Search

Nickel (Ni) exposure is a significant risk factor for kidney dysfunction and oxidative stress injury in humans. Thioredoxin reductase 3 (Txnrd3), an important enzyme in animals, plays a role in maintaining cellular homeostasis and regulating oxidative stress. However, its protective effect against kidney injury has been determined. Melatonin (Mel) has antioxidant and anti-apoptotic effects and therefore may be a preventive and therapeutic agent for kidney injury. Our study aimed to investigate the roles of Mel and Txnrd3 in the treatment of nickel-induced renal injury. We divided 80 wild-type mice and 80 Txnrd3 -/- mice (C57BL/6 N) into a control group treated with saline, Ni group treated with 10 mg/kg NiCl2, Mel group treated with 2 mg/kg Mel, and Ni + Mel group given NiCl2 and Mel for 21 days. Histopathological and ultrastructural observation of the kidney showed that nuclei were wrinkled and mitochondrial cristae were broken in the Ni group, and these changes were significantly attenuated by Mel treatment. Mitochondrial and nuclear damage improved significantly in the Ni + Mel and Txnrd3-/- Ni + Mel groups. Furthermore, NiCl2 exposure decreased T-AOC, SOD, and GSH activities in the kidney. The decreases in antioxidant enzyme activity were attenuated by Mel, and these improvements were abolished by Txnrd3 knockout. NiCl2-induced increases in the mRNA and protein levels of apoptosis factors (Bax, Cyt-c, caspase-3, and caspase-9) were attenuated by Mel treatment, and Txnrd3 knockout abolished the repressive effect of Mel on apoptosis genes. Overall, we concluded that Mel improves oxidative stress and apoptosis induced by NiCl2 by regulating Txnrd3 expression in the kidney. Our results provide evidence for the role of Mel in NiCl2-induced kidney injury and identify Txnrd3 as a potential therapeutic target for renal injury.

Thioredoxin reductase 3 (Txnrd3) plays a crucial role in antioxidant and anti‐cancer activities, and sperm maturation. The damage of heavy metals, including Nickel (Ni), is the most prominent harm in social development, and hampering Txnrd3 might exacerbate Ni‐induced cardiac damage. In this study, a total of 160 8‐week‐old C57BL/N male mice with 25–30 g weight of Txnrd3+/+ wild‐type and Txnrd3−/− homozygote‐type were randomly divided into eight groups. The mice in the control and Ni groups were gavaged with distilled water and a freshly prepared 10 mg/kg NiCl2 solution. Melatonin (Mel) groups were administered at a concentration of 2 mg/kg for 21 days at the mice's 0.1 ml/10 g body weight. Ni exposure up‐regulated the messenger RNA (mRNA) levels of mitochondrial apoptosis (caspase‐3, caspase‐9, cytochrome c, p53, and BAX), autophagy (LC3, ATG 1, ATG 7, and Beclin‐1), and inflammation (TNF‐α, COX 2, IL‐1β, IL‐2, IL‐6, and IL‐7)‐related markers, but down‐regulated the mRNA levels of BCL‐2, p62 and mTOR (p <.05). Ni exposure decreased the expression of BCL‐2 and p62 protein but increased the expression levels of caspase‐3, caspase‐9, cytochrome c, p53, BAX, ATG 7, Beclin‐1, TNF‐α, COX 2, IL‐1β and IL‐2 protein (p <.05). Ni increased the contents of glutathione disulfide (GSSG) and malondialdehyde (MDA) and decreased the activities of catalase (CAT) and total superoxide dismutase (T‐SOD) (p <.05). Decreased Txnrd3 expression significantly exacerbated changes compared to the Ni exposure (p <.05). Mel significantly attenuated these changes, but the effect decreased when Txnrd3 was inhibited (p <.05). In conclusion, decreased Txnrd3 expression promoted Ni‐induced mitochondrial apoptosis and inflammation via oxidative stress and aggravated heart damage in mice. Decreased Txnrd3 expression significantly reduced the protective effect of Mel to Ni exposure. [ABSTRACT FROM AUTHOR]

Background: Txnrd3 as selenoprotein plays key roles in antioxidant process and sperm maturation. Inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease, are becoming significantly increasing disease worldwide in recent years which are proved relative to diet, especially selenium intake. Methods: In the present study, 8-week-old C57BL/6N male Txnrd3-/-, Txnrd3-/ + , Txnrd3 + / + mice, weight 25–30 g, were randomly chosen and each group with 30 mice. Feed 3.5% DSS drinking water and normal water continuously for 7 days. Mouse colon cancer cells (CT26) were cultured in vitro to establish Txnrd3 overexpressed/knocked-down model by cell transfection technology. Morphology and ultrastructure, calcium levels, ROS level, cell death were observed and detected in vivo and vitro. Results: In Txnrd3-/-mice, ulcerative colitis was more severe, the morphological and ultrastructural lesions were also more prominent compared with wild-type mice, accompanied by the significantly increased expression of NLRP3, Caspase1, RIPK3, and MLKL. Overexpression of Txnrd3 could lead to increased oxidative stress through intracellular calcium outflow-induced oxidative stress increase followed by necrosis and pyroptosis pathway activation and further inhibit the growth and proliferation of colon cancer cells. Conclusion: Txnrd3 overexpression leads to intracellular calcium outflow and increased ROS, which eventually leads to necrosis and focal death of colon cancer cells, while causing Txnrd3-/- mice depth of the crypt deeper, weakened intestinal secretion and immune function and aggravate the occurrence of ulcerative colitis. The present study lays a foundation for the prevention and treatment of ulcerative colitis and colon carcinoma in clinic treatment. [ABSTRACT FROM AUTHOR]

Alterations in ROS metabolism and redox signaling are often observed in cancer cells and play a significant role in tumor development and drug resistance. However, the mechanisms by which redox alterations impact cellular sensitivity to anticancer drugs remain elusive. Here we have identified the mitochondrial isoform of thioredoxin reductase 3 (mtTXNRD3), through RT-PCR microarray screen, as a key molecule that confers drug resistance to sorafenib and other clinical anticancer agents. High expression of mtTXNRD3 is detected in drug-resistant leukemia and hepatocellular carcinoma cells associated with significant metabolic alterations manifested by low mitochondrial respiration and high glycolysis. Mechanistically, high mtTXNRD3 activity keeps the mitochondrial thioredoxin2 (Trx2) in a reduced stage that in turn stabilizes several key survival molecules including HK2, Bcl-XL, Bcl-2, and MCL-1, leading to increased cell survival and drug resistance. Pharmacological inhibition of thioredoxin reductase by auranofin effectively overcomes such drug resistance in vitro and in vivo, suggesting that targeting this redox mechanism may be a feasible strategy to treat drug-resistant cancer.

Nickel (Ni) exposure is a significant risk factor for kidney dysfunction and oxidative stress injury in humans. Thioredoxin reductase 3 (Txnrd3), an important enzyme in animals, plays a role in maintaining cellular homeostasis and regulating oxidative stress. However, its protective effect against kidney injury has been determined. Melatonin (Mel) has antioxidant and anti-apoptotic effects and therefore may be a preventive and therapeutic agent for kidney injury. Our study aimed to investigate the roles of Mel and Txnrd3 in the treatment of nickel-induced renal injury. We divided 80 wild-type mice and 80 Txnrd3 -/- mice (C57BL/6 N) into a control group treated with saline, Ni group treated with 10 mg/kg NiCl 2 , Mel group treated with 2 mg/kg Mel, and Ni + Mel group given NiCl 2 and Mel for 21 days. Histopathological and ultrastructural observation of the kidney showed that nuclei were wrinkled and mitochondrial cristae were broken in the Ni group, and these changes were significantly attenuated by Mel treatment. Mitochondrial and nuclear damage improved significantly in the Ni + Mel and Txnrd3-/- Ni + Mel groups. Furthermore, NiCl 2 exposure decreased T-AOC , SOD, and GSH activities in the kidney. The decreases in antioxidant enzyme activity were attenuated by Mel, and these improvements were abolished by Txnrd3 knockout. NiCl 2 -induced increases in the mRNA and protein levels of apoptosis factors (Bax, Cyt-c, caspase-3, and caspase-9) were attenuated by Mel treatment, and Txnrd3 knockout abolished the repressive effect of Mel on apoptosis genes. Overall, we concluded that Mel improves oxidative stress and apoptosis induced by NiCl 2 by regulating Txnrd3 expression in the kidney. Our results provide evidence for the role of Mel in NiCl 2 -induced kidney injury and identify Txnrd3 as a potential therapeutic target for renal injury. [Display omitted] • After Txnrd3 knock-out, the kidney apoptosis of mice was more serious under nickel exposure. • Melatonin alleviates kidney apoptosis caused by nickel exposure but the remission effect was attenuated after Txnrd3 knock-out. • Melatonin reduced oxidative stress to prevent nickel-induced kidney damage. [ABSTRACT FROM AUTHOR]

Ni exposure leads to respiratory diseases in mice. Txnrd3 has been shown to have a protective effect on the body, but there is a paucity of empirical research focusing specifically on lung tissue. Melatonin possesses potent antioxidant, anti-inflammatory, and anti-fibrotic effects. By regulating inflammation-related factors, melatonin can activate the VEGF signaling pathway, ultimately alleviating lung injuries caused by Ni exposure. One hundred and sixty 8-week-old C57BL/6N mice, that were wild-type or Txnrd3−/− mice and 25–30 g in weight, were randomly divided into eight groups, including the NC group, Ni group, melatonin-treated group, and Ni plus melatonin group. Ni (10 mg/kg) was gavaged, and melatonin (2 mg/kg) was administered for 21 days. Inflammatory cells were found in the bronchioles of Txnrd3−/− mice under Ni exposure. Ultrastructural examination revealed that the homozygous-Ni group had a high amount of collagen fibers. The antioxidant capacity studies also revealed that mice lungs underwent oxidative stress. The results of qRT-PCR and WB showed that Ni induced an inflammatory response, which was also aggravated in Txnrd3−/− mice. Melatonin can effectively reduce the above symptoms. In conclusion, Ni causes lung injury by activating the VEGF–VEGFR-2 pathway and Txnrd3 knockout aggravates injury after Ni exposure. Ni exposure activated VEGF in Txnrd3 −/− mice lung tissue. Decreased Txnrd3 expression aggravated Ni-induced inflammation via oxidative stress, aggravating mouse lung tissue damage, activating T helper 1 and T helper 2 cells, secreting multiple inflammatory factors, and activating the TNF-α–NF-κB pathway. A variety of inflammatory factors can further activate the VEGF pathway to activate downstream proteins Src and Rac, exacerbating lung injury caused by Ni exposure. [Display omitted] • Nickel (Ni) induces oxidative stress and inflammation to induce lung injury. • Txnrd3 knockout worsened lung damage after Ni exposure via the VEGF/VEGFR2 axis. • Mel reduces oxidative stress and inflammation to prevent Ni-induced lung damage. [ABSTRACT FROM AUTHOR]

Nickel(Ni) accumulates in the environment due to human activities such as electroplating, alloy production, stainless steel, Ni‑cadmium batteries and industrial production. Ni enriched in humans and animals through food chains, poses a serious health threat. Txnrd3, as a member of the thioredoxin reductase family, has long been thought to be testicular specific and involved in sperm maturation. However, its role in liver diseases still unknown. Melatonin exerts its antioxidant effects directly through its ability to clear free radicals and protects the liver from oxidative damage. Hepatic fibrosis with an ever-increasing incidence year by year, is correlating with outcome and risk of hepatocellular carcinoma. In this study, 60 8-week-old male C57BL/6 wild-type mice and 60 Txnrd3−/− mice were randomly divided into three groups, respectively. Control group was gavaged with distilled water, 10 mg/kg NiCl 2 in Ni group, Ni + Mel group treated with 2 mg/kg melatonin in the morning, 10 mg/kg NiCl 2 in the afternoon, serum and tissue was extracted after 21 days. Results showed that liver function was significantly worse after Ni exposure, morphological and masson staining showed more significant liver fibrosis in Txnrd3−/− mice, damage of organelles in hepatocytes was observed. qPCR and WB results showed activation of the IRE1/Nuclear factor-kappa B/NLRP3 axis during Ni exposure lead to hepatocyte pyroptosis, while upregulation of PERK/TGF-β promoted liver fibrosis process and Txnrd3 knockout exacerbated liver damage during Ni exposure. The above results will lay the theoretical foundation for the monitoring and clinical treatment of Ni exposure. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Thioredoxin systems, involving redox active thioredoxins and thioredoxin reductases, sustain a number of important thioredoxin-dependent pathways. These redox active proteins support several processes crucial for cell function, cell proliferation, antioxidant defense and redox-regulated signaling cascades. Mammalian thioredoxin reductases are selenium-containing flavoprotein oxidoreductases, dependent upon a selenocysteine residue for reduction of the active site disulfide in thioredoxins. Their activity is required for normal thioredoxin function. The mammalian thioredoxin reductases also display surprisingly multifaceted properties and functions beyond thioredoxin reduction. Expressed from three separate genes (in human named TXNRD1, TXNRD2 and TXNRD3), the thioredoxin reductases can each reduce a number of different types of substrates in different cellular compartments. Their expression patterns involve intriguingly com- plex transcriptional mechanisms resulting in several splice variants, encoding a number of protein variants likely to have specialized functions in a cell- and tissue-type restricted manner. The thioredoxin reductases are also targeted by a number of drugs and compounds having an impact on cell function and promoting oxidative stress, some of which are used in treatment of rheumatoid arthritis, cancer or other diseases. However, potential specific or essential roles for different forms of human or mouse thioredoxin reductases in health or disease are still rather unclear, although it is known that at least the murine Txnrd1 and Txnrd2 genes are essential for normal development during embryogenesis. This review is a survey of current knowledge of mammalian thioredoxin reductase function and expression, with a focus on human and mouse and a discussion of the striking complexity of these proteins. Several yet open questions regarding their regulation and roles in different cells or tissues are emphasized. It is concluded that the intriguingly complex regulation and function of mammalian thioredoxin reductases within the cellular context and in intact mammals strongly suggests that their functions are highly fine-tuned with the many pathways involving thioredoxins and thioredoxin-related proteins. These selenoproteins furthermore propagate many functions beyond a reduction of thioredoxins. Aberrant regulation of thiore- doxin reductases, or a particular dependence upon these enzymes in diseased cells, may underlie their presumed therapeutic importance as enzymatic targets using electrophilic drugs. These reductases are also likely to mediate several of the effects on health and disease that are linked to different levels of nutritional selenium intake. The thioredoxin reductases and their splice variants may be pivotal components of diverse cellular signaling pathways, having importance in several redox-related aspects of health and disease. Clearly, a detailed understanding of mammalian thioredoxin reductases is necessary for a full comprehension of the thioredoxin system and of selenium dependent processes in mammals. [Copyright &y& Elsevier]

During epididymal transit, redox remodeling protects mammalian spermatozoa, preparing them for survival in the subsequent journey to fertilization. However, molecular mechanisms of redox regulation in sperm development and maturation remain largely elusive. In this study, we report that thioredoxin-glutathione reductase (TXNRD3), a thioredoxin reductase family member particularly abundant in elongating spermatids at the site of mitochondrial sheath formation, regulates redox homeostasis to support male fertility. Using Txnrd3 -/- mice, our biochemical, ultrastructural, and live cell imaging analyses revealed impairments in sperm morphology and motility under conditions of TXNRD3 deficiency. We find that mitochondria develop more defined cristae during capacitation in wildtype sperm. Furthermore, we show that absence of TXNRD3 alters thiol redox status in both the head and tail during sperm maturation and capacitation, resulting in defective mitochondrial ultrastructure and activity under capacitating conditions. These findings provide insights into molecular mechanisms of redox homeostasis and bioenergetics during sperm maturation, capacitation, and fertilization., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)