Sirtuin Activity Research Articles

Glycolytic inhibition: an effective strategy for developing calorie restriction mimetics.

Calorie restriction mimetics encompass a growing research field directed toward developing treatments that mimic the anti-aging effects of long-term calorie restriction without requiring a change in eating habits. A wide range of approaches have been identified that include (1) intestinal inhibitors of fat and carbohydrate metabolism; (2) inhibitors of intracellular glycolysis; (3) stimulators of the AMPK pathway; (4) sirtuin activators; (5) inhibitors of the mTOR pathway, and (6) polyamines. Several biotech companies have been formed to pursue several of these strategies. The objective of this review is to describe the approaches directed toward glycolytic inhibition. This upstream strategy is considered an effective means to invoke a wide range of anti-aging mechanisms induced by CR. Anti-cancer and anti-obesity effects are important considerations in early development efforts. Although many dozens of candidates could be discussed, the compounds selected to be reviewed are the following: 2-deoxyglucose, 3-bromopyruvate, chrysin, genistein, astragalin, resveratrol, glucosamine, mannoheptulose, and D-allulose. Some candidates have been investigated extensively with both positive and negative results, while others are only beginning to be studied.

Nicotinamide Riboside and Pterostilbene Cooperatively Delay Motor Neuron Failure in ALS SOD1G93A Mice.

Oxidative stress-induced damage is a major mechanism in the pathophysiology of amyotrophic lateral sclerosis (ALS). A recent human clinical trial showed that the combination of nicotinamide riboside (NR) and pterostilbene (PT), molecules with potential to interfere in that mechanism, was efficacious in ALS patients. We examined the effect of these molecules in SOD1G93A transgenic mice, a well-stablished model of ALS. Assessment of neuromotor activity and coordination was correlated with histopathology, and measurement of proinflammatory cytokines in the cerebrospinal fluid. Cell death, Nrf2- and redox-dependent enzymes and metabolites, and sirtuin activities were studied in isolated motor neurons. NR and PT increased survival and ameliorated ALS-associated loss of neuromotor functions in SOD1G93A transgenic mice. NR and PT also decreased the microgliosis and astrogliosis associated with ALS progression. Increased levels of proinflammatory cytokines were observed in the cerebrospinal fluid of mice and humans with ALS. NR and PT ameliorated TNFα-induced oxidative stress and motor neuron death in vitro. Our results support the involvement of oxidative stress, specific Nrf2-dependent antioxidant defenses, and sirtuins in the pathophysiology of ALS. NR and PT interfere with the mechanisms leading to the release of proapoptotic molecular signals by mitochondria, and also promote mitophagy.

Recent Trends on Telomerase Activators, Sirtuin Activators, and Senolytics as a Potential Anti-aging Agent

Recent Trends on Telomerase Activators, Sirtuin Activators, and Senolytics as a Potential Anti-aging Agent

Novel SIRT Inhibitor, MHY2256, Induces Cell Cycle Arrest, Apoptosis, and Autophagic Cell Death in HCT116 Human Colorectal Cancer Cells.

We examined the anticancer effects of a novel sirtuin inhibitor, MHY2256, on HCT116 human colorectal cancer cells to investigate its underlying molecular mechanisms. MHY2256 significantly suppressed the activity of sirtuin 1 and expression levels of sirtuin 1/2 and stimulated acetylation of forkhead box O1, which is a target protein of sirtuin 1. Treatment with MHY2256 inhibited the growth of the HCT116 (TP53 wild-type), HT-29 (TP53 mutant), and DLD-1 (TP53 mutant) human colorectal cancer cell lines. In addition, MHY2256 induced G0/G1 phase arrest of the cell cycle progression, which was accompanied by the reduction of cyclin D1 and cyclin E and the decrease of cyclin-dependent kinase 2, cyclin-dependent kinase 4, cyclin-dependent kinase 6, phosphorylated retinoblastoma protein, and E2F transcription factor 1. Apoptosis induction was shown by DNA fragmentation and increase in late apoptosis, which were detected using flow cytometric analysis. MHY2256 downregulated expression levels of procaspase-8, -9, and -3 and led to subsequent poly(ADP-ribose) polymerase cleavage. MHY2256-induced apoptosis was involved in the activation of caspase-8, -9, and -3 and was prevented by pretreatment with Z-VAD-FMK, a pan-caspase inhibitor. Furthermore, the autophagic effects of MHY2256 were observed as cytoplasmic vacuolation, green fluorescent protein-light-chain 3 punctate dots, accumulation of acidic vesicular organelles, and upregulated expression level of light-chain 3-II. Taken together, these results suggest that MHY2256 could be a potential novel sirtuin inhibitor for the chemoprevention or treatment of colorectal cancer or both.

Mitochondria Control Cortical Cell Fate after Mitosis.

During brain development, the daughter cells of neural stem cells have to make a choice - either to become new stem cells or to differentiate into neurons. In a recent issue of Science, Iwata etal. (2020) show that these fate decisions can be determined after mitosis by mitochondrial remodeling.

The Antioxidant Activities of Betula etnensis Rafin. Ethanolic Extract Exert Protective and Anti-diabetic Effects on Streptozotocin-Induced Diabetes in Rats.

Pathophysiological mechanisms correlating diabetes mellitus with associated complications are still not completely clear, even though oxidative stress seems to play a pivotal role. Literature data suggest that cell damages induced by hyperglycemia, although multifactorial, have a common pathway in oxidative/nitrosative stress. The present study evaluated the effects of Betula etnensis Raf. bark extract, a plant belonging to the Betulaceae family endemic to Sicily, on oxidative stress and in preventing and/or retarding diabetes-associated complications in streptozotocin diabetic rats treated with the extract at dose of 0.5 g/kg body weight per day for 28 consecutive days. The extract administration significant decreased food and water intake, fasting blood glucose, weight loss and polyuria, compared with untreated diabetic animals. Furthermore, oxidative stress markers particularly, lipid hydroperoxides (LOOH) and nitrite/nitrate levels, non-proteic thiol groups (RSH), γ-glutamyl-cysteine-synthetase (γ-GCS) activities and expression, heme oxygenase-1 (HO-1), endothelial and inducible nitric oxide synthases (i-NOS e-NOS) expression, significantly changed by streptozocin treatment, were markedly restored both in plasma and tissues together with nuclear sirtuins activity (Sirt1). Results suggested that B. etnensis bark alcoholic extract is able to counteract oxidative stress and to ameliorate some general parameters related to diabetes.

Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia

Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT myeloid neoplasia (MN), clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.

Interpretable SMILES-based QSAR Model of Inhibitory Activity of Sirtuins 1 and 2.

Sirtuin 1 (Sirt1) and sirtuin 2 (Sirt2) are NAD+-dependent histone deacetylases which play important functional roles in the removal of the acetyl group of acetyllysine substrates. Considering the dysregulation of Sirt1 and Sirt2 as etiological causes of diseases, Sirt1 and Sirt2 are lucrative target proteins for treatment, thus there has been great interest in the development of Sirt1 and Sirt2 inhibitors. This study compiled the bioactivity data of Sirt1 and Sirt2 for the construction of quantitative structure-activity relationship (QSAR) models in accordance with the OECD principles. Simplified molecular-input line-entry system (SMILES)-based molecular descriptors were used to characterize the molecular features of inhibitors while the Monte Carlo method of the CORAL software was employed for multivariate analysis. The dataset was subjected to 3 random splits in which each split separated the data into 4 subsets consisting of training, invisible training, calibration, and external sets. Statistical indices for the evaluation of QSAR models suggested the good statistical quality of models of Sirt1 and Sirt2 inhibitors. Furthermore, mechanistic interpretation of molecular substructures that are responsible for modulating the bioactivity (i.e., promoters of increase or decrease of bioactivity) was extracted via the analysis of correlation weights. It exhibited molecular features involved in Sirt1 and Sirt2 inhibitors. It is anticipated that QSAR models presented herein can be useful as guidelines in the rational design of potential Sirt1 and Sirt2 inhibitors for the treatment of Sirtuin-related diseases.

Development of activity-based probes for the protein deacylase Sirt1

Sirtuins are NAD+-dependent protein deacylases that remove acyl modifications from acyl-lysine residues, resulting in essential cellular signaling. Recognized for their role in lifespan extension, humans encode seven sirtuin isoforms (Sirt1-7), and loss of sirtuin deacylase activity is implicated in many aging-related diseases. Despite being intriguing therapeutic targets, cellular studies of sirtuins are hampered by the lack of chemical probes to measure sirtuin activity independent of sirtuin protein levels. Here, we use a modular, peptide-based approach to develop activity-based probes (ABPs) that directly measure Sirt1 activity in vitro and in cell lysates. ABPs were synthesized containing four elements: (1) thioacetyl-lysine for mechanism-based affinity towards only active sirtuins, (2) either histone H3 lysine-14 (H3K14) or p53 sequences for Sirt1 specificity, (3) a diazirine for covalent labeling upon UV irradiation, and (4) an alkyne for bioorthogonal conjugation to a fluorophore for gel-based detection of active Sirt1. Compared to the H3K14 ABP, the p53 ABP showed increased sensitivity and selective labeling of active Sirt1. Acyl-lysine peptide competition, pharmacological inhibition, and inhibitory post-translational modification of Sirt1 resulted in the loss of p53 ABP labeling both in vitro and in HEK293T cell lysates, consistent with the ABP measuring decreased Sirt1 activity. Furthermore, the p53 ABP measured subcellular Sirt1 activity in MCF7 breast cancer cells. The development of a Sirt1-selective ABP that detects Sirt1 activity with an order of magnitude increased sensitivity compared to previous approaches demonstrates the utility of a modular, peptide-based approach for selective-targeting of the sirtuin protein family and provides a framework for further development of sirtuin-selective chemical probes.

Abstract 6224: Novel antitumor semi-synthetic heliomycin derivatives direct targeting tNOX-NAD+-SIRT1 axis to activate apoptosis/autophagy, as determined by the cellular thermal shift assay (CETSA)

Abstract The antibiotic heliomycin (resistomycin) has been studied since the 1950s, however, its low solubility in aqueous media has restricted its systemic bioavailability and therapeutic potential. We recently synthesized a series of novel aminomethyl derivatives that are readily soluble in aqueous solution. In this study, we examined their antiproliferative properties and underlying molecular mechanisms in p53 wild-type and p53-mutated cancer cells. We continuously monitored the cellular impact of these compounds using the xCELLigence System, a label-free, real-time cell monitoring platform that measures electrical impedance, displaying results as cell index values. The results from the system showed that heliomycin and its derivatives exhibited different biological effects on tumor cells. To further our understanding of the interactions between the novel derivatives and cellular targets, we utilized the cellular thermal shift assay (CETSA). Our CETSA results revealed that some of the derivatives that were directly engaged with tNOX enhanced its thermal stability, which in turn resulted in a marked attenuation of the intracellular NAD+/NADH ratio. This attenuated ratio signifies a decrease in the NAD+-dependent activity of Sirtuin 1 (SIRT1) deacetylase and triggers apoptosis/autophagy, with varying amounts of decrease depending on the cellular environment. We have successfully transformed heliomycin into derivatives that are much more soluble, allowing the more efficient modulating of biological activities - a significant step closer towards finding a novel anti-cancer candidate. Citation Format: Pin Ju Chueh, Atikul Islam, Xiao Qi Chen, Shi Han Chiu, Alexander S. Tikhomirov, Andrey E. Shchekotikhin. Novel antitumor semi-synthetic heliomycin derivatives direct targeting tNOX-NAD+-SIRT1 axis to activate apoptosis/autophagy, as determined by the cellular thermal shift assay (CETSA) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6224.

Mechanism of Action of Ketogenic Diet Treatment: Impact of Decanoic Acid and Beta—Hydroxybutyrate on Sirtuins and Energy Metabolism in Hippocampal Murine Neurons

The ketogenic diet (KD), a high-lipid and low-carbohydrate diet, has been used in the treatment of epilepsy, neurodegenerative disorders, inborn errors of metabolism and cancer; however, the exact mechanism/s of its therapeutic effect is not completely known. We hypothesized that sirtuins (SIRT)—a group of seven NAD-dependent enzymes and important regulators of energy metabolism may be altered under KD treatment. HT22 hippocampal murine neurons were incubated with two important KD metabolites–beta-hydroxybutyrate (BHB) (the predominant ketone body) and decanoic acid (C10), both accumulating under KD. Enzyme activity, protein, and gene expressions of SIRT 1-4, enzyme capacities of the mitochondrial respiratory chain complexes (MRC), citrate synthase (CS) and gene expression of monocarboxylate transporters were measured in control (untreated) and KD-treated cells. Incubation with both–BHB and C10 resulted in significant elevation of SIRT1 enzyme activity and an overall upregulation of the MRC. C10 incubation showed prominent increases in maximal activities of complexes I + III and complex IV of the MRC and ratios of their activities to that of CS, pointing towards a more efficient functioning of the mitochondria in C10-treated cells.

Coronavirus (Covid-19) sepsis: revisiting mitochondrial dysfunction in pathogenesis, aging, inflammation, and mortality.

BackgroundDecline in mitochondrial function occurs with aging and may increase mortality. We discuss mitochondrial contribution to Covid-19 sepsis, specifically the complex interaction of innate immune function, viral replication, hyper-inflammatory state, and HIF-α/Sirtuin pathways.MethodsArticles from PubMed/Medline searches were reviewed using the combination of terms “SARS-CoV-2, Covid-19, sepsis, mitochondria, aging, and immunometabolism”.ResultsEvidence indicates that mitochondria in senescent cells may be dysfunctional and unable to keep up with hypermetabolic demands associated with Covid-19 sepsis. Mitochondrial proteins may serve as damage-associated molecular pattern (DAMP) activating innate immunity. Disruption in normal oxidative phosphorylation pathways contributes to elevated ROS which activates sepsis cascade through HIF-α/Sirtuin pathway. Viral–mitochondrial interaction may be necessary for replication and increased viral load. Hypoxia and hyper-inflammatory state contribute to increased mortality associated with Covid-19 sepsis.ConclusionsAging is associated with worse outcomes in sepsis. Modulating Sirtuin activity is emerging as therapeutic agent in sepsis. HIF-α, levels of mitochondrial DNA, and other mitochondrial DAMP molecules may also serve as useful biomarker and need to be investigated. These mechanisms should be explored specifically for Covid-19-related sepsis. Understanding newly discovered regulatory mechanisms may lead to the development of novel diagnostic and therapeutic targets.

Modulation of Energy Sensing by Leucine Synergy with Natural Sirtuin Activators: Effects on Health Span.

Sirt1 and 5' adenosine monophosphate-activated protein kinase (AMPK) are energy-sensing systems that work cooperatively and regulate mitochondrial biogenesis and fuel metabolism, and mediate, in part, the salutary effects of caloric restriction on lifespan and healthspan. We have shown that leucine activates Sirt1 and enables synergy with sirtuin co-activators. Resveratrol is a widely recognized activator of Sirt1; however, poor bioavailability and rapid metabolism limit effective clinical translation of promising animal data. However, we found that combining low resveratrol doses with leucine increased skeletal muscle and adipocyte Sirt1 activity, mitochondrial biogenesis and fatty acid oxidation; these effects result in increased lifespan and marked reductions in insulin resistance, inflammatory markers, body weight, and visceral adiposity in preclinical models. To translate these data to humans, we assessed the effects of resveratrol (50 mg)/leucine (1.11 g) on glucose dynamics in a 4-week placebo-controlled trial of 36 prediabetic subjects. Leucine-resveratrol reduced insulin resistance (homeostatic model assessment for insulin resistance) 33% with corresponding reductions in glucose and insulin area under the curve in oral glucose tolerance tests. We extended these concepts in preclinical studies using both direct Sirt1 activators and Sirt1 pathway activators. Low-dose (10 nM) NAD+ precursors (nicotinic acid, nicotinamide mononucleotide, and nicotinamide riboside) synergized with leucine to increase Sirt1 activity in adipocytes, hepatocytes, and muscle cells (30-100%, P < .01) and lifespan in Caenorhabditis elegans (25%, P = .025) and to significantly regress atherosclerotic lesion size and macrophage infiltration in a mouse model of atherosclerosis. Thus, synergistic activation of Sirt1 using leucine and a co-activator exerts pleiotropic effects impacting cardiometabolic endpoints.

Dynamic regulation of histone H3 lysine (K) acetylation and deacetylation during prolonged oxygen deprivation in a champion anaerobe.

Trachemys scripta elegans can survive up to three months of absolute anoxia at 3°C and recover with minimal cellular damage. Red-eared sliders employ various physiological and biochemical adaptations to survive anoxia with metabolic rate depression (MRD) being the most prominent adaptation. MRD is mediated by epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms aimed at shutting down cellular processes that are not needed for anoxia survival, while reprioritizing ATP towards cell processes that are vital for anaerobiosis. Histone acetylation/deacetylation are epigenetic modifications that maintain a proper balance between permissive chromatin and restricted chromatin, yet very little is known about protein regulation and enzymatic activity of thewriters and erasers of acetylation during natural anoxia tolerance. As such, this study explored the interplay between transcriptional activators, histone acetyltransferases (HATs), and transcriptional repressors, sirtuins (SIRTs), along with three prominent acetyl-lysine (K) moieties of histone H3 in the liver of red-eared sliders. Western immunoblotting was used to measure acetylation levels of H3-K14, H3-K18, and H3-K56, as well as protein levels of histone H3-total, HATs, and nuclear SIRTs in the liver in response to 5h and 20h anoxia. Global and nuclear enzymatic activity of HATs and enzymatic activity of nuclear SIRTs were also measured. Overall, a strong suppression of HATs-mediated H3 acetylation and SIRT-mediated deacetylation was evident in the liver of red-eared sliders that could play an important role in ATP conservation as part of the overall reduction in metabolic rate.

Sirtuin activation targets IDH-mutant tumors.

Isocitrate dehydrogenase (IDH)-mutant tumors exhibit an altered metabolic state and are critically dependent upon nicotinamide adenine dinucleotide (NAD+) for cellular survival. NAD+ steady-state levels can be influenced by both biosynthetic and consumptive processes. Here, we investigated activation of sirtuin (SIRT) enzymes, which consume NAD+ as a coenzyme, as a potential mechanism to reduce cellular NAD+ levels in these tumors. The effect of inhibition or activation of sirtuin activity, using (i) small molecules, (ii) clustered regularly interspaced short palindromic repeat/CRISPR associated protein 9 gene editing, and (iii) inducible overexpression, was investigated in IDH-mutant tumor lines, including patient-derived IDH-mutant glioma lines. We found that Sirt1 activation led to marked augmentation of NAD+ depletion and accentuation of cytotoxicity when combined with inhibition of nicotinamide phosphoribosyltransferase (NAMPT), consistent with the enzymatic activity of SIRT1 as a primary cellular NAD+ consumer in IDH-mutant cells. Activation of Sirt1 through either genetic overexpression or pharmacologic Sirt1-activating compounds (STACs), an existing class of well-tolerated drugs, led to inhibition of IDH1-mutant tumor cell growth. Activation of Sirt1 can selectively target IDH-mutant tumors. These findings indicate that relatively nontoxic STACs, administered either alone or in combination with NAMPT inhibition, could alter the growth trajectory of IDH-mutant gliomas while minimizing toxicity associated with cytotoxic chemotherapeutic regimens.

SIRT1 Activation by Polydatin Alleviates Oxidative Damage and Elevates Mitochondrial Biogenesis in Experimental Diabetic Neuropathy.

Mitochondrial dysfunction has been implicated as a one of the major factors linked to the development of painful diabetic neuropathy (DN). Several studies have demonstrated that sirtuin (SIRT1) activation recuperates nerve function by activating mitochondrial biogenesis. Polydatin, a resveratrol glycoside, has been explored to improve mitochondrial function via SIRT1 activation. However, the neuroprotective effects of polydatin in DN remain elusive. In this study, polydatin (25 and 50mg/kg, oral) was administered for last 2weeks of 8-week study to diabetic Sprague-Dawley rats weighing 250-300g (post 6-weeks of streptozotocin 55mg/kg, intraperitoneal). Treatment with polydatin significantly attenuated mechanical and thermal hyperalgesia in diabetic rats. Treated diabetic rats also showed improvement in motor/sensory nerve conduction velocities and nerve blood flow. For in vitro studies, Neuro2a cells were exposed to high-glucose (30mM) condition to simulate short-term hyperglycemia. Polydatin was evaluated for its role in SIRT1 and Nrf2 activation at a dose of 5, 10, and 20µM concentrations. Polydatin exposure normalized the mitochondrial superoxides, membrane potentials and improved neurite outgrowth in high-glucose-exposed Neuro2a cells. Increased SIRT1 activation by polydatin resulted in peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) directed mitochondrial biogenesis. SIRT1 activation also facilitated Nrf2-directed antioxidant signaling. Study results inferred that decline in mitochondrial biogenesis and oxidative function in diabetic rats and high-glucose-exposed Neuro2a cells, could be counteracted by polydatin administration, postulated via enhancing SIRT1 and Nrf2 axis.

Sustained Activation of AMPK Enhances Differentiation of Human iPSC-Derived Cardiomyocytes via Sirtuin Activation

SummaryRecent studies suggest that metabolic regulation may improve differentiation of cardiomyocytes derived from induced pluripotent stem cells (iPSCs). AMP-activated protein kinase (AMPK) is a master regulator of metabolic activities. We investigated whether AMPK participates in iPSC-derived cardiomyocyte differentiation. We observed that AMPK phosphorylation at Thr172 increased at day 9 but then decreased after day 11 of differentiation to cardiomyocytes. Inhibition of AMPK with compound C significantly reduced mRNA and protein expression of cardiac troponins TNNT2 and TNNI3. Moreover, sustained AMPK activation using AICAR from days 9 to 14 of differentiation increased mRNA and protein expression of both TNNT2 and TNNI3. AICAR decreased acetylation of histone 3 at Lys9 and 56 and histone 4 at Lys16 (known target sites for nuclear-localized sirtuins [SIRT1, SIRT6]), suggesting that AMPK activation enhances sirtuin activity. Sustained AMPK activation during days 9–14 of differentiation induces sirtuin-mediated histone deacetylation and may enhance cardiomyocyte differentiation from iPSCs.

Inhibition of HDAC6 Attenuates Diabetes-Induced Retinal Redox Imbalance and Microangiopathy.

We investigated the contributing role of the histone deacetylase 6 (HDAC6) to the early stages of diabetic retinopathy (DR). Furthermore, we examined the mechanism of action of HDAC6 in human retinal endothelial cells (HuREC) exposed to glucidic stress. Streptozotocin-induced diabetic rats (STZ-rats), a rat model of type 1 diabetes, were used as model of DR. HDAC6 expression and activity were increased in human diabetic postmortem donors and STZ-rat retinas and were augmented in HuREC exposed to glucidic stress (25 mM glucose). Administration of the HDAC6 specific inhibitor Tubastatin A (TS) (10 mg/kg) prevented retinal microvascular hyperpermeability and up-regulation of inflammatory markers. Furthermore, in STZ-rats, TS decreased the levels of senescence markers and rescued the expression and activity of the histone deacetylase sirtuin 1 (SIRT1), while downregulating the levels of free radicals and of the redox stress markers 4-hydroxynonenal (4-HNE) and nitrotyrosine (NT). The antioxidant effects of TS, consequent to HDAC6 inhibition, were associated with preservation of Nrf2-dependent gene expression and up-regulation of thioredoxin-1 activity. In vitro data, obtained from HuREC, exposed to glucidic stress, largely replicated the in vivo results further confirming the antioxidant effects of HDAC6 inhibition by TS in the diabetic rat retina. In summary, our data implicate HDAC6 activation in mediating hyperglycemia-induced retinal oxidative/nitrative stress leading to retinal microangiopathy and, potentially, DR.

Radiomodulators as Agents of Biological Protection against Oxidative Stress under the Influence of Ionizing Radiation

The potential mechanisms of radioprotective effect of radiomodulators as agents of “biological” protection against oxidative stress in conditions of acute and chronic irradiation at high- and low-dose-rate ionizing radiation are considered. Radiomodulators, as natural antioxidants, prevent lipid peroxidation of cell membranes and reduce radiation toxemia. The radioprotective and radiomitigative properties of natural antioxidants are limited in terms of a dose reduction factor of 1.15–1.2. The dose–effect interrelation of antioxidants has a dome-shaped character; they can be prooxidants under certain conditions. With this mechanism they are also able to reduce acute toxicity of medicines and poisons. Long, low-intensive radiation at more than 100 mSv/year causes the development of oxidative stress with activation of the mechanisms of antioxidant defense upon its further exhaustion with a decrease in the ascorbic acid content in tissues and endogenous reduced thiols. In this case, the use of natural antioxidants allows a reduction in manifestations of oxidative stress via substrate therapy, thereby compensating for vitamin deficiency under the conditions of their intense consumption. At the same time, the delivery of exogenous purine nucleoside favors the synthesis of DNA and RNA in the course of their postradiation repair. In the condition of oxidative stress, the basis of adaptation shifts in the antioxidant system eventually consists of activation of the nuclear factor Nrf2 and NAD-dependent histone deacetylases sirtuins. Via hormesis, plant polyphenols, coumarins, purine nucleosides, and melatonin can modulate the Nrf2 nuclear factor and sirtuin activity and reduce the remote consequences of chronic radiation exposure, such as a reduction of the human lifespan, by a delay of the development of atherosclerosis, cardiovascular, and neurodegenerative diseases, metabolic syndrome, diabetes mellitus, and the risk of carcinogenesis.

Can Functionally Mature Islet β-Cells be Derived from Pluripotent Stem Cells? A Step Towards Ready-To-Use β-Cells in Type 1 Diabetes.

Pluripotent Stem Cells [PSCs] are emerging as an excellent cellular source for the treatment of many degenerative diseases such as diabetes, ischemic heart failure, Alzheimer's disease, etc. PSCderived pancreatic islet β-cells appear to be a promising therapy for type 1 diabetic patients with impaired β-cell function. Several protocols have been developed to derive β-cells from PSCs. However, these protocols produce β-like cells that show low glucose stimulated insulin secretion (GSIS) function and mirror GSIS profile of functionally immature neonatal β-cells. Several studies have documented a positive correlation between the sirtuins (a family of ageing-related proteins) and the GSIS function of adult β-cells. We are of the view that the GSIS function of PSC-derived β-like cells could be enhanced by improving the function of sirtuins in them. Studying the sirtuin expression and activation pattern during the β-cell development and inclusion of the sirtuin activators and inhibitor cocktail (specific to a developmental stage) in the present protocols may help us derive functionally mature, ready-to-use β- cells in-vitro making them suitable for transplantation in type 1 diabetes.