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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: 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: 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

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.

This meta-analysis was conducted to examine the effects of watermelon supplementation on cardiovascular diseases (CVDs) risk factors in randomized controlled trials (RCTs). The comprehensive search was done in Cochrane Library databases, ISI Web of Science, PubMed, and Scopus up to March 2022. A random-effect model was used for computing weighted mean differences (WMD). Standard methods were applied to examine publication bias, sensitivity analysis, and heterogeneity. Of the 8962 identified studies, 9 RCTs were included in the final analysis. Watermelon consumption significantly decreased systolic blood pressure (SBP), totalcholesterol (TC) and low-density lipoprotein (LDL). In addition, watermelon consumption led to a significant increase in fasting blood sugar (FBS). However, there was not any significant difference in other outcomes of interest including diastolic blood pressure (DBP), heart rate (HR), BMI, body fat, and serum levels of arginine, insulin, and CRP after watermelon supplementation. The current findings provide promising evidence of the antihypertensive effect of watermelon. However, due to the lack of evidence in human research, the result regarding the remaining outcomes needs to be used with caution. Furter RCTs with longer follow-ups and larger sample sizes should be done to confirm the current findings.

INTRODUCTION: The efficacy and safety of arginine supplements in erectile dysfunction (ED) remain debatable. AIM: To assess the potential role of arginine supplements on ED as alternatives to phosphodiesterase inhibitors. METHODS: Studies published up to April 2018 that evaluated the efficacy of arginine supplements were identified from multiple databases (Google Scholar, PubMed, Medline, Embase, Kiss, DBpia, and Cochrane databases). Studies comparing arginine supplements with placebo or no treatment; focusing only on patients with mild to moderate severity of ED; and presenting outcomes such as improvement rate, International Index of Erectile Function (IIEF) score, and adverse effects were included. Subgroup analysis for arginine alone and arginine in combination with other substances was further conducted to increase interpretability. MAIN OUTCOME MEASURE: The strength of the association between arginine supplements and ED was assessed using relative odds ratios and weighted mean differences with 95% CI. RESULTS: In total, 10 randomized controlled trials met the inclusion criteria, reporting the outcomes of 540 patients with ED. The analysis demonstrated that arginine supplements with dosage ranging from 1,500 to 5,000 mg significantly improved ED compared with placebo or no treatment (odds ratios, 3.37 [1.29, 8.77], P = .01, I2 = 44). Arginine supplements also caused significant improvements in the IIEF subdomain scores of overall satisfaction, intercourse satisfaction, orgasmic function, and erectile function, whereas the IIEF sexual desire score remain unchanged. The adverse effect rate in the arginine-treated group was 8.3%, and that in the placebo group was 2.3%, none of which were severe. CLINICAL IMPLICATIONS: Arginine supplements can be recommended to patients with mild to moderate ED. STRENGTH & LIMITATIONS: The strength of this study is that it is the first meta-analysis to assess the potential role of arginine supplements in ED compared with placebo or no treatment. A limitation is that the treatment dosage and duration varied among studies, which may have contributed to study heterogeneity. CONCLUSION: The results of our systematic review and meta

l-Arginine supplementation is a potential therapy for treating cardiovascular and metabolic diseases. However, the use of distinct l-arginine sources, intervened populations, and treatment regimens may have yielded confusion about their efficacy. This research constitutes a systematic review and meta-analysis summarizing the effects of l-arginine supplementation compared to placebo in individuals with cardiovascular disease (CVD), obesity, or diabetes. Eligibility criteria included randomized clinical trials and interventions based on oral supplementation of l-arginine with a minimum duration of three days; comparison groups consisted of individuals with the same disease condition receiving an oral placebo substance. The primary outcome was flow-mediated dilation, and secondary outcomes were nitrite/nitrate (NOx) rate and asymmetric dimethylarginine (ADMA). Statistical heterogeneity among studies included in the meta-analyses was assessed using the inconsistency index (I2). Fifty-four full-text articles from 3761 retrieved references were assessed for eligibility. After exclusions, 13 studies were included for data extraction. There was no difference in blood flow after post-ischemic hyperemia between the supplementation of l-arginine and placebo groups before and after the intervention period (standardized mean difference (SMD) = 0.30; 95% confidence intervals (CIs) = -0.85 to 1.46; I2 = 96%). Sensitivity analysis showed decreased heterogeneity when the studies that most favor arginine and placebo were removed, and positive results in favor of arginine supplementation were found (SMD = 0.59; 95% CIs = 0.10 to 1.08; I2 = 75%). No difference was found in meta-analytical estimates of NOx and ADMA responses between arginine or placebo treatments. Overall, the results indicated that oral l-arginine supplementation was not associated with improvements on selected variables in these patients (PROSPERO Registration: CRD42017077289).

OBJECTIVE: A meta-analysis of placebo-controlled trials was conducted to evaluate the effect of L-arginine supplementation on blood pressure (BP) in pregnancy. METHODS: Trials were searched in PubMed, Embase, and Cochrane Library. A total of five trials were included in the meta-analysis. RESULTS: L-arginine supplementation exhibited a mean decrease of 3.07 mmHg (p = 0.004) for diastolic blood pressure and a mean increase of 1.23 weeks (p = 0.002) for gestation age at delivery in pregnancy, but did not reduce systolic BP (p = 0.19) as compared to placebo. CONCLUSION: L-arginine supplementation had a significant effect of lowering diastolic blood pressure and prolonging gestation age in pregnancy.

BACKGROUND: Perioperative immunonutrition, including arginine and omega-3 fatty acids, has been proposed to support postoperative recovery by modulating immune function. AIM: To evaluate the effects of perioperative arginine and omega-3 supplementation on postoperative infectious complications, mortality, hospital length of stay, intensive care unit duration, and inflammatory markers in patients undergoing gastrointestinal cancer surgery. METHODS: In this Pilot Open-Label randomized trial, 35 adult patients scheduled for elective gastrointestinal cancer surgery at Salah Azaiez Institute were randomly assigned to receive either perioperative immunonutrition (n = 18; three daily capsules of omega-3 and one sachet of Arginine+ for 7 days preoperatively and 7 days postoperatively) or standard care (n = 17). Primary endpoints were postoperative infectious complications and 1-month mortality. Secondary endpoints included hospital length of stay, ICU duration, and postoperative biochemical markers. RESULTS: No statistically significant differences were observed between groups in 1-month mortality (p = 0.324), hospital length of stay (median 7 vs. 7 days, p = 0.392), or ICU duration (median 5 vs. 6 days, p = 0.601). Urinary tract infection (5.9% vs. 11.1%, p = 0.939) and wound infection rates (5.9% vs. 11.1%, p = 0.581) were comparable. Importantly, postoperative C-reactive protein and other inflammatory markers did not differ significantly between groups (CRP: 165 vs. 175 mg/L; intergroup p = 0.798). CONCLUSIONS: In this trial, perioperative immunonutrition with arginine and omega-3 fatty acids did not improve postoperative clinical outcomes or inflammatory markers in patients undergoing gastrointestinal cancer surgery. At the administered dose and within a small, heterogeneous cohort, immunonutrition did not provide additional benefit beyond standard care. Larger, adequately powered multicenter trials with optimized dosing are required to clarify its role in gastrointestinal oncology.

BACKGROUND: L-arginine and L-ornithine have previously shown limited short-term immunological benefits in the treatment of periodontitis. The aim of this study was to assess the extended efficacy and durability of the response to L-arginine or L-ornithine as adjuncts to periodontal therapy in adults with periodontitis. MATERIALS AND METHODS: In this study, 75 patients who previously received the course of L-arginine or L-ornithine as adjuncts to professional mechanical plaque removal (PMPR) during a preliminary randomized short-term part of a clinical trial (NCT05042024) were assessed clinically and immunologically (nested) after 12 months follow-up. The immunological assay included immunohistochemical identification of densities of CD68 + and CD163 + single-positive gingival macrophages. All patients did not receive new prescriptions or dietary changes and underwent personalized steps of periodontal treatment during observation. RESULTS: After one year, patients who received L-arginine or L-ornithine exhibited a significant reduction of sites with periodontal pocket depth of 4-5 mm compared to PMPR (p < 0.0001). L-ornithine was associated with BoP decreasing compared to PMPR and L-arginine (95 % CI of odds ratio [1.12-1.46], p = 0.0002; CI [0.72-0.94], p = 0.004), CD68 + and CD163 + macrophages density increasing compared to PMPR (p < 0.001) and L-arginine (p < 0.05). L-arginine resulted in increased density of CD68 + macrophages and elevated CD68 + /CD163 + ratio compared to the PMPR and L-ornithine; CI [0.41-0.63], p = 0.009, CI [1.45-2.72], p < 0.0001. CONCLUSION: After one year, L-ornithine supplementation demonstrated more pronounced clinical benefits than L-arginine, although both can modulate gingival CD68 + and CD163 + macrophages.

IMPORTANCE: Available antidepressants provide inadequate therapeutic responses in many patients with major depressive disorder (MDD), highlighting a substantial unmet need. OBJECTIVE: To evaluate the efficacy and safety of azetukalner, a novel, potent KV7 potassium channel opener, in participants with MDD. DESIGN, SETTING, AND PARTICIPANTS: X-NOVA was a multicenter, proof-of-concept, phase 2, randomized, double-blind, parallel-group, placebo-controlled clinical trial that evaluated azetukalner in participants (adults aged ≥18 to ≤65 years) with moderate to severe MDD in a current depressive episode. Participants were enrolled between April 2022 and October 2023, and data analysis occurred from January 2023 to January 2024. INTERVENTION: Participants were randomized (1:1:1) to 10 mg of azetukalner, 20 mg of azetukalner, or placebo orally once daily with food for 6 weeks, with a 4-week follow-up. Concomitant antidepressant medications were not permitted. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6. Secondary end points included change from baseline at week 6 in the Snaith-Hamilton Pleasure Scale (SHAPS) and Beck Anxiety Inventory. Exploratory end points included change in the Hamilton Depression Rating Scale, 17-Item (HAM-D17) score and change in MADRS at week 1. Frequency and severity of treatment-emergent adverse events (TEAEs) were recorded. RESULTS: Altogether, 168 participants were randomized (56 to placebo, 56 to 10 mg of azetukalner, and 56 to 20 mg of azetukalner); mean (SD) age was 47.2 (13.6) years, and 111 participants (66.5%) were female. The modified intent-to-treat and safety populations consisted of 164 and 167 participants, respectively. The mean (SE) reduction in MADRS scores from baseline to week 6 was -13.90 (1.41) points with placebo, -15.61 (1.34) points with 10 mg of azetukalner, and -16.94 (1.45) points with 20 mg of azetukalner; the mean (SE) reduction with 20 mg of azetukalner vs placebo was clinically meaningful but not statistically significant (-3.04 points; 95% CI, -7.04 to 0.96 points; P = .14) at week 6, while significant at week 1 (-2.66 p

We present a prospective randomized, placebo-controlled trial of intravenous arginine in patients 3-21 years hospitalized with sickle cell disease vaso-occlusive pain episodes (SCD-VOE) at two tertiary-care children's hospitals. Participants were randomized into 1 of 3 arms: Standard-dose (SD; 100 mg/kg/dose) every 8 h, Loading-dose (200 mg/kg followed by SD), or Placebo. The primary outcome was total parenteral opioid use (TPO). Secondary outcomes included time-to-crisis-resolution, pain scores, patient-reported outcomes (PROs), arginine bioavailability, and biomarkers of oxidative stress/mitochondrial function. Of 1548 patients screened, 108 were randomized (36 per study-arm; mean 12.6 ± 3.8 years, 52% female, and 65% hemoglobin-SS). This study did not meet its primary endpoint. TPO, time-to-crisis-resolution, pain scores, and PROs at discharge were similar across arms. Post hoc sensitivity analyses of children 5-16 years old demonstrated nearly double TPO utilization in those receiving placebo versus arginine (n = 87, p = 0.056), achieving significance in patients with plasma arginine < 60 μM. Arginine was low at presentation in 79% of patients (mean 50 ± 28 μM), and increased with arginine therapy (p < 0.001). Arginine bioavailability at VOE presentation inversely correlated with time-to-crisis-resolution (r = -0.39, p = 0.01) after placebo, an association eliminated by arginine supplementation (r = -0.04, p = 0.70). A dose-dependent increase in platelet-mitochondrial activity occurred after arginine versus no change after placebo (p < 0.001); plasma protein-carbonyl levels, a measure of oxidative stress, decreased after arginine therapy (p < 0.001) but increased in the placebo group (p = 0.02). SCD-VOE is associated with an acquired arginine deficiency that correlates with worse clinical outcomes. Arginine improved mitochondrial function and decreased oxidative stress compared to placebo, with clinically relevant opioid-sparing becoming significant in children with the lowest arginine concentration. TRIAL REGISTRATION: Registered with ClinicalTrials.gov (NCT02536170) in August 2015. © 2025 Wiley Periodicals LLC.

BACKGROUND: Taekwondo is a complex martial art that requires speed, balance, agility, and endurance. This study aims to examine the effects of nitrate and L-arginine supplementation on acute aerobic and anaerobic performance, balance, agility, and recovery in elite taekwondo athletes. METHOD: This study was conducted as a double-blind, randomized, crossover study with the participation of 15 experienced taekwondo athletes aged 19.06 ± 0.96 years and 8.93 ± 1.27 years of training experience. Participants visited the laboratory a total of nine times, including a practice session and anthropometric measurements. These visits consisted of eight experimental sessions conducted at 72-hour intervals. The experimental sessions were conducted with nitrate, L-arginine, and a combination of both supplements (NIT*L-ARG) and placebo. Nitrate supplementation was provided by homogenizing fresh spinach (837.40 mg/kg), while L-ARG was given as a single dose of 6 g in powder form three hours before exercise. RESULTS: NIT*L-ARG supplementation significantly improved the anaerobic performance of athletes in Wingate peak power and peak power (w/kg) compared to placebo and in mean power compared to NIT, L-ARG, and PLA. In addition, NIT*L-ARG supplementation significantly improved blood lactate levels and agility performance immediately after Wingate and Shuttle run tests. CONCLUSION: The combined intake of NIT*L-ARG was found to be effective in improving aerobic, anaerobic, and agility performances as well as fatigue levels of athletes. It was determined that taking NIT and L-ARG supplements alone contributed to the improvement of improving athletes' performance in Wingate mean power values and subsequent fatigue level compared to PLA.

L-citrulline (CIT) supplementation seems to improve resistance training performance; yet, whether malate has additive ergogenic effects when combined with CIT is unknown. This randomized, double-blind, placebo-controlled crossover trial aimed to compare the acute effects of CIT versus citrulline malate (CMA) supplementation on neuromuscular performance and exertion and emotional perceptions in young, trained men and women. 43 (21 women; 24.2 ± 3.7 years) participants ingested a placebo, CIT (5.3 g of CIT), or CMA (5.3 g of CIT, 2.7 g of malate) 45 min before three experimental sessions in a counterbalanced manner. We evaluated the upper and lower limb maximal neuromuscular and ballistic performance through the two-point method and countermovement jump. Strength-endurance was assessed across three sets of 10 repetitions in the squat and bench press exercises. Exertion and emotional perceptions were evaluated before and after the assessment and during the strength-endurance assessment. CIT and CMA supplementation did not enhance maximal neuromuscular performance (all p ≥ .061, ηp2≤.066), or ballistic strength (all p ≥ .348, ηp2≤.025). Neither CIT nor CMA supplementation improved strength-endurance as observed in the total number of repetitions (all p ≥ .590, ηp2≤.013), repetitions before reaching velocity loss threshold (all p ≥ .623, ηp2≤.010), mean velocity (all p ≥ .792, ηp2≤.004), mean velocity decline (all p ≥ .293, ηp2≤.029), and mean velocity maintenance (all p ≥ .393 ηp2≤.022), or exertion and emotional perceptions (both p ≥ .306, ηp2≤.028). In conclusion, CIT and CMA supplementation may not increase the neuromuscular performance during low- to moderate-volume resistance training sessions in young, trained adults. This trial was registered at ClinicalTrials.gov (No. NCT05183893).

Given the increasing popularity of CrossFit® as a high-intensity functional training program and the potential benefits of citrulline malate (CM) in enhancing exercise performance through its role as a precursor to L-arginine and nitric oxide production, this study aimed to investigate the acute effects of CM supplementation on CrossFit® performance and cardiovascular function. Using a randomized, double-blind, placebo-controlled, cross-over design, 21 recreationally active participants (mean age 22.2 ± 2.6 years, mean body weight 75.9 ± 10.4 kg) with CrossFit® experience completed the "Cindy" workout under CM and placebo conditions. Participants consumed 4.4 g of CM or a placebo 60 min before the workout, and the performance was measured by the number of rounds completed. Secondary outcomes included heart rate response, time spent in different heart rate intensity zones, and post-exercise recovery time. The results indicated no significant difference in the number of rounds completed between the CM and placebo conditions (13.5 ± 5.2 vs. 13.8 ± 6.7 rounds, respectively; p = 0.587). However, the time spent in zone 4 (80-90% of HR max) was significantly increased in the CM condition (527 ± 395 s vs. 453 ± 334 s; p = 0.017), suggesting a potential benefit for aerobic capacity and anaerobic threshold. No significant differences in post-exercise recovery time were observed (6.6 ± 4.7 h vs. 6.9 ± 4.7 h; p = 0.475). This study highlights the need for further research with larger sample sizes, both genders, and different CM dosages to clarify these findings and better understand CM's role in enhancing athletic performance.

The neurobiological mechanisms underlying the placebo phenomenon in patients with major depressive disorder (MDD) remain largely unknown. The progressive rise in rates of placebo responses within clinical trials over the past two decades may impede the detection of a true signal and thus present a major obstacle in new treatment development. Understanding the mechanisms would have several important implications, including (1) identifying biomarkers of placebo responders (thereby identifying those individuals who could benefit therapeutically from such interventions), (2) opening new avenues for manipulating such mechanisms to maximize symptom reduction, and (3) refining treatments with approaches that decrease (in clinical trials) or increase (in clinical practice) the placebo response. Here we investigated the research question: is the dopaminergic system one of the neurobiological underpinnings of the placebo response within MDD? Inspired by preclinical and clinical findings that have implicated dopamine in the occurrence, prediction, and expectation of reward, we hypothesized that dopaminergic activity in the mesolimbic system is a critical mediator of placebo response in MDD. To test this hypothesis, we designed a double-blind, placebo-controlled, sequential parallel comparison design clinical trial aimed at maximizing placebo antidepressant response. We integrated behavioral, imaging, and hemodynamic probes of mesocorticolimbic dopaminergic pathways within the context of manipulations of psychological constructs previously linked to placebo responses (e.g., expectation of improvement). The aim of this manuscript is to present the rationale of the study design and to demonstrate how a cross-modal methodology may be utilized to investigate the role of reward circuitry in placebo response in MDD.

OBJECTIVES: To investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional treatment (ACT). METHODS: Patients with treatment-naïve early rheumatoid arthritis were randomised in the NORD-STAR trial to ACT, certolizumab pegol, abatacept or tocilizumab, all with methotrexate. Centralised laboratory analyses for ACPA, RF and SE were performed. Clinical Disease Activity Index remission was analysed longitudinally with logistic generalised estimating equations. Differences in treatment effect across RF, ACPA and SE subgroups were assessed with interaction terms at 24 and 48 weeks, adjusted for sex, country, age, body mass index, Disease Activity Score of 28 joints based on C-reactive protein and smoking. RESULTS: In total, 778 patients were included. At 24 weeks, abatacept treatment showed a better response than ACT in the RF and/or ACPA-positive subgroups, but this effect was not significantly different from the negative subgroups. By 48 weeks, abatacept treatment showed better response regardless of RF/ACPA status. No differences were found across RF, ACPA, SE allele, valine at amino acid position 11 or valine-arginine-alanine haplotype subgroups for any biological treatment at 48 weeks. CONCLUSIONS: Based on this randomised controlled trial, abatacept treatment was associated with a better response than ACT in the RF and/or ACPA-positive subgroup at 24 weeks, but this was no longer seen at 48 weeks; adding SE allele-related genetic markers did not strengthen the association. Moreover, ACPA, RF and SE allele-related genotypes were not, alone or in combination, associated with clinical responses of importance sufficiently strongly to warrant implementation in clinical practice. TRIAL REGISTRATION NUMBER: EudraCT 2011-004720-35; ClinicalTrials.gov NCT01491815. © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.

BACKGROUND: Oral care regimens can be explored to improve oral health in patients with gingivitis. This study aimed to evaluate the efficacy of a multicomponent oral care regimen with a dual zinc plus arginine (DZA) toothpaste and cetylpyridinium chloride with zinc lactate (CPC + Zn) mouthwash in reducing gingival bleeding in patients with gingivitis. METHODS: This randomized clinical trial included 94 participants with gingivitis who were randomized into two groups: the DZA/CPC + Zn group, which used a 1450-ppm fluoride toothpaste containing 0.96% zinc plus 1.5% arginine and a fluoride-containing mouthwash with 0.075% CPC and 0.28% zinc lactate, and the control group, which used a 1450-ppm fluoride toothpaste and a placebo mouthwash for 6 months. All participants were examined by a blinded examiner who measured the gingival index, plaque index, and gingival severity index. Data were analyzed using paired t test, independent t test, and analysis of covariance (ANCOVA). RESULTS: Both groups presented statistically significant reductions in all clinical parameters compared to baseline. The DZA/CPC + Zn group exhibited significantly greater reductions in gingival index, gingival severity index, proximal gingival index, plaque index and proximal plaque index compared to the control group at 1, 3, and 6 months. Furthermore, DZA/CPC + Zn significantly decreased the percentage of patients with generalized gingivitis over a 6-month follow-up period. However, differences between the DZA/CPC + Zn and the control groups were not maintained after both groups established similar regimens with fluoride toothpaste. CONCLUSION: The multicomponent oral care regimen consisting of DZA toothpaste and CPC + Zn mouthwash is effective in reducing gingival inflammation and supragingival biofilm in patients with gingivitis. © 2023 American Academy of Periodontology.

AIM: The increasing prevalence of multidrug-resistant Escherichia coli and Klebsiella pneumoniae presents a critical threat to public health. As a first line of defence, efflux pumps promote antibiotic resistance among pathogens. This study aims to assess the potential of efflux pump inhibitors (EPIs) as adjuvants for enhancing antibiotic efficacy against resistant pathogens. METHODS AND RESULTS: This research investigated antibiotic resistance patterns, antibiotic resistance genes, and the effects and expression profiles of efflux pump genes. The study examined bacterial responses to sub-inhibitory levels of antibiotics, both individually and in conjunction with the EPI. The real-time PCR/Quantitative PCR (qPCR) demonstrated that antibiotic exposure led to an upregulation of efflux genes in E. coli and K. pneumoniae, with significant strain-specific differences. The co-administration of EPI resulted in downregulation of efflux genes, indicating successful inhibition of the pumps. Gene expression analyses suggested that PAβN influences the regulation of efflux genes and may trigger oxidative stress responses mediated by global regulators. This implies that EPIs could directly and indirectly affect bacterial physiology. CONCLUSIONS: The results highlight the therapeutic promise of EPIs in combating antibiotic resistance. This study underscores the complexity of efflux-mediated resistance and the need for integrated strategies to mitigate MDR in Gram-negative pathogens. © The Author(s) 2025. Published by Oxford University Press on behalf of Applied Microbiology International. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site-for further information please contact [email protected].

The arginine methyltransferase coactivator-associated arginine methyltransferase 1 (CARM1) is amplified/overexpressed in a variety of cancers, including triple-negative breast cancer (TNBC), spurring the interest of developing CARM1 inhibitors (CARM1i). In this study, we discovered that CARM1i treatment leads to elevated CARM1 levels as well as activation of AKT, which could result in long-term treatment resistance in breast cancer cells. CARM1 methylated MAP2K4 at arginine 58 in TNBC, and methylated-MAP2K4 localized to the nucleus and potentiated the proliferation- and metastasis-promoting functions of MAP2K4 via activation of JNK signaling. Inhibition of MAP2K4 by CARM1i led to AKT activation, which was abrogated by treatment with a PI3K inhibitor. Combining CARM1i and PI3K inhibitor elicited synergistic anticancer effects in TNBC cell lines, organoids, and patient-derived xenografts. This study demonstrates that, through inhibiting MAP2K4 methylation, CARM1i abrogates the feedback loop of MAP2K4 and PI3K signaling, supporting treatment with CARM1i as a therapeutic approach to improve the sensitivity of TNBC to PI3Ki. SIGNIFICANCE: CARM1 mediates MAP2K4 activation and cross-talk with PI3K/AKT signaling, providing potential combination approaches for treating triple-negative breast cancer and explains the paradoxical role of MAP2K4 in ER+ and triple-negative breast cancer. ©2025 American Association for Cancer Research.

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.

OBJECTIVES: Investigating the effect of melatonin (MLT) on the pharmacokinetics and related neurotransmitter and amino acid metabolism of vigabatrin (VGB) in epileptic rats in vivo. METHODS: High performance liquid chromatography was used to examine the pharmacokinetics and tissue distribution of VGB after intragastric administration dosing (50，100，200) mg/kg singly or in combination with melatonin (20 mg/kg) in rats. The single-compartment model of first-order elimination was fitted with the nonlinear mixed-effect model of first-order estimation. Targeting metabolomics were used to measure and analyze the amino acid levels in the hippocampus of kainic acid (KA)-induced epileptic rats treated with VGB alone or coupled melatonin. RESULTS: Melatonin significantly alters the pharmacokinetics of VGB, primarily by lengthening the elimination t1/2, Tmax, MRT and Vz/F, and decreasing the Cmax of both vigabatrin R(-) enantiomer (R-VGB) and vigabatrin S(+) enantiomer (S-VGB). Moreover, the concentrations of R-VGB and S-VGB were increased significantly in the lung and spleen of VGB + MLT group at 15 min compared with that of the VGB group. At 1 h, S-VGB levels increased significantly in spleen. At 4 h, the levels of S-VGB in the hippocampus and R-VGB in the prefrontal cortex increased significantly. Results of targeted metabolomics experiment showed that compared with control group, the level of aminobutyric acid/glutamate (GABA/Glu) in hippocampus of KA-induced epileptic rats was decreased, while glutamate/glutamine (Glu/Gln), tyrosine, dopamine, 3-methoxytyramine, tryptophan, 5-hydroxytryptamine, arginine and phenylalanine were significantly increased. These elevated levels of neurotransmitters and amino acids were decreased in VGB- and VGB + MLT treated group. CONCLUSIONS: MLT affected the pharmacokinetics and tissue distribution of VGB in rats, prolonging its elimination time and improving the tissue distribution. Moreover, it might help VGB improve the imbalance of neurotransmitters and amino acids in the hippocampus of epileptic rats.

Bacterial infections result in 7,700,000 deaths per year globally, with intracellular bacteria causing repeated and resistant infection. No drug is currently licenced for the treatment of intracellular bacteria. A new screening platform mimicking the host milieu has been established to explore phytochemical antibiotic adjuvants. Previously neglected isoprenylated flavonoids were found to be effective against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Specifically, the synergistic effect between glabrol and streptomycin against intracellular bacteria was observed for the first time. The glabrol-streptomycin combination targets bacterial inner membrane phospholipids, disrupts arginine biosynthesis, inhibits cell wall proteins and biofilm formation genes (agrA/B/C/D), and promotes ROS production, causing subsequent membrane and wall damage. To enhance the selective uptake of combination drug into infected cells, hyaluronic acid-streptomycin-lipoic acid-glabrol nanoparticles (HSLGS-S) were designed and synthesized to trigger the intracellular delivery of the glabrol-streptomycin combination. Thus, the treatment can be transported into the infected intracellular region and selectively release the glabrol-streptomycin combination to the bacterial at site. The bioactivity of HSLGS-S in clearing intracellular bacteria was 20-fold higher than that of the glabrol-streptomycin combination alone in vitro and 2- to 10-fold higher in vivo.

BACKGROUND: Combination therapy offers superior therapeutic results compared to monotherapy. However, the outcomes of combination therapy often fall short of expectations, mainly because of increased toxicity from drug interactions and challenges in achieving the desired spatial and temporal distribution of drug delivery. Optimizing synergistic drug combination ratios to ensure uniform targeting and distribution across space and time, particularly in vivo, is a significant challenge. In this study, cRGD-coated liposomes encapsulating optimized synergistic cepharanthine (CEP; a chemotherapy drug) and IR783 (a phototherapy agent) were developed for combined chemotherapy and photothermal therapy in vitro and in vivo. METHODS: An MTT assay was used to evaluate the combination index of CEP and IR783 in five cell lines. The cRGD-encapsulated liposomes were prepared via thin-film hydration, and unencapsulated liposomes served as controls for the loading of CEP and IR783. Fluorescence and photothermal imaging were used to assess the efficacy of CEP and IR783 encapsulated in liposomes at an optimal synergistic ratio, both in vitro and in vivo. RESULTS: The combination indices of CEP and IR783 were determined in five cell lines. As a proof-of-concept, the optimal synergistic ratio (1:2) of CEP to IR783 in 4T1 cells was evaluated in vitro and in vivo. The average diameter of the liposomes was approximately 100 nm. The liposomes effectively retained the encapsulated CEP and IR783 in vitro at the optimal synergistic molar ratio for over 7 d. In vivo fluorescence imaging revealed that the fluorescence signal from cRGD-CEP-IR783-Lip was detectable at the tumor site at 4 h post-injection and peaked at 8 h. In vivo photothermal imaging of tumor-bearing mice indicated an increase in tumor temperature by 32°C within 200 s. Concurrently, cRGD-CEP-IR783-Lip demonstrated a significant therapeutic effect and robust biosafety in the in vivo antitumor experiments. CONCLUSION: The combination indices of CEP and IR783 were successfully determined in vitro in five cell lines. The cRGD-coated liposomes encapsulated CEP and IR783 at an optimal synergistic ratio, exhibiting enhanced antitumor

Oxygen-dependent photodynamic therapy (PDT) is hindered by the limited availability of endogenous oxygen in solid tumors and low tumor accumulation of photosensitizers. Herein, we developed a biocompatible cancer-targeted therapeutic nanosystem based on cRGD conjugated bovine serum albumin (CBSA) co-loaded with a photosensitizer (chlorin e6, Ce6) and a therapeutic protein (cytochrome c, Cytc) for synergistic photodynamic and protein therapy. The nanosystem (Ce6/Cytc@CBSA) can target αVβ3 integrin overexpressed cancer cells to improve tumor accumulation due to incorporation of cRGD. In the intracellular environment, Ce6 is released to produce toxic singlet oxygen upon near-infrared irradiation. At the same time, the therapeutic protein, Cytc, can induce programmed cell death by activating the downstream caspase pathway. Most importantly, Cytc with the catalase-like activity accelerates O2 generation by decomposing excess H2O2 in cancer cells, thereby relieving the PDT-induced hypoxia to enhance therapeutic efficacy. Both in vitro and in vivo studies reveal the significantly improved antitumor effects of the combined photodynamic/protein therapy, indicating that Ce6/Cytc@CBSA shows great potential in synergetic cancer treatments.

Several modern drugs, which are derived from traditional herbal medicine are used in contemporary pharmacotherapy. Currently, the study of drug-plant interactions in pain has increased in recent years, looking for greater efficacy of the drug and reduce side effects. The antinociception induced by intragastric co-administration of the combination of pomegranate peel extract (PoPEx) and acetylsalicylic acid (ASA) was assessed using the isobolographic analysis in formalin test (nociceptive and inflammatory pain). The effective dose that produced 30% of antinociception (ED30) was calculated for both drugs from the logarithmic dose-response curves, subsequently generating a curve with the combination on fixed proportions (1:1) of PoPEx and ASA. Through isobolographic analysis, this experimental ED30 was compared with the calculated theoretical additive ED30. The result was a synergistic interaction, the experimental ED30 was significantly smaller (p < 0.05) than the theoretical ED30. The antinociceptive mechanism of the PoPEx-ASA combination involves the l-Arginine/NO/cGMP pathway, antioxidant capacity, and high content of total phenols. These findings suggest that an interaction between PoPEx and ASA could be a novel treatment for inflammatory and nociceptive pain, also diminish the secondary reactions of ASA.

Purpose: Clinical success of cancer therapy is severely limited by drug resistance, attributed in large part to the loss of function of tumor suppressor genes (TSGs). Developing effective strategies to treat those tumors is challenging, but urgently needed in clinic. Experimental Design: MYOCD is a clinically relevant TSG in lung cancer patients. Our in vitro and in vivo data confirm its tumor suppressive function. Further analysis reveals that MYOCD potently inhibits stemness of lung cancer stem cells. Mechanistically, MYOCD localizes to TGFBR2 promoter region and thereby recruits PRMT5/MEP50 complex to epigenetically silence its transcription. Conclusions: NSCLC cells deficient of MYOCD are particularly sensitive to TGFBR kinase inhibitor (TGFBRi). TGFBRi and stemness inhibitor synergize with existing drugs to treat MYOCD deficient lung cancers. Our current work shows that loss of function of MYOCD creates Achilles' heels in lung cancer cells, which might be exploited in clinic. © The author(s).

The research presented aims at developing Ropinirole hydrochloride (RHCl) nanoemulsion (NE) with nigella oil for Parkinson's disease (PD). In silico study was done to explore interactions of ropinirole and thymoquinone at receptor site (TNF-α and NFK-β). Ropinirole and Thymoquinone forms a hydrogen bond with residue Arginine 201 and residue Arginine 253 with a bond length of 1.89 Å and 2.30 Å at the NF-κβ receptor. NE was optimized using Central Composite Rotatable Design (CCRD). The globule size of chitosan coated NE, Polydispersity index (PDI) and zeta potential were 183.7 ± 5.2 nm, 0.263 ± 0.005, and 24.9 mV respectively. NE exhibited 85.28% transmittance showing the formulation was clear and transparent. TEM showed that NE had spherical globules with no aggregation. The formulation had a stable pH value of 5.8 ± 0.18. In vitro release and permeation studies exhibited 2 folds and 3.4 folds enhancement when compared with the drug suspension. Neurobehavioral activity and biochemical parameters corroborated well with the pharmacokinetic results. Histopathological study and immunohistochemical analysis were performed to get better picture of 6-OHDA induced toxicity and reversal of PD symptoms. Thus, the NE tailored is a promising synergistic approach yielding enticing outcomes for better management of PD related symptoms.

BACKGROUND: Tropomyosin and arginine kinase have been identified as the major allergens in multiple species of crab. Charybdis feriatus is an important commercial crab in this country. OBJECTIVE: To characterize the major allergens of C. feriatus using a proteomics approach and subsequently to identify the allergens involved in cross-reactivity with Portunus pelagicus. METHODS: Raw and boiled extracts of the crabs were prepared from crab meat. The protein profile of the extracts was determined by SDS-PAGE and two-dimensional electrophoresis (2-DE). Major allergens were identified by the immunoblotting test using sera from 50 patients with crab allergy. The major allergens were further identified by 2-DE immunoblotting. The major allergenic spots were then excised, digested by trypsin and identified by mass spectrometry analysis. The immunoblotting inhibition test was performed to study the crossreactivity between red crab and blue crab allergens using sera from 20 patients with allergy to both red and blue crabs. RESULTS: At least 20 protein bands between 13 to 250 kDa were detected in the SDS-PAGE gel of raw extract, while boiled extract procuced fewer protein bands. Proteins of 36 kDa and 41 kDa were recognized as the major allergens of the crab. The major allergenic spot sequences of the 36 and 41 kDa proteins were identified as crab tropomyosin and arginine kinase, respectively. All IgE-binding proteins, including both major allergens, were found to be cross-creative with P. pelagicus allergens. CONCLUSIONS: In addition to tropomyosin, arginine kinase was also identified as the major allergen of C. feriatus among our local crab-allergic patients. Cross-reactivity of this crab with P. pelagicus was demonstrated in this study.

AIM: Desmopressin was hypothesised to prevent post-kidney biopsy bleeding; however, its efficacy in reducing bleeding and bleeding-related complications has yet to be systematically examined. METHODS: Relevant studies from online electronic databases up to 15 May 2025 were identified. Randomised controlled trials (RCT) reporting the efficacy of desmopressin for prevention of adult post-kidney bleeding complications were included. A random-effect meta-analysis, trial sequential analysis and Bayesian meta-analysis were conducted. We assessed the certainty of the evidence (CoE) by using the GRADE methodology. RESULTS: Seven RCTs comprising 827 participants were included. By analysis of all seven studies, desmopressin shows a trend of reducing all post biopsy bleeding events (risk ratio [RR] = 0.77, 95% CI = 0.37-1.59) with very low CoE. In a sensitivity analysis excluding an outlier trial, desmopressin was associated with a lower risk of any bleeding and reduced heterogeneity (RR = 0.56, 95% CI = 0.39-0.80; I2 = 56%; moderate CoE). Desmopressin did not reduce post biopsy gross hematuria (RR: 1.00, 95% CI: 0.42-2.36), severe bleeding needs blood transfusion (RR = 1.46, 95% CI = 0.66-3.23), or invasive intervention (RR = 1.39, 95% CI = 0.38-5.09). A Bayesian analysis estimated a 76% posterior probability of any benefit, although the 95% credible interval indicated imprecision. Desmopressin is also associated with an RR of 4.52 (95% CI = 2.05-9.94; I2 = 0.0%) for hyponatremia. CONCLUSION: Desmopressin may reduce overall bleeding after kidney biopsy; however, low-certainty evidence and imprecise estimates are noted, necessitating further large-scale studies to explore its potential benefit, particularly in high-risk populations. © 2026 Asian Pacific Society of Nephrology.