Carnosine

Postinjury Carnosine Treatment Prevents Neurotrophic Factor Decline in Denervated Muscle and Spinal Cord After Traumatic Injury.

Karolina Kucharova, Tomas Kuruc, Martina Magurova +5 more

Local intraspinal or intramuscular administration of brain-derived or glial cell line-derived neurotrophic factors (BDNF, GDNF) is known to protect neural tissue after traumatic spinal cord injury (SCI). In this study, we investigated whether oral supplementation with antioxidant carnosine, a natural dipeptide, could stimulate endogenous production of these neuroprotective molecules within the neural and muscle microenvironment 6 weeks after SCI. We assessed the effects of 6-week carnosine treatment in female Zucker rats, administered either before (CB-I) or after injury (CA-I). The impact of thoracic SCI and carnosine treatment was evaluated in in/active microenvironments of fore limb and hind limb muscles, along with their corresponding innervation regions. To better understand how carnosine treatment affects the neural microenvironment, we analysed mRNA expression levels of neurotrophic factors and their receptors. We also examined molecules that may indicate which cell types are involved in producing or responding to BDNF or GDNF in the spinal cord. Six weeks after thoracic SCI, we observed better locomotor recovery in CA-I compared to CB-I treated rats. In the hind limb, posttraumatic carnosine treatment prevented SCI-induced reductions in BDNF and GDNF protein levels. Additionally, this treatment blocked the SCI-induced reduction of GDNF protein levels and the oligodendrocyte-specific gene Olig2 in the lumbar and cervical spinal cord segments. Interestingly, the postinjury treatment elevated the gene expression in BDNF receptor- and astrocyte-specific genes in the cervical segments. The finding that carnosine may prevent BDNF and GDNF declines in denervated hind limb muscles positions this dipeptide as a promising candidate for inclusion in future combination therapies.

Multimodal Toxicity of Acrolein and Associated Therapeutic Strategies in Central Nervous System Trauma and Disease.

Nicholas S Race, Koji Uchida, Philip C Burcham +1 more

Acrolein is a highly reactive α,β-unsaturated aldehyde produced endogenously through lipid peroxidation and enzymatic metabolism and exogenously via environmental exposures. Acrolein covalently adducts to DNA and proteins, leading to oxidative stress, mitochondrial dysfunction, and inflammation, including innate immune response activation via natural antibodies. Acrolein is difficult to measure in biological systems, but acrolein-bound covalent products can be measured reliably. Therapeutically, nucleophilic small molecules that scavenge acrolein such as hydralazine, phenelzine, dimercaprol, carnosine, and N-acetylcysteine (NAC) have shown neuroprotective effects in animal models of multiple sclerosis, Parkinson's disease, spinal cord injury, and traumatic brain injury. These effects include preserved membrane and mitochondrial integrity, reduced inflammation, reduced pain, and improved motor, sensory, and cognitive outcomes. Alternative strategies that enhance clearance or inhibit production of acrolein show promise but face limitations. Acrolein is a key pathophysiological mediator and a viable therapeutic target in central nervous system trauma and neurodegenerative diseases.

Preclinical evidence and therapeutic perspectives on carnosine for the treatment of neurodegenerative disorders.

Saviana Antonella Barbati, Giuseppe Carota, Konstantinos Partsinevelos +14 more

Carnosine (β-alanyl-L-histidine) is an endogenous dipeptide widely distributed in mammalian tissues, especially skeletal and cardiac muscle cells, and, to a lesser extent, in the brain. While early interest in carnosine was given because of its role in muscle cell metabolism and athletic performance, it has more recently gained attention for its potential application in several chronic diseases. Specifically, brain aging and neurodegenerative disorders have received particular attention, as a marked reduction in carnosine levels has been described in these conditions. Carnosine exerts a wide range of biological activities, including antioxidant, anti-inflammatory, anti-glycation, metal-chelating, and neuroprotective properties. Mechanistically, it acts by inhibiting the production of advanced glycation end products (AGEs), buffering cellular pH, and regulating intracellular nitric oxide signaling and mitochondrial function. Its safety profile, the lack of toxicity, and significant side effects support its application for long-term therapeutic use. In this review, we aim to recapitulate and discuss the effects, dosages, and administration routes of carnosine in preclinical in vivo models, with a particular focus on neurodegenerative disorders where it has been shown to reduce oxidative stress, suppress neuroinflammation, modulate protein aggregation, and preserve cognitive function, all key features of neurodegeneration. Despite promising findings, there are gaps in the knowledge on how carnosine affects synaptic plasticity, neuronal remodeling, and other processes that play a central role in the pathophysiology of neurodegenerative disorders. Additionally, clinical translation remains challenging due to inconsistencies across in vivo studies in terms of dosage, treatment duration, routes of administration, and disease models, which affect reproducibility and cross-study comparability. Therefore, while carnosine emerges as a multifunctional and well-tolerated molecule, further research is needed to clarify its therapeutic relevance in human diseases. In this review, we also address future perspectives and key methodological challenges that must be overcome to effectively translate carnosine's biological potential into clinical practice.

Carnosine protects against cerebral ischemia/reperfusion injury through promoting microglial M2 polarization via SIRT1/NF-κB signaling pathway.

Ruili Ran, Yutong Wang, Ying Liu +4 more

Ischemic stroke, a leading cause of disability and mortality worldwide, often results in secondary brain injury due to oxidative stress and neuroinflammation following thrombolysis with tissue plasminogen activator (t-PA). Carnosine (CAR), a naturally occurring dipeptide, exhibits anti-inflammatory and neuroprotective properties. But its mechanisms in cerebral ischemia-reperfusion injury (CIRI) remain unclear. In this study, we aim to investigate the role of microglial polarization regulated by SIRT1/NF-κB signaling pathway on CAR therapeutic effect in CIRI. Here, we demonstrate that CAR attenuates neurological deficits and infarct volume in MCAO/R rats while promoting microglial polarization toward the anti-inflammatory M2 phenotype in vitro and in vivo. Mechanistically, CAR activates SIRT1, suppresses NF-κB signaling and downregulates pro-inflammatory cytokines (TNF-α, IL-1β). These effects were reversed by the SIRT1 inhibitor EX527, confirming the pivotal role of the SIRT1/NF-κB pathway. Therefore, our findings highlight CAR's potential as a therapeutic agent for ischemic stroke.

Novel progress in the application of the small molecule drug carnosine for the treatment of several diseases (Review).

Chao Fang, Daihan Xie, Lixin Xie +3 more

Carnosine is a dipeptide composed of β‑alanine and L‑histidine, linked by peptide bonds, and is widely distributed in muscle tissue, the central nervous system (including the brain) and various other organs. As an endogenous bioactive molecule, carnosine plays a crucial role in cellular metabolism and physiological regulation. In recent years, advancements in molecular biology, biochemistry and pharmacology have gradually unveiled the multiple biological functions of carnosine, leading to increased interest in its potential applications for disease therapy. Carnosine exhibits considerable antioxidant and anti‑glycation properties, while also demonstrating unique pharmacological effects related to neuroprotection, anti‑inflammatory responses and immune regulation. These attributes position carnosine as a significant intervention with therapeutic value across various pathophysiological processes associated with different diseases. This review systematically summarizes recent progress on the application of carnosine in disease therapy, focusing on its mechanisms of action and therapeutic roles in neurodegenerative diseases, metabolic disorders, cardiovascular diseases, several types of cancer and ophthalmic conditions. By reviewing existing studies on this topic, this review aims to further explore the diversity of carnosine's roles along with potential mechanisms involved in disease treatment. Ultimately, it aims to provide a theoretical foundation and direction for future research.

Dosing strategies for β-alanine supplementation in strength and power performance: a systematic review.

Si-Wei Ong, Wei-Ling Chen, Kuei-Yu Chien +1 more

β-alanine is a well-established ergogenic aid that enhances muscle carnosine levels and buffering capacity during high-intensity efforts. However, its role in improving strength and power performance remains inconsistent across the literature. This systematic review investigates whether dosing strategy, rather than duration alone, is the critical determinant of efficacy in resistance-trained populations.

Lactic acidosis: implications for human exercise performance.

Simeon P Cairns, Michael I Lindinger

During high-intensity exercise a lactic-acidosis occurs with raised myoplasmic and plasma concentrations of lactate- and protons ([lactate-], [H+] or pH). We critically evaluate whether this causes/contributes to fatigue during human exercise. Increases of [lactate-] per se (to 25 mM in plasma, 50 mM intracellularly) exert little detrimental effect on muscle performance while ingestion/infusion of lactate- can be ergogenic. An exercise-induced intracellular acidosis at the whole-muscle level (pHi falls from 7.1-7.0 to 6.9-6.3), incorporates small changes in slow-twitch fibres (pHi ~ 6.9) and large changes in fast-twitch fibres (pHi ~ 6.2). The relationship between peak force/power and acidosis during fatiguing contractions varies across exercise regimes implying that acidosis is not the sole cause of fatigue. Concomitant changes of other putative fatigue factors include phosphate metabolites, glycogen, ions and reactive oxygen species. Acidosis to pHi 6.7-6.6 at physiological temperatures (during recovery from exercise or induced in non-fatigued muscle), has minimal effect on force/power. Acidosis to pHi ~ 6.5-6.2 per se reduces maximum force (~12%), slows shortening velocity (~5%), and lowers peak power (~22%) in non-fatigued muscles/individuals. A pre-exercise induced-acidosis with ammonium chloride impairs exercise performance in humans and accelerates the decline of force/power (15-40% initial) in animal muscles stimulated repeatedly in situ. Raised [H+]i and diprotonated inorganic phosphate ([H2PO4-]i) act on myofilament proteins to reduce maximum cross-bridge activity, Ca2+-sensitivity, and myosin ATPase activity. Acidosis/[lactate-]o attenuates detrimental effects of large K+-disturbances on action potentials and force in non-fatigued muscle. We propose that depressive effects of acidosis and [H2PO4-]i on myofilament function dominate over the protective effects of acidosis/lactate- on action potentials during fatigue. Raised extracellular [H+]/[lactate-] do not usually cause central fatigue but do contribute to elevated perceived exertion and fatigue sensations by activating group III/IV muscle afferents. Modulation of H+/lactate- regulation (via extracellular H+-buffers, monocarboxylate transporters, carbonic anhydrase, carnosine) supports a role for intracellular acidosis in fatigue. In conclusion, current evidence advocates that severe acidosis in fast-twitch fibres can contribute to force/power fatigue during intense human exercise.

Effects of Carnosine Supplementation on Cognitive Outcomes in Prediabetes and Well-Controlled Type 2 Diabetes: A Randomised Placebo-Controlled Clinical Trial.

Rohit Hariharan, Aya Mousa, Kirthi Menon +10 more

Background: Trends in global ageing underscore the rising burden of age-related cognitive decline and concomitant cardiometabolic diseases, including type 2 diabetes mellitus (T2DM). Carnosine, a naturally occurring dipeptide with anti-inflammatory, antioxidant and anti-glycating properties, has shown promise in animal models and limited human studies for improving cognitive function, insulin resistance and T2DM, but its therapeutic effects on cognition remain unclear. The aim of this study is to assess the effects of carnosine on cognitive function in individuals with prediabetes or well-controlled T2DM. Methods: This is a secondary analysis of a double-blind randomised controlled trial (RCT), whereby 49 adults with prediabetes or early-stage well-controlled T2DM were randomised to receive 2 g of carnosine or identical placebo daily for 14 weeks. At baseline and follow-up, cognitive function was assessed as a secondary outcome using the Digit-Symbol Substitution Test, Stroop test, Trail Making Tests A & B, and the Cambridge Automated Neuropsychological Test Battery (CANTAB). Results: In total, 42 adults (23 males and 19 females) completed the trial. There were no differences in participant anthropometry or cognitive functioning between carnosine and placebo groups at baseline (all p > 0.1). After the 14-week supplementation period, there were no differences between carnosine and placebo groups in change and follow-up values for any cognitive measures including Stroop, Digit Symbol Substitution Sest, Trail Making A/B or CANTAB (all p > 0.05). Adjustments for baseline cognitive scores, diabetic status, level of education, age or interaction effects with participants' sex did not change the results. Conclusions: Carnosine supplementation did not improve cognitive measures in individuals with prediabetes or T2DM in this study. While larger trials may provide further insights, alternative factors-such as the relatively young and healthy profile of our cohort-may have contributed to the lack of observed effect. Future research should examine individuals with existing cognitive impairment or those at higher risk of cognitive decline to better define the therapeutic potential of carnosine in this context.

The Possible Roles of β-alanine and L-carnosine in Anti-aging.

Amin Gasmi, Pavan Kumar Mujawdiya, Roman Lysiuk +9 more

β-alanine (BA), being a non-proteinogenic amino acid, is an important constituent of L-carnosine (LC), which is necessary for maintaining the muscle buffering capacity and preventing a loss of muscle mass associated with aging effects. BA is also very important for normal human metabolism due to the formation of a part of pantothenate, which is incorporated into coenzyme A. BA is synthesized in the liver, and its combination with histidine results in the formation of LC, which accumulates in the muscles and brain tissues and has a well-defined physiological role as a good buffer for the pH range of muscles that caused its rapidly increased popularity as ergogenic support to sports performance. The main antioxidant mechanisms of LC include reactive oxygen species (ROS) scavenging and chelation of metal ions. With age, the buffering capacity of muscles also declines due to reduced concentration of LC and sarcopenia. Moreover, LC acts as an antiglycation agent, ultimately reducing the development of degenerative diseases. LC has an anti-inflammatory effect in autoimmune diseases such as osteoarthritis. As histidine is always present in the human body in higher concentrations than BA, humans have to get BA from dietary sources to support the required amount of this critical constituent to supply the necessary amount of LC synthesis. Also, BA has other beneficial effects, such as preventing skin aging and intestinal damage, improving the stress-- fighting capability of the muscle cells, and managing an age-related decline in memory and learning. In this review, the results of a detailed analysis of the role and various beneficial properties of BA and LC from the anti-aging perspective are presented.

Dissociative Identity Disorder Cotreated With Zinc and L-carnosine: A Case Report.

Kensaku Sakae, Machi Suka, Hiroyuki Yanagisawa

Little is known about the effectiveness of pharmacotherapy in dissociative identity disorder (DID). Zinc is essential for proper brain function. Its deficiency can lead to mental health symptoms, possibly contributing to dissociation. L-carnosine is an endogenous dipeptide with a neuroprotective effect. We report on the case of a 30-year-old woman with DID and comorbid bipolar I disorder who had zinc deficiency and was successfully cotreated with zinc and L-carnosine. She displayed three alternate identities and exhibited signs of emotional/mood instability, flashbacks, binge eating, and self-harm. The patient also displayed several physical symptoms of zinc deficiency. She did not respond to aripiprazole (0.75 mg/d) and clonazepam (1.5 mg/d), but responded marginally to five months of zinc (50 mg/d) supplementation. Simultaneous administration of L-carnosine, gradually increased from 0.5 g/d to 2 g/d over four months, markedly improved her symptoms. Five months after adding 2 g/d L-carnosine, the patient's pronounced alternate identities that people around her could notice no longer appeared. However, the identities that were not noticeable to the people remained. They disappeared completely two years later and reappeared only when zinc and L-carnosine were discontinued during the subsequent three-year follow-up. The patient's severity scores for dissociation and depression were reduced. Furthermore, signs of emotional/mood instability, flashbacks, binge eating, and self-harm improved. The physical symptoms of zinc deficiency eventually resolved. Further investigation of cotreatment with zinc and L-carnosine for DID and related conditions, particularly the contribution of zinc deficiency to dissociation, is necessary.

Topical Transdermal Administration of Supramolecular Self-Assembled Carnosine for Anti-Melanin and Anti-Aging.

De Bai, Zhenyuan Wang, Lin Xie +3 more

The structure of natural proteins has inspired the hypothesis that L-carnosine (LC), acetyl carnosine (AC), and decarboxy carnosine (DC) self-assemble into highly bioactive carnosine with supramolecular structures. These structures are proposed to combat skin pigmentation and aging through the coordination of weak interactions between molecules. Simulations are conducted to ascertain the precise free energies of the potential supramolecular structures and to identify the equilibrium structure. The mechanism of transdermal action of supramolecular carnosine is investigated through experiments and molecular dynamics simulations. The results demonstrate that supramolecular carnosine exhibits a more pronounced reactivity with the skin than LC, primarily due to the interaction of AC and DC with the lipid matrix, which reduces interfacial resistance. The anti-photoaging and anti-glycation cell models demonstrate that supramolecular carnosine upregulates the expression of the Nrf2 protein, activates the antioxidant defense system of melanocytes, inhibits the expression of the receptor for advanced glycosylation end products (AGEs), and reduces the level of AGEs in vivo. Moreover, supramolecular carnosine has demonstrated satisfactory whitening efficacy in cells and clinical efficacy tests, thereby underscoring its considerable potential for biomedical and aesthetic applications.

The Top 5 Can't-Miss Sport Supplements.

Jose Antonio, Flavia Pereira, Jason Curtis +2 more

Background/Objectives: Sports supplements have become popular among fitness enthusiasts for enhancing the adaptive response to exercise. This review analyzes five of the most effective ergogenic aids: creatine, beta-alanine, nitrates, caffeine, and protein. Methods: We conducted a narrative review of the literature with a focus on the sport supplements with the most robust evidence for efficacy and safety. Results: Creatine, one of the most studied ergogenic aids, increases phosphocreatine stores in skeletal muscles, improving ATP production during high-intensity exercises like sprinting and weightlifting. Studies show creatine supplementation enhances skeletal muscle mass, strength/power, and muscular endurance. The typical dosage is 3-5 g per day and is safe for long-term use. Beta-alanine, when combined with the amino acid histidine, elevates intramuscular carnosine, which acts as a buffer in skeletal muscles and delays fatigue during high-intensity exercise by neutralizing hydrogen ions. Individuals usually take 2-6 g daily in divided doses to minimize paresthesia. Research shows significant performance improvements in activities lasting 1-4 min. Nitrates, found in beetroot juice, enhance aerobic performance by increasing oxygen delivery to muscles, enhancing endurance, and reducing oxygen cost during exercise. The recommended dosage is approximately 500 milligrams taken 2-3 h before exercise. Caffeine, a central nervous system stimulant, reduces perceived pain while enhancing focus and alertness. Effective doses range from 3 to 6 milligrams per kilogram of body weight, typically consumed an hour before exercise. Protein supplementation supports muscle repair, growth, and recovery, especially after resistance training. The recommended intake for exercise-trained men and women varies depending on their specific goals. Concluions: In summary, creatine, beta-alanine, nitrates, caffeine, and protein are the best ergogenic aids, with strong evidence supporting their efficacy and safety.

The impact of carnosine on biological ageing - A geroscience approach.

Qian Wang, Saeede Saadati, Robel Hussen Kabthymer +6 more

Biological ageing involves a gradual decline in physiological function and resilience, marked by molecular, cellular, and systemic changes across organ systems. Geroscience, an interdisciplinary field, studies these mechanisms and their role in age-related diseases. Genomic instability, inflammation, telomere attrition, and other indicators contribute to conditions like cardiovascular disease and neurodegeneration. Geroscience identifies geroprotectors, such as resveratrol and metformin, targeting ageing pathways to extend the healthspan. Carnosine, a naturally occurring dipeptide (b-alanine and l-histidine), has emerged as a potential geroprotector with antioxidative, anti-inflammatory, and anti-glycating properties. Carnosine's benefits extend to muscle function, exercise performance, and cognitive health, making it a promising therapeutic intervention for healthy ageing and oxidative stress-related pathologies. In this review, we summarize the evidence describing carnosine's effects in promoting healthy ageing, providing new insights into improving geroscience.

Carnosine ameliorates postoperative cognitive dysfunction of aged rats by limiting astrocytes pyroptosis.

Jiahong Shen, Jiawen Xu, Yuxin Wen +3 more

Postoperative cognitive dysfunction (POCD) is a common postoperative complication in elderly patients, and neuroinflammation is a key hallmark. Recent studies suggest that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-mediated astrocytes pyroptosis is involved in the regulation of neuroinflammation in many neurocognitive diseases, while its role in POCD remains obscure. Carnosine is a natural endogenous dipeptide with anti-inflammatory and neuroprotective effects. To explore the effect of carnosine on POCD and its mechanism, we established a POCD model by exploratory laparotomy in 24-month-old male Sprague-Dawley rats. We found that the administrated of carnosine notably attenuated surgery-induced NLRP3 inflammasome activation and pyroptosis in astrocytes, central inflammation, and neuronal damage in the hippocampus of aged rats. In addition, carnosine dramatically ameliorated the learning and memory deficits of surgery-induced aged rats. Then in the in vitro experiments, we stimulated primary astrocytes with lipopolysaccharide (LPS) after carnosine pretreatment. The results also showed that the application of carnosine alleviated the activation of the NLRP3 inflammasome, pyroptosis, and inflammatory response in astrocytes stimulated by LPS. Taken together, these findings suggest that carnosine improves POCD in aged rats via inhibiting NLRP3-mediated astrocytes pyroptosis and neuroinflammation.

Behavioral and transcriptional effects of carnosine in the central ring ganglia of the pond snail Lymnaea stagnalis.

Veronica Rivi, Giuseppe Caruso, Filippo Caraci +6 more

Carnosine is a naturally occurring endogenous dipeptide with well-recognized anti-inflammatory, antioxidant, and neuroprotective effects at the central nervous system level. To date, very few studies have been focused on the ability of carnosine to rescue and/or enhance memory. Here, we used a well-known invertebrate model system, the pond snail Lymnaea stagnalis, and a well-studied associative learning procedure, operant conditioning of aerial respiration, to investigate the ability of carnosine to enhance long-term memory (LTM) formation and reverse memory obstruction caused by an immune challenge (i.e., lipopolysaccharide [LPS] injection). Exposing snails to 1 mM carnosine for 1 h before training in addition to enhancing memory formation resulted in a significant upregulation of the expression levels of key neuroplasticity genes (i.e., glutamate ionotropic receptor N-methyl-d-aspartate [NMDA]-type subunit 1-LymGRIN1, and the transcription factor cAMP-response element-binding protein 1-LymCREB1) in snails' central ring ganglia. Moreover, pre-exposure to 1 mM carnosine before an LPS injection reversed the memory deficit brought about by inflammation, by preventing the upregulation of key targets for immune and stress response (i.e., Toll-like receptor 4-LymTLR4, molluscan defense molecule-LymMDM, heat shock protein 70-LymHSP70). Our data are thus consistent with the hypothesis that carnosine can have positive benefits on cognitive ability and be able to reverse memory aversive states induced by neuroinflammation.

Dual Effect of Carnosine on ROS Formation in Rat Cultured Cortical Astrocytes.

Fabiola Diniz, Belisa Parmeggiani, Gabriela Brandão +8 more

Carnosine is composed of β-alanine and L-histidine and is considered to be an important neuroprotective agent with antioxidant, metal chelating, and antisenescence properties. However, children with serum carnosinase deficiency present increased circulating carnosine and severe neurological symptoms. We here investigated the in vitro effects of carnosine on redox and mitochondrial parameters in cultured cortical astrocytes from neonatal rats. Carnosine did not alter mitochondrial content or mitochondrial membrane potential. On the other hand, carnosine increased mitochondrial superoxide anion formation, levels of thiobarbituric acid reactive substances and oxidation of 2',7'-dichlorofluorescin diacetate (DCF-DA), indicating that carnosine per se acts as a pro-oxidant agent. Nonetheless, carnosine prevented DCF-DA oxidation induced by H2O2 in cultured cortical astrocytes. Since alterations on mitochondrial membrane potential are not likely to be involved in these effects of carnosine, the involvement of N-Methyl-D-aspartate (NMDA) receptors in the pro-oxidant actions of carnosine was investigated. MK-801, an antagonist of NMDA receptors, prevented DCF-DA oxidation induced by carnosine in cultured cortical astrocytes. Astrocyte reactivity induced by carnosine was also prevented by the coincubation with MK-801. The present study shows for the very first time the pro-oxidant effects of carnosine per se in astrocytes. The data raise awareness on the importance of a better understanding of the biological actions of carnosine, a nutraceutical otherwise widely reported as devoid of side effects.

Catechol chitosan coated dual-loaded liposomes based on oxidation and saccharification mechanisms for enhancing skin anti-aging effects.

Xinying Wang, Linlin Lv, Tongyan Liu +3 more

Skin aging has become a major urgent problem to be solved. Evidence reveals that oxidation and glycosylation are two dominant inducements of aging. Resveratrol (RES) with outstanding anti-oxidant effect and carnosine (CAR) with superb anti-glycation property were selected as two model drugs to evaluate the feasibility of their synergistic anti-aging effect. RES and CAR at the most desired mass ratio, supplying the most superior synergistic anti-aging effects were further encapsulated in liposomes (LP), which were separately coated with chitosan (CS) and catechol chitosan (Cat-CS) to increase the transdermal penetration. Their anti-aging efficacy was explored in human skin fibroblast (HSF) and human immortalized keratinocytes (HaCaT) cells, as well as the back skin of guinea pigs. Herein, RES and CAR at the mass ratio of 2:1 exhibited the most ideal synergistic anti-aging effect. The constructed liposomes have been shown to possess excellent fundamental properties and sustained-release properties. The aging-related indicator levels in the two cells and guinea pigs were obviously improved for the RES + CAR@Cat-CS-LP group. Additionally, skin appearance, tissue morphology, and collagen content were visibly improved, indicating its perfect anti-aging effect. In conclusion, RES + CAR@Cat-CS-LP is expected to be exploited as a potential anti-aging drug delivery system.

The Potential Use of Carnosine in Diabetes and Other Afflictions Reported in Long COVID Patients.

Fabiola Cardoso Diniz, Alan Roger Hipkiss, Gustavo Costa Ferreira

Carnosine is a dipeptide expressed in both the central nervous system and periphery. Several biological functions have been attributed to carnosine, including as an anti-inflammatory and antioxidant agent, and as a modulator of mitochondrial metabolism. Some of these mechanisms have been implicated in the pathophysiology of coronavirus disease-2019 (COVID-19). COVID-19 is caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The clinical manifestation and recovery time for COVID-19 are variable. Some patients are severely affected by SARS-CoV-2 infection and may experience respiratory failure, thromboembolic disease, neurological symptoms, kidney damage, acute pancreatitis, and even death. COVID-19 patients with comorbidities, including diabetes, are at higher risk of death. Mechanisms underlying the dysfunction of the afflicted organs in COVID-19 patients have been discussed, the most common being the so-called cytokine storm. Given the biological effects attributed to carnosine, adjuvant therapy with this dipeptide could be considered as supportive treatment in patients with either COVID-19 or long COVID.

β-Alanine Supplementation in Combat Sports: Evaluation of Sports Performance, Perception, and Anthropometric Parameters and Biochemical Markers-A Systematic Review of Clinical Trials.

Diego Fernández-Lázaro, Emma Marianne Fiandor, Juan F García +5 more

β-alanine does not have an ergogenic effect by itself, but it does as a precursor for the synthesis of carnosine in human skeletal muscle. β-alanine and carnosine together help improve the muscles' functionality, especially in high-intensity exercises such as combat sports. Therefore, β-alanine could be considered a nutritional ergogenic aid to improve sports performance in combat athletes. We aimed to critically review clinical trial evidence on the impact of β-alanine supplementation on sports performance, perception, and anthropometric parameters, as well as circulating biochemical markers in combat athletes. This systematic review was conducted following the specific methodological guidelines of the Preferred Report Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA), the PICOS question model, the Critical Review Form of McMaster, and the PEDro scale. Furthermore, the Cochrane risk-of-bias assessment tool was used. The search was carried out in the SCOPUS, Web of Science (WOS), and Medline (PubMed) databases for studies published from the beginning of the database until July 31, 2023. Of the 41 registers identified, only 7 met the established criteria and were included in this systematic review. Overall, performance parameters related to strength, power, total exercise work capacity, and combat-specific parameters were significantly improved (p < 0.05). Perception parameters increased non-significantly (p > 0.05). Regarding biochemical parameters, carnosine increased significantly (p < 0.05), pH decreased non-significantly (p > 0.05), and the results for blood bicarbonate and blood lactate were heterogeneous. Finally, there was a non-significant (p > 0.05) improvement in the anthropometric parameters of lean mass and fat mass. β-alanine supplementation appears to be safe and could be a suitable nutritional ergogenic aid for combat athletes.

Effect of β-alanine and sodium bicarbonate co-supplementation on the body's buffering capacity and sports performance: A systematic review.

Laura Gilsanz, Jaime López-Seoane, Sergio L Jiménez +1 more

Muscle acidification is one of the main factors causing fatigue during exercise, thus compromising performance. The sport supplements beta alanine (β-A) and sodium bicarbonate (SB) are thought to enhance the effects of the body's buffer systems by reducing H+ concentrations. The aim of this systematic review was to analyze the effects of β-A and SB co-supplementation on the organism's buffering capacity and sport performance. The databases PubMed, Web of Science, Medline, CINAHL and SPORTDiscus were searched until November 2021 following PRISMA guidelines. Randomized controlled trials, at least single-blind, performed in athletes of any age were considered. Nine studies including a total of 221 athletes were identified for review. Athletes were supplemented with β-A and SB while they performed exercise tests to assess physical performance and buffer capacity. Five of the nine studies indicated there was some additional improvement in buffering capacity and performance with co-supplementation, while one study concluded that the effect was comparable to the added effects of the individual supplements. According to the results of the studies reviewed, we would recommend β-A and SB co-supplementation during high intensity exercises lasting between 30 s and 10 min.

The therapeutic potential of carnosine: Focus on cellular and molecular mechanisms.

Giuseppe Caruso, Lucia Di Pietro, Vincenzo Cardaci +2 more

Carnosine is a naturally occurring endogenous dipeptide composed by the ligation of β-alanine and L-histidine performed particularly by tissues with an increased oxidative metabolism such as muscles and brain. In the last 50 years different studies have assessed the role and function of carnosine through numerous in vitro, in vivo, and clinical studies, demonstrating the multimodal mechanism of action of this dipeptide that includes anti-aggregant, antioxidant, and anti-inflammatory activities. In particular its activity has been investigated in experimental models of cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and neurodegenerative disorders, such as cerebral ischemia and Alzheimer's disease (AD). In the present review, we examined the protective role that carnosine could exert in the context of T2DM, CVD, and AD, which show common pathogenic mechanisms including oxidative stress, inflammation, and aggregation phenomena. Carnosine's pharmacodynamic profile is multimodal and combines the systemic anti-inflammatory and antioxidant activities with its anti-aggregant and neuroprotective efficacy in the central nervous system. This enlarged pharmacological activity opens a new path to explore the therapeutic potential of carnosine in all the three diseases, and in particular in patients with T2DM, who often show a history of CVD and also have an increased risk to develop mild cognitive impairment and AD.

Neuroprotective Efficacy of a Nanomicellar Complex of Carnosine and Lipoic Acid in a Rat Model of Rotenone-Induced Parkinson's Disease.

Olga Kulikova, Dmitry Troshev, Daniil Berezhnoy +6 more

Oxidative stress, accompanied by mitochondrial dysfunction, is a key mechanism involved in the pathogenesis of Parkinson's disease (PD). Both carnosine and lipoic acid are potent antioxidants, the applicability of which in therapy is hindered by their limited bioavailability. This study aimed to evaluate the neuroprotective properties of a nanomicellar complex of carnosine and lipoic acid (CLA) in a rotenone-induced rat model of PD. Parkinsonism was induced via the administration of 2 mg/kg rotenone over the course of 18 days. Two doses of intraperitoneal CLA (25 mg/kg and 50 mg/kg) were administered alongside rotenone to assess its neuroprotective effect. At 25 mg/kg CLA decreased muscle rigidity and partially restored locomotor activity in animals that received rotenone. Furthermore, it caused an overall increase in brain tissue antioxidant activity, accompanied by a 19% increase in neuron density in the substantia nigra and increased dopamine levels in the striatum relative to animals that only received rotenone. Based on the acquired results, it may be concluded that CLA have neuroprotective properties and could potentially be beneficial in PD treatment when used in conjunction with the base therapy.

Dietary β-Alanine Intake Assessed by Food Records Does Not Associate With Muscle Carnosine Content in Healthy, Active, Omnivorous Men and Women.

Nathalia Saffioti Rezende, Giulia Cazetta Bestetti, Luana Farias de Oliveira +6 more

β-Alanine (BA) is one of the most widely used sport supplements, due to its capacity to improve high-intensity exercise performance by increasing muscle carnosine (MCarn) content, and consequently, the buffering capacity of the muscle. BA is also available in a variety of animal foods, but little is currently known about the influence of dietary BA intake on MCarn. The aim of the current study was to compile a detailed summary of available data on the BA content of commonly consumed foods, and to explore whether associations could be detected between self-reported dietary BA intake and skeletal MCarn in a group of 60 healthy, active, omnivorous men and women. Dietary BA intake was assessed via 3-day food records, and MCarn content assessed by high-performance liquid chromatography. A series of univariate and multivariate linear regression models were used to explore associations between estimated dietary BA and MCarn. No evidence of associations between dietary BA intake and MCarn were identified, with effect sizes close to zero calculated from models accounting for key demographic variables (f2 ≤ 0.02 for all analyses). These findings suggest that capacity to increase MCarn via dietary strategies may be limited, and that supplementation may be required to induce increases of the magnitude required to improve performance.

The Effect of β-Alanine Supplementation on Performance, Cognitive Function and Resiliency in Soldiers.

Ishay Ostfeld, Jay R Hoffman

β-alanine is a nonessential amino acid that combines with the amino acid histidine to form the intracellular dipeptide carnosine, an important intracellular buffer. Evidence has been well established on the ability of β-alanine supplementation to enhance anaerobic skeletal muscle performance. As a result, β-alanine has become one of the more popular supplements used by competitive athletes. These same benefits have also been reported in soldiers. Evidence accumulated over the last few years has suggested that β-alanine can result in carnosine elevations in the brain, which appears to have broadened the potential effects that β-alanine supplementation may have on soldier performance and health. Evidence suggests that β-alanine supplementation can increase resilience to post-traumatic stress disorder, mild traumatic brain injury and heat stress. The evidence regarding cognitive function is inconclusive but may be more of a function of the stressor that is applied during the assessment period. The potential benefits of β-alanine supplementation on soldier resiliency are interesting but require additional research using a human model. The purpose of this review is to provide an overview of the physiological role of β-alanine and why this nutrient may enhance soldier performance.

Efficacy of 12 weeks oral beta-alanine supplementation in patients with chronic obstructive pulmonary disease: a double-blind, randomized, placebo-controlled trial.

Jana De Brandt, Wim Derave, Frank Vandenabeele +8 more

Beta-alanine (BA) supplementation increases muscle carnosine, an abundant endogenous antioxidant and pH buffer in skeletal muscle. Carnosine loading promotes exercise capacity in healthy older adults. As patients with chronic obstructive pulmonary disease (COPD) suffer from elevated exercise-induced muscle oxidative/carbonyl stress and acidosis, and from reduced muscle carnosine stores, it was investigated whether BA supplementation augments muscle carnosine and induces beneficial changes in exercise capacity, quadriceps function, and muscle oxidative/carbonyl stress in patients with COPD.

Whole-cell biotransformation for large scale production of carcinine in Escherichia coli.

Man Zhao, Xiangting Song, Wei Liu +5 more

Carcinine is a natural imidazole-containing peptide derivative. It is widely used in the cosmetics industry as anti-aging supplement with antioxidant, anti-glycation and glycation reversal functions, and it also has a notable pharmacological effect as anti-tumor drug and in protection against retinopathy. However, a technological method for synthesis and production of carcinine has not been established. In this study, a whole-cell transformation system converting β-alanine and histamine to carcinine by the enzymes Ebony and phosphopantetheine transferase (Sfp) has been developed. The results revealed that the catalytic efficiency of the strain containing the fusion protein of Ebony and Sfp (Sfp-glycine-serine-glycine-Ebony, SGE) in Escherichia coli W3110 (WSGE strain) is significantly higher (7.45 mM) than the combinatorial strain of pET28a-ebony and pACYCDuet-sfp in E. coli BL21(DE3) (BSE strain) (2.17 mM). Under the optimal reaction conditions (25 ℃, pH 7.0, 12.5 g/L wet cells, 20 mM β-alanine and 40 mM histamine), the carcinine can be quickly synthesized within 24 h up to a concentration of 22.63 mM. To achieve a continuous and efficient conversion of the precursors, a batch-feeding catalysis was designed. With this system, β-alanine (40 mM) and histamine (40 mM) could be completely transformed to carcinine (40.34 mM) in 36 h with a productivity of 0.204 g/L h reaching a titer of 7.34 g/L. Hence, the batch-feeding whole-cell biocatalysis is a promising technology for the high yield production of carcinine which can promote the industrial production of carcinine.

Swimming exercise versus L-carnosine supplementation for Alzheimer's dementia in rats: implication of circulating and hippocampal FNDC5/irisin.

Maha A Hegazy, Doaa A Abdelmonsif, Teshreen M Zeitoun +2 more

Recent studies have suggested that irisin may act as a potential neurokine. Exercise and L-carnosine supplementation showed neuroprotective effects in Alzheimer's disease (AD)-like conditions. However, the regulation of irisin in the hippocampus of streptozotocin (STZ)-induced memory impairment and its relation to insulin signalling remain to be investigated. This study was designed to compare the effect of swimming exercise and L-carnosine intake on serum, CSF and hippocampal irisin in rats received intracerebroventricular (ICV) injection of STZ. Rats were recruited in swimming paradigm, received oral carnosine (100 mg/kg/day) or vehicle treated. After 5 weeks, rats were sacrificed after neurobehavioural testing. CSF and serum irisin were determined. Hippocampal tissues were used to assess expression of FNDC5/irisin, BDNF and proteins related to insulin signalling, in addition to β-amyloid peptide and phosphorylated tau protein levels. We observed decreased hippocampal, but not CSF or serum, irisin in ICV-STZ-injected rats. Exercise and carnosine intake almost normalized hippocampal FNDC5/irisin expression which was associated with reduced soluble β-amyloid peptide and phosphorylated tau protein, improved BDNF and insulin signalling proteins, with corresponding mitigated cognitive impairments. However, hippocampal FNDC5/irisin was not correlated with serum or CSF irisin levels. Histologically, both interventions ameliorated the hippocampal damage in STZ-injected rats. The current study reveals that carnosine is equivalent to exercise in reversing cognitive decline and Alzheimer's biomarkers. In both interventions, enhancement of hippocampal FNDC5/irisin and insulin signalling may be involved in mediating these neuroprotective effects.

Comment on "Cores of Reproducibility in Physiology (CORP): quantification of human skeletal muscle carnosine concentration by proton magnetic resonance spectroscopy".

Vinicius da Eira Silva, Joseph Matthews, Bruno Gualano +4 more

Anti-cancer actions of carnosine and the restoration of normal cellular homeostasis.

Mark D Turner, Craig Sale, A Christopher Garner +1 more

Carnosine is a naturally occurring dipeptide found in meat. Alternatively it can be formed through synthesis from the amino acids, β-alanine and L-histidine. Carnosine has long been advocated for use as an anti-oxidant and anti-glycating agent to facilitate healthy ageing, and there have also been reports of it having anti-proliferative effects that have beneficial actions against the development of a number of different cancers. Carnosine is able to undertake multiple molecular processes, and it's mechanism of action therefore remains controversial - both in healthy tissues and those associated with cancer or metabolic diseases. Here we review current understanding of its mechanistic role in different physiological contexts, and how this relates to cancer. Carnosine turns over rapidly in the body due to the presence of both serum and tissue carnosinase enzymes however, so its use as a dietary supplement would require ingestion of multiple daily doses. Strategies are therefore being developed that are based upon either resistance of carnosine analogs to enzymatic turnover, or else β-alanine supplementation, and the development of these potential therapeutic agents is discussed.