The serotonergic hallucinogen psilocybin has shown potential as a treatment for psychiatric conditions like alcohol use disorder (AUD) and depression in clinical studies. Epigenetic mechanisms, including DNA methylation, are hypothesized to contribute to its lasting therapeutic benefits. In this exploratory study, we present the first methylome-wide analysis of psilocybin-induced changes in a cohort of detoxified patients with AUD. The longitudinal study design included three assessment days in 37 patients with blood sampling and acquisition of psychometrics - at baseline, 24 h after administration of psilocybin (25 mg) or placebo (mannitol), and one month after treatment. As the primary endpoints (duration of abstinence and mean alcohol use) in this trial were not reached, our investigation included secondary psychometrics that differed significantly between groups: Beck's Depression Inventory and Beck's Hopelessness Scale. The epigenome-wide association study (EWAS) identified one CpG site in TLE4 (p = 1.1e-7) associated with psilocybin treatment. Screening for differentially methylated regions, we observed altered methylation in the gene RASGRP4 (pFDR = 3.2e-4). Network analysis revealed co-methylation modules related to psilocybin treatment, as well as modules associated with the reduction of depressive symptoms and drinking behavior. Gene ontology analysis indicated involvement of these modules in neuroplasticity and immune functions, suggesting that they may reflect abstinence-related recovery processes. Investigating candidate genes at nominal significance (p < 0.05) uncovered promoter-associated methylation changes in HTR2A and TNF. Interestingly, several of the reported analyses point to immunomodulatory actions of psilocybin. While the findings of this pilot study are limited by the modest sample size, they align well with previous literature and might provide starting points for further, large-scale investigations or hypothesis-driven experiments.

Glucagon-like peptide-1 (GLP-1) receptor agonists have attracted interest as gerotherapeutics, yet clinical-trial evidence for their effects on biological aging is lacking. We report a post hoc exploratory epigenetic age analysis of a 32-week, randomized, double-blind, placebo-controlled phase 2b trial (NCT04019197) of semaglutide in adults with human immunodeficiency virus (HIV)-associated lipohypertrophy (semaglutide n = 45; placebo n = 39). The parent trial's primary endpoint was change in visceral adipose tissue, with secondary cardiometabolic and body-composition endpoints; epigenetic aging was not pre-specified. To address this gap, we profiled peripheral-blood DNA methylation (DNAm) at baseline and week 32 to assess semaglutide versus placebo on first-, second-, and third-generation epigenetic aging measures. In adjusted analyses, semaglutide reduced epigenetic aging across multiple second- and third-generation clocks, including PhenoAge ( - 4.9 years/year, p = 0.004), PCGrimAge ( - 3.1, p = 0.007), GrimAge V2 ( - 2.3, p = 0.009), OMICmAge ( - 2.2, p = 0.009), RetroAge ( - 2.2, p = 0.030), and DunedinPACE ( - 0.09 units, 9% slower, p = 0.01). Systems-based clocks showed parallel reductions in inflammation, brain, and heart aging measures. The post hoc design, modest sample size, HIV-specific cohort, and 32-week follow-up limit generalizability. Prospective trials are needed to determine whether GLP-1 receptor agonists can be repurposed as gerotherapeutics.

Skin glycation, oxidation, carbonylation, and excessive inflammation are well-recognized factors contributing to skin aging and pigmentation. Previous in vitro studies have confirmed vitamin C's antioxidant, anti-glycation, and anti-inflammatory properties, but its in vivo effects remain to be further verified.

Childhood trauma is associated with increased risk of depression and epigenetic alterations in stress-related pathways. Preclinical studies suggest that methyl donors may facilitate DNA methylation changes. This first-in-human trial of epigenetic treatment investigated methyl donor S-adenosylmethionine (SAMe) as add-on to trauma-focused therapy for depression.

Epigenetic dysregulation is associated with the pathogenesis and progression of diffuse large B-cell lymphoma (DLBCL). MYC/BCL2 double-expressor lymphoma (DEL), a distinct population of DLBCL defined by MYC and BCL2 coexpression, refers to poor prognosis after standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. Tucidinostat (or chidamide), an oral, selective histone deacetylase inhibitor, has shown promising activity in DEL.

Strenuous endurance exercise imposes substantial physiological stress on the cardiovascular system and has been associated with transient elevations in cardiac biomarkers. Vitamin D₃ has been suggested to influence oxidative stress and immune responses. In this study, we investigated the effects of vitamin D₃ supplementation on biomarkers of cardiac, muscle, and immune responses following a marathon race.

Gestational nutrient restriction can reduce fetal growth efficiency, while melatonin supplementation can mitigate some of these negative outcomes. This study investigated placental fatty acid (FA) transporter gene expression and maternal-fetal FA concentrations in cattle supplemented with dietary melatonin during late gestational nutrient restrictions. Brangus heifers (n = 29) were fed a diet of 100% of National Research Council (NRC) requirements (ADQ) or 60% of NRC requirements (RES) from d 160 to d 240 of gestation. These groups were then randomly assigned to receive 20 mg of melatonin daily or no supplement, resulting in four treatment groups (ADQ-CON, n = 7; ADQ-MEL, n = 7; RES-CON, n = 7; RES-MEL, n = 8). On d 240, heifers underwent cesarean sections, in which amniotic fluid and blood samples from both the dam and fetus were collected to determine FA profiles. Placentomes were collected to determine transporter transcript abundance. Maternal concentrations of monounsaturated FA (P = 0.001) and total omega-3 (P = 0.041) were increased in RES versus ADQ-fed dams. Melatonin supplementation did not alter maternal FA profiles (P ≥ 0.081). Fetal concentrations of total omega-6 (n-6) were increased (P < 0.05) in RES-CON versus ADQ-CON, whereas ADQ-MEL and RES-MEL did not differ. Fetal concentrations of total branch chain fatty acids (BCFA) were increased (P < 0.05) in ADQ-MEL versus RES-MEL. Interestingly, maternal concentrations of C16:0, were increased (P = 0.015) in RES vs ADQ-fed dams, while the opposite was observed for amniotic fluid concentrations of C16:0 which were decreased (P = 0.003) in RES vs ADQ-fed dams. Amniotic fluid concentrations of total BCFA were decreased (P = 0.019) in RES versus ADQ-fed dams. Both caruncular and cotyledonary transcript abundance of CASR were decreased (P < 0.05) in RES-CON versus ADQ-CON, while melatonin supplementation rescued this depression in the cotyledon. Both caruncular and cotyledonary transcript abundance of SLC27A1 were increased (P < 0.05) in RES versus ADQ-fed dams. These results indicate that maternal melatonin supplementation differentially altered placental FA transporter transcript abundance and fetal FA profiles, demonstrating context-dependent effects under adequate versus restricted maternal nutrition.

Large-scale randomized trials have found that multivitamin-multimineral (MVM) supplements and cocoa flavanols may benefit several age-related chronic conditions among older adults, but it remains unclear whether these two supplements directly slow the biological aging process. This prespecified ancillary study evaluated the 2-year effect of a daily MVM (Centrum Silver) and cocoa extract (500 mg cocoa flavanols per day, including 80 mg (-)-epicatechin) on five DNA methylation measures of biological aging (PCHannum, PCHorvath, PCPhenoAge, PCGrimAge and DunedinPACE) among 958 participants (482 women and 476 men) in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). Compared with placebo, daily MVM supplementation modestly reduced the rate of increase of second-generation epigenetic clocks, with a between-group difference in yearly change of -0.113 years (95% confidence interval (CI) -0.205 to -0.020; P = 0.017) for PCGrimAge and -0.214 years (-0.410 to -0.019; P = 0.032) for PCPhenoAge. MVM had a stronger effect on PCGrimAge among those with accelerated biological aging at baseline (-0.236 [-0.380 to -0.091]) compared with those with normal or decelerated biological aging (-0.013 [-0.130 to 0.104]; P = 0.018 for interaction). Cocoa extract did not have an effect on the five epigenetic clocks tested. Although the statistically significant but small effects of daily MVM supplementation on slowing biological aging are encouraging, additional studies are needed to determine the clinical relevance of daily MVM supplementation on epigenetic clocks and whether such effects can help explain the beneficial effects of MVM supplementation on aging-related chronic conditions.

Breast cancer is the most commonly diagnosed cancer in women globally. Our previous MIRACLE trial (NCT02313051) demonstrated that everolimus plus letrozole (E + L) significantly improves progression-free survival compared with letrozole (L) monotherapy in premenopausal patients with endocrine therapy-resistant, hormone receptor-positive, HER2-non-amplified advanced breast cancer. This study aims to investigate spatially resolved biomarkers linked to survival benefits from E + L to guide precision therapies. Patients from MIRACLE were stratified by overall survival (OS ≤ 3 vs. >3 years). Spatial Whole Transcriptome Atlas analysis was used to evaluate tumor-, immune-, and stroma-specific gene expression, co-expression network patterns, and survival correlations. Among patients with shorter survival (OS ≤ 3 years), we identified a distinctive gene interaction network characterized by tumor-derived S100A9 and CALML5, which is associated with mTORC1 activation. This finding suggests that tasquinimod, an S100A9 inhibitor, could be a viable therapeutic option. Additionally, an interaction between CALML5 and SLPI across tumor and immune areas indicated a potential role in maintaining tumor integrity and mitigating immune-mediated damage. Conversely, patients with longer survival (OS > 3 years) exhibited SERPINA1 as a hub gene linked to estrogen receptor activation, and an interaction between FKBP5 and SESN3 associated with AKT/mTORC1 inhibition within tumor-rich regions. Furthermore, the interaction between MMP11 and COL16A1 in stroma-rich regions suggests that cancer-associated fibroblasts may contribute to improved outcomes. Our study underscores the critical role of spatial gene expression analysis in elucidating the tumor microenvironment and its impact on prognosis in patients undergoing E + L treatment, thereby opening new avenues for targeted interventions.

Endometriosis is a chronic, multifactorial disorder. Reactive oxygen species (ROS) and oxidative stress (OS) contribute to the development of endometriosis by affecting apoptosis-related genes in granulosa cells. N-acetylcysteine (NAC) is an antioxidant that reduces OS. This randomized controlled trial aimed to investigate the effects of NAC on serum levels of superoxide dismutase (SOD) and total antioxidant capacity (TAC), as well as the expression of apoptotic genes in granulosa cells. Infertile women with endometriosis were enrolled and administered either NAC (1200 mg/day; n = 11) or placebo (n = 14). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum SOD and TAC levels. The expression of Bcl-2, Bax, and Caspase-3 genes in granulosa cells was evaluated by Real-Time Polymerase Chain Reaction. NAC treatment increased serum SOD and TAC levels. Additionally, the expression of pro-apoptotic genes Bax and Caspase-3 in granulosa cells decreased compared to the placebo group, while the expression of the anti-apoptotic gene Bcl-2 increased. We conclude that administration of N-acetylcysteine (NAC) can reduce apoptosis in granulosa cells of women with infertility due to endometriosis.

Recurrence and metastasis significantly impact the survival outcomes of gastric cancer (GC) patients. Weifuchun (WFC), a well-established traditional Chinese medicine formulation, has been widely used in clinical practice for treating gastric disorders and as an adjunctive therapy following GC surgery.

Lowering mutant huntingtin (HTT) gene products is a promising approach for slowing the progression of Huntington's disease (HD), a monogenic neurodegenerative disease caused by an expansion mutation in the HTT gene (NCBI Gene ID: 3064). Branaplam, an orally available HTT messenger RNA splicing modulator, reduces HTT protein levels in vitro and in animal models, and is the first splicing modulator to be evaluated in individuals with HD. Here we present the design and results of VIBRANT-HD, a randomized phase 2b study of branaplam in HD, along with preclinical findings in nonhuman primates. VIBRANT-HD utilized an innovative study design informed by our preclinical data, including targeted safety monitoring measures (for example, neurofilament light chain measurements in blood, nerve conduction studies), and staggered cohorts to capture potential neurotoxic effects early. Of the 21 participants in the initial cohort receiving branaplam 56 mg weekly, 18 (85.7%) showed at least one sign or symptom of peripheral neuropathy. This safety signal, along with dose-modeling results triggered the early termination of VIBRANT-HD. The primary outcome, a decrease in cerebrospinal fluid mutant HTT levels versus placebo, was summarized descriptively, making branaplam the first splicing modulator to lower mutant HTT levels in the cerebrospinal fluid of individuals with HD. Increased neurofilament light chain levels observed in most participants reversed after treatment discontinuation. ClinicalTrials.gov identifier: NCT05111249.

DNA methylation plays an important role in systemic lupus erythematosus (SLE) pathogenesis by regulating immune cell function and disease progression. Dietary factors, particularly methyl-donor micronutrients such as folic acid and vitamin B12, may influence DNA methylation patterns and autoimmune responses. However, their specific effects in SLE, especially in adipose tissue that is a key modulator of systemic inflammation, remain unclear. Given the high prevalence of obesity in SLE and its impact on disease severity, understanding the interaction between nutritional status, epigenetics, and immune dysregulation is crucial. This study examines whether folic acid and vitamin B12 supplementation modulate adipose tissue DNA methylation in female SLE patients, considering their nutritional status, to uncover potential mechanisms influencing disease progression and therapeutic response. This is a randomized, double-blind, placebo-controlled trial with premenopausal women with inactive SLE, classified as normal weight (NW, n = 23) or excess body weight (EBW, n = 27). Participants received daily supplementation of folic acid (400 mcg) and vitamin B12 (2000 mcg) or placebo for 12 weeks. Phenotypic characteristics and adipose tissue DNA methylation profiles were assessed before and after intervention using the Illumina EPIC BeadChip platform.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, primarily used to treat type 2 diabetes, exhibit cardioprotective effects by improving myocardial energy metabolism, reducing oxidative stress, and modulating inflammation and fibrosis, which are critical in the context of acute myocardial infarction (AMI). Our research aims to explore the molecular mechanisms of SGLT2 inhibitors, with a focus on their influence on non-coding RNAs through sirtuins pathways, to identify novel biomarkers and therapeutic strategies for preventing heart failure following AMI.

MicroRNAs (miRNAs), which are non-coding RNAs of approximately 20 nucleotides in length, have attracted attention for their involvement in various biological processes and the regulation of diseases. However, the effects of foods and supplements on miRNA expression in vivo remain unclear. Onion extract tablets (OET) alleviate male menopausal symptoms and stress; however, their effects on miRNA expression in vivo are unknown. Herein, we investigated the effects of OET on miRNA expression in vivo. A randomized, double-blind, placebo-controlled study was conducted on 19 healthy Japanese participants (men and women) aged 30-65 years. Participants consumed either a placebo tablet (PT) or OET which included 30 mg of sulfur-containing amino acids daily for 2 weeks. MiRNAs prepared from plasma samples before and after intake were comprehensively analyzed using next-generation sequencing. A comparison of the variation before and after intake showed that the expression levels of three miRNAs, miR-106b-5p, miR-339-3p, and miR-181b-5p, were significantly increased in the OET group than in the PT group. Receiver operating characteristic analysis of these miRNAs also showed that miR-106b-5p had the highest discriminatory power. To our knowledge, this study is the first to show that consumption of onion extract can modulate miRNA expression in humans.

To investigate the impact of glucocorticoid (GC) exposure on clock gene expression in human skeletal muscle and fat, circadian variations in peripheral interstitial glucose levels, blood pressure, total and bioactive GC levels, and sleep quality.

This study aimed to assess the efficacy of ezetimibe in combination with metformin versus metformin alone in patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes mellitus. Patients were randomly divided into two groups: one receiving ezetimibe and metformin (Met + EZY) and the other receiving metformin alone (Met group) for six months. Parameters were measured at baseline (T1), after three months (T2), and after six months (T3). The findings indicated that insulin levels and HOMA-IR exhibited a significant decrease from T1 to T2 in the Met + EZY group (p < 0.05). Malondialdehyde (MDA) and triglycerides levels also demonstrated significant decreases from T1 to T2 in the Met + EZY group (p < 0.05). The expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and adiponectin (ADIPO) showed a significant increase from T1 to T2 in the Met + EZY group (p < 0.01). Additionally, ADIPO expression showed a significant increase from T1 to T3 (p < 0.001) in both groups. When comparing the two treatment groups, PPAR-γ and ADIPO expression were significantly higher in the Met + EZY group during T2 and T3 compared to the Met group (p < 0.001). Combination therapy appears to be more effective than metformin treatment alone and should be used cautiously.

IL-13 has been implicated as a key contributor to the pathogenesis of eosinophilic esophagitis (EoE) partly on the basis of the finding that cendakimab (a humanized monoclonal anti-IL-13 antibody) significantly improved esophageal eosinophils, endoscopic severity, histology grade and stage, and clinician's assessment of severity in the HEROES phase 2 trial.

This study aimed to investigate whether the consumption of Origanum majorana tea (Omt) affects oxidative stress biomarkers, potentially alleviating symptoms or slowing disease progression in volunteers with idiopathic Parkinson's disease (PD).

Osteoarthritis (OA) is a debilitating disease of joints. Currently, there are no optimal treatment options to cure OA.