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Nicorandil protects against coronary microembolization-induced myocardial injury by suppressing cardiomyocyte pyroptosis via the AMPK/ txnip/NLRP3 signaling pathway

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EUROPEAN JOURNAL OF PHARMACOLOGY 2022年第0期936卷 000-000页

作者： Liu, Yangchun Shu, Jin Liu, Tao Xie, Jian Li, Tao Li, Haoliang Li, Lang First Affiliated Hosp Guangxi Med Univ Cardiothorac Surg Intens Care Unit Nanning Guangxi Peoples R China First Affiliated Hosp Guangxi Med Univ Dept Cardiol Nanning Guangxi Peoples R China First Affiliated Hosp Guangxi Med Univ Dept Cardiol 21 Shuangyong Rd Nanning 530021 Guangxi Peoples R China

Background: Coronary microembolization (CME) is a common and intractable complication of coronary revas-cularization, which leads to perioperative myocardial injury, cardiac dysfunction, and poor prognosis. Nicorandil is widely used for the management of ischemic heart diseases, but the cardioprotective effects of nicorandil beyond anti-angina in CME-induced myocardial injury are worthy of further exploration. Therefore, the present study investigated the effect of nicorandil on CME-induced cardiomyocyte pyroptosis and explored the under-lying ***: A rat model of CME was established via the injection of microspheres into the left ventricle. A cell model of H9c2 cardiomyocytes stimulated by lipopolysaccharide (LPS) and hypoxia mimicked the microenvironment induced by CME. Nicorandil or the adenosine monophosphate-activated protein kinase (AMPK)-specific inhibitor compound C (CC) was administered before CME induction and cell modeling. Cardiac function, histological alterations in the myocardium, myocardial injury biomarkers in serum and cell culture supernatant, cell viability, adenosine triphosphate (ATP) level, superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, reactive oxygen species (ROS) activity, mitochondrial membrane potential, and pyroptosis-associated index were assessed after the animal and cell modeling of ***: Nicorandil pretreatment attenuated cardiac dysfunction and myocardial injury following CME. Nicor-andil also alleviated oxidative stress and mitochondrial damage. Moreover, nicorandil promoted AMPK activa-tion, reduced the expression of thioredoxin-interacting protein (txnip), inhibited the activation of the NOD-like receptor pyrin containing 3 (NLRP3) inflammasome, and mitigated cardiomyocyte pyroptosis. However, co -treatment with CC reversed the cardioprotective effects of ***: Nicorandil pretreatment inhibits cardiomyocyte pyroptosis and alleviates CME-induced myocardial injury via the AM

关键词： Nicorandil Coronary microembolization Myocardial injury Cardiomyocyte Pyroptosis AMPK txnip NLRP3

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Paeoniflorin ameliorates diabetic liver injury by targeting the txnip-mediated NLRP3 inflammasome in db/db mice

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INTERNATIONAL IMMUNOPHARMACOLOGY 2022年 109卷 108792页

作者： Wang, Anli Gong, Yingjie Pei, Zhixin Jiang, Ling Xia, Lingling Wu, Yonggui Anhui Med Univ Affiliated Hosp 1 Dept Infect Dis Hefei 230032 Anhui Peoples R China Anhui Med Univ Affiliated Hosp 1 Dept Nephropathy Hefei 230032 Anhui Peoples R China Anhui Med Univ Ctr Sci Res Hefei 230022 Anhui Peoples R China

Background: Diabetic liver injury (DLI) is a complication that damages the quality of life in diabetes patients. While paeoniflorin (PF) exhibits anti-inflammatory and antioxidant effects, no data are available on whether PF protects against DLI. Therefore, we evaluated the effects of PF on hepatic steatosis and inflammation in db/db mice, a type 2 diabetes ***: In this study, we investigated the effects of PF on DLI using diabetic mice model (db/db mice) and high glucose (HG)-induced mouse AML12 cells. The effects of PF on txnip-mediated NLRP3 inflammasome in vivo and in vitro were evaluated by Western bloting, RT-PCR, immunohistochemistry (IHC) and immunofluorescence (IF) analysis. Through molecular docking experiments and cellular thermal shift assay (CETSA), we studied the binding ability of PF to thioredoxin-interacting protein (txnip). We use txnip siRNA to knock down txnip in AML12 ***: We found that PF reversed abnormal liver function and liver steatosis in db/db mice, while blocking the release of inflammatory cytokines. These effects are associated with PF inhibition of the txnip/NLRP3 signaling pathway. Molecular docking experiments and CETSA also demonstrated that txnip is a likely target of PF. In HG-treated AML12 cells, txnip knockdown eliminated the beneficial effects of ***: Using a combination of animal and in vitro experiments, this study demonstrated for the first time that PF ameliorates DLI through targeting the txnip-activated NLRP3 inflammasome. Thus, PF may be a po-tential therapeutic agent against DLI.

关键词： T2DM Diabetic liver injury Inflammation Paeoniflorin txnip NLRP3

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miR-146a-5p/txnip axis attenuates intestinal ischemia-reperfusion injury by inhibiting autophagy via the PRKAA/mTOR signaling pathway

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BIOCHEMICAL PHARMACOLOGY 2022年 197卷 114839-114839页

作者： Liu, Zhenzhen Leng, Wenting Zhang, Jianmin Zhang, Guangru Liu, Disheng Zhao, Zhiyu Chen, Feng Shi, Yajing Hao, Yingxiang Lv, Jipeng Wan, Zhanhai Zhang, Yan Liu, Xin Liu, Yongqiang Leng, Yufang Lanzhou Univ Sch Clin Med 1 Lanzhou Peoples R China Lanzhou Univ Sch Clin Med 2 Lanzhou Peoples R China Lanzhou Univ Dept Anesthesiol Hosp 1 Lanzhou 730000 Gansu Peoples R China

Autophagy is being increasingly recognized as an important regulator of intestinal ischemia-reperfusion(I/R) injury, but its exact role is still debated. Emerging evidence suggests that miR-146a-5p is involved in the initiation and development of I/R injury, but its role in intestinal I/R injury remains unclear. The present study generated an intestinal I/R mouse model and an oxygen glucose deprivation/reoxygenation (OGD/R) Caco-2 cell model and found that autophagy was increased and contributed to the intestinal injury and cell death induced by I/R and OGD/R. In addition, in both I/R and OGD/R models, the miR-146a-5p expression level was decreased and accompanied by an increase in txnip expression. By transfecting cells with an miR-146a-5p inhibitor or mimic, we observed that miR-146a-5p inhibits autophagy during OGD/R by targeting txnip;this was confirmed by the dual luciferase reporter gene assay. Additionally, through overexpression and knockdown cell lines, we established that txnip regulates autophagy during intestinal I/R via the PRKAA/mTOR pathway. The interaction between txnip and p-PRKAA was verified by immunofluorescence co-localization and immunoprecipitation assays. Moreover, we confirmed that txnip is indispensable for miR-146a-5p-mediated cell protection. Finally, we observed that miR-146a-5p overexpression inhibits autophagy and attenuates intestinal I/R injury via the PRKAA/mTOR pathway by targeting txnip in vivo. In conclusion, this study highlights the role of miR-146a-5p in regulating autophagy by targeting txnip, suggesting that miR-146a-5p may be a novel drug target for intestinal I/R therapy.

关键词： Intestinal ischemia-reperfusion Autophagy miR-146a-5p txnip PRKAA mTOR

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PARP-1 regulates inflammasome activity by poly-ADP-ribosylation of NLRP3 and interaction with txnip in primary macrophages

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CELLULAR AND MOLECULAR LIFE SCIENCES 2022年第2期79卷 108-108页

作者： Chiu, Ling-Ya Huang, Duen-Yi Lin, Wan-Wan Natl Taiwan Univ Coll Med Dept Pharmacol Rm 111911F1Sec 1Ren Ai Rd Taipei 100 Taiwan Natl Def Med Ctr Dept & Grad Inst Pharmacol Taipei Taiwan Taipei Med Univ Grad Inst Med Sci Taipei Taiwan

Poly(ADP-ribose) polymerase-1 (PARP-1) plays an essential role in DNA repair by catalyzing the polymerization of ADP-ribose unit to target proteins. Several studies have shown that PARP-1 can regulate inflammatory responses in various disease models. The intracellular Nod-like receptor NLRP3 has emerged as the most crucial innate immune receptor because of its broad specificity in mediating immune response to pathogen invasion and danger signals associated with cellular damage. In our study, we found NLRP3 stimuli-induced caspase-1 maturation and IL-1 beta production were impaired by PARP-1 knockout or PARP-1 inhibition in bone marrow-derived macrophages (BMDM). The step 1 signal of NLRP3 inflammasome activation was not affected by PARP-1 deficiency. Moreover, ATP-induced cytosolic ROS production was lower in Parp-1(-/-) BMDM, resulting in the decreased inflammasome complex assembly. PARP-1 can translocate to cytosol upon ATP stimulation and trigger the PARylation modification on NLRP3, leading to NLRP3 inflammasome assembly. PARP-1 was also a bridge between NLRP3 and thioredoxin-interacting protein (txnip) and participated in NLRP3/txnip complex formation for inflammasome activation. Overall, PARP-1 positively regulates NLRP3 inflammasome activation via increasing ROS production and interaction with txnip and NLRP3, leading to PARylation of NLRP3. Our data demonstrate a novel regulatory mechanism for NLRP3 inflammasome activation by PARP-1. Therefore, PARP-1 can serve as a potential target in the treatment of IL-1 beta associated inflammatory diseases.

关键词： PARP-1 Inflammasome txnip NLRP3 ROS

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txnip Links Anticipatory Unfolded Protein Response to Estrogen Reprogramming Glucose Metabolism in Breast Cancer Cells

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ENDOCRINOLOGY 2022年第1期163卷 bqab212-bqab212页

作者： Wang, Yuanzhong Chen, Shiuan Beckman Res Inst City Hope Dept Canc Biol 1500 E Duarte Rd Duarte CA 91010 USA

Estrogen and estrogen receptor (ER) play a fundamental role in breast cancer. To support the rapid proliferation of ER+ breast cancer cells, estrogen increases glucose uptake and reprograms glucose metabolism. Meanwhile, estrogen/ER activates the anticipatory unfolded protein response (UPR) preparing cancer cells for the increased protein production required for subsequent cell proliferation. Here, we report that thioredoxin-interacting protein (txnip) is an important regulator of glucose metabolism in ER+ breast cancer cells, and estrogen/ER increases glucose uptake and reprograms glucose metabolism via activating anticipatory UPR and subsequently repressing txnip expression. In 2 widely used ER+ breast cancer cell lines, MCF7 and T47D, we showed that MCF7 cells express high txnip levels and exhibit mitochondrial oxidative phosphorylation (OXPHOS) phenotype, while T47D cells express low txnip levels and display aerobic glycolysis (Warburg effect) phenotype. Knockdown of txnip promoted glucose uptake and Warburg effect, while forced overexpression of txnip inhibited glucose uptake and Warburg effect. We further showed that estrogen represses txnip expression and activates UPR sensor inositol-requiring enzyme 1 (IRE1) via ER in the breast cancer cells, and IRE1 activity is required for estrogen suppression of txnip expression and estrogen-induced cell proliferation. Our study suggests that txnip is involved in estrogen-induced glucose uptake and metabolic reprogramming in ER+ breast cancer cells and links anticipatory UPR to estrogen reprogramming glucose metabolism.

关键词： estrogen breast cancer glucose metabolism txnip unfolded protein response

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Gap junctions amplify TRPV4 activation-initiated cell injury via modification of intracellular Ca²⁺and Ca²⁺-dependent regulation of txnip

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CHANNELS 2020年第1期14卷 246-256页

作者： Zhang, Xiling Mao, Zhimin Huang, Yanru Zhang, Zhen Yao, Jian China Med Univ Affiliated Hosp 4 Dept Urol Shenyang Peoples R China Univ Yamanashi Interdisciplinary Grad Sch Med Dept Adv Biomed Res Div Mol SignalingChuo Ku Kofu Yamanashi Japan

The elevated intracellular Ca(2+)and oxidative stress are well-reported mechanisms behind renal tubular epithelial injury initiated by various insults. Given that TRPV4 and connexin43 (Cx43) channels are activated by a wide range of stimuli and regulate both intracellular Ca(2+)and redox status, we speculated an involvement of these channels in renal tubular cell injury. Here, we tested this possibility and explored the potential underlying mechanisms. Our results demonstrated that exposure of renal tubular epithelial cells to aminoglycoside G418 led to cell death, which was attenuated by both TRPV4 and gap junction (Gj) inhibitor. Activation of TRPV4 caused cell damage, which was associated with an early increase in Cx43 expression and function. Inhibition of Cx43 with chemical inhibitor or siRNA largely prevented TRPV4 activation-induced cell damage. Further analysis revealed that TRPV4 agonists elicited a rise in intracellular Ca(2+)and caused a Ca2+-dependent elevation in txnip (a negative regulator of the antioxidant thioredoxin). In the presence of Gj inhibitor, however, these effects of TRPV4 were largely prevented. The depletion of intracellular Ca(2+)with Ca(2+)chelator BAPTA-AM or downregulation of txnip with siRNA significantly alleviated TRPV4 activation-initiated cell injury. Collectively, our results point to a critical involvement of TRPV4/Cx43 channel interaction in renal tubular cell injury through mechanisms involving a synergetic induction of intracellular Ca(2+)and oxidative stress. Channel interactions could be an important mechanism underlying cell injury. Targeting channels could have therapeutic potential for the treatment of acute tubular cell injury.

关键词： TRPV4 connexin43 txnip oxidative stress cell injury

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Omentin-1 attenuates adipose tissue inflammation via restoration of txnip/NLRP3 signaling in high-fat diet-induced obese mice

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FUNDAMENTAL & CLINICAL PHARMACOLOGY 2020年第6期34卷 721-735页

作者： Zhou, Hongli Zhang, Zuo Qian, Guisheng Zhou, Jiyin Army Med Univ Affiliated Hosp 2 Natl Drug Clin Trial Inst Chongqing 400037 Peoples R China Army Med Univ Affiliated Hosp 2 Inst Resp Dis Chongqing 400037 Peoples R China

Omentin-1 is an adipokine expressed by the adipose tissue and is reduced in obesity. This study was designed to calculate the protective efficiency and mechanism of omentin-1 against inflammation of the adipose tissue in obese mice. A transgenic mouse model with omentin-1 protein overexpression was established by crossing omentin-1 transgenic mice with Fabp4-Cre mice. Obesity was induced in the mice by feeding them a high-fat diet for 10 weeks. Fabp4-Cre-mediated overexpression of omentin-1 significantly increased serum omentin-1 level, serum anti-inflammatory factor levels, and expression of M2-specific mRNAs;inhibited body weight and adipose tissue weight gain;improved glucose tolerance, insulin tolerance, and insulin sensitivity;decreased serum levels of insulin and proinflammatory factors, adipocyte size, and expression of M1-specific mRNAs;suppressed macrophage infiltration;downregulated expression of proinflammatory factors;upregulated expression of anti-inflammatory factors;and inhibited thioredoxin-interacting protein (txnip)/NOD-like receptor 3 (NLRP3) signaling in the adipose tissue of obese mice. An NLRP3 inhibitor (20 mg/kg MCC950) exhibited the same effects as overexpression of omentin-1. Pretreatment with omentin-1 inhibited lipopolysaccharide-induced inflammation via txnip/NLRP3 signaling in RAW 264.7 macrophages. These findings suggest that omentin-1 suppresses adipose tissue inflammation in obese mice, at least partly, via inhibiting the txnip/NLRP3 signaling pathway.

关键词： adipose tissue inflammation obese mice Omentin-1 overexpression txnip NLRP3 signaling pathway

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Rapid and persistent loss of txnip in HT22 neuronal cells under carbonyl and hyperosmotic stress

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NEUROCHEMISTRY INTERNATIONAL 2020年 132卷 104585页

作者： Dafre, Alcir Luiz Schmitz, Ariana Ern Maher, Pamela Univ Fed Santa Catarina Biochem Dept BR-88040900 Florianopolis SC Brazil Salk Inst Biol Studies Cellular Neurobiol Lab 10010 N Torrey Pines Rd La Jolla CA 92037 USA Catolica Joinville Ctr Univ BR-89203005 Joinville SC Brazil

Thioredoxin interacting protein (txnip) binds to thioredoxin thereby limiting its activity, but it also promotes internalization of glucose transporters, participates in inflammasome activation, and controls autophagy. Published data and this work demonstrate that txnip responds to a number of apparently unrelated stresses, such as serum deprivation, pH change, and oxidative, osmotic and carbonyl stress. Interestingly, we noticed that hyperosmotic (NaCl) and carbonyl (methylglyoxal, MGO) stresses in HT22 neuronal cells produced a rapid loss of txnip (half-life similar to 12 min), prompting us to search for possible mechanisms controlling this txnip loss, including pH change, serum deprivation, calcium metabolism and inhibition of the proteasome and other proteases, autophagy and MAPKs. None of these routes stopped the txnip loss induced by hyperosmotic and carbonyl stress. Besides transcriptional, translational and microRNA regulation, there is evidence indicating that mTOR and AMPK also control txnip expression. Indeed, AMPK-deficient mouse embryonic fibroblasts failed to respond to phenformin (AMPK activator) and compound C (AMPK inhibitor), while rapamycin induced a marked increase in txnip levels, confirming the known AMPK/mTOR control over txnip. However, the txnip loss induced by NaCl or MGO were observed even in AMPK deficient MEFs or after mTOR inhibition, indicating AMPK/mTOR does not participate in this rapid txnip loss. These results suggest that rapid txnip loss is a general and immediate response to stress that can improve energy availability and antioxidant protection, eventually culminating in better cell survival.

关键词： txnip VDUP2 Hyperosmotic stress Carbonyl stress AMPK Stress resistance

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Endoplasmic reticulum stress may activate NLRP3 inflammasomes via txnip in preeclampsia

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CELL AND TISSUE RESEARCH 2020年第3期379卷 589-599页

作者： Yang, Yong Li, Jianxin Han, Ting-Li Zhou, Xiaobo Qi, Hongbo Baker, Philip N. Zhou, Wei Zhang, Hua Chngqing Hlth Ctr Women & Children Dept Obstet 120 Longshan Rd Chongqing 400021 Peoples R China Chongqing Med Univ Affiliated Hosp 1 Dept Obstet & Gynecol 1 Youyi Rd Chongqing 400016 Peoples R China Chongqing Med Univ Canada China New Zealand Joint Lab Maternal & Fet 1 Yixueyuan Rd Chongqing 400016 Peoples R China Univ Leicester Coll Med Biol Sci & Psychol POB 138 Leicester LE1 9HN Leics England

Preeclampsia (PE) development is often associated with placental immune and inflammatory dysregulation, as well as endoplasmic reticulum (ER) stress. However, the mechanisms linking ER stress and inflammatory dysregulation to PE have not been elucidated. It has been reported that thioredoxin-interacting protein (txnip), which can bind with and activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome, is a key point in immune regulation. Recent experimental evidence suggests that activated NLRP3 inflammasomes can activate interleukin-1 beta (IL-1 beta) production in the placenta of patients with PE. The objective of the current study was to explore if txnip plays a critical signaling role linking ER stress with NLRP3 inflammasome activation in PE. We hypothesized that ER stress would induce txnip production, which would bind with NLRP3 inflammasomes to activate IL-1 beta production. These cells showed a higher protein level of NLRP3 and IL-1 beta, as well as a higher enzymatic activity of caspase-1, indicating enhanced inflammatory dysregulation and ER stress. Cells transfected with txnip siRNA showed reduced NLRP3 inflammasome activation. Cells treated with 4-phenylbutyric acid, an inhibitor of ER stress, showed a similar result. Outgrowth of the explant with txnip lentivirus in H/R or tunicamycin (inducers of ER stress) was also measured to verify our hypothesis. These findings demonstrated that txnip could influence inflammatory dysregulation by mediating ER stress and NLRP3 inflammasome activation in PE. This novel mechanism may further explain the inflammation observed at the maternal-fetal interface, which leads to placental dysfunction in a patient with PE.

关键词： Preeclampsia (PE) Inflammation Endoplasmic reticulum (ER) stress NLRP3 txnip

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BRAFi induced demethylation of miR-152-5p regulates phenotype switching by targeting txnip in cutaneous melanoma

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APOPTOSIS 2020年第3-4期25卷 179-191页

作者： Li, Kezhu Tang, Mingrui Tong, Shuang Wang, Chenchao Sun, Qiang Lv, Mengzhu Sun, Xu Wang, Ting Jin, Shifeng China Med Univ Affiliated Hosp 1 Dept Plast Surg 155 Nanjing North St Shenyang 110001 Liaoning Peoples R China

Treatment of advanced BRAF(V600)-mutant melanoma using BRAF inhibitors (BRAFi) eventually leads to drug resistance and selects for highly metastatic tumor cells. We compared the most differentially dysregulated miRNA expression profiles of vemurafenib-resistant and highly-metastatic melanoma cell lines obtained from GEO DataSets. We discovered miR-152-5p was a potential regulator mediating melanoma drug resistance and metastasis. Functionally, knockdown of miR-152-5p significantly compromised the metastatic ability of BRAFi-resistant melanoma cells and overexpression of miR-152-5p promoted the formation of slow-cycling phenotype. Furthermore, we explored the cause of how and why miR-152-5p affected metastasis in depth. Mechanistically, miR-152-5p targeted txnip which affected metastasis and BRAFi altered the methylation status of MIR152 promoter. Our study highlights the crucial role of miR-152-5p on melanoma metastasis after BRAFi treatment and holds significant implying that discontinuous dosing strategy may improve the benefit of advanced BRAF(V600)-mutant melanoma patients.

关键词： miR-152-5p Melanoma Metastasis BRAFi txnip

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