Magnesium (Malate)

BACKGROUND AND OBJECTIVE: Sunitinib malate is used to treat advanced renal cell carcinoma, gastrointestinal stromal, and pancreatic tumors. Wide variability in drug exposure is reported for both sunitinib and its active metabolite (SU12662). This review aimed to summarize reported population pharmacokinetics studies of sunitinib and to identify the factors affecting the pharmacokinetics of sunitinib and SU12662. METHODS: A systematic search was undertaken using Scopus, Web of Science, and PubMed databases following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies were included in the review if population pharmacokinetic modeling approach was used for sunitinib and/or SU12662 in adult and/or pediatric population. Data quality was assessed using the percent compliance rate of each study. RESULTS: A total of 1820 articles were retrieved, and subsequently, 14 studies that met the inclusion criteria were included in the systematic review. Most of the studies reported two-compartment model with first-order absorption and elimination to describe sunitinib and SU12662. Body surface area, age, sex, ethnicity, tumor type, and ABCB1 and ABCG2 genotype were the significant covariates that affected the pharmacokinetics of sunitinib and SU12662. CONCLUSIONS: According to the published data from the reported studies, various covariates alter sunitinib and SU12662 exposure and thus have the potential to influence the clinical outcome of sunitinib treatment. Predictive performance assessment of these published models should be performed before implementing these models during the routine clinical practice. The summarized significant covariates affecting pharmacokinetics (PK) of sunitinib and SU12662 will facilitate model-informed precision dosing of sunitinib therapy in a clinical setting. © 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

The utilization of biomarkers for the diagnosis and management of autism spectrum disorders (ASD) remains a relatively unexplored frontier in clinical practice. Proteomics and metabolomics are important tools for revealing key biomarkers and evaluating biological pathways in ASD. We conducted an individual meta-analysis to compare the consistency of biomarkers of ASD from central nervous system (brain and cerebrospinal fluid), circulatory system (blood), and non-invasive samples (urine, saliva, and faeces) and performed pathway enrichment analyses to identify pathways enriched in ASD. After screening 926 proteomics and 619 metabolomics articles, we collected data from 10 studies involving 940 differential proteins and 16 studies assessing a total of 748 differential metabolites. In brain tissue, blood, and urine of ASD cases and controls, flotillin-2 (FLOT2), apolipoprotein E (ApoE), and EH domain-containing protein 3 (EHD3) exhibit differential expression, while vinculin (VCL) displays variations in saliva, blood, and urine. Similarly, in case-control studies, gelsolin (GSN) shows differential expression in brain tissue, saliva, and urine, and malate dehydrogenase 2 (MDH2) in brain tissue, blood, and saliva. Hippuric acid and salicyluric acid were simultaneously found in the brain, blood, urine, and faeces. In terms of pathways, glycolysis/gluconeogenesis, carbon metabolism, and glutathione metabolism were enriched in the brain as well as in saliva or urine. In our study, we identified six shared protein and two metabolic markers in central nervous system, circulatory system, and non-invasive samples, underscoring their potential value for ASD diagnosis and management, warranting further research. © 2024. Springer-Verlag GmbH Germany, part of Springer Nature.

This analytical review summarizes literature data and our own research on HSP70-dependent mechanisms of neuroprotection and discusses potential pharmacological agents that can influence HSP70 expression to improve neurological outcomes and effective therapy. The authors formed a systemic concepts of the role of HSP70-dependent mechanisms of endogenous neuroprotection aimed at stopping the formation of mitochondrial dysfunction, activation of apoptosis, desensitization of estrogen receptors, reduction of oxidative and nitrosative stress, prevention of morpho-functional changes in brain cells during cerebral ischemia, and experimentally substantiated new target links for neuroprotection. Heat shock proteins (HSPs) are an evolutionarily integral part of the functioning of all cells acting as intracellular chaperones that support cell proteostasis under normal and various stress conditions (hyperthermia, hypoxia, oxidative stress, radiation, etc.). The greatest curiosity in conditions of ischemic brain damage is the HSP70 protein, as an important component of the endogenous neuroprotection system, which, first of all, performs the function of intracellular chaperones and ensures the processes of folding, holding and transport of synthesized proteins, as well as their degradation, both under normoxic conditions and stress-induced denaturation. A direct neuroprotective effect of HSP70 has been established, which is realized through the regulation the processes of apoptosis and cell necrosis due to a long-term effect on the synthesis of antioxidant enzymes, chaperone activity, and stabilization of active enzymes. An increase in the level of HSP70 leads to the normalization of the glutathione link of the thiol-disulfide system and an increase in the resistance of cells to ischemia. HSP 70 is able to activate and regulate compensatory ATP synthesis pathways during ischemia. It was found that in response to the cerebral ischemia formation, HIF-1a is expressed, which initiates the launch of compensatory mechanisms for energy production. Subsequently, the regulation of these processes switches to HSP70, which "prolongs" the action of HIF-1a, and also independently maintains

Fazio, C, Elder, CL, and Harris, MM. Efficacy of alternative forms of creatine supplementation on improving performance and body composition in healthy subjects: a systematic review. J Strength Cond Res 36(9): 2663-2670, 2022-Novel forms of creatine have appeared in the marketplace with substantial claims of improved efficacy compared to creatine monohydrate (CrM). The purpose of this study was to conduct a systematic review on alternative forms of creatine to determine (a) whether they are effective ergogenic aids and (b) whether they outperform CrM. A separate comparison was conducted to determine average cost of various forms of creatine. Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Medline, and Google Scholar were systematically reviewed according to PRISMA guidelines. The design of the review was set to answer the PICOS model (subjects, interventions, comparators, outcomes, and study design). Seventeen randomized placebo controlled clinical trials examining exercise performance outcomes and body composition were included in the analysis. Magnesium-creatine chelate and creatine citrate, malate, ethyl ester, nitrate, and pyruvate were the only forms researched in the literature. Of these studies, only 3 studies compared the alternative creatine form to CrM, making it difficult to compare efficacy to CrM. There were no consistent findings of performance enhancement among alternative forms of creatine when compared to placebo. A review of the marketplace shows that CrM is the lowest cost form of creatine. Due to the paucity of studies on alternative forms of creatine as well as high prices on the market of these alternative forms, CrM remains as the most extensively studied form of creatine that shows efficacy, safety, and lowest cost to consumer.

BACKGROUND: Alzheimer's disease (AD) comprises 60-70% of diagnosed dementia cases, and is characterized by the deposition of β-amyloid peptide and the formation of neurofibrillary tangles of tau protein. Resveratrol is a neuroprotective agent acting in the prevention of redox impairment in addition to exerting anti-apoptotic actions on brain cells. An ability to reduce neuronal damage in patients with AD has been suggested by preclinical studies. OBJECTIVES: The aim of this systematic review was to investigate the evidence in the published literature from studies that evaluated the effects of supplementation with resveratrol, alone or in a solution with glucose and malate (RGM), on the functional and cognitive performance of patients with AD, as assessed by validated instruments. METHODS: A systematic literature search was performed in MEDLINE, CENTRAL, Embase, CINAHL, Web of Science, and Scopus databases including articles published up to August 2021. Randomized, placebo-controlled, clinical trials that reported cognitive and functional performance, as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), Cooperative Study of Alzheimer's Disease-Activities of Daily Living (ADCS-ADL), or the Mini Mental State Examination (MMSE), in AD patients treated with resveratrol, alone or as RGM, were included. RESULTS: After 1855 studies were identified, 24 RCTs underwent full-text review, with 20 studies excluded because they did not meet the inclusion criteria. Thus, four RCTs were included in the qualitative analyses. The findings demonstrate that there are still few studies in humans, but they showed that this polyphenol acts in the delay of cognitive impairment in patients with AD, when administered alone or in combination with glucose and malate. CONCLUSIONS: Supplementation with resveratrol seems to influence the progressive cognitive and functional decline in AD patients, when compared with a placebo group. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021229234. © 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Although the ergogenic mechanisms of supplementation with citrulline malate are well known, unclear findings regarding variables of muscle strength have been recorded. Such misleading findings in the literature illustrate the need for well-conducted meta-analysis research to elucidate the possible ergogenic impact, which could have major practical consequences for athletes and recreational practitioners seeking to optimize gains in muscle strength. The objective of this systematic review was to summarize the existing literature that evaluated the effects of citrulline malate supplementation on muscle strength outcomes from resistance exercise in resistance-trained individuals. A systematic electronic search in Medline and Scientific Electronic Library Online (SciELO) was completed in August 2020 identifying randomized controlled trials investigating the effect of citrulline malate supplementation on muscle strength in resistance-trained adults. A subsequent meta-analysis was performed. The meta-analysis involved four studies and 138 assessments (69 in citrulline-malate and 69 in placebo groups). We did not observe an overall effect favoring citrulline-malate supplementation (SMD95% = 0.13 [-0.21; 0.46]). Considering the lower (SMD95% = 0.06 [-0.47; 0.60]) and upper (SMD95% = 0.17 [-0.26; 0.60]) limbs, a non-significant overall effect was identified. The mean effects were similar for "limbs" (upper vs lower) [p = 0.763]. Accordingly, our findings suggest that citrulline malate supplementation does not improve muscle strength in healthy and resistance-trained individuals (PROSPERO registration number: CRD42020159338).

Citrulline malate (CitMal) is a dietary supplement that is suggested to enhance strength training performance. However, there is conflicting evidence on this matter. Thus, the purpose of this meta-analysis was to determine whether supplementing with CitMal prior to strength training could increase the total number of repetitions performed before reaching voluntary muscular failure. A systematic search was conducted wherein the inclusion criteria were double-blind, placebo-controlled studies in healthy participants that examined the effect of CitMal on repetitions to failure during upper body and lower body resistance exercises. The Hedges's g standardized mean differences (SMD) between the placebo and CitMal trials were calculated and used in a random effect model. Two separate subanalyses were performed for upper body and lower body exercises. Eight studies, including 137 participants who consisted of strength-trained men (n = 101) and women (n = 26) in addition to untrained men (n = 9), fulfilled the inclusion criteria. Across the studies, 14 single-joint and multijoint exercises were performed with an average of 51 ± 23 total repetitions during 5 ± 3 sets per exercise at ∼70% of one-repetition maximum. Supplementing with 6-8 g of CitMal 40-60 min before exercise increased repetitions by 3 ± 5 (6.4 ± 7.9%) compared with placebo (p = .022) with a small SMD (0.196). The subanalysis for the lower body resulted in a tendency for an effect of the supplement (8.1 ± 8.4%, SMD: 0.27, p = .051) with no significant effect for the upper body (5.7 ± 8.4%, SMD: 0.16, p = .131). The current analysis observed a small ergogenic effect of CitMal compared with placebo. Acute CitMal supplementation may, therefore, delay fatigue and enhance muscle endurance during high-intensity strength training.

BACKGROUND: Citrulline is one of the non-essential amino acids that is thought to improve exercise performance and reduce post-exercise muscle soreness. We conducted a systematic review and meta-analysis to determine the effect of citrulline supplements on the post-exercise rating of perceived exertion (RPE), muscle soreness, and blood lactate levels. METHODS: A random effects model was used to calculate the effect sizes due to the high variability in the study design and study populations of the articles included. A systematic search of PubMed, Web of Science, and ClinicalTrials.gov was performed. Eligibility for study inclusion was limited to studies that were randomized controlled trials involving healthy individuals and that investigated the acute effect of citrulline supplements on RPE, muscle soreness, and blood lactate levels. The supplementation time frame was limited to 2 h before exercise. The types and number of participants, types of exercise tests performed, supplementation protocols for L-citrulline or citrulline malate, and primary (RPE and muscle soreness) and secondary (blood lactate level) study outcomes were extracted from the identified studies. RESULTS: The analysis included 13 eligible articles including a total of 206 participants. The most frequent dosage used in the studies was 8 g of citrulline malate. Citrulline supplementation significantly reduced RPE (n = 7, p = 0.03) and muscle soreness 24-h and 48-h after post-exercise (n = 7, p = 0.04; n = 6, p = 0.25, respectively). However, citrulline supplementation did not significantly reduce muscle soreness 72-h post-exercise (n = 4, p = 0.62) or lower blood lactate levels (n = 8, p = 0.17). CONCLUSION: Citrulline supplements significantly reduced post-exercise RPE and muscle soreness without affecting blood lactate levels.

Elevated atmospheric CO2 (eCO2) concentration can increase root exudation into soils, which improves plant tolerance to abiotic stresses. This review used a meta-analysis to assess effect sizes of eCO2 on both efflux rates and total amounts of some specific root exudates, and dissected whether eCO2 enhances plant's resistance to nutrient deficiency and ion toxicity via root exudates. Elevated CO2 did not affect efflux rates of total dissolved organic carbon, a measure of combined root exudates per unit of root biomass or length, but increased the efflux amount of root systems per plant by 31% which is likely attributed to increased root biomass (29%). Elevated CO2 increased efflux rates of soluble-sugars, carboxylates, and citrate by 47%, 111%, and 16%, respectively, but did not affect those of amino acids and malate. The increased carbon allocation to roots, increased plant requirements of mineral nutrients, and heightened detoxification responses to toxic ions under eCO2 collectively contribute to the increased efflux rates despite lacking molecular evidence. The increased efflux rates of root exudates under eCO2 were closely associated with improved nutrient uptake whilst less studies have validated the associations between root exudates and resistance to toxic ions of plants when grown under eCO2. Future studies are required to reveal how climate change (eCO2) affect the efflux of specific root exudates, particularly organic anions, the corresponding nutrient uptake and toxic ion resistance from plant molecular biology and soil microbial ecology perspectives. Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.

Gonzalez, AM and Trexler, ET. Effects of citrulline supplementation on exercise performance in humans: A review of the current literature. J Strength Cond Res 34(5): 1480-1495, 2020-L-citrulline, a nonessential amino acid found primarily in watermelon, has recently garnered much attention for its potential to augment L-arginine bioavailability, nitric oxide production, and exercise performance. Over the past decade, L-citrulline has received considerable scientific attention examining potentially ergogenic properties for both aerobic and anaerobic exercise performance. Thus, the purpose of this article is to summarize the theoretical rationale behind L-citrulline supplementation and to comprehensively review the available scientific evidence assessing the potential ergogenic value of L-citrulline supplementation on vascular function and exercise performance in humans. In addition, research that has investigated the potential synergistic effects of L-citrulline with other dietary ingredients (e.g., arginine, antioxidants, nitrates, and branched-chain amino acids) is reviewed. Oral L-citrulline and citrulline malate supplementation have shown to increase plasma citrulline and arginine concentrations, along with total nitrate and nitrite concentrations. Although blood flow enhancement is a proposed mechanism for the ergogenic potential of L-citrulline, evidence supporting acute improvements in vasodilation and skeletal muscle tissue perfusion after supplementation is scarce and inconsistent. Nevertheless, several studies have reported that L-citrulline supplementation can enhance exercise performance and recovery. Given the positive effects observed from some investigations, future studies should continue to investigate the effects of both acute and chronic supplementation with L-citrulline and citrulline malate on markers of blood flow and exercise performance and should seek to elucidate the mechanism underlying such effects.

BACKGROUND: Dapagliflozin (DAPA) has shown major nephroprotective effects, improving kidney metabolism and oxigenation. Lipidomics and metabolomics are powerful tools for understanding such effects, providing a comprehensive look at how SGLT2 inhibitors might change the metabolic landscape beyond their primary glucose-lowering action. We investigated changes in plasma metabolomic/lipidomic profile and urinary excretion of metabolites that could occur independent of increased diuresis. METHODS: A two-armed, parallel-design, randomized clinical trial was conducted in subjects with type 2 diabetes and hypertension who received treatment with DAPA 10 mg/day or hydrochlorothiazide 12.5 mg/day for four weeks. Lipidomics and metabolomics were performed by high resolution mass spectrometry in fasting plasma and 24-hour urine samples collected before and after treatment. RESULTS: Compared to hydrochlorothiazide, DAPA significantly increased plasma isoleucine, methionine, citrate, β-hydroxybutyrate and decreased lactate. DAPA induced plasma lipid remodeling towards a significant raise in free fatty acids (FFAs) and some sphingomyelins and lysophosphatidylcholines containing these fatty acids. A significant change was observed in plasma medium- and short-chain acylcarnitines, positively correlated with changes in plasma FFAs and β-hydroxybutyrate. In addition, DAPA, but not hydrochlorothiazide, significantly increased 24-h urinary excretion of several amino-acids, lactate, TCA cycle metabolites, β-hydroxybutyrate and electrolytes, except for a decrease in malate excretion. CONCLUSIONS: DAPA treatment has major effects on the plasma lipidomic and the urine metabolomic profiles, with significant increased renal excretion of several metabolites, especially amino-acids, independently of increased diuresis. These data offer insights into the complex metabolic pathways leading to kidney protection by SGLT2 inhibitors. CLINICAL TRIAL INFORMATION: European Union Drug Regulating Authorities Clinical Trials No. 2015-004164-11. © 2025. The Author(s).

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: Pre-season training is critical for developing tolerance to high physical demands in professional soccer, and nitric oxide (NO) precursors such as dietary nitrate (NO3-) and citrulline malate (CM) can support performance and recovery during this demanding phase. This study aimed to examine the effects of a four-week supplementation protocol combining 500 mg of NO3- from amaranth extract and 8 g of CM (NIT + CM) on external training load and post-match recovery in professional female soccer players during pre-season. Methods: A randomized, double-blind, placebo-controlled trial was conducted with 34 female soccer players who received either the NIT + CM product or a placebo for four weeks during pre-season. Global positioning system (GPS)-derived external load was recorded throughout the intervention. Performance tests-a countermovement jump (CMJ) test and the Wingate anaerobic test (WAnT)-and blood sampling for plasma NO3- and nitrite (NO2-) concentrations were conducted at baseline and the day after a competitive match. Results: The supplementation with NIT + CM increased maximal speed (Vmax) throughout training and match play. During post-match testing, the NIT + CM group exhibited a significantly smaller decline in mean (Pmean) and minimum (Pmin) power during the WAnT, along with reduced power loss in both the first (0-15 s) and second (15-30 s) intervals. Plasma NO3- concentrations significantly increased from baseline in the NIT + CM group and remained elevated 24 h after the final dose, confirming sustained systemic exposure. Conclusions: Chronic NIT + CM supplementation may enhance Vmax and help preserve anaerobic performance the day after a match. These effects could reflect improved tolerance to high training loads and sustained NO3- availability during recovery.

PURPOSE: This study aimed to investigate and compare the effects of chronic supplementation with L-Citrulline (LC) vs. L-Citrulline DL-malate (CM) on resistance training (RT) performance. METHODS: Thirty-three resistance-trained men were randomly assigned to ingest LC (8 g), CM (12 g), or Placebo (PL) daily, along with participation in a 6-week RT protocol. Muscular strength (1-repetition maximum [1RM] for hack squat [HS] and bench press [BP]), muscular endurance (repetitions to failure [RTF] for HS, leg extension [LE], BP, and incline press [IP]), rating of perceived exertion (RPE), and blood biomarkers (lactate, urea, and nitric oxide metabolites [NOX]) were assessed before and after the intervention. This study was registered on irct.ir (IRCTID: IRCT20221128056642N1). RESULTS: Comparing mean ∆ scores revealed a significant difference between LC and PL (p < 0.001) and between CM and PL (p = 0.026) for total upper body (the sum of BP and IP) RTF, but only a trend for difference between LC and PL (p = 0.070) for total lower body (the sum of HS and LE) RTF. A significant time effect for NOX was detected only for LC (p = 0.014) and CM (p = 0.003). In addition, a significant difference between CM and PL (p = 0.009) and a marginally significant difference between LC and PL (p = 0.057) was detected regarding post-exercise NOX values at post-intervention. There were no other between-group differences for any outcome measure. CONCLUSION: Chronic citrulline supplementation seems to enhance upper body muscular endurance and post-exercise NOX response to RT, but there is no apparent difference between LC and CM in these aspects.

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.

BACKGROUND: Citrulline malate (CM), especially when used in conjunction with physical exercise, has demonstrated potential as a non-pharmacological adjunct in the management of hypertension. Nevertheless, its impact on nocturnal blood pressure dipping remains unexplored. OBJECTIVE: Evaluate the impact of a single dose of CM on nocturnal blood pressure dipping after exercise in hypertensive individuals. METHODS: In a double-blind, placebo-controlled, parallel-group clinical trial, twenty hypertensive adults (55 ± 16 years) were randomly assigned to either a CM (6 g) or placebo (6 g of corn starch) group (PLA). Resting blood pressure was measured after a 20-min period of comfortable seating in a calm environment. Both groups underwent 40 min of treadmill running/walking at an intensity of 60-70% of their reserve heart rate, 120 min after ingesting the substances. Ambulatory blood pressure monitoring was employed to measure blood pressure over 24 h. RESULTS: No significant differences in systolic blood pressure values were observed between the CM and PLA groups at rest, during wakefulness, sleep, or over a 24-h period. However, CM exhibited a significant reduction in diastolic blood pressure in several metrics: delta 24 h (-14 mmHg vs -6 mmHg, p = 0.047), delta wakefulness (-12 mmHg vs -4 mmHg, p = 0.024), percent delta 24 h (-16% vs -6%, p = 0.024), and percent delta wakefulness (-14% vs -4%, p = 0.013). No significant differences were found between CM and PLA in terms of systolic and diastolic nocturnal absolute reductions (-13 mmHg vs -12 mmHg, p = 0.808, and -13 mmHg vs -8 mmHg, p = 0.273, respectively) or nocturnal percentage decrease (-9.9% vs -9.4%, p = 0.844, and -15.3% vs -11.7%, p = 0.399, respectively). CONCLUSIONS: The study found no significant changes in the post-exercise nocturnal blood pressure dip following a single dose of CM supplementation. However, a notable reduction in diastolic blood pressure was observed during the waking period and over the average 24-h monitoring period. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: ClinicalTrials.gov platform (NCT03378596). Effects of 3 days of citrulline malate supplementation on short-duration repeated

Citrulline malate (CM) is purported to be an ergogenic aid during various types of exercise performance. However, the effects of CM on repeated sprint performance (RSP) are under-explored. In a placebo-controlled, double-blind, counterbalanced cross-over design, male university-level team sport athletes (n = 13) performed two familiarization trials, after which CM or placebo (PLA) (8 × 1 g tablets each day) were taken on the 2 days prior to, and with breakfast on the morning of, each main experimental trial. The main experimental trials employed a RSP protocol consisting of 10 repetitions of 40 m maximal shuttle run test (MST) with a 30 s interval between the start of each sprint. Sprint times and heart rate were recorded throughout the MST, and blood lactate concentrations were measured before, immediately after, and 5 min after completing the MST. CM resulted in better RSP compared to PLA, as indicated by a lower sprint performance decrement (Sdec: CM, 4.68% ± 1.82% vs. PLA, 6.10% ± 1.83%; p = 0.03; ES = 0.77), which was possibly influenced by the fastest sprint time being faster in CM (CM, 8.16 ± 0.34 s vs. PLA, 8.29 ± 0.39 s; p = 0.011; ES = 0.34). There were no differences between CM and PLA in average sprint time (p = 0.54), slowest sprint time (p = 0.48), blood lactate concentrations (p = 0.73) or heart rate (p = 0.18), nor was there a condition × time interaction effect across the 10 sprints (p = 0.166). Three days of CM supplementation (8 g daily) attenuated the sprint performance decrement during short-duration high-intensity exercise in the form of running RSP in male university-level team sport athletes. © 2024 The Authors. European Journal of Sport Science published by Wiley‐VCH GmbH on behalf of European College of Sport Science.

BACKGROUND: Nemonoxacin malate is a novel non-fluorinated quinolone for oral and intravenous (IV) administration. This phase 3, multicentre, randomised, double-blind, double-dummy, parallel-controlled clinical trial (NCT02205112) evaluated the efficacy and safety of IV nemonoxacin vs. levofloxacin for the treatment of community-acquired pneumonia (CAP) in adult patients. METHODS: Eligible patients were randomised to receive 500 mg nemonoxacin or levofloxacin via IV infusion, once daily for 7-14 days. The primary endpoint was the clinical cure rate at the test-of-cure (TOC) visit in the modified intent-to-treat (mITT) population. Secondary efficacy and safety were also compared between nemonoxacin and levofloxacin. RESULTS: Overall, 525 patients were randomised and treated with nemonoxacin (n = 349) or levofloxacin (n = 176). The clinical cure rate was 91.8% (279/304) for nemonoxacin and 85.7% (138/161) for levofloxacin in the mITT population (P > 0.05). The clinical efficacy of nemonoxacin was non-inferior to levofloxacin for treatment of CAP. Microbiological success rate with nemonoxacin was 88.8% (95/107) and with levofloxacin was 87.8% (43/49) (P > 0.05) at the TOC visit in the bacteriological mITT population. The incidence of drug-related adverse events (AEs) was 37.1% in the nemonoxacin group and 22.2% in the levofloxacin group. These AEs were mostly local reactions at the infusion site, nausea, elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST), and QT interval prolongation. The nemonoxacin-related AEs were mostly mild and resolved after discontinuation of nemonoxacin. CONCLUSIONS: Nemonoxacin 500 mg IV once daily for 7-14 days is effective and safe and non-inferior to levofloxacin for treating CAP in adult patients.

Tricarboxylic acid cycle intermediates (TCAi) have been proposed to act as myokines that influence energy metabolism. We determined if 2-weeks of low-calorie diet with interval exercise (LCD + INT) would increase TCAi more than a low-calorie diet (LCD). Twenty-three women were randomized to 2-weeks of LCD (n = 12, 48.4 ± 2.5 years, 37.8 ± 1.5 kg/m2, ~1200 kcal/d) or LCD + INT (n = 11, 47.6 ± 4.3 years, 37.9 ± 2.3 kg/m2; 60 min/d supervised INT of 3 min 90% & 50% HRpeak). TCAi and amino acids (AA) were measured at 0 min of a 75 g OGTT, while glucose, insulin, and FFA were obtained at 0, 30, 60, 90, 120, and 180 min to assess total area under the curve (tAUC180min) and insulin resistance (IR; tAUC180min of Glucose × Insulin). Fuel use (indirect calorimetry) was also collected at 0, 60, 120, and 180 min as was fitness (VO2peak) and body composition (BodPod). Treatments reduced weight (p < 0.001), fasting RER (p = 0.01), and IR (p = 0.03), although LCD + INT increased VO2peak (p = 0.02) and maintained RER tAUC180min (p = 0.05) versus LCD. Treatments increased FFA tAUC180min (p = 0.005), cis-aconitate, isocitrate, and succinate (p ≤ 0.02), as well as reduced phenylalanine and tryptophan, cysteine (p ≤ 0.005). However, LCD + INT increased malate, citrate, α-ketoglutarate, and alanine more than LCD (p ≤ 0.04). Thus, INT enhanced LCD effects on some TCAi in women with obesity independent of IR. © 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.

This meta-analysis and meta-regression evaluated how malic acid supplementation modulates rumen fermentation and its consequences for growth performance, nutrient digestibility, and carcass traits in lambs. Effect sizes (ES) were estimated using a random-effects model. Dietary composition was explored by meta-regression as a key source of heterogeneity, and subgroup analyses were used to compare free malic acid (FMA) and malate. Ruminal pH was not affected by malic acid supplementation. In contrast, total volatile fatty acid concentration increased with malic acid supplementation, particularly in studies using FMA. No effects were detected for propionate concentration, whereas acetate concentration increased (ES = 0.502; p = 0.036). A tendency toward a reduced ruminal acetate proportion was observed (ES = -0.683; p = 0.072). Malic acid supplementation tended (p = 0.057) to increase body weight gain (BWG; ES = 0.325) and final body weight (FBW; ES = 0.234). Malic acid supplementation did not affect carcass traits or overall nutrient digestibility. Meta-regression consistently identified fiber intake-related variables as major moderators of the effects of malic acid. Overall, the effects of malic acid supplementation on lamb performance appear to be primarily driven by its modulation of rumen fermentation and strongly conditioned by dietary context.

The study unveils potential toxic effects of a widespread organophosphate pesticide, monocrotophos, in a non-target model organism Drosophila melanogaster. Monocrotophos has been used in cotton, sugarcane, and paddy fields for many decades. Hence, a wide range of non-target organisms are get exposed to this pesticide. For the present study, five sub-lethal concentrations of monocrotophos were selected for chronic toxicity testing, which are below the determined LC50 value (0.68 µg/mL). Drosophila larvae were exposed to different sub-lethal concentrations of monocrotophos through food media from their 1st instar stage to 3rd instar stage. The present study aims to explore the reactive oxygen species generation by thioredoxin reductase activity, glutathione content, along with H2-DCFDA staining, which shows a significant amount of oxidative stress generation in both quantitative and qualitative means. MTT assay has been performed in brain tissue, which reflected a lower number of viable brain cells in treated larvae. Moreover, nuclear fragmentation in brain tissue by DAPI staining indicates the genotoxic potential of the test chemical. Acetylcholinesterase activity was found to be significantly decreased in the treated ones. Meanwhile, chronic sub-lethal exposure significantly reduced the metabolic activity, which was evident in cytosolic glucose content, glucose 6 phosphate dehydrogenase enzyme activity, and malate dehydrogenase enzyme activity. As both enzymes are closely linked with glucose metabolism, so decreased glucose level and both enzyme activity indicate altered metabolic status in cells. Poor brain health and altered metabolism status in monocrotophos-exposed larvae manifested impairment in crawling, phototaxic and embedding behavior in Drosophila. The overall study indicates monocrotophos mediated redox-imbalance, deficiency in metabolism, and compromised brain health untimely visible in poor behavioral responses. As this pesticide is able to contaminate different environmental compartments thus these hazardous effects will inevitably impact many non-target organisms. Observations of the present study can also be extrapolated to other non-target organ

Placental insufficiency causes fetal hypoxemia and hypoglycemia and is a major driver of fetal growth restriction (FGR). In FGR skeletal muscle, mitochondrial respiration is reduced, partially due to altered mitochondrial protein abundance. We have shown that maternal oxygen and fetal glucose supplementation alleviate fetal hypoxemia and hypoglycemia and improve skeletal muscle satellite cell proliferation. However, its effects on muscle mitochondrial respiratory function and proteomic profiles remain unknown. Here, we tested whether correcting fetal hypoxemia and hypoglycemia restores mitochondrial oxidative phosphorylation and normalizes mitochondrial proteomic profiles in FGR sheep skeletal muscle. Placental insufficiency and FGR were induced by maternal hyperthermia during gestation. Near-term fetuses were chronically catheterized and received 7-10 days of maternal tracheal oxygen insufflation and fetal intravenous (IV) glucose infusion (FOG) or maternal air insufflation and fetal IV saline infusion (FAS). Both were compared with normally grown control fetuses without supplementation (CON). Principal component analysis of the mitochondrial proteome indicated that FOG clustered closer to CON than to FAS. Abundances of 48 of 80 proteins that were differentially expressed in FAS versus CON returned to CON levels with FOG supplementation. Mitochondria isolated from CON and FOG muscle had similar glutamate/malate-driven state 3 (ADP-stimulated) respiration, and both rates were greater than FAS mitochondria. Mitochondrial complex I activity was lower in FAS compared with CON, and FOG showed an intermediate level that was not different from either group. Together, these findings indicate that prenatal oxygen and glucose supplementation rescued mitochondrial respiratory dysfunction and partially normalized mitochondrial proteome in FGR skeletal muscle.NEW & NOTEWORTHY Using a sheep model of placental insufficiency, we showed that prenatal oxygen and glucose supplementation improved mitochondrial respiration and partially normalized mitochondrial proteomic profiles in growth-restricted fetal skeletal muscle. These findings highlight that targeted prenatal correction

Robust microbial cell factories (MCFs) are pivotal for sustainable biomanufacturing. The industrial model chassis Saccharomyces cerevisiae is often constrained by its dominant ethanol biosynthesis to produce other biochemicals. To overcome this limitation, we employed a dominant-metabolism compromised intermediate (DMCI) chassis strategy to reconfigure the central metabolism of S. cerevisiae. We first constructed a non-ethanol-producing DMCI chassis by integrating a heterologous 2,3-butanediol (2,3-BDO) pathway and sequentially deleting all three pyruvate decarboxylase genes (PDC1, PDC5, and PDC6). Genome-scale modeling was utilized to verify and optimize the flux distribution towards 2,3-BDO synthesis as DMCI chassis. This platform was subsequently engineered to produce various C2-C4 chemicals, including d-lactate, acetoin, and malate. Fed-batch fermentation demonstrated the industrial viability of these MCFs, achieving titers of 100, 80, 55, and 30 g/L for 2,3-BDO, d-lactate, malate, and succinate, respectively. Furthermore, to enhance the suitability for organic acid production, we employed adaptive laboratory evolution (ALE) to obtain a weak-acid tolerant mutant B3-ALE. Genomic and functional analyses of B3-ALE identified mutations in genes related to cell wall integrity, membrane trafficking, and oxidative stress response with six weak-acid tolerant biological parts. Collectively, this work establishes a versatile and robust non-ethanol producing yeast chassis with improved environmental resilience, offering a practical yeast platform and strategic guidance for the cost-effective production of value-added biochemicals.

Strategies that support repeated high-intensity sprint performance are of considerable interest in competitive sprinting and team sports; however, evidence regarding acute citrulline malate (CM) supplementation during recovery intervals remains limited. This study examined the effects of acute CM supplementation on repeated 100 m sprint performance and rating of perceived exertion (RPE) in trained sprinters. Eleven trained male collegiate sprinters (100 m personal best: 11.22 ± 0.47 s; range: 10.35-12.16 s) completed randomized, double-blind, crossover trials (CM vs. placebo) on separate days. Each trial consisted of two maximal 100 m sprints separated by an 80-90 min recovery interval, during which 8 g of CM or placebo was ingested. Sprint performance was primarily evaluated using wind-adjusted 100 m sprint time based on Mureika's model. A significant condition × trial interaction was observed for wind-adjusted sprint time (p = 0.010), with a greater improvement in the CM condition (p = 0.008). RPE (Borg 6-20 scale) before the second sprint was lower (p = 0.004) following CM supplementation. These findings suggest that acute CM supplementation may modestly support repeated sprint performance under extended recovery conditions; however, the results should be interpreted with caution.

Background/Objectives: MYC-driven tumors exhibit significant glutamine addiction, but the metabolic adaptation mechanisms enabling their survival under glutamine deprivation remain incompletely understood. Malic enzymes catalyze the oxidative decarboxylation of malate to pyruvate while generating NADPH, linking central carbon metabolism to redox homeostasis. This study investigates whether and how ME1 and ME2 mediate cell adaptation to glutamine starvation and explores their functional division in relation to p53 status. Methods: Using MYC-amplified, p53-mutant (G266E) SF188 glioblastoma cells, we performed siRNA-mediated knockdown, overexpression, and rescue experiments. Cell survival was assessed by trypan blue exclusion and Annexin V/PI staining. ROS levels and NADP+/NADPH ratios were measured by DCFH-DA fluorescence and enzymatic assays. Metabolite tracing was conducted using [U-13C5] glutamine followed by LC-MS. Key findings were validated in additional cell lines including HCT116, U2OS and MDA-MB-231. Results: ME1 and ME2 promote SF188 cell survival under glutamine deprivation, an effect that depends on their catalytic activity but is independent of TCA cycle anaplerosis. ME1 maintains redox balance by generating NADPH, and antioxidant treatment rescues the survival defect caused by ME1 knockdown. In contrast, ME2 does not contribute to redox regulation but stabilizes mutant p53 (G266E) via proteasome inhibition. Both of these pro-survival functions are attenuated upon MYC knockdown, suggesting a dependency on MYC expression. Across all cell lines tested, ME1 and ME2 also promote survival through redox maintenance, although the isoform responsible for antioxidant function differs. Conclusions: ME1 and ME2 support metabolic adaptation to glutamine starvation through distinct, isoform-specific mechanisms that depend on MYC expression and p53 mutation status. These findings suggest malic enzymes as potential therapeutic targets in MYC-driven, p53-mutant tumors.

Biodegradable plastics are materials that can be decomposed by the action of microbes into water, CO2, and biomass. They are attractive materials to solve the issue of serious environmental pollution due to plastic disposal. Some biodegradable plastics are produced entirely from petroleum-based precursors. The production of new biodegradable plastics and their precursors from CO2 and persistent organic or bio-based compounds using visible-light driven redox with biocatalytic processes is one of the effective resolutions for the environmental issues of plastic pollution and global warming. In this review article, recent research on the visible-light driven production of CO2-based biodegradable plastics and their precursors using a system of light-driven redox and biocatalytic processes is introduced. As a first example, an overview of research into the production of biodegradable plastics, poly(hydroxybutyrate) (PHB) and their precursors such as acetate, shikimic acid, acetoin and so on from CO2 using a semiconductor photocatalyst-based photoredox system with a microbial cell as a biocatalytic process is provided. As a second example, an overview is provided of studies on the production of biodegradable plastic precursors, 3-hydroxybutyrate, L-malate and fumarate from CO2 and small organic molecules using an organic dye-based photoredox system with an electron donor, an electron mediator and enzyme-based biocatalytic processes.

Phosphate (Pi) deficiency impairs plant development and decreases productivity owing to its critical functions in terms of cell structure, metabolism, and photosynthesis. Here, we assessed the determinate growth program of Arabidopsis primary roots exposed to Pi scarcity to clarify the role of citrate and malate in the expression of the mitotic cyclin CycB1 and changes in the meristem, transition zone, and elongation zone. The transfer of seedlings from high-Pi medium to low-Pi medium, but not to high-Pi medium, inhibits root growth, cell division, and elongation, aspects that are restored upon the application of each organic acid. On the other hand, the exhaustion of the meristem under low Pi related to the loss of auxin and the cytokinin response in columella cells is reversed by organic acids, according to the expression of the DR5:GUS and ARR5:GUS gene constructs, respectively. Histological detection of iron levels at the tip of the primary root and the formation of abundant root hairs, which indicate the repression of mitosis and the advancement of differentiation, decreases with malate and citrate and with the application of ferrozine, an iron chelator, suggesting a relevant role of chelators at the rhizosphere to reduce the adaptive pressure of phosphate scarcity on root growth.

Lentinula edodes, a mushroom valued both nutritionally and medicinally, produces polysaccharides as its principal bioactive compounds, known for their significant pharmacological effects. However, low yields have limited their large-scale industrial application. To address this limitation, the present study conducted a systematic analysis of transcriptional dynamics and identified critical genes and pathways involved in polysaccharide biosynthesis. This study integrated real-time monitoring of polysaccharide production during fermentation with transcriptomic analysis, enabling an initial identification of the key metabolic pathways involved in polysaccharide synthesis in L. edodes. The study revealed that intracellular polysaccharides (IPS) reached a maximum concentration of 0.47 g/L, total polysaccharides (TPS) peaked at 0.97 g/L, and extracellular polysaccharides (EPS) attained 0.56 g/L. Fluctuations in the activities of key enzymes involved in polysaccharide biosynthesis-hexokinase (HK), phosphoglucose isomerase (PGI), phosphoglucomutase (PGM), UDP-glucose dehydrogenase (UGD), and UDP-glucose pyrophosphorylase (UGP) had a marked impact on polysaccharide accumulation. Among these, PGM exhibited the highest activity, reaching 566.14 mg protein/min on day 16, and showed a strong positive correlation with IPS production (r = 0.98). Transcriptomic analysis further identified 5609 differentially expressed genes (DEGs), including 2789 upregulated and 2820 downregulated genes. KEGG pathway enrichment analysis revealed the involvement of multiple metabolic pathways in polysaccharide metabolism in L. edodes. These included starch and sucrose metabolism, glycolysis/gluconeogenesis, the pentose phosphate pathway, galactose metabolism, and the tricarboxylic acid (TCA) cycle. Several key enzymes were identified as central to polysaccharide biosynthesis, notably phosphoglucomutase (PGM), glutamine synthetase (GS), glycogen-branching (GBE), UDP-glucose pyrophosphorylase (UGP), pyruvate kinase (PK), β-1,3-Glucan Synthase (FKS), hexokinase (HK), phosphoglucose isomerase (PGI), 6-phosphogluconate dehydrogenase (6PGDH), transketolase (TKT), UDP-glucose 4-epimerase (GALE), malate

Update in Redox Biol. 2026 Sep;95:104266. doi: 10.1016/j.redox.2026.104266. Photoreceptor (PR) loss causes vision loss in many blinding diseases, and effective therapies to prevent this cell loss are lacking. Aspartate aminotransferases (GOTs), located in the cytosol (GOT1) and mitochondria (GOT2), are key components of the malate-aspartate shuttle, which transfers reducing equivalents from cytosol to mitochondria. Previous work has implicated the GOTs as potential modulators of blinding retinal disease. To determine the roles of GOT1 and GOT2 in rod PRs, we generated rod PR-specific Got1 or Got2 conditional knockout mice (Got1 or Got2 cKO). We previously showed that Got1 cKO causes PR degeneration and is accompanied by NADH accumulation and a decreased retinal NAD+/NADH ratio. Here, we show that NADH oxidation via metabolic or genetic means prolongs PR survival in Got1 cKO animals, implicating NADH accumulation, or reductive stress, as a key driver of PR degeneration. In contrast, Got2 cKO causes minimal PR degeneration and alterations in retinal NADH and the NAD+/NADH ratio that oppose reductive stress. Interestingly, GOT2, but not GOT1, is decreased in multiple models of PR degeneration, including retinal detachment (RD) where the NAD+/NADH ratio favors a reductive state. Notably, loss of Got2 in PRs demonstrates a neuroprotective effect after experimental RD suggesting decreased GOT2 expression may be part of a stress response to promote PR survival. Overall, this study illustrates the differential dependence on the GOTs for PR health, provides evidence that an overly reductive environment is detrimental to PR survival, and identifies GOT2 as a novel therapeutic target with potentially broad application in blinding diseases.