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Autodock Vina version 1.1.2 (RRID:SCR_011958) for docking. The grid box's dimensions were fixed at XYZ=30Å × 30Å × 30Å which was found to be the best size for the default exhaustiveness (=8), and the ligand binding site was positioned in the middle of the grid box. The details of spatial dimensions (along XYZ axis) and the grid box’s size which were specified in a configuration file. Using AutoDock vina version 1.1.2's (RRID:SCR_011958) command line interface, docking was accomplished. The log file created listed the binding modes along with their corresponding binding energies. With the help of BIOVIA Discovery studio visualizer 2021, the binding modes were created as a single file in ‘pdbqt’ format, and all non-bonded interactions were recorded.

Structural stability of the docked complexes was monitored using MD simulation with Gromacs 2020.5 (RRID:SCR_014565). The protein topology was created using Gromos96 force field and the PRODRG server was utilized to create the topology of the ligand. The docked complexes were solvated using ‘Simple Point Charge’ (SPC) water model in a cuboidal box with adequate size to accommodate the complete complex at the center.The modeled systems were neutralized using required number of counter ions (Na+ / Cl-). The undesirable contacts and steric conflicts were then removed from the neutralized systems using steepest descent followed by conjugate gradient methods for 50,000 steps each. The NVT ensemble used to maintain constant number of atoms, volume, and temperature, further NPT ensemble was used to maintain constant pressure. NVT and NPTensembles were used to maintain temperature. The temperature and pressure were set constant at 300K and 1 bar respectively, during the equilibration of 1ns. Further, followed by 1ns of equilibration, unrestrained MD simulation was performed for a period of 100ns in solvent. The Particle Mesh Ewald (PME) method was used to handle coulomb electrostatic interactions, while the LINear Constraint Solver (LINCS)s algorithmwas used to limit H-bonds. Using a cut-off value of 14 Å, the non-bonded contacts were trimmed. The trajectories generated were analyzed using some of the inbuild gromacs tools like ‘gmx rms,’ ‘gmx rmsf,’ ‘gmx hbond,’ ‘gmx gyrate,’ ‘gmx sasa,’ etc. and other additional packages for specific analysis wherever required. Conformational changes at the secondary structural level were monitored by using Dictionary of Protein Secondary Structure (DSSP) software (RRID:SCR_002725).

Understanding the basis of biological diversity remains a central problem in evolutionary biology. Using microbial systems, adaptive diversification has been studied in (a) spatially heterogeneous environments, (b) temporally segregated resources, and (c) resource specialization in a homogeneous environment. However, it is not well understood how adaptive diversification can take place in a homogeneous environment containing a single resource. Starting from an isogenic population of yeast Saccharomyces cerevisiae, we report rapid adaptive diversification, when propagated in an environment containing melibiose as the carbon source. The diversification is driven due to a public good enzyme α-galactosidase, which hydrolyzes melibiose into glucose and galactose. The diversification is driven by mutations at a single locus, in the GAL3 gene in the S. cerevisiae GAL/MEL regulon. We show that metabolic co-operation involving public resources could be an important mode of generating biological diversity. Our study demonstrates sympatric diversification of yeast starting from an isogenic population and provides detailed mechanistic insights into the factors and conditions responsible for generating and maintaining the population diversity.

Age-related diseases are associated with increased morbidity in the past few decades and the cost associated with the treatment of these age-related diseases exerts a substantial impact on social and health care expenditure. Anti-aging strategies aim to mitigate, delay and reverse aging-associated diseases, thereby improving quality of life and reducing the burden of age-related pathologies. The natural dietary antioxidant supplementation offers substantial pharmacological and therapeutic effects against various disease conditions. Astaxanthin is one such natural carotenoid with superior antioxidant activity than other carotenoids, as well as well as vitamins C and E, and additionally, it is known to exhibit a plethora of pharmacological effects. The present review summarizes the protective molecular mechanisms of actions of astaxanthin on age-related diseases of multiple organs such as Neurodegenerative diseases [Alzheimer's disease (AD), Parkinson's disease (PD), Stroke, Multiple Sclerosis (MS), Amyotrophic lateral sclerosis (ALS), and Status Epilepticus (SE)], Bone Related Diseases [Osteoarthritis (OA) and Osteoporosis], Cancers [Colon cancer, Prostate cancer, Breast cancer, and Lung Cancer], Cardiovascular disorders [Hypertension, Atherosclerosis and Myocardial infarction (MI)], Diabetes associated complications [Diabetic nephropathy (DN), Diabetic neuropathy, and Diabetic retinopathy (DR)], Eye disorders [Age related macular degeneration (AMD), Dry eye disease (DED), Cataract and Uveitis], Gastric Disorders [Gastritis, Colitis, and Functional dyspepsia], Kidney Disorders [Nephrolithiasis, Renal fibrosis, Renal Ischemia reperfusion (RIR), Acute kidney injury (AKI), and hyperuricemia], Liver Diseases [Nonalcoholic fatty liver disease (NAFLD), Alcoholic Liver Disease (AFLD), Liver fibrosis, and Hepatic Ischemia-Reperfusion (IR) Injury], Pulmonary Disorders [Pulmonary Fibrosis, Acute Lung injury (ALI), and Chronic obstructive pulmonary disease (COPD)], Muscle disorders (skeletal muscle atrophy), Skin diseases [Atopic dermatitis (ATD), Skin Photoaging, and Wound healing]. We have also briefly discussed astaxanthin's protective effects on reproductive health.

Impairment of antioxidant enzymes activities has been well reported in several human diseases. Effective anti-ageing strategies involving antioxidant supplementation and/or caloric restriction (CR) are receiving a great attention to mitigate free radical-mediated oxidative damage in several disease conditions to improve active longevity. Therefore, in this work, we have evaluated the protective effect of quercetin under non restriction (NR) and CR conditions on the sensitivity of Saccharomyces cerevisiae mutant strains (sod1∆, sod2∆, cta1∆, ctt1∆, tsa1∆ and glr1∆) deficient in antioxidant defence systems (superoxide dismutase, catalase, thioredoxin peroxidase and glutathione reductase) against H2 O2 -induced oxidative stress. Our results demonstrate that quercetin in combination with CR has strongly reduced the H2 O2 -mediated stress in the yeast mutant cells compared to NR conditions. Furthermore, we show that quercetin in combination with CR enhanced the percentage viability of yeast cells during chronological ageing. Our research findings suggest that antioxidant supplementation in combination with CR might have potent beneficial effects than individual therapies against free radical-mediated oxidative stress. SIGNIFICANCE AND IMPACT OF THE STUDY: Oxidative stress results from an imbalance between free radicals and antioxidant defense systems in our body. Supplementation with exogenous antioxidants is necessary to neutralize the free radical mediated damage. Polyphenols are a group of naturally occurring plant compounds with strong free radical-scavenging activity and exhibits potent anti-aging property by mitigating oxidative stress. On the other hand, caloric restriction (CR) has been reported to be a popular leading anti-aging approach to ameliorate age-associate macromolecular damages in various chronic human diseases. Evaluation of protective effects of antioxidant supplementation in combination with CR against free radical mediated oxidative stress is pivotal for the development of novel anti-aging strategies to improve active longevity.

Adaptive diversification of an isogenic population, and its molecular basis has been a subject of a number of studies in the last few years. Microbial populations offer a relatively convenient model system to study this question. In this context, an isogenic population of bacteria (E. coli,B. subtilis, andPseudomonas) has been shown to lead to genetic diversification in the population, when propagated for a number of generations. This diversification is known to occur when the individuals in the population have access to two or more resources/environments, which are separated either temporally or spatially. Here, we report adaptive diversification in an isogenic population of yeast,S. cerevisiae, when propagated in an environment containing melibiose as the carbon source. The diversification is driven due to a public good, enzyme α-galactosidase, leading to hydrolysis of melibiose into two distinct resources, glucose and galactose. The diversification is driven by a mutations at a single locus, in theGAL3gene in the GAL/MEL regulon in the yeast.

Breast cancer is one of the leading causes of death in humans worldwide and is the most common type of cancer in women. Several factors are responsible for the development of breast cancer in women. Disturbances in various molecular pathways and the concomitant altered expression of several molecular markers have been well reported. Despite the potent beneficial effects of various therapeutic strategies such as surgery, chemotherapy, and radiotherapy, the associated detrimental side effects of these strategies has spurred the scientific community to search for alternatives. Phytotherapy is one such potential therapeutic strategy involving the usage of traditional medicinal plants to target various molecular markers altered during cancer and thereby to protect from cancer without inducing side effects. In this chapter we explain the possible beneficial effects of a few traditional Indian medical plants against breast cancer.

Adaptive trajectories of populations have been focus of number of studies. However, adaptive trajectories have not been studied in the context of reverse evolution. By reverse evolution, we mean a scenario where selection is reversed. In this work, we use evolution (and reversal from) of multicellularity inS. cerevisiaeas a model to answer this question. When selected for fast-settling variants, multicellularity evolves rapidly in the organism. On reversing selection, unicellularity evolves from the multicellular clusters. However, the dynamic trajectories of the two processes are different. In this context, evolution is not reversed dynamically at a phenotypic level. The phenotypic reversal is not driven by reversal of the original mutations during the forward evolution. Overall, our results show that the dynamics of molecular and phenotypic trajectories of evolution are distinct, and reversal of selection leads to unique trajectories of phenotypic reversal.

Background and Aim Aging is associated with oxidative stress and altered cholinergic and mitochondrial function. Crocin is a carotenoid antioxidant that quenches free radicals and protects cells and tissues from oxidation in biological systems. The aim of the present study is to investigate the effect of oral supplementation of Crocin on age-associated oxidative stress, cholinergic, and mitochondrial function in rat cerebral cortex. Main methods The middle-aged (15 months old) rats were segregated into three groups (n = 6): Control (ad-libitum fed +0.9% saline as vehicle), Cro 50 (ad-libitum fed + crocin 50 mg/kg/day), Cro 150 (ad-libitum fed + crocin 150 mg/kg/day). The experiment was scheduled for 45 days. The serum and brain parameters were estimated after euthanasia. Key findings Crocin supplementation of Cro 50 and Cro 150 displayed a relative decline in body weight gain during the experimental period and significantly reduced age-associated serum triglyceride level over control. In rat cerebral cortex, age-associated macromolecular damage, decline in endogenous antioxidants and an increase in intracellular calcium concentration were significantly reversed due to oral supplementation of Crocin. Cro 150 significantly improved acetylcholine content as a consequence of acetylcholinesterase inhibition. Further, remarkable mitochondrial function was observed in Cro 150 over the control group as determined by citrate synthase and cytochrome C oxidase enzyme activities. Significance Oral supplementation of Crocin significantly reversed age-associated oxidative stress and neuroinflammatory markers. Meanwhile, Cro 150 remarkably improved cholinergic and mitochondrial function over the control group and facilitated further delay in the aging process due to enhanced cognitive effect.

Background & Objective: Aging is characterized by gradual accumulation of macromolecular damage leading to progressive loss of physiological function and increased susceptibility to diverse diseases. Effective anti-aging strategies involving caloric restriction or antioxidant supplementation are receiving growing attention to attenuate macromolecular damage in age associated pathology. Method: In the present study, we for the first time investigated the effect of quercetin, caloric restriction and combined treatment (caloric restriction with quercetin) on oxidative stress parameters, acetylcholinesterase and ATPases enzyme activities in the cerebral cortex of aged male Wistar rats. 21 months aged rats were divided into four groups (n=6-8) such as group 1-fed ad libitum (AL); group 2-quercetin supplementation of 50 mg/kg b.w/day for 45 days fed ad libitum (QUER); group 3: caloric restricted (CR) (fed 40% reduced AL for 45 days); group 4-fed 40% CR and 50 mg/kg b.w/day QUER for 45 days (CR + QUER). Group 5-three month age old rats served as young control (YOUNG). Results: Our results demonstrate that combined treatment of caloric restriction and quercetin significantly improved the age associated decline in the activities of endogenous antioxidant enzymes [such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)] and glutathione (GSH) content and attenuated elevated levels of protein carbonyl content (PCC), lipid peroxidation, lipofuscin, reactive oxygen species (ROS), and nitric oxide (NO). Furthermore, it is also observed that combined treatment ameliorated age associated alterations in acetylcholine esterase (AChE) and adenosine triphosphatases (ATPases) such as Na+/K+-ATPase and Ca+2-ATPase (but not Mg+2- ATPase) enzyme activities. Conclusion: Finally, we conclude that combined treatment of caloric restriction and quercetin (but not either treatment alone) in late life is an effective anti-aging therapy to counteract the age related accumulation of oxidative macromolecular damage.

The decline in metabolic homeostasis over time leads to various physiological disorders. Disruption of this homeostasis results in hyperglycemia (elevated levels of glucose) and accumulation of free radicals, which subsequently favor pro-inflammatory cytokines induction. The extent of metabolic imbalance depends on various lifestyle activities such as diet, physical activity, stress and sleep disturbance. Chronic increase in blood glucose level results in individual organ related pathologies. Carotenoids (tetraterpenoids) are a class of natural pigments made of isoprene subunits with or without oxygen moiety with potent antioxidant and anti-inflammatory properties. Further, on regular dietary supplementation, they lower the risk of metabolic syndrome and thereby maintain homeostasis. In this review, the mechanisms by which carotenoids restore metabolic homeostasis under hyperglycemia associated pathological conditions were discussed.

We investigated the protective effect of a natural polyphenol, magnolol, on Saccharomyces cerevisiae cells under oxidative stress, and during aging. Our results showed the sensitivity of S. cerevisiae antioxidant gene deficient mutants (sod1∆, sod2∆, cta1∆, ctt1∆, gtt2∆ and tsa1∆) against hydrogen peroxide (H2O2) and menadione stress was rescued by magnolol as demonstrated in spot and colony forming unit counts. Yeast cells pretreated with magnolol showed decreased intracellular oxidation, lipid peroxidation and an increased level of reduced glutathione. Further, SOD1, CTA1 and GTT2 gene expression was examined by reverse transcription-polymerase chain reaction, and was found that magnolol significantly attenuated the upregulation of SOD1 and CTA1 genes under oxidative stress. Finally, longevity of the wild type and sod1 mutant cells were extended by magnolol, and also enhance stress resistance against oxidant stress during chronological aging.

Cellular homeostasis maintained by several cellular processes such as autophagy, apoptosis, inflammation, oxidative stress, aging, and neurodegeneration, contribute to cell growth and development. Cancer cells undergo aberrant changes from a normal cell that show abnormal behaviour such as reduced apoptosis and autophagy, increased oxidative stress and inflammation. Various pharmacological and genetic inhibitors have been reported as drug candidates to control cancer cells, but the use of natural molecules as anti-cancer agents are limited. There is an emerging need for the development of alternative natural therapeutic agents that maintain cellular homeostasis without affecting cell viability and physiology. This review highlights the multifunctional roles of Trehalose, a natural disaccharide that can target various cellular processes in the cancer. Trehalose possessing an antioxidant activity also has effect on cancer, which is explained through targeting cell progression, angiogenesis and metastasis pathways at molecular level targeting EGFR, PI3K, Akt, VEGF and MMP 9 proteins inside the cell.

Oxidative stress-mediated neurodegeneration is responsible for 12% mortality around the globe. Alzheimer's Disease (AD) and Parkinson's Disease (PD) are the most prevalent neurodegenerative diseases, associated with modulation of acetylcholine levels and amyloid beta accumulation & dopamine level and alpha-synuclein oligomerization, respectively. Therefore, a better understanding of their pathological mechanisms reveals novel target proteins and encourages exploitation of suitable lead molecules. In the present study, targets for AD and PD were sought not only to suppress the pathological condition but to restore the normal physiological function. In this view, activation of retinoic acid receptor alpha can be formulated as a novel target to improve choline acetyltransferase transcription that works together with acetylcholine esterase and beta-secretase 1 inhibition against AD. Likewise, inhibition of Polo-like kinase 2 fails to phosphorylate alpha-synuclein and motivates efficient autophagic clearance. Therefore, PLK2 inhibition, together with L-DOPA supplementation and monoamine oxidase B inhibition widens the therapeutic options for PD. As oxidative stress is the major factor for neurodegeneration, AMPK activation stabilizes energy metabolism and Sirtuin 1 (histone deacetylase 1) activation enhances AMPK, PGC1a and Nrf gene expressions. Phytochemical extracts from saffron stigma were broadly appreciated on memory enhancement and cognition. However, the exact mechanism was not established. Therefore, this inspires the exploitation of phytochemicals in saffron stigma extract using in-silico tools, to anticipate lead molecules that interact with various neurodegeneration associated protein targets.

Aging brain is characterized by a change in biomolecular composition leading to a diverse range of neurological diseases. Anti-aging research is of current interest, to lessen the burden of age-related macromolecular damage through antioxidant supplementation and caloric restriction. However, data concerning the effect of these anti-aging regimens on age-related biomolecular changes in rat brain is still lacking. In the present study, for the first time, we employed Fourier transform infrared (FTIR) spectroscopy, to investigate the effect of quercetin, caloric restriction (CR) and combination of both on alterations in the composition of lipids and proteins of aged rat brain cerebral cortex. Aged male Wistar rats (21 months old) were divided into four groups: Control (CONT), fed pellet diet; Quercetin (QUER), fed quercetin (50 mg/kg/day); CR (caloric restriction) (fed 40% reduced CONT), and CRQ (40% CR and 50 mg/kg/day QUER). Three-month-old rats served as young control (YOUNG). Our short-term study (45 days) shows decreased band area of unsaturated lipids, decreased area ratios of olefinic/lipid and CH2 antisymmetric stretching (2925 cm−1)/lipids in CONT group compared to young rats, suggesting age-associated lipid peroxidation in aged rats. A slight decrease in the frequency of CH2 antisymmetric mode of lipids (whereas no change in CH2 symmetric mode), but a decrease in bandwidths of both CH2 antisymmetric and symmetric modes of lipids was observed for CONT group compared to YOUNG. Further, a significant decrease in the peak area of infrared bands of proteins and an increase in the peak area of the C O band of lipids was observed in the CONT group. Our data also show that lower levels of α-helical structures and higher levels of random coils, representing altered protein secondary structure composition in the CONT group compared to YOUNG group. Reduction in neuronal cell density and shrinked nucleus was also observed in aged rats. Increase in the accumulation of oxidative mediated damage to macromolecules and diminished antioxidant levels, could be the possible reason for the age-related alterations in the composition of lipids and proteins. However, the combination of quercetin and CR, but not either treatment alone, significantly prevented the age associated alterations in the lipid and protein profiles in the rat cerebral cortex. Further, our results help to understand the mechanism of action of antioxidants under non-restriction and CR conditions, this might help in the development of novel anti-aging treatments to ameliorate oxidative stress in age-related disorders.

The Saccharomyces cerevisiae TEL1 gene is an ortholog of the human ATM (Ataxia telangiectasia mutated) gene. S. cerevisiae tel1 mutant (tel1∆) lacking Tel1p, share some of the cellular defects with ATM mutation that includes prevention of oxidative damage repair, premature aging and apoptosis. In the present study, we investigated the protective effects of quercetin on the sensitivity of yeast S. cerevisiae tel1∆ cells exposed to oxidative, apoptotic and DNA damaging stress and viability of tel1∆ cells during chronological aging. Quercetin improved the stress resistance of tel1∆ cells when challenged with oxidants such as hydrogen peroxide (H(2)O(2)), menadine bisulphite (MBS) and tertiary butyl hydroperoxide (t-BHP) by scavenging reactive oxygen species (ROS). Quercetin protected the tel1∆ cells from acetic acid-induced apoptotic cell death and sensitivity against hydroxyurea. We found that quercetin attenuated ROS accumulation and apoptotic markers in tel1∆ cells and therefore an increase in cell viability during chronological aging. Our results from the S. cerevisiae model, suggest that use of quercetin as a food supplement might alleviate oxidative stress mediated DNA damage, apoptosis and age related damaging effects in AT patients and also improve health beneficial effects in humans.

The yeast Saccharomyces cerevisiae PEP4 gene encodes vacuolar endopeptidase proteinase A (Pep4p), which is a homolog of the human CTSD gene that encodes cathepsin D. Mutation of CTSD gene in human resulted in a number of neurodegenerative diseases. In this study, we have shown that yeast pep4 mutant cells are highly sensitive to oxidative and apoptotic stress induced by hydrogen peroxide and acetic acid, respectively. pep4∆ cells also showed accumulation of reactive oxygen species (ROS), apoptotic markers, and reduced chronological lifespan. In contrast, quercetin pretreatment protected the pep4 mutant from oxidative and apoptotic stress-induced sensitivity by scavenging ROS and reducing apoptotic markers. The percentage viability of quercetin-treated pep4∆ cells was more pronounced and increased stress resistance against oxidant, apoptotic, and heat stress during chronological aging. From our experimental results, we concluded that quercetin protects yeast pep4 mutant cells from oxidative stress and apoptosis, thereby increasing viability during chronological aging.