L-Arginine

OBJECTIVE: This study aims to investigate the effects of l-citrulline supplementation and watermelon intake on blood pressure (BP) in middle-aged and elderly individuals. METHODS: Data analysis was conducted using RevMan 5.4.1 software, employing a random effects model to statistically analyze the pooled effect sizes of the obtained systolic blood pressure (SBP) and diastolic blood pressure (DBP) data. Results are reported as weighted mean differences (WMD) with 95 % confidence intervals (95 % CI). RESULTS: A total of 15 randomized controlled trials (RCTs) investigating the effects of l-citrulline supplementation and watermelon intake on BP in middle-aged and elderly individuals were included, comprising 24 datasets involving 415 participants. The results indicate that l-citrulline supplementation and watermelon intake significantly reduced SBP (-4.02 mmHg [95 % CI: -6.54 to -1.50], P = 0.002) and DBP (-2.54 mmHg [95 % CI: -4.27 to -0.81], P = 0.004) in the elderly. Subgroup analysis showed that the combined supplementation of l-citrulline and l-arginine significantly decreased SBP (-10.44 mmHg [95 % CI: -13.57 to -7.31], P < 0.00001) and DBP (-4.86 mmHg [95 % CI: -7.93 to -1.79], P = 0.002) in this population. CONCLUSION: l-citrulline supplementation and watermelon intake overall lowered BP in middle-aged and elderly individuals. Subgroup analysis indicates that the combined supplementation of l-citrulline and l-arginine is superior to l-citrulline or watermelon supplementation alone. These findings provide new dietary recommendations for BP management in the elderly, suggesting that dietary interventions can effectively improve cardiovascular health and reduce the risk of cardiovascular disease (CVD).

BACKGROUND & AIMS: Sickle cell disease (SCD), a neglected chronic genetic blood disorder that severely impacts the pediatric population, often leading to premature death, is associated with compromised nutritional status. This study aimed to evaluate the effect of nutritional supplementation in SCD-related complications. METHODS: A systematic review with searches in PubMed, Scopus and Web of Science was performed. Randomized controlled trials (RCT) assessing diet or supplements as complementary therapy for children and adolescents with SCD were included (PROSPERO:CRD42024532369). The data for outcomes of interest (efficacy, safety) were pooled by means of pairwise and network meta-analyses with ranking (p-score) analysis. The results were presented as odds ratio or mean differences with 95 % confidence intervals (NMAstudio2.0). RESULTS: Twenty RCTs were included (2002-2023) (n = 2058), analyzing 9 dietary supplements on different regimens. All patients were in use of hydroxyurea as active treatment. Supplementation with fatty acids (n = 3 studies) and l-arginine (n = 4) presented higher efficacy and safety, significantly improving pain intensity, vaso-occlusive crises (VOC) and inflammation when compared to usual care/placebo (p < 0.05). Vitamin D3 (n = 6) at different dosages may reduce respiratory complications and length of hospital stay, yet further studies are needed to confirm its significant effects. Evidence is limited and of poor quality regarding the effects of add-on vitamin A (n = 2), magnesium sulfate (n = 2) and zinc (n = 4) for this population. CONCLUSIONS: The complementary use of certain supplements (fatty acids, l-arginine, vitamin D3) can enhance the management of VOC and improve patients' physiological functions. These supplements are often affordable and can contribute towards the reduction of opioid use and shorten patients' hospital stays - especially in low/middle-income countries where resources are scarce. Although further studies are needed to refine these findings (e.g., appropriate doses/regimens), practical guidelines and decision-makers may benefit from updated evidence.

BACKGROUND: Evidence suggests L-arginine may be effective at reducing pre-eclampsia and related outcomes. However, whether L-arginine can prevent or only treat pre-eclampsia, and thus the target population and timing of initiation, remains unknown. OBJECTIVES: To evaluate the effects of L-arginine and L-citrulline (precursor of L-arginine) on the prevention and treatment of pre-eclampsia. SEARCH STRATEGY: MEDLINE, Embase, CINAHL, Global Index Medicus and the Cochrane Library were searched through 7 February 2024. SELECTION CRITERIA: Trials administering L-arginine or L-citrulline to pregnant women, with the comparison group receiving placebo or standard care, were included. DATA COLLECTION AND ANALYSIS: Meta-analyses were conducted separately for prevention or treatment trials, using random-effects models. MAIN RESULTS: Twenty randomised controlled trials (RCTs) (2028 women) and three non-randomised trials (189 women) were included. The risk of bias was 'high' in eight RCTs and showed 'some concerns' in 12. In prevention trials, L-arginine was associated with a reduced risk of pre-eclampsia (relative risk [RR] 0.52; 95% confidence interval [CI], 0.35, 0.78; low-certainty evidence, four trials) and severe pre-eclampsia (RR 0.23; 95% CI, 0.09, 0.55; low-certainty evidence, three trials). In treatment trials, L-arginine may reduce mean systolic blood pressure (MD -5.64 mmHg; 95% CI, -10.66, -0.62; very low-certainty evidence, three trials) and fetal growth restriction (RR 0.46; 95% CI, 0.26, 0.81; low-certainty evidence, two trials). Only one study (36 women) examined L-citrulline and reported no effect on pre-eclampsia or blood pressure. CONCLUSIONS: L-arginine may be promising for pre-eclampsia prevention and treatment, but findings should be interpreted cautiously. More trials are needed to determine the optimal dose and time to commence supplementation and support clinical decision-making. © 2025 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.

BACKGROUND: Nutritional supplements are widely used by swimmers, but the effectiveness of various supplements and the identification of the most effective intervention require further investigation. PURPOSE: This paper evaluated and compared the effectiveness of various nutrition-based interventions on swimming performance through both direct and indirect comparisons. METHODS: PubMed, Embase, Web of Science, Cochrane Library, and SPORTDiscus databases were thoroughly searched up to 4 April 2024. The risk of bias was judged using the Cochrane risk of bias tool. A random-effect model was adopted to compute standardized mean differences (SMD) and 95% confidence intervals (CI). RESULTS: L-arginine (Arg) demonstrated superior performance to the placebo (SMD = -1.66, 95% CI [-2.92, -0.44]), emerging as the most effective intervention for reducing 100 swimming time (SUCRA = 89.5%). Beta-alanine (BA) was the best intervention for improving blood lactate (SUCRA = 80%). Creatine combined with sodium bicarbonate (Creatine_NaHCO3) significantly increased blood pH compared to the placebo (SMD = 3.79, 95% CI [1.85, 5.80]), with a SUCRA score of 99.9%, suggesting it is the most effective intervention for this parameter. No prominent differences were noted among the interventions in 50 m time, 200 m time, heart rate, and body mass. CONCLUSIONS: Dietary supplements might provide benefits for improving swimming performance. Arg emerged as the most efficacious modality for reducing 100 m time. BA proved to be the preeminent strategy for decreasing blood lactate. Creatine_NaHCO3 was distinguished as the optimal approach for improving blood pH.

BACKGROUND: Numerous studies have explored the effects of L-arginine, whether administered in the form of a supplement or through infusion during cardioplegia, on cardiac and inflammatory markers in individuals undergoing coronary artery bypass grafting (CABG). However, these studies presented contradictory findings. Consequently, the objective of this study was to investigate the impact of l-arginine on these markers by analyzing available randomized controlled trials (RCTs). METHODS: We performed an extensive search across various databases, including Embase, Medline/PubMed, Web of Science, Scopus, Cochrane Library, and Google Scholar, covering research published until December 2023. To analyze the mean changes in inflammatory and cardiac markers between the L-arginine and control groups, we calculated the weighted mean difference (WMD) along with the corresponding 95% confidence interval (CI) using a random-effects model. RESULTS: A total of 393 RCTs were identified during the initial search. After screening and selection, 7 trials were included. In a meta-analysis of three trials that reported troponin T levels, we found a significant impact of L-arginine on reducing troponin T levels (WMD = -0.61 ng/ml; 95% CI: -1.07, -0.15). Our analysis also showed that L-arginine had a noticeable impact on decreasing interleukin-6 (IL-6) levels (WMD = -7.72 pg/ml; 95% CI: -15.05, -0.39). However, we found no considerable impact of L-arginine treatment on creatine phosphokinase-MB (CPK-MB), tumor necrosis factor-alpha (TNF-α), and troponin I compared to the placebo groups. CONCLUSIONS: Our findings suggest that L-arginine may benefit patients undergoing CABG, as it helps reduce inflammatory reactions and limits myocardial ischemia. This study registered in the PROSPERO database (Registration No. CRD42024508341). © 2024. The Author(s).

BACKGROUND: Although nutraceutical-based treatments are often offered for erectile dysfunction (ED), their efficacy remains doubtful, and the choice of one substance over the other is challenged by the dearth of head-to-head comparative studies. AIM: We aimed to compare the efficacy of available nutraceutical interventions, alone or in combination with phosphodiesterase type 5 inhibitors (PDE5i), in improving erectile function in men with ED through a network meta-analysis (NMA), which incorporates direct and indirect evidence into one model thus generating a hierarchy of effectiveness. METHODS: PubMed, Scopus, Web of Sciences, and Cochrane Library databases were searched for randomized placebo-controlled trials (RCTs) assessing the effect of any nutraceutical regimen in improving erectile function when compared to each other, placebo, and/or PDE5i in men with ED. Data were included in a random-effects NMA, where efficacy of treatments was ranked by surface under the cumulative ranking curve (SUCRA). Two NMAs were also conducted separately for organic and non-organic ED. Reciprocal comparisons between all treatments were analyzed by league tables. OUTCOMES: The main outcome was the standardized mean difference in the score of the International Index of Erectile Function (IIEF)-5 or IIEF-6. RESULTS: Fifteen RCTs provided information on 1000 men with ED. In the overall NMA, compared to placebo, the combination propionyl L-carnitine (PLC) + acetyl L-carnitine (ALC) + Sildenafil was associated with the highest SUCRA (97%) in improving erectile function score, followed by L-Arginine + Tadalafil (84%), Sildenafil (79%), Tadalafil (72%), and L-Arginine (52%). No other treatment regimen showed efficacy with statistical significance. In patients with organic ED, the efficacy of Sildenafil and Tadalafil was significantly improved by PLC + ALC and L-Arginine, respectively. On the contrary, in non-organic ED, nutraceuticals did not improve the therapeutic performance of daily Tadalafil. CLINICAL IMPLICATIONS: This NMA contributes valuable insights into the potential of nutraceutical interventions for ED. STRENGTHS AND LIMITATIONS: We employed strict inclusion criteria relat

BACKGROUND: Sickle cell disease (SCD) refers to a group of genetic disorders characterized by the presence of an abnormal haemoglobin molecule called haemoglobin S (HbS). When subjected to oxidative stress from low oxygen concentrations, HbS molecules form rigid polymers, giving the red cell the typical sickle shape. Antioxidants have been shown to reduce oxidative stress and improve outcomes in other diseases associated with oxidative stress. Therefore, it is important to review and synthesize the available evidence on the effect of antioxidants on the clinical outcomes of people with SCD. OBJECTIVES: To assess the effectiveness and safety of antioxidant supplementation for improving health outcomes in people with SCD. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 15 August 2023. SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials comparing antioxidant supplementation to placebo, other antioxidants, or different doses of antioxidants, in people with SCD. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed the risk of bias and certainty of the evidence, and reported according to Cochrane methodological procedures. MAIN RESULTS: The review included 1609 participants in 26 studies, with 17 comparisons. We rated 13 studies as having a high risk of bias overall, and 13 studies as having an unclear risk of bias overall due to study limitations. We used GRADE to rate the certainty of evidence. Only eight studies reported on our important outcomes at six months. Vitamin C (1400 mg) plus vitamin E (800 mg) versus placebo Based on evidence from one study in 83 participants, vitamin C (1400 mg) plus vitamin E (800 mg) may not be better than placebo at reducing the frequency of crisis (risk ratio (RR) 1.18, 95% confidence interval (CI) 0.64 to 2.18), the severity of pain (RR 1.33, 95% CI 0.40 to 4.37), or adverse effects (AE), of which the most common were headache, nausea, fatigue, diarrhoea, and epigastric pain (RR 0.56, 95% CI 0.31 to 1.00). Vitamin C plus vitamin E may increase the risk of SCD-related complications (acute chest syndrome: RR 2.66, 95% CI 0.77 to

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.

The repercussions on oxidative and inflammatory stress markers under the effects of arginine and citrulline in response to exercise are not fully reached. We completed a systematic review to investigate the effects of L-Citrulline or L-Arginine on oxidative stress and inflammatory biomarkers following exercise. EMBASE, MEDLINE (PubMed), Cochrane Library, CINAHL, LILACS, and Web of Science databases were used to record the trials. This study includes randomized controlled trials (RCTs) and non-RCTs with subjects over 18 years old. Those under the intervention protocol consumed L-Citrulline or L-Arginine, and the controls ingested placebo. We recognized 1080 studies, but only 7 were included (7 studies in meta-analysis). We observed no difference between pre- vs. post-exercise for oxidative stress (subtotal = -0.21 [CI: -0.56, 0.14], p = 0.24, and heterogeneity = 0%. In the sub-group "L-Arginine" we found a subtotal = -0.29 [-0.71, 0.12], p = 0.16, and heterogeneity = 0%. For the "L-Citrulline" subgroup we observed a subtotal = 0.00 [-0.67, 0.67], p = 1.00, and heterogeneity was not applicable. No differences were observed between groups (p = 0.47), and I² = 0%) or in antioxidant activity (subtotal = -0.28 [-1.65, 1.08], p = 0.68, and heterogeneity = 0%). In the "L-Arginine" sub-group, we found a subtotal = -3.90 [-14.18, 6.38], p = 0.46, and heterogeneity was not applicable. For the "L-Citrulline" subgroup, we reported a subtotal = -0.22 [-1.60, 1.16], p = 0.75, and heterogeneity was not applicable. No differences were observed between groups (p = 0.49), and I² = 0%), inflammatory markers (subtotal = 8.38 [-0.02, 16.78], p = 0.05, and heterogeneity = 93%. Tests for subgroup differences were not applicable, and anti-inflammatory markers (subtotal = -0.38 [-1.15, 0.39], p = 0.34 and heterogeneity = 15%; testing for subgroup differences was not applicable). In conclusion, our systematic review and meta-analysis found that L-Citrulline and L-Arginine did not influence inflammatory biomarkers and oxidative stress after exercise.

BACKGROUND & AIMS: Previous research established that the availability of l-arginine affects placental vascular development and fetal growth. However, practical details associated with the effects of l-arginine supplementation on the neonatal outcomes of hypertensive disorder (HD) and intrauterine growth restriction (IUGR) pregnancies are limited. METHODS: The PubMed, ScienceDirect, and Web of Science databases were searched for peer-reviewed literature published by September 30, 2021 to investigate the operational details of l-arginine supplementation in improving neonatal outcomes in complicated pregnancies. Standardized mean difference (SMD) and weighted mean difference (WMD) of continuous variables, as well as the risk ratio (RR) for categorical variables were pooled by random-effects models. RESULTS: The results indicated that l-arginine supplementation increased the plasma nitric oxide (NO) concentrations in IUGR pregnancies (SMD: 0.71; 95% CI: 0.45, 0.97; I2 = 0%), but decreased the risk of preeclampsia in HD mothers (RR: 0.49; 95% CI: 0.31, 0.76; I2 = 0%). Administration with l-arginine elevated birth weights both in hypertensive and IUGR pregnant women, with WMDs of 194.70 g (95% CI: 58.21, 331.20; I2 = 44.2%) and 134.00 g (95% CI: 43.53, 224.46; I2 = 42.4%), respectively. However, the intervention had no effect on gestational age except in HD pregnancies (WMD: 7.05 d; 95% CI: 3.16, 10.95; I2 = 36.5%). l-arginine administration during pregnancy significantly reduced the small for gestational age (SGA) risk of fetus both in HD (RR: 0.51; 95% CI: 0.31, 0.83; I2 = 0.0%) and IUGR mothers (RR: 0.46; 95% CI: 0.25, 0.88; I2 = 0.0%). Subgroup analyses revealed that l-arginine supplementation at <4 g/d dosage or for ≥1-month duration or in the third trimester had a greater effect on birth weights in HD women without proteinuria, but a higher l-arginine dosage was more beneficial for extending gestational age and reducing the risk of SGA in older pregnancies. Additionally, intravenous infusion of l-arginine, but not oral administration, significantly increased birth weight in IUGR pregnancies with elevated NO concentrations, although the recommended amount should

ETHNOPHARMACOLOGICAL RELEVANCE: Acute Pancreatitis (AP) is a pancreatic inflammatory disease lacking specific therapeutics. Da-Cheng-Qi Decoction (DCQD) has been proven to alleviate the severity and mortality of AP. However, its underlying mechanisms remain to be fully elucidated. AIM OF THE STUDY: This study aimed to explore DCQD's dynamic metabolic regulatory effects on AP patients and potential pharmacodynamic substances via serum metabolomics and serum pharmacochemistry analysis, with validation in animal models. MATERIALS AND METHODS: AP patients were randomized into conventional therapy (Con) and Con + DCQD groups. Fasting venous blood samples were collected at four time points (admission, 24 h/96 h post-admission, pre-discharge) for biochemical assays and UHPLC-Q-Exactive-Orbitrap-MS analysis. Metabolomics was used to screen AP-related biomarkers, evaluate the two regimens' reversal effects, and compare inter-group differences in metabolic recovery trajectories. Prototypes and metabolites of DCQD were identified, with potential pharmacodynamic substances screened via correlation analysis with AP biomarkers. L-arginine-induced SAP mouse model was used for validation. RESULTS: Serum amylase normalization and C-reactive protein decline were accelerated in Con + DCQD group. Both regimens reversed AP-related energy, amino acid, and lipid metabolic disorders. Adjuvant DCQD therapy accelerated inflammation alleviation and energy homeostasis restoration in early stage, and improved lipid metabolism more comprehensively in middle-to-late stage, with efficacy validated in SAP mice. Forty-eight and 35 blood-migrated components were identified in patients and mice, respectively, with 8 key pharmacodynamic substances screened. CONCLUSIONS: Integrating serum metabolomics and multi-time-point monitoring, this study delineated AP's metabolic recovery trajectory and clarified DCQD's efficacy and dynamic metabolic regulation, providing guidance for its clinical application.

Lower limb arterial disease is among the most common vascular disorders, with its incidence rising significantly in aging populations, thus posing a major social and healthcare challenge. Currently, L-arginine is considered by vascular surgery experts as a compound with therapeutic potential in intermittent claudication, though its clinical efficacy remains insufficiently confirmed. The aim of this study was to evaluate the efficacy and safety of oral L-arginine supplementation in patients with atherosclerotic lower limb ischemia, with particular regard to lipid metabolism disorders. A randomized study included 100 patients (62 men and 38 women) over 50 years of age with Fontaine stage II ischemia. The study group received oral L-arginine at a dose of 6 g/day for 30 and 60 days. Clinical parameters were assessed, including the ankle-brachial index (ABI) and pain-free walking distance (PFWD), along with oxidative stress markers (serum nitric oxide (NO) concentration, total antioxidant status (TAS)) and lipid profile (total, HDL, and LDL cholesterol, and triglycerides). In both study and control groups, subgroups with hypertriglyceridemia, hypercholesterolemia, and mixed hyperlipidemia were additionally identified. Evaluations were performed at baseline, day 30, and day 60. After 30 and 60 days, significant increases in NO and TAS levels (p<0.001), as well as extended PFWD (p<0.001), were observed across all subgroups receiving L-arginine compared with controls. No significant effects were observed on ABI (right or left) or on cholesterol and triglyceride concentrations. These findings support the potential role of L-arginine as a supportive therapy in the management of atherosclerotic complications, particularly by improving oxidative balance and exercise tolerance.

OBJECTIVE: Excessive intake of electrolyte sports drinks (ESDs) among adolescents and athletes is associated with dental erosion due to their low pH, while their sugar content increases the risk of dental caries. This study aimed to evaluate and compare the protective effects of incorporating either L-arginine or Salvadora persica (Miswak) extract into an ESD on enamel surface properties. MATERIALS AND METHODS: Extracted human premolars were randomly assigned to three groups (n = 6): (1) plain ESD, (2) ESD with 1% L-arginine (Arg-ESD), and (3) ESD with 10% Salvadora persica extract (Mis-ESD). Each specimen was immersed in its respective solution for 5 min daily over 7 days. Post-treatment assessments included enamel microhardness (VHN), surface roughness (Sa), colour change (ΔE), Ca/P ratio, and scanning electron microscopy (SEM) for surface morphology. A taste acceptability survey was conducted in adult volunteers. Statistical analysis used one-way ANOVA (α = 0.05). In addition, a small panel of adult volunteers (n = 20) evaluated the taste acceptability of the modified formulations after providing informed consent. RESULTS: Both Arg-ESD and Mis-ESD significantly increased enamel microhardness and reduced surface roughness compared to plain ESD (P < 0.01), with Mis-ESD showing the greatest improvements. Mis-ESD also enhanced colour stability (P < 0.001). SEM images confirmed preservation of enamel structure, particularly in Mis-ESD specimens. Taste testing indicated good palatability for both modified formulations. CONCLUSION: Incorporating Salvadora persica extract into ESDs significantly improved enamel resistance to erosion and enhanced aesthetic properties. Miswak-enriched ESDs could serve as a preventive option for dental erosion. CLINICAL RELEVANCE: Formulating ESDs with Salvadora persica may reduce their erosive potential while preserving taste acceptability, offering a novel, consumer-friendly strategy to protect enamel in high-risk populations. © 2025. The Author(s).

This study aimed to evaluate the effects of short-term oral L-arginine (ARG) supplementation on vascular parameters, nitric oxide (NO) concentration, and muscular performance during upper limb resistance exercise in healthy young men. A randomized, double-blind, crossover design was used with 16 recreationally trained men. Participants ingested ARG (3.2-9.6 g/day) or placebo for 4 days, separated by a 14-day washout. On the fourth day, they completed three sets of biceps curls at 65% of one-repetition maximum to concentric failure. Primary outcomes included total repetitions performed and fatigue ratio. Secondary outcomes comprised brachial artery diameter, peak systolic velocity, blood flow (velocity-time integral), vascular resistance index, plasma NO, and blood lactate concentrations. No significant differences were observed between ARG and placebo in muscular endurance (total repetitions, p = .305), volume load, or fatigue ratio. Plasma NO levels did not differ between conditions (p = .522). Although brachial artery diameter significantly increased 1-min postexercise in the ARG condition compared with placebo (p = .023), no differences were found for velocity-time integral, peak systolic velocity, resistance index, or blood pressure. Blood lactate concentrations rose after exercise in both groups, with a nonsignificant value in the ARG condition (p = .09 at 9-min postexercise). Short-term oral ARG supplementation did not enhance muscular endurance, systemic NO concentration, or vascular function during upper limb resistance exercise in healthy young men. Although a minor increase in brachial artery dilation was observed shortly after exercise, the effect was transient and insufficient to support meaningful ergogenic benefits.

Background/Objectives: Watermelon (Citrullus lanatus) is a natural dietary source of L-citrulline and L-arginine, the two amino acids involved in nitric oxide (NO) production and vasodilation. Pre-clinical and clinical studies using isolated amino acids or watermelon extracts suggest blood pressure (BP)-lowering potential; however, limited research has been conducted on the impact of watermelon flesh (WM) on BP in adults at risk for hypertension. Therefore, the primary objective of this study was to assess the effect of daily WM intake for four weeks on 24 h ambulatory BP in adults with elevated blood pressure. The secondary outcomes of this study include changes in glucose and insulin markers, lipid profile, NO, L-citrulline, L-arginine, asymmetric dimethylarginine (ADMA) concentrations, and the L-arginine/ADMA ratio. Methods: In this randomized, placebo controlled parallel study design, 39 adults (age: 41 ± 14 years, BMI: 31 ± 6 kg/m2, mean ± SD) with elevated BP were randomly assigned to one of three groups for a 4-week intervention: control (0 g WM), WM-1 cup (152 g/day), or WM-2 cups (304 g/day). Ambulatory BP was measured over 24 h at baseline and the end of the intervention period. Fasting plasma samples were analyzed for metabolic biomarkers on a clinical analyzer and NO using a colorimetric assay. L-citrulline, L-arginine, and ADMA were analyzed using an ultra-high-performance liquid chromatography triple quadrupole mass spectrometer (UHPLC-QQQ-MS/MS). Statistical analyses were conducted using SPSS software (IBM SPSS Statistics, Version 29.0.0). Results: After 4 weeks, mean 24 h ambulatory BP was 130.2 ± 3.9 mm Hg (control), 130 ± 3.2 mm Hg (WM-1 cup), and 124.9 ± 3.9 mm Hg (WM-2 cups), with no statistically significant differences between study interventions (p > 0.05). Similarly, no significant changes were observed in fasting plasma glucose, insulin, lipid profile, or NO concentrations. However, plasma L-arginine concentrations and L-arginine/ADMA ratios significantly increased in the WM groups compared to the control (p = 0.009) after adjusting for age, BMI, race, and gender in the statistical model. Conclusion: Overall, BP was not significantly dif

Polycystic ovary syndrome is a complex heterogenous reproductive endocrine disorder affecting mainly reproductive age women worldwide. The syndrome primarily is associated with hyperandrogenism, hyperinsulinemia, menstrual irregularity, infertility, hormonal dysregulation and obesity. Here, we examined the effects of Acetyl-L-Carnitine, L-Arginine, CoQ10, (Carnitine + Arginine + CoQ10) and Metformin, alone and in combination, on PCOS management. The trial included 63 females diagnosed with PCOS. The participants were treated with either Carnitine + Arginine + CoQ10 alone (nutraceutical group) or in combination with metformin (combination group) for six months. The outcome measures included demographic, anthropometric, clinical, endocrine, metabolic, quality of Life and stress response of the participants. Over 24 weeks, both treatment regimens improved metabolic, hormonal, and psychological outcomes in women with PCOS. Repeated-measures ANCOVA showed significant group × time interactions for BMI (p < .001, η2 = .220), waist circumference (p < .001, η2 = .314), and hip circumference (p < .001, η2 = .428), favoring the combination group. Hormonal responses varied: DHEAS (p = .045, η2 = .082), FAI (p < .001, η2 = .223), testosterone (p = .004, η2 = .113), and prolactin (p = .032, η2 = .072) declined more in the combination group, whereas LH decreased more in the nutraceutical group (p < .001, η2 = .231). Quality of life improved significantly in both arms, with greater gains in the combination group (p = .037, η2 = .071). Oxidative stress (MDA) also declined significantly in both groups (p = .003), with larger numerical reductions in the combination arm (- 22% vs - 6%), though between-group differences were not significant (p = .329). Both nutraceutical and combination therapies led to significant improvements in metabolic, hormonal, and psychological outcomes in women with PCOS over 24 weeks. Repeated-measures ANCOVA confirmed greater reductions in BMI, waist and hip circumference, DHEAS, FAI, testosterone, and prolactin, as well as superior quality-of-life gains with combination therapy. Nutraceutical therapy exerted stronger effects on LH suppression, while oxid

This study investigated the effects of combined L-arginine (Arg) and citrulline-malate (CM) supplementation on aerobic, anaerobic, and high-intensity interval training in healthy, trained men. Both Arg and CM are widely marketed for their potential ergogenic effects, as Arg serves as a precursor to nitric oxide (NO), which may support vasodilation, muscle contractility, and exercise performance. Arg and CM are hypothesized to exert synergistic effects due to their complementary roles in NO synthesis. Citrulline can potentially enhance and prolong Arg availability, thereby amplifying NO-mediated vasodilation, nutrient delivery, and muscle performance during exercise. In this randomized, double-blind, placebo-controlled trial, 46 healthy, trained men aged 24.8 ± 5.0 years were divided into 3 exercise groups subjected to consuming 0.15 g/kg bodyweight of Arg and 0.1 g/kg bodyweight of CM prior. The participants were then randomly divided into three groups based on the exercise protocol:: the Wingate Anaerobic Test (n = 16), a 20 min CrossFit workout 'Cindy' (n = 16) consisting of continuous rounds of pull-ups, push-ups, and air squats to measure functional fitness and muscular endurance, or the Harvard Step Test (n = 14) a measurement of cardiovascular endurance and recovery. This design allowed for the evaluation of supplementation effects across multiple exercise modalities. The results revealed no significant improvement in performance with supplementation in comparison to placebo, except for a shorter time to reach peak power in the Wingate test. Findings suggest that the combined acute supplementation of Arg and CM, at the given dosages, may not provide substantial benefits for aerobic and anaerobic or CrossFit performance in active individuals. Future research with larger sample sizes and higher dosages, potentially adjusted for muscle mass, is recommended to determine whether chronic supplementation might yield greater ergogenic effects. © 2025. The Author(s).

BACKGROUND: Preoperative physical frailty is a significant predictor of adverse postoperative outcomes in older patients undergoing cardiac surgery. Inflammation plays a crucial role in the development of frailty and contributes to postoperative complications. This study investigated the effects of preoperative beta-hydroxy-beta-methylbutyrate (HMB), arginine, and glutamine supplementation on inflammatory markers, nutritional status, and renal function in older patients undergoing cardiac surgery. METHODS: This was a secondary analysis of a single-center, open-label, randomized controlled trial. Patients aged ≥65 years scheduled for elective cardiac surgery were randomized to receive either HMB supplementation (1200 mg HMB, 7000 mg l-glutamine, and 7000 mg L-arginine, twice daily) or routine care for at least two weeks before surgery. Serum levels of tumor necrosis factor-alpha (TNF-α), and other biochemical markers were measured at baseline, pre-surgery, and two weeks post-surgery. RESULTS: Forty-four patients (mean age 72.5 years, 36 % women) were analyzed. Preoperative HMB supplementation significantly reduced pre-surgery serum TNF-α levels compared to the control group (0.85 ± 0.28 pg/mL vs. 1.10 ± 0.44 pg/mL, p = 0.039). However, this difference was not observed two weeks post-surgery. No significant differences were observed in C-reactive protein levels or other nutritional markers between the two groups at any time point. CONCLUSIONS: Preoperative supplementation with a combination of HMB, glutamine, and arginine was effective in reducing preoperative TNF-α levels in older patients undergoing cardiac surgery, suggesting a potential anti-inflammatory effect. This anti-inflammatory effect suggests a potential mechanism for improving postoperative outcomes and warrants further investigation. Registration number of Clinical Trial: UMIN000030490 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034773).

Comment in JAMA. 2025 Oct 21;334(15):1333-1335. doi: 10.1001/jama.2025.10869. IMPORTANCE: Effective and well-tolerated pharmacotherapies for generalized anxiety disorder (GAD), which is one of the most common psychiatric disorders, are needed. OBJECTIVE: To determine the dose-response relationship of MM120 (lysergide D-tartrate) in adults with moderate to severe GAD. DESIGN, SETTINGS, AND PARTICIPANTS: This phase 2b, multicenter, randomized, double-blind, placebo-controlled study enrolled 198 adults aged 18 to 74 years with a primary GAD diagnosis who presented with moderate to severe symptoms (defined by a Hamilton Anxiety Rating Scale [HAM-A] score ≥20) and was conducted at 22 outpatient psychiatric research sites in the US from August 2022 to August 2023. The anxiety and depression end point assessments were conducted by independent central raters who were blinded to the trial protocol, treatment allocation, and study visit date. The last date of follow-up was November 27, 2023. INTERVENTIONS: Participants were randomized to receive a single (freebase equivalent) treatment dose with 25 µg (n = 39), 50 µg (n = 40), 100 µg (n = 40), or 200 µg (n = 40) of MM120 or placebo (n = 39). MAIN OUTCOME AND MEASURES: The primary outcome was a dose-response relationship assessed using the multiple comparison procedure modeling (MCP-Mod) method for change in HAM-A score at 4 weeks (score range, 0-56; higher scores indicate greater severity; ≤7 indicates no or minimal anxiety; 8-14, mild; 15-23, moderate; and ≥24, severe). The minimal clinically important difference was 2.5 points. RESULTS: Of the 198 participants randomized, 194 were included in the full analysis set (mean age, 41.3 [SD, 13.6] years; 56.7% were female; and 3.6% were Asian, 7.7% were Black or African American, and 83.0% were White). The dose-response relationship assessed using the MCP-Mod method for change in HAM-A score at week 4 was statistically significant for the 100-µg and the 200-µg dose groups vs placebo (least-squares mean difference, -5.0 points [95% CI, -9.6 to -0.4 points] with 100 µg of MM120 and -6.0 points [95% CI, -9.8 to -2.0 points] with 200 µg of MM120) but the 25-µg and 50-µg dose grou

Pain is the clinical hallmark of sickle cell disease (SCD), with painful Vaso-occlusive episodes (VOEs) being the common medical emergencies associated with an increased mortality rate. The current study aimed to evaluate the efficacy of L-arginine as an adjuvant therapy for children with SCD and VOE, as well as its effect on Tricuspid Regurgitant Jet Velocity (TRJV) during VOE. The primary outcome was to evaluate the efficacy of L-arginine on pain intensity. This double-blind, randomized, controlled, and parallel prospective study was carried out on 40 SCD children who presented with VOE and met the inclusion criteria. The mean ± SD of age was 8.8 ± 3.2 years, and 62.5% were males. They were randomized into two groups; Group 1 included 20 patients who received L-Arginine (100 mg/kg/dose three times/day for 15 doses or until their discharge) plus standard therapy. Group 2 consisted of 20 patients who received a placebo in addition to standard therapy. Total analgesic use, daily pain score, time to crisis resolution, and length of hospital stay were recorded. Routine laboratory investigations, serum L-Arginine, asymmetric dimethyl-arginine (ADMA) levels and the Arginine/ADMA ratio were assessed. Moreover, Echocardiography was performed to assess TRJV. All these parameters were assessed at baseline (during painful crisis), at discharge, and during the clinically asymptomatic state. As regards the age, sex, consanguinity, or family history there were no statistically significant difference between all of the studied groups. L-arginine therapy significantly decreased pain score at the 3rd day of admission(p-value 0.036), total analgesic use (p-value <0.001), time to crisis resolution (p-value 0.011), length of hospital stays (p-value 0.016), and TRJV (p-value < 0.001). Additionally, serum L-arginine level and Arginine/ADMA ratio (p-value <0.001) were increased upon arginine treatment. Additionally, statistically significant differences in the serum L-arginine level, serum ADMA level, Arginine/ADMA ratio, and TRJV were reported during painful crisis compared to the asymptomatic state. L-arginine Supplementation improved painful VOE symptoms in SCD children and decrea

The role of metabolic state reprogramming in modulating antibiotic susceptibility has attracted growing interest as a promising strategy to combat antimicrobial resistance. Our study revealed that L-arginine potentiates chloramphenicol's bactericidal activity by at least two orders of magnitude against multidrug-resistant Edwardsiella tarda via the coordinated modulation of three interconnected metabolic pathways: the tricarboxylic acid cycle disruption, redox homeostasis alteration, and phenylalanine metabolic suppression. Mechanistically, L-arginine-mediated tricarboxylic acid cycle inhibition diminished NADH production and compromised proton motive force, thereby depleting cellular energy supply and impairing drug efflux capacity. Concurrently, L-arginine disturbed the bacterial redox balance, which normally provides antibiotic resistance, by both lowering total antioxidant capacity and raising reactive oxygen species production. Furthermore, L-arginine suppressed phenylalanine metabolism, whereas trans-cinnamate restored antioxidant defenses and proton motive force, diminishing antibiotic resistance. These findings expanded the understanding of metabolic modulation's role in combating antibiotic resistance and offered theoretical support for the development of new antimicrobial strategies.IMPORTANCEThe global crisis of antimicrobial resistance demands innovative strategies to revitalize existing antibiotics. Our work addresses this urgent need by demonstrating that L-arginine acts as a powerful potentiator of chloramphenicol, enhancing its bactericidal efficacy by over 100-fold against multidrug-resistant Edwardsiella tarda. More significantly, we elucidate a novel, dual-pathway mechanism: arginine concurrently disrupts the TCA cycle and phenylalanine metabolism, which collectively alter the cellular redox state and compromise the proton motive force. This study is the first to uncover this sophisticated metabolic interplay, providing not only a promising adjuvant strategy but also a new conceptual framework for combating resistant bacterial infections by targeting core metabolism. Our findings, therefore, hold substantial potential for both basic science an

BACKGROUND: Positive allosteric modulators (PAMs) of muscarinic receptors (M) have been shown to effectively prevent cognitive dysfunctions associated with dementias, but little is known about their impact on NO֗-dependent pathways, in particular eNOS expression, L-arginine metabolism and its derivatives (ADMA/SDMA/NMMA) production. METHODS: Biochemical studies were performed in frontal cortices, hippocampi and plasma samples from mice that were administered with MK-801 (schizophrenia-related dementa) or scopolamine (Alzheimer's disease model) for 14 days alone or together with muscarinic receptors modulators: VU0357017 (M1) and VU0152100 (M4). Western blot was used to measure eNOS, DDAH1 and PRMT5, while mass spectrometry was used to measure the levels of L-arginine derivatives. Behavioral studies aimed to investigate the procognitive effects of the combined administration of PAMs with NO• releasers, spermineNONOate or DETANONOate were performed in novel object recognition (NOR) test, in scopolamine- or MK-801- induced amnesia. RESULTS: Our results indicate that MK-801 or scopolamine disturb eNOS, DDAH1, PRMT5 expression, and L-arginine bioavailability. VU0357017 or VU0152100 prevented scopolamine or MK-801-induced eNOS dysfunction, but L-arginine derivatives synthesis was inhibited only in MK-801 model. Synergistic effect with NO֗ releasers was observed in NOR. CONCLUSIONS: eNOS expression and L-arginine bioavailability may contribute to antipsychotic action of VU0357017 or VU0152100. The antialzheimer's effect to a lesser extend involves normalization of L-arginine metabolism. The joint administration of the compounds with NO֗ releaser could be proposed as synergistic treatment for both schizophrenia and Alzheimer's disease.

DNA damage repair is a critical physiological process. The combined treatment of L-arginine (L-Arg) and 5-fluorouracil (5-FU) significantly inhibits cell proliferation, enhances nitric oxide (NO) production via inducible nitric oxide synthase (iNOS), and promotes the accumulation of reactive oxygen species (ROS). This heightened oxidative stress triggers DNA damage and apoptosis, as evidenced by a substantial increase in the Bax/Bcl-2 ratio; the activation of caspase-9, caspase-3, and PARP cleavage; and increased level of phosphorylated p53. Moreover, the combination treatment induces G2/M phase arrest, with a significant increase in p-H2AX (Ser 139) (known as γ-H2AX) expression, indicating extensive DNA damage. Mechanistically, the combined treatment modulates DNA damage response pathways by downregulating DNA-PKcs. Concurrently, it enhances the phosphorylation of ATM, ATR, CHK1, CHK2, and BRCA1. Additionally, the L-Arg and 5-FU combination downregulates PI3K/AKT signaling. AZD-7648 (a DNA-PKcs inhibitor) and LY294002 (a PI3K inhibitor) enhance p-ATM and p-ATR activation, resulting in elevated apoptosis and increased γ-H2AX expression. In contrast, the inhibition of ATM/ATR by CGK733 suppresses this response, reducing apoptosis and DNA damage signaling. Additionally, the ROS scavengers NAC and iNOS, when applied separately, restore p-AKT and DNA-PKcs expression; suppress the upregulation of p-ATM, p-ATR, and γ-H2AX; and ultimately reduce apoptosis. These findings are validated in a DEN-induced rat liver cancer model. In summary, 5-FU and L-Arg synergistically increase iNOS/NO-driven ROS accumulation, inducing γ-H2AX-marked DNA damage through dual modulation of repair pathways (inhibiting PI3K/AKT/DNA-PKcs while activating ATM/ATR), ultimately triggering p53-mediated G2/M arrest and apoptosis in hepatocellular carcinoma cells.

Cisplatin is a chemotherapeutic drug that induces nephrotoxicity through inflammation and oxidative stress. Hydrogen sulfide (H2S) and nitric oxide (NO) are gaseous signaling molecules with cytoprotective potential in renal damage. The current study evaluated the nephroprotective potential of sodium hydrosulfide (NaHS), an H2S donor, and L-arginine, a NO precursor, against cisplatin-induced nephrotoxicity, even under NO synthase inhibition. Wistar rats were treated with cisplatin (5 mg/kg) to induce nephrotoxicity while administered with L-NG-nitro-L-arginine methyl (L-NAME), NaHS, and L-arginine either alone or in combination for 28 days. Renal function was assessed by monitoring various parameters, including body weight and urinary flow. Moreover, H2S, NO, creatinine level and clearance, blood urea nitrogen (BUN), electrolyte levels, and oxidative stress were monitored in body fluids. The findings revealed that L-NAME exacerbated cisplatin-induced nephrotoxicity, which was evident from reduced weights (P < .0001) and elevated urine output (P < .01), H2S (P < .0001), NO (P < .0001), creatinine (P < .01), and BUN (P < .0001) levels, along with reduced sodium and potassium (P < .0001) and elevated oxidative stress markers (P < .001) in plasma compared with healthy rats. The treatment with NaHS and L-arginine markedly protected against L-NAME + cisplatin-induced nephrotoxicity as the parameters were reinstated, including urine output (P < .01), H2S (P < .01), NO (P < .0001), creatinine (P < .05), and BUN (P < .01) levels compared with L-NAME + cisplatin rats. Moreover, coadministration of NaHS + L-arginine restored the sodium (P < .0001) and potassium (P < .01) levels in plasma and mitigated oxidative stress (P < .05). The results suggested that H2S and NO mitigated L-NAME + cisplatin-induced nephrotoxicity by ameliorating the L-NAME + cisplatin-induced oxidative stress. SIGNIFICANCE STATEMENT: The therapeutic validation of the mentioned agents would be beneficial in the treatment of renal dysfunction.

Localized drug delivery system possesses significant potential for enhancing therapeutic efficacy by maximizing drug accumulation at tumor sites while minimizing systemic toxicity. In this study, we developed an injectable pH-responsive nanosuspension (OE-I-m@MTA) integrating chemotherapy, photothermal therapy, and nitric oxide (NO)-mediated gas therapy. An orthoester compound (OE) was synthesized as a liquid excipient. Mitoxantrone (MIT) and the NO donor L-arginine (L-Arg) were loaded into mesoporous silica nanoparticles (MSN), which were further encapsulated by H22 tumor cell membranes to give a biomimetic nanoparticles (m@MTA). Subsequently, m@MTA and indocyanine green (ICG) were dispersed within the OE matrix to form an injectable nanosuspension (OE-I-m@MTA). Upon peritumoral injection, the OE component demonstrated dual advantages: pH-responsive dissolution in the acidic tumor microenvironment and enhanced tissue permeability, synergistically promoting deep tumor penetration of the biomimetic nanoparticles. Under 808 nm laser irradiation, OE-I-m@MTA exhibited triple therapeutic effects, effectively inhibiting the proliferation of cancer cells. This multimodal approach achieved remarkable tumor suppression, with a tumor growth inhibition rate of 93.86 %. The orthoester based nanosuspension provide a novel combinatorial therapeutic paradigm for localized cancer treatment.

Background: The dietary supplement citrulline might increase nitric oxide levels, leading to vasodilation and improved blood flow, potentially benefiting athletes' aerobic exercise performance. However, rapid oxidative impairment of the L-arginine/nitric oxide (NO) pathway limits these effects. This is countered by Bergamot Polyphenolic Fraction Gold® (BPFG), a strong natural antioxidant. To investigate L-citrulline + BPFG supplementation's effects, we performed a randomized, double-blind, placebo-controlled pilot trial on athletic performance and blood flow in trained athletes (cyclists). Methods: Random assignment of 90 male athletes resulted in nine different groups: placebo for Group 1, BPFG at 500 and 1000 mg daily for Groups 2 and 3, L-citrulline at 1000 and 2000 mg/daily for Groups 4 and 5, and the combination product of BPFG plus citrulline (N.O. Max) for Groups 6-9. Baseline and 3-month pre- and post-exercise biochemical, reactive vasodilation (RHI), and maximal oxygen consumption measurements were taken for all subjects. Results: Three months of the combination of BPFG and L-citrulline (N.O. Max) produced a significant synergistic effect, markedly increasing NO (p < 0.001 vs. placebo) release and RHI (p < 0.001 vs. placebo). Cardiorespiratory fitness improved significantly with the BPFG and L-citrulline combination, resulting in substantially higher VO2 max, VT1, VT2, and peak power and a significantly lower heart rate (p < 0.01 vs. placebo). No harmful adverse effects were observed. Conclusions: N.O. Max supplementation, providing beneficial effects on the antioxidant state and preserving the vascular endothelium might be a supplementation strategy to improve athletic performance and potentiate results. Given the small sample size, this study serves as a pilot, and further research is needed to validate these findings on a larger scale.

This study was conducted to characterize the interaction between the systemic and local peripheral antinociceptive effect of diclofenac, a nonsteroidal anti-inflammatory drug. As well as the effect of local peripheral administration of NG -nitro-L-arginine methyl ester (L-NAME) - a nitric oxide synthesis inhibitor - on the antinociceptive effect of diclofenac. The antinociceptive effect of diclofenac in a fixed-ratio combination of local or intraperitoneal delivery diclofenac was evaluated using the formalin test. Pain-related behavior was quantified in terms of the number of flinches of the injected paw with formalin. Isobolographic analysis was employed to characterize the interaction between the two routes. ED 30 values were estimated for each route, and an isobologram was constructed. Diclofenac and its fixed-ratio combination produced a dose-dependent antinociceptive effect in the second phase, but not in the first phase of the formalin test. The analysis revealed that the simultaneous administration of diclofenac through the two routes was synergistic. Pretreatment of the injured paw with L-NAME partially blocked local, systemic, and simultaneous local and systemic diclofenac-induced antinociception. The obtained results show a synergism after simultaneous administration of diclofenac through two different routes. In addition, it is found that either the local or systemic antinociceptive effect of diclofenac involves the activation of the nitric oxide pathway at the peripheral level.

The synergistic effect of nanosilver fluoride (NSF) with L-arginine on early carious lesions was evaluated. NSF was synthesized from chitosan, acetic acid, silver nitrate, sodium borohydride, and sodium fluoride. NSF + Arg was synthesized by adding L-arginine. After demineralization the enamel slabs from extracted molar, remineralization agents were applied by randomly dividing them into five groups (n = 15): sodium fluoride varnish (NaF), silver diamine fluoride (SDF), NSF, NSF + Arg, and control. The surface microhardness (SMH), remineralization effects using microcomputed tomography and color changes using a spectrophotometer were measured before and after pH cycling. SMH was analyzed by Kruskal-Wallis test with Dunn's test. Remineralization effects, and color changes were analyzed using the one-way analysis of variance with Duncan's test; p-value < 0.05 was considered significant. SMH recovered to similar levels in all groups (p > 0.05), except in the control group after pH cycling. The NSF + Arg and SDF groups showed a higher remineralization than the NaF and NSF groups (p < 0.05). SDF caused the largest discoloration (p < 0.05). The other groups showed no difference in discoloration. NSF + Arg could be an alternative to SDF given its ability to remineralize early caries lesions without discoloration. © 2025. The Author(s).

The stabilization of protein therapeutics against aggregation is crucial for maintaining their efficacy and safety. This study investigated the synergistic effects of cyclodextrins (CDs) and electrolytes at high concentrations on the stabilization of immunoglobulin G (IgG), insulin, and adeno-associated virus (AAV) vectors. The effects of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) combined with various electrolytes were evaluated using human plasma-derived IgG as a model protein. The HP-β-CD and L(+)-arginine hydrochloride combination synergistically increased the onset temperature of protein aggregation and inhibited the formation of soluble and insoluble aggregates during long-term storage. Notably, this synergistic effect was not observed when sucrose was used instead of HP-β-CD. Similar synergistic effects were observed with insulin and AAV vectors. The findings suggest that the stabilization mechanism could potentially involve enhanced interactions between HP-β-CD and IgG, preventing protein-protein interactions. However, the combination did not synergistically improve the solubility of free aromatic amino acids, including tyrosine and tryptophan. This study highlights the potential of using the combination of CDs and electrolytes as a promising formulation strategy for stabilizing complex protein therapeutics. Further studies are needed to elucidate the underlying mechanisms and generalize the approach to other proteins with varying physicochemical properties.

Conventional therapeutic agents are no longer adequate against leishmaniasis. This complex condition continues to have a high mortality rate and public health impact. The present study aimed to explore an extensive array of experiments to monitor the biological activities of 6-shogaol, a major component of ginger, and meglumine antimoniate (MA or Glucantime®). The binding affinity of 6-shogaol and inducible nitric oxide synthase (iNOS), a major enzyme catalyzing nitric oxide (NO) from L-arginine was the source for the docking outline. The inhibitory effects of 6-shogaol, MA, and mixture were assessed using colorimetric and macrophage assays. Antioxidant activity was inferred by UV-visible spectrophotometry. Variably expressed genes were measured by quantifiable real-time polymerase chain reaction. Apoptotic and cell cycle profiles were analyzed by flow cytometry. Moreover, a DNA fragmentation assay was performed by electrophoresis and antioxidant metabolites include superoxide dismutase (SOD), catalase (CAT), and also nitric oxide (NO) by enzyme-linked immunosorbent assay. 6-shogaol and MA exhibited multiple synergistic mechanisms of action. These included a remarkable leishmanicidal effect, potent antioxidative activity, a high safety index, upregulation of M1 macrophages/Th1-associated cytokines (including, γ-interferon, interleukin-12p40, tumor necrotizing factor-alpha, and associated iNOS), significant cell division capture at the sub-G0/G1 phase, a high profile of apoptosis through DNA fragmentation of the nuclear components. In addition, the activity of NO was substantially elevated by treated intracellular amastigotes, while SOD and CAT activities were significantly diminished. This study is exclusive because no similar investigation has inclusively been conducted before. These comprehensive mechanistic actions form a logical foundation for additional advanced study. © 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.