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BACKGROUND: Fetal nutrient supply depends on maternal status. Pregnant women tend to pay close attention to their health and diet, and micronutrient supplementation is widely practiced. Overweight and obese pregnant women exhibit altered metabolism, inflammation, and placental function. These may limit the efficacy of nutritional supplementation in this population. Robust evidence on supplement efficacy and safety in this high-risk group is lacking. To evaluate the effects of antenatal nutritional supplementation on perinatal outcomes in women with pre-pregnancy overweight or obesity, we conducted a systematic review and meta-analysis. METHODS: We searched PubMed, Embase, and the Cochrane Library to 16 July 2025 for randomized controlled trials (RCTs) comparing any nutritional supplement versus placebo in pregnant women with body mass index (BMI) ≥ 25 kg/m2. Nineteen RCTs (3482 participants) were included; risk ratios (RR) with 95% confidence intervals (CI) were pooled using fixed- or random-effects models. RESULTS: Supplements did not alter birth weight (SMD 0.04; 95% CI -0.04 to 0.11) or overall cesarean section risk. Probiotic supplementation increased preterm birth risk by 86% (RR 1.86; 95% CI 1.09-3.18). Inositol reduced preterm birth (RR 0.28; 95% CI 0.13-0.64) and preeclampsia (RR 0.40; 95% CI 0.19-0.83). Unsaturated fatty acids lowered macrosomia incidence (RR 0.53; 95% CI 0.29-0.95). CONCLUSION: Routine unsaturated fatty acids and inositol supplementation should be considered for overweight or obese pregnant women to reduce macrosomia, preterm birth, preeclampsia, and gestational hypertension. Chronic or prophylactic probiotic supplementation is not recommended. © 2026 Japan Society of Obstetrics and Gynecology.

AIMS: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-age women, associated with insulin resistance, hyperandrogenism, and menstrual irregularities. Nutraceutical interventions-bioactive compounds derived from foods or supplements that provide health benefits beyond basic nutrition-may support conventional therapy. This study aimed to systematically evaluate the effects of nutraceutical interventions on reproductive and metabolic outcomes in PCOS. MATERIALS AND METHODS: This systematic review and meta-analysis was registered in PROSPERO (CRD42024521879) and followed PRISMA 2020. Searches were performed in PubMed, Embase, Cochrane Library, Web of Science, and regional databases (January 2013-December 2024) and included 78 eligible studies. Eligible randomized and quasi-experimental studies assessed nutraceuticals such as vitamin D, inositol, and quercetin. Risk of bias was evaluated with standardized tools; certainty of evidence was graded by GRADE. RESULTS: Seventy-eight studies met inclusion criteria. Nutraceutical interventions significantly reduced fasting insulin (MD = -2.14 μIU/mL; 95% CI -3.12 to -1.16) and luteinizing hormone (MD = -1.34 mIU/mL; 95% CI -2.10 to -0.58) and increased sex-hormone-binding globulin (MD = +3.72 nmol/L; 95% CI 1.35 to 6.09). Vitamin D supplementation showed the strongest metabolic and hormonal improvements. Results for ovarian follicle count and menstrual bleeding were inconsistent. CONCLUSIONS: Nutraceutical interventions targeting metabolic and hormonal regulation may complement lifestyle therapy in women with PCOS. Interpretation is limited by study heterogeneity and variable methodological quality. No external funding was received. © 2025 John Wiley & Sons Ltd.

BACKGROUND: Anxiety disorders (AnxDs) are highly prevalent and often untreated or unresponsive to treatment. Although proton magnetic resonance spectroscopy (1H-MRS) studies of AnxDs have been conducted for over 25 years, a consensus regarding neurometabolic abnormalities in these conditions is lacking. METHODS: A systematic review and meta-analysis of 1H-MRS studies of AnxDs (social anxiety disorder, generalized anxiety disorder, and panic disorder) identified 25 published datasets meeting inclusion criteria. These compared neurometabolites between 370 patients and 342 controls, including n-acetlyaspartate (NAA), total creatine, total choline (tCho), myo-inositol, glutamate, glutamate+glutamine, GABA, and lactate. RESULTS: Across AnxDs, tCho was significantly reduced in prefrontal cortex and across all cortical regions. Effect sizes for cortical tCho were significantly more negative in studies with better measurement quality, with Hedges' g = -0.64 and an 8% mean reduction. NAA was unchanged in prefrontal cortex but reduced across all cortical regions (after exclusions). These abnormalities did not differ between the three disorders. No other neurometabolites differed significantly. DISCUSSION: Reduced choline-containing compounds in cortical regions is a consistent, transdiagnostic abnormality in AnxDs. Notably, arousal-related neuromodulators, including norepinephrine, alter membrane phospholipid homeostasis and methylation reactions, which influence brain tCho levels. This suggests that chronically elevated arousal in AnxDs may increase neurometabolic demand for choline compounds without a proportionate increase in brain uptake, leading to reduced tCho levels. Reduced cortical NAA suggests compromised neuronal function in AnxDs. Future studies may clarify the clinical significance of reduced cortical tCho and the possibility that appropriate choline supplementation could have therapeutic benefit in anxiety disorders. © 2025. The Author(s).

BACKGROUND: Nutritional supplements are known to ameliorate polycystic ovary syndrome (PCOS) and have been shown to modulate endocrine and metabolic markers, oxidative stress markers and inflammatory biomarkers in patients with PCOS. A variety of nutritional supplements have been applied in clinics, but a more comprehensive ranking of their efficacy has not yet been investigated. OBJECTIVES: To assess the comparative effectiveness of nutritional supplements in women with PCOS. METHODS: A systematic search was conducted across PubMed, EMBASE, Web of Science, and the Cochrane Library for randomized controlled trials (RCTs) that met the inclusion criteria up to October 12, 2023. We performed a network meta-analysis (NMA) to evaluate the effectiveness of various nutritional supplements on different indicators of PCOS by synthesizing both direct and indirect evidence from the trials. RESULTS: Seventy-nine RCTs involving 5,501 participants were enrolled in the NMA. It suggested that chromium was notably effective in improving follicle-stimulating hormone levels, total antioxidant capacity, and very low-density lipoprotein levels. Soy isoflavones were more beneficial for enhancing glutathione levels and reducing malondialdehyde levels. Inositol significantly decreased total cholesterol and triglyceride levels, while curcumin was most effective in improving low-density and high-density lipoprotein cholesterol levels. Additionally, Omega-3 was superior in reducing homeostatic model assessment of insulin resistance levels. No significant differences were observed in total testosterone, sex hormone-binding globulin, dehydroepiandrosterone, high-sensitivity C-reactive protein, and plasma nitric oxide levels between the supplements and placebo. CONCLUSIONS: Chromium, inositol, and Omega-3 were found to be beneficial for improving lipid profile. For improving obesity, sex hormone levels, inflammatory factors and oxidative stress indicators of PCOS patients, carnitine, chromium, and soy isoflavones are effective options, respectively. These findings confirm that nutritional supplements can effectively alleviate PCOS symptoms, potentially providing valuable guidance for the cli

OBJECTIVE: There has been substantial research conducted recently on the effect of myo-inositol (MI) on human reproduction. However, it still remains ambiguous about the therapeutic efficacy of MI in infertile women undergoing in vitro fertilization embryo transfer (IVF-ET). This systematic review and meta-analysis was carried out to investigate the efficacy of MI on IVF outcomes. METHODS: Literatures were searched in the PubMed, Web of Science, Cochrane Library, ScienceDirect and Wanfang databases. The methodological quality was assessed using the Cochrane Risk of Bias tool. Data were pooled using a random- or fixed-effects model according to study heterogeneity. The results are expressed as odds ratio (OR) or mean difference (MD) with 95% confidence intervals (CIs). Heterogeneity was measured by the I2 statistic. The protocol was prospectively registered with PROSPERO (CRD42024582149). RESULTS: Eleven eligible studies with 981 participants reported the IVF outcomes of the MI group versus the control group. The synthesis results showed that the metaphase II (MII) oocyte rate was higher in the MI group than in the control group (OR 1.55, 95% CI 1.04-2.31, P=0.03). For polycystic ovary syndrome (PCOS) women, as well as non-obese PCOS women, a statistically significant improvement in MII oocyte rate were assumed after taking MI (OR 1.97, 95% CI 1.20-3.25, P<0.01; OR 1.92, 95% CI 1.09-3.37, P=0.02) while there is no statistically significant advancement showed in the poor ovary responder (POR) women(OR 0.97, 95% CI 0.35-2.68, P=0.95). The fertilization rate was higher in the MI group than in the control group (OR 1.62, 95% CI 1.21-2.16, P<0.01), for PCOS, non-obese PCOS and POR women (OR 1.59, 95% CI 1.16-2.18, P<0.01; OR 1.87, 95% CI 1.52-2.31, P<0.01; OR 2.42, 95% CI 1.48-3.95, P<0.01). CONCLUSIONS: Our results suggest that MI supplementation improves the MII oocyte rate and the fertilization rate. More high-grade evidence from prospective randomized studies is warranted. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024582149.

Clinicians often consider the use of dietary supplements to assist in lowering thyroid autoantibody titres in patients with Hashimoto's thyroiditis (HT). Currently, different supplements differ in their ability to reduce autoantibody levels. The purpose of this article is to compare the ability of different supplements to lower autoantibody titres and restore TSH levels through a systematic literature review. We obtained information from the PubMed, Web of Science, Embase, and Cochrane databases, as well as the China National Knowledge Infrastructure (CNKI). Selected studies included those using selenium, Vitamin D, Myo-inositol, and Myo-inositol in combination with selenium for the treatment of HT patients with euthyroidism. These data were combined using standardised mean differences (SMDs) and assessed using a random effects model. A total of 10 quantitative meta-analyses of case-control studies were selected for this meta-analysis. Compared to the placebo group, the use of selenium supplements was able to significantly reduce the levels of thyroid peroxidase autoantibodies (TPOAb) (SMD: -2.44, 95% CI: -4.19, -0.69) and thyroglobulin autoantibodies (TgAb) (SMD: -2.76, 95% CI: -4.50, -1.02). During a 6-month treatment, the use of Myo-inositol, Vitamin D alone, and the combination of selenium, and Myo-inositol did not effectively reduce TPOAb (Myo-inositol: SMD:-1.94, 95% CI: -6.75, 2.87; Vitamin D: SMD: -2.54, 95% CI: -6.51,1.42; Se+Myo-inositol: SMD: -3.01, 95% CI: -8.96,2.93) or TgAb (Myo-inositol: SMD:-2.02, 95% CI: -6.52, 2.48; Vitamin D: SMD: -2.73, 95% CI: -6.44,0.98; Se+Myo-inositol: SMD: -3.64, 95% CI: -9.20,1.92) levels. Therefore, we recommend that patients with HT(Hashimoto's Thyroiditis) be given an appropriate amount of selenium as an auxiliary treatment during standard-of-care treatment.

INTRODUCTION: The efficacy of myo-inositol supplementation to treat gestational diabetes remains controversial, and this meta-analysis aims to study the efficacy of myo-inositol supplementation on metabolic status for gestational diabetes. METHODS: Several databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systemically searched from inception to October 2021, and we included the randomized controlled trials (RCTs) assessing the effect of myo-inositol supplementation on the outcomes of women with gestational diabetes. Gestational diabetes was diagnosed if at least one threshold of glucose concentration was exceeded and the three thresholds included 92, 180, and 153 mg/dl for 0, 1 and 2 h, respectively, after a 75-g, 2-h glucose tolerance test. RESULTS: Four RCTs and 317 patients were included in this meta-analysis. Compared with routine treatment in pregnant women with gestational diabetes, myo-inositol supplementation could lead to remarkably decreased treatment requirement with insulin (odd ratio [OR] = 0.24; 95% confidence interval [CI] = 0.11-0.52; p = .0003) and homeostasis model assessment of insulin resistance (HOMA-IR, standard mean difference [SMD]= -1.18; 95% CI= -1.50 to -0.87; p < .00001), but demonstrated no obvious impact on birth weight (SMD= -0.11; 95% CI= -0.83 to 0.61 g; p = .76), cesarean section (OR = 0.82; 95% CI = 0.46-1.47; p = .51) or the need of NICU (OR = 0.88; 95% CI = 0.03-26.57; p = .94). CONCLUSIONS: Myo-inositol supplementation is effective to decrease the need of insulin treatment and HOMA-IR for gestational diabetes.

Ovarian aging is a major factor for female subfertility. Multiple antioxidants have been applied in different clinical scenarios, but their effects on fertility in women with ovarian aging are still unclear. To address this, a meta-analysis was performed to evaluate the effectiveness and safety of antioxidants on fertility in women with ovarian aging. A total of 20 randomized clinical trials with 2617 participants were included. The results showed that use of antioxidants not only significantly increased the number of retrieved oocytes and high-quality embryo rates but also reduced the dose of gonadotropin, contributing to higher clinical pregnancy rates. According to the subgroup analysis of different dose settings, better effects were more pronounced with lower doses; in terms of antioxidant types, coenzyme Q10 (CoQ10) tended to be more effective than melatonin, myo-inositol, and vitamins. When compared with placebo or no treatment, CoQ10 showed more advantages, whereas small improvements were observed with other drugs. In addition, based on subgroup analysis of CoQ10, the optimal treatment regimen of CoQ10 for improving pregnancy rate was 30 mg/d for 3 mo before the controlled ovarian stimulation cycle, and women with diminished ovarian reserve clearly benefited from CoQ10 treatment, especially those aged <35 y. Our study suggests that antioxidant consumption is an effective and safe complementary therapy for women with ovarian aging. Appropriate antioxidant treatment should be offered at a low dose according to the patient's age and ovarian reserve. This study was registered at PROSPERO as CRD42022359529.

Background: The administration of omega-3 polyunsaturated fatty acid supplements is recommended as an adjuvant therapy for adults diagnosed with major depressive disorder. The evaluation of replicated data in combination treatment with omega-3 has been extensively conducted in adults over the past decade. However, the generalizability of these findings to pediatric groups is still uncertain. The objectives of this evaluation were twofold: (1) to evaluate the effectiveness of omega-3 and associated combination therapies in reducing the severity of depressive symptoms, and (2) to include remission rates (i.e., reduction of more than 50% in depression symptoms) as a measure of therapeutic efficacy. Methods: We conducted a literature search on PubMed/EMBASE from inception to October 2023. Data analyses were conducted using Stata (version 17.0). Results: We identified a total of 3168 articles. After eligibility screening of identified studies, nine studies (n = 561 participants) were included in our analysis herein. Pairwise comparisons revealed no significant improvement in depression symptoms for any intervention versus placebo. However, a clustered ranking plot identified omega-3 plus inositol as the most effective treatment for pediatric depression (77.3% efficacy). Omega-3 paired with psychoeducational psychotherapy significantly lowered the remission rate compared to placebo (standardized mean difference = 0.44, 95% confidence interval: 0.00-0.87, p = 0.048), resulting in a 91.5% remission rate, making it the most effective treatment in the study. Conclusions: Taken together, this network meta-analysis presents compelling evidence supporting the antidepressant effects of omega-3 in pediatric groups with depression. Future research should aim to investigate omega-3 as monotherapy for young individuals with depression, as well as investigate the efficacy of omega-3 in comparison to psychosocial interventions for affected individuals.

BACKGROUND: This study aimed to systematically review the effect of selenium and inositol combination on thyroid function, autoimmune characteristics in thyroid diseases. RESEARCH DESIGN AND METHODS: To identify eligible studies, a systematic search was conducted in the PubMed/MEDLINE, Science-Direct, CINHAL, EMBASE, SCOPUS, Psychinfo, Cochrane, ProQuest, and Web of Science were searched using the main concepts, and all English-written articles that were published between 2007 and 2022 and had an available full text were examined. RESULTS: The data analysis of this research revealed that after the simultaneous use of selenium and inositol supplements, the level of Triiodothyronine(T3) increased by 0.105 in patients with thyroid disorders although this increase was not significant (P-value: 0.228). The level of Thyroxine (T4) significantly increased by 0.06 (P-value: 0.04). Anti-Thyroid Peroxidase Antibody (TPOAb) titer decreased by 119.36%, which was not significant (P-value: 0.070). Finally, the level of Thyroid-stimulating hormone (TSH) decreased by 1.45%, which was a significant change (P-value: 0.001). CONCLUSION: It was observed that simultaneous use of selenium and inositol supplements did not change the T3 and TPOAb titer levels; however, it leads to a decrease in TSH and increase in T4 levels. Further studies are required due to the limited number of studies.

OBJECTIVE: Impulsivity is a transdiagnostic risk factor for numerous health morbidities and is strongly associated with early relapse and poor treatment outcomes in addictions and mood-disorders. Lithium carbonate can be helpful in moderating the impulsive behaviors associated with mania, possibly mediated by reduced myo-inositol activity following inhibition of the enzyme inositol monophosphatase (IMPase). We tested the hypothesis that impulsivity-as motor disinhibition, decisions without adequate information, and stronger preferences for small immediate rewards over larger later rewards-can be moderated by the IMPase inhibitor ebselen in healthy adult volunteers. METHODS: One hundred and thirty healthy adults completed a between-subjects, double-blind, placebo-controlled protocol. Over 2 days, participants received a previously validated dose of 1800 mg of ebselen or placebo before completing tests of impulsivity and decision-making. RESULTS: There were no substantive changes in any measure of impulsivity following treatment with ebselen compared with placebo. Neither was there any convincing evidence of stronger treatment effects in high-trait impulsive participants compared with low-trait participants. CONCLUSION: These results fail to replicate findings that ebselen administration moderates validated measures of impulsivity in healthy adults, at least at doses shown to reduce myo-inositol within the medial prefrontal cortex and produce changes in emotional processing and reward-based learning. © 2026 The Author(s). Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons Ltd.

BACKGROUND: India ranks second in the global diabetes epidemic, with about 89 million individuals living with Type 2 diabetes mellitus (T2DM). We compared the efficacy and safety of fixed-dose combination (FDC) of glimepiride, voglibose, and extended-release metformin (GLIME+VOGLI+MET-ER) with voglibose and metformin (VOGLI+MET) and glimepiride and metformin (GLIME+MET). METHODS: A Phase IV, randomized, open-label, active-controlled study was performed in adult patients with T2DM poorly controlled with metformin. Patients received twice daily doses of GLIME+VOGLI+MET-ER (1 + 0.2 + 500 mg: Trivolib 1, 2 + 0.2 + 500 mg: Trivolib 2); or VOGLI+MET (0.2 + 500 mg, 0.3 + 500 mg) or GLIME+MET (1 + 500 mg, 2 + 500 mg). The primary endpoint was the change in HbA1c from baseline. RESULTS: Of the 458 patients screened, 399 were randomized (GLIME+VOGLI+MET-ER [n = 133], VOGLI+MET (n = 135), and GLIME+MET [n = 131]). The mean baseline HbA1c was ~8.35% (~67.77 mmol/mol). All the treatments showed a significant reduction in HbA1c at Weeks 12 and 24. Mean change in % (mmol/mol) HbA1c was significantly more with GLIME+VOGLI+MET-ER versus VOGLI+MET and GLIME+MET at Week 12 (-1.02 ± 0.60 [-11.2 ± 6.52] vs. -0.68 ± 0.64 [-7.49 ± 6.95], p < 0.001 and -0.88 ± 0.49 [-9.65 ± 5.34], p = 0.0154) and Week 24 (-1.57 ± 0.74 [-17.2 ± 8.14] vs. -1.11 ± 0.80 [-12.2 ± 8.79], p < 0.001 and -1.28 ± 0.60 [-14.0 ± 6.56], p = 0.0002). Overall, 49 adverse events (AEs) were reported in 32/399 (8.0%) patients. One patient each in GLIME+VOGLI+MET-ER and VOGLI+MET groups had level 1 hypoglycemia requiring no management. No severe or serious AEs were reported. CONCLUSIONS: In adult patients with T2DM inadequately controlled on metformin monotherapy, GLIME+VOGLI+MET-ER demonstrated superior HbA1c reduction compared with VOGLI+MET and GLIME+MET at Weeks 12 and 24. Study medications were safe and well-tolerated. TRIAL REGISTRATION: Clinical Trial Registry India-CTRI/2020/11/029080 [Registered on: 12/11/2020]. © 2026 Sun Pharma Laboratories Limited. Journal of Diabetes published by Ruijin Hospital, Shanghai JiaoTong University School of Medicine and John Wiley & Sons Australia, Ltd.

BACKGROUND: PCOS is a common condition among women of reproductive age, marked by irregular menstrual cycles, hyperandrogenism, and ultrasound abnormalities. Infertility treatments such as metformin and myoinositol often have side effects and low adherence. Ziziphus jujuba has the potential in improving PCOS outcomes, prompting this study to compare its effect on pregnancy rates with conventional therapies. METHODS: This double-blind, randomized trial involved 196 infertile PCOS patients (ages 18-45), with 49 participants in each group. Participants were randomly assigned to four groups: metformin (500 mg daily), myoinositol (2000 mg daily), Ziziphus jujuba hydroalcoholic extract (15 g daily), or placebo (sachet/pill) for 12 weeks. Biochemical (FBG, lipid profile, ALT, AST, ESR, CRP, TyG index) and anthropometric (weight, BMI, waist circumference) measurements were taken pre- and post-study. Ovulation induction with letrozole was performed, and pregnancy occurrence was the primary endpoint, assessed via Beta hCG and ultrasound 6-7 weeks after treatment. RESULTS: No significant differences in pregnancy as primary outcome were found (Ziziphus jujuba: 10, Metformin: 7, Myoinositol: 5, Placebo: 4; p > 0.05). However, significant improvements in cholesterol, TG, HDL cholesterol, and FBG were observed in the Ziziphus jujuba compared to other groups (p < 0.05). CONCLUSION: The Ziziphus jujuba extract demonstrated significant improvements in FBG levels, lipid profiles, and insulin resistance; however, it did not significantly increase pregnancy occurrence compared to metformin, and myoinositol. No serious adverse effects were observed, with only one participant reporting mild constipation. These findings suggest that while Ziziphus jujuba shows promise in metabolic management of PCOS, its efficacy in enhancing fertility outcomes requires further investigation or consideration in combination therapies. TRIAL REGISTRATION: Registered at the Mashhad Medical University of Medical Science: IR.MUMS.MEDICAL.REC.1402.191. The date of enrolment of the first patient into the trial is January 21, 2023. © 2025. The Author(s).

OBJECTIVES: Asprosin is a newly discovered adipokine associated with insulin resistance and diabetes mellitus. Currently, its role during gestation is under investigation, as asprosin seems to increase during pregnancy, contributing to the onset of complications, like gestational diabetes. Considering the beneficial effects of myo-inositol to support the physiological pregnancy, recovering and preventing adverse maternal and fetal outcomes, we aimed to evaluate the effects of its supplementation on serum asprosin levels in pregnant women. DESIGN: We enrolled 40 patients at the early stages of pregnancy and randomly distributed them to a study group, which received 2-g myo-inositol and 200-μg folic acid twice a day, or to a control group, which received the sole folic acid. RESULTS: After 20-22 weeks of treatment, we recorded a decrease of serum asprosin values as well as of HOMA-IR index in the group supplemented with myo-inositol, while the group that took only folic acid showed an increase in asprosin levels and no worsening of insulin resistance indices (HOMA-IR index). LIMITATIONS: The small number of patients could be a limitation of the study. CONCLUSIONS: Asprosin may be modulated by myo-inositol. This opens the possibility of considering this adipokine as a useful marker of insulin resistance to assess in pregnant women and to efficaciously target in clinical practice. Trial Registration: ClinicalTrials.gov identifier: NCT05943158.

Introduction: Polycystic ovary syndrome (PCOS) is associated with increased cardiovascular risk later in life. Insulin resistance, common in PCOS, heightens the risk of type 2 diabetes, dyslipidemia, hypertension, and cardiovascular disease. This study explored whether insulin sensitizers could modify traditional cardiovascular risk factors, through influence on insulin resistance. Objectives: To evaluate the impact of Metformin and Myoinositol therapy on glycemic and lipid profiles in PCOS patients, based on body mass index (BMI). Methods: A prospective, randomized clinical study was conducted at the UC for Endocrinology in Skopje (2022-2023). Women aged 18-40 with PCOS (Rotterdam 2003 criteria) were assigned to either Metformin (1500 mg XR) or Myoinositol (2 g + 200 mg folic acid TID) for 6 months. Parameters monitored included BMI, fasting plasma glucose (FPG), HOMA-IR, total cholesterol, LDL-C, HDL-C, triglycerides, lipid accumulation product (LAP), and TG/HDL ratio. Results: Baseline BMI significantly influenced HDL, triglycerides, TG/HDL, and LAP. Myoinositol significantly improved cholesterol regardless of BMI. Among patients with BMI ≥25 kg/m², Metformin significantly reduced FPG (4.65 ± 0.5 vs 5.01 ± 0.3 mmol/L) and HOMA-IR (2.25 ± 0.6 vs 2.94 ± 1.1 mmol/L). HOMA-IR positively correlated with TG/HDL ratio (R=0.2086, p=0.016). Conclusion: Myoinositol improved cholesterol in PCOS patients regardless of BMI. Metformin significantly affected glycemic control in overweight patients. The TG/HDL ratio may serve as a predictive marker for insulin resistance in PCOS. © 2025 Aleksandra Stevchevska et al., published by Macedonian Academy of Sciences and Arts.

Comment in JAMA. 2025 Oct 7;334(13):1147-1148. doi: 10.1001/jama.2025.14399. IMPORTANCE: Pregnant individuals with polycystic ovary syndrome (PCOS) present with a higher risk of pregnancy complications, including gestational diabetes, preeclampsia, and preterm birth. Myo-inositol supplementation may reduce these risks. OBJECTIVE: To determine whether daily supplementation with myo-inositol during pregnancy among individuals with PCOS reduces the risk of a composite outcome of gestational diabetes, preeclampsia, and preterm birth. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled, randomized trial was conducted at 13 hospitals in the Netherlands. Pregnant individuals with PCOS who were between 8 and 16 weeks' gestation were enrolled between June 2019 and March 2023. Final follow-up was complete on December 27, 2023. Analyses were conducted July 2024. INTERVENTIONS: Participants were randomized on a 1:1 basis to receive sachets with either myo-inositol, 2 g, with 0.2 mg of folic acid twice daily (n = 230) or matching placebo with 0.2 mg of folic acid only (n = 234) until delivery. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of gestational diabetes, preeclampsia, or preterm birth (before 37 weeks' gestation). RESULTS: Among 464 participants, the mean (SD) age was 31.5 (3.8) years; 18 participants (3.9%) reported Asian race and 395 (86.1%) reported White race. The prevalence of biochemical hyperandrogenism was higher at baseline in the myo-inositol group than the placebo group (29.0% [53 of 180] vs 18.5% [37 of 193]). A primary outcome event occurred in 25.0% (n = 56) of participants in the myo-inositol group and 26.8% (n = 61) in the placebo group (relative risk, 0.93 [95% CI, 0.68-1.28]; P = .67). CONCLUSIONS AND RELEVANCE: Myo-inositol supplementation during pregnancy did not reduce the incidence of a composite of gestational diabetes, preeclampsia, or preterm birth in patients with PCOS. TRIAL REGISTRATION: onderzoekmetmensen.nl Identifier: NL67329.078.18.

OBJECTIVES: Asprosin, a novel adipokine primarily secreted by white adipose tissue, has been implicated in the pathogenesis of insulin resistance and metabolic dysfunction. Its elevated levels characterize patients with polycystic ovary syndrome (PCOS) exhibiting metabolic alterations. Aim of this work was to evaluate the effects of insulin sensitizer administration, as inositols, on asprosin levels and then compare these results with the effects of metformin treatment. MATERIAL AND METHODS: 30 patients with PCOS were enrolled in this study and randomly divided into two groups: (i) group 1 assumed a dietary supplement based on 40:1 myo-inositol (MI)/D-chiro-inositol (DCI), (ii) group 2 assumed metformin (MET), for 12-16 weeks of treatment. RESULTS: The reduction of serum asprosin levels in patients with PCOS after treatment with MET and MI/DCI is the most intriguing result. Its levels decreased more in the inositol group, although they did not reach statistical significance probably due to the lower number of patients. CONCLUSIONS: The observed dysregulation of asprosin levels in PCOS highlights a potential link between this novel adipokine and the pathophysiology of the disorder, suggesting a modulatory effect of the combined 40:1 MI/DCI on asprosin levels. Of course, further studies may contribute to disclosing molecular mechanisms underlying asprosin reduction and open toward new perspectives.

OBJECTIVE: Exploring whether ultra-brief pulse electroconvulsive therapy (ECT) reduces the occurrence of postoperative delirium in patients with schizophrenia (SCZ), and its effects on cholinesterase, inflammatory markers, and hippocampal neural metabolites. METHODS: From August 2022 to August 2023, inpatients at the Affiliated Brain Hospital of Nanjing Medical University diagnosed with SCZ according to the International Statistical Classification of Diseases and Related Health Problems (Tenth Edition ICD-10) and aged 18-55 years were studied. Patients were randomly divided into ultra-brief pulse (UBP) and brief pulse (BP) groups, receiving ultra-brief pulse ECT (pulse width 0.25 ms) or brief pulse ECT (pulse width 1.0 ms). Assessments were conducted before and 24 h after ECT sessions, including evaluations of delirium, psychiatric symptoms, magnetic resonance spectroscopy (MRS) for hippocampal metabolites, and serum markers. Delirium was assessed using the Richmond Agitation-Sedation Scale (RASS) and the Confusion Assessment Method for the Intensive Care Unit (ICU-CAM). MRS measured changes in hippocampal metabolites, including N-acetyl-aspartate (NAA), creatinine (Cr), myo-inositol (MI), and choline (Cho). Serum markers included twelve cytokines, C-reactive protein (CRP), and cholinesterase (ChE). Statistical analyses used chi-square tests and independent sample t-tests. RESULTS: No significant differences were found between the UBP and BP groups in baseline demographic and clinical data, cholinesterase levels, inflammatory markers, hippocampal spectra, ECT sessions, and BPRS scores post-treatment. However, the incidence of delirium was significantly different between UBP and BP groups (χ2 = 3.49, p = 0.046), with the BP group having a higher incidence of delirium. Post-treatment, cholinesterase levels in the UBP group were significantly higher than those in the BP group (t = 0.52, p < 0.001). Levels of CRP, IL-6, IL-8, IL-10, IL-1β, and TNF-α were significantly lower in the UBP group compared to the BP group. Right hippocampal NAA/Cr and left hippocampal NAA/MI levels were significantly lower in the UBP group than in the BP group post-treatment. CONCLUSION: C

Our aim is to evaluate the effect of a structured stress reduction intervention based on mindfulness during pregnancy on the maternal brain. We report a secondary analysis of IMPACT BCN, a randomized clinical trial including pregnant women randomly allocated to 8-week Mindfulness-Based Stress Reduction (n = 41) or usual care (without any intervention, n = 35). Maternal magnetic resonance (MR) was performed in the third trimester, cluster-wise analysis was used to assess cortical morphometric differences, and proton magnetic resonance spectroscopy (1H-MRS) to evaluate the metabolic characteristics. Mindfulness status was evaluated using the Five Facet Mindfulness Questionnaire (FFMQ). Results showed that participants from Stress reduction group had significantly larger surface areas in the right superior frontal region as compared to the Usual care group (90%CI: 0.023-0.029, p = 0.03). The1H-MRS revealed that Stress reduction group participants, had higher concentrations of myo-inositol (adjusted mean difference D 0.37 mol/L, 95%CI 0.05-0.69) as compared to Usual care. Participants who had high mindfulness on FFMQ facets of non-judgmental (D 358.5 mm2, 95%CI 53.5-663.6) and non-reactivity (D 362.3 mm2, 95%CI 18.8-705.7) had larger right superior frontal area. In conclusion, Mindfulness-Based Stress Reduction program during pregnancy has a significant effect on maternal brain structure and is associated with metabolite concentration changes. © 2025. The Author(s).

BACKGROUND: In a multinational randomized controlled trial, we previously showed that maternal supplementation with myo-inositol, probiotics, and micronutrients was associated with reduced incidence of rapid infant weight gain and high body mass index (BMI) at two years among offspring. It was unclear whether these differences in weight gain and body mass were due to reduced adiposity. Therefore, we aimed to determine whether there were any differences in body composition. METHODS: Body composition was measured using bioelectrical impedance spectroscopy at six weeks, six months, one year, and two years among offspring born to mothers who received a nutritional intervention (n = 268) or control (n = 264) supplement preconception and during pregnancy. RESULTS: There were no group-level differences in body composition, except at two years, when fat-free mass was greater among control offspring [adjusted mean difference (aMD) 0.14 kg, 95% confidence interval (CI) 0.03, 0.25, P = 0.012]. However, there were no differences in mean percentage fat mass (%FM) at any time. In both groups, rapid weight gain [Δ weight > 0.67 standard deviation (SD) from birth to one year] was associated with greater %FM (aMD 2.0% at six months, 2.0% at one year, 1.4% at two years) compared with those who did not have rapid weight gain. Likewise, high BMI (≥ 95 percentile) at two years was associated with greater %FM (aMD 2.5%). CONCLUSIONS: A maternal nutritional intervention did not lead to differences in average offspring body composition in the first two years of life. However, fewer offspring from the supplemented group experienced rapid weight gain and high BMI, characterized by greater %FM. © 2025. The Author(s).

Orthosiphon stamineus Benth, commonly used in Southeast Asia for its medicinal properties, is traditionally employed to treat diabetes and hypertension. Scientific research has validated that O. stamineus extract exhibits significant vasodilatory action on rat aorta. This effect is primarily due to the synergistic interaction among key compounds: eupatorin, sinensetin and 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (TMF). Our previous publication identified the optimum formulation, G28, which contains eupatorin, sinensetin and TMF in the ratio of EC20:EC15:EC5. Therefore, the aim of this study was to investigate the antihypertensive effect and mechanism of action of formulation G28. In this study, aortic rings from spontaneously hypertensive rats (SHRs) and Sprague-Dawley (SD) rats were used to examine the vasodilation mechanisms. The antihypertensive effect of G28 was also assessed through repeated-dose administration in SHRs. G28 exhibited stronger vasorelaxant effects in SHR versus SD rat aortic rings, indicating higher potency under hypertensive conditions. The effect was partially endothelium-dependent, as endothelium removal reduced responses in both aortic rings. G28 retained efficacy with Nω-Nitro-1-arginine methyl ester, methylene blue and 1H-[1,2,4]Ox-adiazolol[4,3-α]quinoxaline-1-one, suggesting involvement of the NO/sGC/cGMP pathway. Additionally, G28's effect diminished with glibenclamide, barium chloride, 4-aminopyrine and tetraethylammonium, indicating potassium channel involvements. The vasorelaxant effect was not significantly altered by indomethacin, atropine, or propranolol (in SD rats only), suggesting independence from the cyclooxygenase, beta-adrenergic (in SD rats only) and muscarinic pathways. G28 also reduced intracellular Ca²⁺ in vascular smooth muscle by antagonising voltage-gated calcium channel and Inositol triphosphate receptor. In vivo, G28 significantly reduced blood pressure in SHRs over 21 days of oral administration, underscoring its potential for hypertension control. G28 shows strong antihypertensive effects via NO/sGC/cGMP, potassium and calcium channels. Its sustained blood pressure reduction in SHRs highlights potential as a p

Background: Energy drinks (EDs) are non-alcoholic, functional beverages sold worldwide in more than 165 countries. These products are very popular and often consumed by children, teenagers, and young adults to improve physical performance, reduce drowsiness, and improve memory and concentration with increased intellectual effort. However, their consumption is associated with an increased risk of various health consequences. Objectives: The purpose of this non-systematic review was to discuss the components of EDs and their effects, summarize the AEs reported in the literature associated with the consumption of EDs, and briefly characterize the possible ED-related drug interactions. Methods: Scientific evidence was extracted by searching the databases PubMed and Google Scholar. In addition, the reference lists of the retrieved papers were reviewed and cross-referenced to reveal additional relevant scientific evidence. Results: The most common ingredients in EDs are caffeine, taurine, glucuronolactone, B vitamins, the vitamin-like compound inositol, and sweeteners (sugar, fructose, glucose-fructose syrup or artificial sweeteners). Although it is difficult to conclusively prove a cause-and-effect relationship between the consumption of EDs and the observed pathophysiological abnormalities, most scientific evidence (mostly clinical case reports) indicates that both occasional and especially chronic use of EDs is associated with the occurrence of numerous adverse effects (AEs). Among these, the best documented AEs are those on the cardiovascular system. It should also be noted that the components of EDs (primarily caffeine) may have drug interactions; therefore, EDs may be an important factor influencing the safety of pharmacotherapy in patients consuming EDs. Conclusions: Consuming energy drinks lead to various health problems and may interfere with pharmacotherapy due to the potential development of drug interactions. Due to the widespread availability of EDs, their suggestive advertising aimed at the youngest customers, and ambiguous regulations, new legislative policies are required to limit the widespread consumption of such products and their negative health ef

Thermal processing of food is likely to form acrylamide (AA) and elaidic acid (EA), which are both mainly metabolized by the liver. The two substances are associated with the pathogenesis of liver disease. In the current study, we investigated the toxic effects of the combined action of AA and EA on HSC-T6 cells, and the mechanism of apoptosis exacerbated by the co-exposure. The results showed a synergistic effect of AA and EA, which exacerbated the damage and oxidative stress (OS) in HSC-T6. Meanwhile, the expression of endoplasmic reticulum stress (ERS) proteins, such as GRP78 and CHOP, was increased, the ERS pathway was activated, and Ca2+ in cells was increased, which exacerbated mitochondrial damage, and opened IP3R-Grp75-VDAC1 channel. Both ERS and mitochondrial damage caused the process of cell apoptosis. Inhibition of ERS by 4-phenylbutyric acid (4-PBA) significantly reversed the synergistic effects on mitochondrial damage via ERS, suggesting that AA and EA exacerbated mitochondrial damage through ERS-mediated Ca2+ overload. AA and EA synergistically damaged the function of mitochondria through exacerbating ERS and led to cell apoptosis.

Preclinical and clinical studies have identified the ghrelin receptor [growth hormone secretagogue receptor (GHSR)1a] as a potential target for treating alcohol use disorder. A recent phase 1a clinical trial of a GHSR1a antagonist/inverse agonist, PF-5190457, in individuals with heavy alcohol drinking identified a previously undetected major hydroxy metabolite of PF-5190457, namely PF-6870961. Here, we further characterized PF-6870961 by screening for off-target interactions in a high-throughput screen and determined its in vitro pharmacodynamic profile at GHSR1a through binding and concentration-response assays. Moreover, we determined whether the metabolite demonstrated an in vivo effect by assessing effects on food intake in male and female rats. We found that PF-6870961 had no off-target interactions and demonstrated both binding affinity and inverse agonist activity at GHSR1a. In comparison with its parent compound, PF-5190457, the metabolite PF-6870961 had lower binding affinity and potency at inhibiting GHSR1a-induced inositol phosphate accumulation. However, PF-6870961 had increased inhibitory potency at GHSR1a-induced β-arrestin recruitment relative to its parent compound. Intraperitoneal injection of PF-6870961 suppressed food intake under conditions of both food restriction and with ad libitum access to food in male and female rats, demonstrating in vivo activity. The effects of PF-6870961 on food intake were abolished in male and female rats knockout for GHSR, thus demonstrating that its effects on food intake are in fact mediated by the GHSR receptor. Our findings indicate that the newly discovered major hydroxy metabolite of PF-5190457 may contribute to the overall activity of PF-5190457 by demonstrating inhibitory activity at GHSR1a. SIGNIFICANCE STATEMENT: Antagonists or inverse agonists of the growth hormone secretagogue receptor (GHSR)1a have demonstrated substantial potential as therapeutics for alcohol use disorder. We here expand understanding of the pharmacology of one such GHSR1a inverse agonist, PF-5190457, by studying the safety and pharmacodynamics of its major hydroxy metabolite, PF-6870961. Our data demonstrate biased inverse agonism

Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that link extracellular stimuli to Ca2+ signals. Ca2+ release from intracellular stores is "quantal": low IP3 concentrations rapidly release a fraction of the stores. Ca2+ release then slows or terminates without compromising responses to further IP3 additions. The mechanisms are unresolved. Here, we synthesize a high-affinity partial agonist of IP3Rs and use it to demonstrate that quantal responses do not require heterogenous Ca2+ stores. IP3Rs respond incrementally to IP3 and close after the initial response to low IP3 concentrations. Comparing functional responses with IP3 binding shows that only a tiny fraction of a cell's IP3Rs mediate incremental Ca2+ release; inactivation does not therefore affect most IP3Rs. We conclude, and test by simulations, that Ca2+ signals evoked by IP3 pulses arise from rapid activation and then inactivation of very few IP3Rs. This allows IP3Rs to behave as increment detectors mediating graded Ca2+ release.

Deoxynivalenol (DON) is a vital virulence factor of Fusarium graminearum, which causes Fusarium head blight (FHB). We recently found that validamycin A (VMA), an aminoglycoside antibiotic, can be used to control FHB and inhibit DON contamination, but its molecular mechanism is still unclear. In this study, we found that both neutral and acid trehalase (FgNTH and FgATH) are the targets of VMA in F. graminearum, and the deficiency of FgNTH and FgATH reduces the sensitivity to VMA by 2.12- and 1.79-fold, respectively, indicating that FgNTH is the main target of VMA. We found FgNTH is responsible for vegetative growth, FgATH is critical to sexual reproduction, and both of them play an important role in conidiation and virulence in F. graminearum. We found that FgNTH resided in the cytoplasm, affected the localization of FgATH, and positively regulated DON biosynthesis; however, FgATH resided in vacuole and negatively regulated DON biosynthesis. FgNTH interacted with FgPK (pyruvate kinase), a key enzyme in glycolysis, and the interaction was reduced by VMA; the deficiency of FgNTH affected the localization of FgPK under DON induction condition. Strains with a deficiency of FgNTH were more sensitive to demethylation inhibitor (DMI) fungicides. FgNTH regulated the expression level of FgCYP51A and FgCYP51B by interacting with FgCYP51B. Taken together, VMA inhibits DON biosynthesis by targeting FgNTH and reducing the interaction between FgNTH and FgPK, and synergizes with DMI fungicides against F. graminearum by decreasing FgCYP51A and FgCYP51B expression. © 2021 The Authors. Molecular Plant Pathology published by British Society for Plant Pathology and John Wiley & Sons Ltd.

Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1High;CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High;CHD7Low xenograft model.

Histamine H1 receptor ligands used clinically as antiallergics rank among the most widely prescribed and over-the-counter drugs in the world. They exert the therapeutic actions by blocking the effects of histamine, due to null or negative efficacy towards Gαq-phospholipase C (PLC)-inositol triphosphates (IP3)-Ca2+ and nuclear factor-kappa B cascades. However, there is no information regarding their ability to modulate other receptor responses. The aim of the present study was to investigate whether histamine H1 receptor ligands could display positive efficacy concerning receptor desensitization, internalization, signaling through Gαq independent pathways or even transcriptional regulation of proinflammatory genes. While diphenhydramine, triprolidine and chlorpheniramine activate ERK1/2 (extracellular signal-regulated kinase 1/2) pathway in A549 cells, pre-treatment with chlorpheniramine or triprolidine completely desensitize histamine H1 receptor mediated Ca2+ response, and both diphenhydramine and triprolidine lead to receptor internalization. Unlike histamine, histamine H1 receptor desensitization and internalization induced by antihistamines prove to be independent of G protein-coupled receptor kinase 2 (GRK2) phosphorylation. Also, unlike the reference agonist, the recovery of the number of cell-surface histamine H1 receptors is a consequence of de novo synthesis. On the other hand, all of the ligands lack efficacy regarding cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) mRNA regulation. However, a prolonged exposure with each of the antihistamines impaires the increase in COX-2 and IL-8 mRNA levels induced by histamine, even after ligand removal. Altogether, these findings demonstrate the biased nature of histamine H1 receptor ligands contributing to a more accurate classification, and providing evidence for a more rational and safe use of them.

At present, computational methods for drug repositioning are mainly based on the whole structures of drugs, which limits the discovery of new functions due to the similarities between local structures of drugs. In this article, we, for the first time, integrated the features of chemical-genomics (substructure-domain) and pharmaco-genomics (domain-indication) based on the assumption that drug-target interactions are mediated by the substructures of drugs and the domains of proteins to identify the relationships between substructure-indication and establish a drug-substructure-indication network for predicting all therapeutic effects of tested drugs through only information on the substructures of drugs. In total, 83 205 drug-indication relationships with different correlation scores were obtained. We used three different verification methods to indicate the accuracy of the method and the reliability of the scoring system. We predicted all indications of olaparib using our method, including the known antitumor effect and unknown antiviral effect verified by literature, and we also discovered the inhibitory mechanism of olaparib toward DNA repair through its specific sub494 (o = C-C: C), as it participates in the low synthesis of the poly subfunction of the apoptosis pathway (hsa04210) by inhibiting the Inositol 1,4,5-trisphosphate receptor(s) (ITPRs) and hydrolyzing poly (ADP ribose) polymerases. ElectroCardioGrams of four drugs (quinidine, amiodarone, milrinone and fosinopril) demonstrated the effect of anti-arrhythmia. Unlike previous studies focusing on the overall structures of drugs, our research has great potential in the search for more therapeutic effects of drugs and in predicting all potential effects and mechanisms of a drug from the local structural similarity. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Renal ischemia-reperfusion injury (R-IRI) is the main cause of acute renal failure. Carvedilol has been shown to protect against R-IRI. However, the underlying mechanisms are still not completely clarified. This study aimed to investigate the role of lipid signaling in mediating carvedilol protective effects against R-IRI in insulin-resistant mice by using two different lipid signaling modulators, quercetin and lithium chloride (LiCl). Mice were fed high-fructose, high-fat diet (HFrHFD) for 16 weeks to induce insulin resistance. At the end of feeding period, mice were randomly distributed into five groups; Sham, R-IRI, Carvedilol (20 mg/kg, i.p.), Carvedilol + Quercetin (10 mg/kg, i.p.), Carvedilol + LiCl (200 mg/kg, i.p.). R-IRI was performed by applying 30 min of unilateral renal ischemia followed by one hour of reperfusion. Quercetin and LiCl were administered 30 min before carvedilol administration and carvedilol was administered 30 min before ischemia. Changes in kidney function tests, histopathology, fibrosis area, lipid signaling, inflammatory, apoptosis and oxidative stress markers in the kidney were measured. Results showed that R-IRI decreased kidney function, impaired renal tissue integrity, modulated lipid signaling and increased renal inflammation, apoptosis and oxidative stress. Carvedilol treatment decreased the detrimental effects induced by R-IRI. In addition, pre-injection of both quercetin and LiCl potentiated the reno-protective effects of carvedilol against R-IRI independent of changes in lipid mediators like phosphatidyl inositol 4,5 bisphosphate (PIP2) and diacylglycerol (DAG). In conclusion, quercetin and LiCl potentiate the protective effects of carvedilol against R-IRI in HFrHFD-fed mice by reducing inflammation and oxidative stress independent of lipid signaling.