Role of L-Arginine in Nitric Oxide Synthesis and Health in Humans.
TL;DR: As a functional amino acid (AA), Larginine (Arg) serves not only as a building block of protein but also as an essential substrate for the synthesis of nitric oxide (NO), creatine, polyamines, homoarginines, and agmatine in mammals as discussed by the authors.
Abstract: As a functional amino acid (AA), L-arginine (Arg) serves not only as a building block of protein but also as an essential substrate for the synthesis of nitric oxide (NO), creatine, polyamines, homoarginine, and agmatine in mammals (including humans). NO (a major vasodilator) increases blood flow to tissues. Arg and its metabolites play important roles in metabolism and physiology. Arg is required to maintain the urea cycle in the active state to detoxify ammonia. This AA also activates cellular mechanistic target of rapamycin (MTOR) and focal adhesion kinase cell signaling pathways in mammals, thereby stimulating protein synthesis, inhibiting autophagy and proteolysis, enhancing cell migration and wound healing, promoting spermatogenesis and sperm quality, improving conceptus survival and growth, and augmenting the production of milk proteins. Although Arg is formed de novo from glutamine/glutamate and proline in humans, these synthetic pathways do not provide sufficient Arg in infants or adults. Thus, humans and other animals do have dietary needs of Arg for optimal growth, development, lactation, and fertility. Much evidence shows that oral administration of Arg within the physiological range can confer health benefits to both men and women by increasing NO synthesis and thus blood flow in tissues (e.g., skeletal muscle and the corpora cavernosa of the penis). NO is a vasodilator, a neurotransmitter, a regulator of nutrient metabolism, and a killer of bacteria, fungi, parasites, and viruses [including coronaviruses, such as SARS-CoV and SARS-CoV-2 (the virus causing COVID-19). Thus, Arg supplementation can enhance immunity, anti-infectious, and anti-oxidative responses, fertility, wound healing, ammonia detoxification, nutrient digestion and absorption, lean tissue mass, and brown adipose tissue development; ameliorate metabolic syndromes (including dyslipidemia, obesity, diabetes, and hypertension); and treat individuals with erectile dysfunction, sickle cell disease, muscular dystrophy, and pre-eclampsia.
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TL;DR: Adhesion-enhanced self-healing multifunctional PC/GO/Met hydrogels with stimuli-responsive metformin release ability and easy removability have shown a promoting effect on the healing of chronic athletic diabetic wounds and provide a local-specific drug dual-response release strategy for the treatment of type II diabetic feet.
Abstract: In view of the lack of a specific drug-sustained release system that is responsive to chronic wounds of the type II diabetic foot, and the demands for frequent movement at the foot wound, pH/glucose dual-responsive metformin-released adhesion-enhanced self-healing easy-removable antibacterial antioxidant conductive hemostasis multifunctional phenylboronic acid and benzaldehyde bifunctional polyethylene glycol-co-poly(glycerol sebacic acid)/dihydrocaffeic acid and l-arginine cografted chitosan (PEGS-PBA-BA/CS-DA-LAG, denoted as PC) hydrogel dressings were constructed based on the double dynamic bond of the Schiff-base and phenylboronate ester. It was further demonstrated that the PC hydrogel promotes wound healing by reducing inflammation and enhancing angiogenesis in a rat type II diabetic foot model. In addition, the addition of metformin (Met) and graphene oxide (GO), as well as their synergy, were confirmed to better promote wound repair in vivo. In summary, adhesion-enhanced self-healing multifunctional PC/GO/Met hydrogels with stimuli-responsive metformin release ability and easy removability have shown a promoting effect on the healing of chronic athletic diabetic wounds and provide a local-specific drug dual-response release strategy for the treatment of type II diabetic feet.
235 citations
TL;DR: In this paper, an updated systematic overview of the current evidence on the functional contribution of L-Arginine in COVID-19, describing its actions on endothelial cells and the immune system and discussing its potential as a therapeutic tool, emerged from recent clinical experimentations.
Abstract: l-Arginine is involved in many different biological processes and recent reports indicate that it could also play a crucial role in the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Herein, we present an updated systematic overview of the current evidence on the functional contribution of L-Arginine in COVID-19, describing its actions on endothelial cells and the immune system and discussing its potential as a therapeutic tool, emerged from recent clinical experimentations.
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TL;DR: In this article, the authors discuss how to mitigate antimicrobial resistance and develop prebiotic and probiotic alternatives to in-feed antibiotics in animal production, while helping reduce greenhouse gas emissions, minimize the urinary and fecal excretion of nitrogenous and other wastes to the environment, and sustain animal agriculture (including aquaculture).
Abstract: Consumption of high-quality animal protein plays an important role in improving human nutrition, growth, development, and health. With an exponential growth of the global population, demands for animal-sourced protein are expected to increase by 60% between 2021 and 2050. In addition to the production of food protein and fiber (wool), animals are useful models for biomedical research to prevent and treat human diseases and serve as bioreactors to produce therapeutic proteins. For a high efficiency to transform low-quality feedstuffs and forages into high-quality protein and highly bioavailable essential minerals in diets of humans, farm animals have dietary requirements for energy, amino acids, lipids, carbohydrates, minerals, vitamins, and water in their life cycles. All nutrients interact with each other to influence the growth, development, and health of mammals, birds, fish, and crustaceans, and adequate nutrition is crucial for preventing and treating their metabolic disorders (including metabolic diseases) and infectious diseases. At the organ level, the small intestine is not only the terminal site for nutrient digestion and absorption, but also intimately interacts with a diverse community of intestinal antigens and bacteria to influence gut and whole-body health. Understanding the species and metabolism of intestinal microbes, as well as their interactions with the intestinal immune systems and the host intestinal epithelium can help to mitigate antimicrobial resistance and develop prebiotic and probiotic alternatives to in-feed antibiotics in animal production. As abundant sources of amino acids, bioactive peptides, energy, and highly bioavailable minerals and vitamins, animal by-product feedstuffs are effective for improving the growth, development, health, feed efficiency, and survival of livestock and poultry, as well as companion and aquatic animals. The new knowledge covered in this and related volumes of Adv Exp Med Biol is essential to ensure sufficient provision of animal protein for humans, while helping reduce greenhouse gas emissions, minimize the urinary and fecal excretion of nitrogenous and other wastes to the environment, and sustain animal agriculture (including aquaculture).
32 citations
TL;DR: In this article , the authors designed a survey (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), assessing several symptoms that have been associated with Long-CoVID to be administered nationwide to COVID-19 survivors; the survey also included effort perception, measured using the Borg scale.
Abstract: Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms.We designed a survey (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), assessing several symptoms that have been associated with Long-COVID to be administered nationwide to COVID-19 survivors; the survey also included effort perception, measured using the Borg scale. Patients receiving the survey were divided in two groups, with a 2:1 ratio: the first group included patients that received L-Arginine + Vitamin C, whereas the second group received a multivitamin combination (alternative treatment).1390 patients successfully completed the survey. Following a 30-day treatment in both groups, the survey revealed that patients in the L-Arginine + Vitamin C treatment arm had significantly lower scores compared to patients who had received the multivitamin combination. There were no other significant differences between the two groups. When examining effort perception, we observed a significantly lower value (p < 0.0001) in patients receiving L-Arginine + Vitamin C compared to the alternative-treatment arm.Our survey indicates that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of attenuating its typical symptoms and improving effort perception.
28 citations
TL;DR: Amino acids (AAs) are the building blocks of proteins that have both structural and metabolic functions in humans and other animals as mentioned in this paper, and proteinogenic AAs are alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, histidine, isoleucine, leucine and lysine, methionine, phenylalanine.
Abstract: Amino acids (AAs) are the building blocks of proteins that have both structural and metabolic functions in humans and other animals. In mammals, birds, fish, and crustaceans, proteinogenic AAs are alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. All animals can synthesize de novo alanine, asparagine, aspartate, glutamate, glutamine, glycine, proline, and serine, whereas most mammals (including humans and pigs) can synthesize de novo arginine. Results of extensive research over the past three decades have shown that humans and other animals have dietary requirements for AAs that are synthesizable de novo in animal cells. Recent advances in analytical methods have allowed us to determine all proteinogenic AAs in foods consumed by humans, livestock, poultry, fish, and crustaceans. Both plant- and animal-sourced foods contain high amounts of glutamate, glutamine, aspartate, asparagine, and branched-chain AAs. Cysteine, glycine, lysine, methionine, proline, threonine, and tryptophan generally occur in low amounts in plant products but are enriched in animal products. In addition, taurine and creatine (essential for the integrity and function of tissues) are absent from plants but are abundant in meat and present in all animal-sourced foods. A combination of plant- and animal products is desirable for the healthy diets of humans and omnivorous animals. Furthermore, animal-sourced feedstuffs can be included in the diets of farm and companion animals to cost-effectively improve their growth performance, feed efficiency, and productivity, while helping to sustain the global animal agriculture (including aquaculture).
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5,415 citations
TL;DR: This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in the authors' understanding of this enzyme family.
Abstract: This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family. There is now information on the enzyme structure at all levels from primary (amino acid sequence) to quaternary (dimerization, association with other proteins) structure. The crystal structures of the oxygenase domains of inducible NOS (iNOS) and vascular endothelial NOS (eNOS) allow us to interpret other information in the context of this important part of the enzyme, with its binding sites for iron protoporphyrin IX (haem), biopterin, L-arginine, and the many inhibitors which interact with them. The exact nature of the NOS reaction, its mechanism and its products continue to be sources of controversy. The role of the biopterin cofactor is now becoming clearer, with emerging data implicating one-electron redox cycling as well as the multiple allosteric effects on enzyme activity. Regulation of the NOSs has been described at all levels from gene transcription to covalent modification and allosteric regulation of the enzyme itself. A wide range of NOS inhibitors have been discussed, interacting with the enzyme in diverse ways in terms of site and mechanism of inhibition, time-dependence and selectivity for individual isoforms, although there are many pitfalls and misunderstandings of these aspects. Highly selective inhibitors of iNOS versus eNOS and neuronal NOS have been identified and some of these have potential in the treatment of a range of inflammatory and other conditions in which iNOS has been implicated.
3,418 citations
TL;DR: Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS), which can be expressed in many cell types in response to lipopolysaccharide, cytokines, or other agents.
Abstract: Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates and require the cofactors reduced nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R-)5,6,7,8-tetrahydrobiopterin (BH(4)). All NOS bind calmodulin and contain haem. Neuronal NOS (nNOS, NOS I) is constitutively expressed in central and peripheral neurons and some other cell types. Its functions include synaptic plasticity in the central nervous system (CNS), central regulation of blood pressure, smooth muscle relaxation, and vasodilatation via peripheral nitrergic nerves. Nitrergic nerves are of particular importance in the relaxation of corpus cavernosum and penile erection. Phosphodiesterase 5 inhibitors (sildenafil, vardenafil, and tadalafil) require at least a residual nNOS activity for their action. Inducible NOS (NOS II) can be expressed in many cell types in response to lipopolysaccharide, cytokines, or other agents. Inducible NOS generates large amounts of NO that have cytostatic effects on parasitic target cells. Inducible NOS contributes to the pathophysiology of inflammatory diseases and septic shock. Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins.
3,077 citations
TL;DR: Physiological roles and relationships between the pathways of arginine synthesis and catabolism in vivo are complex and difficult to analyse, owing to compartmentalized expression of various enzymes at both organ and subcellular levels.
Abstract: Arginine is one of the most versatile amino acids in animal cells, serving as a precursor for the synthesis not only of proteins but also of nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine. Of the enzymes that catalyse rate-controlling steps in arginine synthesis and catabolism, argininosuccinate synthase, the two arginase isoenzymes, the three nitric oxide synthase isoenzymes and arginine decarboxylase have been recognized in recent years as key factors in regulating newly identified aspects of arginine metabolism. In particular, changes in the activities of argininosuccinate synthase, the arginases, the inducible isoenzyme of nitric oxide synthase and also cationic amino acid transporters play major roles in determining the metabolic fates of arginine in health and disease, and recent studies have identified complex patterns of interaction among these enzymes. There is growing interest in the potential roles of the arginase isoenzymes as regulators of the synthesis of nitric oxide, polyamines, proline and glutamate. Physiological roles and relationships between the pathways of arginine synthesis and catabolism in v i v o are complex and difficult to analyse, owing to compartmentalized expression of various enzymes at both organ (e.g. liver, small intestine and kidney) and subcellular (cytosol and mitochondria) levels, as well as to changes in expression during development and in response to diet, hormones and cytokines. The ongoing development of new cell lines and animal models using cDNA clones and genes for key arginine metabolic enzymes will provide new approaches more clearly elucidating the physiological roles of these enzymes. Correspondence may be addressed to either Dr. G. Wu (e-mail g-wu@tamu.edu) or Dr. S. M. Morris, Jr. (e-mail sid@hoffman.mgen.pitt.edu) at the addresses given.
2,553 citations
TL;DR: Dietary supplementation with one or a mixture of these functional AA, which include arginine, cysteine, glutamine, leucine, proline, and tryptophan, may be beneficial for ameliorating health problems at various stages of the life cycle and optimizing efficiency of metabolic transformations to enhance muscle growth, milk production, egg and meat quality and athletic performance.
Abstract: Recent years have witnessed the discovery that amino acids (AA) are not only cell signaling molecules but are also regulators of gene expression and the protein phosphorylation cascade. Additionally, AA are key precursors for syntheses of hormones and low-molecular weight nitrogenous substances with each having enormous biological importance. Physiological concentrations of AA and their metabolites (e.g., nitric oxide, polyamines, glutathione, taurine, thyroid hormones, and serotonin) are required for the functions. However, elevated levels of AA and their products (e.g., ammonia, homocysteine, and asymmetric dimethylarginine) are pathogenic factors for neurological disorders, oxidative stress, and cardiovascular disease. Thus, an optimal balance among AA in the diet and circulation is crucial for whole body homeostasis. There is growing recognition that besides their role as building blocks of proteins and polypeptides, some AA regulate key metabolic pathways that are necessary for maintenance, growth, reproduction, and immunity. They are called functional AA, which include arginine, cysteine, glutamine, leucine, proline, and tryptophan. Dietary supplementation with one or a mixture of these AA may be beneficial for (1) ameliorating health problems at various stages of the life cycle (e.g., fetal growth restriction, neonatal morbidity and mortality, weaning-associated intestinal dysfunction and wasting syndrome, obesity, diabetes, cardiovascular disease, the metabolic syndrome, and infertility); (2) optimizing efficiency of metabolic transformations to enhance muscle growth, milk production, egg and meat quality and athletic performance, while preventing excess fat deposition and reducing adiposity. Thus, AA have important functions in both nutrition and health.
2,047 citations