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Context: The anti-diabetic medicine metformin has been reported as an anti-ageing drug candidate as it mimics the benefits of caloric restriction and reduces ageing-related oxidative stress in various experimental organisms., Objective: We investigated the possible anti-oxidative role of metformin against rotenone-induced oxidative stress and cytotoxicity in erythrocytes of Wistar rats. Rotenone is a well-known inducer of oxidative stress which leads to a cellular redox imbalance., Materials and Methods: We have co-exposed the experimental rats with rotenone (2.5 mg/kg, i.p.) and metformin (300 mg/kg, orally) for 30 days to investigate the protective effects of metformin on various rotenone-induced impaired oxidative stress biomarkers in rat erythrocytes., Results: We found that a significant alleviation in the levels of rotenone-induced pro-oxidant and anti-oxidant markers following exposure of metformin., Discussion and Conclusions: Our findings suggest that metformin supplementation shows a protective role in against rotenone-induced redox imbalance and cytotoxicity in rat erythrocytes.

Aging is associated with decreased cellular cysteine uptake, which acts as a precursor for glutathione biosynthesis. Whey protein, a liquid aspect of milk, is an effective cysteine delivery system. The study was undertaken to evaluate the potential role of whey protein concentrate (WPC) on the redox biomarkers during aging. Male Wistar rats were divided into following four groups: young control (4 months old); young treated with WPC (300 mg/kg b.w./day orally); old (24 months old) control; old treated with WPC for 28 days. After treatment, changes in body weight, lipid profile and levels of redox biomarkers were determined. A marked decrease in prooxidants such as reactive oxygen species, lipid peroxidation and protein carbonyl and significant (p ≤ 0.05) increase in antioxidants such as reduced glutathione and GST levels were observed after WPC supplementation in old age rats. We also found marked decrease in the level of sialic acid and AGEs after WPC supplementation. In conclusion, WPC provides protection against age-dependent redox imbalance which might be attributed to its antioxidant activity., (© 2020. Akadémiai Kiadó Zrt.)

Brain aging is an intricate and natural phenomenon exclusively characterized by oxidative stress, accumulation of oxidatively damaged macromolecules, and alterations in structure and function of neurons that further increase the risk factor for most of the neurodegenerative diseases. In addition, age-dependent defective autophagy has also been implicated to favor the pathogenesis and prevalence of the neurological diseases. Therefore, the development of strategies that delay aging and the concomitant neurological disorders remain elusive. Thus, the present study was undertaken to investigate the effect of rapamycin-induced activation of autophagy on aging-related oxidative stress, cell death, neuroinflammation, and neurodegeneration in rat brain. Our data demonstrated the significant age-related oxidative stress, apoptotic cell death, elevated inflammatory response, and reduced level of markers associated with rejuvenation and neural integrity, including the activities of ion channel transporters (Na + /K + -ATPase and Ca 2+ -ATPase) and acetylcholinesterase in the brain of old aged rats. Furthermore, rapamycin (0.5 mg/kg b.w. for 28 days) induced activation of autophagy provided significant protection to aging rat brain by reducing the aging-induced oxidative stress, apoptotic cell death, and markers of neurodegeneration. Thus, our data confirmed that autophagy plays a pivotal role in delaying brain aging plausibly by maintaining the cellular homeostasis, and structural and functional integrity of cells in the brain.

N-acetyl-l-cysteine (NAC) is a precursor of cysteine, which is known to increase the level of glutathione (GSH) in the brain. Several neurodegenerative changes linked to oxidative stress take place in the aging brain. This study aimed to assess the neuroprotective effect of NAC supplementation on age-dependent neurodegeneration in the rat brain. Young (4 months) and old (24 months) Wistar rats (n = 6 rats/group) were supplemented with NAC (100 mg/kg b.w. orally) for 14 days. Enzymatic and nonenzymatic antioxidants such as superoxide dismutase and catalase, and GSH and total thiol respectively, prooxidants such as protein carbonyl, advanced oxidation protein products, reactive oxygen species, and malondialdehyde were assessed in the brain homogenates. Furthermore, nitric oxide level, acetylcholinesterase activity, and Na + /K + -ATPase activity were measured and gene expression studies were also performed. The results indicated that NAC augmented the level of enzymatic and nonenzymatic antioxidants with a significant reduction in prooxidant levels in old rats. NAC supplementation also downregulated the expression of inflammatory markers (TNF-α, IL-1β, IL-6) and upregulated the expression of marker genes associated with aging (sirtuin-1) and neurodegeneration (neuron-specific enolase, neuroglobin, synapsin-I, myelin basic protein 2) in old rats. The present findings support a neuroprotective role of NAC which has therapeutic implication in controlling age-related neurological disorders.

Whey protein concentrate (WPC) is a rich source of sulfur-containing amino acids and is consumed as a functional food, incorporating a wide range of nutritional attributes. The purpose of this study is to evaluate the neuroprotective effect of WPC on rat brain during aging. Young (4 months) and old (24 months) male Wistar rats were supplemented with WPC (300 mg/kg body weight) for 28 days. Biomarkers of oxidative stress and antioxidant capacity in terms of ferric reducing antioxidant potential (FRAP), lipid hydroperoxide (LHP), total thiol (T-SH), protein carbonyl (PC), reactive oxygen species (ROS), nitric oxide (NO), and acetylcholinesterase (AChE) activity were measured in brain of control and experimental (WPC supplemented) groups. In addition, gene expression and histopathological studies were also performed. The results indicate that WPC augmented the level of FRAP, T-SH, and AChE in old rats as compared with the old control. Furthermore, WPC-treated groups exhibited significant reduction in LHP, PC, ROS, and NO levels in aged rats. WPC supplementation also downregulated the expression of inflammatory markers (tumor necrosis factor alpha, interleukin (IL)-1β, IL-6), and upregulated the expression of marker genes associated with autophagy (Atg3, Beclin-1, LC3B) and neurodegeneration (neuron specific enolase, Synapsin-I, MBP-2). The findings suggested WPC to be a potential functional nutritional food supplement that prevents the progression of age-related oxidative damage in Wistar rats.

Erythrocyte membrane is a suitable model to study various metabolic and physiological functions as it undergoes variety of biochemical changes during aging. An age-dependent modulatory effect of rapamycin on erythrocyte membrane functions is completely unknown. Therefore, the present study was undertaken to investigate the effect of rapamycin on age-dependent impaired activities of transporters/exchangers, altered levels of redox biomarkers, viz. protein carbonyl (PC), lipid hydroperoxides (LHs), total thiol (-SH), sialic acid (SA) and intracellular calcium ion [Ca 2+ ]i, and osmotic fragility of erythrocyte membrane. A significant reduction in membrane-bound activities of Na + /K + -ATPase (NKA) and Ca 2+ -ATPase (PMCA), and levels of -SH and SA was observed along with a simultaneous induction in Na + /H + exchanger (NHE) activity and levels of [Ca 2+ ]i, PC, LH and osmotic fragility in old-aged rats. Rapamycin was found to be a promising age-delaying drug that significantly reversed the aging-induced impaired activities of membrane-bound ATPases and altered levels of redox biomarkers.

Erythrocytes are particularly vulnerable toward age-dependent oxidative stress-mediated damage. Caloric restriction mimetics (CRMs) may provide a novel strategy for the maintenance of redox balance as well as effective treatment of age-associated diseases. Herein, we have investigated the beneficial effect of cotreatment with CRM-candidate drugs, rapamycin (an immunosuppressant drug and inhibitor of mammalian target of rapamycin) and metformin (an antidiabetic biguanide and activator of adenosine monophosphate kinase), against aging-induced oxidative stress in erythrocytes and plasma of aging rats. Male Wistar rats of age 4 (young) and 24 months (old) were coexposed to rapamycin (0.5 mg/kg body weight [b.w.]) and metformin (300 mg/kg b.w.), and data were compared with the response of rats receiving an independent exposure to these chemicals at similar doses. The exposure of individual candidate drugs significantly reversed the age-dependent alterations in the endpoints associated with oxidative stress such as reactive oxygen species, ferric reducing ability of plasma, malondialdehyde, reduced glutathione, plasma membrane redox system, plasma protein carbonyl, and acetyl cholinesterase in erythrocytes and plasma of aging rats. However, the cotreatment with rapamycin and metformin showed a significant augmented effect compared with individual drug interventions on reversal of these age-dependent biomarkers of oxidative stress, suggesting a synergistic response. Thus, the findings open up further possibilities for the design of new combinatorial therapies to prevent oxidative stress- and age-associated health problems.

Autophagy is an evolutionary conserved catabolic process that ensures continuous removal of damaged cell organelles and long-lived protein aggregates to maintain cellular homeostasis. Although autophagy has been implicated in amyloid-β (Aβ) production and deposition, its role in pathogenesis of Alzheimer's disease remains elusive. Thus, the present study was undertaken to assess the cytoprotective and neuroprotective potential of autophagy on Aβ-induced oxidative stress, apoptosis and neurotoxicity in human neuroblastoma SH-SY5Y cells. The treatment of Aβ1-42 impaired the cell growth and redox balance, and induced apoptosis and neurotoxicity in SH-SY5Y cells. Next, the treatment of rapamycin (RAP) significantly elevated the expression of autophagy markers such as microtubule-associated protein-1 light chain-3 (LC3), sequestosome-1/p62, Beclin-1, and unc-51-like kinase-1 (ULK1) in SH-SY5Y cells. RAP-induced activation of autophagy notably alleviated the Aβ1-42-induced impairment of redox balance by decreasing the levels of pro-oxidants such as reactive oxygen species, lipid peroxidation and Ca 2+ influx, and concurrently increasing the levels of antioxidant enzymes such as superoxide dismutase and catalase. The RAP-induced autophagy also ameliorated Aβ1-42-induced loss of mitochondrial membrane potential and apoptosis. Additionally, the activated autophagy provided significant neuroprotection against Aβ1-42-induced neurotoxicity by elevating the expression of neuronal markers such as synapsin-I, PSD95, NCAM, and CREB. However, 3-methyladenine treatment significantly exacerbated the neurotoxic effects of Aβ1-42. Taken together, our study demonstrated that the activation of autophagy provided possible neuroprotection against Aβ-induced cytotoxicity, oxidative stress, apoptosis, and neurotoxicity in SH-SY5Y neuronal cells.

An imbalanced cellular redox system promotes the production of reactive oxygen species (ROS) that may lead to oxidative stress-mediated cell death. Erythrocytes are the best-studied model of antioxidant defense mechanism. The present study was undertaken to investigate the effect of the immunosuppressant drug rapamycin, an inducer of autophagy, on redox balance of erythrocytes and blood plasma of oxidatively challenged rats. Male Wistar rats were oxidatively challenged with HgCl 2 (5 mg/kg body mass (b.m.)). A significant (p < 0.05) induction in ROS production, plasma membrane redox system (PMRS), intracellular Ca 2+ influx, lipid peroxidation (LPO), osmotic fragility, plasma protein carbonyl (PCO) content, and plasma advanced oxidation protein products (AOPP) and simultaneously significant reduction in glutathione (GSH) level and ferric reducing ability of plasma (FRAP) were observed in rats exposed to HgCl 2 . Furthermore, rapamycin (0.5 mg/kg b.m.) provided significant protection against HgCl 2 -induced alterations in rat erythrocytes and plasma by reducing ROS production, PMRS activity, intracellular Ca 2+ influx, LPO, osmotic fragility, PCO content, and AOPP and also restored the level of antioxidant GSH and FRAP. Our observations provide evidence that rapamycin improves redox status and attenuates oxidative stress in oxidatively challenged rats. Our data also demonstrate that rapamycin is a comparatively safe immunosuppressant drug.

Increasing evidence support bimodal action of nitric oxide (NO) both as a promoter and as an impeder of oxygen free radicals in neutrophils (PMNs), however impact of high oxidative stress on NO generation is less explored. In the present study, we comprehensively investigated the effect of high oxidative stress on inducible nitric oxide synthase (iNOS) expression and NO generation in human PMNs. Our findings suggest that PMA or diamide induced oxidative stress in PMNs from healthy volunteers, and high endogenous ROS in PMNs of chronic myeloid leukemia (CML) patients attenuate basal as well as LPS/cytokines induced NO generation and iNOS expression in human PMNs. Mechanistically, we found that under high oxidative stress condition, S-glutathionylation of NFκB (p50 and p65 subunits) severely limits iNOS expression due to its reduced binding to iNOS promoter, which was reversed in presence of DTT. Furthermore, by using pharmacological inhibitors, scavengers and molecular approaches, we identified that enhanced ROS generation via NOX2 and mitochondria, reduced Grx1/2 expression and GSH level associated with NFκB S-glutathionylation in PMNs from CML patients. Altogether data obtained suggest that oxidative status act as an important regulator of NO generation/iNOS expression, and under enhanced oxidative stress condition, NOX2-mtROS-NFκB S-glutathionylation is a feed forward loop, which attenuate NO generation and iNOS expression in human PMNs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Fisetin as a caloric restriction mimetic (CRM) exerts numerous beneficial effects on different aging model systems. The effect of fisetin on erythrocyte membrane functions against induced aging is not very clear. The potential role of fisetin in the modulation of erythrocytes membrane-bound transporters during natural and induced aging in rats was assessed. Male Wistar rats were used for natural and D-galactose (D-gal) induced aging model. After supplementation with fisetin, the activities of different membrane transporters and biomarkers of oxidative stress were evaluated. Fisetin modulated membrane transporters such as calcium-ATPase, sodium potassium-ATPase and sodium hydrogen exchanger during senescence-induced as well as in natural aging. Fisetin also protected oxidative modifications in rat aging. Fisetin supplementation improves the ionic homeostasis, a factor that is involved in the aetiology of several age-associated diseases, in naturally old as well as D-gal induced aged rats. [ABSTRACT FROM AUTHOR]

Aim In the present study, attempts have been made to evaluate the potential role of fisetin, a caloric restriction mimetic (CRM), for neuroprotection in D-galactose (D-gal) induced accelerated and natural aging models of rat. Main methods Fisetin was supplemented (15 mg/kg b.w., orally) to young, D-gal induced aged (D-gal 500 mg/kg b.w subcutaneously) and naturally aged rats for 6 weeks. Standard protocols were employed to measure pro-oxidants, antioxidants and mitochondrial membrane potential in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuronal, aging as well as inflammatory marker genes. We have also evaluated apoptotic cell death and synaptosomal membrane-bound ion transporter activities in brain tissues. Key findings Our data demonstrated that fisetin significantly decreased the level of pro-oxidants and increased the level of antioxidants. Furthermore, fisetin also ameliorated mitochondrial membrane depolarization, apoptotic cell death and impairments in the activities of synaptosomal membrane-bound ion transporters in aging rat brain. RT-PCR data revealed that fisetin up-regulated the expression of autophagy genes (Atg-3 and Beclin-1), sirtuin-1 and neuronal markers (NSE and Ngb), and down-regulated the expression of inflammatory (IL-1β and TNF-α) and Sirt-2 genes respectively in aging brain. Significance The present study suggests that fisetin supplementation may provide neuroprotection against aging-induced oxidative stress, apoptotic cell death, neuro-inflammation, and neurodegeneration in rat brain. [ABSTRACT FROM AUTHOR]

Introduction: The role of increased oxidative stress and alterations to the nitric oxide (NO) pathway have been implicated in major depressive disorder (MDD). The two pathways interact closely with each other but have not been studied simultaneously in MDD. This study aimed to assess and compare the levels of oxidative and nitrosative stress in the neutrophils (PMNs) of drug-naive MDD patients and their first-degree relatives. Methods: 29 drug-naive MDD patients and 27 healthy first-degree relatives and healthy controls aged 18–45 years were included in this study. An assessment of the levels of reactive oxygen species (ROS), nitrites, neuronal NO synthase (nNOS), and myeloperoxidase in PMNs, and cortisol in serum was carried out. Results: Compared to healthy controls, the generation of free radicals, myeloperoxidase activity, and nNOS mRNA expression in PMNs, and cortisol level in serum were significantly higher in drug-naive depression patients. Indeed, increased levels of myeloperoxidase and serum cortisol were also noted in first-degree relatives. The total nitrite content in the PMNs and plasma however was significantly lower in both patients and first-degree relatives. Interestingly, a positive correlation was established in the ROS levels in the PMNs, plasma and neutrophil nitrite, and the serum cortisol level between MDD patients and their first-degree relatives. Conclusion: The results of this study contribute towards a better understanding of the familial association of depressive disorder, and demonstrate for the first time that neutrophil ROS/RNS, plasma nitrite, and serum cortisol levels are positively correlated between MDD patients and their first-degree relatives. However, further studies in larger, more diverse samples are needed to extend these pathways as potential biomarkers to identify persons at high risk for psychopathology at an early stage. [ABSTRACT FROM AUTHOR]

Metformin, a biguanide drug commonly used to treat type 2 diabetes, has been noted to function as a caloric restriction mimetic. Its antidiabetic effect notwithstanding, metformin is currently being considered an antiaging drug candidate, although the molecular mechanisms have not yet been unequivocally established. This study aims to examine whether short-term metformin treatment can provide protective effects against oxidative stress in young and old-age rats. Young (age 4 months) and old (age 24 months) male Wistar rats were treated with metformin (300 mg/kg b.w.) for 4 weeks. At the end of the treatment period, an array of biomarkers of oxidative stress were evaluated, including plasma antioxidant capacity measured in terms of ferric reducing ability of plasma (FRAP), reactive oxygen species (ROS), lipid peroxidation (MDA), reduced glutathione (GSH), total plasma thiol (SH), plasma membrane redox system (PMRS), protein carbonyl (PCO), advanced oxidation protein products (AOPPs), and advanced glycation end products (AGEs) in control and experimental groups. Metformin treatment resulted in an increase in FRAP, GSH, SH, and PMRS activities in both age groups compared to respective controls. On the other hand, treated groups exhibited significant reductions in ROS, MDA, PCO, AOPP, and AGE level. Save for FRAP and protein carbonyl, the effect of metformin on all other parameters was more pronounced in old-aged rats. Metformin caused a significant increase in the PMRS activity in young rats, however, the effect was less pronounced in old rats. These findings provide evidence with respect to restoration of antioxidant status in aged rats after short-term metformin treatment. The findings substantiate the putative antiaging role of metformin. [ABSTRACT FROM AUTHOR]