LABORATORY INVESTIGATION
·
2021
·Vol. 101
·期 9
·1118-1129
·
IF 5.662
Wang Xin,Li Xing-Liang,Qin Li-Jie
Myocardial injury is a severe complication of sepsis and contributes substantially to the death of critically ill patients. Long non-coding RNAs (lncRNAs) participate in the pathogenesis of sepsis-induced myocardial injury. In this study, we investigated the role of lncRNA X-inactive specific transcript (XIST) in septic myocardial injury and explored its mechanism. Lipopolysaccharide (LPS)-stimulated H9C2 cells and rats subjected to cecal ligation and puncture (CLP) were used as the in vitro and in vivo models. After exposure to LPS, XIST and c-Fos levels were upregulated, but miR-150-5p was downregulated in H9C2 cardiomyocytes and myocardial tissues. XIST affected viability, apoptosis, and pyroptosis in LPS-challenged H9C2 cells. Moreover, XIST knockdown attenuated LPS-induced injury in H9C2 cells by targeting the miR-150-5p/c-Fos axis. c-Fos could bound to the promoter of the TXNIP/XIST gene and enhanced TXNIP/XIST expression. Silencing of XIST improved cardiac function and survival rate and reduced apoptosis and pyroptosis by regulating the miR-150-5p/c-Fos axis in septic rats in vivo. Taken together, our data show that XIST/miR-150-5p/c-Fos axis affected septic myocardial injury, which may indicate a novel therapeutic strategy for sepsis-induced myocardial injury.
研究领域:
分子生物学
·
心脏病学
·
传染病学
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药理学
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DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR ENDOCRINOLOGY
·
2022
·
IF 4.369
Ying Wang,Jiyu Yang,Yu Wang,Yao Chen,Yiran Wang,Hongying Kuang,Xiaoling Feng
Polycystic ovary syndrome (PCOS) is a complex endocrine disease . Thioredoxin-interacting protein (TXNIP) promotes oxidative stress and triggers inflammation. Herein, we investigated the role and potential mechanism of TXNIP in PCOS. In a mouse model of dehydroepiandrosterone (DHEA)-induced PCOS, we found that TXNIP was upregulated in the ovaries , especially in granulosa cells (GCs). TXNIP was also upregulated in testosterone (T)-treated GCs in vitro. Knockdown of TXNIP by lentivirus-constructed shRNA attenuated T-induced GC injury and oxidative stress, as well as inflammation and the NLRP3 inflammasome . The mechanism by which TXNIP promotes inflammation may involve TXNIP dissociation from the TXNIP-TRX complex and binding to NLRP3 to form the inflammasome. Additionally, we verified that knockdown of TXNIP ameliorated ovarian injury and inflammation in mice with DHEA-induced PCOS in vivo. Collectively, we demonstrated that TXNIP is involved in GC inflammation by promoting NLRP3 inflammasome activation in PCOS.
研究领域:
内分泌学
·
生殖医学
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分子生物学
·
炎症
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PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2023
·
IF 3.8
Hao Zhao,Xin Lin,Qingfeng Chen,Xiaoyue Wang,Yongya Wu,Xiaoxia Zhao
Sepsis-induced cardiomyopathy (SIC) has high morbidity and mortality. Quercetin (QUE) has been used to treat many inflammatory diseases related to pyroptosis . However, its effect on SIC has not been reported before. We aimed to explore the therapeutic mechanism of QUE on SIC. We found that the expression levels of NOX2, markers of myocardial injury and inflammatory factors related to pyroptosis were upregulated in the serum of SIC patients. QUE improved the viability and reduced the death rate of LPS-treated H9C2 cells. It could downregulate the expression level of NOX2 and alleviate NOX2-induced mitochondrial damage to inhibit the ROS-mediated NF-κB/TXNIP pathway thus ameliorating cell pyroptosis. Overexpression of NOX2 partially attenuated the anti-pyroptotic effects of QUE on LPS-treated H9C2 cells in vitro. Besides, the results of animal experiments reported that the mitochondrial damage was reduced by QUE treatment, which subsequently inhibited the ROS-mediated NF-κB/TXNIP pathway to ameliorate cell pyroptosis to further alleviate myocardial injury in CLP-induced rats in vivo. To conclude, QUE suppressed the NOX2/ROS-mediated NF-κB/TXNIP signaling pathway to ameliorate pyroptosis of cardiomyocytes to relieve SIC.
研究领域:
药理学
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心脏病学
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免疫学
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细胞生物学
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分子生物学
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PubMed
高影响因子
PHYTOMEDICINE
·
2021
·
IF 5.34
Xiaohui Wang,Lu Wang,Renchao Dong,Kai Huang,Changyuan Wang,Jiangning Gu,Haifeng Luo,Kexin Liu,Jingjing Wu,Huijun Sun,Qiang Meng
Background Chemical liver injury is one of the main causes of acute liver failure and death. To date, however, treatment strategies for acute liver injury have been limited. Therefore, there is an urgent need to find new therapeutic targets and effective drugs. NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome is a complex of multiple proteins that has been shown to induce cell death under inflammatory and stress pathologic conditions and is thought to provide new targets for the treatment of a variety of diseases. Purpose The purpose of this study was to investigate whether luteolin has a protective effect on the liver and further elucidate whether it is realized through the thioredoxin interacting protein (TXNIP)-NLRP3 axis. Study design Acute hepatic injury in mice caused by intraperitoneal injection of lipopolysaccharide (LPS) was treated with or without luteolin. Methods Male C57BL/6 mice and mouse primary hepatocytes were selected. TXNIP protein knockdown was achieved by siRNA , qPCR and Western blot were performed to explore the mechanism of luteolin in alleviating acute liver injury. Results The results indicated that luteolin had a markedly protective effect on acute liver injury induced by LPS in mice by inhibiting the TXNIP-NLRP3 axis. Luteolin inhibits NLRP3 inflammasome activation by suppressing TXNIP, apoptosis associated speck-like protein containing a CARD domain (ASC), caspase-1, interleukin-1β (IL-1β) and IL-18 to reduce liver injury. In addition, luteolin inhibits LPS-induced liver inflammation by inhibiting the production of inflammation-related gene tumor necrosis factor-α (TNF-α), IL-10, and IL-6. What's more, luteolin alleviated LPS-induced hepatocyte injury by inhibiting oxidative stress and regulating MDA , SOD , and GSH levels. However, the protective effect of luteolin on acute LPS-induced liver injury in mice was blocked by si-TXNIP in vitro . Conclusions These combined data showed that luteolin may alleviate LPS-induced liver injury through the TXNIP-NLPR3 axis, providing new therapeutic targets and therapeutic drugs for subsequent studies.
研究领域:
药理学
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免疫学
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肝病学
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分子生物学
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DOI
PubMed
高影响因子
NEUROSCIENCE
·
2024
·
IF 2.9
Tao Ye,Ning Zhang,Yunting He,Chunyan Chen,Qiqi Zha,Anbang Zhang,Xiuqi Sun,Xuemei Wu
Cerebral ischemia–reperfusion injury is frequently associated with neuroinflammation. The modulation of microglial polarization presents a promising approach for addressing cerebral ischemia–reperfusion injury. While electroacupuncture preconditioning has demonstrated efficacy in the management of ischemic stroke, the underlying therapeutic mechanisms remain inadequately understood. The investigation focused on elucidating the relationship between alterations in the TLR4/NF-κB/TXNIP/NLRP3 signaling pathway and microglial polarization subsequent to EA pretreatment. Established a middle cerebral artery occlusion (MCAO) rat model following electroacupuncture (EA) treatment at the Baihui (GV 20) acupoint. Male Sprague-Dawley rats were randomly assigned to the sham, Ischemia/Reperfusion (I/R), I/R + EA groups (n = 6). The results of Nissl Staining and TUNEL Stainingl showed that the number of curative neurons increased significantly after pretreatment, indicating an improvement in neuron formation and an increase in the number of austenite. The level of apoptosis in brain tissue in the I/R group was significantly higher than that in the sham operation group. Electroacupuncture pretreatment can effectively inhibit apoptosis occurrence. In addition, electric acupuncture pretreatment protects rat blood–brain barrier integrity and mitochondrial function. After treatment, the number of M1-type microglia decreased, while the number of M2-type microglia increased. These results suggest that EA preconditioning may alleviate neurological deficits and neuronal apoptosis caused by cerebral I/R injury, while maintaining the integrity of the blood–brain barrier and promoting microglial polarization through the TLR4/NF-κB/TXNIP/NLRP3 signaling pathway. Our findings establish a new molecular mechanism and theoretical foundation for electroacupuncture therapy of ischemic stroke.
研究领域:
神经科学
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免疫学
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药理学
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中医
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PubMed
高影响因子
JOURNAL OF MOLECULAR HISTOLOGY
·
2026
·Vol. 57
·期 3
·142
·
IF 2.6
Ye Chunhua,Liu Hua,Ming Zhu,Yi Qinjun,Xiang Rong,Chen Yifu
This study investigated the role of TNF receptor associated factor 6 (TRAF6) in glomerular podocyte pyroptosis. An in vitro LN cell model was established by treating mouse glomerular podocyte MPC5 cells with 100 ng/ml LPS for 12 h. Concurrently, LN cells were treated with TRAF6 knockdown and TXNIP overexpression or NLRP3 activation (Nigericin). MRL/lpr mice were treated with adenovirus vector expressing sh-TRAF6 for in vivo validation. LPS treatment decreased cell viability, increased cell death, elevated Desmin mRNA, malondialdehyde, TRAF6, TXNIP, interleukin (IL)-1β, and IL-18, reduced Nephrin and Podocin mRNA (podocyte markers), superoxide dismutase, and glutathione levels, enhanced cell pyroptosis and lactate dehydrogenase concentration, and activated the NLRP3 inflammasome pathway. TRAF6 knockdown suppressed LPS-stimulated podocyte damage, oxidative stress, and pyroptosis. TRAF6 interacted with TXNIP at the protein level, and TRAF6 increased TXNIP protein expression. The protective functions of TRAF6 silencing on MPC5 cells were counteracted upon TXNIP overexpression or NLRP3 activation. In vivo, TRAF6 knockdown regulated the TXNIP/NLRP3 inflammasome pathway to alleviate renal tissue pathological changes and fibrosis in LN mice. In conclusion, TRAF6 activates the NLRP3 inflammasome pathway through regulating TXNIP, thereby accelerating LPS-induced oxidative stress, pyroptosis, and damage to glomerular podocytes. Hence, TRAF6 may be a promising therapeutic target for LN. Graphical abstract The alternative text for this image may have been generated using AI.
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2023
·
IF 15.1
Dongju Zhao,Chao Tian,Meng Cheng,Fan Yang,Chunxiao Tian,Yining Liu,Ziyao Chen,Gaoju Pang,Hui Shen,Jin Chang,Yan Dou
NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome is a key drug target for Parkinson’s disease (PD) therapeutics. Identifying the underlying upstream mechanisms of assembly formation is crucial for clarifying the exact pharmacological effects, but currently remains elusive for most drugs. Here, we develop a carrier-free nanomedicine (NanoQC) derived from natural phytochemical quercetin (QC) to mitigate neuroinflammation and neurodegeneration for PD treatment and demonstrate that it attenuates aberrant inflammasome assembly and activation through inhibiting the deubiquitination of NLRP3 and blocking its interaction with thioredoxin-interacting protein (TXNIP). Intranasal NanoQC administration alleviates nigral dopaminergic neuronal loss and striatal dopamine depletion, while improving nigral dopaminergic neuronal excitability and hippocampal synaptic plasticity, relieving olfactory dysfunction, ultimately ameliorating motor and memory impairments in PD mice. This work demonstrates the great promise of NanoQC inhibiting the upstream mechanisms of NLRP3 inflammasome assembly to combat PD, providing novel insight for precise target identification of nanomedicines.
研究领域:
神经科学
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药理学
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纳米技术
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分子生物学
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DOI
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2022
·
IF 7.129
Ning Li,Liuding Wen,Fangyu Wang,Tianlin Wang,Tiange Li,Mingwu Qiao,Lianjun Song,Erkigul Bukyei,Xianqing Huang
It is well known that lead-induced neurotoxicity is closely related to oxidative stress. According to previous reports, wheat germ peptides (WGPs) isolated from wheat germ have been shown to have potent antioxidant capacity. This study hypothesized that WGPs could protect PC12 cells from lead-induced oxidative stress. Here, the protecting-efficacies of WGPs were investigated in PC12 cells that were pretreated with WGPs (200 μM, 4 h) and exposed to lead (10 μM, 24 h). The antioxidant capacity was assessed by cell viability, ROS, MDA, SOD, CAT, GR, GPx, GSH, and GSSG. The experimental results showed that WGP3, WGP8, and WGP9 could reverse the reduction of cell viability caused by lead exposure. Lead exposure causes oxidative stress by increasing the levels of ROS and MDA. Moreover, the decrease in the levels of SOD, CAT, GPx, GR, and GSH/GSSG could be observed. However, WGP3, WGP8, and WGP9 can protect PC12 cells against lead-induced oxidative stress by reversing these phenomena. The protein expression of TXNIP, Keap1, and Nrf2 was characterized by western blotting, and the results illustrated that lead exposure up-regulated the expression of TXNIP and Keap1 and down-regulated the expression of Nrf2, and WGP3, WGP8, and WGP9 could improve the antioxidant capacity of PC12 cells by reversing this phenomenon. Therefore, the present study demonstrated that WGP3, WGP8, and WGP9 may protect against lead-induced oxidative stress in PC12 cells by regulating the TXNIP/Keap1/Nrf2 pathway.
研究领域:
神经毒理学
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氧化应激
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细胞生物学
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药理学
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DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2026
·Vol. 60
·期 32
·22274-22286
·
IF 12.2
Liu Xinwei,Zhao Jiayi,Zhang Yinqing,Zhu Lingyan
Microplastics are ubiquitous in the
atmosphere and may be inhaled
into the respiratory system to cause adverse health effects. Photoaging
of microplastics in the atmosphere is inevitable, which changes their
toxic effects greatly, yet the impacts and underlying mechanisms remain
poorly understood. In this study, poly(vinyl chloride) microplastics
(PVC-MPs), commonly detected in the atmosphere, were selected to investigate
the effects of photoaging on pulmonary toxicological responses at
7 days after a single intratracheal instillation in a mouse model.
Photoaging enhanced the abundance of oxygen-containing functional
groups on the particle surface, surface hydrophilicity, and oxidative
potential. Upon a short-term intratracheal exposure, photoaged PVC-MPs
(A-PVC) induced more severe pulmonary inflammation and epithelial
barrier dysfunction than the virgin PVC-MPs (V-PVC), as evidenced
by increased protein leakage and lactate dehydrogenase release in
bronchoalveolar lavage fluid and disruption of tight junction proteins.
Transcriptomic analysis revealed enrichment of the NOD-like receptor
signaling pathway and activated TXNIP–NLRP3 inflammasome axis. In vitro tests with BEAS-2B cells indicated that more A-PVC
was adsorbed on the cell membrane, likely due to increased membrane
affinity than V-PVC, thus triggering excessive ROS generation and
leading to TXNIP-dependent NLRP3 activation and tight junction disruption.
Inhibition of ROS, TXNIP, or NLRP3 attenuated inflammasome activation
and preserved barrier integrity. These findings demonstrate that environmental
photoaging exacerbated short-term pulmonary toxicity of PVC-MPs through
a ROS–TXNIP–NLRP3-mediated inflammatory amplification
axis.
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高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·1-17
·
IF 3.9
Chen Dongzhui,Yin Feifei,Yang Pin,Xia Wanrong,Huang Yi,Feng Yue,Yang Li,Lin Shuqiang,Zhang Qiuyue
Bronchopulmonary dysplasia (BPD) is one of the most common respiratory diseases in preterm infants. Studies have shown that ferroptosis is involved in the pathogenesis of BPD, and thioredoxin-interacting protein (TXNIP)-mediated oxidative stress also plays a role in its development. The solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling pathway is one of the key pathways regulating ferroptosis. This study aimed to investigate the mechanism by which TXNIP regulates SLC7A11/GPX4 pathway-mediated ferroptosis in BPD. Mice were randomly divided into ten treatment groups: Air, Hyperoxia, Hyperoxia + RSL3, Hyperoxia + Ferrostatin-1, Hyperoxia + Ad-shNC, Hyperoxia + Ad-shTXNIP, Hyperoxia + Ad-vector, Hyperoxia + Ad-TXNIP, Hyperoxia + Ad-shSLC7A11, and Hyperoxia + Ad-shTXNIP + Ad-shSLC7A11. Lung tissues were collected for hematoxylin and eosin (H&E) staining to observe pathological changes, and transmission electron microscopy (TEM) was used to examine mitochondrial morphology. Real-time quantitative polymerase chain reaction (qPCR) was performed to measure the mRNA expression of TXNIP, SLC7A11, and GPX4. Western blotting was used to analyze the protein levels of TXNIP, SLC7A11, and GPX4. GPX4 activity was determined using an enzyme-linked immunosorbent assay (ELISA). Additionally, glutathione (GSH), malondialdehyde (MDA), and ferrous iron (Fe 2+ ) levels in lung tissues were measured using corresponding detection kits. H&E staining and TEM confirmed successful modeling of lung injury after hyperoxia. MDA and Fe 2+ increased, GSH decreased, and GPX4 activity declined after hyperoxia. TXNIP mRNA and protein were upregulated by hyperoxia, while SLC7A11 and GPX4 were downregulated. Ferroptosis activation exacerbated lung injury, whereas inhibition alleviated it. TXNIP overexpression using adenovirus serotype 5 (Ad5) aggravated ferroptosis in BPD, and this was ameliorated by TXNIP knockdown. Knockdown of the upstream signal SLC7A11 increased ferroptosis in BPD, and simultaneous knockdown of TXNIP and SLC7A11 reversed the ferroptosis reduction. In conclusion, in the BPD model, TXNIP expression was increased, and TXNIP promoted ferroptosis by downregulating the SLC7A11/GPX4 pathway. These findings suggest that gene therapy targeting TXNIP knockdown using adenovirus as a vector may serve as a therapeutic strategy for BPD.
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PubMed
高影响因子
PEDIATRIC RESEARCH
·
2024
·
IF 3.1
Hu Yingying,Nan Yan,Lin Hongzhou,Zhao Qianlei,Chen Tingting,Tao Xiaoyue,Ding Bingqing,Lu Liying,Chen Shangqin,Zhu Jianghu,Guo Xiaoling,Lin Zhenlang
Background Hypoxic-ischemic encephalopathy (HIE) is caused by perinatal hypoxia and subsequent reductions in cerebral blood flow and is one of the leading causes of severe disability or death in newborns. Despite its prevalence, we currently lack an effective drug therapy to combat HIE. Celastrol (Cel) is a pentacyclic triterpene extracted from Tripterygium Wilfordi that can protect against oxidative stress, inflammation, and cancer. However, whether Cel can alleviate neonatal hypoxic-ischemic (HI) brain damage remains unclear. Methods Here, we established both in vitro and in vivo models of HI brain damage using CoCl 2 -treated PC12 cells and neonatal rats, respectively, and explored the neuroprotective effects of Cel in these models. Results Analyses revealed that Cel administration reduced brain infarction size, microglia activation, levels of inflammation factors, and levels of oxidative stress markers by upregulating levels of p-AMPKα, Nrf2, HO-1, and by downregulating levels of TXNIP and NLRP3. Conversely, these beneficial effects of Cel on HI brain damage were largely inhibited by AMPKα inhibitor Compound C and its siRNA. Conclusions We present compelling evidence that Cel decreases inflammation and oxidative stress through the AMPKα/Nrf2/TXNIP signaling pathway, thereby alleviating neonatal HI brain injury. Cel therefore represents a promising therapeutic agent for treating HIE. Impact
We firstly report that celastrol can ameliorate neonatal hypoxic-ischemic brain injury both in in vivo and in vitro, which represents a promising therapeutic agent for treating related brain injuries.
Celastrol activates the AMPKα/Nrf2/TXNIP signaling pathway to relieve oxidative stress and inflammation and thereby alleviates neonatal hypoxic-ischemic brain injury.
研究领域:
神经科学
·
药理学
·
儿科
·
分子生物学
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DOI
PubMed
高影响因子
Cells
·
2024
·Vol. 13
·期 24
·2070
·
IF 5.1
Wei-Jian Nong,Xin-Yi Tong,Jian-Ming Ouyang
Endoplasmic reticulum stress (ERS) can activate pyroptosis through CHOP and TXNIP; however, the correlation between this process and the formation of kidney stones has not been reported. The purpose is to investigate the effects of calcium oxalate monohydrate (COM) and calcium oxalate dihydrate (COD) on ERS and pyroptosis in HK-2 cells and to explore the formation mechanism of calcium oxalate stones. HK-2 cells were injured by 3 μm COM and COD. COM and COD significantly upregulated the expression levels of GRP78, CHOP, TXNIP, and pyroptosis-related proteins (NLRP3, caspase-1, GSDMD-N, and IL-1β). Fluorescence colocalization revealed that COM induced pyroptosis by inducing the interaction between TXNIP and NLRP3. Both COM and COD crystals can induce ERS and pyroptosis in HK-2 cells. COM induces the interaction with NLRP3 by the upregulation of CHOP and TXNIP and then promotes pyroptosis, while COD only promotes pyroptosis by the upregulation of CHOP. The cytotoxicity and the ability of COM to promote crystal adhesion and aggregation are higher than COD, suggesting that COM is more dangerous for calcium oxalate kidney stone formation.
研究领域:
细胞生物学
·
肾脏病学
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泌尿科学
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分子生物学
·
病理学
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DOI
高影响因子
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