In a randomised controlled trial (RCT), we compared the effects of treatment with furosemide + small volumes of hypertonic saline solution (HSS) with those of furosemide alone in patients with decompensated heart failure (HF), and their effects on inflammatory and remodelling markers and epigenetic signatures.

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.

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.

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.

About 15-20% of breast cancers (BC) overexpress Human Epidermal Growth Factor Receptor 2 (HER2+), and 50% of them are also oestrogen receptor positive (ER+). Patients with ER+/HER2+ BC with a limited response to systemic therapies are at an increased risk of relapse, thus understanding the mechanisms of resistance is crucial. This study investigates the changes in gene signature expression (ΔGSE) within ER+/HER2+ tumours and their intrinsic subtype (IS) in response to peri-operative aromatase inhibitors (POAI).

People with human immunodeficiency virus (HIV, PWH) exhibit increased cardiovascular disease (CVD) risk and accelerated biological aging. REPRIEVE demonstrated that pitavastatin reduced major adverse cardiovascular events (MACE) in antiretroviral therapy (ART)-treated PWH with low-to-moderate traditional cardiovascular risk. It remains unknown whether statin therapy can modulate epigenetic aging in PWH.

Ovarian cancer is among the most lethal malignancies in women. The advent of PARP inhibitors (PARPi) has improved outcomes. However, treatment-related toxicity remains a critical challenge, impacting patient quality of life and treatment adherence.

Metformin reduces the incidence of breast cancer in patients with obesity and type 2 diabetes. However, our knowledge of the effects of metformin on breast cancer recurrence is limited. Within the randomized double-blind placebo-controlled phase II trial MetBreCS, we examined changes in breast tissue from breast cancer survivors with BMI > 25 kg/m2 after treatment with metformin. To identify metformin-regulated signaling pathways, we integrated the transcriptomic, metabolomic and steroid hormone profiles using bivariate and functional analyses. We identified MS4A1, HBA2, MT-RNR1, MT-RNR2, EGFL6 and FDCSP expression to be differentially expressed in breast tissues from metformin-treated postmenopausal women. The integration of transcriptomic and metabolomic profiles revealed down-regulation of immune response genes associated with reduced levels of arginine and citrulline in the metformin-treated group. The integration of transcriptomic and steroid hormone profiles showed an enrichment of steroid hormone biosynthesis and metabolism pathways with highly negatively correlated CYP11A1 and CYP1B1 expression in breast tissue from postmenopausal metformin-treated women. Our results indicate that postmenopausal breast cancer survivors treated with metformin have specific changes in breast tissue gene expression that may prevent the development of new tumors.Trial registration: MetBreCs trial is registered at European Union Clinical Trials Register (EudraCT Protocol # 2015-001001-14) on 07/10/2015.

Cholangiocarcinoma (CCA) is one of the most aggressive cancers with a poor prognosis. Current treatment strategies involve hepatobiliary surgery, chemotherapy, radiotherapy, and supportive care; however, the success of these treatments remains limited. Therefore, this study investigated the potential of Atractylodes lancea (Thunb) D.C. (AL) in limiting the progress of CCA by targeting the expression of cancer-related genes involved in immune responses and circulating tumor cells. The study was part of Phase 2A clinical trial in advanced-stage intrahepatic iCCA (iCCA) patients: Group 1 (n = 16) received low-dose AL (capsule formulation of the standardized extract of AL: CMC-AL) with standard supportive care, Group 2 (n = 16) received high-dose AL with standard supportive care, and Group 3 (n = 16) received standard supportive care alone. Venous whole blood samples (EDTA, 5 ml) were collected from each patient on Day 1 and Day 90 and the non-CCA subjects (n = 16) on Day 1. Fifty-nine samples (48 and 11 samples for Day 1 and Day 90, respectively) were processed for total RNA isolation. Gene expression was evaluated using reverse transcription followed by a PCR array. Regardless of dosage, gene expression patterns in the AL-treated groups closely resembled those of the healthy subjects. Specifically, cancer-associated genes, including VEGF-A, NR4A3, Ki-67, and EpCAM, were significantly down-regulated. Additionally, the expression levels of immune-related genes were modulated in AL-treated patients. The treatment groups exhibited lower levels of the pro-inflammatory cytokine IL-6, increased expression of the anti-inflammatory cytokine IL-10, and cell-mediated immune-related molecules such as CTLA4 and PFR1. These findings suggest the potential of AL for iCCA treatment. However, additional studies are required to confirm the correlation between gene and protein expression profiles, as well as CTCs profile.

Coronavirus disease 2019 (COVID-19) has been associated with impaired endothelial and vascular function. We investigated whether intervention with glycocalyx dietary supplement (GDS), containing glucosamine sulfate and fucoidan, improves endothelial glycocalyx and vascular function after COVID-19 infection.

CDK4/6 inhibitors (CDK4/6i) combined with hormone therapies have demonstrated clinical benefit in HR+, HER2- breast cancer patients. However, the onset of resistance remains a concern and highlights a need for therapeutic strategies to improve outcomes. The objective of this study was to develop an in vitro model to better understand the mechanisms of resistance to CDK4/6i + hormone therapies and identify therapeutic strategies with potential to overcome this resistance.

Progesterone supplementation reverses 83% of transcript changes in the secretory endometrium induced by postovulatory mifepristone, potentially mitigating its antiprogestogenic effects.