Antioxidants and Redox Signaling
ISSN / EISSN: 15230864 / 15577716
Published by: Mary Ann Liebert Inc
Total articles ≅ 4,773
Latest articles in this journal
Antioxidants and Redox Signaling; https://doi.org/10.1089/ars.2022.0185
Significance: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, which may be due to sedentary lifestyles with less physical activity and over nutrition as well as an increase in the aging population; however, the contribution of pollutants, environmental chemicals and nonessential metals to the increased and persistent CVDs needs more attention and investigation. Among environmental contaminant nonessential metals, antimony has been less addressed. Recent Advances: Among environmental contaminant nonessential metals, several metals such as lead, arsenic, and cadmium have been associated with the increased risk of CVDs. Antimony has been less addressed, but its potential link to CVDs is being gradually recognized. Critical Issues: Several epidemiological studies have revealed significant deleterious effects of antimony on the cardiovascular system in absence or presence of other nonessential metals. There has been less focus on whether antimony alone can contribute to the pathogenesis of CVDs and the proposed mechanisms of such possible effects. This review addresses this gap in knowledge by presenting the current available evidence that highlights the potential role of antimony in the pathogenesis of CVDs, most likely via antimony-mediated redox dyshomeostasis. Future Directions: More direct evidence from pre-clinical and mechanistic studies is urgently needed to evaluate the possible roles of antimony in mitochondrial dysfunction and epigenetic regulation in CVDs.
Antioxidants and Redox Signaling; https://doi.org/10.1089/ars.2022.0098
Significance: Diabetes has been long recognized as an independent risk factor for cancer, but there is insufficient mechanistic understanding of biological mediators that bridge two disorders together. Understanding the pathogenic association between diabetes and cancer has become the focus of many studies, and findings are potentially valuable for the development of effective preventive or therapeutic strategies for both disorders. Recent advances: A summary of literature reveals a possible connection between diabetes and cancer through the family of protein disulfide isomerase (PDIs). Historical as well as the most recent findings on the structure, biochemistry and biology of the PDI family were summarized in this review. Critical Issues: PDIs in general function as redox enzymes and protein chaperones to control the quality of proteins by correcting or otherwise eliminating misfolded proteins in conditions of oxidative stress and endoplasmic reticulum (ER) stress, respectively. However, individual members of the PDI family may contribute uniquely to the pathogenesis of diabetes and cancer. Studies of exemplary members such as PDIA1, PDIA6 and PDIA15 were reviewed to highlight their contributions in the pathogenesis of diabetes and cancer and how they can be potential links bridging the two disorders through the crosstalk of signaling pathways. Future directions: Apparently ubiquitous presence of the PDIs creates difficulties and challenges for scientific community to develop targeted therapeutics for the treatment of diabetes and cancer simultaneously. Understanding molecular contribution of individual PDI in the context of specific disease may provide some insights into the development of mechanism-based, target-directed therapeutics.
Antioxidants and Redox Signaling; https://doi.org/10.1089/ars.2022.0065
Aims: Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease globally, which is defined as an excess accumulation of fat caused by the imbalance of lipogenesis and lipid catabolism. Recently, increasing evidence suggests that peroxiredoxin 6 (PRDX6) is involved in the pathogenesis and progression of NAFLD. However, little is known regarding its role in liver lipid catabolism. Results: We found that PRDX6 level was significantly increased in liver tissues after high-fat diet (HFD) treatment. PRDX6 knockout (KO) exacerbated HFD-induced hepatic steatosis. PRDX6 KO did not affect mRNA and protein levels of peroxisome proliferator-activated receptor alphaα (PPARα). However, PRDX6 KO decreased the mRNA and protein levels of carnitine palmitoyltransferase-1alpha (CPT-1α) and acyl-CoA oxidase 1 (ACOX1), the target genes of PPARα. PRDX6 KO also did not activate AMPKα/PGC-1α, the upstream signal of PPARα. However, PRDX6 KO reduces the levels of PPARα activators, the oxidized fatty acids (9 and 13-hydroxyoctadecadienoic acid) in HFD rats. More interestingly, PRDX6 promoted the production of oxidized fatty acids by hydrolyzing oxidized low-density lipoprotein (Ox-LDL), which depends on its phospholipase A2 (PLA2) activity. PRDX6 mutation on its PLA2 and its competitive phospholipase inhibitor inhibited the production of the oxidized fatty acids as well as the activation of PPARα. Furthermore, PRDX6 overexpression enhanced the transcriptional activation of PPARα. Innovation and Conclusion: This study elucidates for the first time the role of PLA2 enzyme activity of PRDX6 in fatty acid oxidation and reveals a novel mechanism of PRDX6 involved in liver steatosis.
Antioxidants and Redox Signaling; https://doi.org/10.1089/ars.2022.0142
Iron is an essential element for every life on earth as a primary media for electron flow. Sulfur compounds as sulfhydryls counteract catalytic activity of iron whereas sulfur overdose is also toxic. In aerobic organisms, oxygen is the major media for electron transfer with higher intracellular mobility, which cooperates with the iron system. Based on the importance of iron, there is no active pathway to excrete iron outside the body in higher species. Whereas bacterial infection causes a scramble for iron in situ, cancer can be the outcome of the side effects of long use of iron and oxygen. Ferroptosis is a recently coined cell death, defined as catalytic Fe(II)-dependent regulated necrosis accompanied by lipid peroxidation. Researchers recently recognized that ferroptosis is involved in a variety of physiological and pathological contexts, including embryonic erythropoiesis, aging, neurodegeneration and cancer cell death. Alternatively, carcinogenesis is a process to obtain iron addiction with ferroptosis-resistance, based on rodent animal studies. Here we propose that ferroptosis is three-dimensionally regulated by iron, sulfur and oxygen, which correspond to oxidants, antioxidants and membrane fluidity with susceptibility to lipid peroxidation, respectively. Whereas life attempts to prevent ferroptosis, ferroptotic cells eventually emit iron-loaded ferritin as extracellular vesicles to maintain monopoly of iron.
Antioxidants and Redox Signaling; https://doi.org/10.1089/ars.2022.0106
Significance: Mitochondrial proteins regulate the oxidative phosphorylation, cellular metabolism and free radical generation. Redox modulation alters the mitochondrial proteins and instigates the damage to dopaminergic neurons. Toxicants contribute to Parkinson’s disease (PD) pathogenesis in conjunction with aging and genetic factors. While oxidative modulation of a number of mitochondrial proteins is linked to xenobiotic exposure, little is known about its role in the toxicant-induced PD. Understanding the role of redox modulation of mitochondrial proteins in complex cellular events leading to neurodegeneration is highly relevant. Recent Advances: Many toxicants are shown to inhibit complex I or III and elicit free radical production that alters the redox status of mitochondrial proteins. Implication of redox modulation of the mitochondrial proteins makes them a target to comprehend the underlying mechanism of toxicant-induced PD. Critical Issues: Owing to multi-factorial etiology, exploration of onset and progression and treatment outcomes need a comprehensive approach. The article explains about a few mitochondrial proteins, which undergo redox changes along with the promising strategies, which help to alleviate the toxicant-induced redox imbalance leading to neurodegeneration. Future Directions: Although mitochondrial proteins are linked to PD, their role in toxicant-induced Parkinsonism is not yet completely known. Preservation of antioxidant defense machinery could alleviate the redox modulation of mitochondrial proteins. Targeted antioxidant delivery, use of metal chelators and activation of nuclear factor erythroid 2-related factor 2 and combinational therapy that encounters multiple free radicals, could ameliorate the redox modulation of mitochondrial proteins and thereby PD progression.
Antioxidants and Redox Signaling; https://doi.org/10.1089/ars.2022.0034
Aims: Reactive oxygen species are highly reactive molecules generated in different subcellular compartments. Both the dopamine D5 receptor (D5R) and endoplasmic reticulum-resident peroxiredoxin-4 (PRDX4) play protective roles against oxidative stress. This study is aimed at investigating the interaction between PRDX4 and D5R in regulating oxidative stress in the kidney. Results: Fenoldopam (FEN), a D1R and D5R agonist, increased PRDX4 protein expression, mainly in non-lipid rafts, in D5R-HEK 293 cells. FEN increased the co-immunoprecipitation of D5R and PRDX4 and their colocalization, particularly in the endoplasmic reticulum. The efficiency of Förster resonance energy transfer was increased with FEN treatment measured with fluorescence lifetime imaging microscopy. Silencing of PRDX4 increased hydrogen peroxide production, impaired the inhibitory effect of FEN on hydrogen peroxide production, and increased the production of interleukin-1, tumor necrosis factor, and caspase-12 in renal cells. Furthermore, in Drd5-/- mice, which are in a state of oxidative stress, renal cortical PRDX4 was decreased whereas interleukin-1 , tumor necrosis factor, and caspase-12 were increased, relative to their normotensive wild-type Drd5+/+ littermates. Innovation: Our findings demonstrate a novel relationship between D5R and PRDX4 and the consequent effects of this relationship in attenuating hydrogen peroxide production in the endoplasmic reticulum and the production of proinflammatory cytokines. This study provides the potential for the development of biomarkers and new therapeutics for renal inflammatory disorders, including hypertension. Conclusion: PRDX4 interacts with D5R to decrease oxidative stress and inflammation in renal cells which may have potential of translational significance.
Antioxidants and Redox Signaling; https://doi.org/10.1089/ars.2022.0134
Significance: Herbs are widely used worldwide. However, inappropriate use of some of the herbs can lead to herb-induced liver injury (HILI). Intriguingly, HILI incidents are on the rise and our understanding of the underlying etiologies is in progress, and hence an update on the current status of incidents as well as our understanding on the etiologies of HILI is appropriate. Recent Advances: HILI reports due to the use of some herbs that are traditionally considered to be safe are also on the rise. Furthermore, HILI due to the use of certain herbs in combination with other herbs (herb-herb interaction, HHI)) or non-herb components (herb-drug interaction, HDI) have also been reported, suggesting a potentially important new type of inappropriate use of herbs. Critical Issues: Updated overviews focusing on the epidemiology, etiology, phenotypes, and risk factors of HILI, as well as HDI and HHI; and analysis on several types of newly reported “toxic” effects of herbs based on types of hepatotoxicity and the HILI mechanisms. Future Direction: HILI will continue to be a significant public health challenge in the near future. In the light of the lack of broadly available guidelines and regulations for proper and safe uses of herbs worldwide, raising the public awareness of HILI will remain one of the most effective measures. In particular, it should include a better understanding of the contributing factors; a more detail sub-classification and description of HILI, better characterization of the components/substances that could induce HILI; and development of HILI diagnosis based on RUCAM.
Antioxidants and Redox Signaling; https://doi.org/10.1089/ars.2022.0119
Aims: We confirmed that GCLC protein rapidly decreased at the same time P-JNK increased after APAP treatment. Therefore, our aims were to determine if JNK was directly responsible for decreased causing impaired recovery of GSH and if this was an important factor in determining APAP hepatotoxicity. Results: Immunoprecipitation of JNK after APAP identified binding to GCLC. Expression of a site directed mutated canonical JNK docking site in GCLC was resistant to degradation and lead to rapid restoration of GSH and inhibited sustained JNK activation. The JNK-resistant GCLC markedly protected against necrosis and ALT elevation. The proteolytic loss of GCLC was abrogated by inhibition of the proteosome, ubiquitination, or calpain. Innovation: We addressed the aims by preparing mutated Gclc resistant to JNK induced degradation. The results allowed us to identify impaired GSH recovery as an important contributor to early progression of APAP toxicity after the metabolism of APAP and initial GSH depletion had occurred. Conclusion: Activated JNK interacts directly with GCLC and leads to proteolytic degradation of GCLC. Degradation of GCLC impairs GSH recovery after APAP allowing the continued activation of JNK. Conversely, rapid recovery of GSH inhibits the sustained activation of the MAP Kinase cascade and dampens APAP toxicity by suppressing the continued activation of JNK.
Antioxidants and Redox Signaling; https://doi.org/10.1089/ars.2022.0055
Significance: Acrylamide (AA) widely exists in the environment. Studies have demonstrated that AA has neurotoxicity and potential carcinogenicity in humans, and genotoxicity and severe hepatotoxicity in animals. As the critical metabolism organ for AA, the liver is the primary attacking target of AA. This review summarizes the recent advances in hepatotoxicity mechanism through AA-induced oxidative stress in rodent livers and hepatic cell lines, this is beneficial to assess risks of AA exposure and explore effective intervention methods for AA hepatotoxicity. Recent Advances: Accumulating evidences have indicated that AA-induced oxidative stress is responsible for its hepatotoxicity. The changes in homological and biochemical indexes such as activities of hepatic antioxidant enzymes have been elucidated with the occurrence and development of oxidative stress. Also, the molecular mechanisms underlying AA-induced hepatotoxicity through oxidative stress have been mainly explained by apoptosis, inflammatory and autophagic pathways. Critical Issues: This review is focusing on the molecular mechanism of hepatotoxicity through AA-induced oxidative stress, this can provide a theoretical basis for the assessment of AA-induced health risk and finding potential intervention targets. Future Directions: Epigenetic modifications like miRNAs and modulation of the gut microbiome involved in AA toxification pathway must be investigated, and will provide novel insights to unravel the toxification mechanism and intervention strategy for AA hepatotoxicity.
Antioxidants and Redox Signaling; https://doi.org/10.1089/ars.2021.0273
Aims: Myocardial fibrosis after myocardial infarction (MI) leads to heart failure. Nitration of protein can alter its function. cAMP-response element binding protein (CREB) is a key transcription involved in myocardial fibrosis. However, little is known about the role of nitrated CREB in MI-induced myocardial fibrosis. Meanwhile, downstream transcription genes of CREB in myocardial fibrosis have not been identified. This study aims to verify the hypothesis that nitrated CREB promotes MI-induced myocardial fibrosis via regulating the transcription of col1a2 and cxcl12. Results: Our study showed that (i) the level of nitrative stress was elevated and nitrated CREB was higher in myocardium after MI. Tyr182, 307 and 336 were the nitration sites of CREB; (ii) with the administration of FeTMPyP (scavenger of ONOO-), CREB phosphorylation, nuclear translocation, binding activity to TORC2 (transducers of regulated CREB-2) were attenuated; (iii) the expressions of ECM proteins were up-regulated and down-regulated in accordance with the expression alteration of CREB both in vitro and in vivo; (iv) CREB accelerated transcription of col1a2 and cxcl12 after MI directly. With the administration of FeTMPyP, ECM proteins expressions were attenuated, meanwhile, the mRNA level of col1a2 and cxcl12 were alleviated as well. Innovation and Conclusion: Nitration of transcription factor CREB participates in MI-induced myocardial fibrosis through enhancing its phosphorylation, nuclear translocation and binding activity to TORCs, among which CREB transcript col1a2 and cxcl12 directly. These data indicated that nitrated CREB might be a potential therapeutic target against MI-induced myocardial fibrosis.