The abnormal inflammatory responses due to the lung tissue damage and ineffective repair/resolution in response to the inhaled toxicants result in the pathological changes associated with chronic respiratory diseases. Investigation of such pathophysiological mechanisms provides the opportunity to develop the molecular phenotype-specific diagnostic assays and could help in designing the personalized medicine-based therapeutic approaches against these prevalent diseases. As the central hubs of cell metabolism and energetics, mitochondria integrate cellular responses and interorganellar signaling pathways to maintain cellular and extracellular redox status and the cellular senescence that dictate the lung tissue responses. Specifically, as observed in chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis, the mitochondria-endoplasmic reticulum (ER) crosstalk is disrupted by the inhaled toxicants such as the combustible and emerging electronic nicotine-delivery system (ENDS) tobacco products. Thus, the recent research efforts have focused on understanding how the mitochondria-ER dysfunctions and oxidative stress responses can be targeted to improve inflammatory and cellular dysfunctions associated with these pathologic illnesses that are exacerbated by viral infections. The present review assesses the importance of these redox signaling and cellular senescence pathways that describe the role of mitochondria and ER on the development and function of lung epithelial responses, highlighting the cause and effect associations that reflect the disease pathogenesis and possible intervention strategies.

Cardiovascular disease is the leading cause of the death for both men and women. Although baseline heart physiology and the response to disease are known to differ by sex, little is known about sex differences in baseline molecular signaling, especially with regard to redox biology. In this review, we describe current research on sex differences in cardiac redox biology with a focus on the regulation of nitric oxide and aldehyde signaling. Furthermore, we argue for a new perspective on cardiovascular sex differences research, one that focuses on baseline redox biology without the elimination or disruption of sex hormones.

The yeast peroxiredoxin Ahp1, like related anti-oxidant enzymes in other species, undergoes urmylation, a lysine-directed conjugation to ubiquitin-like modifier Urm1. Ahp1 assembles into a homodimer that detoxifies peroxides via forming intersubunit disulfides between peroxidatic and resolving cysteines that are subsequently reduced by the thioredoxin system. Although urmylation coincides with oxidative stress, it is unclear how this modification happens on a molecular level and whether it affects peroxiredoxin activity. Here, we report that thioredoxin mutants decrease Ahp1 urmylation in yeast and each subunit of the oxidized Ahp1 dimer is modified by Urm1 suggesting coupling of urmylation to dimerization. Consistently, Ahp1 mutants unable to form dimers, fail to be urmylated as do mutants that lack the peroxidatic cysteine. Moreover, Ahp1 urmylation involves at least two lysine residues close to the catalytic cysteines and can be prevented in yeast cells exposed to high organic peroxide concentrations. Our results elucidate redox requirements and molecular determinants critical for Ahp1 urmylation, thus providing insights into a potential link between oxidant defense and Urm1 utilization in cells.

Atrial fibrillation (AF) occurs in up to 11% of cancer patients treated with ibrutinib. The pathophysiology of ibrutinib promoted AF is complicated, as there are multiple interactions involved; the detailed molecular mechanisms underlying this are still unclear. Here, we aimed to determine the electrophysiological and molecular mechanisms of burst-pacing-induced AF in ibrutinib-treated mice. The results indicated differentially expressed proteins in ibrutinib-treated mice, identified through proteomic analysis, were found to play a role in oxidative stress-related pathways. Finally, treatment with an inhibitor of NADPH oxidase (NOX) prevented and reversed AF development in ibrutinib-treated mice. It was showed that the related protein expression of reactive oxygen species (ROS) in the ibrutinib group was significantly increased, including NOX2, NOX4, p22-phox, XO and TGF-β protein expression. It was interesting that ibrutinib group also significantly increased the expression of ox-CaMKII, p-CaMKII (Thr-286) and p-RyR2 (Ser2814), causing enhanced abnormal sarcoplasmic reticulum (SR) Ca2+ release and mitochondrial structures, as well as atrial fibrosis and atrial hypertrophy in ibrutinib-treated mice, and apocynin reduced the expression of these proteins. Ibrutinib-treated mice were also more likely to develop AF, and AF occurred over longer periods. In conclusion, our study has established a pathophysiological role for ROS signaling in atrial cardiomyocytes, and it may be that ox-CaMKII and p-CaMKII (Thr-286) are activated by ROS to increase AF susceptibility following ibrutinib treatment. We have also identified the inhibition of NOX as a potential novel AF therapy approach.

Background We aimed to determine sphingolipid levels and examine apoptotic pathways in human retinal pigment epithelial cells (ARPE-19) undergoing endoplasmic reticulum (ER) stress. Methods Cells were treated with tunicamycin (TM) to induce ER stress and tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, was administered to decrease cytotoxicity. Cell viability was measured by MTT assay. Levels of C16–C24 sphingomyelins (SM) and C16–C24 ceramides (CERs) were determined by LC-MS/MS. Glucose-regulated protein 78-kd (GRP78) and nuclear factor kappa-b subunit 1 (NFκB1) gene expressions were evaluated by quantitative PCR analysis, while GRP 78, NF-κB p65, cleaved caspase-3 and caspase-12 protein levels were assesed by immunofluorescence. Ceramide-1-phosphate (C1P) levels were determined by immunoassay, while caspase −3 and −12 activity in cell lysates were measured via a fluorometric method. Results Induction of ER stress in TM treated groups were confirmed by significantly increased mRNA and protein levels of GRP78. TM significantly decreased cell viability compared to controls. Treatment with TUDCA along with TM significantly increased cell viability compared to the TM group. A significant increase was observed in C22–C24 CERs, C1P, caspase-3, caspase-12, NFκB1 mRNA and NF-κB p65 protein levels in cells treated with TM compared to controls. Administration of TUDCA lead to a partial decrease in GRP78 expression, NFκB1 mRNA, NF-κB p65 protein, C22–C24 CERs and C1P levels along with a decrease in caspase-3 and -12 activity. Conclusions The results of this study reveal the presence of increased long chain CERs, C1P and apoptotic markers in retinal cells undergoing ER stress.

In this paper of the special issue dedicated for the Olympics 2020, we put the light on an exciting facet of exercise-oncology, which may still be unknown to some audience. Accumulating convincing evidences show that exercise reduces cancer progression and recurrence mainly in colon and breast cancer patients. Interestingly, the positive effects of exercise on cancer outcomes were mainly observed when patients practiced vigorous exercise of 6 METs or more. At the molecular level, experimental studies highlighted that regular vigorous exercise could reduce tumor growth by driving changes in immune system, metabolism, hormones, systemic inflammation, angiogenesis and redox status. In the present review, we describe the main redox-sensitive mechanisms mediated by exercise. These redox mechanisms are of particular therapeutic interest as they may explain the emerging preclinical findings proving that the association of vigorous exercise with chemotherapy or radiotherapy improves the anti-cancer responses of both interventions. Clinical and preclinical studies converge to support the practice of exercise as an adjuvant therapy that improves cancer outcomes. The understanding of the underpinning molecular mechanisms of exercise in cancer can open new avenues to improve cancer care in patients.

Studies revealed that the use of renin-angiotensin-aldosterone system antagonism is not associated with a statistically significant reduction in the risk of cardiovascular events in patients with chronic kidney disease (CKD) compared with that in the general population. We tested the hypothesis that indoxyl sulfate (IS) can interfere with the protective effect of valsartan-mediated on endothelial function in vitro and neovascularization in mice underwent subtotal nephrectomy. In human aortic endothelial cells, we first demonstrated that IS impaired the valsartan-mediated phosphorylation of eNOSThr495, nitric oxide production and tube formation via NADPH oxidase (NOX) and protein kinase C (PKC) phosphorylation, but this effect was suppressed by cotreatment with apocynin and calphostin C. In vivo, IS attenuated valsartan-induced angiogenesis in Matrigel plugs in mice. Moreover, in subtotal nephrectomy mice who underwent hindlimb ischemic surgery, valsartan significantly increased the mobilization of endothelial progenitor cells in circulation as well as the reperfusion of blood flow and density of CD31+ capillaries in ischemic limbs. However, IS attenuated the protective effect of valsartan-induced neovascularization and increased the expression of p-PKCαSer657 and p-eNOSThr497 in ischemic limbs. Cotreatment of apocynin and calphostin C reversed the IS impaired-neovascularization and decreased the expression of p-PKCαSer657 and p-eNOSThr497 in ischemic limbs. Our study suggests that the NOX/PKC/eNOS signaling pathway plays a pivotal role in the IS-mediated inhibition of valsartan-conferred beneficial effects on endothelial function in vitro and neovascularization in subtotal nephrectomy mice. We proposed a novel causative role for IS in cardiovascular complications in CKD patients.

Mutations in mitochondrial DNA can be inherited or occur de novo leading to several debilitating myopathies with no curative option and few or no effective treatments. Allotopic expression of recoded mitochondrial genes from the nucleus has potential as a gene therapy strategy for such conditions, however progress in this field has been hampered by technical challenges. Here we employed codon optimization as a tool to re-engineer the protein-coding genes of the human mitochondrial genome for robust, efficient expression from the nucleus. All 13 codon-optimized constructs exhibited substantially higher protein expression than minimally-recoded genes when expressed transiently, and steady-state mRNA levels for optimized gene constructs were 5-180 fold enriched over recoded versions in stably-selected wildtype cells. Eight of thirteen mitochondria-encoded oxidative phosphorylation (OxPhos) proteins maintained protein expression following stable selection, with mitochondrial localization of expression products. We also assessed the utility of this strategy in rescuing mitochondrial disease cell models and found the rescue capacity of allotopic expression constructs to be gene specific. Allotopic expression of codon optimized ATP8 in disease models could restore protein levels and respiratory function, however, rescue of the pathogenic phenotype for another gene, ND1 was only partially successful. These results imply that though codon-optimization alone is not sufficient for functional allotopic expression of most mitochondrial genes, it is an essential consideration in their design.

Mechanisms underlying the pathogenesis of pulmonary fibrosis remain incompletely understood. Emerging evidence suggests changes in mitochondrial quality control are a critical determinant in many lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, pulmonary hypertension, acute lung injury, lung cancer, and in the susceptibility to pulmonary fibrosis. Once thought of as the kidney-bean shaped powerhouses of the cell, mitochondria are now known to form interconnected networks that rapidly and continuously change their size to meet cellular metabolic demands. Mitochondrial quality control modulates cell fate and homeostasis, and diminished mitochondrial quality control results in mitochondrial dysfunction, increased reactive oxygen species (ROS) production, reduced ATP production, and often induces intrinsic apoptosis. Here, we review the role of the mitochondria in alveolar epithelial cells, lung macrophages, and fibroblasts within the context of pulmonary fibrosis.

Cold physical plasma is a partially ionized gas investigated as a new anticancer tool in selectively targeting cancer cells in monotherapy or in combination with therapeutic agents. Here, we investigated the intrinsic resistance mechanisms of tumor cells towards physical plasma treatment. When analyzing the dose-response relationship to cold plasma-derived oxidants in 11 human cancer cell lines, we identified four ‘resistant’ and seven ‘sensitive’ cell lines. We observed stable intracellular glutathione levels following plasma treatment only in the ‘resistant’ cell lines indicative of altered antioxidant mechanisms. Assessment of proteins involved in GSH metabolism revealed cystine-glutamate antiporter xCT (SLC7A11) to be significantly more abundant in the ‘resistant’ cell lines as compared to ‘sensitive’ cell lines. This decisive role of xCT was confirmed by pharmacological and genetic inhibition, followed by cold physical plasma treatment. Finally, microscopy analysis of ex vivo plasma-treated human melanoma punch biopsies suggested a correlation between apoptosis and basal xCT protein abundance. Taken together, our results demonstrate that xCT holds the potential as a biomarker predicting the sensitivity of tumor cells towards plasma treatment.

Cathepsin K (Cat K) is expressed in cancer cells, but the effect of Cat K on apoptosis is still elusive. Here, we showed that inhibition of Cat K sensitized the human carcinoma cells to anti-cancer drug through up-regulation of Bim. Inhibition of Cat K increased USP27x expression, and knock down of USP27x markedly blocked Cat K-induced up-regulation of Bim expression. Furthermore, inhibition of Cat K induced proteasome-dependent degradation of regulatory associated protein of mammalian target of rapamycin (Raptor). Down-regulation of Raptor expression increased mitochondrial ROS production, and mitochondria specific superoxide scavengers prevented USP27x-mediated stabilization of Bim by inhibition of Cat K. Moreover, combined treatment with Cat K inhibitor (odanacatib) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reduced tumor growth and induced cell death in a xenograft model. Our results demonstrate that Cat K inhibition enhances anti-cancer drug sensitivity through USP27x-mediated the up-regulation of Bim via the down-regulation of Raptor.

Stem cells and the niche in which they reside feature a complex microenvironment with tightly regulated homeostasis, cell-cell interactions and dynamic regulation of metabolism. A significant number of organoid models has been described over the last decade, yet few methodologies can enable single cell level resolution analysis of the stem cell niche metabolic demands, in real-time and without perturbing integrity. Here, we studied the redox metabolism of Lgr5-GFP intestinal organoids by two emerging microscopy approaches based on luminescence lifetime measurement – fluorescence-based FLIM for NAD(P)H, and phosphorescence-based PLIM for real-time oxygenation. We found that exposure of stem (Lgr5-GFP) and differentiated (no GFP) cells to high and low glucose concentrations resulted in measurable shifts in oxygenation and redox status. NAD(P)H-FLIM and O2-PLIM both indicated that at high ‘basal’ glucose conditions, Lgr5-GFP cells had lower activity of oxidative phosphorylation when compared with cells lacking Lgr5. However, when exposed to low (0.5 mM) glucose, stem cells utilized oxidative metabolism more dynamically than non-stem cells. The high heterogeneity of complex 3D architecture and energy production pathways of Lgr5-GFP organoids were also confirmed by the extracellular flux (XF) analysis. Our data reveals that combined analysis of NAD(P)H-FLIM and organoid oxygenation by PLIM represents promising approach for studying stem cell niche metabolism in a live readout.

Glutathione is the most abundant intracellular low molecular weight thiol in cells and tissues, and plays an essential role in numerous cellular processes, including antioxidant defenses, the regulation of protein function, protein localization and stability, DNA synthesis, gene expression, cell proliferation, and cell signaling. Sexual dimorphisms in glutathione biology, metabolism and glutathione-dependent signaling have been reported for a broad range of biological processes, spanning the human lifespan from early development to aging. Sex-depended differences with regard to glutathione and its biology have also been reported for a number of human pathologies and diseases such as neurodegeneration, cardiovascular diseases and metabolic disorders. Here we review the latest literature in this field and discuss the potential impact of these sexual dimorphisms in glutathione biology on human health and diseases.

Atherosclerosis is a chronic inflammatory disease of the vasculature characterised by the infiltration of activated neutrophils and macrophages at sites of damage within the vessel wall, which contributes to lesion formation and plaque progression. Selenomethionine (SeMet) is an organic form of selenium (Se), an essential trace element that functions in the regulation of the immune response by both bolstering the endogenous thioredoxin and glutathione antioxidant defence systems and by directly scavenging damaging oxidant species. This study evaluated the effect of dietary SeMet supplementation within a high fat diet fed apolipoprotein E deficient (ApoE−/-) mouse model of atherosclerosis. Dietary supplementation with SeMet (2 mg/kg) increased the tissue concentration of Se, and the expression and activity of glutathione peroxidase, compared to non-supplemented controls. Supplementation with SeMet significantly reduced atherosclerotic plaque formation in mouse aortae, resulted in a more stable lesion phenotype and improved vessel function. Concurrent with these results, SeMet supplementation decreased lesion accumulation of M1 inflammatory type macrophages, and decreased the extent of extracellular trap release from phorbol myristate acetate (PMA)-stimulated mouse bone marrow-derived cells. Importantly, these latter results were replicated within ex-vivo experiments on cultured neutrophils isolated from acute coronary syndrome patients, indicating the ability of SeMet to alter the acute inflammatory response within a clinically-relevant setting. Together, these data highlight the potential beneficial effect of SeMet supplementation as a therapeutic strategy for atherosclerosis.

The formation of reactive oxygen species (ROS) is a well-documented process in noise-induced hearing loss (NIHL). We have also previously shown that activation of 5’ adenosine monophosphate-activated protein kinase (AMPKα) at its catalytic residue T172 is one of the key reactions triggering noise-induced outer hair cell (OHC) death. In this study, we are addressing the link between ROS formation and activation of AMPKα in OHCs after noise exposure. In-vivo treatment of CBA/J mice with the antioxidant N-acetyl cysteine (NAC) reduced noise-induced ROS formation (as assessed by the relative levels of 4-hydroxynonenal and 3-nitrotyrosine) and activation of AMPKα in OHCs. Forskolin, an activator of adenylyl cyclase (AC) and an antioxidant, significantly increased cyclic adenosine monophosphate (cAMP) and decreased ROS formation and noise-induced activation of AMPKα. Consequently, treatment with forskolin attenuated noise-induced losses of OHCs and NIHL. In HEI-OC1 cells, H2O2-induced the activation of AMPKα and cell death were inhibited by the application of forskolin. The sum of our data indicates that noise activates AMPKα in OHCs through formation of ROS and that noise-exposure-induced OHC death is mediated by a ROS/AMPKα-dependent pathway. Forskolin may serve as a potential compound for prevention of NIHL.

Background C-reactive protein (CRP) is a well-recognized biomarker of inflammation, which can be used as a predictor of cardiovascular disease. Evidence have suggested exposure to multiple metals/metalloids may affect immune system and give rise to cardiovascular disease. However, it is lack of study to comprehensively evaluate the association of multiple metals and CRP, the interactions between metals, and the gene-metal interaction in relation to CRP levels. Aims To explore the associations of multiple plasma metals with serum CRP, and to test the interactions between metals, and gene-metal interactions on the levels of serum CRP. Methods We included 2882 participants from the Dongfeng-Tongji cohort, China, and measured 23 plasma metals and serum CRP concentrations. The genetic risk score (GRS) was calculated based on 7 established CRP-associated variants. For metals which were associated with the levels of CRP, we further tested the interactions between metals on CRP, and analyzed the gene-metal interactions on CRP. Results The median level for CRP in the total population was 1.17 mg/L. After multivariable adjustment, plasma copper was positively associated with serum CRP (FDR < 0.001), whereas selenium was negatively associated with serum CRP (FDR = 0.01). Moreover, selenium and zinc attenuated the positive association between high plasma copper and CRP (P for interaction < 0.001). Participants with a higher GRS had a higher CRP level, with the increase in ln-transformed CRP per increment of 5 risk alleles were 0.64 for weighted GRS, and 0.54 for unweighted GRS (both P < 0.001). Furthermore, the genetic association with CRP was modified by copper concentration (P for interaction < 0.001). Conclusions Our results suggest that serum CRP is positively associated with plasma concentration of copper, and inversely associated with selenium. Plasma zinc, selenium and CRP genetic predisposition would modify the associations between plasma copper and serum CRP.

Oxidative stress is a major cause of adverse outcomes in preeclampsia (PE). Ferroptosis, i.e. programmed cell death from iron-dependent lipid peroxidation, likely mediates PE pathogenesis. We evaluated specific markers for ferroptosis in normal and PE placental tissues, using in vitro (trophoblasts) and in vivo (rat) models. Increase in malondialdehyde content and total Fe2+ along with reduced the glutathione content and glutathione peroxidase activity was observed in PE placenta. While the trophoblasts experienced death under hypoxia, inhibitors of ferroptosis, apoptosis, autophagy, and necrosis increased the cell viability. Microarrays, bioinformatic analysis, and luciferase reporter assay revealed that upregulation of miR-30b-5p in PE models plays a pivotal role in ferroptosis, by downregulating Cys2/glutamate antiporter and PAX3 and decreasing ferroportin 1 (an iron exporter) expression, resulting in decreased GSH and increased labile Fe2+. Inhibition of miR-30b-5p expression and supplementation with ferroptosis inhibitors attenuated the PE symptoms in rat models, making miR-30b-5p a potential therapeutic target for PE.

Chemical modifications of DNA and RNA regulate genome functions or trigger mutagenesis resulting in aging or cancer. Oxidations of macromolecules, including DNA, are common reactions in biological systems and often part of regulatory circuits rather than accidental events. DNA alterations are particularly relevant since the unique role of nuclear and mitochondrial genome is coding enduring and inheritable information. Therefore, an alteration in DNA may represent a relevant problem given its transmission to daughter cells. At the same time, the regulation of gene expression allows cells to continuously adapt to the environmental changes that occur throughout the life of the organism to ultimately maintain cellular homeostasis. Here we review the multiple ways that lead to DNA oxidation and the regulation of mechanisms activated by cells to repair this damage. Moreover, we present the recent evidence suggesting that DNA damage caused by physiological metabolism acts as epigenetic signal for regulation of gene expression. In particular, the predisposition of guanine to oxidation might reflect an adaptation to improve the genome plasticity to redox changes.

Oxidative stress perturbs vascular homeostasis leading to endothelial dysfunction and cardiovascular diseases. Vascular reactive oxygen species (ROS) reduce nitric oxide (NO) bioactivity, a hallmark of cardiovascular and metabolic diseases. We measured steady-state vascular NO levels through the quantification of heme nitrosylated hemoglobin (5-coordinate-α-HbNO) in venous erythrocytes of healthy human subjects using electron paramagnetic resonance (EPR) spectroscopy. To examine how ROS may influence HbNO complex formation and stability, we identified the pro- and anti-oxidant enzymatic sources in human erythrocytes and their relative impact on intracellular redox state and steady-state HbNO levels. We demonstrated that pro-oxidant enzymes such as NADPH oxidases are expressed and produce a significant amount of ROS at the membrane of healthy erythrocytes. In addition, the steady-state levels of HbNO were preserved when NOX (e.g. NOX1 and NOX2) activity was inhibited. We next evaluated the impact of selective antioxidant enzymatic systems on HbNO stability. Peroxiredoxin 2 and catalase, in particular, played an important role in endogenous and exogenous H2O2 degradation, respectively. Accordingly, inhibitors of peroxiredoxin 2 and catalase significantly decreased erythrocyte HbNO concentration. Conversely, steady-state levels of HbNO were preserved upon supplying erythrocytes with exogenous catalase. These findings support HbNO measurements as indicators of vascular oxidant stress and of NO bioavailability and potentially, as useful biomarkers of early endothelial dysfunction.

The ketone body β-hydroxybutyrate is no longer viewed simply as a metabolic intermediate, as it regulates a broad range of physiological processes at cellular and systemic levels. Particularly, β-hydroxybutyrate functions as a stress response molecule and orchestrates an antioxidant defense program to maintain redox homeostasis in response to environmental and metabolic challenges, such as ischemia. This property of β-hydroxybutyrate might be key for the beneficial effect of calorie restriction on stress response and disease processes.

Emerging evidence suggests that oroxylin A exhibits antitumor effects by inducing cell apoptosis. However, the involved molecular mechanisms have not been elucidated. Here we report that the apoptosis induced by oroxylin A was dependent on p62-mediated activation of caspase-8 in hepatocellular carcinoma cells. Furthermore, oroxylin A also caused p62/SQSTM1 proteolysis at Asp329 by activating caspase-8. Further studies confirm that mutation in p62 (D329H and D329G) was resistant to oroxylin A-mediated p62 cleavage and apoptosis. Due to the absence of the KIR domain that interacts with Keap1, the cleaved p62 reduced the stability of Nrf2, thereby causing oxidative stress and increasing ROS levels. In vivo, p62 similarly contributed to oroxylin A-exerted antitumor effect in xenograft model inoculated SMMC-7721 tumor. In conclusion, our findings indicated that oroxylin A triggered apoptosis through caspase-8 activation and p62/SQSTM1 proteolysis.

Triple-negative breast cancer (TNBC) cells, which do not express genes for estrogen receptor (ER), progesterone receptor (PR), and Her2/neu, develop highly aggressive and metastatic tumors resistant to chemo- and hormonal therapies. We found that expression of glutathione peroxidase-1 (Gpx1) is silenced in the non-TNBC cells but significantly maintained in the TNBC cell lines. Such Gpx1 expression plays a vital role in the metastasis of TNBC cells by regulating cell adhesion. Transcriptomic and signaling pathway analyses demonstrate that depletion of Gpx1 essentially impairs cell adhesion/spreading by down-regulating FAK/c-Src activation. Mechanistically, Gpx1 interacts with FAK kinase and prevents the kinase inactivation by H2O2, not lipid hydroperoxide. As a result, depletion of Gpx1 suppresses lung metastasis of TNBC cells in vivo. Overall, our study identifies that Gpx1 is a redox safeguard of FAK kinase and its inhibition may provide an effective way to control the metastasis of deadly malignant TNBC.

Doxorubicin (DOX), or Adriamycin, an anthracycline antibiotic discovered serendipitously as a chemotherapeutic drug several decades ago, is still one of the most effective drugs for treating various adult and pediatric cancers (breast cancer, Hodgkin's disease, lymphoblastic leukemia). However, one of the major side effects of the continuous use of DOX is dose-dependent, long-term, and potentially lethal cardiovascular toxicity (congestive heart failure and cardiomyopathy) in cancer survivors many years after cessation of chemotherapy. In addition, predisposition to cardiotoxicity varied considerably among individuals. The long-held notion that DOX cardiotoxicity is caused by reactive oxygen species formed from the redox-cycling of DOX semiquinone lacks rigorous proof in a chronic animal model, and administration of reactive oxygen species detoxifying agents failed to reverse DOX-induced cardiac problems. In this review, I discuss the pros and cons of the reactive oxygen species pathway as a primary or secondary mechanism of DOX cardiotoxicity, the role of topoisomerases, and the potential use of mitochondrial-biogenesis-enhancing compounds in reversing DOX-induced cardiomyopathy. New approaches for well-designed clinical trials that repurpose FDA-approved drugs and naturally occurring polyphenolic compounds prophylactically to prevent or mitigate cardiovascular complications in both pediatric and adult cancer survivors are needed. Essentially, the focus should be on enhancing mitochondrial biogenesis to prevent or mitigate DOX-induced cardiotoxicity.

The human HEAT repeat-containing protein 1 (HEATR1), consisting of 2144 amino acids, is a member of the UTP10 family and contains one HEAT repeat at its C-terminal. HEATR1 has been reported to regulate cytotoxic T lymphocytes and rRNA synthesis, while its functions in tumors are poorly understood. Here, we found that HEATR1 competed with Keap1 for binding to p62/sequestosome 1 (SQSTM1), resulted in up-regulation of Keap1, which then inhibited Nrf2 signaling in pancreatic cancer cells. HEATR1 knockdown enhanced proliferation and gemcitabine resistance of pancreatic cancer cells. Moreover, HEATR1 deficiency significantly improved xenografts growth and led to gemcitabine resistance in pancreatic cancer cell-derived xenografts through up-regulating Nrf2 signaling. By analyzing tumor tissue samples from pancreatic cancer patients, we found that low expression of HEATR1 was closely correlated with poor prognosis and clinicopathological features. Collectively, we suggest that HEATR1 deficiency promote proliferation and gemcitabine resistance of pancreatic cancer through up-regulating Nrf2 signaling, indicating that HEATR1 may be a promising therapeutic target for pancreatic cancer.

Enduring brain dysfunction is amid the highly manifested symptoms in veterans with Gulf War Illness (GWI). Animal studies have established that lasting brain dysfunction in GWI is concomitant with augmented oxidative stress, inflammation, and declined neurogenesis in the brain, and systemic inflammation. We hypothesize that drugs capable of restoring redox homeostasis in GWI will improve cognitive and mood function with modulation of neuroinflammation and neurogenesis. We examined the efficacy of monosodium luminol-GVT (MSL), a drug that promotes redox homeostasis, for improving cognitive and mood function in GWI rats. Young rats were exposed to GWI-related chemicals and moderate restraint stress for four weeks. Four months later, GWI rats received different doses of MSL or vehicle for eight weeks. Behavioral analyses in the last three weeks of treatment revealed that GWI rats receiving higher doses of MSL displayed better cognitive and mood function associated with reinstatement of redox homeostasis. Such restoration was evident from the normalized expression of multiple genes encoding proteins involved in combating oxidative stress in the brain and the return of several oxidative stress markers to control levels in the brain and the circulating blood. Sustained redox homeostasis by MSL also resulted in antiinflammatory and pro-neurogenic effects, which were apparent from reduced densities of hypertrophied astrocytes and activated microglia, and increased neurogenesis with augmented neural stem cell proliferation. Moreover, MSL treatment normalized the concentration of multiple proinflammatory markers in the circulating blood. Thus, MSL treatment is an efficient strategy for reinstating redox homeostasis in an animal model of GWI, which resulted in alleviation of both brain and systemic inflammation, improved neurogenesis, and better cognitive and mood function.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma accounting for 5–8% of malignant tumours in children and adolescents. Children with high risk disease have poor prognosis. Anti-RMS therapies include surgery, radiation and combination chemotherapy. While these strategies improved survival rates, they have plateaued since 1990s as drugs that target differentiation and self-renewal of tumours cells have not been identified. Moreover, prevailing treatments are aggressive with drug resistance and metastasis causing failure of several treatment regimes. Significant advances have been made recently in understanding the genetic and epigenetic landscape in RMS. These studies have identified novel diagnostic and prognostic markers and opened new avenues for treatment. An important target identified in high throughput drug screening studies is reactive oxygen species (ROS). Indeed, many drugs in clinical trials for RMS impact tumour progression through ROS. In light of such emerging evidence, we discuss recent findings highlighting key pathways, epigenetic alterations and their impacts on ROS that form the basis of developing novel molecularly targeted therapies in RMS. Such targeted therapies in combination with conventional therapy could reduce adverse side effects in young survivors and lead to a decline in long-term morbidity.

RAS proteins are critical regulators of signaling networks controlling diverse cellular functions such as cell proliferation and survival and its mutation are among the most powerful oncogenic drivers in human cancers. Despite intense efforts, direct RAS-targeting strategies remain elusive due to its “undruggable” nature. To that end, bulk of the research efforts has been directed towards targeting upstream and/or downstream of RAS signaling. However, the therapeutic efficacies of these treatments are limited in the long run due to the acquired drug resistance in RAS-driven cancers. Interestingly, recent studies have uncovered a potential role of RAS in redox-regulation as well as the interplay between ROS and RAS-associated signaling networks during process of cancer initiation and progression. More specifically, these studies provide ample evidence to implicate RAS as a redox-rheostat, manipulating ROS levels to provide a redox-milieu conducive for carcinogenesis. Importantly, the understanding of RAS-ROS interplay could provide us with novel targetable vulnerabilities for designing therapeutic strategies. In this review, we provide a brief summary of the advances in the field to illustrate the dual role of RAS in redox-regulation and its implications in RAS signaling outcomes and also emerging redox-based strategies to target RAS-driven cancers.

Reactive oxygen species (ROS) are a group of short-lived, highly reactive, oxygen-containing molecules that can induce DNA damage and affect the DNA damage response (DDR). There is unequivocal pre-clinical and clinical evidence that ROS influence the genotoxic stress caused by chemotherapeutics agents and ionizing radiation. Recent studies have provided mechanistic insight into how ROS can also influence the cellular response to DNA damage caused by genotoxic therapy, especially in the context of Double Strand Breaks (DSBs). This has led to the clinical evaluation of agents modulating ROS in combination with genotoxic therapy for cancer, with mixed success so far. These studies point to context dependent outcomes with ROS modulator combinations with Chemotherapy and radiotherapy, indicating a need for additional pre-clinical research in the field. In this review, we discuss the current knowledge on the effect of ROS in the DNA damage response, and its clinical relevance.