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txnip deficiency attenuates renal fibrosis by modulating mTORC1/TFEB-mediated autophagy in diabetic kidney disease

RENAL FAILURE 2024年第1期46卷 2338933页

作者： Du, Yunxia Wu, Ming Song, Shan Bian, Yawei Shi, Yonghong Hebei Med Univ Dept Pathol Shijiazhuang Peoples R China Hebei Key Lab Kidney Dis Shijiazhuang Peoples R China Hebei Med Univ Inst Med & Hlth Sci Ctr Metab Dis & Canc Res Shijiazhuang Peoples R China Hebei Med Univ Dept Pathol Shijiazhuang 050017 Peoples R China

Thioredoxin-interacting protein (txnip) is an important regulatory protein for thioredoxin (TRX) that elicits the generation of reactive oxygen species (ROS) by inhibiting the redox function of TRX. Abundant evidence suggests that txnip is involved in the fibrotic process of diabetic kidney disease (DKD). However, the potential mechanism of txnip in DKD is not yet well understood. In this study, we found that txnip knockout suppressed renal fibrosis and activation of mammalian target of rapamycin complex 1 (mTORC1) and restored transcription factor EB (TFEB) and autophagy activation in diabetic kidneys. Simultaneously, txnip interference inhibited epithelial-to-mesenchymal transformation (EMT), collagen I and fibronectin expression, and mTORC1 activation, increased TFEB nuclear translocation, and promoted autophagy restoration in HK-2 cells exposed to high glucose (HG). Rapamycin, an inhibitor of mTORC1, increased TFEB nuclear translocation and autophagy in HK-2 cells under HG conditions. Moreover, the TFEB activators, curcumin analog C1 and trehalose, effectively restored HG-induced autophagy, and abrogated HG-induced EMT and collagen I and fibronectin expression in HK-2 cells. Taken together, these findings suggest that txnip deficiency ameliorates renal fibrosis by regulating mTORC1/TFEB-mediated autophagy in diabetic kidney diseases. {Graphical abstract}

关键词： Autophagy diabetic kidney disease mTORC1 txnip TFEB

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Disrupting CISD2 function in cancer cells primarily impacts mitochondrial labile iron levels and triggers txnip expression

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FREE RADICAL BIOLOGY AND MEDICINE 2021年 176卷 92-104页

作者： Karmi, Ola Sohn, Yang-Sung Zandalinas, Sara, I Rowland, Linda King, Skylar D. Nechushtai, Rachel Mittler, Ron Univ Missouri Sch Med Dept Surg Christopher S Bond Life Sci Ctr 1201 Rollins St Columbia MO 65201 USA Hebrew Univ Jerusalem Alexander Silberman Inst Life Sci Edmond J Safra Campus Givat Ram IL-91904 Jerusalem Israel Univ Missouri Coll Agr Food & Nat Resources Div Plant Sci & Interdisciplinary Plant Grp Christopher S Bond Life Sci Ctr 1201 Rollins St Columbia MO 65201 USA

The CISD2 (NAF-1) protein plays a key role in regulating cellular homeostasis, aging, cancer and neurodegenerative diseases. It was found to control different calcium, reactive oxygen species (ROS), and iron signaling mechanisms. However, since most studies of CISD2 to date were conducted with cells that constitutively lack, overexpress, or contain mutations in CISD2, the relationships between these different signaling processes are unclear. To address the hierarchy of signaling events occurring in cells upon CISD2 disruption, we developed an inducible system to express CISD2, or the dominant-negative H114C inhibitor of CISD2, in human breast cancer cells. Here, we report that inducible disruption of CISD2 function causes an immediate disruption in mitochondrial labile iron (mLI), and that this disruption results in enhanced mitochondrial ROS (mROS) levels. We further show that alterations in cytosolic and ER calcium levels occur only after the changes in mLI and mROS levels happen and are unrelated to them. Interestingly, disrupting CISD2 function resulted in the enhanced expression of the tumor suppressor thioredoxin-interacting protein (txnip) that was dependent on the accumulation of mLI and associated with ferroptosis activation. CISD2 could therefore regulate the expression of txnip in cancer cells, and this regulation is dependent on alterations in mLI levels.

关键词： CISD2 NAF-1 Oxidative stress Reactive oxygen species (ROS) Iron homeostasis Iron-sulfur cluster [Fe-S] Ferroptosis txnip Mitochondria Cancer

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The Effect of Verapamil on txnip Gene Expression, GLP1R mRNA, FBS, HbA1c, and Lipid Profile in T2DM Patients Receiving Metformin and Sitagliptin

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DIABETES THERAPY 2021年第10期12卷 2701-2713页

作者： Malayeri, Alireza Zakerkish, Mehrnoosh Ramesh, Farrokh Galehdari, Hamid Hemmati, Ali Asghar Angali, Kambiz A. Ahvaz Jundishapur Univ Med Sci Sch Pharm Dept Pharmacol Ahvaz Iran Ahvaz Jundishapur Univ Med Sci Hlth Res Inst Dept Internal Med Diabet Res Ctr Ahvaz Iran Shahid Chamran Univ Ahvaz Dept Genet Fac Sci Ahvaz Iran Ahvaz Jundishapur Univ Med Sci Sch Pharm Med Plant Res Ctr Ahvaz Iran Ahvaz Jundishapur Univ Med Sci Sch Hlth Dept Biostat & Epidemiol Ahvaz Iran

Introduction: Type 2 diabetes mellitus (T2DM) is the most common type of diabetes. A decrease in the number of pancreatic beta cells is a pathological sign of diabetes, and to date there is no drug treatment that targets damage to these cells. Pancreatic beta cells have a weak antioxidant system and are highly sensitive to oxidative stress reactions that occur within cells. Thioredoxin interacting protein (txnip) inhibits thioredoxin, which is part of the intracellular antioxidant system, thereby accelerating oxidative stress and apoptosis of pancreatic beta cells. Verapamil is a non-dihydropyridine calcium channel blocker. The efficacy of this drug to improve beta cell survival and glucose homeostasis by inhibiting txnip expression has been demonstrated in in vitro studies. Although several retrospective studies have shown a lower incidence of T2DM with verapamil treatment, no prospective intervention studies have determined the efficacy of this drug in patients with T2DM. Methods: The aim of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of oral verapamil administration in T2DM patients. In this 90-day study, the effects of verapamil on fasting blood sugar (FBS), hemoglobin A1C (HbA1c), and the lipid profile were evaluated and compared with those of the placebo. Results: There was a significant decrease in HbA1c (about 0.5%) in the verapamil group at the end of the intervention period. The effects of verapamil on txnip gene expression and glucagon-like peptide-1 receptor (GLP1R) mRNA were compared with those of the placebo (at baseline, after 15 and 30 days, and at the end of the study). During the first month of the study, decreased txnip gene expression and increased GLP1R mRNA were associated with the administration of verapamil when compared with the placebo, although the differences were not significant. Conclusion: Verapamil can lead to better control of T2DM by reducing txnip gene expression and increasing be

关键词： Type 2 diabetes Randomized controlled trials Verapamil txnip

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Chronic intermittent hypoxia-induced mitochondrial dysfunction mediates endothelial injury via the txnip/NLRP3/IL-1? signaling pathway

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FREE RADICAL BIOLOGY AND MEDICINE 2021年 165卷 401-410页

作者： Yan, Ya Ru Zhang, Liu Lin, Ying Ni Sun, Xian Wen Ding, Yong Jie Li, Ning Li, Hong Peng Li, Shi Qi Zhou, Jian Ping Li, Qing Yun Shanghai Jiao Tong Univ Ruijin Hosp Dept Resp & Crit Care Med Sch Med Shanghai 200025 Peoples R China Shanghai Jiao Tong Univ Inst Resp Dis Sch Med Shanghai 200025 Peoples R China

Oxidative stress and inflammation induced by chronic intermittent hypoxia (CIH) are trigger factors of cardiovascular diseases in patients with obstructive sleep apnea (OSA). This study aimed to investigate the role of CIHinduced mitochondrial dysfunction in vascular endothelial injury both in vivo and in vitro. Human umbilical vein endothelial cells and Sprague Dawley rats were exposed to CIH. CIH promoted the production of intracellular reactive oxygen species, caused mitochondrial dysfunction, and induced cell apoptosis in human umbilical vein endothelial cells. RNA-Seq analysis revealed that the NOD-like receptor signaling pathway was involved in endothelial injury induced by CIH. txnip/NLRP3/IL-1? pathway was found to be upregulated by CIH. Knockdown of TNXIP rescued the endothelial cells from CIH-induced apoptosis, indicating that activation of the txnip/NLRP3/IL-1? pathway mediated the CIH-induced endothelial apoptosis. Administration of the mitochondria-targeted antioxidant mito-TEMPO improved mitochondrial function and suppressed upregulation of the txnip/NLRP3/IL-1? pathway, thereby alleviating CIH-induced endothelial apoptosis. In vivo experiments confirmed the results, where mito-TEMPO was found to ameliorate endothelial injury in rat aortas exposed to CIH. The results imply that CIH-induced mitochondrial dysfunction mediates endothelial injury implication of txnip/NLRP3/IL-1? signaling pathway.

关键词： Obstructive sleep apnea Chronic intermittent hypoxia Mitochondrial dysfunction txnip NLRP3 inflammasome Endothelial injury

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Effect of Sleeve Gastrectomy on Plasma Thioredoxin-Interacting Protein (txnip)

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OBESITY SURGERY 2021年第11期31卷 4829-4835页

作者： Chu, Yuxiao Widjaja, Jason Hong, Jian Dolo, Ponnie Robertlee Zhu, Xiaocheng Yao, Libin Xuzhou Med Univ Affiliated Hosp Dept Gastrointestinal Surg Xuzhou 221002 Jiangsu Peoples R China

Purpose The mechanism in which bariatric surgery induces diabetes remission is still poorly understood. This study proposes Thioredoxin-interacting protein (txnip) as a possible factor for the anti-diabetic mechanism after sleeve gastrectomy (SG). Materials and Methods Plasma txnip level in obesity patients with diabetes (T2D, N = 20), obesity patients without diabetes (NDO, N = 20), and patients without obesity and diabetes (lean, N = 10) were assessed before surgery and at 1 and 12 months after SG. Results Preoperative txnip level was significantly higher in T2D (196.4 +/- 76.0 pg/ml) and NDO (149.7 +/- 94.1 pg/ml) patients when compared with lean patients (98.7 +/- 22.7 pg/ml) (p-value < 0.05). At 1 month and 12 months postoperatively, the txnip levels were reduced significantly from the preoperative levels in the T2D and NDO patients (p-value < 0.05). Before surgery, a correlation between txnip and fasting blood glucose (FBG) (r(2) = 0.1585, p-value = 0.0109), HbA1C (r(2) = 0.2120, p-value = 0.0028), and insulin (r(2) = 0.1217, p-value = 0.0274) was observed. At 12 months after surgery, the reduction of txnip was also correlated with the degree of FBG (r(2) = 0.1038, p-value = 0.0426), HbA1C (r(2) = 0.2459, p-value = 0.0011), and insulin (r(2) = 0.1365, p-value = 0.0190) reduction. Conclusion Plasma txnip level is elevated in obesity patients with/without diabetes. SG resulted in a significant reduction of plasma txnip level which is correlated with the degree of FBG, HbA1C, and insulin reduction. Regulation of txnip could be part of the mechanism of diabetes remission after bariatric surgery.

关键词： Sleeve gastrectomy txnip Type 2 diabetes Obesity Diabetes remission

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W2476 represses txnip transcription via dephosphorylation of FOXO1 at Ser319

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CHEMICAL BIOLOGY & DRUG DESIGN 2021年第5期97卷 1089-1099页

作者： Zhong, Li Liu, Qing Liu, Qiaofeng Zhang, Shikai Cao, Yongbing Yang, Dehua Wang, Ming-Wei Chinese Acad Sci Natl Ctr Drug Screening CAS Key Lab Receptor Res Shanghai Inst Mat Med Shanghai 201203 Peoples R China Univ Chinese Acad Sci Beijing Peoples R China Fudan Univ Sch Pharm Shanghai Peoples R China Shanghai Univ Tradit Chinese Med Shanghai TCM Integrated Hosp Shanghai Peoples R China

Thioredoxin-interacting protein (txnip) overexpression is implicated in the pathogenesis of type 2 diabetes. Previous studies have shown that a small molecule compound (W2476) was able to improve beta-cell dysfunction and exert therapeutic effects in diabetic mice via repression of txnip signaling pathway. The impact of W2476 on txnip transcription was thus investigated using the chromatin immunoprecipitation method. It was found that W2476 promotes competitive binding of forkhead box O1 transcription factor (FOXO1) to the carbohydrate response element (ChoRE) sequence associated with ChoRE-binding protein (ChREBP)/Mlx interacting protein-like(Mlx) complexes. This interaction hinders the attachment of histone acetyltransferase p300 and reduces histone H4 acetylation on the txnip promoter, leading to decreasing txnip transcription.

关键词： chromatin immunoprecipitation diabetes transcription txnip W2476

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miR-125b enhances metastasis and progression of cancer via the txnip and HIF1α pathway in pancreatic cancer

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CANCER BIOMARKERS 2021年第1期31卷 27-38页

作者： Wang, Pengli Zheng, Dan Qi, Hongyang Gao, Qi Xinxiang Cent Hosp Dept Gastroenterol 56 Jinsui Ave Xinxiang 453000 Henan Peoples R China Xinxiang Cent Hosp Dept Endocrinol Xinxiang Henan Peoples R China

BACKGROUND: MicroRNAs (miRNAs) play potential role in the development of various types of cancer conditions including pancreatic cancer (PC) targeting several cellular processes. Present study was aimed to evaluate function of miR-125b and the mechanism involved in PC. METHODS: Cell migration, MTT and BrdU study was done to establish the migration capability, cell viability and cell proliferation respectively. Binding sites for miR-125b were recognized by luciferase assay, expression of protein by western blot and immunofluorescence assay. In vivo study was done by BALB/c nude xenograft mice for evaluating the function of miR-125b. RESULTS: The study showed that expression of miR-125b was elevated in PC cells and tissues, and was correlated to proliferation and migration of cells. Also, over-expression of miR-125b encouraged migration, metastasis and proliferation of BxPC-3 cells, the suppression reversed it. We also noticed that thioredoxin-interacting protein (txnip) was the potential target of miR-125b. The outcomes also suggested that miR-125b governed the expression of txnip inversely via directly attaching to the 3'-UTR activating hypoxia-inducible factor 1 alpha (HIF1 alpha). Looking into the relation between HIFI cx and txnip, we discovered that txnip caused the degradation and export of HIF1 alpha by making a complex with it. CONCLUSION: The miR-125b-txnip-HIF1 alpha pathway may serve useful strategy for diagnosing and treating PC.

关键词： Pancreatic cancer miR-125b HIF1 alpha txnip

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Intestinal metabolite UroB alleviates cerebral ischemia/reperfusion injury by promoting competition between TRIM65 and txnip for binding to NLRP3 inflammasome in response to neuroinflammation (vol 1870, 167056, 2024)

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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 2024年第7期1870卷 167056页

作者： Luo, Jing Luo, Yujia Chen, Jialei Gao, Yu Tan, Junyi Yang, Yongkang Yang, Changhong Jiang, Ning Luo, Yong Chongqing Med Univ Affiliated Hosp 1 Dept Neurol Chongqing Peoples R China Chongqing Med Univ Dept Pathol Chongqing Peoples R China Chongqing Med Univ Mol Med Diagnost & Testing Ctr Chongqing Peoples R China Chongqing Med Univ Affiliated Hosp 1 Dept Pathol Chongqing Peoples R China Chongqing Med Univ Affiliated Hosp 1 Dept Orthoped Chongqing Peoples R China Chongqing Med Univ Coll Basic Med Sci Mol Med & Canc Res Ctr Chongqing Peoples R China Chengdu Univ Clin Med Coll Dept Clin Med Chengdu Peoples R China Chongqing Med Univ Dept Bioinformat Chongqing Peoples R China

Our previous research suggests that targeting NLRP3 inflammasomes holds promise for mitigating cerebral ischemia/reperfusion injury. The gut metabolite Urolithin B (UroB) has been shown to inhibit the neuroinflammation. However, the specific role of UroB in cerebral ischemia/reperfusion injury and its potential impact on NLRP3 inflammasome remain unclear. In this study, acute stroke was simulated using the MCAO model in male Sprague-Dawley rats. UroB was intraperitoneally administered after 1 h of reperfusion. The effects of UroB on brain tissue were evaluated, including infarct volume, brain edema, and neurobehavioral changes. Western blotting and immunofluorescence were performed to investigate the effect of UroB on inflammation-related proteins. Furthermore, TRIM65 knockdown and txnip overexpression experiments elucidated the role of UroB in NLRP3 inflammasome activation. The ( demonstrate the neuroprotective effect of UroB in acute stroke, reducing brain tissue damage and improving motor function. Mechanistically, UroB modulated neuroinflammation by influencing txnip and TRIM65 protein expression, as well as competitive binding to the NLRP3 inflammasome, attenuating cerebral ischemia/reperfusion injury. In conclusion, the potential of UroB as a protective agent against cerebral ischemia/reperfusion injury in acute stroke stands out as it regulates TRIM65 and txnip competitive binding to the NLRP3 inflammasome. These findings suggest that UroB is a promising drug candidate for the treatment of acute stroke.

关键词： Cerebral ischemia/reperfusion NLRP3 inflammasome Neuroinflammation TRIM65 txnip UroB

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A novel link between melatonin and circ_0005753/PTBP1/txnip regulatory network in the modulation of osteogenic potential in mesenchymal stem cells

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CHEMICAL BIOLOGY & DRUG DESIGN 2024年第1期103卷 e14380页

作者： Tu, Wei Zhu, Shuying Li, Fan Xu, Chengyun Tu, Weiping Chen, Yanxia Nanchang Univ Endocrine Dept Affiliated Hosp 2 Nanchang Jiangxi Peoples R China Nanchang Univ Affiliated Hosp 2 Dept Nephrol Nanchang Jiangxi Peoples R China Nanchang Univ Dept Nephrol Affiliated Hosp 2 1 Minde Rd Nanchang 330006 Jiangxi Peoples R China

Labeled with pluripotent potential, the transplantation of bone marrow mesenchymal stem cells (BMSCs) is considered as a promising strategy for treating osteoporosis (OP). Melatonin (MEL) has been investigated to be an essential regulator involved in bone metabolism, as well as BMSCs differentiation. Circular RNAs (circRNAs) are a unique kind of non-coding RNA and play an important regulatory role in OP. However, whether circRNAs are implicated in the effects of MEL on BMSCs osteogenic differentiation remains largely indeterminate. Expression of circ_0005753 in human BMSCs with MEL treatment, clinical specimens diagnosed with OP, either with ovariectomy (OVX)-induced mice, was measured by RT-qPCR. Western blot was conducted to analyze protein levels of osteogenesis-related molecules (Opg, RUNX2, ALP, BMP4) and txnip. RNA immunoprecipitation (RIP) and RNA pull-down assays were performed to validate the binding relationship among circ_0005753, PTBP1, and txnip. Alkaline phosphatase (ALP) and alizarin red staining (ARS) were performed to evaluate osteogenic capacity of BMSCs. OP mouse model was established by ovariectomy, as evaluated pathologic changes via hematoxylin-eosin (HE), Masson, and Immunohistochemistry (IHC) staining. Expression of circ_0005753 was remarkably decreased during MEL-induced osteogenic differentiation of BMSCs. Interestingly, not only circ_0005753 knockdown significantly promoted osteogenic differentiation of BMSCs, but circ_0005753 overexpression also weakened osteogenic differentiation induced by MEL treatment. Mechanistically, circ_0005753 maintained the stabilization of txnip mRNA via recruiting PTBP1. Additionally, reinforced circ_0005753 abrogated MEL-mediated protective effects on OP pathogenesis in a mouse model. This work shows that MEL facilitates osteogenic differentiation of BMSCs via the circ_0005753/PTBP1/txnip axis, which may shed light on the development of a novel therapeutic strategy to prevent OP.

关键词： bone marrow mesenchymal stem cells circ_0005753 melatonin osteogenic differentiation PTBP1 txnip

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Ranolazine ameliorates T1DM-induced testicular dysfunction in rats;role of NF-κB/txnip/GSDMD-N/IL-18/Beclin-1 κ B/txnip/GSDMD-N/IL-18/Beclin-1 signaling pathway

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EUROPEAN JOURNAL OF PHARMACOLOGY 2024年 977卷 176744页

作者： Samaha, Mahmoud M. Nour, Omnia A. Mansoura Univ Fac Pharm Dept Pharmacol & Toxicol Mansoura 35516 Egypt

Approximately 90% of diabetic males have varying degrees of testicular dysfunction. The current study investigates the possible beneficial consequences of ranolazine against T1DM-induced testicular dysfunction in rats. Thirty-two male Sprague Dawley rats were assorted into 4 groups;normal, diabetic (single 50 mg/kg STZ, I. P.) and ranolazine (40 and 80 mg/kg, orally). The present investigation revealed that the hypoglycemic impact of ranolazine significantly improved the testicular weight and body weight of the final rats, as well as the concentration of blood testosterone, sperm count, and viability, all of which were associated with STZ-induced testicular dysfunction. Furthermore, as demonstrated by elevated reduced glutathione (GSH) activity and lowered malondialdehyde (MDA) levels, diabetic rats administered ranolazine showed a noteworthy improvement in the oxidant/antioxidant ratio. Furthermore, a substantial rise in beclin-1 concentration was seen in conjunction with a significant decrease in thioredoxin-interacting protein (txnip) and interleukin-18 (IL-18) concentrations when ranolazine was administered. Although ranolazine exhibited a reduction in inflammation as seen by lower expression of nuclear factor-kappa B (NF-kappa B) and cluster of differentiation (CD68) in the testicles, these biochemical findings were validated by improvements in the morphological and histopathological outcomes of both the pancreatic and testicular tissues. In conclusion, daily oral administration of ranolazine (40 and 80 mg/kg) for 8 weeks could be a promising therapy for T1DM-induced testicular dysfunction through its dose-dependent antioxidant and anti-inflammatory effects.

关键词： T1DM STZ Ranolazine txnip Beclin-1 NF-kappa B

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