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Hydrogen Sulfide and Carnosine: Modulation of Oxidative Stress and Inflammation in Kidney and Brain Axis: Emerging evidence indicates that the dysregulation of cellular redox homeostasis and chronic inflammatory processes are implicated in the pathogenesis of kidney and brain disorders. In this light, endogenous dipeptide carnosine (β-alanyl-L-histidine) and hydrogen sulfide (H2S) exert cytoprotective actions through the modulation of redox-dependent resilience pathways during oxidative stress and inflammation. Several recent studies have elucidated a functional crosstalk occurring between kidney and the brain. The present paper also explores the respective role of H2S and carnosine in the modulation of oxidative stress and inflammation in the kidney–brain axis.

Keywords: carnosine, COVID-19, angiotensin-converting enzyme 2 (ACE2), practitioner, molecular docking, modeling, carnosines, glucose, diabetic nephropathy cellular stress response,oxidative stress,vitagenes, creatine monohydrate, anaerobic capacity, muscular fatigue, ergogenic aids, carnosine, chronic disease, protocol, systematic review, randomized controlled trials, L-histidine, β-alanine, brain, cognition, treatment, psychiatry, neurology, nervous system, general diabetes, other metabolic, e.g. iron, porphyria, lipid disorders, imidazole dipeptides, biological activity, aging, children, serum carnosinase deficiency, aging, ROS, anti-senescence factors, carnosine, protein glycation, skin aging, facial contour, redefining, carnosine, Alteromonas, l-Carnosine, Liver cancer, ROS, Inhibition, Natural

Summary of Abstracts:

Hydrogen Sulfide and Carnosine: Modulation of Oxidative Stress and Inflammation in Kidney and Brain Axis Emerging evidence indicates that the dysregulation of cellular redox homeostasis and chronic inflammatory processes are implicated in the pathogenesis of kidney and brain disorders. In this light, endogenous dipeptide carnosine (β-alanyl-L-histidine) and hydrogen sulfide (H2S) exert cytoprotective actions through the modulation of redox-dependent resilience pathways during oxidative stress and inflammation. Several recent studies have elucidated a functional crosstalk occurring between kidney and the brain. The present paper also explores the respective role of H2S and carnosine in the modulation of oxidative stress and inflammation in the kidney–brain axis. It suggests that these activities are likely mediated, at least in part, via hormetic processes, involving Nrf2 (Nuclear factor-like 2), Hsp 70 (heat shock protein 70), SIRT-1 (Sirtuin-1), Trx (Thioredoxin), and the glutathione system. Metabolic interactions at the kidney and brain axis level operate in controlling and reducing oxidant-induced inflammatory damage and therefore, can be a promising potential therapeutic target to reduce the severity of renal and brain injuries in humans.

Carnosine to Combat Novel Coronavirus (nCoV): Molecular Docking and Modeling to Cocrystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. The current paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 cocrystallized with nCoV spike protein. Results: Carnosine emerged as the best-known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the protein–protein structure, carnosine bound with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. Conclusion: Carnosine has promising inhibitory interactions with host ACE2 and nCoV spike protein and hence could offer a potential mitigating effect against the current COVID-19 pandemic.

Space Flight Diet-Induced Deficiency and Response to Gravity-Free Resistive Exercise Immune system dysregulation is among the many adverse effects incurred by astronauts during space flights. Omega-3 fatty acids, β-alanine, and carnosine are among the many nutrients that contribute to immune system health. For space flight, crewmembers are prescribed a diet with a macronutrient composition of 55% carbohydrate, 30% fat, and 15% protein.

Carnosine Activates Cellular Stress Response in Podocytes and Reduces Glycative and Lipoperoxidative Stress Carnosine improves diabetic complications, including diabetic nephropathy, in in vivo models. To further understand the underlying mechanism of nephroprotection, we studied the effect of carnosine under glucose-induced stress on cellular stress response proteins in murine immortalized podocytes, essential for glomerular function. In podocytes, carnosine induced cellular stress tolerance and resilience pathways and was highly effective in reducing high-glucose-induced glycative and lipoperoxidative stress. Carnosine in moderate concentrations exerted a direct podocyte molecular protective action.

Comparative Cerebroprotective Potential of d- and l-Carnosine Following Ischemic Stroke in Mice Carnosine is an attractive therapeutic agent for acute ischemic stroke based on its robust preclinical cerebroprotective properties and wide therapeutic time window. However, large doses are needed for efficacy because carnosine is rapidly degraded in serum by carnosinases.

Carnosine as a Possible Drug for Zinc-Induced Neurotoxicity and Vascular Dementia Increasing evidence suggests that the metal homeostasis is involved in the pathogenesis of various neurodegenerative diseases including senile type of dementia such as Alzheimer’s disease, dementia with Lewy bodies, and vascular dementia.

Effects of Beta-Alanine on Muscle Carnosine and Exercise Performance: A Review of the Current Literature Muscle carnosine has been reported to serve as a physiological buffer, possess antioxidant properties, influence enzyme regulation, and affect sarcoplasmic reticulum calcium regulation.Beta-alanine (β-ALA) is a non-essential amino acid.

Effects of supplementation with carnosine and other histidine-containing dipeptides on chronic disease risk factors and outcomes: protocol for a systematic review of randomised controlled trials Ageing of populations globally, coupled with the obesity epidemic, has resulted in the rising prevalence of chronic diseases including diabetes, cardiovascular diseases, cancers and neurodegenerative disorders. Prevention of risk factors that contribute to these diseases is key in managing the global burden of chronic diseases. Recent studies suggest that carnosine, a dipeptide with anti-inflammatory, antioxidative and antiglycating properties may have a role in the prevention of chronic diseases.

The Potential of Carnosine in Brain-Related Disorders: A Comprehensive Review of Current Evidence Neurological, neurodegenerative, and psychiatric disorders represent a serious burden because of their increasing prevalence, risk of disability, and the lack of effective causal/disease-modifying treatments. There is a growing body of evidence indicating potentially favourable effects of carnosine, which is an over-the-counter food supplement, in peripheral tissues. Although most studies to date have focused on the role of carnosine in metabolic and cardiovascular disorders, the physiological presence of this di-peptide and its analogues in the brain together with their ability to cross the blood-brain barrier as well as evidence from in vitro, animal, and human studies suggest carnosine as a promising therapeutic target in brain disorders.

Does supplementation with carnosine improve cardiometabolic health and cognitive function in patients with pre-diabetes and type 2 diabetes? study protocol for a randomised, double-blind, placebo-controlled trial Carnosine, an over-the-counter food supplement, has a promising potential for the prevention and treatment of chronic diseases such as type 2 diabetes (T2DM), cardiovascular and neurodegenerative diseases through its anti-inflammatory, antiglycation, antioxidative and chelating effects.

Use of Carnosine for Oxidative Stress Reduction in Different Pathologies The main properties and biological effects of the antioxidant carnosine, the natural dipeptide β-alanyl-L-histidine, are considered. Data on the effective use of carnosine in different pathologies are presented. Special attention is paid to issues of use of carnosine in neurologic and mental diseases, in alcoholism as well as in physiological states accompanied by activation of free-radical processes and formation of oxidative stress. Results of experiments on rats showed that carnosine accelerates the metabolizing of cortisol and noradrenaline released into blood of animals under stress, showing the mediation effect of carnosine. Decrease in level of stress hormones in blood leads to a decrease in the severity of OS. In addition, carnosine is not addictive; there is no danger of overdose, and it does not accumulate in the organism during long-term administration because its surplus is cleaved by the enzyme carnosinase into amino acids that are easily eliminated from the organism. Further, the antiglycating [23, 24] and the anticrosslinking [25] properties of carnosine have been shown, which are, in essence, reflections of its antioxidant effects, the ability to block oxidation of biomolecules. In culture of human cells, it has been shown that addition of carnosine into the medium at concentrations close to physiological (20–50 mM) increases longevity of the cells. Carnosine is applied successfully in cardiological practice. Addition of L-carnosine in cardioplegic solution during stopped heart operations allows increasing the operation duration severalfold without signs of necrotic damage of tissues of the heart in the operative field. Use of carnosine in metabolic syndrome is promising, a state accompanied by oxidative stress and inflammation leading to development of diabetes and cardiovascular diseases. Carnosine was reported to have application also in schizophrenia. A randomized double-blind placebo-controlled study revealed that carnosine inclusion (2.0 g/days) as an addition to basic therapy in treatment of patients with schizophrenia improved their cognitive functions. The protective activity of carnosine against zinc-induced neurotoxicity and its molecular mechanisms such as cellular Zn influx and Zn-induced gene expression were investigated using hypothalamic neurons (GT1-7 cells). The findings showed that carnosine could be effective in the treatment of vascular dementia, as Zn-induced neurotoxicity plays a crucial role in the pathogenesis of this disorder, and carnosine inhibits Zn-induced neuronal death. Dietary supplementation with carnosine has been shown to suppress stress in animals and improve behaviour, cognition, and well-being in human subjects. It has been reported that in alcoholic patients oxidative stress contributes strongly to forming somatic complications [64], disturbance of immune status [65], and induction of apoptosis [66]. In alcoholism, formation of OS can be increased by ethanol, the concentration of which significantly exceeds the norm in patients, as well as the toxic metabolite of ethanol-acetaldehyde, whose level also increases in the organism during alcoholic intoxication. Acetaldehyde can bind with many biological molecules (proteins of plasma, hemoglobin, factors of coagulant system of blood, lipids, etc.), forming with them aldehydic adducts that are deposited and accumulated in different tissues (liver, brain, heart, muscles, and intestines) [67, 68]. We have carried out several investigations on the effects of carnosine in alcoholism. In experiments in vitro, it is shown that addition of carnosine in tests with blood of alcoholics leads to increase in resistance of erythrocytes to acid hemolysis, promoting preservation of normal morphology of these cells. These results show that intake of carnosine effectively reduces severity of OS in the organism of alcoholic patients. Undesirable side effects were not observed. The mechanism of positive effect of carnosine on severity of OS in alcoholic patients remains unclear. However, our data on the ability of carnosine to prevent oxidative damage of proteins and lipids of blood induced by ethanol or acetaldehyde in vitro [77] show the ability of this dipeptide to protect biomolecules against direct toxic effects of ethanol and its metabolites. The geroprotective effect of carnosine is mentioned in many publications where antioxidant, antiglycating, and anticrosslinking properties of carnosine are considered, because it was proven in the course of aging of the organism products of carbonylation, glycation, and cross-linking accumulate, which are well neutralized by carnosine. Developments on the use of carnosine in the cosmetic industry are promising, which is confirmed by the available data on the ability of carnosine to prevent structural changes of collagen in skin and to prevent loss of its elasticity [81].

Carnosine and Related Peptides: Therapeutic Potential in Age-Related Disorders Imidazole dipeptides (ID), such as carnosine (β-alanyl-L-histidine), are compounds widely distributed in excitable tissues of vertebrates. ID are also endowed of several biochemical properties in biological tissues, including antioxidant, bivalent metal ion chelating, proton buffering, and carbonyl scavenger activities. Furthermore, remarkable biological effects have been assigned to such compounds in age-related human disorders and in patients whose activity of serum carnosinase is deficient or undetectable. Nevertheless, the precise biological role of ID is still to be unraveled. In the present review we shall discuss some evidences from clinical and basic studies for the utilization of ID as a drug therapy for age-related human disorders.

Carnosine and Carnosine-Related Antioxidants: A Review First isolated and characterized in 1900 by Gulewitsch, carnosine (beta-alanyl-L-hystidine) is a dipeptide commonly present in mammalian tissue, and in particular in skeletal muscle cells; it is responsible for a variety of activities related to the detoxification of the body from free radical species and the by-products of membrane lipids peroxidation, but recent studies have shown that this small molecule also has membrane-protecting activity, proton buffering capacity, formation of complexes with transition metals, and regulation of macrophage function. It has been proposed that carnosine could act as a natural scavenger of dangerous reactive aldehydes from the degradative oxidative pathway of endogenous molecules such as sugars, polyunsaturated fatty acids (PUFAs) and proteins. In particular, it has been recently demonstrated that carnosine is a potent and selective scavenger of alpha,beta-unsaturated aldehydes, typical by-products of membrane lipids peroxidation and considered second messengers of the oxidative stress, and inhibits aldehyde-induced protein-protein and DNA-protein cross-linking in neurodegenerative disorders such as Alzheimer's disease, in cardiovascular ischemic damage, in inflammatory diseases. The research for new and more potent scavengers for HNE and other alpha,beta-unsaturated aldehydes has produced a consistent variety of carnosine analogs, and the present review will resume, through the scientific literature and the international patents, the most recent developments in this field.

Carnosine, diabetes and Alzheimer’s disease It has been proposed that carnosine can inhibit generation of many of the protein alterations accompanying aging, especially those associated with AD and diabetes and its complications. Carnosine is an antioxidant [9–11] and antiglycating agent that inhibits sugar- mediated protein crosslinking [12–14] and also chelates a number of metal ions (including copper and zinc) [15]. Carnosine reacts with methylglyoxal [16,17] and it has been described as a glyoxalase mimetic [18]. The dipeptide can react with a number of deleterious aldehydic products of lipid peroxidation (i.e., acetaldehyde, acro- lein, formaldehyde, malondialdehyde and hydroxynonenal) and thereby suppress their toxicity [19–22]. Carnosine can also react with glycated proteins and inhibit advanced gly- cation end product formation. [23] There is also some evidence from animal studies that carnosine can inhibit some of the deleterious effects of a high fructose diet [24]. In conclusion, it is suggested that carnosine, an almost non- toxic natural product, satisfies the criteria proposed by Maher and Schubert [1], that lead compounds should possess for eventual devel- opment of drugs to combat AD and T2D. There is evidence of carnosine’s efficacy from animal models. Unfortunately, as noted in general by Maher and Schubert [1], the fact that carnosine and many of its related structures are not patentable may be an impediment to their immediate exploration by the commercial sector. Perhaps charities and the public sector might be encouraged to explore carnosine’s therapeutic potential to help keep at bay these two conditions that threaten to overwhelm future medical provision.

Novel Facial Cream Containing Carnosine Inhibits Formation of Advanced Glycation End-Products in Human Skin Accumulation of advanced glycation end- products (AGEs) in skin has been associated with skin aging. Inhibition of glycation of proteins of extracellular matrix may help skin texture and appearance. The objective of the study was to demonstrate the antiglycation activity of topically ap- plied carnosine and novel facial cream (FC) containing carno- sine in human skin explants ex vivo. Conclusion: Topically applied carnosine protects against the glycation induced by MG. Novel FC-CARN signif- icantly reduced levels of AGEs in both epidermis and reticular dermis in human skin explants.

Carnosine as a Potential Anti-senescence Drug The polypotent effects of carnosine which are described throughout this journal and the wider litera- ture make it an ideal candidate as a so-called “geropro- tector”—an agent which may delay or prevent some conditions intrinsic with old age. Analysis of these data shows that carnosine acts as a true antiox- idant protector rather than as an anabolic drug; the weight of the animals treated with carnosine was not significantly different from that of the control animals.

Novel Facial Cream Containing Carnosine Inhibits Formation of Advanced Glycation End-Products in Human Skin Accumulation of advanced glycation end-products (AGEs) in skin has been associated with skin aging. Inhibition of glycation of proteins of extracellular matrix may help skin texture and appearance. The objective of the study was to demonstrate the antiglycation activity of topically applied carnosine and novel facial cream (FC) containing carnosine in human skin explants ex vivo. Methods: Glycation was induced in human skin explants by methylglyoxal (MG) in culture media.

Redefining face contour with a novel anti-aging cosmetic product: an open-label, prospective clinical study Skin aging is accelerated by multiple extrinsic factors: ultraviolet radiation, smoking and pollution increase oxidative activity, damaging cellular and extracellular components such as DNA, proteins, and lipids. With age, collagen and hyaluronic acid levels decline, resulting in loss of elasticity and moisture of the skin. Over time this damage leads to characteristic signs that make the skin look older: altered facial contour, sagging skin, wrinkles, and an uneven complexion. This study evaluated the anti-aging effects of a new facial cream formulated with carnosine, Alteromonas ferment extract, crosspolymer hyaluronic acid, and a tripeptide. After 56 days of use of the investigational product, a redefining effect was observed, with a significant decrease in sagging jawline (7%). Skin was significantly more hydrated (12%), firmer (29%), and more elastic (20%) (P<0.001 for all). On complexion assessment, skin texture (a measure of skin smoothness) and spots (brown and red skin lesions) also improved significantly (12% and 6% decrease, respectively). In the subjective self-evaluation, the majority of subjects reported that the skin was visibly tightened and more elastic, flexible, and moisturized (91%, 88%, 91%, and 90%, respectively). The product was well tolerated with no adverse events reported during the study. This new cosmetic product demonstrated anti-aging effects after 56 days of use, most notably a redefined facial contour and improved complexion. It is a safe and effective anti-aging product.

Carnosine and cancer: A perspective The application of carnosine in medicine has been discussed since several years, but many claims of therapeutic effects have not been substantiated by rigorous experimental examination. In the present perspective, a possible use of carnosine as an anti-neoplastic therapeutic, especially for the treatment of malignant brain tumours such as glioblastoma is discussed. Possible mechanisms by which carnosine may perform its anti-tumourigenic effects are outlined and its expected bioavailability and possible negative and positive side effects are considered. Finally, alternative strategies are examined such as treatment with other dipeptides or β-alanine.

Investigations on in vitro anti-carcinogenic potential of l-carnosine in liver cancer cells Carnosine significantly inhibited the growth of the SNU-423 cells (p < 0.05). The inhibitory effect of l-carnosine was confirmed by results from mitochondrial fragmentation assay. The relative fluorescent unit was increased in a dose-dependent manner by l-carnosine, with values of 79.43, 186.87 and 400.89 for 0.6, 0.8 and 1 mg/mL of l-carnosine, respectively (p < 0.05). These results demonstrate that l-carnosine exerts anti-carcinogenic effects in human liver cancer cells.

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