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SIRT6-mediated transcriptional suppression of txnip is critical for pancreatic beta cell function and survival in mice

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DIABETOLOGIA 2018年第4期61卷 906-918页

作者： Qin, Kunhua Zhang, Ning Zhang, Zhao Nipper, Michael Zhu, Zhenxin Leighton, Jake Xu, Kexin Musi, Nicolas Wang, Pei Univ Texas Hlth Sci Ctr San Antonio Dept Mol Med San Antonio TX 78229 USA Univ Texas Hlth Sci Ctr San Antonio Dept Cell Syst & Anat 7703 Floyd Curl Dr San Antonio TX 78229 USA Univ Texas Hlth Sci Ctr San Antonio Barshop Inst Longev & Aging Studies San Antonio TX 78229 USA

Aims/hypothesis Better understanding of how genetic and epigenetic components control beta cell differentiation and function is key to the discovery of novel therapeutic approaches to prevent beta cell dysfunction and failure in the progression of type 2 diabetes. Our goal was to elucidate the role of histone deacetylase sirtuin 6 (SIRT6) in beta cell development and homeostasis. Methods Sirt6 endocrine progenitor cell conditional knockout and beta cell-specific knockout mice were generated using the Cre-loxP system. Mice were assayed for islet morphology, glucose tolerance, glucose-stimulated insulin secretion and susceptibility to streptozotocin. Transcriptional regulatory functions of SIRT6 in primary islets were evaluated by RNA-Seq analysis. Reverse transcription-quantitative (RT-q) PCR and immunoblot were used to verify and investigate the gene expression changes. Chromatin occupancies of SIRT6, H3K9Ac, H3K56Ac and active RNA polymerase II were evaluated by chromatin immunoprecipitation. Results Deletion of Sirt6 in pancreatic endocrine progenitor cells did not affect endocrine morphology, beta cell mass or insulin production but did result in glucose intolerance and defective glucose-stimulated insulin secretion in mice. Conditional deletion of Sirt6 in adult beta cells reproduced the insulin secretion defect. Loss of Sirt6 resulted in aberrant upregulation of thioredoxin-interacting protein (txnip) in beta cells. SIRT6 deficiency led to increased acetylation of histone H3 lysine residue at 9 (H3K9Ac), acetylation of histone H3 lysine residue at 56 (H3K56Ac) and active RNA polymerase II at the promoter region of txnip. SIRT6-deficient beta cells exhibited a time-dependent increase in H3K9Ac, H3K56Ac and txnip levels. Finally, beta cell-specific SIRT6-deficient mice showed increased sensitivity to streptozotocin. Conclusions/interpretation Our results reveal that SIRT6 suppresses txnip expression in beta cells via deacetylation of histone H3 and plays a critic

关键词： Beta cell Diabetes H3K9Ac Insulin secretion SIRT6 txnip

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txnip regulates pulmonary inflammation induced by Asian sand dust

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REDOX BIOLOGY 2024年 78卷 103421页

作者： Pak, So-Won Kim, Woong-Il Lee, Se-Jin Park, Sin-Hyang Cho, Young-Kwon Kim, Joong-Sun Kim, Jong-Choon Kim, Sung-Hwan Shin, In-Sik Chungnam Natl Univ Coll Vet Med 77 Yong Bong Ro Gwangju 61186 South Korea Chonnam Natl Univ BK21 FOUR Program 77 Yong Bong Ro Gwangju 61186 South Korea Cheongju Univ Coll Hlth Sci 298 Daesung Ro Cheongju 28503 Chungbuk South Korea Korea Inst Toxicol KIT Jeonbuk Branch Jeongeup Si 53212 Jeonbuk South Korea

Asian sand dust (ASD), a seasonal dust storm originating from the deserts of China and Mongolia, affects Korea and Japan during the spring, carrying soil particles and a variety of biochemical components. Exposure to ASD has been associated with the onset and exacerbation of respiratory disorders, although the underlying mechanisms remain unclear. This study investigates ASD-induced pulmonary toxicity and its mechanistic pathways, focusing on the role of thioredoxin-interacting protein (txnip). Using txnip knock-out (KO) mice and adenoassociated virus (AAV)-mediated txnip overexpression transgenic mice, we explored how txnip modulates ASD-induced pulmonary inflammation. Mice were exposed to ASD via intranasal administration on days 1, 3, and 5 to induce inflammation. ASD exposure led to significant pulmonary inflammation, evidenced by increased inflammatory cell counts and elevated cytokine levels in bronchoalveolar lavage fluid, as well as heightened protein expression of the txnip/NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. txnip KO mice exhibited attenuated airway inflammation and downregulation of the NLRP3 inflammasome compared to wild-type controls, while AAV-mediated txnip overexpression mice showed exacerbated inflammatory responses, including elevated NLRP3 inflammasome expression, compared to AAV-GFP controls. These findings suggest that txnip is a key regulator of ASD-induced pulmonary inflammation.

关键词： Asian sand dust Pulmonary inflammation txnip NLRP3 Inflammasome

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txnip mediates the differential responses of A549 cells to sodium butyrate and sodium 4-phenylbutyrate treatment

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CANCER MEDICINE 2017年第2期6卷 424-438页

作者： Jin, Xuefang Wu, Nana Dai, Juji Li, Qiuxia Xiao, XiaoQiang Wenzhou Med Univ Sch Basic Med Sci Wenzhou Peoples R China Wenzhou Med Univ Inst Genom Med Wenzhou Peoples R China Wenzhou Med Univ Affiliated Hosp 1 Dept Gen Surg Wenzhou Peoples R China Shantou Univ Chinese Univ Hong Kong Joint Shantou Int Eye Ctr Shantou Peoples R China

Sodium butyrate (NaBu) and sodium 4-phenylbutyrate (4PBA) have promising futures in cancer treatment;however, their underlying molecular mechanisms are not clearly understood. Here, we show A549 cell death induced by NaBu and 4PBA are not the same. NaBu treatment induces a significantly higher level of A549 cell death than 4PBA. A gene expression microarray identified more than 5000 transcripts that were altered (>1.5-fold) in NaBu- treated A549 cells, but fewer than 2000 transcripts that were altered in 4PBA. Moreover, more than 100 cell cycle-associated genes were greatly repressed by NaBu, but slightly repressed by 4PBA;few genes were significantly upregulated only in 4PBA-treated cells. Gene expression was further validated by other experiments. Additionally, A549 cells that were treated with these showed changes in glucose consumption, caspase 3/7 activation and histone modifications, as well as enhanced mitochondrial superoxide production. txnip was strongly induced by NaBu (30-to 40-fold mRNA) but was only slightly induced by 4PBA (two to fivefold) in A549 cells. txnip knockdown by shRNA in A549 cells significantly attenuated caspase 3/7 activation and restored cell viability, while txnip overexpression significantly increased caspase 3/7 activation and cell death only in NaBu-treated cells. Moreover, txnip also regulated NaBu-but not 4PBA-induced H4K5 acetylation and H3K4 trimethylation, possibly by increasing WDR5 expression. Finally, we demonstrated that 4PBA induced a mitochondrial superoxide- associated cell death, while NaBu did so mainly through a txnip-mediated pathway. The above data might benefit the future clinic application.

关键词： A549 cells butyrate histone modification mitochondrial superoxide txnip

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txnip deficiency mitigates podocyte apoptosis via restraining the activation of mTOR or p38 MAPK signaling in diabetic nephropathy

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EXPERIMENTAL CELL RESEARCH 2020年第2期388卷 111862-000页

作者： Song, Shan Qiu, Duojun Wang, Yuhan Wei, Jinying Wu, Haijiang Wu, Ming Wang, Shuai Zhou, Xinbo Shi, Yonghong Duan, Huijun Hebei Med Univ Dept Pathol 361 East Zhongshan Rd Shijiazhuang 050017 Hebei Peoples R China Hebei Key Lab Kidney Dis Shijiazhuang Hebei Peoples R China Tangshan Workers Hosp Digest Dept Tangshan City Peoples R China

Thioredoxin-interacting protein (txnip), is identified as an inhibitor of the thiol oxidoreductase thioredoxin that acts endogenously, and is increased by high glucose (HG). In this study, we investigated the potential function of txnip on apoptosis of podocytes and its potential mechanism in vivo and in vitro in diabetic nephropathy (DN). txnip silencing attenuated HG-induced apoptosis and obliterated the activation of signaling pathways of mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) in conditionally immortalized mouse podocytes. Furthermore, the Raptor and Rictor shRNAs, mTOR specific inhibitor KU-0063794 and p38 MAPK inhibitor SB203580 were used to assess the role of mTOR or p38 MAPK pathway on podocyte apoptosis induced by HG. The Rictor and Raptor shRNAs and KU-0063794 appeared to reduce HG induced apoptosis in podocytes. Simultaneously, SB203580 could also restrain HG-induced apoptosis in podocytes. Streptozotocin rendered equivalent diabetes in txnip -/- (TKO) and wild-type (WT) control mice. txnip deficiency mitigated renal injury in diabetic mice. Additionally, txnip deficiency also descended the apoptosis-related protein and Nox4 levels, the mTOR signaling activation and the p38 MAPK phosphorylation in podocytes of diabetic mice. All these data indicate that txnip deficiency may mitigate apoptosis of podocytes by inhibiting p38 MAPK or mTOR signaling pathway in DN, underlining txnip as a putative target for therapy.

关键词： Diabetic nephropathy txnip Apoptosis mTOR p38 MAPK

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txnip mediated the oxidative stress response in glomerular mesangial cells partially through AMPK pathway

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BIOMEDICINE & PHARMACOTHERAPY 2018年 107卷 785-792页

作者： Xu, Wenwei Wang, Ling Li, Jimin Cai, Yingying Xue, Yaoming Southern Med Univ Nanfang Hosp Dept Endocrinol & Metab 1838 Guangzhou Ave North Guangzhou Guangdong Peoples R China

Background: Thioredoxin-interacting protein (txnip) plays an important role in the development of diabetic nephropathy. In the present study, we investigated role of txnip on oxidative stress in glomerular mesangial cells (GMCs) cultured in high glucose or normal glucose, and explored the potential mechanism related to txnip as well. Methods: Oxidative stress in GMCs under high or normal glucose was detected. txnip knockdown by specific siRNA or over expression by pcDNA3.0-txnip vector was performed to evaluate the role of txnip on injury of GMCs caused by oxidative stress. Activator of AMPK AICAR and AMPK inhibitor Compound C were treated the GMCs. Reactive oxygen species (ROS) and mitochondrial membrane potential were detected by flow cytometry. Activities of superoxide dismutase (SOD) and superoxide dismutase (CAT) were measured by ELISA. Activity of thioredoxin (Trx) was determined using Trx activity assay kit. mRNA expression of AMPK, txnip, Trx1 and Trx2 were tested by qRT-PCR. Expressions of P-AMPK, txnip and fibronectin proteins were detected by Western blotting. Results: High glucose induced the increase of ROS level, activation of txnip, but restricted mitochondrial membrane potential and activities of p-AMPK, SOD and CAT, and Trx. txnip siRNA and AICAR inhibited high glucose-induced oxidative stress response in GMCs and fibronectin expression, but promoted cell viability. In contrast, pcDNA3.0-txnip and Compound C increased oxidative stress response in normal glucose cultured GMCs, but decreased cell viability. The combined effect of txnip siRNA and AICAR on the inhibition of oxidative stress was obviously stronger than that of single use of txnip siRNA. Conclusion: txnip facilitates the oxidative stress response in GMCs partially through AMPK pathway, which may provide potential therapeutic target for diabetic nephropathy treatment.

关键词： txnip AMPK Fibronectin Oxidative stress Glomerular mesangial cell

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txnip knockdown alleviates hepatocyte ischemia reperfusion injury through preventing p38/JNK pathway activation

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2018年第3期502卷 409-414页

作者： Zhang, Yong Miao, Liang-Sheng Cai, Ying-Min He, Jia-Xuan Zhang, Zhen-Ni Wu, Gang Zheng, Juan Xi An Jiao Tong Univ Affiliated Hosp 2 Dept Anesthesiol 157 West 5th Rd Xian 710004 Shaanxi Peoples R China Weinan Cent Hosp Dept Anesthesiol Weinan Shaanxi Peoples R China

Hepatic ischemia and reperfusion (I/R) injury is a major cause of liver damage during liver transplantation, resection surgery, shock, and trauma. It has been reported that txnip expression was upregulated in a rat model of hepatic I/R injury. However, the role of txnip in the hepatic I/R injury is little known. In our study, we investigated the biological role of txnip and its potential molecular mechanism in the human hepatic cell line (HL7702 cells). Using oxygen-glucose deprivation and reoxy-genation (OGD/R) to create a cell model of hepatic I/R injury, we found that the mRNA and protein expression levels of txnip were upregulated in HL7702 cells exposed to OGD/R. txnip overexpression remarkably promoted OGD/R-induced cell apoptosis and lactate dehydrogenase (LDH) release, both of which were significantly decreased by txnip knockdown. The production of malondialdehyde (MDA) was also increased by txnip overexpression, but was reduced by txnip knockdown. Moreover, txnip overexpression significantly upregulated the phosphorylation of p38 and JNK, which was remarkably inhibited by txnip knockdown. Additionally, p38-specific inhibitor SB203580 abrogated the effect of txnip overexpression on OGD/R-induced cell injury. Taken together, these results indicated that txnip knockdown alleviated hepatocyte I/R injury through preventing p38/JNK pathway activation. Thus, txnip might offer a novel potential therapeutic target for the treatment of hepatic I/R injury. (C) 2018 Elsevier Inc. All rights reserved.

关键词： txnip Hepatic ischemia reperfusion injury Cell apoptosis p38/JNK pathway

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txnip mediated by EZH2 regulated osteogenic differentiation in hBmscs and MC3T3-E1 cells through the modulation of oxidative stress and PI3K/AKT/Nrf2 pathway

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CONNECTIVE TISSUE RESEARCH 2024年第4期65卷 293-303页

作者： Zhou, Weibo Zhu, Chunhui Zhou, Fulin Changzhou 2 Peoples Hosp Dept Orthoped 188 Gehu Lake RdWujin Dist Changzhou 213000 Jiangsu Peoples R China

BackgroundPrevious research has identified a significant role of Thioredoxin-interacting protein (txnip) in bone loss. The purpose of this investigation was to assess the role and the underlying molecular mechanisms of txnip in the osteogenic differentiation of human bone marrow stromal cells (hBMSCs) and pre-osteoblast MC3T3-E1 *** bone marrow stem cells (hBMSCs) and MC3T3-E1 cells were used to induce osteogenic differentiation. The expression of genes and proteins was assessed using RT-qPCR and western blot, respectively. ChIP assay was used to validate the interaction between genes. The osteogenic differentiation ability of cells was reflected using ALP staining and detection of ALP activity. The mineralization ability of cells was assessed using ARS staining. DCFCA staining was employed to evaluate the intracellular ROS ***, downregulation of txnip and upregulation of EZH2 were observed during osteogenesis in hBMSCs and MC3T3-E1 cells. Additionally, it was discovered that EZH2 negatively regulates txnip expression in these cells. Furthermore, experiments indicated that the knockdown of txnip stimulated the activation of the PI3K/AKT/Nrf2 signaling pathway in hBMSCs and MC3T3- E1 cells, thus inhibiting the production of reactive oxygen species (ROS). Further functional experiments revealed that overexpression of txnip inhibited the osteogenic differentiation in hBMSCs and MC3T3-E1 cells by enhancing ROS produc-tion. On the other hand, knockdown of txnip promoted the osteogenic differentiation capacity of hBMSCs and MC3T3-E1 cells through the activation of the PI3K/AKT/Nrf2 *** conclusion, this study demonstrated that txnip expression, under the regulation of EZH2, plays a crucial role in the osteogenic differentiation of hBMSCs and MC3T3-E1 cells by regulating ROS production and the PI3K/AKT/Nrf2 pathway.

关键词： txnip oxidative stress PI3K/AKT/Nrf2 pathway osteogenic differentiation

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Oroxindin inhibits macrophage NLRP3 inflammasome activation in DSS-induced ulcerative colitis in mice via suppressing txnip-dependent NF-κB pathway

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中国药理学报（英文版） 2020年第6期41卷 771-781页

作者： Qi Liu Rui Zuo Kai Wang Fei-fei Nong Ya-jun Fu Shao-wei Huang Zeng-feng Pan Yi Zhang Xia Luo Xiang-liang Deng Xiao-xue Zhang Lian Zhou Yang Chen School of Pharmaceutical Sciences Guangzhou University of Chinese Medicine Guangzhou 510006 China First Affiliated Hospital of Guangzhou University of Chinese Medicine Guangzhou 510405 China School of Chinese Medicine Guangdong Pharmaceutical University Guangzhou 510006 China 4Department of Laboratory Medicine Affiliated Puai Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 China

Oroxindin is a flavonoid isolated from the traditional Chinese medicine Huang-Qin,which has shown various pharmacological activities including anti-inflammatory,antitumor,antioxidant,*** far,the effect of oroxindin on colonic inflammation and the underlying mechanism remain *** this study,we investigated the tissue distribution of oroxindin and its therapeutic effects on ulcerative colitis (UC) as well as the underlying *** model was established in mice by administrating dextran sulfate sodium (DSS) in drinking water for 7 *** first showed that oroxindin was largely absorbed by the colon as an active ingredient after normal mice received Huang-Qin-Tang,a traditional Chinese medicine *** mice were then treated with oroxindin (12.5,25,50 mg-kg-1 ·d-1,i.g.) for 10 *** found that oroxindin treatment greatly suppressed massive macrophages infiltration and attenuated pathological changes in colonic ***,oroxindin treatment significantly inhibited the generation of IL-13 and IL-18 in the colon via inhibiting the nucleotide-binding oligomerization domain-like receptor 3 (NLRP3)inflammasome formation and *** cultured macrophages,LPS induced NLRp3 inflammasome formation and caspase-1 activation,which were suppressed by oroxindin (12.5-50 μM).In LPS-treated macrophages,oroxindin dose-dependently restored the expression of txnip protein,leading to suppressing txnip-dependent NF-κB *** conclusion,these results demonstrate that oroxindin could be absorbed by the colon and attenuate inflammatory responses via inhibiting NLRP3 inflammasome formation and activation,which is related to the inhibitory effect on txnip-dependent NF-κB-signaling ***,oroxindin has the potential of becoming an effective drug for treating UC.

关键词： ulcerative colitis oroxindin NLRP3 inflammasome txnip NF-KB signaling anti-inflammatory

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Cadmium-induced pyroptosis is mediated by PERK/txnip/NLRP3 signaling in SH-SY5Y cells

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ENVIRONMENTAL TOXICOLOGY 2023年第9期38卷 2219-2227页

作者： Li, Zhihui Shi, Yan Wang, Yougang Qi, Haomin Chen, Haiyu Li, Jinquan Li, Li Hubei Univ Natl & Local Joint Engn Res Ctr High throughput Dr Sch Life Sci Hubei Prov Key Lab Biotechnol Chinese Tradit MedS Wuhan Peoples R China Wuhan Univ Sci & Technol Brain Sci & Adv Technol Inst Sch Med Hubei Prov Key Lab Occupat Hazard Identificat & Co Wuhan Peoples R China Wuhan Univ Sci & Technol Brain Sci & Adv Technol Inst Sch Med Wuhan 430081 Peoples R China Hubei Univ Sch Life Sci Hubei Prov Key Lab Biotechnol Chinese TraditionalM Wuhan 430070 Peoples R China

Cadmium (Cd) is a hypertoxic heavy metal that may be exposed to environmental pollutants by humans and animals. It can lead to cognitive disfunction, and is linked to neurodegenerative diseases. Cadmium reportedly can induce endoplasmic reticulum (ER) stress, but few studies have concentrated on it in nerve cells, and the connection between ER stress and neuroinflammation. In this study, in vitro experiments on SH-SY5Y neuroblastoma cells were carried out. We aimed at exploring whether Cd attributed to the cell pyroptosis and the role of PERK in promoting this form of cell damage which can induce strong inflammatory responses. Our results demonstrated that CdCl2 treatment induced excess reactive oxygen species (ROS) production, caused significant modifications in the expression of PERK and increased txnip, NLRP3, IL-1 beta, IL-18, and caspase1 in SH-SY5Y cells. In addition, scavenging ROS with N-acetylcysteine or inhibiting the expression of PERK by using GSK2606414, rescued the SH-SY5Y cells from cadmium-induced pyroptosis. In conclusion, the results suggest that Cd induces pyroptotic death of SH-SY5Y cells through ER stress, and this may be the potential mechanism of Cd incurring neurological diseases.

关键词： cadmium NLRP3 PERK pyroptosis txnip

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Thioredoxin-Interacting Protein(txnip) Regulates Parkin/PINK1-mediated Mitophagy in Dopaminergic Neurons Under High-glucose Conditions: Implications for Molecular Links Between Parkinson’s Disease and Diabetes

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Neuroscience Bulletin 2020年第4期36卷 346-358页

作者： Cun-Jin Su Zhu Shen Ru-Xiao Cui Ya Huang De-Lai Xu Feng-Lun Zhao Jie Pan Ai-Ming Shi Tong Liu Yun-Li Yu Department of Pharmacy The Second Affiliated Hospital of Soochow UniversitySuzhou 215004China Institute of Neuroscience Soochow UniversitySuzhou 215004China Department of Clinical Pharmacology The Second Affiliated Hospital of Soochow UniversitySuzhou 215004China

Patients with diabetes mellitus have a higher risk of developing Parkinson’s disease(PD). However, the molecular links between PD and diabetes remain *** this study, we investigated the roles of thioredoxininteracting protein(txnip) in Parkin/PINK1-mediated mitophagy in dopaminergic(DA) cells under high-glucose(HG) conditions. In streptozotocin-induced diabetic mice,txnip was upregulated and autophagy was inhibited in the midbrain, while the loss of DA neurons was accelerated by hyperglycemia. In cultured PC12 cells under HG, txnip expression was upregulated and the intracellular reactive oxygen species(ROS) levels increased, leading to cell death. Autophagic flux was further blocked and PINK1 expression was decreased under HG conditions. Parkin expression in the mitochondrial fraction and carbonyl cyanide 3-chlorophenylhydrazone(CCCP)-induced co-localization of COX IV(marker for mitochondria) and LAMP1(marker for lysosomes) were also significantly decreased by HG. Overexpression of txnip was sufficient to decrease the expression of both PINK1 and Parkin in PC12 cells, while knockdown of the expression of txnip by si RNA decreased intracellular ROS and attenuated cellular injury under HG. Moreover, inhibition of txnip improved the CCCP-induced co-localization of COX IV and LAMP1 in PC12 cells under HG. Together, these results suggest that txnip regulates Parkin/PINK1-mediated mitophagy under HG conditions, and targeting txnip may be a promising therapeutic strategy for reducing the risk of PD under hyperglycemic conditions.

关键词： Diabetes mellitus Parkinson’s disease High glucose txnip Mitophagy PC12 cells

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