Disturbed Redox Research Articles

Strawberry extract attenuates oxidative stress in 3T3-L1 cells

BACKGROUND: High levels of reactive oxygen species (ROS) within the adipose tissue promote a disturbed redox balance and influence its function, impairing adipogenesis, inducing insulin resistance and stimulating adipocyte hypertrophy. Supplementation with antioxidant rich foods can reverse some of these effects. Strawberry is well known as a good source of phytochemicals; however, whether strawberry suppresses increased oxidative stress in 3T3-L1 cells remain unclear. OBJECTIVE: The purpose of the present work was to determine the antioxidant potential of a strawberry extract in 3T3-L1 mouse embryo fibroblast cell line. METHODS: 3T3-L1 pre-adipocytes were induced to differentiate into adipocytes in the presence or absence of different concentrations of the strawberry extract. At the end of the differentiation period, intracellular ROS production, thiobarbituric acid reactive substances (TBARS) content, as well as superoxide dismutase (SOD) and catalase (CAT) activities and gene expressions were evaluated. RESULTS: In this study, we confirmed that strawberry extract markedly inhibited increased-oxidative stress in 3T3L1 cells by suppressing intracellular ROS production and decreasing TBARS content. Likewise, SOD and CAT activities and gene expressions were increased. CONCLUSIONS: This paper provides evidence that strawberry extract is able to scavenging free radicals and activate endogenous defense systems, highlighting its potential capacity to modulate obesity induced- inflammatory states.

Effect of the Aqueous Extract of Lantana grisebachii Stuck Against Bioaccumulated Arsenic-Induced Oxidative and Lipid Dysfunction in Rat Splenocytes

ABSTRACTArsenic (As) is a worldwide immunotoxic agent that is in contaminated waters and consumed by mammals. Phytotherapy may counteract its harmful effects. Lantana grisebachii Stuck (LG, Verbenaceae) and its extract are proposed as protective, given vvits in vitro bioactivity. The aim was to determine the protective capacity of the aqueous LG extract on splenocytes exposed in vivo to arsenic. Splenocytes were obtained from an arsenicosis model (Wistar rats consuming orally 0 [control; C] or 5 mg/Kg/d of As) that received 0–100 mg/Kg/d of LG extract for 30 days. As content (total reflection X-ray fluorescence), fatty acid profile (gas chromatography), γ-glutamyl transpeptidase activity (Szasz method), peroxides (xylenol orange-based assay), and nitrites (Griess reaction) were then assayed in viable splenocytes. Data were analyzed with ANOVA and the Tukey's test (p < .05). It was observed that the splenocytes contained 2.2 mg/Kg of this elemental arsenic. With γ-glutamyl transpeptidase inhibition and consequent triggering of hydroperoxides (p < .05), it was observed to increase saturated fatty acids and alter lipid profiles. LG treatment avoided damaging effects with values similar to unexposed C (p < .05), and cellular arsenic concentration (p < .0001). In conclusion, the aqueous extract of L. grisebachii counteracted arsenic toxicity in rat splenocytes by preventing its cellular accumulation and induction of lipid and redox disturbances, which may impair immune function.

Magnesium isoglycyrrhizinate ameliorates liver fibrosis and hepatic stellate cell activation by regulating ferroptosis signaling pathway

Ferroptosis is recently reported as a new mode of regulated cell death. It is triggered by disturbed redox homeostasis, overloaded iron and increased lipid peroxidation. Howerver, the role of ferroptosis in hepatic fibrosis remains obscure. In the current study, we attempted to investigate the effect of Magnesium isoglycyrrhizinate (MgIG) on ferroptosis in liver fibrosis, and to further clarify the possible mechanisms. Our data showed that MgIG treatment markedly attenuated liver injury and reduced fibrotic scar formation in the rat model of liver fibrosis. Moreover, experiments in vitro also confirmed that MgIG treatment significantly decreased expression of hepatic stellate cell (HSC) activation markers. Interestingly, HSCs treated by MgIG presented morphological features of ferroptosis. Furthermore, MgIG treatment remarkably induced HSC ferroptosis by promoting the accumulation of iron and lipid peroxides, whereas inhibition of ferroptosis by specific inhibitor ferrostatin-1 (Fer-1) completely abolished MgIG-induced anti-fibrosis effect. More importantly, our results determined that heme oxygenase-1 (HO-1) was in the upstream position of MgIG-induced HSC ferroptosis. Conversely, HO-1 knockdown by siRNA evidently blocked MgIG-induced HSC ferroptosis and in turn exacerbated liver fibrosis. Overall, our research revealed that HO-1 mediated HSC ferroptosis was necessary for MgIG to ameliorate CCl4-induced hepatic fibrosis.

The Arabidopsis catalase triple mutant reveals important roles of catalases and peroxisome-derived signaling in plant development.

Hydrogen peroxide (H2 O2 ) is generated in many metabolic processes. As a signaling molecule, H2 O2 plays important roles in plant growth and development, as well as environmental stress response. In Arabidopsis, there are three catalase genes, CAT1, CAT2, and CAT3. The encoded catalases are predominately peroxisomal proteins and are critical for scavenging H2 O2 . Since CAT1 and CAT3 are linked on chromosome 1, it has been almost impossible to generate cat1/3 and cat1/2/3 mutants by traditional genetic tools. In this study, we constructed cat1/3 double mutants and cat1/2/3 triple mutants by CRISPR/Cas9 to investigate the role of catalases. The cat1/2/3 triple mutants displayed severe redox disturbance and growth defects under physiological conditions compared with wild-type and the cat2/3 double mutants. Transcriptome analysis showed a more profound transcriptional response in the cat1/2/3 triple mutants compared to the cat2/3 mutants. These differentially expressed genes are involved in plant growth regulation as well as abiotic and biotic stress responses. In addition, expression of OXI1 (OXIDATIVE SIGNAL INDUCIBLE 1) and several MAPK cascade genes were changed dramatically in the catalase triple mutant, suggesting that H2 O2 produced in peroxisomes could serve as a peroxisomal retrograde signal.

Glutathione and arginine levels: Predictors for acetaminophen-associated asthma exacerbation?

Glutathione and arginine levels: Predictors for acetaminophen-associated asthma exacerbation?

Effects of Redox Disturbances on Intestinal Contractile Reactivity in Rats Fed with a Hypercaloric Diet.

Few studies have associated the effects of changes in caloric intake and redox disturbances in the gastrointestinal tract. Therefore, the present study aimed at evaluating the hypercaloric diet consumption influence on the contractile reactivity of intestinal smooth muscle, morphology, and oxidative stress of rat ileum. Wistar rats were randomly divided into groups that received a standard diet and fed with a hypercaloric diet for 8 weeks. Animals were euthanized, and the ileum was isolated to isotonic contraction monitoring. Morphology was evaluated by histological staining and oxidative stress by quantification of malondialdehyde levels and total antioxidant activity. Cumulative concentration-response curves to KCl and carbachol were attenuated in rats fed with a hypercaloric diet compared to those that received a standard diet. In addition, an increase in caloric intake promotes a rise in the thickness of the longitudinal smooth muscle layer of rat ileum and tissue malondialdehyde levels, characterizing lipid peroxidation, as well as a decrease in the antioxidant activity. Thus, it was concluded that the consumption of a hypercaloric diet impairs rat intestinal contractility due to mechanisms involving modifications in the intestinal smooth muscle architecture triggered by redox disturbances.

Impaired pentose phosphate pathway in the development of 3D MCF-7 cells mediated intracellular redox disturbance and multi-cellular resistance without drug induction

Although metabolic reprogramming and redox imbalance are widely reported to be involved in chemo-resistance in cancer treatment, much more attention was paid to anti-cancer drug induced effect. Our previous studies showed that cancer cells can develop P-gp overexpression-mediated intrinsic drug resistance in the formation of 3D MCF-7 multi-cellular layers (MCLs) without any drug induction. However, whether metabolic reprogramming and redox imbalance functioned during this progress remained unrevealed. In our present study, LC-Q/TOF-MS and GC-MS were used in combination for analysing intracellular metabolites. The contribution of pentose phosphate pathway (PPP) and its related redox status were checked by chemical interfering and silencing/over-expression of glucose-6-phosphate dehydrogenase (G6PD). The downstream products of G6PD were assayed by quantitative real-time PCR, western blot and flow cytometry. Results showed that not only G6PD expression but also G6PD activity was significantly lowered along with 3D MCF-7 cells culture time. Impaired PPP disturbed redox-cycling, generated reactive oxygen species (ROS), which triggered cell cycle arrest and caused the switch to Chk2/p53/NF-κB pathway-mediated P-gp induction. Our results provided a new attempt to associate intrinsic small molecule metabolites (impaired PPP) communicating with cell signalling pathways through disturbed intracellular redox status to elucidate multi-cellular resistance (MCR) in 3D MCF-7 cells, which improved the understanding of the mechanisms of P-gp up-regulation in MCR with metabolomic and related redox status support.

Oxidative Stress in the Local and Systemic Events of Apical Periodontitis.

Oxidative stress is involved in the pathogenesis of a variety of inflammatory disorders. Apical periodontitis (AP) usually results in the formation of an osteolytic apical lesion (AL) caused by the immune response to endodontic infection. Reactive oxygen species (ROS) produced by phagocytic cells in response to bacterial challenge represent an important host defense mechanism, but disturbed redox balance results in tissue injury. This mini review focuses on the role of oxidative stress in the local and associated systemic events in chronic apical periodontitis. During endodontic infection, ligation of Toll-like receptors (TLRs) on phagocytes' surface triggers activation, phagocytosis, synthesis of ROS, activation of humoral and cellular responses, and production of inflammatory mediators, such as, cytokines and matrix metalloproteinases (MMPs). The increment in ROS perturbs the normal redox balance and shifts cells into a state of oxidative stress. ROS induce molecular damage and disturbed redox signaling, that result in the loss of bone homeostasis, increased pro-inflammatory mediators, and MMP overexpression and activation, leading to apical tissue breakdown. On the other hand, oxidative stress has been strongly involved in the pathogenesis of atherosclerosis, where a chronic inflammatory process develops in the arterial wall. Chronic AP is associated with an increased risk of cardiovascular diseases (CVD) and especially atherogenesis. The potential mechanisms linking these diseases are also discussed.

Acute telomerase components depletion triggers oxidative stress as an early event previous to telomeric shortening

Loss of function of dyskerin (DKC1), NOP10 and TIN2 are responsible for different inheritance patterns of Dyskeratosis congenita (DC; ORPHA1775). They are key components of telomerase (DKC1 and NOP10) and shelterin (TIN2), and play an important role in telomere homeostasis. They participate in several fundamental cellular processes by contributing to Dyskeratosis congenita through mechanisms that are not fully understood. Presence of oxidative stress was postulated to result from telomerase ablation. However, the resulting disturbed redox status can promote telomere attrition by generating a vicious circle, which promotes cellular senescence. This fact prompted us to study if acute loss of DKC1, NOP10 and TINF2 can promote redox disequilibrium as an early event when telomere shortening has not yet taken place. We generated siRNA-mediated (DKC1, NOP10 and TINF2) cell lines by RNA interference, which was confirmed by mRNA and protein expression analyses. No telomere shortening occurred in any silenced cell line. Depletion of H/ACA ribonucleoproteins DKC1 and NOP10 diminished telomerase activity via TERC down-regulation, and produced alterations in pseudouridylation and ribosomal biogenesis. An increase in the GSSG/GSH ratio, carbonylated proteins and oxidized peroxiredoxin-6 was observed, in addition to MnSOD and TRX1 overexpression in the siRNA DC cells. Likewise, high PARylation levels and high PARP1 protein expression were detected. In contrast, the silenced TINF2 cells did not alter any evaluated oxidative stress marker. Altogether these findings lead us to conclude that loss of DKC1 and NOP10 functions induces oxidative stress in a telomere shortening independent manner.

The disturbed redox-balance in pulmonary fibrosis is modulated by the plant flavonoid quercetin

Idiopathic pulmonary fibrosis (IPF) is characterized by a disturbed pulmonary redox balance associated with inflammation. To restore this balance, antioxidants are often suggested as therapy for IPF but previous clinical trials with these compounds and their precursors have not been successful in the clinic. The exogenous antioxidant quercetin, which has a versatile antioxidant profile and is effective in restoring a disturbed redox balance, might be a better candidate. The aim of this study was to evaluate the protective effect of quercetin on oxidative and inflammatory markers in IPF. Here, we demonstrate that IPF patients have a significantly reduced endogenous antioxidant defense, shown by a reduced total antioxidant capacity and lowered glutathione and uric acid levels compared to healthy controls. This confirms that the redox balance is disturbed in IPF. Ex vivo incubation with quercetin in blood of both IPF patients and healthy controls reduces LPS-induced production of the pro-inflammatory cytokines IL-8 and TNFα. This anti-inflammatory effect was more pronounced in the blood of the patients. Our pro-fibrotic in vitro model, consisting of bleomycin-triggered BEAS-2B cells, shows that quercetin boosts the antioxidant response, by increasing Nrf2 activity, and decreases pro-inflammatory cytokine production in a concentration-dependent manner. Collectively, our findings implicate that IPF patients may benefit from the use of quercetin to restore the disturbed redox balance and reduce inflammation.

NRF2 Activation Impairs Quiescence and Bone Marrow Reconstitution Capacity of Hematopoietic Stem Cells.

Tissue stem cells are maintained in quiescence under physiological conditions but proliferate and differentiate to replenish mature cells under stressed conditions. The KEAP1-NRF2 system plays an essential role in stress response and cytoprotection against redox disturbance. To clarify the role of the KEAP1-NRF2 system in tissue stem cells, we focused on hematopoiesis in this study and used Keap1-deficient mice to examine the effects of persistent activation of NRF2 on long-term hematopoietic stem cells (LT-HSCs). We found that persistent activation of NRF2 due to Keap1 deficiency did not change the number of LT-HSCs but reduced their quiescence in steady-state hematopoiesis. During hematopoietic regeneration after bone marrow (BM) transplantation, persistent activation of NRF2 reduced the BM reconstitution capacity of LT-HSCs, suggesting that NRF2 reduces the quiescence of LT-HSCs and promotes their differentiation, leading to eventual exhaustion. Transient activation of NRF2 by an electrophilic reagent also promotes the entry of LT-HSCs into the cell cycle. Taken together, our findings show that NRF2 drives the cell cycle entry and differentiation of LT-HSCs at the expense of their quiescence and maintenance, an effect that appears to be beneficial for prompt recovery from blood loss. We propose that the appropriate control of NRF2 activity by KEAP1 is essential for maintaining HSCs and guarantees their stress-induced regenerative response.

Serum and whole blood Zn, Cu and Mn profiles and their relation to redox status in lung cancer patients

Disturbed redox status may be critical to lung cancerogenesis, however little research has been conducted on general changes in total redox status in lung cancer. Levels and activities of antioxidants, especially enzymatic ones, are related to trace element concentration. Trace element status is often disturbed in cancers, however no studies concerning the association between redox and trace element status have been performed for lung cancer. We hypothesized that disturbed redox status in lung cancer patients is partially determined by trace elements while their distribution amongst blood compartments may differ compared to healthy subjects.Blood samples from lung cancer patients (n=44) and control subjects (n=44) were collected to assess redox and trace element status. Serum and whole blood Cu and Mn levels were determined with GF-AAS, and Zn–with F-AAS. In serum the total antioxidant status (TAS) was determined with the commercial kit TAS (Randox, UK), total oxidant status (TOS) was determined based on the method developed by Erel and the oxidative stress index (OSI) was calculated. Total protein (T-Prot), albumin (Alb), uric acid (UA) and total bilirubin (T-Bil) concentrations were measured with an auto-analyser (Konelab 20i, Thermoscientific, USA), SOD and CAT activity − with commercially available kits (Cayman, USA).The level of TAS, T-Prot, Alb, T-Bil, the activity of SOD, the concentration of whole blood Mn as well as serum and whole blood Zn were lower while TOS, OSI, serum Cu levels and serum Cu:Zn ratios were higher in lung cancer patients compared to the control group. In the lung cancer group TAS correlated positively with Alb and UA, serum Zn and negatively with whole blood Mn. Additionally, SOD positively correlated with the whole blood Mn and Cu:Zn ratio, while CAT − negatively with the whole blood Cu:Zn ratio. In the lung cancer sub-group at clinical stage I–II, TOS additionally negatively correlated with whole blood Zn, and CAT negatively with serum Cu and Cu:Zn ratio. In advanced lung cancer, we found a positive correlation between TAS and serum Zn, and a negative one − with serum Cu:Zn ratio. We observed a similar correlation between endogenous non-enzymatic antioxidants and TAS in the control group, however considerably fewer correlations between trace elements and antioxidants were observed.This study supports the hypothesis that disturbed redox status in lung cancer patients is linked with alterations in trace element status regarding Zn, Mn and Cu. Moreover, the type of biological fluid influences both − alterations in the metal profile and relationships with redox status parameters.

Oral administration of probiotic Lactobacillus paraplantarum BGCG11 attenuates diabetes-induced liver and kidney damage in rats

The aim of this study was to assess the effect of the probiotic Lactobacillus paraplantarum BGCG11 on the regulatory pathways that underlie the defense responses of the liver and kidney in diabetic rats. Probiotic-treated diabetic rats exhibited decreased hyperglycemia, glycated hemoglobin, triacylglycerols and a reduction in advanced glycation end products of serum proteins. The probiotic treatment adjusted the redox imbalance in the liver and kidney of diabetic rats, reduced the level of DNA damage, increased the activity of the pro-survival Akt kinase, decreased procaspase 3 degradation and lowered the level of inflammatory mediator C/EBPβ. Administration of probiotic to diabetic rats attenuated fibrotic process activated in the liver and kidneys as judged by the increase in E-cadherin and decreases in α-smooth muscle actin and fibronectin. In summary, the probiotic administration had an ameliorating effect on diabetes-associated disturbed redox homeostasis, inflammation and fibrosis, which underline the development of diabetic complications.

Abstract 170: Differential Regulation of miRNA and mRNA Expression in the Myocardium of Nrf2 Knockout Mice

Background: Preclinical studies indicate that disruption of the transcription factor nuclear factor, erythroid 2 like 2 (Nrf2) leads to pathological oxidative stress in several tissues. However, the transcriptional role of Nrf2 in the heart, a highly aerobic organ sensitive to redox disturbances and aberrant microRNA (miRNA) activity, remains elusive. Here, we tested the hypothesis that Nrf2 ablation disrupts cardiac miRNA abundance leading to impaired transcriptional regulation of the myocardial defense system. Methods: Age-matched wild-type (WT) and Nrf2 knockout (Nrf2 -/- ) mice (n=3-6/group) were used in this study. Independent next-generation sequencing experiments were conducted to evaluate differential expression of mRNA and miRNA in the heart. Real-time qPCR was used to validate RNA sequencing (RNAseq) data. Results: RNAseq for mRNA uncovered 152 differentially expressed genes (DEGs) in Nrf2 -/- hearts, of which 129 were downregulated relative to WT. Novel DEGs previously unreported as Nrf2 targets were detected and Gene Ontology analysis revealed the enrichment (p&lt;0.05) of several biological processes distinct from canonical Nrf2 function including; wound healing, protein folding, cytokine response, cell migration and adhesion. In line with previous reports, altered regulation of apoptosis, stress response and oxidative metabolism was also implicated in Nrf2 -/- DEG signatures. Next, small RNAseq detected a total of 27 miRNAs (11 up and 16 downregulated) altered in Nrf2 -/- mice. Validation by qPCR revealed a significant (p&lt;0.05) decrease in miR-10b-5p, miR-674-3p, miR-3535, and miR-378c while miR-30b-5p, miR-208a-5p, miR-350-3p, miR-582-5p, and miR-1249-3p were increased. In silico integration of RNAseq data discovered complementarity between 39 repressed mRNAs and 4 upregulated miRNAs; miR-30b-5p, miR-208a-5p, miR-350-3p, and miR-582-5p. These miRNAs may cooperatively regulate expression in Nrf2 -/- hearts as 22 DEGs matched with 2 or more miRNAs. Conclusion: Our results highlight novel mRNA targets and indicate that Nrf2 regulates a subset of cardiac miRNAs. Biological changes distinct from canonical Nrf2 function suggest that regulatory cross-talk with miRNAs contribute to unique roles for Nrf2 in the myocardium.

Molecular Mechanisms Underlying the Anti-depressant Effects of Resveratrol: a Review.

Major depression is a public health problem, affecting 121 million people worldwide. Patients suffering from depression present high rates of morbidity, causing profound economic and social impacts. Furthermore, patients with depression present cognitive impairments, which could influence on treatment adherence and long-term outcomes. The pathophysiology of major depression is not completely understood yet but involves reduced levels of monoamine neurotransmitters, bioenergetics, and redox disturbances, as well as inflammation and neuronal loss. Treatment with anti-depressants provides a complete remission of symptoms in approximately 50% of patients with major depression. However, these drugs may cause side effects, as sedation and weight gain. In this context, there is increasing interest in studies focusing on the anti-depressant effects of natural compounds found in the diet. Resveratrol is a polyphenolic phytoalexin (3,4',5-trihydroxystilbene; C14H12O3; MW 228.247g/mol) and has been found in peanuts, berries, grapes, and wine and induces anti-oxidant, anti-inflammatory, and anti-apoptotic effects in several mammalian cell types. Resveratrol also elicits anti-depressant effects, as observed in experimental models using animals. Therefore, resveratrol may be viewed as a potential anti-depressant agent, as well as may serve as a model of molecule to be modified aiming to ameliorate depressive symptoms in humans. In the present review, we describe and discuss the anti-depressant effects of resveratrol focusing on the mechanism of action of this phytoalexin in different experimental models.

ROS-modulated therapeutic approaches in cancer treatment.

Reactive oxygen species (ROS) are produced in cancer cells as a result of increased metabolic rate, dysfunction of mitochondria, elevated cell signaling, expression of oncogenes and increased peroxisome activities. Certain level of ROS is required by cancer cells, above or below which lead to cytotoxicity in cancer cells. This biochemical aspect can be exploited to develop novel therapeutic agents to preferentially and selectively target cancer cells. We searched various electronic databases including PubMed, Web of Science, and Google Scholar for peer-reviewed english-language articles. Selected articles ranging from research papers, clinical studies, and review articles on the ROS production in living systems, its role in cancer development and cancer treatment, and the role of microbiota in ROS-dependent cancer therapy were analyzed. This review highlights oxidative stress in tumors, underlying mechanisms of different relationships of ROS and cancer cells, different ROS-mediated therapeutic strategies and the emerging role of microbiota in cancer therapy. Cancer cells exhibit increased ROS stress and disturbed redox homeostasis which lead to ROS adaptations. ROS-dependent anticancer therapies including ROS scavenging anticancer therapy and ROS boosting anticancer therapy have shown promising results in vitro as well as in vivo. In addition, response to cancer therapy is modulated by the human microbiota which plays a critical role in systemic body functions.

P 109 - Effect of URB597 on phospholipid metabolism in the heart of hypertensive rats

Since hypertension is involved in redox and endocannabinoid systems disturbances, chronic administration of URB597, a FAAH inhibitor, that modulates the level of endocannabinoids, particularly anandamide, may regulate hypertensive metabolic consequences. Therefore, the aim of this study was to compare the effects of chronic administration of URB597 to SHRs and DOCA-salt rats on cardiac metabolism associated with redox system and lipid metabolism. It was shown that both primary and secondary hypertension is associated with enhanced cardiac inflammation and redox imbalance, resulting in increased lipid peroxidation products and endocannabinoids generation. URB597 administration decreasing FAAH activity enhanced endocannabinoids level, particularly in DOCA-salt heart. However in SHRs heart additional increase in MDA level was observed. Lipid mediators were involved in inflammatory response by PPARa expression in DOCA-salt rats and by PPARg expression in SHRs hearts. URB597 administration to normotensive rats also affected cardiac oxidative metabolism and endocannabinoids system, resulting in an enhanced level of MDA and endocannabinoids in Wistar rats. It can be concluded that lipid metabolism in heart rats with secondary hypertension and their control rats is more susceptible to chronic URB597 action and may lead to stronger cardiac disorders.

Interplay between mitochondrial metabolism and oxidative stress in ischemic stroke: An epigenetic connection.

The advent of epigenetics brought in a tectonic shift in the understanding of molecular basis of complex diseases like ischemic stroke (IS). Substantial scientific inquiry into the epigenetic basis of neurodegenerative diseases has bolstered the idea that altered carbon flux into central carbon metabolism and disturbed redox states govern the attendant transcriptional profiles through stochastic epigenetic changes. In view of an increasing understanding of the link between mitochondrial energy metabolism, oxidative stress and epigenetics in IS, the hitherto underappreciated 'neuroenergetics' is gaining sustained attention. Defined metabolic transitions during IS are necessarily a function of transiently altered abundance of critical metabolic substrates of Krebs cycle and other pathways viz., acetyl-CoA, citrate, 2-oxo-glutarate, succinate, fumarate, S-adenosyl methionine, β-hydroxybutyrate and cofactors (NAD+, FAD, ATP, vitamin C) in neuronal mitochondria. These changes impinge on the cellular transcriptome by regulating the activity of several chromatin modifying enzymes that bring about epigenomic transition through alteration in DNA methylation and histone post translational modifications. This triggers downstream signaling cascades that circumstantially evoke adaptive and cell death responses during IS. Indeed, they also prevail on the functionality of neuronal network, brain plasticity and neurogenesis during post stroke recovery. Understanding the epigenetic underpinnings of IS that explicitly alter the brain transcriptomes could open new vistas of therapeutic opportunity. In the current review, we present an update on various aspects linking mitochondrial energy metabolism, oxidative stress and epigenetic modifications in the pathological setting of IS.

New insights into redox homeostasis as a therapeutic target in B-cell malignancies.

Purpose of reviewThe goal of this review is to summarize recent advances in our understanding of the regulation of redox homeostasis and the subtype-specific role of antioxidant enzymes in B-cell-derived malignancies. Furthermore, it presents selected prooxidative therapeutic strategies against B-cell neoplasms.Recent findingsRecent reports have shown that the disturbed redox homeostasis in B-cell malignancies is regulated by cancer-specific signaling pathways and therefore varies between the individual subtypes. For instance, in a subtype of diffuse large B-cell lymphoma with increased oxidative phosphorylation, elevated reactive oxygen species are accompanied by higher levels of thioredoxin and glutathione and inhibition of either of these systems is selectively toxic to this subtype. In addition, growing number of small molecule inhibitors targeting antioxidant enzymes, such as auranofin, SK053, adenanthin, or decreasing glutathione level, such as imexon, buthionine sulfoximine, and L-cysteinase, trigger specific cytotoxic effects against B-cell malignancies. Lastly, attention is drawn to recent reports of effective treatment modalities involving prooxidative agents and interfering with redox homeostasis provided by stromal cells.SummaryRecent findings reveal important differences in redox homeostasis within the distinct subsets of B-cell-derived malignancies that can be therapeutically exploited to improve existing treatment and to overcome drug resistance.

High-sucrose diet induces diabetic-like phenotypes and oxidative stress in Drosophila melanogaster: Protective role of Syzygium cumini and Bauhinia forficata.

Diet is a key component for development and longevity of organisms. Here, the fruit fly was used to evaluate the detrimental effects caused by consumption of high-sucrose diets (HSD), namely phenotypic responses linked to insulin signaling and oxidative stress. The protective effects of extracts from medicinal plants Syzygium cumini and Bauhinia forficata were investigated. HSD intake (15% and 30%) delayed the time to pupation and reduced the number of white pupae. In adult flies, the intake of diets was associated with mortality and increased levels of glucose+trehalose, triacylglycerols and hydrogen peroxide. Indeed, 30% HSD induced body-weight loss, mitochondrial dysfunction and changes in acetylcholinesterase, δ-aminolevulinate dehydratase and antioxidant enzymes activity. Catalase, superoxide dismutase, keap1, HSP70, dILP-5 and Insulin receptor mRNA levels were over-expressed in flies emerged from 30% HSD. The extract treatments blunted the developmental alterations elicited by diets. Syzygium cumini extract was more efficient than B. forficata in reducing hyperglycaemia, redox disturbances and the changes in mRNA expression of insulin receptor.