Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms?

MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.

Modulatory effects of supplementation of Lentinula edodes mycelia extract and l-arginine on the therapeutic efficacy of immunogenic chemotherapy in colon cancer-bearing mice.

Some chemotherapeutic drugs can induce cancer cell death and enhance antitumor T-cell immunity in cancer-bearing hosts. Immunomodulatory reagents could augment such chemotherapy-induced effects. We previously reported that oral digestion of Lentinula edodes mycelia (L.E.M.) extract or  l-arginine supplementation can augment antitumor T-cell responses in cancer-bearing mice. In this study, the effects of L.E.M. extract with or without  l-arginine on the therapeutic efficacy of immunogenic chemotherapy by 5-fluorouracil (5-FU)/oxaliplatin (L-OHP) and/or cyclophosphamide (CP) are examined using two mouse colon cancer models. In MC38 and CT26 cancer models, therapy with 5-FU/L-OHP/CP significantly suppressed tumor growth, and supplementation with L.E.M. extract halved the tumor volumes. However, the modulatory effect of L.E.M. extract was not significant. In the CT26 cancer model, supplementation with L.E.M. extract and  l-arginine had no clear effect on tumor growth. In contrast, their addition to chemotherapy halved the tumor volumes, although the effect was not significant. There was no difference in the cytotoxicity of tumor-specific cytotoxic T cells generated from CT26-cured mice treated by chemotherapy alone versus chemotherapy combined with L.E.M. extract/ l-arginine. These results indicate that the antitumor effects of immunogenic chemotherapy were too strong to ascertain the effects of supplementation of L.E.M. extract and  l-arginine, but these reagents nonetheless have immunomodulatory effects on the therapeutic efficacy of immunogenic chemotherapy in colon cancer-bearing mice.

Dual-Fuel Propelled Nanomotors with Two-Stage Permeation for Deep Bacterial Infection in the Treatment of Pulpitis.

Bacterial infection-induced inflammatory response could cause irreversible death of pulp tissue in the absence of timely and effective therapy. Given that, the narrow structure of root canal limits the therapeutic effects of passive diffusion-drugs, considerable attention has been drawn to the development of nanomotors, which have high tissue penetration abilities but generally face the problem of insufficient fuel concentration. To address this drawback, dual-fuel propelled nanomotors (DPNMs) by encapsulating L-arginine (L-Arg), calcium peroxide (CaO2 ) in metal-organic framework is developed. Under pathological environment, L-Arg could release nitric oxide (NO) by reacting with reactive oxygen species (ROS) to provide the driving force for movement. Remarkably, the depleted ROS could be supplemented through the reaction between CaO2 with acids abundant in the inflammatory microenvironment. Owing to high diffusivity, NO achieves further tissue penetration based on the first-stage propulsion of nanomotors, thereby removing deep-seated bacterial infection. Results indicate that the nanomotors effectively eliminate bacterial infection based on antibacterial activity of NO, thereby blocking inflammatory response and oxidative damage, forming reparative dentine layer to avoid further exposure and infection. Thus, this work provides a propagable strategy to overcome fuel shortage and facilitates the therapy of deep lesions.

Efficacy of L-arginine and Pycnogenol ® in the treatment of male erectile dysfunction: a systematic review and meta-analysis.

Background: The objective of this meta-analysis was to review clinical trials of the combination of Pycnogenol ® and L-arginine (PAL) in the treatment of erectile dysfunction in men and to observe the effect of PAL combined therapy on sexual function in patients with erectile dysfunction (ED), and we hope to provide more choices of drugs for treating patients with ED. Methods and analysis: The study was constructed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We searched seven databases from inception to 15 February 2023, for a comprehensive search of clinical trials using relevant keywords. Continuous variables in this meta-analysis were calculated using the mean difference and 95% confidence interval. All relevant statistical analyses were performed using RevMan v. 5.4 software. Results: Three studies with 184 patients were included in the present meta-analysis. There were no significant differences in the basic characteristics of the included studies. The results of the current meta-analysis showed that there were significant differences in the international index of erectile function scores (erectile domain), intercourse satisfaction scores, orgasmic function scores, overall satisfaction scores, and sexual desire scores between the combination treatment group and the control group. There was no significant difference in improving the testosterone levels between the two groups. Conclusion: These results indicate that the combination of PAL may have a significant effect on improving sexual function in patients with mild to moderate ED. This study will provide clinicians with more options for treating patients with ED. More randomized controlled trials are needed in the future to further demonstrate the effect of combination therapy on sexual function in patients with ED. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#myprosperoUnique, Identifier: CRD42023411781.

Enteral citrulline supplementation versus placebo on SOFA score on day 7 in mechanically ventilated critically ill patients: the IMMUNOCITRE randomized clinical trial.

BACKGROUND: Restoring plasma arginine levels through enteral administration of L-citrulline in critically ill patients may improve outcomes. We aimed to evaluate whether enteral L-citrulline administration reduced organ dysfunction based on the Sequential Organ Failure Assessment (SOFA) score and affected selected immune parameters in mechanically ventilated medical intensive care unit (ICU) patients. METHODS: A randomized, double-blind, multicenter clinical trial of enteral administration of L-citrulline versus placebo for critically ill adult patients under invasive mechanical ventilation without sepsis or septic shock was conducted in four ICUs in France between September 2016 and February 2019. Patients were randomly assigned to receive enteral L-citrulline (5 g) every 12 h for 5 days or isonitrogenous, isocaloric placebo. The primary outcome was the SOFA score on day 7. Secondary outcomes included SOFA score improvement (defined as a decrease in total SOFA score by 2 points or more between day 1 and day 7), secondary infection acquisition, ICU length of stay, plasma amino acid levels, and immune biomarkers on day 3 and day 7 (HLA-DR expression on monocytes and interleukin-6). RESULTS: Of 120 randomized patients (mean age, 60 ± 17 years; 44 [36.7%] women; ICU stay 10 days [IQR, 7-16]; incidence of secondary infections 25 patients (20.8%)), 60 were allocated to L-citrulline and 60 were allocated to placebo. Overall, there was no significant difference in organ dysfunction as assessed by the SOFA score on day 7 after enrollment (4 [IQR, 2-6] in the L-citrulline group vs. 4 [IQR, 2-7] in the placebo group; Mann‒Whitney U test, p = 0.9). Plasma arginine was significantly increased on day 3 in the treatment group, while immune parameters remained unaffected. CONCLUSION: Among mechanically ventilated ICU patients without sepsis or septic shock, enteral L-citrulline administration did not result in a significant difference in SOFA score on day 7 compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02864017 (date of registration: 11 August 2016).

Dietary Supplements for Erectile Dysfunction: Analysis of Marketed Products, Systematic Review, Meta-Analysis and Rational Use.

The use of nutraceutical products to enhance male sexual performance has a long history, especially with regard to the treatment of erectile dysfunction (ED). Alternative treatments for ED are becoming increasingly popular, with growing interest from consumers, as well as increased revenue for manufacturers. Dietary supplements (DSs), which are a mixture of active ingredients, are mainly sold online. In randomized controlled trials, the molecules contained in DSs have demonstrated varying degrees of effectiveness, or even have no evidence to support their use. However, none of the studies carried out provided sufficient evidence to consider these products a first-line therapy. Therefore, the combination of the various active ingredients, especially in relation to the daily dose, leaves doubts about the real effectiveness. In order to evaluate the potential efficacy of DS formulations, we analyzed the products marketed in Italy using a scoring approach. A systematic review of the literature was performed to evaluate the effect of DS and to detect the active ingredients able to improve erectile function-called effective ingredients (EIs)-and their minimal effective daily dose (mED). A metanalysis identified some nutraceuticals, such as Panax ginseng, Tribulus terrestris and L-arginine, that are able to improve male sexual function. Based on the scoring system, 2 (8%) supplements matched with the cluster of higher expected efficacy, 3 (12%) with the lower efficacy cluster and 20 (80%) matched with the criterion of no expected efficacy. DSs marketed in Italy are usually blends of many substances that are frequently employed at a negligible dose or without any evidence.

Citrulline in the management of patients with urea cycle disorders.

BACKGROUND: Treatment recommendations for urea cycle disorders (UCDs) include supplementation with amino acids involved in the urea cycle (arginine and/or citrulline, depending on the enzyme deficiency), to maximize ammonia excretion through the urea cycle, but limited data are available regarding the use of citrulline. This study retrospectively reviewed clinical and biological data from patients with UCDs treated with citrulline and/or arginine at a reference center since 1990. The aim was to describe the prescription, impact, and safety of these therapies. Data collection included patient background, treatment details, changes in biochemical parameters (plasma ammonia and amino acids concentrations), decompensations, and patient outcomes. RESULTS: Overall, 79 patients (median age at diagnosis, 0.9 months) received citrulline and/or arginine in combination with a restricted protein diet, most with ornithine transcarbamylase (n = 57, 73%) or carbamoyl phosphate synthetase 1 (n = 15, 19%) deficiencies. Most patients also received ammonium scavengers. Median follow-up was 9.5 years and median exposure to first treatment with arginine + citrulline, citrulline monotherapy, or arginine monotherapy was 5.5, 2.5, or 0.3 years, respectively. During follow-up, arginine or citrulline was administered at least once (as monotherapy or in combination) in the same proportion of patients (86.1%); the overall median duration of exposure was 5.9 years for arginine + citrulline, 3.1 years for citrulline monotherapy, and 0.6 years for arginine monotherapy. The most common switch was from monotherapy to combination therapy (41 of 75 switches, 54.7%). During treatment, mean ammonia concentrations were 35.9 µmol/L with citrulline, 49.8 µmol/L with arginine, and 53.0 µmol/L with arginine + citrulline. Mean plasma arginine concentrations increased significantly from the beginning to the end of citrulline treatment periods (from 67.6 µmol/L to 84.9 µmol/L, P < 0.05). At last evaluation, mean height and weight for age were normal and most patients showed normal or adapted behavior (98.7%) and normal social life (79.0%). Two patients (2.5%) experienced three treatment-related gastrointestinal adverse reactions. CONCLUSIONS: This study underlines the importance of citrulline supplementation, either alone or together with arginine, in the management of patients with UCDs. When a monotherapy is considered, citrulline would be the preferred option in terms of increasing plasma arginine concentrations.

Determining effects of nitrate, arginine, and ferrous on antibiotic recalcitrance of clinical strains of Pseudomonas aeruginosa in biofilm-inspired alginate encapsulates.

BACKGROUND: Biofilms play a role in recalcitrance and treatability of bacterial infections, but majority of known antibiotic resistance mechanisms are biofilm-independent. Biofilms of Pseudomonas aeruginosa, especially in cystic fibrosis patients infected with the alginate producing strains in their lungs, are hard to treat. Changes in growth-related bacterial metabolism in biofilm affect their antibiotic recalcitrance which could be considered for new therapies designed based on these changes. In this study, effects of nitrate, arginine, and ferrous were investigated on antibiotic recalcitrance in alginate-encapsulated P. aeruginosa strains isolated from cystic fibrosis patients in the presence of amikacin, tobramycin, and ciprofloxacin. Also, expression of an efflux pump gene, mexY, was analyzed in selected strains in the presence of amikacin and ferrous. METHODS: Clinical P. aeruginosa strains were isolated from cystic fibrosis patients and minimum inhibitory concentration of amikacin, tobramycin, and ciprofloxacin was determined against all the strains. For each antibiotic, a susceptible and a resistant or an intermediate-resistant strain were selected, encapsulated into alginate beads, and subjected to minimal biofilm eradication concentration (MBEC) test. After determining MBECs, sub-MBEC concentrations (antibiotics at concentrations one level below the determined MBEC) for each antibiotic were selected and used to study the effects of nitrate, arginine, and ferrous on antibiotic recalcitrance of encapsulated strains. Effects of ferrous and amikacin on expression of the efflux pump gene, mexY, was studied on amikacin sensitive and intermediate-resistant strains. One-way ANOVA and t test were used as the statistical tests. RESULTS: According to the results, the supplements had a dose-related effect on decreasing the number of viable cells; maximal effect was noted with ferrous, as ferrous supplementation significantly increased biofilm susceptibility to both ciprofloxacin and amikacin in all strains, and to tobramycin in a resistant strain. Also, treating an amikacin-intermediate strain with amikacin increased the expression of mexY gene, which has a role in P. aeruginosa antibiotic recalcitrance, while treating the same strain with ferrous and amikacin significantly decreased the expression of mexY gene, which was a promising result. CONCLUSIONS: Our results support the possibility of using ferrous and arginine as an adjuvant to enhance the efficacy of conventional antimicrobial therapy of P. aeruginosa infections.

Clinical study on the efficacy and tolerability of an oral supplement based on arginine, l-cystine, zinc and B6 vitamin (Cystiphane®) in patients with telogen effluvium.

BACKGROUND: Telogen effluvium (TE) is a common cause of non-cicatricial hair loss with no treatment-standardized protocol. The aim of our study was to evaluate the efficacy, tolerability, and patient compliance of a treatment with an oral supplement based on arginine, l-cystine, zinc and B6 vitamin (Cystiphane®, Laboratoires Bailleul, Geneva, Switzerland) with hair-growth properties, administered 4 times daily, in patients affected by TE. METHODS: We recruited 20 patients, aged between 18 and 70 years old, affected by TE. Patients were asked to take the oral supplement as a monotherapy, four tablets daily, in one or two administrations during meals. The study lasted 3 months. We evaluated the efficacy and tolerability of the treatment both qualitatively by collecting the clinician's opinion through a clinical evaluation and clinical-anamnestic form filled in by the researcher, and quantitatively through global photography and trichoscopy. We collected the patient's opinion through a self-assessment test, at the beginning of the recruitment and after 3 months of treatment. RESULTS: Eighteen patients were evaluated. After 3 months of taking the supplement, the researcher rated an average improvement of 2.89 at the clinical evaluation. For what concerns hair quantity, at the control trichoscopy, the mean trichoscopic value had risen to +2.055, whereas for hair diameter the mean trichoscopic diameter value had increased to +1.83. After 3 months of treatment, patients gave an average efficacy opinion of 3.61. CONCLUSIONS: The oral supplement has proved effective as an adjuvant in the treatment of TE in our cohort of patients.

Comparative Effects of Different Nutritional Supplements on Inflammation, Nutritional Status, and Clinical Outcomes in Colorectal Cancer Patients: A Systematic Review and Network Meta-Analysis.

Nutritional supplements have been widely used in colorectal cancer (CRC) patients. The aim of this network meta-analysis (NMA) was to compare the effects of different nutritional supplements on inflammation, nutritional status, and clinical outcomes in CRC patients. Four electronic databases were searched until December 2022. Randomized controlled trials (RCTs) comparing nutritional supplements of omega-3 fatty acids (omega-3), arginine, vitamin D, glutamine, probiotics, or their combinations with placebo or standard treatment were selected. The outcomes were inflammatory indicators, nutritional indicators, and clinical outcomes. A random-effects Bayesian NMA was performed to rank the effect of each supplement. In total, 34 studies involving 2841 participants were included. Glutamine was superior in decreasing tumor necrosis factor-α (MD -25.2; 95% CrI [-32.62, -17.95]), whereas combined omega-3 and arginine supplementation was more effective in decreasing interleukin-6 (MD -61.41; 95% CrI [-97.85, -24.85]). No nutritional supplements significantly maintained nutritional indicators in CRC patients. Regarding clinical outcomes, glutamine ranked highest in reducing the length of hospital stay (MD -3.71; 95% CrI [-5.89, -1.72]) and the incidence of wound infections (RR 0.12; 95% CrI [0, 0.85]), and probiotics were rated as best in reducing the incidence of pneumonia (RR 0.38; 95% CrI [0.15, 0.81]). Future well-designed RCTs are needed to further confirm these findings.

Differential benefits of physical training associated or not with l-arginine supplementation in rats with metabolic syndrome: Evaluation of cardiovascular, autonomic and metabolic parameters.

Metabolic syndrome (MetS) is characterized by endocrine-metabolic and cardiac alterations that increase the risk of cardiovascular disease, dyslipidemia, and type-2 diabetes mellitus. Dietary supplementation with l-Arginine (L-Arg) is beneficial for fat loss, while chronic aerobic exercise has several benefits in reversing cardiovascular, autonomic, and metabolic dysfunctions caused by obesity. However, the association between these two approaches has not yet been described. This study aimed to evaluate the possible benefits of physical training, with or without l-Arg-supplementation, on cardiovascular, autonomic, and metabolic parameters in rats with MetS, which was induced by the subcutaneous administration of monosodium glutamate at 4 mg g-1day-1 in rats from the first to fifth day of life. Physical training on a treadmill and supplementation with l-Arg-in adulthood were carried out concomitantly for 8 weeks. After this, the animals underwent femoral artery catheterization to record their cardiovascular parameters and autonomic modulation. Organs and blood were removed to measure levels of nitrite, glucose, and hepatic steatosis. In adult rats with MetS, supplementation with l-Arg-in combination with physical training reduced hypertension, tachycardia, adipose tissue mass, free fatty acids, and hepatic steatosis. Supplementation with l-Arg-and physical training separately was beneficial in reducing several aspects of MetS, but a combination of both was especially effective in reducing adipose tissue and hepatic steatosis. Together, the two therapies can form a good strategy to combat MetS.

In Situ Hybridization of Polymeric Curcumin to Arginine-Derived Carbon Quantum Dots for Synergistic Treatment of Bacterial Infections.

Effective infectious keratitis treatment must eliminate the pathogen, reduce the inflammatory response, and prevent persistent damage to the cornea. Infectious keratitis is generally treated with broad-spectrum antibiotics; however, they have the risk of causing corneal epithelial cell damage and drug resistance. In this study, we prepared a nanocomposite (Arg-CQDs/pCur) from arginine (Arg)-derived carbon quantum dots (Arg-CQDs) and polymeric curcumin (pCur). Partial carbonization of arginine hydrochloride in the solid state by mild pyrolysis resulted in the formation of CQDs, which exhibited enhanced antibacterial activity. pCur was formed by the polymerization of curcumin, and further crosslinking reduced its cytotoxicity and improved antioxidative, anti-inflammatory, and pro-proliferative activities. The pCur in situ conjugated with Arg-CQDs to form the Arg-CQDs/pCur nanocomposite, which showed a minimum inhibitory concentration of ca. 10 µg mL-1, which was >100-fold and >15-fold lower than that of the precursor arginine and curcumin, respectively, against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. The Arg-CQDs/pCur nanocomposite with combined antibacterial, antioxidative, anti-inflammatory, pro-proliferative properties, and long-term retention on cornea enabled synergistic treatment of bacterial keratitis. In a rat model, it can effectively treat P. aeruginosa-induced bacterial keratitis at a concentration 4000-fold lower than the commercially used drug, Sulmezole eye drops. Arg-CQDs/pCur nanocomposites have great potential for application in antibacterial and anti-inflammatory nanoformulations for clinical use to treat infectious diseases.

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study.

OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria.

Analysis of a maternal health medicines pipeline database 2000-2021: New candidates for the prevention and treatment of fetal growth restriction.

OBJECTIVE: The Accelerating Innovation for Mothers project established a new database of candidate medicines under development between 2000 and 2021 for five pregnancy-related conditions, including fetal growth restriction. The objective was to assess medicines for fetal growth restriction and their potential for clinical use globally. DESIGN: Landscape analysis. SETTING: Global (focus on low- and middle-income countries, LMICs). SAMPLE: Drugs, dietary supplements and biologics under investigation for prevention or treatment of fetal growth restriction. METHODS: A research pipeline database of medicines was created through searching AdisInsight, PubMed and various grant and clinical trial databases. Analysis of clinical and preclinical candidates were descriptive. MAIN OUTCOMES MEASURES: Fetal growth restriction candidates in clinical development were identified and ranked as high, medium or low potential based on prespecified criteria, including efficacy, safety and accessibility. RESULTS: Of the 444 unique candidates in the database across all five pregnancy-related conditions, 63 were for fetal growth restriction. Of these, 31 were in clinical development (phases I, II or III) and 32 were in preclinical development. Three candidates, aspirin, l-arginine and vitamin D, were ranked as having high potential as preventive agents. There were no high-potential candidates for treating fetal growth restriction, although five candidates were ranked as having medium potential: allylestrenol, dalteparin, omega-3 fatty acids, tadalafil, and United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP). CONCLUSIONS: l-Arginine, aspirin and vitamin D are promising, high-potential preventative agents for fetal growth restriction. Based on the medicines pipeline, new pharmacological agents for fetal growth restriction are unlikely to emerge in the near future.

L-arginine and lisinopril supplementation protects against sodium fluoride-induced nephrotoxicity and hypertension by suppressing mineralocorticoid receptor and angiotensin-converting enzyme 3 activity.

Sodium fluoride (NaF) is one of the neglected environmental toxicants that has continued to silently cause toxicity to both humans and animals. NaF is universally present in water, soil, and atmosphere. The persistent and alarming rate of increase in cardiovascular and renal diseases caused by chemicals such as NaF in mammalian tissues has led to the use of various drugs for the treatment of these diseases. The present study aimed at evaluating the renoprotective and antihypertensive effects of L-arginine against NaF-induced nephrotoxicity. Thirty male Wistar rats (150-180 g) were used in this study. The rats were randomly divided into five groups of six rats each as follows: Control, NaF (300 ppm), NaF + L-arginine (100 mg/kg), NaF + L-arginine (200 mg/kg), and NaF + lisinopril (10 mg/kg). Histopathological examination and immunohistochemistry of renal angiotensin-converting enzyme (ACE) and mineralocorticoid receptor (MCR) were performed. Markers of renal damage, oxidative stress, antioxidant defense system, and blood pressure parameters were determined. L-arginine and lisinopril significantly (P < 0.05) ameliorated the hypertensive effects of NaF. The systolic, diastolic, and mean arterial blood pressure of the treated groups were significantly (P < 0.05) reduced compared with the hypertensive group. This finding was concurrent with significantly increased serum bioavailability of nitric oxide in the hypertensive rats treated with L-arginine and lisinopril. Also, there was a significant reduction in the level of blood urea nitrogen and creatinine of hypertensive rats treated with L-arginine and lisinopril. There was a significant (P < 0.05) reduction in markers of oxidative stress such as malondialdehyde and protein carbonyl and concurrent increase in the levels of antioxidant enzymes in the kidney of hypertensive rats treated with L-arginine and lisinopril. The results of this study suggest that L-arginine and lisinopril normalized blood pressure, reduced oxidative stress, and the expression of renal ACE and mineralocorticoid receptor, and improved nitric oxide production. Thus, L-arginine holds promise as a potential therapy against hypertension and renal damage.

A modulatory effect of L-arginine supplementation on anticancer effects of chemoimmunotherapy in colon cancer-bearing aged mice.

Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) are increased in cancer-bearing aged hosts. Arginase-I in MDSCs degrades L-arginine, an amino acid required for T cell activation and proliferation. In this study, we compared the therapeutic efficacy of 5-fluorouracil (5-FU)/oxaliplatin (L-OHP) and cyclophosphamide (CP) between young and aged colon cancer-bearing mice. Therapy with 5-FU/L-OHP and CP significantly suppressed the in vivo growth of CT26 and MC38 colon carcinomas in syngeneic young mice, whereas this effect was attenuated in aged mice. L-arginine monotherapy showed no effect in aged mice. However, additional therapy with anti-programmed cell death (PD)-1 antibody and L-arginine supplementation boosted the effect of chemoimmunotherapy in aged mice, and some mice were cured. During all combination therapy, tumor-specific cytotoxic T lymphocytes (CTLs) were generated from mice with non-progressing tumor, but not from those with progressing tumor. Plasma L-arginine levels were lower in aged than young mice, and chemotherapy tended to decrease the plasma L-arginine levels in aged mice. Compared to young mice, CT26-bearing aged mice decreased arginase activity, arginase-I expression, and the proportion of monocytic MDSCs in tumor tissues, whereas contrasting results were observed in MC38-bearing aged mice. Importantly, the induction of tumor-specific CTLs was impaired at lower doses of L-arginine in vitro, and the infiltration of CTLs into CT26 tissues after chemoimmunotherapy was promoted by L-arginine administration in vivo. These results indicate that chemoimmunotherapy was less effective in cancer-bearing aged mice, but that L-arginine supplementation can modulate its therapeutic efficacy via its effect on tumor-specific CTLs.

The effect of l-arginine supplementation on amelioration of oxygen support in severe COVID-19 pneumonia.

BACKGROUND & AIMS: l-Arginine (l-Arg) has been shown to help reduce respiratory support requirements in coronavirus disease 2019 (COVID-19), in an Italian study. We investigated the effect of l-Arg supplementation on the reduction in respiratory support for patients with severe COVID-19 pneumonia in an Indian population. METHODS: A parallel-group, triple-blinded, randomized controlled trial (RCT) was conducted on patients with severe COVID-19 pneumonia on oxygen (O2) support. Patients received either 3 g of oral l-Arg or placebo, daily under supervision, until they were off O2 support, or for a maximum of 10 days, whichever was earlier. The primary outcome was cessation in O2 support. Other outcomes were time to cessation of O2 support, duration of hospitalization, and incidence of adverse thrombotic events. RESULTS: We did an intention-to-treat analysis on 74 patients who were randomized into l-Arg (n = 38) or placebo group (n = 36). There were no significant differences between the two groups in the outcomes. At end of the study, 28 patients (73.6%) in l-Arg and 26 patients (72.2%) in the placebo group were weaned off oxygen support. The median number of days to the cessation of O2 support estimated using Kaplan Meir survival analysis, was 3 days in the l-Arg group (95% confidence interval [CI]: 1.2, 4.7) and 5 days in the placebo group (95% CI, 4.1,5.8); P = 0.27. CONCLUSION: In this group of patients with severe COVID-19 pneumonia, l-Arg supplementation did not show any significant difference in outcomes when compared to placebo supplementation.

Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial.

Long COVID, a condition characterized by symptom and/or sign persistence following an acute COVID-19 episode, is associated with reduced physical performance and endothelial dysfunction. Supplementation of l-arginine may improve endothelial and muscle function by stimulating nitric oxide synthesis. A single-blind randomized, placebo-controlled trial was conducted in adults aged between 20 and 60 years with persistent fatigue attending a post-acute COVID-19 outpatient clinic. Participants were randomized 1:1 to receive twice-daily orally either a combination of 1.66 g l-arginine plus 500 mg liposomal vitamin C or a placebo for 28 days. The primary outcome was the distance walked on the 6 min walk test. Secondary outcomes were handgrip strength, flow-mediated dilation, and fatigue persistence. Fifty participants were randomized to receive either l-arginine plus vitamin C or a placebo. Forty-six participants (median (interquartile range) age 51 (14), 30 [65%] women), 23 per group, received the intervention to which they were allocated and completed the study. At 28 days, l-arginine plus vitamin C increased the 6 min walk distance (+30 (40.5) m; placebo: +0 (75) m, p = 0.001) and induced a greater improvement in handgrip strength (+3.4 (7.5) kg) compared with the placebo (+1 (6.6) kg, p = 0.03). The flow-mediated dilation was greater in the active group than in the placebo (14.3% (7.3) vs. 9.4% (5.8), p = 0.03). At 28 days, fatigue was reported by two participants in the active group (8.7%) and 21 in the placebo group (80.1%; p < 0.0001). l-arginine plus vitamin C supplementation improved walking performance, muscle strength, endothelial function, and fatigue in adults with long COVID. This supplement may, therefore, be considered to restore physical performance and relieve persistent symptoms in this patient population.

High-Throughput Metabolomics Integrated Network Pharmacology Reveals the Underlying Mechanism of Paeoniae Radix Alba Treating Rheumatoid Arthritis.

OBJECTIVE: The mechanism of action and potential targets of Paeoniae RadixAlba (Baishao, B) in the treatment of adjuvant-induced arthritis (AIA) rats are explained using metabolomics and network pharmacology techniques, and the research evidence for the development of anti-rheumatoid arthritis (RA) drugs is enriched. METHODS: The rats were injected with Freund's complete adjuvant (CFA) to induce arthritis. We then measured the general physical characteristics, examined their X-rays and histopathology to evaluate the pathological condition of the inflammation models, and conducted metabolomics studies on the change in urine metabolism caused by CFA. The lyophilized powder of B at a dose of 2.16 g/kg was orally administered to the rats continuously for 28 days, and the therapeutic effect was evaluated. Network pharmacology prediction shows that B contains the target action of the ingredient, and the simulation of the target molecular docking, in combination with the metabolomics analysis results, shows that B has a potential role in the treatment of AIA rats. RESULTS: B can reduce the paw swelling and pathological changes in rats caused by CFA, reverse the levels of 12 urine biomarkers, and regulate histidine metabolism, phenylalanine metabolism, arginine, proline metabolism, pyrimidine metabolism, etc. The prediction of the active ingredient target in B indicates that it may act as an inflammatory signaling pathway in anti-RA, among them being paeoniflorin, palbinone, beta-sitosterol, kaempferol, and catechin, which are the significant active ingredients. CONCLUSION: The metabolomics results revealed the markers and metabolic mechanisms of urinary metabolic disorders in rats with AIA, demonstrated the efficacy of the therapeutic effect of B, and identified the key ingredients in B, providing theoretical support for the subsequent development and utilization of B.