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PubMed2026

Non-coding RNAs and Mitochondrial Dysfunction in Alzheimer's Disease: A Systematic Review.

Alzheimer's disease (AD) is responsible for 70% of dementia cases worldwide, with tau hyperphosphorylation and amyloid-β plaque accumulation representing its core pathological hallmarks. Genetic predisposition, oxidative stress, and neuroinflammation contribute to disease onset and progression. Non-coding ribonucleic acids (ncRNAs) are a class of RNAs which control gene expression and whose dysregulation in AD patients has been linked to amyloid production, neuroinflammation, and mitochondrial dysfunction, which ranges from impaired energy metabolism to disrupted mitochondrial biogenesis and dynamics. Our descriptive systematic review surveyed the involvement of ncRNAs in mitochondrial dysfunction in AD across experimental and clinical literature. We identified multiple microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) that directly regulate mitophagy, mitochondrial biogenesis, mitochondrial autophagic, and apoptotic pathways, mitochondrial dynamics, and protein import mechanisms in AD models. Among the most important candidates demonstrating clinical dysregulation, miR-140 and lncRNA NEAT1 regulate mitophagy, while miR-9, miR-34a, miR-146a, miR-155, and miR-485 are implicated in mitochondrial biogenesis and miR-204 in mitochondrial autophagy. LncRNA BDNF-AS, miR-148a-3p, miR-21-5p, and miR-103a-3p emerged as regulators of the mitochondrial apoptosis pathway with confirmed clinical dysregulation. Multiple ncRNAs control mitochondrial dynamics, of which miR-195, miR-124, and miR-455-3p have also been studied in AD patients. Additionally, several ncRNAs were found to indirectly regulate mitochondrial fission, autophagy, and apoptosis, although the underlying mechanisms require further characterization. Thus, while ncRNA-centered AD research is in its early stages, current mechanistic and translational evidence supports mitochondrially relevant ncRNAs as promising candidates for biomarker and therapeutic development.

Alzheimer Disease↗

PubMed2026

Mitochondrial dysfunction in muscle cells induced by snoring vibrations.

Snoring-related vibrations have been proposed as a pathogenic factor contributing to upper airway muscle dysfunction in patients with obstructive sleep apnea (OSA). To investigate whether exposure to snoring vibration is linked to muscle weakness, we used an in vitro vibration model to examine its effects on mitochondrial homeostasis in L6 muscle cells at 8, 12, 24, and 48 h. The findings were then compared with mitochondrial alterations in the upper airway muscles from snorers and patients with OSA. Proteomic analysis of L6 myoblasts revealed extensive remodeling of the mitochondrial proteome at 8 h, affecting pathways involved in oxidative phosphorylation, protein import, ribosome biogenesis, and RNA processing. Respiratory chain remodeling was subunit-specific, with increased abundance of selected components of Complexes I, IV, and V, including NDUFS4, COX5A, and ATP5PD. However, reductions in spliceosome-associated factors, such as SRSF2 and DDX46, along with alterations in mitochondrial ribosomal proteins, indicated impaired RNA processing and protein synthesis. Furthermore, both proteomic and transcriptomic analyses revealed activation of a mechanosensing-mechanotransduction axis, with early upregulation of integrin subunits and mechanosensitive ion channels, followed by transient activation of focal adhesion signaling. Despite transcriptional upregulation of selected Complex IV subunits Cox5a and Cox6a2, this response was accompanied by accumulation of unspliced pre-mRNA, indicating impaired RNA processing efficiency and a decoupling between transcript and protein levels. Real-time Seahorse assay revealed a collapse of mitochondrial respiration and glycolytic reserve at 8 h. Although mitochondrial oxygen consumption recovered after 48 h, the ability to dynamically upregulate glycolysis remained impaired. In patients, muscle capillarization was impaired, COX activity was reduced, and mitochondrial organization was disrupted. Moreover, transcription of Complex IV subunits COX5A and COX6A2 was, as in vibrated L6 cells, upregulated, suggesting a mismatch between transcript levels and protein expression. We conclude that snoring-induced vibrations are an unrecognized stressor that disrupts mitochondrial homeostasis in muscle by impairing RNA processing, protein synthesis, and mechanotransduction-driven mitochondrial remodeling, leading to transcript-protein uncoupling and likely muscle dysfunction.

Humans↗

PubMed2026

Thyroid-joint crosstalk: a systematic review and meta-analysis of thyroid autoimmunity and dysfunction in juvenile idiopathic arthritis.

BACKGROUND: Recent observational studies outlined the concomitant presence of autoimmune diseases in children with juvenile idiopathic arthritis (JIA), including endocrine autoimmunity. Despite the growing evidence of thyroid involvement in JIA, available data are heterogeneous and fragmented. We aimed to systematically review the available evidence on the prevalence of thyroid autoantibody positivity and thyroid dysfunction in patients with JIA. METHODS: PubMed/Medline, Cochrane, and Scopus databases were approached to identify studies reporting data on thyroid autoantibody positivity and dysfunction in children with JIA. RESULTS: A total of 15 studies were included in the final analysis, encompassing 19 015 children with JIA (13 225 females, 69.6%) with a weighted mean age of 8.0 years (range 1.8-21 years). The pooled prevalence estimates of antithyroid antibody positivity and thyroid dysfunction were 0.04 (95% CI: 0.03-0.05) and 0.04 (95% CI: 0.03-0.08), respectively. The risk difference for thyroid autoantibody positivity between children with JIA and controls was 0.08 (95% CI: 0.02-0.14). Possible risk factors were analyzed: the presence of family history for thyroid autoimmune disease (odds ratio - OR 3.91, 95% CI 1.86-8.25), concurrent Antinuclear Antibodies (ANA) positivity (OR 1.62, 95% CI 1.13-2.31), and older age (MD 2.10 years, 95% CI 1.32-2.89) were associated with thyroid autoantibody positivity and/or thyroid dysfunction in children with JIA. No significant difference emerged for the specific JIA form. CONCLUSION: Thyroid dysfunction may be detected in children with JIA, with a significant risk difference in comparison to healthy controls. Specific clinical characteristics, such as family history, ANA positivity, and older age at JIA onset, may suggest which patients should benefit from thyroid autoantibody screening.

Humans↗

PubMed2026

Impact of renal dysfunction on immediate versus staged revascularization of non-culprit lesions in patients with ST segment elevation myocardial infarction: a pre-specified subgroup analysis of the randomized MULTISTARS AMI trial.

BACKGROUND: Renal dysfunction might affect outcomes in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD) undergoing percutaneous coronary intervention (PCI). METHODS: In MULTISTARS AMI, patients with STEMI and MVD were randomized to immediate or staged PCI of non-culprit lesions. In this pre-specified analysis, patients were stratified according to the presence of renal dysfunction at baseline, defined at an estimated glomerular filtration rate (eGFR) of 60 ml/min/1.73 m2. Patients with an eGFR < 30 ml/min/1.73 m2 were excluded from the trial. The primary endpoint was a composite of death, non-fatal myocardial infarction, stroke, unplanned revascularization, or hospitalization for heart failure at 1 year. RESULTS: In MULTISTARS AMI, 108 (13%) of 832 patients had renal dysfunction. The primary endpoint occurred more frequently in patients with renal dysfunction (19.4% vs. 11.2%, unadjusted HR 1.82, 95% CI 1.13-2.94), primarily driven by higher rates of death. Among patients with renal dysfunction, the rates of the primary end point were 14.5% and 24.5% in the immediate and staged PCI groups (unadjusted HR 0.55, 95% CI 0.23-1.33). There was no interaction between renal dysfunction and the randomized treatment assignment with respect to the primary end point (adjusted HR 1.30, 95% CI 0.8-2.20, pint 0.82). The occurrence of acute renal insufficiency was statistically similar in patients with renal dysfunction who underwent immediate and staged PCI (10.9% vs. 18.9%, unadjusted HR 0.61, 95% CI 0.22-1.72, pint 0.09). Renal dysfunction at baseline emerged as a strong risk factor for the development of acute renal insufficiency (adjusted HR 5.0, 95% CI 2.30-10.70, p < 0.01). CONCLUSIONS: Outcomes with immediate compared to staged multivessel PCI did not appear significantly altered by the presence of renal dysfunction at baseline. (Supported by Boston Scientific; MULTISTARS AMI ClinicalTrials.gov number, NCT03135275).

Humans↗

PubMed2026

A Dynamic Nomogram to Predict Metabolic Dysfunction-Associated Fatty Liver Disease in Patients with Metabolic Syndrome.

BACKGROUND: Metabolic syndrome (MetS) involves multiple metabolic disorders. This study aimed to identify high-risk populations for metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with MetS and to establish a dynamic predictive nomogram. METHODS: A total of 627 patients with MetS from six regions in Zhejiang Province were enrolled and categorized into MAFLD and non-MAFLD groups, then randomly assigned to training and validation sets at a ratio of 7:3. Independent predictors of MAFLD were identified using least absolute shrinkage and selection operator regression and multivariable logistic regression analyses. These predictors were then used to construct a dynamic nomogram. RESULTS: A total of 627 patients with MetS were included in the final analysis, of whom 77.0% (483/627) were diagnosed with MAFLD. Multivariable logistic regression analysis identified body mass index (BMI), waist circumference (WC), total cholesterol (TC), alanine aminotransferase (ALT), MetS-defined dysglycemia, and education level as independent risk factors for MAFLD. MetS-defined dysglycemia showed the highest odds ratio (OR) for MAFLD development [OR = 1.87, 95% confidence interval (CI): 1.07-3.29]. Although the number of MetS components and the metabolic syndrome score were significantly associated with MAFLD in univariate analysis, they were not independently associated with MAFLD in the multivariate model. A dynamic nomogram for predicting MAFLD risk in patients with MetS was developed and internally validated. The area under the receiver operating characteristic curve was 0.834 (95% CI: 0.787-0.880) in the training set and 0.839 (95% CI: 0.771-0.899) in the validation set, indicating strong predictive performance. Bootstrap internal validation demonstrated good agreement between predicted and observed outcomes in calibration curves. Decision curve analysis further indicated favorable clinical applicability of the nomogram. CONCLUSION: BMI, WC, TC, ALT, MetS-defined dysglycemia, and education level are independent risk factors for MAFLD. A dynamic nomogram for predicting MAFLD risk in patients with MetS was successfully developed and validated.

Humans↗

PubMed2026

Efficacy of dapagliflozin on hepatic steatosis and fibrosis in patients with type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease: a pre-specified single-arm analysis from a randomized controlled trial.

AIM: To evaluate the association of dapagliflozin therapy with changes in hepatic steatosis and non-invasive fibrosis surrogate markers in patients with type 2 diabetes mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) over 12 months. METHODS: This is a pre-specified single-arm analysis from a randomised, open-label, parallel-group trial. Of 54 participants randomised to dapagliflozin 10 mg daily, 50 (92.6%) completed the 12-month follow-up and were included in the per-protocol analysis. Assessments at baseline, 3, 6, and 12 months included transient elastography (CAP and LSM), ultrasonography, and biochemical tests. Primary endpoints were changes in hepatic steatosis (CAP) and non-invasive fibrosis surrogates (LSM). RESULTS: Significant reductions were observed in hepatic steatosis (CAP: 316.7 to 245.7 dB/m; mean change - 71.02 dB/m, 95% CI: -63.4 to - 78.6; p < 0.001) and in liver stiffness as a non-invasive fibrosis surrogate (LSM: 8.59 to 7.28 kPa; mean change - 1.31 kPa, 95% CI: -0.92 to - 1.70; p < 0.001). Improvements were also observed in glycaemic control, body weight, lipid profile, liver enzymes, ultrasonographic steatosis grading, and serum fibrosis markers. Genitourinary infections were the most frequently reported adverse events (32%); no serious adverse events were recorded. CONCLUSIONS: Dapagliflozin was associated with significant improvements in hepatic steatosis, non-invasive fibrosis surrogate markers, metabolic parameters, and liver function in T2DM patients with MASLD over 12 months. These findings provide region-specific evidence for an Indian population and support further controlled investigation. However, these findings should be interpreted in light of the pre-specified single-arm design of this analysis, the open-label methodology, relatively small sample size, and the absence of liver biopsy confirmation.

Humans↗

PubMed2026

Protein sorting and proteostasis mechanisms in CFTR-related exocrine pancreas dysfunction: A systematic narrative review.

The pancreas consists of exocrine and endocrine compartments. In the exocrine pancreas, cystic fibrosis transmembrane conductance regulator (CFTR) functions mainly in ductal epithelial cells as a chloride and bicarbonate channel. Its activity depends on proper protein folding, trafficking, and localization to the apical membrane. This systematic narrative review aims to synthesize the available evidence on the role of protein sorting machinery in CFTR channelopathies and its contribution to exocrine pancreatic dysfunction. A thorough search was conducted using PRISMA criteria on PubMed, Wiley Online Library, and Scopus for studies published in English between January 2000 and November 2025. Twenty studies that met the inclusion criteria were included in this review. Pathogenic CFTR variants impair protein folding, endoplasmic reticulum (ER) exit, and endosomal recycling, resulting in reduced apical membrane expression and stability. These defects disrupt the localization of associated transporters and secretory proteins, impair ductal bicarbonate secretion, alter zymogen handling, and promote acinar injury, although these claims are supported mainly by indirect experimental models and therefore require clinical confirmation. CFTR channelopathies in the exocrine pancreas encompass both ion transport defects and broader disruptions of protein sorting machinery. CFTR may contribute to the assembly, stabilization, or localization of selected apical transport complexes, and its loss can secondarily alter epithelial organization. Therapeutic approaches targeting both channel correction and intracellular trafficking may improve pancreatic function and mitigate disease progression.

Humans↗

PubMed2026

Hypothalamic-Pituitary Axis Involvement in Primary Central Nervous System Lymphoma.

CONTEXT: Primary central nervous system lymphoma (PCNSL) is a rare malignancy that may involve the hypothalamic-pituitary axis (HPA), leading to underrecognized but clinically significant endocrine dysfunction. OBJECTIVE: This work aims to characterize the spectrum and patterns of HPA-related endocrine disturbances in patients with PCNSL. DATA SOURCES: A systematic search was conducted in PubMed, EMBASE, Scopus, and Web of Science, supplemented by gray literature. The search concluded in February 2025. STUDY SELECTION: We included studies reporting adult PCNSL cases with documented dysfunction of at least one hormonal axis. Exclusion criteria were preexisting hypopituitarism or lack of endocrine data. DATA EXTRACTION: Data on demographics, tumor localization, hormonal axes affected, radiological findings, treatment, and outcomes were extracted. Risk of bias was assessed using JBI tools. RESULTS: Ninety-nine cases met the inclusion criteria. Diffuse large B-cell lymphoma accounted for 84% of cases. Endocrine dysfunction included isolated adenohypophyseal involvement (46%), neurohypophyseal (8%), and combined (45%). The most affected pituitary axes were the gonadal and thyroid axes, with 89.7% and 89.2% involvement, respectively. Hypothalamic tumors were strongly associated with combined dysfunction (odds ratio = 9.47; 95% CI, 3.76-23.86; P < .001). Persistent endocrinopathy was more frequent in progressive disease. No direct association was found between endocrine dysfunction and mortality. CONCLUSION: HPA dysfunction in PCNSL is frequent and often underdiagnosed. Hypothalamic involvement is associated broader hormonal impairment. Routine hormonal screening and multidisciplinary management should be standard in PCNSL care to minimize complications and improve outcomes.

Humans↗

PubMed2026

Differential contributions of mt-Tr and Cs variants to developmental cochlear defects and mitochondrial dysfunction in A/J mice.

A/J mice exhibit early-onset hearing loss linked to Cdh23, mitochondrial tRNA-Arg (mt-Tr), and citrate synthase (Cs) variants. Although developmental cochlear defects have been identified in juvenile A/J mice, the hierarchical contributions of mt-Tr versus Cs remain unclear. Using reciprocal intercross-derived strains to decouple mitochondrial haplotypes from nuclear factors, we demonstrate that the mitochondrial background is the primary determinant of auditory dysfunction. Mice with A/J mtDNA (AXB strains) displayed significantly higher ABR thresholds, accelerated hair cell attrition, and severe stereocilia dysmorphology compared to those with B6 mtDNA (BXA strains), occurring largely independently of the Cs genotype. While the Cs mutation exacerbated hearing loss, its impact was secondary to that of the dominant mitochondrial background. Systemic behavioral assessments and mitochondrial assays confirmed that A/J mitochondria exert a more profound metabolic impact than the Cs mutation. Our findings establish that the mitochondrial genomic background, with the mt-Tr locus as a prominent candidate variant, serves as the principal driver of developmental cochlear defects and early-onset hearing loss in A/J mice, while the nuclear Cs mutation acts as a synergistic modifier. This study underscores the critical role of mitonuclear crosstalk in inner ear maturation and provides new insights into the etiology of hereditary hearing loss.

Animals↗

PubMed2026

Metabolic Stress Testing Reveals Persistent Lipid-Handling Dysfunction in Women With Polycystic Ovary Syndrome Despite Exercise Training.

AIM: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and metabolic dysfunction, yet baseline metabolomic studies show inconsistent findings. We investigated whether metabolic abnormalities in PCOS emerge under physiological stress and how these responses are modified by exercise training. MATERIALS AND METHODS: Twelve women with PCOS and 10 controls completed hyperinsulinaemic-euglycaemic clamps with randomised saline or lipid infusion, before and after 8 weeks of supervised exercise. Plasma metabolomics (163 metabolites) were measured at baseline, post-infusion and post-clamp. Linear mixed-effects models assessed Group × Timepoint × Intervention interactions. RESULTS: No baseline metabolite differences were observed between groups. A significant three-way interaction (p = 0.008) indicated condition-dependent trajectory divergence. Post hoc analysis revealed a specific divergence during post-exercise lipid challenge (p = 0.048). Women with PCOS showed reduced suppression of ether-linked phosphatidylcholines during insulin-stimulated lipid loading (PC ae C44:4, p = 0.031), despite exercise-induced improvements in fitness and normalisation of amino acid profiles. Exploratory metabolite ratios suggested impaired substrate coordination under stress. CONCLUSIONS: Metabolic defects in PCOS are stress-dependent and not detectable at rest. Exercise training improves resting metabolism but reveals persistent impairment in adaptive lipid handling during combined insulin and lipid challenges, suggesting impaired coordination of substrate supply during metabolic stress. TRIAL REGISTRATION: ClinicalTrials.gov identifier: ISRCTN42448814.

Humans↗

PubMed2026

Impaired toilet training and bladder and bowel dysfunction in children with developmental coordination disorder - an underreported issue.

BACKGROUND & OBJECTIVE: Children with Developmental Coordination Disorder (DCD) face significant, yet often overlooked, challenges beyond motor impairments, including difficulties with toilet training and bladder and bowel dysfunctions (BBD). This study aims to explore whether children with DCD exhibit greater difficulties in these areas compared to typically developing children (TDC). METHOD: This cross-sectional case-control study included 84 children aged 5-8 years (42 DCD, 42 TDC), matched by school-grade and sex (33 boys and 9 girls per group). Parents completed the Vancouver Symptom Score for Dysfunctional Elimination Syndrome (VSSDES) to assess BBD symptoms, the Dutch DCD-questionnaire (DCD-Q) to evaluate motor coordination, and additional questions regarding toilet training, elimination diagnosis, and co-occurring conditions. Correlations and exploratory group differences were analysed. RESULTS: Parents of children with DCD reported significantly more toilet training difficulties than parents of controls (p < 0.001), including persistent accidents (47.6% vs. 9.5%), prolonged training (45.2% vs. 4.8%), and difficulties recognizing urination urgency (40.5% vs. 2.4%). The parental report of delayed attainment of bowel and bladder control (p < 0.05) and BBD rates (p < 0.001) was also significantly higher in children with DCD. Exploratory analyses indicated that the prevalence of these outcomes was not significantly different between children with DCD with and without co-occurring ADHD or autism, suggesting a possible primary association with DCD. Additionally, across both children with DCD and TDC, poorer motor skills were associated with more BBD symptoms (r = -0.474, p < 0.001). CONCLUSION: Children with DCD have a higher prevalence of toilet training difficulties and BBD compared to TDC, potentially affecting their psychosocial well-being. Greater awareness is crucial for timely and targeted care. Notably, the study's design, directly comparing children diagnosed with DCD to matched TDC, provides new insights into the prevalence of elimination difficulties in this population.

Humans↗

PubMed2026

Efficacy and Safety of Bimagrumab in Adults With Obesity and Metabolic Dysfunction: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

AIMS: This study aims to systematically evaluate the efficacy of bimagrumab on body composition and glucose parameters in adults with obesity and metabolic dysfunction and its safety profile. METHODS: We searched MEDLINE, PubMed, Embase, and the Cochrane Library on April 20, 2026, for randomized controlled trials (RCTs) assessing bimagrumab treatment in adults with obesity, insulin resistance, or type 2 diabetes mellitus (T2DM). The risk of bias was assessed using the Cochrane Risk of Bias tool (RoB 2), and meta-analyses of efficacy and safety data were conducted using R software. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system was used to assess the strength of evidence. The study was registered with PROSPERO (CRD420261377110). RESULTS: Of the 134 retrieved records, 4 RCTs (enrolling 268 participants) were included. The included population represented a broad spectrum of metabolic dysfunction, from obesity and nondiabetic insulin resistance to established T2DM. Compared with placebo, bimagrumab treatment significantly reduced total weight (mean difference [MD] -4.85 kg, 95% confidence interval [CI] -6.82 to -2.88), fat mass (-4.72 kg [-8.05 to -1.40]), and glycated haemoglobin (HbA1c) (-0.13% [-0.23 to -0.03]) and significantly increased total lean mass (1.66 kg [0.81 to 2.51]). However, bimagrumab led to an increase in low-density lipoprotein (LDL) concentrations of 0.47 mmol/L [0.03 to 0.91] and significantly increased incidences of discontinuation (risk ratio [RR] 5.75 [1.61 to 20.46]), muscle spasms (RR 10.44 [4.23 to 25.75]), and diarrhoea (RR 4.91 [2.38 to 10.11]). CONCLUSION: Bimagrumab effectively reversed adverse effects on body composition in obese individuals, resulting in significant fat reduction, increased skeletal muscle mass, and improved glycemic control, suggesting that bimagrumab is a promising new target for personalized metabolic therapy.

Humans↗

PubMed2026

Incidence of Cirrhosis in Fibrotic Metabolic Dysfunction-Associated Steatohepatitis: A Meta-Analysis of Placebo Arms from Randomized Clinical Trials.

BACKGROUNDS AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) with stage F2-F3 fibrosis represents the main target population for emerging pharmacotherapies. However, data on short-term progression to cirrhosis (F4) in this group remain limited. We aimed to evaluate the incidence of cirrhosis in placebo-treated patients with fibrotic MASH in randomized controlled trials (RCTs). METHODS: In this single-arm meta-analysis, we systematically searched PubMed and Cochrane Library from inception to December 13, 2024, for pharmacological Phase ≥ 2 RCTs reporting cirrhosis events (detected in liver biopsy or clinical signs) among patients with fibrotic MASH receiving placebo. Incidence rates were pooled using generalized linear mixed models with Clopper-Pearson confidence intervals (CIs). RESULTS: We identified a total of 11 RCTs, including 586 patients with fibrotic MASH. Total follow-up was 657.23 person-years (PYs), with 83 cirrhosis events reported. The pooled incidence rate was 13.09 per 100 PYs (95% CI 7.81 to 21.12, I2 = 75.6%, τ2 = 0.682). In subgroup analysis, the incidence of cirrhosis was 3.40 per 100 PYs in MASH F2 (95% CI 1.10 to 10.02, I2 = 0%, τ2 = 0) and 17.90 per 100 PYs (95% CI 10.63 to 28.55, I2 = 70.2%, τ2 = 0.561) in MASH F3, with significant differences between stages (p = 0.006). Sensitivity analyses showed consistent estimates. Most RCTs were judged to have a low risk of bias. CONCLUSIONS: This study provides stage-specific data on cirrhosis incidence in fibrotic MASH, highlighting the high short-term risk associated with MASH F3 in trial settings. These data may inform benchmarks to guide event expectations, enrichment strategies, sample size assumptions, and the interpretation of future MASH clinical trials.

Humans↗

PubMed2026

Targeted Nrf2 activation improves vascular endothelial function with aging and prevents vascular dysfunction following disuse in younger and older adults.

Aging and physical inactivity/disuse contribute to cardiovascular disease, which is attributable, in part, to vascular endothelial dysfunction associated with impaired nuclear-factor erythroid 2-related factor 2 (Nrf2) signaling. However, the ability to augment Nrf2 activation and its effects on age- and disuse-related vascular dysfunction in humans remains limited. In a double-blind, randomized, placebo-controlled study design 20 younger adults (8M/12F, age 27 ± 7 y) and 24 older adults (12M/12F, age 67 ± 8 y) were randomized to receive either placebo or PB125 (200 mg/day, Nrf2 activator) across three visits: baseline, 2 weeks of supplementation, and following either 5 days of bed rest (old) or 2 weeks of limb immobilization (young). Brachial and popliteal artery flow-mediated dilation (FMD), passive leg movement-induced (PLM) leg blood flow (LBF) and vascular conductance (LVC) and serum antioxidant status (superoxide dismutase, SOD) were assessed at each timepoint. Compared to placebo, 2 weeks of PB125 increased brachial (PB125: 2.8 ± 1.5 to 3.8 ± 1.3%, p < 0.0001) and popliteal FMD (PB125: 1.5 ± 1.5 to 2.3 ± 1.4%, p = 0.033) in older, but not younger adults (both, p > 0.27). During bed rest, PB125 preserved brachial (3.8 ± 1.3 to 3.6 ± 1.4%, p = 0.543) and popliteal FMD (2.3 ± 1.4 to 2.7 ± 1.4%, p = 0.269), LVC (1.1 ± 0.8 to 1.1 ± 1.5 AUC, p = 0.530) and circulating SOD concentrations (28.3 ± 7.2 to 28.6 ± 8.6 U/mL, p = 0.888) in older adults compared to placebo (all, p < 0.05). Following limb immobilization, PB125 preserved popliteal FMD (4.4 ± 2.8 to 3.4 ± 1.8%, p = 0.302) in younger adults compared to placebo (p < 0.05). These findings demonstrate targeted Nrf2 activation with PB125 improves age-related vascular endothelial dysfunction while preserving vascular function and antioxidant capacity following periods of disuse.

Humans↗

PubMed2026

Effects of multistrain probiotic supplementation on hepatic function and anthropometric parameters in patients with metabolic dysfunction-associated steatotic liver disease: a double-blind, randomized controlled trial.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly prevalent on a global scale. The gut microbiota is integral to its pathogenesis, prompting extensive research into microbiota modulation as a potential adjunctive therapeutic strategy. AIM: The study aimed to evaluate the effect of multistrain probiotics supplementation on hepatic function in patients with MASLD in a double-blind, randomized, controlled trial. The primary outcomes were changes in Fibrosis-4 index (FIB-4) and fatty liver index (FLI). Secondary outcomes included changes in anthropometric parameters, selected biochemical markers, and other liver-related indices. METHODS: A total of 64 patients with MASLD were randomly assigned to two groups receiving either placebo (C) or a probiotic mixture (PRO) containing the following bacterial strains: 50% Lactococcus lactis Rosell-1058, 25% Lacticaseibacillus casei Rosell-215, 12.5% Lactobacillus helveticus Rosell-52, 12.5% Bifidobacterium bifidum Rosell-71 for 12 wk. RESULTS: Significant group × time interactions were observed for FIB-4 (Q = 0.007), with reduction in the PRO group and increase in the C group (-0.05 vs. 0.10; P = 0.002). No significant interaction was found for FLI (Q = 0.942). Significant group × time interactions were also observed for aspartate aminotransferase (-2.87 vs. 1.87 U/L; Q = 0.003) and APRI (-0.03 vs. 0.02; Q = 0.001), favoring the PRO group (P < 0.001 for both). No significant changes were observed in anthropometric parameters, glucose levels, or lipid profile. CONCLUSIONS: In patients with MASLD, the 12-wk probiotic supplementation had a modest but statistically significant effect on FIB-4, aspartate aminotransferase, and APRI, with no significant effect on FLI or anthropometric and metabolic parameters. These findings suggest that this probiotic formulation may have potential benefits for liver function in MASLD. However, long-term studies incorporating imaging-based and histological endpoints are required to determine the clinical significance of these findings.

Humans↗

PubMed2026

Premeal insulin administration lowers postprandial blood glucose and increases myocardial microvascular blood flow in people with type 1 diabetes: a randomised, crossover clinical trial.

AIMS/HYPOTHESIS: We aimed to evaluate whether prandial insulin timing affects vascular function in people with type 1 diabetes. Our hypothesis was that premeal insulin administration would lead to greater myocardial microvascular blood flow (MBF) via blunting postprandial hyperglycaemia. METHODS: People with type 1 diabetes between 18 and 35 years of age with BMI <30 kg/m2 underwent two protocols with a 1:1 randomised crossover design wherein prandial insulin was injected either 15 min before or 15 min after meal intake began. To provide a physiological comparison, age-, sex- and BMI-matched control participants completed one study where they consumed the same meal but received no exogenous insulin. Glucose, insulin, vascular function (including ultrasound measures of myocardial and skeletal muscle microvascular perfusion, aortic stiffness, brachial artery endothelial function) and biomarkers of systemic inflammation and endothelial dysfunction were assessed at baseline and then 2 h after meal ingestion within each protocol. The primary outcome was change in myocardial MBF within each protocol. Study personnel assessing outcomes were masked to group assignment. RESULTS: Eighteen people with type 1 diabetes and 18 matched control participants were analysed within each protocol. Glucose area under the curve was significantly greater (p=0.015) in the postmeal insulin study compared with the premeal insulin study in participants with type 1 diabetes. Myocardial microvascular flow velocity significantly increased (p=0.031) with premeal insulin administration in people with type 1 diabetes and this consequently led to greater myocardial MBF (p=0.044). There were no changes in myocardial MBF within the other protocols. Changes in vital signs were similar between all protocols. CONCLUSIONS/INTERPRETATION: Appropriately timed premeal insulin led to lower postprandial blood glucose along with increased myocardial MBF in people with type 1 diabetes. Further work is needed to determine the underlying aetiology of these changes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04730882.

Humans↗

PubMed2026

High-Dose Intravenous Vitamin C and Mortality and Organ Dysfunction in Severe Burn Injury: The VICTORY Randomized Clinical Trial.

IMPORTANCE: Severe burn injury triggers systemic inflammation that can lead to multiple organ dysfunctions and death. High-dose intravenous vitamin C has been proposed to mitigate these effects, but strong evidence in patients with burn injury is lacking. OBJECTIVE: To evaluate the efficacy of high-dose intravenous vitamin C in patients with severe burn injury. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled phase 3 trial conducted across 24 burn centers in North, Central, and South America; Europe; and Asia. Adults (≥18 years) with deep second- and/or third-degree burns covering 20% or more of total body surface area and requiring skin grafting were enrolled between August 18, 2020, and September 12, 2025. Final follow-up was completed in March 2026. The trial was stopped early after the first prespecified interim analysis for futility/harm. INTERVENTIONS: Patients were randomly assigned (1:1) to receive intravenous vitamin C (50 mg/kg every 6 hours for 96 hours) or matched placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of 28-day mortality and persistent organ dysfunction (defined as dependence on mechanical ventilation, kidney replacement therapy, or vasopressor/inotrope support at day 28). The main secondary outcome was time to discharge alive from hospital within 90 days. RESULTS: Among 238 patients enrolled (mean age, 48.9 [SD, 19.1] years; 79% male; mean total body surface area, 37.0% [SD, 14.6%]), 120 were assigned to vitamin C and 118 to placebo. The primary composite outcome occurred in 49 patients (40.8%) in the vitamin C group and 35 patients (29.7%) in the placebo group (adjusted risk ratio [RR], 1.28 [95% CI, 0.99-1.65]; P = .06), crossing the prespecified futility/harm threshold and prompting early trial termination. Time to discharge alive from hospital within 90 days was not improved (adjusted subdistribution hazard ratio, 0.85 [95% CI, 0.62-1.16]; P = .31). Twenty-eight-day mortality was higher in the vitamin C group (15.0% vs 7.6%; adjusted RR, 1.96 [95% CI, 1.32-2.90]; P = .001), as was hospital mortality (23.3% vs 16.1%; adjusted RR, 1.44 [95% CI, 1.03-2.00]; P = .03). CONCLUSIONS AND RELEVANCE: Among patients with severe burn injury, high-dose intravenous vitamin C did not reduce 28-day mortality and persistent organ dysfunction and is possibly harmful. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04138394.

Humans↗

PubMed2026

Ultra-high-field 7T MRI reveals neural abnormalities of attention networks in relation to cognitive impairment in hypertension.

Hypertension is a significant risk factor for cognitive impairment (CI), yet the corresponding neural network abnormalities remain underexplored. In this study, we examined the associations among global and domain-specific cognitive dysfunction, neuroimaging measures, and blood pressure in a subgroup of hypertensive patients with CI (N = 41) from a randomized controlled trial who underwent ultra-high-field 7 T MRI. Structural atrophy related to CI was localized to regions overlapping the attention networks. Both whole-brain and within-network dysfunction of the attention networks were associated with worse global cognitive performance. Notably, hyperconnectivity within key attention network hubs, including the right anterior insula and posterior intraparietal sulcus, was associated with declined processing speed in hypertensive patients, mediating the association between pulse pressure and processing speed. These findings provide new insights into the neural pathophysiology of hypertension-related CI and suggest potential network-based targets for intervention.

Magnetic Resonance Imaging↗