promoting TRIM7-driven Bok mRNA degradation and FAM213A antioxidant effect. This study uncovered that high NLRP6 expression-driven mitochondria-mediated apoptosis could participate in podocyte injury and the suppression of NLRP6 by gastrodin may be an attractive therapeutic approach for podocyte injury.
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DOI
PubMed
高影响因子
Frontiers in Nutrition
·
2022
·
IF 6.59
Qianqian Yao,Linlin Fan,Nan Zheng,Christophe Blecker,Véronique Delcenserie,Huiying Li,Jiaqi Wang
Gut microbiota dysbiosis, together with goblet cells dysfunction has been observed in ulcerative colitis cases. This study aims to evaluate the potential of 2′-fucosyllactose (2′-FL) supplementation in inhibiting intestinal inflammation through regulating gut microbiota, protecting goblet cells, and stimulating mucin secretion. 2′-FL was orally administered to C57BL/6J mice daily (400 mg/kg bw) for 21 days and 5% dextran sulfate sodium (DSS) was used to induce the colitis in the last 7 days. Meanwhile, fecal microbiota transplantation (FMT) was conducted to test the roles of gut microbiota in the remission of colitis by 2′-FL. Gut microbiota alteration was analyzed through 16S ribosomal RNA (16S rRNA) sequencing. Periodic acid-Schiff (PAS), immunofluorescence staining, as well as mucin 2 (MUC2) and NOD-like receptor family pyrin domain containing 6 (NLRP6) messenger RNA (mRNA) expression in colon fragments was performed and detected. The results showed that the DSS + 2′-FL mice were found to have a slower rate of weight loss, lower disease activity index (DAI) scores, and longer colon lengths than the DSS group ( p < 0.05), so in the FMT recipient mice which received fecal microbiota from the DSS + 2′-FL group. In addition, the data revealed that 2′-FL relieved the disorder of DSS-induced gut microbiota, including decreasing the high abundance of mucin-utilizing bacteria in the DSS group, such as Bacteroides, Lachnospiraceae NK4A136, Lachnospiraceae , and Bacteroides vulgatus . PAS and immunofluorescence staining showed that 2′-FL treatment promoted the recovery of goblet cells and enhanced MUC2 and NLRP6 expression, which was also observed in the FM (DSS + 2′-FL) group. Moreover, NLRP6, which has been proved to be a negative regulator for Toll-like receptor 4/myeloid differential protein-8/nuclear factor-kappa B (TLR4/MyD88/NF-κB) pathway, was upregulated by 2′-FL in colon tissue. In conclusion, this study suggests that 2′-FL ameliorates colitis in a gut microbiota-dependent manner. The underlying protective mechanism associates with the recovery of goblet cells number and improves MUC2 secretion through TLR4-related pathway.
研究领域:
免疫学
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微生物学
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胃肠病学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2021
·Vol. 12
·期 10
·4484-4495
·
IF 5.396
Wanxiu Cao,Robert W. Li,Yaoxian Chin,Yuming Wang,Changhu Xue,Qingjuan Tang
Most athletes continually endure mental and physical stress from intense exercise. Fructo-oligosaccharide (FOS) can reduce physical exhaustion, but the concrete mechanism behind it still needs further research. In this study, the effect of FOS on colonic mucosal barriers was investigated using an exercise-induced stress mouse model. Except for control individuals, mice were subject to cycles of 2-day exercise (at 20 rpm) interleaved by 5-day rest. The mice experienced a total of 6 days of exercise during the feeding period. FOS improved common indicators of exhaustion, such as glycogen storage in muscle. 16S rRNA data supported that changes in the gut microbiome were also closely related to stress status. Notably, Anaerotruncus was increased in mice under stress, while FOS facilitated the growth of Dorea, which is negatively associated with exhaustion. The RNA-seq analysis revealed that FOS could maintain the integrity of colonic epithelial barriers. For example, FOS significantly restored the expression of tight junctions (Occludin and Zonula occludens-1) in the colon, which was impaired under a stress state. Besides, the NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammasome might contribute to the protection of the colonic mucosa by promoting the secretion of IL-18, Mucin2 (Muc2) and intestine lectin 1 (Itln1) in FOS-treated individuals. In short, FOS administration attenuated the damage of colonic mucosal barriers in exercise-induced stressed mice.
研究领域:
营养学
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运动生理学
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胃肠生物学
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分子生物学
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微生物组研究
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产品关联
DOI
PubMed
高影响因子
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