Glycine

Regulating dietary Arginine (Arg) levels in the diet of broilers has been a focus of researchers due to the potential economic benefit to the industry. This meta-analysis evaluated the effects of dietary guanidinoacetic acid (GAA) supplementation on the production performance of broiler chickens fed diets that were either adequate or deficient in Arg or energy. Through studies, the basal diet generally met standard requirements for broilers, with deficiencies in Arg or energy being experientially induced. The meta-analysis using weighted random-effects models revealed that dietary GAA improved average daily gain (ADG; P < 0.001) by 2.17% and 1.08% during starter and finisher periods, respectively. Concomitantly, the feed conversion ratio (FCR; P < 0.001) also improved by 2.37% and 2.41% in the starter and finisher periods, respectively, with minimal evidence of publication bias for these key traits. However, significant heterogeneity (I² > 90%) indicated strong between-study variances. In broilers fed Arg-deficient diets, GAA supplementation only showed minimal effect to reduce the detrimental effect of an Arg-deficient diet (-4.75 vs. -3.64% ADG reduction), suggesting its limited Arg-sparing function. Under low energy diet, GAA restored ADG to levels equivalent to those of energy-sufficient diets. In the finisher phase, comparable but less pronounced effects were observed, suggesting reduced responsiveness with age. Dose-response evaluation suggested no difference in ADG or FCR between low and high GAA inclusion, suggesting low GAA level is more effective. Meta-regression models identified feed intake and arginine intake as the dominant predictors of ADG, and including GAA consistently improved model accuracy and increased ADG compared to the control diet. The meta-refgression suggested that 0.06% GAA supplementation increased final body weight by approximately 2.11% (60 g) in Ross 308 broilers. Collectively, the results confirm that GAA exerts a robust, dose-limited benefit of growth efficiency in broiler chickens, thereby supporting its incorporation into Arg or energy deficient diets that would have potential economic benefit.

Chronic kidney disease (CKD) is commonly complicated by anemia. Treating dialysis-dependent patients with anemia, including daprodustat and other inhibitors of prolyl hydroxylase of hypoxia-inducible factor, recombinant human erythropoietin (rhEPO), and iron supplements. We conducted this study to test our postulation; daprodustat is superior to rhEPO and other conventional treatments respecting efficacy and safety parameters. We made systematic search through PubMed, Web of Science, Scopus, and Cochrane. Seven unique trials were eventually included for systematic review; six of them with a sample size of 759 patients entered our network meta-analysis (NMA). Daprodustat 25-30 mg was associated with the greatest change in serum hemoglobin (MD=1.86, 95%CI= [1.20; 2.52]), ferritin (MD= -180.84, 95%CI= [-264.47; -97.20]), and total iron binding capacity (TIBC) (MD=11.03, 95%CI= [3.15; 18.92]) from baseline values. Dialysis-dependent patients with anemia had a significant increment in serum Hemoglobin and TIBC and a reduction in serum ferritin, in a dose-dependent manner, when administered daprodustat. Copyright: Hammad Ali Fadlalmola et al.

Supplementation of feed with organic zinc (Zn) has long been discussed as an alternative to inorganic Zn in pigs, but its effects on growth performance are mixed. This meta-analysis was conducted to provide a comprehensive evaluation of the influence of organic Zn on the growth performance of weanling pigs, on the basis of average daily gain (ADG), average daily feed intake (ADFI), and feed to gain ratio (F/G). We screened the PubMed and Web of Science databases (published before December 31, 2022; limited to English) systematically and contrasted organic Zn supplementation with inorganic Zn supplementation. There were 680 retrievals of studies, of which 16 (1389 pigs, 37 records) were eligible to analyze. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated using a random-effects model. The subgroup analysis was classified as organic Zn source (Zn-amino acid (Zn-AA), Zn-glycine (Zn-Gly), Zn-methionine (Zn-Met), Zn-Lysine (Zn-Lys), proteinate complex Zn (Zn-Pro), chitosan-Zn (Zn-CS) or Zn-lactate (Zn-Lac)) and Zn additive dose (low, medium, or high, i.e., lower than, equal to or higher than the requirement of NRC). Organic Zn addition in the weaning phase increased the ADG (P < 0.001) and the ADFI (P = 0.023) and decreased the F/G (P < 0.001). Specifically, for the organic sources, only Zn-CS supplementation presented significant effects on the ADG (P < 0.001), ADFI (P = 0.011), and F/G (P < 0.001). Moreover, medium-dose organic Zn supplementation had positive effects on ADG (P = 0.012), ADFI (P = 0.018), and F/G (P < 0.001). Our results indicate that organic Zn added to diets greatly improves the growth performance of weanling pigs. © 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

CONTEXT: Iron deficiency and anemia have serious consequences, especially for children and pregnant women. Iron salts are commonly provided as oral supplements to prevent and treat iron deficiency, despite poor bioavailability and frequently reported adverse side effects. Ferrous bisglycinate is a novel amino acid iron chelate that is thought to be more bioavailable and associated with fewer gastrointestinal (GI) adverse events as compared with iron salts. OBJECTIVE: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the effects of ferrous bisglycinate supplementation compared with other iron supplements on hemoglobin and ferritin concentrations and GI adverse events. DATA SOURCES: A systematic search of electronic databases and grey literature was performed up to July 17, 2020, yielding 17 RCTs that reported hemoglobin or ferritin concentrations following at least 4 weeks' supplementation of ferrous bisglycinate compared with other iron supplements in any dose or frequency. DATA EXTRACTION: Random-effects meta-analyses were conducted among trials of pregnant women (n = 9) and children (n = 4); pooled estimates were expressed as standardized mean differences (SMDs). Incidence rate ratios (IRRs) were estimated for GI adverse events, using Poisson generalized linear mixed-effects models. The remaining trials in other populations (n = 4; men and nonpregnant women) were qualitatively evaluated. DATA ANALYSIS: Compared with other iron supplements, supplementation with ferrous bisglycinate for 4-20 weeks resulted in higher hemoglobin concentrations in pregnant women (SMD, 0.54 g/dL; 95% confidence interval [CI], 0.15-0.94; P < 0.01) and fewer reported GI adverse events (IRR, 0.36; 95%CI, 0.17-0.76; P < 0.01). We observed a non-significant trend for higher ferritin concentrations in pregnant women supplemented with ferrous bisglycinate. No significant differences in hemoglobin or ferritin concentrations were detected among children. CONCLUSION: Ferrous bisglycinate shows some benefit over other iron supplements in increasing hemoglobin concentration and reducing GI adverse events among pregnant women. More trials are

BACKGROUND AND AIMS: Our aim in this meta-analysis was to determine the effect of soy and soy product supplementation on serum adiponectin levels. METHOD: A systematic search was conducted using Medline (PubMed and Web of Science), Scopus, and Cochrane Library for eligible trials up to August 2020. A random-effects model was used to pool calculated effect sizes. RESULTS: Seven trials were included in the overall analysis. Our analysis showed that soy and soy product supplementation did not significantly affect adiponectin concentrations (WMD = -0.77 μg/ml, 95% CI: -0.61, 2.15, P = 0.27) in comparison with a placebo. The between-study heterogeneity was high (I2: 68.2%, P = 0.004). Subgroup analysis, based on participants' health status and duration of the supplementation, could not detect the potential source of the observed heterogeneity. In addition, subgroup analysis showed that the effect was not statistically significant in all subgroups. CONCLUSION: Overall, soy and soy product supplementation did not change the circulatory adiponectin levels. In addition, the results were not affected by the participant's health status and duration of supplementation. However, further studies are needed to confirm the present results.

The aim of this report was to determine the impact of flaxseed, soy and red clover, and their bioactive substances on the lipid profile in postmenopausal women in cardiovascular diseases prevention. We used the following databases: MEDLINE (PubMed), EMBASE and the Cochrane Library. Meta-analysis indicates that the intake of flaxseed by postmenopausal women is associated with a statistically significant reduction in total cholesterol (TC) levels (weighted-mean difference (WMD) = -0.26; 95% confidence interval (95% CI): -0.38 to -0.13; p = 0.0001), low-density lipoprotein cholesterol (LDL-C) levels (WMD = -0.19; 95% CI: -0.30 to -0.08; p = 0.0006), and high-density lipoprotein cholesterol (HDL-C) levels (WMD = -0.06; 95% CI: -0.11 to -0.01; p = 0.0150). The effect of soy protein on the lipid profile showed a significant decrease in TC levels: WMD = -0.15; 95% CI: -0.25-0.05; p = 0.0048, LDL-C levels: WMD = -0.15; 95% CI: -0.25-0.05; p = 0.0067, as well as a significant increase in HDL-C levels: WMD = 0.05; 95% CI: 0.02-0.08; p = 0.0034. Changes in the lipid profile showed a significant reduction in TC levels after the use of red clover (WMD = -0.11; 95% CI: -0.18--0.04; p = 0.0017) and a significant increase in HDL-C levels (WMD = 0.04; 95% CI: 0.01 to 0.07; p = 0.0165). This meta-analysis provides evidence that consuming flaxseed, soy and red clover can have a beneficial effect on lipids in postmenopausal women and suggest a favorable effect in preventing cardiovascular diseases.

BACKGROUND: Dysfunction of the N-methyl-D-aspartate glutamate receptor is involved in the putative pathology of schizophrenia. There is growing interest in the potential of N-methyl-D-aspartate receptor modulators to improve the symptoms of schizophrenia, but the evidence for the use of glutamatergic agents for augmenting schizophrenia remains inconclusive. AIMS: We conducted a meta-analysis to test the efficacy and safety of N-methyl-D-aspartate receptor modulator supplements in patients with schizophrenia. METHODS: Following a systemic search in MEDLINE, Embase, Cochrane and Scopus, 40 double-blinded, randomised, placebo-controlled trials involving 4937 patients with schizophrenia were included in this meta-analysis. The change in the severity of symptoms among patients with schizophrenia was defined as the primary outcome, whereas the safety profiles of the intervention, including the discontinuation rate and adverse events, were defined as secondary outcomes. RESULTS: When added to antipsychotic treatments, N-methyl-D-aspartate receptor modulators improved multiple schizophrenia symptoms, particularly negative symptoms, and had satisfactory side effects and safety profile. Among the seven glutamatergic agents analysed, glycine, D-serine and sarcosine had better treatment profiles than other agents, and NMDA receptor co-agonists, as a group, provided a reduction in schizophrenia symptoms compared to antipsychotic treatments without supplementation. Augmentation with N-methyl-D-aspartate receptor modulators was only effective among patients treated with antipsychotics other than clozapine. CONCLUSIONS: The results indicate that N-methyl-D-aspartate receptor modulators, particularly with glycine, D-serine and sarcosine, are more beneficial than the placebo in treating schizophrenia, and the effects extended to both positive and negative symptoms, when augmented with antipsychotics other than clozapine.

8. J Psychopharmacol. 2021 Mar;35(3):236-252. doi: 10.1177/0269881120965937. Epub 2021 Jan 6. Efficacy of N-methyl-D-aspartate receptor modulator augmentation in schizophrenia: A meta-analysis of randomised, placebo-controlled trials. Goh KK(1)(2), Wu TH(2)(3), Chen CH(1)(2)(4), Lu ML(1)(2)(4).

BACKGROUND: Anemia is a common complication for patients with kidney disease. Roxadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), which is a newly approved oral drug for anemia. We performed this study to build evidence regarding efficacy and safety of roxadustat in kidney disease patients with or without dialysis. METHODS: We searched the databases of PubMed, Embase, Cochrane library and clinicaltrials.gov from the inception to July 20, 2020. The randomized controlled trials (RCTs) which compared roxadustat with placebo or other therapies in the treatment of anemia in kidney disease patients were included. Data were extracted from eligible studies and pooled in a meta-analysis model using RevMan5.3 and stata13.0 software. RESULTS: Eight RCTs with 1010 patients were included in our analysis. We found that roxadustat significantly increased hemoglobin (Hb) level (1.10 g/dL, 95% CI [0.52 g/dL, 1.67 g/dL], p = 0.0002), total iron-binding capacity (TIBC) (58.71 µg/dL, 95% CI [44.10 µg/dL, 73.32 µg/dL], p < 0.00001), iron level (9.28 µg/dL, 95% CI [0.11 µg/dL, 18.45 µg/dL], p = 0.05) compared with control group in kidney disease patients. In addition, our result showed that a significant reduction in hepcidin level (- 31.96 ng/mL, 95% CI [- 35.05 ng/mL, - 28.87 ng/mL], p < 0.00001), ferritin (- 44.82 ng/mL, 95% CI [- 64.42 ng/mL, - 25.23 ng/mL], p < 0.00001) was associated with roxadustat. No difference was found between roxadustat and control group in terms of oral iron supplementation, adverse events (AEs), serious adverse events (SAEs), infection, myocardial infraction, stroke, heart failure and death. CONCLUSIONS: Roxadustat has higher mean Hb level than placebo or EPO. Due to the short follow-up period and the lack of critical data, more RCTs are needed to prove long-term safety and effectiveness of roxadustat in the future.

BACKGROUND: Soy products contain several compounds with anti-inflammatory properties like genistein and daidzein which reported to act through different pathways. Present study conducted considering the inconsistent results and lack of any comprehensive review regarding randomized controlled trials which assess the effect of soy products on inflammatory markers. METHODS: Following electronic databases were searched up to March 2020: PubMed, Scopus, ISI web of science, and Cochrane Library All randomized trials which assessed the effect of soy product supplementation on c-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were included for last analysis. Treatment effects were expressed as mean difference (MD) and the standard deviation (SD) of outcomes. To estimate the overall effect the random-effects model was employed. RESULTS: Finally, 51 randomized trial were included for present study. Last analysis showed that soy product supplementation lead to significant reduction in CRP (MD -0.27 mg/L; 95% CI: -0.51, -0.02, p = 0.028) but it did not affect IL-6 (MD 0.0 pg/ml; 95% CI: -0.06, 0.06, p = 0.970) and TNF-α (MD = -0.04 pg/ml; 95% CI: -0.11, 0.03, p = 0.252). Subgroup analysis showed that soy supplementation had a significant impact on decreasing IL-6 and TNF-α levels when studies had a long-term intervention (≥12 weeks) and used low dose isoflavone (<100 mg/day). CONCLUSION: In conclusion, present systematic review and meta-analysis found a significant reduction in CRP levels after soy supplementation whiles IL-6 and TNF-α did not affect.

Background/Objectives: Soy flour has been proposed as a functional ingredient to improve the protein and fiber content of foods; however, its metabolic and sensory effects, particularly in individuals at elevated risk for metabolic disease, remain insufficiently characterized. This randomized, repeated-measures study examined whether substituting refined wheat or corn flour with soy flour influences postprandial glucose and insulin plasma concentrations, appetite ratings, and product acceptability in adults with overweight or obesity. Methods: Participants (N = 17) attended at least three separate visits during which they consumed, in random order, a food matrix with 0% (control), 10%, or 30% soy flour substitution. Food matrices included breads (n = 10), tortillas (n = 10), and arepas (n = 8); some participants completed more than one matrix. Postprandial plasma glucose and insulin concentrations were measured at baseline and at 15, 30, 60, 90, and 120 min post-ingestion. Subjective hunger, satiety, and product liking were assessed using a 10 cm visual analog scale. Results: Compared with the control condition, substituting 30% of refined flour with soy flour significantly reduced the area under the concentration-time curve for postprandial glucose for breads (p = 0.03) and arepas (p = 0.04), and reduced plasma glucose concentrations at 90-120 min for tortillas (p = 0.0009). In contrast, postprandial insulin concentrations and subjective hunger and satiety ratings did not differ across substitution levels or food matrices (all p > 0.05). Importantly, even 30% soy flour substitution maintained product liking. Conclusions: Incorporating up to 30% soy flour may improve postprandial glycemic responses without compromising overall liking, supporting its potential as a practical food reformulation strategy to improve metabolic health in populations at increased risk of metabolic disease.

OBJECTIVES: To investigate the potential benefits of Xanthan-based chlorhexidine gel application in addition to professional mechanical plaque removal (PMPR) in the treatment of peri-implant mucositis (PM). MATERIAL AND METHODS: Subjects diagnosed with PM were consecutively included in this randomized split-mouth study. All participants received a single session of PMPR using titanium curettes, followed by the application of an air-polishing glycine powder device. Implants allocated to the Test group were additionally treated with local delivery of Xanthan-based chlorhexidine gel. Clinical evaluation was performed at T0 (i.e., baseline), at 30 (T1), 90 (T2) and 180 days (T3) after treatment, while treatment success was evaluated at T2 and T3. Change in bleeding on probing (BoP) was considered as primary outcome measure. A logistic multivariate regression model was developed to explore the predictive role of implant and patient-level variables on primary outcome measure. RESULTS: Fifty-nine patients (mean age: 65.4 ± 8.7 years; 54.2% male; 88.1% non-smokers) and 182 implants completed the study. At T1, only the Test group displayed a significant reduction in BoP (p < 0.001), PPD (p = 0.021) and PI (p = 0.021) compared to T0, while at T2 and T3 clinical improvements were recorded within both groups without any statistically significant difference between groups (p > 0.05). T2 Treatment success as well as the frequency distribution of complete (BoP = 0) and partial (BoP ≤ 1, ≤ 2, ≤ 3) disease resolution did not significantly differ between groups (p > 0.05). Multiple regression model revealed that smoking (p = 0.008), and implant position (i.e., premolar p = 0.009) did significantly affect the primary outcome measure. CONCLUSION: The adjunctive use of XanCHX gel did not result in any statistically significant clinical benefit compared to PMPR alone in the treatment of PM up to 6 months, despite the reported clinical positive effects within the first month after treatment. © 2026 The Author(s). Clinical Implant Dentistry and Related Research published by Wiley Periodicals LLC.

Metabolic dysfunction associated steatotic liver disease (MASLD), a globally prevalent chronic liver disease, has only limited pharmacological options. Both metformin and Ganwei, health supplements containing a potent inducer of glycine N-methyltransferase (GNMT), have shown great promise for the treatment of MASLD. We conducted a 4-arm, randomized, placebo-controlled trial to investigate the safety and efficacy of metformin and Ganwei for patients with MASLD. Between September 2021 and March 2023, 64 patients with MASLD were randomly assigned at a 1:1:1:1 ratio to receive metformin alone (arm A, n = 16), a combination of metformin and Ganwei (arm B, n = 16), a placebo alone (arm C, n = 16) or Ganwei alone (arm D, n = 16) for 6 months. The primary liver steatosis outcome was assessed by control attenuation parameter (CAP) and kilopascal (kPa) scores via FibroScan. The key secondary outcomes included safety, liver function and patients' metabolic profiles. At 6 months after treatment, significant improvements in liver steatosis were observed in patients treated with Ganwei alone (repeated-measures ANOVA test, p = 0.048 and 0.048 for CAP and kPa scores, respectively) but not in patients treated with placebo and other arms. By employing a 6-point steatosis grade scale, the Ganwei alone arm exhibited a statistically significant improvement over the placebo-controlled arm (mean score 1.1 ± 1.8 vs. 0.1 ± 0.7, p = 0.036). Located in the promoter region of the GNMT gene, the SNP rs10948059 polymorphism is known to affect GNMT promoter activity. Interestingly, genotype analysis revealed that the improvement in liver steatosis in the Ganwei alone arm was restricted to patients harboring the T allele at GNMT rs10948059 (C/T and T/T vs. C/C, p < 0.05). No serious adverse events were observed in any of the treatment arms. Our study demonstrated that Ganwei may be an effective treatment option for MASLD patients. Improvement in liver steatosis by Ganwei was affected by GNMT promotor activity. Clinical trial registration: NCT06244550.

Comment in doi: 10.1001/jamanetworkopen.2026.1201. IMPORTANCE: Acute respiratory distress syndrome (ARDS) represents a frequent and serious complication after cardiovascular surgery. Although sivelestat, a specific neutrophil elastase inhibitor, has demonstrated therapeutic potential in preliminary studies, the evidence remains limited by methodological constraints of observational designs and underpowered studies. OBJECTIVE: To evaluate the efficacy of sivelestat vs placebo in reducing the incidence of postoperative ARDS and associated complications among patients undergoing major cardiovascular procedures. DESIGN, SETTING, AND PARTICIPANTS: This single-center, randomized, placebo-controlled clinical trial conducted at a tertiary care academic medical center om China enrolled 424 participants between February 15, 2024, and April 16, 2025, with a 90-day postoperative follow-up period. Participants were consecutive patients scheduled for cardiovascular surgery, including coronary artery bypass grafting, valve surgeries, ascending aortic reconstruction, combined procedures, congenital heart defect repairs, and cardiac tumor resections. INTERVENTIONS: Participants were randomly allocated (1:1) to receive either continuous intravenous sivelestat (0.2 mg/kg/h), initiated immediately on intensive care unit (ICU) admission postoperatively and continued for up to 7 days or until ICU discharge; or volume-matched 0.9% sodium chloride placebo administered on an identical schedule. MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence of ARDS. Secondary outcomes included serial measurements of inflammatory biomarkers, including interleukin 6 and interleukin 8, tumor necrosis factor, systemic immune-inflammation index, and serum neutrophil elastase, on postoperative days 1, 3, 5, and 7, along with ARDS-related clinical outcomes including death, pneumonia, and reintubation. Analysis was performed on an intention-to-treat basis. RESULTS: Among 424 randomized patients, 382 completed the trial (mean [SD] age, 62.9 [6.2] years; 210 male [55.0%]). Adverse events monitored for safety did not differ between groups. The sivelestat group had significantly lower rates of A

Chronic, low-grade inflammation is a hallmark of many noncommunicable diseases. Diets enriched with tomatoes and soy are associated with better health outcomes in inflammation-related illnesses, with lycopene and isoflavones considered key bioactive components, respectively. On the basis that whole food combinations may exert greater effects than isolated phytochemicals, we examine the anti-inflammatory and metabolic effects of tomato-soy juice compared to a low carotenoid tomato juice control in obesity. Twelve healthy adults with obesity were provided either tomato-soy juice (54 mg lycopene/d, 189.9 mg isoflavones/d) or a low carotenoid tomato juice (no isoflavones) daily for 4 weeks, then crossed over to the other treatment following a washout period. Plasma carotenoids, cytokines, and the urine metabolome were measured pre- and post-interventions. Plasma lycopene significantly increased by 2.48-fold after tomato-soy intake. IL-5, IL-12p70, and GM-CSF significantly decreased (p < 0.05), and TNF-α trended downward (p = 0.052) following tomato-soy. Soy isoflavone metabolites primarily distinguished post-tomato-soy urine profiles. Both interventions induced some shared metabolomic changes in the urine, indicating tomato-driven effects independent of lycopene. Overall, tomato-soy intake reduced pro-inflammatory cytokines and altered urine metabolomic profiles in obesity, supporting future studies using this functional food product for other inflammation-related conditions. © 2026 The Author(s). Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.

BACKGROUND: Specific metabolites detected in biofluids after food intake have been proposed as objective markers to address limitations with traditional dietary assessment methods. Although hundreds of metabolites have been associated with foods or food groups, they require validation. OBJECTIVES: The aim of this study was to develop a panel from the proposed biomarkers of dietary intake reflecting major food groups and compare them against known and self-reported dietary intakes. METHODS: A randomized crossover trial of 3 interventions, including a day of foods consumed under observation, was performed. Each feeding day was of 3 food groups (e.g., whole grains, dairy, and fish) with optional snacks (e.g., fruit, chicken, and legumes) but absent of 3 other food groups (e.g., meat, vegetables, nuts, and seeds). Fasted whole blood and 24-h urine samples were analyzed by liquid chromatography mass spectrometry to detect previously proposed biomarkers of food intake. Urinary sodium was measured. Pairwise correlation coefficients and generalized linear modeling (GLM) considered relationships between biomarkers and food groups. Comparisons were drawn between self-reported and known dietary intakes. RESULTS: Twenty-one participants [mean age 24.8, standard deviation (SD) 6.0 y, body mass index: 24.1; SD: 4.0] completed the trial. GLM coefficients indicated fish intake was associated with 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid [62.15 (95% confidence interval: 35.00, 89.29)], wholegrain intake with 3,5-dihydroxybenzoic acid [87.32 (24.28, 150.35)] and fruit intake with fructose [5.39 (2.53, 8.25)], and s-methylcysteine [5.91 (1.24, 10.58)]. GLM rate ratios indicated chicken intake was associated with 3-methylhistidine [0.19 (0.07, 0.31)], anserine [0.21 (0.05, 0.37)], and carnosine [0.11 (0.03, 0.19)], legume intake with glycine betaine [0.21 (0.02, 0.40)] and vegetable intake with sulforaphane [0.30 (0.20, 0.47)], S-methylcysteine [0.23 (0.14, 0.45)], methoxytyramine [0.21 (0.08, 0.35)], and β-carotene [0.05 (0.02, 0.08)]. There was no association between 24-h urinary sodium and known sodium intake [0.11 (-0.06, 0.28)]. Self-reported dietary intake was associ

BACKGROUND: Erythropoietic protoporphyria is a rare genetic disorder of heme biosynthesis characterized by protoporphyrin-IX accumulation, painful phototoxic reactions, and hepatobiliary disease, for which no disease-modifying therapies are approved. OBJECTIVE: To evaluate the efficacy and safety of bitopertin, an inhibitor of glycine transporter 1, in adults with erythropoietic protoporphyria. METHODS: In this randomized, double-blind, phase 2 study, patients received once-daily oral bitopertin 20 mg, bitopertin 60 mg, or placebo for 17 weeks. The primary endpoint was percentage change from baseline in whole-blood metal-free protoporphyrin-IX levels at day 121. RESULTS: Patients received bitopertin 20 mg (n = 26), 60 mg (n = 25), or placebo (n = 24). At day 121, the percentage change from baseline in whole-blood metal-free protoporphyrin-IX versus placebo was -29.6% (P = .004) with bitopertin 20 mg and -49.8% (P < .001) with bitopertin 60 mg. Bitopertin was associated with a reduced incidence of phototoxic reactions. Bitopertin was well tolerated with no notable safety concerns identified. LIMITATIONS: Small sample size, short follow-up period, and no formal adjustments for between-group multiple-pairwise comparisons. CONCLUSIONS: Bitopertin significantly reduced protoporphyrin-IX levels, showed improved measures of sunlight tolerance, and had a favorable safety profile in patients with erythropoietic protoporphyria.

INTRODUCTION: Erythropoiesis-stimulating agents (ESAs) and iron supplementation are standard treatments for chronic kidney disease (CKD)-related anemia. Targeting higher hemoglobin values in CKD increases cardiovascular risk. Whether the increased risk is from higher ESA doses or higher hemoglobin levels is uncertain, but alternative therapies are sought for patients requiring high ESA doses. Phase 3 INNO2VATE trials in patients with dialysis-dependent CKD (DD-CKD) demonstrated vadadustat's noninferiority compared with darbepoetin alfa. To determine vadadustat's potential to treat anemia, including in patients requiring high ESA doses, its safety and efficacy were compared with those of darbepoetin alfa across prespecified baseline ESA dose subgroups in the prevalent DD-CKD INNO2VATE trial. METHODS: We compared the safety and efficacy of vadadustat versus darbepoetin alfa across prespecified baseline ESA dose subgroups (low [≤ 90 U/kg/week], intermediate [> 90 and < 300 U/kg/week], or high [≥ 300 U/kg/week]) in the INNO2VATE prevalent trial. The primary safety endpoint was time to first adjudicated major adverse cardiovascular event (MACE). Primary and secondary efficacy endpoints were mean hemoglobin level change from baseline at weeks 24-36 and weeks 40-52, respectively. FINDINGS: Compared with darbepoetin alfa, first MACE hazard ratios for vadadustat were 0.99 (95% CI, 0.81-1.23), 0.93 (95% CI, 0.74-1.18), and 0.62 (95% CI, 0.34-1.14) for low, intermediate, and high baseline ESA dose subgroups, respectively (interaction p = 0.92). Vadadustat was noninferior to darbepoetin alfa in hemoglobin change from baseline to primary evaluation period, with mean differences (vadadustat-darbepoetin alfa) of -0.10 g/dL (95% CI, -0.19 to -0.02), -0.20 g/dL (95% CI, -0.30 to -0.09), and -0.39 g/dL (95% CI, -0.67 to -0.11) for low, intermediate, and high ESA dose subgroups, respectively. DISCUSSION: Comparing safety and efficacy by baseline ESA dose among patients with CKD on maintenance dialysis, vadadustat was noninferior to darbepoetin alfa for all ESA dose subgroups, including patients with high baseline ESA requirements. © 2025 The Author(s). Hemodialysis International

TOURMALINE-MM3 (NCT02181413) and -MM4 (NCT02312258) were phase 3 studies of fixed-duration, single-agent ixazomib maintenance in post-transplant (TOURMALINE-MM3)/transplant-ineligible (TOURMALINE-MM4) patients with newly diagnosed multiple myeloma (NDMM) that demonstrated improved median progression-free survival (PFS) for ixazomib vs placebo. We present the final overall survival (OS) analyses for each study separately. In both studies, eligible patients were randomized 3:2 to receive ixazomib maintenance (3 mg [cycles 1-4], 4 mg [from cycle 5 if tolerated]) or matching placebo for ≤26 cycles, or until progressive disease/unacceptable toxicity. At median follow-up of approximately 8 years (TOURMALINE-MM3) and 5 years (TOURMALINE-MM4), median OS was not reached in either arm in MM3 (hazard ratio [HR], 1.025; 95% confidence interval [CI], 0.789-1.332; p = 0.850), and was 64.8 (ixazomib) vs 69.5 (placebo) months in MM4 (HR, 1.090; 95% CI, 0.861-1.381; p = 0.473). No new safety signals were identified in either study; incidence of new primary malignancies was low. Despite meeting their primary endpoints (PFS), neither final OS analysis of TOURMALINE-MM3/-MM4 showed statistically significant differences between fixed-duration ixazomib maintenance and placebo in patients with NDMM. The growing number of available, highly effective salvage treatments with novel mechanisms of action make demonstrating an OS advantage in front-line myeloma studies increasingly challenging. © 2025. Takeda Development Center Americas, Inc. (TDCA).

OBJECTIVE: This study extends prior work on soy hydrolysate by developing a sprinkle food formula and evaluating its iron bioavailability and effectiveness in improving iron status among adolescent girls over an eight-week intervention. METHOD: The soybean hydrolysate was produced through sequential steam blasting and enzymatic hydrolysis. It was characterized by its molecular weight distribution-predominantly <15 kDa-and amino acid composition, with high levels of glutamic acid, aspartic acid, and arginine, known for their iron-binding properties. A randomized controlled trial (RCT) was conducted involving 106 female adolescents, comparing serum ferritin levels before and after an eight-week intervention with either the hydrolysate-fortified or control sprinkle product. RESULT: A significant increase in serum ferritin levels was observed among participants with low baseline ferritin (<11 ng/mL) who consumed the soy-hydrolysate-fortified formula, indicating enhanced iron absorption. No significant improvement was detected in participants with normal ferritin but low hemoglobin levels, suggesting that the benefit of soy hydrolysate is more pronounced in individuals with depleted iron stores. Baseline dietary intake and serum profiles were similar between groups, indicating that the benefits observed were likely due to the bioactive properties of soy hydrolysate, especially its amino acid composition and molecular weight that support iron absorption. CONCLUSION: Fortification with hydrolyzed soybean peptides represents a promising strategy to improve iron status and reduce the risk of anemia, while the applied processing method offers an effective, value-added use of agricultural resources.

Acquired pure red cell aplasia (aPRCA) is rare and challenging to treat. We investigated the efficacy and safety of sirolimus plus roxadustat in patients with aPRCA (Chinese Clinical Trial Register number, ChiCTR2200065107). We enrolled 82 patients with aPRCA in this prospective single-arm, open-label, multicenter trial between October 2022 and January 2024. Treatment response and safety files were evaluated. The median age was 63 years. Seven patients withdrew during the trial period. Sirolimus plus roxadustat produced an overall response (OR) in 65 patients (90.3%) 3 months after initiation, which included a complete response (CR) in 39 (54.2%) and a partial response in 26 (36.1%). The 3-month CR rate was significantly higher in the newly diagnosed group (65.9% vs. 38.7%; P = 0.022). The 6-month OR rate in the entire cohort was 93.0% (CR, 77.5%; PR, 15.5%). The mean hemoglobin concentration increased from 5.5 ± 1.6 g/dL at baseline to 11.6 ± 2.5 g/dL after 6 months of treatment. The proportions of patients who achieved transfusion independence within 1, 2, and 3 months of treatment were 57.4%, 76.6%, and 89.5%, respectively. The Functional Assessment of Chronic Illness Therapy-Fatigue Scale score and SF-36 survey score significantly improved after treatment. Treatment-related adverse events occurred in 24 patients (29.2%), and four events (4.9%) were grade ≥3. Sirolimus plus roxadustat is a promising treatment for aPRCA and has an acceptable safety profile, which warrants further investigation in a randomized setting. © 2026. The Author(s).

AIM: To develop and validate a robust LC - MS/MS method for the simultaneous quantification of endogenous deoxycholic acid (DCA), 1β-hydroxydeoxycholic acid (1β-OH-DCA), 1β-hydroxydeoxycholic acid glycine conjugate (1β-OH-G-DCA), and 1β-hydroxydeoxycholic acid taurine conjugate (1β-OH-T-DCA) in human plasma as biomarkers for the assessment of CYP3A-mediated drug-drug interactions (DDI). MATERIALS AND METHODS: A surrogate matrix was employed for the preparation of calibration standards and quality control samples. Analytical quantification was achieved using protein precipitation extraction coupled with UHPLC - MS/MS analysis. RESULTS: A multiplex LC - MS/MS assay was successfully developed and validated for the simultaneous quantification of DCA (4-2000 ng/mL), 1β-OH-DCA (0.05-100 ng/mL), 1β-OH-G-DCA (0.05-100 ng/mL), and 1β-OH-T-DCA (0.05-100 ng/mL) in human plasma. The method effectively addressed the analytical challenges associated with developing an integrated assay for endogenous analytes spanning markedly different concentration ranges and was compliant with the ICH M10 bioanalytical method validation guidance. CONCLUSION: This is the first report describing the development and validation of a 4-in-1 LC - MS/MS method for the simultaneous quantification of DCA, 1β-OH-DCA, 1β-OH-G-DCA, and 1β-OH-T-DCA in human plasma. The assay provides a robust bioanalytical platform for evaluating CYP3A-mediated DDIs and offers a methodological framework applicable to other multiplexed methods for endogenous biomarkers. Plain Language Summary: Patients treated for a medical condition may receive multiple drugs at the same time. Sometimes, receiving multiple drugs together can affect how each drug works, change their levels, or influence how quickly they are cleared by the body. This is called a drug–drug interaction (DDI), and it can reduce treatment success or cause dangerous side effects. A common type of DDI occurs when one drug interferes with the enzymes that metabolize another, leading to increased or decreased drug levels. Among these enzymes, the CYP3A4 plays a key role in processing many widely used medicines. Therefore, understanding CYP3A4-mediated DDI is ess

Activation of the hypoxia-inducible factor-2 (HIF-2) pathway represents a promising strategy for the treatment of renal anemia. Here, we identify compound 48 (ZG-2686), a 3-(benzamido)pyrazolopyridine derivative, as a novel and potent HIF-2α agonist (Emax = 375.7 ± 9.7%, EC50 = 0.25 ± 0.05 μM). Molecular dynamics (MD) simulations provided detailed insights into the binding mode of 48 with the HIF-2α/β complex. In cellular assays, 48 synergistically enhanced HIF-2α-dependent EPO gene expression when combined with the clinically approved prolyl hydroxylase domain (PHD) inhibitor Vadadustat. To further exploit this synergy, we designed and synthesized the bifunctional codrug 50 (ZG-2688), linking 48 with Vadadustat. Notably, codrug 50 induced superior upregulation of EPO levels in vivo compared to coadministration of the two individual agents. Together, these findings demonstrate the first rationally designed codrug integrating an HIF-2α agonist and a PHD inhibitor, highlighting a new direction for the development of renal anemia therapies.

Diabetic nephropathy is still a chief reason for morbidity and mortality in persons with renal dysfunction. Thymoquinone, a primary constituent of black seed oil extracted from Nigella sativa, has anti-inflammatory, antioxidant, anticancer, and antimicrobial properties. Glycine, an amino acid and neurotransmitter, participates in diverse physiological mechanisms. This study investigated the nephroprotective role of thymoquinone and glycine against streptozotocin (STZ)-induced diabetic nephropathy. Forty-two adult male Swiss albino rats were segregated into seven groups, each comprising six. These groups consisted of control normal rats; rats administered 60-mg STZ/kg (nephropathy); nephropathy rats treated with oral doses of 20-mg/kg/day thymoquinone (T20) or 30-mg/kg/day thymoquinone (T30); nephropathy rats treated with oral doses of 50-mg/kg/day glycine (G50) or 100-mg/kg/day glycine (G100); (T + G) nephropathy rats receiving combination therapy of 30-mg/kg/day thymoquinone and 100-mg/kg/day glycine. Various biochemical factors, including glutathione (GSH), total antioxidant capacity (TAC), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), total and myocardial creatine kinase (CK), kidney function parameters, blood electrolytes (Na, K, Cl, Ca, and P), and kidney histopathology, were assessed. The combined therapy of thymoquinone and glycine demonstrated enhanced efficacy in improving biochemical profiles, antioxidant levels, anti-inflammatory responses, and renal structure compared to monotherapies employing thymoquinone or glycine. The confluence of thymoquinone and glycine potentially operates through manifold pathways, encompassing the regulation of oxidative stress and modulation of inflammatory cascades. This study elucidates the potential synergistic benefits of integrating thymoquinone and glycine in diabetic nephropathy management, thereby heralding novel avenues for therapeutic interventions. © 2025. The Author(s).

Hydrophobic bile acid-mediated hepatobiliary injury is a major driver of cholestasis progression. Most anticholestasis treatments being tested clinically are based on a single agent, which does not always sufficiently alleviate bile acid toxicity to slow disease progression. This study investigates a therapeutic strategy of combining glycine-conjugated β-muricholic acid (Gly-βMCA) and fibroblast growth factor-15 (FGF15) to alleviate bile acid hepatobiliary toxicity in Cyp2c70 KO mice that lack endogenous muricholic acid (MCA) synthesis and have a "humanized" hydrophobic bile acid pool composition. The effects of the single and combination treatments on bile acid metabolism, liver injury, and gut microbiome were investigated in female Cyp2c70 KO mice with progressive cholangiopathy and portal fibrosis. While all three treatments significantly reduced biochemical and histologic features of liver injury, the Gly-βMCA and FGF15 combination achieved a remarkably higher reduction in both bile acid pool size and hydrophobicity than either single treatment. Mechanistically, this resulted from synergistically increased biliary hydrophilic MCA species derived from Gly-βMCA, inhibited intestine endogenous bile acid absorption by Gly-βMCA, and repressed cholesterol 7α-hydroxylase (CYP7A1) by FGF15, which counteracted the undesirable farnesoid X receptor antagonism activity of Gly-βMCA. Furthermore, a hydrophobic bile acid pool in Cyp2c70 KO mice was associated with markedly reduced beneficial Lactobacillaceae family bacteria abundance, which was enriched by Gly-βMCA and the combination treatments. In conclusion, the Gly-βMCA and FGF15 combination shows enhanced efficacy in decreasing humanized bile acid pool size and hydrophobicity and holds potential as a therapeutic strategy to decrease bile acid burden in cholestasis.

Streptococcus agalactiae (GBS) is a major pathogen causing severe infections in human and economic loss in animal farming, where β-lactams remain first-line therapy. However, emerging β-lactam resistance, including WHO-priority penicillin-resistant strains, threatens clinical efficacy, creating an urgent need for resistance-breaking adjuvants. In this study, we demonstrate that DL-Propargylglycine (PAG), an inhibitor of cystathionine-γ-lyase inhibitor, exclusively synergizes with β-lactams to reverse resistance in ampicillin-resistant GBS (AR-GBS) and other streptococci, overcoming tolerance in persisters and biofilms. Mechanistically, PAG potentiates antibiotic lethality through dual pathways: metabolic activation via enhanced central carbon metabolism for ROS production and cell envelope remodeling via concurrent downregulation of peptidoglycan biosynthesis genes and upregulation of capsular polysaccharide synthesis. This disrupts cell wall architecture, increases membrane permeability and accelerates antibiotic influx. While in vivo therapeutic efficacy in zebrafish was limited, PAG represents an adjuvant that overcomes β-lactam resistance through metabolic and membrane remodeling, paving the way for optimized derivatives.

1β-Hydroxydeoxycholic acid (1β-OH DCA) in plasma has been shown to be a promising biomarker to assess drug-drug interaction (DDI) with a strong CYP3A inducer or a strong CYP3A inhibitor. The changes in total 1β-OH DCA (sum of 1β-OH DCA, 1β-OH glycine deoxycholic acid, and 1β-OH taurine deoxycholic acid equivalents) were more significant than those observed from 4β-hydroxycholesterol, which has been limited to the identification of CYP3A inducers, not CYP3A inhibitors. The significant reduction in total 1β-OH DCA in response to strong CYP3A inhibitors led us to further explore its utility as a biomarker for DDI with moderate CYP3A inhibitors. Building from the previously reported biomarker method, we further improved the quantified assay by introducing the stable labeled 1β-OH DCA internal standard, optimizing the extraction and chromatographic conditions for better sample cleanup and separation of these biomarkers from other endogenous components in human plasma. Inhibition with a moderate CYP3A inhibitor fluconazole resulted in notable changes in these biomarkers, with 39%, 39%, and 18% reductions in total 1β-OH DCA Cmax, area under the curve (AUC; 0-24 hours after administration of fedratinib), and AUC (0-216 hours after administration of fedratinib), respectively, compared with those without fluconazole. The geometric mean ratio of total 1β-OH DCA AUC (0-24 hours after administration of fedratinib) and Cmax showed good correlations with the geometric mean ratio of fedratinib (CYP3A4 substrate) exposures with and without fluconazole administration. To our knowledge, these preliminary data demonstrate for the first time that total 1β-OH DCA in plasma has the potential to serve as a biomarker covering a wide range of CYP3A activity, complementing current DDI assessment strategies, including DDI prediction with a moderate CYP3A inhibitor. SIGNIFICANCE STATEMENT: This study reported the use of total 1β-hydroxydeoxycholic acid (1β-OH DCA) (sum of 1β-OH DCA and its glycine and taurine conjugate equivalents) plasma concentration as a biomarker to predict drug-drug interaction with a moderate CYP3A inhibitor. Fluconazole inhibition led to a 40% decrease in total 1β-OH

The increasing global use of pesticides in crop pest control has raised concerns about toxic interactions. This study investigates the interaction between glyphosate and cypermethrin formulations concerning cell death and genotoxicity. Three models were applied to assess whether the combined effects were additive, antagonistic, or synergistic: "Linear Interaction Effect", "Combination Subthresholding," and "Cooperative Effect". Key indicators, such as apoptotic nuclei, caspase 3/7 activity, early and late apoptosis, micronuclei frequency, and mitotic abnormalities, were evaluated. Results showed synergistic effects on early and late apoptosis, as indicated by the "Linear Interaction Effect" model, while morphological apoptosis markers and micronuclei frequency displayed additive effects. Caspase 3/7 activity induction was synergistic, though no interaction was observed in the combination effect. These findings suggest that agrochemical mixtures cause more severe toxic effects than individual chemicals, emphasizing the need for mechanistic studies on common environmental contaminant mixtures.

BACKGROUND: Iclepertin is a selective inhibitor of glycine transporter 1 recently investigated as a novel treatment for cognitive impairment associated with schizophrenia. Iclepertin is a potential mild inducer of liver cytochrome P450 3A4, which metabolises ethinylestradiol and levonorgestrel, which are used in combined oral contraceptives (OCs). OBJECTIVES: This trial investigated the potential drug interaction effect of steady-state iclepertin on the steady-state pharmacokinetics of combined OCs. METHODS: This phase I, non-randomised, open-label, two-period, fixed-sequence trial was conducted in healthy pre-menopausal female volunteers aged 18-35 years. In period 1, participants received a combined OC (ethinylestradiol 30 µg/levonorgestrel 150 µg once daily; reference treatment). In period 2, participants received a combined OC and iclepertin 10 mg once daily (test treatment). Primary pharmacokinetic endpoints of ethinylestradiol or levonorgestrel in plasma at steady state over a uniform dosing interval τ were area under the concentration-time curve (AUCτ,ss) and maximum and minimum measured concentration (Cmax,ss and Cmin,ss); drug interaction potential was estimated by geometric mean ratios (test treatment/reference treatment) with two-sided 90% confidence intervals (CIs) using analysis of variance. Safety assessments included monitoring adverse events (AEs). RESULTS: In total, 19 participants entered the trial; 17 were treated (periods 1 and 2). Steady-state pharmacokinetics of ethinylestradiol and levonorgestrel were similar with and without iclepertin; geometric mean ratios for AUCτ,ss, Cmax,ss, and Cmin,ss were slightly above 100%, and 90% CIs were within standard bioequivalence boundaries (80-125%). The number of on-treatment AEs was similar in period 1 (n = 13) and period 2 (n = 15); AEs were of mild-to-moderate severity. CONCLUSION: Iclepertin 10 mg had no meaningful effect on the pharmacokinetics of ethinylestradiol and levonorgestrel, suggesting that these drugs can be administered concomitantly. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05613777; registered on 18 October 2023). Plain Language Summary: In this study, researchers looked at a new d

The antibiotic susceptibility/resistance of bacteria is influenced by their metabolic states. In tobramycin-resistant Edwardsiella tarda (LTB4-RTOB), a dynamic metabolic state is observed, characterized by a general reduction in most metabolites as the minimum inhibitory concentration increases. Among these, aspartate downregulation emerges as the most critical biomarker. Exogenous aspartate enhances the efficacy of tobramycin, enabling it to effectively kill both lab-evolved and clinically isolated multidrug-resistant (MDR) E. tarda, as demonstrated in an animal model. Aspartate increases intracellular tobramycin levels in a concentration- and time-dependent manner by promoting drug uptake. Metabolic reprogramming analysis of LTB4-RTOB and clinically isolated MDR strain WY28 reveals that exogenous aspartate restores downregulated metabolites, primarily enhancing alanine, aspartate, and glutamate metabolism; the pyruvate cycle; and glycine, serine, and threonine metabolism. These changes elevate the proton motive force and membrane permeability, thereby increasing tobramycin uptake. The resulting intracellular drug concentration surpasses the bactericidal threshold, effectively overcoming resistance in both LTB4-RTOB and clinical MDR E. tarda. These findings identify aspartate as a potent metabolic reprogramming agent that potentiates aminoglycosides by boosting intracellular drug accumulation, offering a strategy to combat antibiotic-resistant E. tarda.IMPORTANCEEdwardsiella tarda is a significant pathogen that causes edwardsiellosis in aquaculture, resulting in substantial economic losses while also posing a global public health threat. The increasing prevalence of antibiotic-resistant E. tarda strains has further exacerbated this challenge. The present study used a metabolic state-reprogramming approach to identify an ideal biomarker as an antibiotic adjuvant to increase conventional antibiotics that are already resistant. Exogenous aspartate most effectively potentiated tobramycin to lab-evolved and clinical isolated MDR E. tarda in vitro and in in vivo models (fish and mice). Mechanistically, aspartate enhanced tobramycin uptake in MDR E. tarda by overcomin