Regulation Of Redox Homeostasis Research Articles

SOD2 in platelets: with age comes responsibility

SOD2 in platelets: with age comes responsibility

Alteration of Lipid Metabolism in Prostate Cancer: Multifaceted Oncologic Implications.

Cancer is increasingly recognized as an extraordinarily heterogeneous disease featuring an intricate mutational landscape and vast intra- and intertumor variability on both genetic and phenotypic levels. Prostate cancer (PCa) is the second most prevalent malignant disease among men worldwide. A single metabolic program cannot epitomize the perplexing reprogramming of tumor metabolism needed to sustain the stemness of neoplastic cells and their prominent energy-consuming functional properties, such as intensive proliferation, uncontrolled growth, migration, and invasion. In cancerous tissue, lipids provide the structural integrity of biological membranes, supply energy, influence the regulation of redox homeostasis, contribute to plasticity, angiogenesis and microenvironment reshaping, mediate the modulation of the inflammatory response, and operate as signaling messengers, i.e., lipid mediators affecting myriad processes relevant for the development of the neoplasia. Comprehensive elucidation of the lipid metabolism alterations in PCa, the underlying regulatory mechanisms, and their implications in tumorigenesis and the progression of the disease are gaining growing research interest in the contemporary urologic oncology. Delineation of the unique metabolic signature of the PCa featuring major aberrant pathways including de novo lipogenesis, lipid uptake, storage and compositional reprogramming may provide novel, exciting, and promising avenues for improving diagnosis, risk stratification, and clinical management of such a complex and heterogeneous pathology.

Carrier-Free Immunotherapeutic Nano-Booster with Dual Synergistic Effects Based on Glutaminase Inhibition Combined with Photodynamic Therapy.

The immunotherapeutic effect elicited by photodynamic therapy (PDT) is attenuated by tumor defense mechanisms associated with glutamine metabolism, including the metabolic regulation of redox homeostasis and the limitation of the immunosuppressive tumor microenvironment (ITM). Herein, a carrier-free immunotherapeutic nanobooster C9SN with dual synergistic effects was constructed by the self-assembly of glutaminase (GLS) inhibitor compound 968 (C968) and photosensitizer Chlorin e6. C968-mediated GSH deprivation through inhibiting glutamine metabolism prevented PDT-generated reactive oxygen species from being annihilated by GSH, amplifying intracellular oxidative stress, which caused severe cell death and also enhanced the immunogenic cell death (ICD) effect. In addition, genome-wide analysis was carried out using RNA-sequencing to evaluate the changes in cell transcriptome induced by amplifying oxidative stress. Thereafter, neoantigens generated by the enhanced ICD effect promoted the maturation of dendritic cells, thereby recruiting and activating cytotoxic T lymphocytes (CTLs). Meanwhile, C9SN remodeled the ITM by blocking glutamine metabolism to polarize M2-type tumor-associated macrophages (TAMs) into M1-type TAMs, which further recruited and activated the CTLs. Ultimately, this immunotherapeutic nanobooster suppressed primary and distant tumors. This "kill two birds with one stone" strategy would shed light on enhancing tumor immunogenicity and alleviating tumor immunosuppression to improve the immunotherapeutic effect of PDT.

The bridge between cell survival and cell death: reactive oxygen species-mediated cellular stress.

As a requirement of aerobic metabolism, regulation of redox homeostasis is indispensable for the continuity of living homeostasis and life. Since the stability of the redox state is necessary for the maintenance of the biological functions of the cells, the balance between the pro-oxidants, especially ROS and the antioxidant capacity is kept in balance in the cells through antioxidant defense systems. The pleiotropic transcription factor, Nrf2, is the master regulator of the antioxidant defense system. Disruption of redox homeostasis leads to oxidative and reductive stress, bringing about multiple pathophysiological conditions. Oxidative stress characterized by high ROS levels causes oxidative damage to biomolecules and cell death, while reductive stress characterized by low ROS levels disrupt physiological cell functions. The fact that ROS, which were initially attributed as harmful products of aerobic metabolism, at the same time function as signal molecules at non-toxic levels and play a role in the adaptive response called mithormesis points out that ROS have a dose-dependent effect on cell fate determination. See also Figure 1(Fig. 1).

Mitochondrial NIR imaging probe mitigating oxidative damage by targeting HDAC6.

Despite the apparent copious fluorescent probes targeting mitochondria, the development of low cytotoxic probes is still needed for improving validation of mitochondrial function assessment. Herein, we report a novel cyanine-based NIR fluorescent probe, T2, which selectively targets mitochondria with significantly low toxicity by modulating the intracellular redox status. Additionally, T2 inhibits oxidative stress-induced cell death in cortical neurons. This study provides new insight into developing low-toxic mitochondrial imaging agents by regulating redox homeostasis.

Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.

The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment.

Superoxide dismutase SOD-3 regulates redox homeostasis in the intestine.

There are four cellular superoxide dismutase paralogs in C. elegans . The role of these superoxide dismutases in redox homeostasis remains largely unknown. Here, we generated the integrated redox reporter rxRFP to detect changes in redox homeostasis using live fluorescence imaging. We found that sod-3 deletion contributes to oxidative stress elevation. Deletions in additional paralogs ameliorate the oxidative stress of sod-3 . Complete elimination of all four paralogs elicits the same increase in rxRFP fluorescence as in the sod-3 single mutation, suggesting a compensatory role of other sod s. Our results suggest that SOD-3 plays a key role in regulating gut redox homeostasis.

Dusp1 regulates thermal tolerance limits in zebrafish by maintaining mitochondrial integrity.

Temperature tolerance restricts the distribution of a species. However, the molecular and cellular mechanisms that set the thermal tolerance limits of an organism are poorly understood. Here, we report on the function of dual-specificity phosphatase 1 (DUSP1) in thermal tolerance regulation. Notably, we found that dusp1 -/- zebrafish grew normally but survived within a narrowed temperature range. The higher susceptibility of these mutant fish to both cold and heat challenges was attributed to accelerated cell death caused by aggravated mitochondrial dysfunction and over-production of reactive oxygen species in the gills. The DUSP1-MAPK-DRP1 axis was identified as a key pathway regulating these processes in both fish and human cells. These observations suggest that DUSP1 may play a role in maintaining mitochondrial integrity and redox homeostasis. We therefore propose that maintenance of cellular redox homeostasis may be a key mechanism for coping with cellular thermal stress and that the interplay between signaling pathways regulating redox homeostasis in the most thermosensitive tissue (i.e., gills) may play an important role in setting the thermal tolerance limit of zebrafish.

Glutathione Protects against Paraquat-Induced Oxidative Stress by Regulating Intestinal Barrier, Antioxidant Capacity, and CAR Signaling Pathway in Weaned Piglets.

Endogenous glutathione (GSH) effectively regulates redox homeostasis in the body. This study aimed to investigate the regulatory mechanism of different dietary levels of GSH supplementation on the intestinal barrier and antioxidant function in a paraquat-induced stress-weaned piglet model. Our results showed that dietary 0.06% GSH supplementation improved the growth performance of weaned piglets under normal and stressful conditions to some degree and decreased the diarrhea rate throughout. Exogenous GSH improved paraquat-induced changes in intestinal morphology, organelle, and permeability and reduced intestinal epithelial cell apoptosis. Moreover, GSH treatment alleviated intestinal oxidative stress damage by upregulating antioxidant (GPX4, CnZnSOD, GCLC, and GCLM) and anti-inflammatory (IL-10) gene expression and downregulating inflammatory cytokines (IFN-γ and IL-12) gene expression. Furthermore, GSH significantly reduced the expression levels of constitutive androstane receptor (CAR), RXRα, HSP90, PP2Ac, CYP2B22, and CYP3A29, and increased the expression levels of GSTA1 and GSTA2 in the jejunum and ileum of paraquat-induced piglets. We conclude that exogenous GSH protects against oxidative stress damage by regulating the intestinal barrier, antioxidant capacity, and CAR signaling pathway.

Nuclear factor erythroid 2-related factor 2-mediated signaling and metabolic associated fatty liver disease

Oxidative stress is a key driver in the development and progression of several diseases, including metabolic associated fatty liver disease (MAFLD). This condition includes a wide spectrum of pathological injuries, extending from simple steatosis to inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma. Excessive buildup of lipids in the liver is strictly related to oxidative stress in MAFLD, progressing to liver fibrosis and cirrhosis. The nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of redox homeostasis. NRF2 plays an important role for cellular protection by inducing the expression of genes related to antioxidant, anti-inflammatory, and cytoprotective response. Consistent evidence demonstrates that NRF2 is involved in every step of MAFLD deve-lopment, from simple steatosis to inflammation, advanced fibrosis, and ini-tiation/progression of hepatocellular carcinoma. NRF2 activators regulate lipid metabolism and oxidative stress alleviating the fatty liver disease by inducing the expression of cytoprotective genes. Thus, modulating NRF2 activation is crucial not only in understanding specific mechanisms underlying MAFLD progression but also to characterize effective therapeutic strategies. This review outlined the current knowledge on the effects of NRF2 pathway, modulators, and mechanisms involved in the therapeutic implications of liver steatosis, inflammation, and fibrosis in MAFLD.

Molecular cloning and characterization of a thioredoxin-like protein gene in rotifer Brachionus plicatilis

The thioredoxin-like protein exists widely, in various organisms, as a regulator of redox homeostasis. In this study, the full-length cDNA of a thioredoxin-like protein gene from rotifer Brachionus plicatilis (designated as BpTXNL) was obtained by 5′ rapid amplification of cDNA end (RACE) technology. The complete cDNA of BpTXNL was 1111 bp, and contained a 5′ untranslated region (UTR) of 69 bp, a 3’ UTR of 163 bp with a polyadenylate additional signal and a polyadenylation site (PAS), and an open reading frame (ORF) of 878 bp, encoding 292 amino acids. The calculated molecular weight and the theoretical isoelectric point (pI) of the deduced BpTXNL peptide were 32.7 kDa and 4.97, respectively. The deduced protein sequence of BpTXNL contained a thioredoxin domain with the conserved redox-active site at 33CGPC36 and a proteasome-interacting thioredoxin (PITH) domain. Phylogenetic analysis demonstrated that BpTXNL was clustered with TXNLs of Strongyloides ratti and Caenorhabditis elegans. The temporal mRNA expression level of BpTXNL significantly decreased at 6 h, then increased to the peak 24h after the 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) challenge, while the mRNA transcripts of BpTXNL significantly increased and reached the peaks twice, at 6 h and 24 h after the lipopolysaccharide (LPS) challenge. The recombinant BpTXNL protein quickly exhibited a concentration-dependent antioxidant capacity and the peak occurred at 55 min in the 20 μM group. All these results showed that BpTXNL possesses an antioxidant capacity, and that it may be involved in the regulation of excessive reactive oxygen species (ROS) during environmental stress or pathogen invading.

A chemical approach for the specific generation of cysteine sulfinylation

Oxidative modifications of protein cysteines play a crucial role in regulating redox homeostasis, redox signaling, and protein function. One of the modifications involves the oxidation of a cysteine thiol to a sulfinic acid (R-SO2H) which has been considered a marker for oxidative stress and an important activator for certain proteins. Here we report a protocol for the selective formation of sulfinic acids on cysteine residues in a simple 3-step operation under mild conditions: thiol-blocking, oxidation, and reduction. The specificity and efficiency of the method were demonstrated by using both small molecule substrates and a protein model.

Продукция активных форм кислорода при действии ультрафиолетового-В излучения на клетки дрожжей

The present investigation is devoted to the study of the effect of ultraviolet-B (UV-B) radiation on the survival and production of reactive oxygen species in yeast cells. It has been determined that under the action of UV-B radiation on cells, depending on its dose, the rate of oxidation of the dye 2',7'-dichlorodihydrofluorescein diacetate (H2DCF•DA) increases and a high intensity of DCF fluorescence is observed. When cells are modified with ascorbic acid before irradiation, the rate of H2DCF oxidation and the intensity of DCF fluorescence decreases. The survival rate of modified cells is increased. Ascorbic acid reduces the amount of ROS in the suspension of irradiated cells. At high doses (4.5-10 erg/mm2) of irradiation, the antioxidant effect of ascorbic acid in yeast cells is negligible. The concentration of 2-4 dinitrophenol (DNF) 10-7 M was determined as a protector, in which the substance potentially contributes to the manifestation of the effect of "soft uncoupling" in cells and, under the influence of UV-B radiation on yeast cells, helps to reduce the production of reactive oxygen species and an increase in survival. High concentrations (10–3M–10–5 M) of DNP adversely affect the survival of yeast cells and ROS production. So, it can be concluded that under the action of UV-B rays on yeast cells, antioxidants can possibly participate in the regulation of redox homeostasis.

Efficacy of endophytic SB10 and glycine betaine duo in alleviating phytotoxic impact of combined heat and salinity in Glycine max L. via regulation of redox homeostasis and physiological and molecular responses

Adverse environmental stresses occurring simultaneously exhibit a lethal effect on crop productivity at the global level. Here, we investigated the individual and synergistic effects of endophytic T. virens SB10 and glycine betaine (GB) on the physiological and biochemical responses of Glycine max L. to alleviate the devastating effects of combined heat and salinity (HS) stress. Screening against HS stress tolerance showed that SB10 has significant tolerance against heat stress and produces hormones such as gibberellins and indole-3-acetic acid upon GB amendment of the growth medium under HS stress. Moreover, the current findings illustrated that the synergistic application of SB10 and GB was effective in alleviating the negative effects of HS stress on plant growth and physiology. The findings revealed that SB10 + GB led to a reduction in proline accumulation and Na+ uptake. It also maintained a high K+/Na + ratio by regulating GmHKT1 and GmSOS1 expression and enhanced macronutrient uptake (N, Ca, K) in plants. In turn, plants exhibited a higher growth rate and gaseous exchange attributes coupled with the upregulation of APX, SOD, POD, and GSH antioxidant activities and transcript accumulation of GmSOD1 and GmAPX1 to overcome HS-induced oxidative damage. Furthermore, SB10 + GB downregulated DREB2, DREB1B, and GmNCED3 expression and resulted in the reduced accumulation of endogenous ABA while enhancing endogenous SA accumulation via upregulation of PAL genes. In addition, enhanced accumulation of bioactive gibberellins (GA1, GA3, GA4, and GA7) was detected under HS stress in the SB10 + GB treatment group. Moreover, SB10 + GB also significantly regulated GmHsp90A2 and GmHsfA2 expression in tolerance against HS stress. The combination of SB10 and GB was shown to be an effective and alternative approach for growing G. max at high temperature coupled with saline conditions for sustainable agriculture.

Phenotypic plasticity of vascular smooth muscle cells in vascular calcification: Role of mitochondria.

Vascular calcification (VC) is an important hallmark of cardiovascular disease, the osteo-/chondrocyte phenotype differentiation of vascular smooth muscle cells (VSMCs) is the main cause of vascular calcification. Accumulating evidence shows that mitochondrial dysfunction may ultimately be more detrimental in the VSMCs calcification. Mitochondrial participate in essential cellular functions, including energy production, metabolism, redox homeostasis regulation, intracellular calcium homeostasis, apoptosis, and signal transduction. Mitochondrial dysfunction under pathological conditions results in mitochondrial reactive oxygen species (ROS) generation and metabolic disorders, which further lead to abnormal phenotypic differentiation of VSMCs. In this review, we summarize existing studies targeting mitochondria as a treatment for VC, and focus on VSMCs, highlighting recent progress in determining the roles of mitochondrial processes in regulating the phenotype transition of VSMCs, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, mitochondrial energy metabolism, and mitochondria/ER interactions. Along these lines, the impact of mitochondrial homeostasis on VC is discussed.

Regulation of innate immunity by Nrf2.

The transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) has been mainly investigated as a regulator of redox homeostasis. However, research over the past years has implicated Nrf2 as an important regulator of innate immunity. Here, we discuss the role of Nrf2 in the innate immune response, highlighting the interaction between Nrf2 and major components of the innate immune system. Indeed, Nrf2 has been shown to widely control the immune response by interacting directly or indirectly with important innate immune components, including the toll-like receptors-Nuclear factor kappa B (NF-kB) pathway, inflammasome signaling, and the type-I interferon response. This indicates an essential role for Nrf2 in diseases related to microbial infections, inflammation, and cancer. Yet, further studies are required to determine the exact mechanism underpinning the interactions between Nrf2 and innate immune players in order to allow a better understanding of these diseases and leverage new therapeutic strategies.

Exogenous Glutathione Promotes the Proliferation of Pinus koraiensis Embryonic Cells and the Synthesis of Glutathione and Ascorbic Acid.

Somatic embryogenesis (SE), which leads to the formation of embryonic callus (EC) tissue, is the most promising method for large-scale production and selective breeding of woody plants. However, in many species, SE suffers from low proliferation rates, hindering the production of improved plant materials. One way of improving proliferation rates is achieved by improving the redox status of the culture medium. In this study, we investigated the effects of exogenous glutathione (GSH) and L-buthionine sulfoximine (BSO, the inhibitor of glutathione synthase) on the EC proliferation rate in Korean pine (Pinus koraiensis), using cell lines with both high (F: 001#-001) and low (S: 001#-010) proliferation potential. We found that exogenous GSH promoted cell proliferation in both cell lines, while exogenous BSO inhibited proliferation in both cell lines. At 35 d with exogenous GSH treatment, the fresh weight of F and S cell lines increased by 35.48% and 48.39%, respectively, compared with the control. The exogenous application of GSH increased the intracellular levels of GSH, total GSH (T-GSH), oxidized glutathione (GSSG), ascorbic acid (ASA), total ASA (T-ASA), and the ratios of GSH:T-GSH and ASA:T-ASA in both F and S cell lines. Furthermore, exogenous GSH increased the activity of both glutathione reductase (GR) and dehydroascorbate reductase (DHAR) while decreasing the activity of ascorbate peroxidase (APX) in both cell lines. It appears that the application of exogenous GSH promotes a reducing cultural environment, which is conducive to EC proliferation in Korean pine. By helping to reveal the mechanism whereby GSH regulates redox homeostasis in Korean pine EC cells, we have laid the foundation for a large-scale breeding of Korean pine somatic embryogenesis technology system.

Biochemical regulatory processes in the control of oxidants and antioxidants production in the brain of rats with iron and copper chronic overloads.

Iron [Fe(II)] and copper [Cu(II)] overloads in rat brain are associated with oxidative stress and damage. The purpose of this research is to study whether brain antioxidant enzymes are involved in the control of intracellular redox homeostasis in the brain of rats male Sprague-Dawley rats (80-90g) that received drinking water supplemented with either 1.0g/L of ferrous chloride (n = 24) or 0.5g/L cupric sulfate (n = 24) for 42days. Nicotinamide adenine dinucleotide phosphate(NADPH) oxidase, superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione transferase (GT) activities in brain were determined by spectrophotometric methods and NO production by the content of nitrite concentration in the organ. Chronic treatment with Fe(II) and Cu(II) led to a significant decrease of nitrite content and SOD activity in brain. Activity of NADPH oxidase increased with Cu(II) treatment. Concerning Fe(II), catalase and GT activities increased in brain after 28 and 4days of treatment, respectively. In the case of Cu(II), catalase activity decreased whereas GT activity increased after 2 and 14days, respectively. The regulation of redox homeostasis in brain involves changes of the activity of these enzymes to control the steady state of oxidant species related to redox signaling pathways upon Cu and Fe overload. NO may serve to detoxify cells from superoxide anion and hydrogen peroxide with the concomitant formation of peroxynitrite. However, the latest is a powerful oxidant which leads to oxidative modifications of biomolecules. These results suggest a common pathway to oxidative stress and damage in brain for Cu(II) and Fe(II).

N-acetylcysteine combined with insulin alleviates the oxidative damage of cerebrum via regulating redox homeostasis in type 1 diabetic mellitus canine

Neurodegenerative diseases are one of the major complications of type 1 diabetes mellitus (T1DM). The effect of insulin monotherapy on controlling blood glucose and neurodegeneration associated with diabetes is unsatisfactory. It is revealed that oxidative stress is a key element in T1DM. Therefore, N-acetylcysteine (NAC) was used together with insulin to investigate the therapeutic effect on neuronal damage in T1DM in this study. A total of 40 beagles were randomly divided into 5 groups (control group, DM group, insulin monotherapy group, NAC combined with insulin group, and NAC monotherapy group) to explore the effects of NAC on alleviating the oxidative damage in cerebrum. Our results showed that the contents of H2O2, 8-OHdg and MDA were apparently increased in DM group, while DNA and lipid oxidative damage was alleviated by the treatment of NAC and insulin. Histopathology revealed the sparse of neurofibrils and vacuolar degeneration in DM group. Additionally, compared with the control group, the mRNA expression levels of HO-1, nqo1, GCLC and GSTM1 were significantly decreased in DM group, while the opposite trend could be shown under NAC combined with insulin treatment. Meanwhile, the tight junction proteins of ZO-1, occludin and Claudin-1 were up-regulated with the treatment of NAC combined with insulin. Additionally, NAC further alleviated oxidative damage by enhancing the activity of GSH, Trx and TrxR and reducing the activity of catalase, GSSG and Grx to maintain redox homeostasis. These results demonstrated that NAC combined with insulin exerted protective effects against T1DM-induced cerebral injury via maintaining cerebral redox homeostasis.

Tracing and regulating redox homeostasis of model benthic ecosystems for sustainable aquaculture in coastal environments.

Aquaculture in coastal environments has an increasingly important role in the world’s food supply; however, the accumulation of organic compounds on seafloors due to overfeeding adversely affects benthic ecosystems. To assess the ecological resilience of aquafarms to nutrient influx, we investigated the redox homeostasis of benthic ecosystems using a marine oligochaete as a model benthic organism in aquaculture fields. Real-time monitoring of the redox potential of a model benthic ecosystem constructed in an electrochemical reactor allowed evaluation of the homeostatic response of the system to nutrient addition. Although the detrimental effects of overfeeding were confirmed by irreversible potential changes in the sediment, redox homeostasis was reinforced through a cooperative relationship between oligochaetes and sediment microorganisms. Specifically, the oligochaetes exhibited reversible changes in metabolism and body position in response to dynamic changes in the sediment potential between −300 and 500 mV, thereby promoting the decomposition of organic compounds. The potential-dependent changes in metabolism and body position were reproduced by artificially manipulating the sediment potential in electrochemical reactors. Given the importance of benthic animals in sustaining coastal ecosystems, the electrochemical monitoring and physiologic regulation of marine oligochaetes could offer an intriguing approach toward sustainable aquaculture.