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Mitigation of nicotine-induced podocyte injury through inhibition of thioredoxin interacting protein

Biomedicine and Pharmacotherapy 2025年 187卷 118110-118110页

作者： Datta, Sayantap Rahman, Mohammad Atiqur Koka, Saisudha Boini, Krishna M. Department of Pharmacological and Pharmaceutical Sciences College of Pharmacy University of Houston Houston TX United States Department of Pharmaceutical Sciences Irma Lerma College of Pharmacy Texas A&M University Kingsville TX United States

Nicotine has been reported to initiate NLRP3 inflammasome formation and activation in different pathological conditions. The current study assessed whether thioredoxin-interacting protein (txnip) mediates nicotine-induced NLRP3 inflammasome activation and consequent podocyte injury. Co-immunoprecipitation analysis demonstrated that nicotine-induced txnip/NLRP3 interaction in podocytes relative to control groups. However, pre-treatment with txnip inhibitors, verapamil (Vera) or SRI-37330 (SRI) attenuates nicotine-induced txnip/NLRP3 interaction. Confocal microscopic analysis showed that nicotine treatment significantly increased the colocalization of Nlrp3 with Asc, Nlrp3 with caspase-1 and Nlrp3 with txnip in podocytes compared to control cells. Pretreatment with txnip inhibitor Vera or SRI abolished nicotine-induced Nlrp3/Asc, Nlrp3/caspase-1 or Nlrp3/txnip colocalization. Correspondingly, nicotine treatment significantly increased the caspase-1 activity and IL-1β production compared to control cells. However, prior treatment with txnip inhibiting Vera or SRI significantly attenuated the nicotine-induced caspase-1 activity and IL-1β production. Further immunofluorescence analysis showed that nicotine treatment significantly decreased podocin and nephrin expression compared to control cells. However, pretreatment with txnip inhibiting Vera or SRI attenuated the nicotine-induced podocin and nephrin reduction. In addition, confocal, flow cytometry and biochemical analysis showed that nicotine treatment significantly increased desmin expression, apoptosis and cell permeability compared to control cells. However, prior treatment with txnip inhibiting Vera or SRI significantly attenuated the nicotine-induced desmin expression, apoptosis and cell permeability. Taken together, our results demonstrate that txnip/NLRP3 interaction constitutes a potentially key signalling mechanism driving nicotine-induced NLRP3 inflammasome formation, activation and subsequent podocyte damag

关键词： Inflammasome Podocyte Smoking txnip

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The crucial role of thioredoxin interacting protein in the liver insulin resistance induced by di (2-ethylhexyl) phthalates

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FOOD AND CHEMICAL TOXICOLOGY 2022年 164卷 113045页

作者： Zhang, Wang Xu, Peng Li, Jing-ya Anhui Med Univ Hefei Third Clin Coll Peoples Hosp Hefei 3 Dept Pharm Hefei 230022 Peoples R China Anhui Univ Chinese Med Dept Pathol Hefei 230012 Peoples R China

The widespread usage of plastic products in human life has led to extensive exposure to plasticizers and resulted in serious health problems for humans, which has become a focus of toxicology research in the world. We aimed to explore the potential mechanism of liver insulin resistance induced by di(2-ethylhexyl) phthalate (DEHP) and working on a novel treatment to alleviate insulin resistance caused by excessive exposure to DEHP. For this purpose, in vivo and in vitro experiments were conducted, and the pivotal factors in the insulin signaling pathway were analyzed. In vivo study showed DEHP could lead to liver injury and insulin resistance. DEHP could break the balance of oxidative stress and cause accumulation of inflammatory factors. Genomics and proteomics experiment results revealed that DEHP could inhibit the mRNA and protein expression of insulin receptor, insulin receptor substrate, PI3K/Akt/mTOR, and glucose transporter 4. Nevertheless, the liver insulin resistance induced by DEHP could be reversed by Verapamil (thioredoxin interacting protein (txnip) inhibitor). Thus, we confirmed that DEHP caused insulin resistance by affecting the txnip in liver, further damaging the conduction of insulin signaling pathway. Therefore, adding Verapamil to the treatment of patients with insulin resistance due to plasticizers might be more effective.

关键词： DEHP txnip Insulin resistance Liver Glucose transporter 4

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EGCG-derived polymeric oxidation products enhance insulin sensitivity in db/db mice

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REDOX BIOLOGY 2022年 51卷 102259-102259页

作者： Wu, Ximing Yang, Mingchuan He, Yufeng Wang, Fuming Kong, Yashuai Ling, Tie-Jun Zhang, Jinsong Anhui Agr Univ Sch Tea & Food Sci Lab Redox Biol State Key Lab Tea Plant Biol & Utilizat Hefei 230036 Peoples R China

The present study investigated the influence of epigallocatechin-3-gallate (EGCG) and its autoxidation products on insulin sensitivity in db/db mice. Compared to EGCG, autoxidation products of EGCG alleviated diabetic symptoms by suppressing the deleterious renal axis of the renin-angiotensin system (RAS), activating the beneficial hepatic axis of RAS, and downregulating hepatic and renal SELENOP and txnip. A molecular weight fraction study demonstrated that polymeric oxidation products were of essential importance. The mechanism of action involved coating polymeric oxidation products on the cell surface to protect against cholesterol loading, which induces abnormal RAS. Moreover, polymeric oxidation products could regulate RAS and SELENOP at doses that were far below cytotoxicity. The proof-of-principal demonstrations of EGCG-derived polymeric oxidation products open a new avenue for discovering highly active polymeric oxidation products based on the oxidation of naturally occurring polyphenols to manage diabetes and other diseases involving abnormal RAS.

关键词： Type 2 diabetes Renin-angiotensin system Insulin sensitivity EGCG autoxidation Products SELENOP txnip

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Chrysin mitigates bleomycin-induced pulmonary fibrosis in rats through regulating inflammation, oxidative stress, and hypoxia

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INTERNATIONAL IMMUNOPHARMACOLOGY 2020年第PartA期89卷 107011-107011页

作者： Kseibati, Mohammed O. Sharawy, Maha H. Salem, Hatem A. Mansoura Univ Dept Pharmacol & Toxicol Fac Pharm Mansoura 35516 Egypt

Pulmonary fibrosis is a chronic condition characterized by fibroblast proliferation, and the infiltration of inflammatory cells that can initiate local tissue hypoxia. In this study the effect of chrysin (50 mg/kg/orally) in a model of bleomycin (BLM)-induced pulmonary fibrosis was studied. Chrysin managed to decrease mortality rate associated with BLM instillation and it managed to improve lung architecture and lung fibrosis by decreasing hydroxyproline content and transforming growth factor-beta 1 (TGF-beta 1) protein expression. Chrysin showed anti-inflammatory effect displayed by the decrease in inflammatory cells infiltrates, the decline in permeability of the alveolar/capillary barrier and the reduction in lactate dehydrogenase (LDH) activity. Chrysin demonstrated potent antioxidant effect by decreasing lipid peroxidation, increasing antioxidant defense mechanisms by increasing superoxide dismutase (SOD) activity and reduced glutathione (GSH) content. Additionally, the effect of chrysin on nitric oxide (NOx) content was assessed, where chrysin decreased NOx, increased the protein expression of endothelial nitric oxide synthase (eNOS), and decreased inducible nitric oxide synthase (iNOS) protein expression. Chrysin also succeeded in decreasing thioredoxin-interacting protein (txnip), the negative regulator of thioredoxin system, showing potent antioxidant effect. Finally, both tissue and bronchoalveolar lavage fluid contents of hypoxia inducible factor one alpha (HIF1 alpha) were decreased by chrysin indicating that chrysin decreased local tissue hypoxia. In conclusion, this study exposed a possible proof that chrysin could mitigate pulmonary fibrosis induced by BLM through its anti-inflammatory, antioxidant, antifibrotic effects and its effect in alleviating hypoxia.y

关键词： Bleomycin Chrysin HIF1 alpha Nitric oxide TGF-beta 1 txnip

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Thioredoxin, thioredoxin interacting protein and transducer and activator of transcription 3 in gestational diabetes

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MOLECULAR BIOLOGY REPORTS 2020年第2期47卷 1199-1206页

作者： Pasternak, Yael Ohana, Meital Biron-Shental, Tal Cohen-Hagai, Keren Benchetrit, Sydney Zitman-Gal, Tali Meir Med Ctr Dept Obstet & Gynecol Kefar Sava Israel Tel Aviv Univ Sackler Fac Med Tel Aviv Israel Meir Med Ctr Dept Hypertens & Nephrol Nephrol Lab Kefar Sava Israel

To evaluate changes in the inflammatory response of thioredoxin (TXN), thioredoxin interacting protein (txnip), transducer and activator of transcription 3, NF?B-p50 and STAT3 at the level of maternal serum, placenta, and umbilical cord blood of women with gestational diabetes mellitus type 2 (GDMA2) compared to normal pregnancies (NP). Thirty pregnant women (20 with GDMA2 and 10 NP) were recruited during admission for delivery. Blood samples were obtained from the parturients and umbilical cords, as well as placental tissue for mRNA and protein extraction. txnip mRNA expression was significantly increased in maternal serum of women with GDMA2 compared to NP women. txnip mRNA was significantly decreased in GDMA2 placentas and cord blood compared to NP. TXN/txnip mRNA ratio showed significantly high absolute values in placental and cord blood (2.39 and 1.66) respectively, compared to maternal ratio (1.084) (P<0.001). TXN/txnip placenta protein ratio showed similar values between GDMA2 and NP (0.98 and 0.86;P=0.7). STAT3 and its target protein SOCS3, as well as NF?B-p50 mRNA expression were significantly increased in placentas of GDMA2. NF?B-p50 mRNA expression was significantly decreased in cord blood compared to both maternal and placental mRNA expression. Pro-inflammatory changes are expressed by low mRNA TXN/txnip ratio in maternal blood of GDMA2 patients, but not in placental and umbilical cord blood samples. This, as well as the feedback role of SOCS3 in STAT3 pathway and NF?B-p50 expression, may indicate that the placenta has a role in protecting the fetus from damage due to inflammatory response, which is common in diabetes.

关键词： GDMA2 txnip TXN SOCS3 STAT3 NF?B-p50

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Panax notoginseng saponin R1 attenuates allergic rhinitis through AMPK/ Drp1 mediated mitochondrial fission

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BIOCHEMICAL PHARMACOLOGY 2022年 202卷 115106页

作者： Zhang, Yalin Song, Yilan Wang, Chongyang Jiang, Jingzhi Liu, Siqi Bai, Qiaoyun Li, Liangchang Jin, Hainan Jin, Yongde Yan, Guanghai Yanbian Univ Jilin Key Lab Immune & Targeting Res Common Allerg Yanji 133002 Peoples R China Yanbian Univ Affiliated Hosp Dept Otorhinolaryngol Yanji 133000 Peoples R China Yanbian Univ Dept Anat Histol & Embryol Med Coll Yanji 133002 Peoples R China Yanbian Univ Affiliated Hosp Dept Otorhinolaryngol 1327Juzi Rd Yanji 133000 Jilin Peoples R China Yanbian Univ Dept Anat Histol & Embryol Med Coll 977Gongyuan Rd Yanji 133002 Jilin Peoples R China

We investigated whether Panax notoginseng saponin (PNS-R1) attenuates allergic rhinitis (AR) through AMPK/ Drp1-mediated mitochondrial fission. AR model was established in mice by Ovalbumin (OVA). In vitro, human nasal epithelial cells (HNEpCs) were stimulated using recombinant human interleukin 13 (IL-13). PNS-R1 was administrated in vivo and in vitro. Then, HE staining of nasal tissue, ELISA detection of immunoglobulin E (IgE) and proinflammatory cytokine levels in serum and nasal lavage fluid, flow cytometry analysis of Th1/Th2 ratio and apoptosis, TUNEL staining, Western blot, detection of reactive oxygen species (ROS) and mitochondrial ROS, immunofluorescence analysis of Tom20 and mitochondrial fission protein Drp1 co-localization, and mitochon-drial membrane potential detection, were performed. PNS-R1 attenuated allergic symptoms in AR mice, decreased OVA-specific IgE, IL-4, IL-6, IL-8, IL-13, and TNF-alpha levels, and restored the Th1/Th2 imbalance. Meanwhile, we found that PNS-R1 treatment significantly reduced apoptosis, ROS production, and co-localization of Tom20 and Drp1 in the nasal epithelium of AR mice. In vitro, we found that PNS-R1 upregu-lated mitochondrial membrane potential and reduced ROS and mitochondrial ROS production as well as Cleaved-caspase-3/9, Bax, Cyt-c, Apaf-1 expression and mitochondrial fission. Mechanistically, we found that PNS-R1 downregulated Drp1 phosphorylation (Ser 616) and Drp1 translocation in an AMPK-dependent manner, promoted MFN2 expression, and reduced txnip, NLRP3, Caspase-1, and IL-1 beta expression. PNS-R1 may protect mitochondrial integrity by inhibiting AMPK/Drp1 and txnip/NLRP3 signaling pathway, thereby alleviating AR symptoms in mice. PNS-R1 may have great potential as a therapeutic agent for AR.

关键词： PNS-R1 Mitochondrial fission AMPK Drp1 txnip NLRP3

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Dose-dependent renoprotective impact of Lactoferrin against glycerol-induced rhabdomyolysis and acute kidney injury

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LIFE SCIENCES 2022年第0期302卷 000-000页

作者： Madkour, Ahmed H. Helal, Manar G. Said, Eman Salem, Hatem A. Mansoura Univ Fac Pharm Dept Pharmacol & Toxicol Mansoura 35516 Egypt New Mansoura Univ Fac Pharm Mansoura 7723730 Egypt

Acute kidney injury (AKI) is a clinical disorder with a serious impact on the quality of patients' lives. Considering its increased worldwide prevalence, investigating novel therapeutic approaches for the management of AKI has been inevitable. Lactoferrin (LF), a glycoprotein belonging to the transferrin family, is known to play an important role in regulating iron homeostasis. This study aimed to evaluate the renoprotective effect of LF (30, 100, and 300 mg/kg orally) against glycerol (GLY)-induced rhabdomyolysis (RM) in rats. RM was induced by a single intramuscular injection of GLY 50% (10 mL/kg) after 24-h water deprivation in male Sprague-Dawley rats. LF administration conferred significant dose-dependent renoprotective impact against GLY-induced RM as evidenced by the decreased renal/somatic index and the significant improvement in renal functions as confirmed by the significant increase in creatinine clearance, decrease in serum creatinine and blood urea nitrogen, and improvement in albuminuria and proteinuria. Redox homeostasis was significantly restored in a dose-dependent manner as well. Moreover, serum interleukin-113 (IL-113) was significantly decreased with a parallel significant decrease in renal NOD-like receptor family pyrin domain containing 3 (NLRP3) and thioredoxin interacting protein (txnip), kidney injury molecule-1 (KIM-1), caspase-3 expression, nuclear factor kappa B (NF-kappa B), cluster of differentiation (CD68) expression, and a significant increase in renal nuclear factor erythroid 2-related factor 2 (NRF2) expression. Ultimately, LF administration was associated with a significant amelioration of GLY-induced renal necrotic and inflammatory alterations. In conclusion, the observed dose-dependent nephroprotective effect of LF can be attributed to its modulatory impact on inflammatory/apoptotic/oxidative signaling.

关键词： Glycerol Lactoferrin Renoprotection NLRP3 txnip Caspase-3

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Retrospective analysis of the relationship between elevated plasma levels of txnip and carotid intima-media thickness in subjects with impaired glucose tolerance and early Type 2 diabetes mellitus

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DIABETES RESEARCH AND CLINICAL PRACTICE 2015年第2期109卷 372-377页

作者： Zhao, Yongcai Li, Xinsheng Tang, Shiling CangZhou Cent Hosp Dept Endocrinol Cangzhou Peoples R China

Aims: Accelerated atherosclerosis is the major cause of mortality in diabetic patients and increased oxidative stress probably plays an important role in its development. The aim of our study was to evaluate the relationship between thioredoxin-interacting protein (txnip) as an oxidative stress parameter and carotid artery intima-media thickness (CIMT) as an indicator of atherosclerosis in patients with early-state diabetes and impaired glucose tolerance. Methods: The study was a retrospective analysis of 90 patients with impaired glucose regulation (IGR), 80 patients with early Type 2 diabetes mellitus (T2DM), and 80 subjects with normal glucose tolerance (NGT) as the control group. It was conducted at the endocrine outpatient clinic and hospital department of Cangzhou Central Hospital (Cangzhou, China) from June 2012 to Oct. 2013. Plasma txnip was measured to evaluate the level of oxidative stress. CIMT was assessed by carotid artery ultrasonography. Soluble vascular cell adhesion molecule-1 (sVCAM-1), a risk indicator for endothelial dysfunction, was also measured. Results: Compared to the NGT control, patients with IGR showed significantly higher plasma levels of txnip (P < 0.05). Compared to the IGR group, patients with T2DM also had significantly higher plasma levels of txnip (P < 0.05). CIMT was significantly higher in the subjects with abnormal glucose metabolism than in the NGT group (P < 0.05). CIMT showed positive correlations with both txnip and sVCAM-1 levels (r = 0.56 and r = 0.49, respectively, both P < 0.01). Conclusions: The present study showed that plasma levels of txnip may be a useful predictor of subclinical atherosclerosis in Type 2 diabetic patients. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

关键词： Glucose tolerance test Glucose metabolism disorders Carotid intima-media thickness Ultrasonography Type 2 diabetes mellitus txnip

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A novel txnip-based mechanism for Cx43-mediated regulation of oxidative drug injury

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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE 2015年第10期19卷 2469-2480页

作者： Gao, Kun Chi, Yuan Zhang, Xiling Zhang, Hui Li, Gang Sun, Wei Takeda, Masayuki Yao, Jian Univ Yamanashi Interdisciplinary Grad Sch Med & Engn Dept Mol Signaling Chuo Ku Yamanashi Japan Nanjing Univ Chinese Med Affiliated Hosp Dept Nephrol Nanjing Jiangsu Peoples R China Univ Yamanashi Interdisciplinary Grad Sch Med & Engn Dept Urol Chuo Ku Yamanashi Japan Liaoning Canc Hosp & Inst Dept Urol Shenyang Liaoning Peoples R China

Gap junctions (GJs) play an important role in the regulation of cell response to many drugs. However, little is known about their mechanisms. Using an invitro model of cytotoxicity induced by geneticin (G418), we explored the potential signalling mechanisms involved. Incubation of cells with G418 resulted in cell death, as indicated by the change in cell morphology, loss of cell viability and activation of caspase-3. Before the onset of cell injury, G418 induced reactive oxygen species (ROS) generation, activated oxidative sensitive kinase P38 and caused a shift of connexin 43 (Cx43) from non-phosphorylated form to hyperphosphorylated form. These changes were largely prevented by antioxidants, suggesting an implication of oxidative stress. Downregulation of Cx43 with inhibitors or siRNA suppressed the expression of thioredoxin-interacting protein (txnip), activated Akt and protected cells against the toxicity of G418. Further analysis revealed that inhibition of txnip with siRNA activated Akt and reproduced the protective effect of Cx43-inhibiting agents, whereas suppression of Akt sensitized cells to the toxicity of G418. Furthermore, interference of txnip/Akt also affected puromycin- and adriamycin-induced cell injury. Our study thus characterized txnip as a presently unrecognized molecule implicated in the regulatory actions of Cx43 on oxidative drug injury. Targeting Cx43/txnip/Akt signalling cascade might be a promising approach to modulate cell response to drugs.

关键词： connexin 43 gap junction oxidative stress cytotoxicity txnip Akt

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CircECE1 activates energy metabolism in osteosarcoma by stabilizing c-Myc

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MOLECULAR CANCER 2020年第1期19卷 151-151页

作者： Shen, Shuying Yao, Teng Xu, Yining Zhang, Deguang Fan, Shunwu Ma, Jianjun Zhejiang Univ Sir Run Run Shaw Hosp Dept Orthopaed Surg Med Coll 3 East Qingchun Rd Hangzhou 310016 Peoples R China Key Lab Musculoskeletal Syst Degenerat & Regenera 3 East Qingchun Rd Hangzhou 310016 Peoples R China Zhejiang Univ Sir Run Run Shaw Hosp Dept Head & Neck Surg Med CollInst Microinvas Surg 3 East Qingchun Rd Hangzhou 310016 Zhejiang Peoples R China

Background Osteosarcoma (OS) is the most common malignant bone tumor and has a poor prognosis. The potential involvement of circular RNAs (circRNAs) in OS progression remains unexplored. Here, we report that CircECE1, a circular RNA derived from human ECE1, plays a critical role in energy metabolism in OS. Methods The RIP chip sequence assay was performed to confirm CircECE1, through overexpression or knockdown of CircECE1 to verify its function in 143B and U2OS. RNA immunoprecipitation and immunoprecipitation were used to verify CircECE1's regulation of protein c-Myc and co- immunoprecipitation was used to verified the competitive binding relationship between CircECE1 and SPOP. The influence of CircECE1 on energy metabolism was evaluated by seahorse experiment, western blot, and immunohistochemistry. Results We found that CircECE1 is highly expressed in OS tissues and cells and that CircECE1 knockdown suppresses tumor proliferation and metastasis both in vitro and in vivo. Further, CircECE1 significantly promotes glucose metabolism in OS cells in vitro and in vivo. Mechanistically, CircECE1 interacts with c-Myc to prevent speckle-type POZ-mediated c-Myc ubiquitination and degradation. C-Myc inhibits thioredoxin binding protein (txnip) transcription and subsequently activates the Warburg effect. Conclusions CircECE1 regulates the Warburg effect through the c-Myc/txnip axis. CircECE1 mediated signal transduction plays a important role in OS process and energy metabolism. These findings may identify novel targets for OS molecular therapy.

关键词： Osteosarcoma CircECE1 C-Myc Glucose metabolism txnip

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