Administration of Glutaredoxin-1 Attenuates Liver Fibrosis Caused by Aging and Non-Alcoholic Steatohepatitis

Tsukahara, Yusuke; Ferrán, Beatriz; Minetti, Erika T; Chong, Brian S. H.; Gower, Adam C.; Bachschmid, Markus; Matsui, Reiko

doi:10.3390/antiox11050867

Cited by 7 publications

(5 citation statements)

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“…This suggests that neonatal proteins are more susceptible to protein oxidation, which makes early life oxidative stress a very important programming factor. We have already demonstrated the effects of early life oxidative stress over the development of neonatal diseases [1,4,7,21,26,44,45], while several adult diseases are also associated with protein oxidation [38,39,[46][47][48][49]. At 12 weeks of age, many of the variables that were decreased early in life were increased in similar proportions at 12 weeks, as a rebound effect.…”

Section: Discussionmentioning

confidence: 94%

Disturbances of the Lung Glutathione System in Adult Guinea Pigs Following Neonatal Vitamin C or Cysteine Deficiency

2023

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In premature infants receiving parenteral nutrition, oxidative stress is a trigger for the development of bronchopulmonary dysplasia, which is an important factor in the development of adult lung diseases. Neonatal vitamin C and glutathione deficiency is suspected to induce permanent modification of redox metabolism favoring the development of neonatal and adult lung diseases. A total of 64 3-day-old guinea pigs were fed an oral diet that was either complete or deficient in vitamin C (VCD), cysteine (CD) (glutathione-limiting substrate) or both (DD) for 4 days. At 1 week of age, half of the animals were sacrificed while the other started a complete diet until 12 weeks of age. At 1 week, the decrease in lung GSH in all deficient groups was partially explained by the oxidation of liver methionine-adenosyltransferase. mRNA levels of kelch-like ECH-associated protein 1 (Keap1), glutathione-reductase (Gsr) and glutaredoxin-1 (Glrx) were significantly lower only in CD but not in DD. At 12 weeks, glutathione levels were increased in VCD and CD. Keap1, Gsr and Glrx mRNA were increased, while glutathione-reductase and glutaredoxin proteins were lower in CD, favoring a higher glutathionylation status. Both neonatal deficiencies result in a long-term change in glutathione metabolism that could contribute to lung diseases’ development.

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Section: Discussionmentioning

confidence: 94%

Disturbances of the Lung Glutathione System in Adult Guinea Pigs Following Neonatal Vitamin C or Cysteine Deficiency

2023

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“…Intriguingly, the MR target gene ZBTB16 was found to be the strongest downregulated DEG in aged fibroblasts by macrophage MR deficiency. ZBTB16, a transcription factor and epigenetic regulator involved in protein–protein interactions, cell proliferation, and differentiation, has been associated with oxidative stress, metabolic syndrome, and fibrosis [ 54 , 60 ]. Regulation of ZBTB16 expression is complex and can be modulated by several signaling pathways involved in cellular stress responses, including oxidative stress and inflammation [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Mineralocorticoid receptor promotes cardiac macrophage inflammaging

Fraccarollo,

Geffers,

Galuppo

et al. 2024

Basic Res Cardiol

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Inflammaging, a pro-inflammatory status that characterizes aging and primarily involving macrophages, is a master driver of age-related diseases. Mineralocorticoid receptor (MR) activation in macrophages critically regulates inflammatory and fibrotic processes. However, macrophage-specific mechanisms and the role of the macrophage MR for the regulation of inflammation and fibrotic remodeling in the aging heart have not yet been elucidated. Transcriptome profiling of cardiac macrophages from male/female young (4 months-old), middle (12 months-old) and old (18 and 24 months-old) mice revealed that myeloid cell-restricted MR deficiency prevents macrophage differentiation toward a pro-inflammatory phenotype. Pathway enrichment analysis showed that several biological processes related to inflammation and cell metabolism were modulated by the MR in aged macrophages. Further, transcriptome analysis of aged cardiac fibroblasts revealed that macrophage MR deficiency reduced the activation of pathways related to inflammation and upregulation of ZBTB16, a transcription factor involved in fibrosis. Phenotypic characterization of macrophages showed a progressive replacement of the TIMD4+MHC-IIneg/low macrophage population by TIMD4+MHC-IIint/high and TIMD4–MHC-IIint/high macrophages in the aging heart. By integrating cell sorting and transwell experiments with TIMD4+/TIMD4–macrophages and fibroblasts from old MRflox/MRLysMCre hearts, we showed that the inflammatory crosstalk between TIMD4– macrophages and fibroblasts may imply the macrophage MR and the release of mitochondrial superoxide anions. Macrophage MR deficiency reduced the expansion of the TIMD4– macrophage population and the emergence of fibrotic niches in the aging heart, thereby protecting against cardiac inflammation, fibrosis, and dysfunction. This study highlights the MR as an important mediator of cardiac macrophage inflammaging and age-related fibrotic remodeling.

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“…Two of the articles [ 73 , 74 ] feature the specific roles of Grx1 in liver fibrosis and lung fibrosis. Importantly, the data presented in these papers suggest a potential therapeutic role for Grx1 as an anti-fibrotic agent.…”

Section: Highlights Of the Special Issue On Glutathione And Glutaredoxinmentioning

confidence: 99%

“…Importantly, the data presented in these papers suggest a potential therapeutic role for Grx1 as an anti-fibrotic agent. Thus, Reiko Matsui and her coworkers [ 73 ] showed that the overexpression of Grx1 inhibits age-induced hepatic apoptosis and liver fibrosis in mice. On the other hand, high-fat and high-fructose diet-induced non-alcoholic steatohepatitis (NASH) leads to the downregulation of Grx1 and higher levels of S-glutathionylated proteins in the liver; overexpression of Grx-1 significantly decreases the expression of Zbtb16 and leads to the reversal of NASH progression by attenuating inflammatory and fibrotic processes.…”

Section: Highlights Of the Special Issue On Glutathione And Glutaredoxinmentioning

confidence: 99%

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Glutathione and Glutaredoxin—Key Players in Cellular Redox Homeostasis and Signaling

Chai

Mieyal

2023

Antioxidants

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This Special Issue of Antioxidants on Glutathione (GSH) and Glutaredoxin (Grx) was designed to collect review articles and original research studies focused on advancing the current understanding of the roles of the GSH/Grx system in cellular homeostasis and disease processes. The tripeptide glutathione (GSH) is the most abundant non-enzymatic antioxidant/nucleophilic molecule in cells. In addition to various metabolic reactions involving GSH and its oxidized counterpart GSSG, oxidative post-translational modification (PTM) of proteins has been a focal point of keen interest in the redox field over the last few decades. In particular, the S-glutathionylation of proteins (protein-SSG formation), i.e., mixed disulfides between GSH and protein thiols, has been studied extensively. This reversible PTM can act as a regulatory switch to interconvert inactive and active forms of proteins, thereby mediating cell signaling and redox homeostasis. The unique architecture of the GSH molecule enhances its relative abundance in cells and contributes to the glutathionyl specificity of the primary catalytic activity of the glutaredoxin enzymes, which play central roles in redox homeostasis and signaling, and in iron metabolism in eukaryotes and prokaryotes under physiological and pathophysiological conditions. The class-1 glutaredoxins are characterized as cytosolic GSH-dependent oxidoreductases that catalyze reversible protein S-glutathionylation specifically, thereby contributing to the regulation of redox signal transduction and/or the protection of protein thiols from irreversible oxidation. This Special Issue includes nine other articles: three original studies and six review papers. Together, these ten articles support the central theme that GSH/Grx is a unique system for regulating thiol-redox hemostasis and redox-signal transduction, and the dysregulation of the GSH/Grx system is implicated in the onset and progression of various diseases involving oxidative stress. Within this context, it is important to appreciate the complementary functions of the GSH/Grx and thioredoxin systems not only in thiol-disulfide regulation but also in reversible S-nitrosylation. Several potential clinical applications have emerged from a thorough understanding of the GSH/Grx redox regulatory system at the molecular level, and in various cell types in vitro and in vivo, including, among others, the concept that elevating Grx content/activity could serve as an anti-fibrotic intervention; and discovering small molecules that mimic the inhibitory effects of S-glutathionylation on dimer association could identify novel anti-viral agents that impact the key protease activities of the HIV and SARS-CoV-2 viruses. Thus, this Special Issue on Glutathione and Glutaredoxin has focused attention and advanced understanding of an important aspect of redox biology, as well as spawning questions worthy of future study.

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Administration of Glutaredoxin-1 Attenuates Liver Fibrosis Caused by Aging and Non-Alcoholic Steatohepatitis

Cited by 7 publications

References 54 publications

Disturbances of the Lung Glutathione System in Adult Guinea Pigs Following Neonatal Vitamin C or Cysteine Deficiency

Disturbances of the Lung Glutathione System in Adult Guinea Pigs Following Neonatal Vitamin C or Cysteine Deficiency

Mineralocorticoid receptor promotes cardiac macrophage inflammaging

Glutathione and Glutaredoxin—Key Players in Cellular Redox Homeostasis and Signaling

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