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Behavioural brain research · 2026
The precise regulation of the sleep-wake cycle relies on the coordinated interplay of multiple brain regions, diverse neuronal subtypes, and various neurotransmitter systems. In the neural structures of the midbrain, the ventral tegmental area (VTA) functions as a key neuromodulatory hub. Traditionally, it was thought to regulate reward and motivation primarily; however, recent studies have increasingly established its pivotal role in the sleep-wake rhythm. Based on the VTA's anatomical and cellular heterogeneity, this paper comprehensively summarizes the functional specificity and corresponding circuit mechanisms of dopaminergic (DA), glutamatergic (GLU) and GABAergic (GABA) neurons in sleep-wake regulation. Existing evidence indicates that dopaminergic and glutamatergic neurons jointly form a core arousal-promoting network through their subtype-specific long-range projections. In contrast, GABA neurons facilitate non-rapid eye movement (NREM) sleep and constrain excessive arousal activation via inhibitory projections and local negative feedback loops. Within a unified rhythmic framework, the synergy and counterbalance among these three neuronal subtypes provide a structural basis for the VTA to maintain the stability of sleep-wake states and enable their flexible transition. Furthermore, the interactions between the VTA and other arousal-promoting systems, including orexin, norepinephrine, and serotonin, further expand its functional hierarchy within the whole-brain sleep regulatory network. Meanwhile, circadian modulation of the VTA dopaminergic system maintains sleep-wake and emotional homeostasis. Finally, this paper discusses current limitations in refining neuronal subtypes, causal verification of mechanisms, and clinical translation. It highlights the scientific potential of using the VTA as a target in the management of sleep disorders.
The Journal of clinical psychiatry · 2026
Objective: Cognitive impairment associated with schizophrenia (CIAS) is a key driver of functional deficits in patients with this disorder. CIAS may involve deficient NMDA receptor-dependent neurotransmission. Negative allosteric modulators (NAMs) of γ-aminobutyric acid (GABA) type A (GABAA) α5 receptors enhance their activity and improve cognition in rodents and nonhuman primates. We tested whether prolonged treatment with basmisanil-a selective GABAA α5 NAM-improved CIAS. Methods: This 24-week placebo-controlled phase 2b study in patients with CIAS diagnosed according to DSM-5 was conducted between November 2016 and December 2019. Two hundred thirteen patients were randomized to 80 mg of basmisanil, 240 mg of basmisanil, or placebo twice a day. Recruitment into the 80 mg group was stopped after a planned futility analysis. The primary outcome was the MATRICS Consensus Cognitive Battery (MCCB) neurocognitive composite score evaluated in the efficacy analysis population (EAP) in the placebo (n=76) and basmisanil 240 mg arms only (n=77, total EAP n=153). Secondary outcome measures included specific hippocampal and prefrontal-dependent cognitive tasks, functional outcomes, and symptoms. Novel study design features addressing potential sources of heterogeneity in drug response and learning and practice effects included stratification by cognitive trajectories and age as well as repeated administration of the MCCB test battery during screening. Results: Twenty-four weeks of treatment with basmisanil was well tolerated without improving cognitive or functional measures overall or in any of the stratified subgroups. Practice and learning effects were not observed at week 12. Conclusion: Basmisanil did not improve cognitive deficits. Although unsuccessful, some results offer insight into important factors that should facilitate the design of more informative trials. Trial Registration: ClinicalTrials.gov identifier: NCT02953639.
Human brain mapping · 2025
Little is known about the neurometabolic effects of cannabis use. Using meta-analytic modeling of proton magnetic resonance spectroscopy (1H-MRS) studies, this study aimed to assess the differences in brain metabolite levels associated with cannabis use (PROSPERO: CRD42020209890) to inform treatment development for cannabis use disorder (CUD). Hedge's g with random-effects modeling was used, and heterogeneity and publication bias indices were assessed. A complete literature search was conducted, and 15 studies met the inclusion criteria (e.g., 1H-MRS, cannabis group compared to a control group, brain region-specific results, necessary data to complete modeling). There were 29 models across gray matter regions in the brain. All models had between 2 and 5 studies (k), indicating that results should be interpreted with caution due to the limited number of available studies. Compared to the control groups, the cannabis-using groups showed lower levels of GABA and N-acetylaspartate in the anterior cingulate cortex (k = 3); lower glutamate in the basal ganglia/striatum (k = 2); and lower glutamine and myo-inositol in the thalamus (k = 2; although the two effect sizes came from the same sample). This is the first meta-analysis to consolidate the extant 1H-MRS studies focused on the neurometabolic effects of cannabis. Despite the few studies available, the evidence suggests cannabis use may impact important neural processes, including glutamatergic and GABAergic functioning (glutamate, glutamine, and GABA), neural health (N-acetylaspartate), and glial functioning (myo-inositol). The findings should be interpreted with caution considering the small sample size; the inability to test the impact of demographic, substance use, and methodological factors; and the heterogeneity of studies. Understanding the neurobiological effects of cannabis may inspire novel pharmacotherapy and/or psychosocial interventions for CUD.
Journal of affective disorders · 2025
Mood disorders are linked to inflammation, suggesting anti-inflammatory treatments may influence mood regulation. Magnetic Resonance Spectroscopy (MRS) is effective in monitoring neurochemical changes associated with neuroinflammation and tracking the neurophysiological effects of anti-inflammatory agents. This systematic review summarizes clinical trials investigating the effects of anti-inflammatory agents on brain MRS measures in individuals with, or at risk for, mood disorders. We conducted a systematic review following PRISMA 2020 guidelines in PubMed, Scopus, Embase, and Web of Science to identify relevant studies published before April 2024. Clinical trials evaluating the effects of anti-inflammatory agents on MRS measures in mood disorders were included. Two reviewers independently screened studies, extracted data, and assessed the risk of bias using the Effective Public Health Practice Project tool. Ten studies were included. Omega-3 increased N-acetyl aspartate (NAA) in the corpus callosum in bipolar disorder (BD) and reduced choline (Cho) and creatine (Cr) in the anterior cingulate cortex (ACC) in offspring of BD patients. N-acetylcysteine was associated with higher NAA, glutamate, and glutamine (Glx) and lower myo-inositol levels in the ACC in major depressive disorder (MDD). Ebselen reduced inositol and Glx concentrations in the ACC in MDD. Infliximab reduced Glx in the prefrontal cortex in BD, and lovastatin increased NAA in the ACC and decreased the Cho/Cr ratio in the left basal ganglia in manic BD. Anti-inflammatory agents induce neurochemical changes in mood disorders that can be measured with MRS. These shifts may relate to symptom improvement. Further research is needed to elucidate the mechanisms underlying these effects.
Psychiatry research · 2025
Aggressive behaviours pose a significant threat to both individual and societal security. Increasing evidence suggests that individuals exhibiting such behaviours demonstrate altered neurochemical levels including metabolites, neurotransmitters and receptors. However, findings from previous studies have shown inconsistencies. This study aimed to elucidate these neurochemical alterations through a case-control meta-analysis. A comprehensive literature search was conducted using Web of Science, Medline, and PubMed databases, identifying forty eligible studies (registration number: CRD420251014162). The neurochemicals examined included indictors of serotonin (5-HT), dopamine, N-acetyl aspartate (NAA), glutamate, glutamine, choline, creatine, phosphocreatine, myo-inositol, gamma-aminobutyric acid, homovanillic acid, norepinephrine, 3-methoxy-4-hydroxy-phenylglycol, neuropeptide Y-like immunoreactivity, and substance P-like immunoreactivity. These studies investigated neurochemical changes in the cerebrospinal fluid (CSF) and various brain regions, including the prefrontal cortex, orbital frontal cortex, anterior cingulate cortex, middle temporal gyrus, medial temporal lobe, parietal cortex, striatum, thalamus, amygdala, hippocampus, midbrain, and brainstem. Our meta-analysis revealed a significant reduction in NAA levels in the prefrontal cortex of individuals exhibiting aggressive behaviours compared to controls. Furthermore, NAA levels demonstrated a negative correlation with the severity of aggressive behaviours. The findings for the other neurochemicals all did not reach statistical significance. These findings suggest that reduced prefrontal NAA levels may serve as a neurobiological correlate of aggressive behaviours, with implications for developing assessment tools and targeted interventions.
Scientific reports · 2025
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.
BMC psychiatry · 2025
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. 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. 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. Compared with BP ECT, UBP ECT may reduce the incidence of delirium post-treatment in SCZ without a significant difference in efficacy. The higher cholinesterase levels in the UBP group suggest that UBP ECT may reduce neuronal asynchronous depolarization, cholinergic disorder, and pro-inflammatory responses, thereby reducing the impact on delirium. These findings provide partial scientific evidence for elucidating the mechanisms underlying ECT.
Ginekologia polska · 2025
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. 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. 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. 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.
Molecular psychiatry · 2025
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. 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. 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. 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.
JAMA · 2025
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. 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. 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. 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. The primary outcome was a composite of gestational diabetes, preeclampsia, or preterm birth (before 37 weeks' gestation). 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). Myo-inositol supplementation during pregnancy did not reduce the incidence of a composite of gestational diabetes, preeclampsia, or preterm birth in patients with PCOS. onderzoekmetmensen.nl Identifier: NL67329.078.18.
Nutritional neuroscience · 2026
Obesity can lead to cerebral consequences that are mediated by peripheral inflammation and, consequently, neuroinflammation. Brain metabolites play a pivotal role in regulating neuroinflammation and maintaining neuronal health. Magnetic Resonance Spectroscopy (MRS) can effectively capture neurometabolic changes. This systematic review aimed to understand the evaluation of MRS-based common neurometabolites and their alteration patterns in obesity and identify vulnerable brain regions of interest. A systematic literature search was conducted with Scopus, PubMed, and Google scholar search engines, using appropriate queries that included all the original research articles published in English and performed MRS on obese humans irrespective of age and gender. A total of eight studies were selected for evidence synthesis. The sample size of the studies ranged from n = 23 to n = 115. The majority of the studies (n = 7) were cross-sectionally designed. The most altered neurometabolites were N-acetyl aspartate and Myo Inositol. The most explored brain region was the occipitoparietal grey matter, including the posterior cingulate gyrus. Discussion: The altered neurometabolites support the obesity and neuroinflammation interrelationship. However, the evidence is reported from the pool of correlational studies that do not establish a causal relationship between obesity and neurometabolic alterations. Additionally, the limitations of in vivo MRS are to be considered for reporting the inferences. The available information was based on obesity assessment with BMI and was limited to racial homogeneity of the western population. Thus, with diversity in ethnicity and obesity diagnosis methods, more clinical research is required to generalize the findings.
International journal of molecular sciences · 2025
Multiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disorder marked by inflammation, demyelination, and neuronal loss within the central nervous system. Despite advances in diagnostics, current tools remain insufficiently sensitive and specific. Metabolomics has emerged as a promising approach to explore MS pathophysiology and discover novel biomarkers. This PRISMA-guided systematic review included 29 original studies using validated metabolomic techniques in adult patients with MS. Biological samples analyzed included serum, cerebrospinal fluid, and feces. Consistent metabolic alterations were identified across several pathways. The kynurenine pathway demonstrated a shift toward neurotoxic metabolites, alongside reductions in microbial-derived indoles, indicating inflammation and gut dysbiosis. Energy metabolism was impaired, with changes in glycolysis, tricarboxylic acid (TCA) cycle, and mitochondrial function. Lipid metabolism showed widespread dysregulation involving phospholipids, sphingolipids, endocannabinoids, and polyunsaturated fatty acids, some modulated by treatments such as ocrelizumab and interferon-β. Nitrogen metabolism was also affected, including amino acids, peptides, and nucleotides. Non-classical and xenobiotic metabolites, such as myo-inositol, further reflected host-microbiome-environment interactions. Several studies demonstrated the potential of metabolomics-based machine learning to distinguish MS subtypes. These findings highlight the value of metabolomics for biomarker discovery and support its integration into personalized therapeutic strategies in MS.
BMC infectious diseases · 2025
Tuberculosis (TB) is the leading cause of death from a single infectious agent, with approximately 1.2 million deaths reported in 2023. While TB primarily affects the lungs, it can also spread to other organs, where it is classified as extrapulmonary TB. Tuberculous meningitis (TBM) is the most severe form of extrapulmonary TB, affecting 1–5% of TB cases. Delayed diagnosis contributes to its high mortality and severe neurological complications, with approximately 10% of affected individuals dying or suffering permanent neurological damage. When combined with adjunctive therapy, early detection and treatment can significantly improve survival outcomes. Currently, many studies have identified potential biomarkers of TBM; however, to date, there is no clear consensus on the markers altered in TBM. Hence, we conducted a systematic review aimed at identifying metabolites and proteins that are significantly altered in TBM when compared with healthy controls. Three databases — PubMed, Scopus, and Web of Science — were scanned by two independent reviewers for potential articles that met our inclusion and exclusion criteria. After quality assessment, 17 studies were included, comprising a total of 963 participants (healthy control, n = 576; TBM, n = 387). Metabolites and proteins identified as being significantly altered across studies included alanine, isoleucine, myo-inositol, valine, arachidonate 5-lipoxygenase (ALOX5), apolipoprotein B (APOB), and glial fibrillary acidic protein (GFAP), which were detected in serum, urine, brain tissue, and cerebrospinal fluid samples. These markers have potential diagnostic value for TBM. However, further validation is needed to determine their specificity to reliably distinguish TBM from other neurological infections, which could improve early diagnosis and patient outcomes in TBM. The online version contains supplementary material available at 10.1186/s12879-025-11740-6.
International journal of molecular sciences · 2025
Parkinson's Disease (PD) is the fastest-growing neurological disorder, characterized by the degeneration of dopaminergic neurons. Treatments remain symptomatic, and objective biomarkers for therapeutic response are lacking. This review aims to evaluate the potential of Proton Magnetic Resonance Spectroscopy (1H-MRS) to provide objective and reproducible biomarkers for monitoring treatment response in PD. This systematic review followed PRISMA guidelines. Articles were searched in PubMed, Web of Science, Scopus, and Embase, and studies employing 1H-MRS to evaluate pharmacological treatments in PD were included, analyzing pre- and post-treatment changes. Six studies were included, investigating cannabinoids, dopamine agonists, monoamine oxidase B inhibitors, and levodopa. Key metabolites analyzed were N-acetylaspartate, Creatine, Choline, myo-Inositol, and Glx (glutamate+glutamine). Increases in NAA, a marker of neuronal integrity and mitochondrial function, suggested neuroprotective mechanisms of dopaminergic drugs, while stable Cho and mI levels, markers of membrane metabolism and inflammatory processes, suggested limited short-term responsiveness. This is the first systematic review evaluating 1H-MRS for monitoring neurometabolic changes induced by pharmacological treatments in PD. Observed metabolite changes appear to reflect treatment mechanisms and potential neuroprotective properties. Findings suggest that 1H-MRS may serve as an objective biomarker for assessing therapeutic efficacy and potential neuroprotective drug effects, although further studies are needed to confirm its clinical utility.
Revista brasileira de ginecologia e obstetricia : revista da Federacao Brasileira das Sociedades de Ginecologia e Obstetricia · 2025
This review evaluated myo-inositol supplementation's effectiveness in pregnant women at high risk for Gestational Diabetes Mellitus (GDM). A systematic search in PubMed/MedLine, Cochrane, and VHL databases was conducted using the following terms: "inositol," "diabetes," "gestational diabetes," and "prevention," with no limits on publication period or language. The reference lists were scanned for additional articles. Relevant studies were identified by screening titles, abstracts, and full texts, following inclusion and exclusion criteria and eliminating duplicates. One additional study was added after reviewing references. Guided by the PRISMA Statement, data were extracted using Microsoft Excel. The primary outcome was GDM incidence; secondary outcomes included maternal, birth, neonatal health, and adverse effects. Five studies were included. Myo-inositol supplementation significantly decreased the incidence of GDM in all studies. One study noted significant weight loss. Three studies found no reduction in insulin treatment needs with myo-inositol supplementation. One study showed a decrease in macrosomia incidence. No decrease in cesarean delivery rates was verified, though one study noted reduced hypertensive disorders' incidence with myo-inositol. Four studies evidenced no reduction in premature birth or shoulder dystocia. There was no significant difference in hypoglycemia incidence in three studies. One study showed a decrease in Neonatal Intensive Care Unit admissions with myo-inositol supplementation. One patient reported headaches. Due to study divergences, no clinical recommendations can be made. However, myo-inositol supplementation appears effective in reducing GDM incidence in at-risk pregnant women.
The Journal of clinical endocrinology and metabolism · 2026
Benign thyroid nodules (BTNs) are highly prevalent, and current treatment options are primarily invasive. There is a need for effective, noninvasive alternatives. To systematically evaluate the efficacy of repurposed pharmacologic agents in reducing the size of BTNs. MEDLINE, EMBASE, Cochrane databases, and Scopus were searched from inception to December 18, 2024. We included preclinical and clinical studies evaluating repurposed drugs for BTNs in adults. Of 1499 records screened, 20 studies met inclusion criteria: 6 randomized controlled trials (RCTs), 6 prospective cohorts, 3 retrospective observational studies, 3 case reports, 1 cross-sectional study, and 1 preclinical study. Data were extracted independently in duplicate using a standardized form. Narrative synthesis was conducted due to heterogeneity. Metformin was the most frequently evaluated agent (7 studies), with 5 studies (including 2 RCTs) reporting statistically significant reductions in dominant nodule volume. One prospective study demonstrated a reduction in the maximum nodule diameter, which was not statistically significant, and 1 RCT showed no changes in nodule size after intervention. Statins (4 studies) and somatostatin analogues (4 studies) showed mixed results. Myo-inositol with selenium, herbal formulations, and immune checkpoint inhibitors showed promise in single studies or case reports. Metformin shows the most consistent potential for noninvasive reduction of BTN size, particularly in patients with metabolic comorbidities. However, current evidence is limited and heterogeneous. Further large-scale studies are needed to confirm efficacy and guide clinical use.
Frontiers in nutrition · 2025
Polycystic ovary syndrome (PCOS) affects 5-15% of reproductive-aged women and involves significant metabolic dysregulation, for which nutritional interventions show therapeutic potential. Methods: This umbrella meta-analysis synthesizes evidence from 46 randomized trials (n = 30,133) to evaluate dietary supplements targeting core PCOS pathways. This umbrella meta-analysis synthesizes evidence from 46 randomized trials (n = 30,133) to evaluate dietary supplements targeting core PCOS pathways. Key nutraceuticals demonstrate clinically relevant benefits: myo-inositol significantly improves insulin sensitivity (HOMA-IR SMD = -0.81) and SHBG levels (SMD = 9.65) by enhancing glucose transporter activity; probiotics reduce systemic inflammation (CRP SMD = -0.82) via gut-microbiota modulation; omega-3 fatty acids ameliorate dyslipidemia (LDL-C SMD = -9.57; HDL-C SMD = 2.31) through anti-inflammatory mechanisms. Plant-derived compounds like curcumin lower fasting glucose (SMD = -3.43) via NF-ĸB pathway inhibition, while green tea catechins reduce adiposity. Significant heterogeneity arises from variations in supplement bioavailability, dosing protocols, and patient metabolic phenotypes. Nevertheless, consistent evidence confirms that targeted nutrient supplementation modulates insulin signaling, lipid metabolism, and hormonal balance in PCOS. Emerging research priorities include personalized nutrition protocols leveraging nutrigenomic interactions and antioxidant-rich formulations (e.g., vitamin E, selenium). This work establishes a mechanistic foundation for integrating evidence-based nutraceuticals-particularly myo-inositol, probiotics, and omega-3s-into PCOS management, offering clinically actionable strategies while highlighting needs for standardized dosing and bioavailability studies. https://www.crd.york.ac.uk/PROSPERO/view/CRD42024602681.
Journal of pregnancy · 2025
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. 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. 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). The small number of patients could be a limitation of the study. 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.
NeuroImage. Clinical · 2026
Major Depressive Disorder (MDD) diagnoses have drastically increased in the United States from 6.5% to 21-30% since 2019, burdening individuals and society alike. Despite considerable efforts to understand the pathogenesis of MDD, the heterogeneity of the disorder has made it difficult to delineate its underpinnings, highlighting the need for biomarker identification. This study assessed the concentrations of key neurometabolites in the anterior cingulate cortex (ACC) in people with MDD (average n = 496) compared to healthy controls (average n = 404). We conducted a systematic review that ultimately led to the inclusion of n = 43 proton magnetic resonance spectroscopy (1H-MRS) studies for meta-analysis. Average concentrations of eight neurometabolites were compared using a random effects model. We found that subjects with MDD had significantly decreased N-acetylaspartate (NAA; Hedges' g = -0.16, 95% CI -0.299 to -0.030, p = 0.017), and gamma-aminobutyric acid (GABA; Hedges' g = -0.26, 95% CI -0.434 to -0.082, p = 0.004), and increased levels of glutamine (Gln; Hedges' g = 0.21, 95% CI 0.105 to 0.311, p < 0.001) in the ACC. Subgroup analyses suggested significantly increased NAA detected by magnets stronger than 1.5 Tesla only, glutamate (Glu) in the dorsal ACC only and significantly increased myo-inositol (mI) and choline (Cho) in exclusively unmedicated subjects. This study provides a summative picture of the neurometabolic profile of the ACC in people with MDD and provides a foundation for the development of biomarker-based diagnostic criteria and novel pharmacological treatments.
Frontiers in endocrinology · 2026
This umbrella review aimed to synthesize and appraise the evidence regarding the efficacy of inositol for Polycystic Ovary Syndrome (PCOS) by integrating meta-analyses of randomized controlled trials(RCTs), thereby assessing the robustness of the existing body of evidence. We searched four databases from inception to August 2025 for relevant RCT meta-analyses. Primary outcomes included hormonal profiles, glycolipid metabolism, anthropometrics, and reproductive outcomes. Quality was assessed using AMSTAR-2 and GRADE. Thirteen meta-analyses were included. AMSTAR-2 ratings were 23.1% high, 53.8% low, and 23.1% very low quality. GRADE assessment of 85 evidence items revealed no high-quality evidence; 18.9% were moderate, 40% low, and 41.1% very low quality. Pooled analyses demonstrated that inositol significantly improved multiple outcomes compared to placebo/FA: it reduced serum luteinizing hormone (LH: MD -3.43 IU/L, 95% CI [-4.29, -2.56], P < 0.00001), total testosterone (TT), free testosterone (FT: MD -0.02 nmol/L, 95% CI [-0.02, -0.01], P < 0.00001), improved sex hormone-binding globulin (SHBG: MD 36.72 nmol/L, 95% CI [28.52, 44.91], P < 0.00001), and androstenedione. Benefits were also observed for homeostatic model assessment of insulin resistance (HOMA-IR: MD -1.14, 95% CI [-1.35, -0.94], P < 0.00001), fasting insulin (FI: MD -23.40 pmol/L, 95% CI [-32.80, -14.01], P < 0.00001), triglycerides, and reproductive outcomes (live births: Risk Ratio [RR] 2.29, 95% CI [1.07, 4.93], P = 0.03; ovulation rate: RR 2.75, 95% CI [1.71, 4.41], P < 0.0001). However, versus metformin(MET), its effects on most parameters were not significant, except for triglycerides and pregnancy rates. Cross-subgroup analysis of inositol subtypes indicated MI/MI+FA was superior for metabolic and reproductive outcomes, while D-chiro-inositol monotherapy should be used with caution in clinical practice; combination therapy did not consistently outperform monomers. Inositol improves core PCOS manifestations. Supported by moderate-quality evidence for effects on TT, FT, SHBG, HOMA-IR, and pregnancy/ovulation rates, it is a promising therapy. Differential efficacy of inositol subtypes may inform personalized treatment. However, outcomes based on low-quality evidence require cautious interpretation and should not solely guide clinical decisions, highlighting the need for larger, rigorous trials. https://www.crd.york.ac.uk/prospero/, identifier CRD420251146691.