Search Results (25,874)

Background/Objectives: Insulin resistance (IR) is a relevant metabolic concern in patients with rheumatic diseases; however, data regarding its clinical influence on the systemic sclerosis (SSc) phenotype is lacking. This study aimed to evaluate the characteristics of patients exhibiting IR in a monocentric SSc cohort. Methods: We conducted a cross-sectional study on 178 SSc patients, stratified according to the presence of IR, defined as a HOMA-IR value >1.85 for men and >2.07 for women, based on thresholds previously validated in the Estudio Epidemiológico de la Insuficiencia Renal en España (EPIRCE) cross-sectional study. The rationale for applying the current cut-offs is based on its discriminative potential when using sex- and age-specific thresholds in a nondiabetic population. This approach is particularly applicable to SSc, where the prevalence of diabetes is very low and the median ages of the two cohorts are comparable. Data collected included demographic-, clinical-, laboratory-, pulmonary function-, capillaroscopic-, and treatment-related parameters. A multivariable logistic regression model was used to identify independent predictors of IR. Results: Patients with IR (n = 76) had a significantly higher prevalence of diffuse cutaneous subset (26.3% vs. 11.8%, p = 0.012) and interstitial lung disease (39.5% vs. 17.6%, p = 0.001), along with the positivity for anti-Scl70 antibodies and the current presence of musculoskeletal symptoms (p = 0.021) and digital ulcers (p = 0.037). As expected, body mass index (BMI) was significantly higher in the IR population (24.6 ± 5.2 vs. 22.9 ± 4.1, p = 0.012), along with fasting glucose, insulin, HOMA-IR, and HbA1c levels. IR patients exhibited higher percentages of dyslipidemia and liver steatosis. Medications such as hydroxychloroquine, statins, and Iloprost were more frequently used in the IR group; as for corticosteroids usage (21.1% vs. 5.9%, p = 0.002), however, cumulative glucocorticoid dosage did not differ between the groups. In multivariable analysis, BMI (OR 1.09; p = 0.038) and interstitial lung disease (ILD) (OR 3.03; p = 0.034) were independent predictors of IR. Conclusions: In SSc, IR is associated with ILD, digital ulcers, musculoskeletal involvement, and anti-Scl70 autoantibodies. Full article

Background: Sarcopenia is a clinically important complication of chronic liver disease (CLD), but its underlying mechanisms may differ according to disease etiology. Quantitative MRI biomarkers, including proton density fat fraction (PDFF) and magnetic resonance elastography (MRE), may help characterize etiology-specific patterns of muscle loss. This study aimed to explore etiology-specific associations between MRI-derived biomarkers and sarcopenia, with a particular focus on metabolic dysfunction-associated steatohepatitis (MASH) and viral hepatitis. Methods: This retrospective single-center study included 131 CLD patients (77 with MASH, 54 with viral hepatitis) who underwent MRI, including PDFF and MRE. Sarcopenia was defined by L2 skeletal muscle index thresholds (<42 cm²/m² for men, <38 cm²/m² for women). Muscle identification was performed by automatic threshold-based segmentation by a single observer. Multivariable logistic regression analyses incorporating interaction terms were performed to evaluate whether associations between MRI biomarkers and sarcopenia differed by etiology. Results: Sarcopenia was present in 56% of patients. In the overall cohort, older age (OR = 1.05, p = 0.01), lower PDFF (OR = 0.93, p = 0.03), and lower liver stiffness (OR = 0.51, p = 0.006) were independently associated with sarcopenia. A significant interaction between BMI and disease etiology was observed (p = 0.02). Subgroup analyses suggested that in MASH, sarcopenia was associated with aging, hepatic fat depletion, and lower stiffness. In contrast, in viral hepatitis, it tended to be associated with higher stiffness and lower BMI. Conclusion: MRI-derived hepatic fat and stiffness reflect distinct etiologic patterns of sarcopenia in CLD—metabolically depleted in MASH and fibrosis-related in viral hepatitis. These findings suggest that sarcopenia in MASH and viral hepatitis may reflect different underlying phenotypic patterns, highlighting the importance of considering disease etiology in imaging-based sarcopenia assessment. The results should be interpreted as hypothesis-generating and warrant validation in prospective studies. Full article

Background/Objectives: Vedolizumab (VDZ), a monoclonal antibody targeting α4β7 integrin, is used in Crohn’s disease (CD) management, yet patients’ responses vary, underscoring the need for pharmacogenomic (PGx) markers. This study aimed to identify PGx pathways associated with suboptimal VDZ response using a rare-variant analytical framework. Methods: DNA from 63 CD patients treated with VDZ as first-line advanced therapy underwent whole-exome sequencing. Clinical response at week 14 classified patients as optimal responders (ORs) or suboptimal responders (SRs). Sequencing data were processed using GATK Best Practices, annotated with variant effect predictors, and filtered for rare damaging variants (damaging missense and high-confidence loss-of-function; minor allele frequency < 0.05). Variants were mapped to genes specific for SRs and ORs, and analyzed for pathway enrichment using the Reactome database. Rare-variant burden and composition differences were assessed with Fisher’s exact test and SKAT-O gene-set association analysis. Results: Suboptimal VDZ response was associated with pathways related to membrane transport (ABC-family proteins, ion channels), L1–ankyrin interactions, and bile acid recycling, while optimal response was associated with pathways involving MET signaling. SKAT-O identified lipid metabolism-related pathways as significantly different—SRs harbored variants in pro-inflammatory lipid signaling and immune cell trafficking genes (e.g., PIK3CG, CYP4F2, PLA2R1), whereas ORs carried variants in fatty acid oxidation and detoxification genes (e.g., ACADM, CYP1A1, ALDH3A2, DECR1, MMUT). Conclusions: This study underscores the potential of exome-based rare-variant analysis to stratify CD patients and guide precision medicine approaches. The identified genes and pathways are potential PGx markers for CD patients treated with VDZ. Full article

Kidney cells are exposed to a wide range of physiological and pathological stresses, including hormonal changes, mechanical forces, hypoxia, hyperglycemia, and inflammation. These insults can trigger adaptive responses, but when they persist, they can lead to organelle stress. Organelles such as mitochondria, the endoplasmic reticulum, and primary cilia sustain cellular metabolism and tissue homeostasis. When organelle stress occurs, it disrupts cellular processes and organelle communication, leading to metabolic dysfunction, inflammation, fibrosis, and progression of kidney disease. Sex and hormonal factors play a significant role in the development of renal disorders. Many glomerular diseases show distinct differences between the sexes. Chronic Kidney Disease is more common in women, while men often experience a faster decline in kidney function, partly due to the influence of androgens. Additionally, the loss of female hormonal protection after menopause highlights the importance of sex as a factor in renal susceptibility. This narrative review synthesizes preclinical evidence on how sexual dimorphism and sex hormones affect organelle stress in mitochondria, the endoplasmic reticulum, and primary cilia, from 33 studies identified through a non-systematic literature search of the PubMed database, to provide an overview of how these mechanisms contribute to sex-specific differences in kidney disease pathophysiology. Full article

Background/Objectives: Preeclampsia is a leading cause of maternal and perinatal morbidity worldwide, yet its underlying mechanisms remain unclear. Polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA), are essential for placental development and vascular function, but evidence on their role in preeclampsia is inconsistent. This study aimed to compare serum DHA levels between women with preeclampsia and normotensive pregnant women and to examine their association with disease severity and maternal and perinatal outcomes. Methods: A total of 145 pregnant women aged 18–40 years were enrolled, including 47 with newly diagnosed preeclampsia (PE) and 98 normotensive controls. PE was defined according to the ACOG 2019 criteria. Serum DHA levels were measured using ELISA in fasting blood samples collected at the first visit. Results: Maternal serum DHA levels did not differ significantly between preeclampsia and control groups (p = 0.571); they were similar across control, mild PE, and severe PE groups. DHA showed a negative correlation with neutrophil-to-lymphocyte ratio (r = −0.305) and maternal hospitalization duration (r = −0.334). Independent predictors of PE included nulliparity (OR: 4.43), advanced age (OR: 1.14), elevated BMI (OR: 1.29), and low albumin (OR: 0.77). After adjusting for age and BMI, DHA was an independent negative predictor of IUGR (OR: 0.65). Conclusions: DHA levels: Placental and/or fetal DHA metabolism may be impaired in patients with preeclampsia. Although DHA was not associated with the development of PE, it was a negative predictor of IUGR. DHA reduces the length of maternal hospital stay through its anti-inflammatory effect. Full article

Lipodystrophy is a rare group of metabolic disorders characterized by the abnormal distribution of body fat, which can lead to various metabolic complications due to the body’s inability to adequately process carbohydrates and fat. We report the case of a female, aged 53 years, who was admitted as an outpatient for progressive weight loss of the upper part of the body (face, neck, arms, and chest), dyspeptic complaints, fatigue, mild insomnia, and anxious behavior. Her medical history was characterized by the presence of dyslipidemia, hypertension, and a minor stroke episode. However, she denied any family-relevant medical history. Although the clinical perspective suggested a possible late onset of partial acquired lipodystrophy, due to the imaging exam that revealed an enlarged liver with inhomogeneous structure with multiple nodular lesions, scattered over both lobes, a lot of lab work-ups and complementary studies were performed. Eventually, a liver biopsy was performed by a laparoscopic approach during cholecystectomy, the histology consistent with metabolic disease-associated steatohepatitis (MASH). In conclusion, given their heterogeneity and rarity, lipodystrophies may be either overlooked or misdiagnosed for other entities. Barraquer–Simons syndrome (BSS) may be associated with liver disease, including cirrhosis and liver failure. Liver lipodystrophy in BSS may sometimes feature steatosis with a focal, multi-nodular aspect, multiplying the diagnostic burden. Liver lipodystrophy may manifest as asymptomatic fat accumulation but may progress to severe conditions, representing one of the major causes of mortality in BSS, apart from the cardio-vascular comorbidities. Given the potential of severe outcomes, it is mandatory to correctly assess the stage of liver disease since the first diagnosis. Full article

Biophotons are non-thermal and non-bioluminescent ultraweak photon emissions, first hypothesised by Gurwitsch as a regulatory mechanism in cell division, and then experimentally observed in living organisms. Today, two main hypotheses explain their origin: stochastic decay of excited molecules and coherent electromagnetic fields produced in biochemical processes. Recent interest focuses on the role of biophotons in cellular communication and disease monitoring. This study presents the first campaign of biophoton emission measurements from cultured astrocytes and glioblastoma cells, conducted at Fondazione Pisana per la Scienza (FPS) using two ultra-sensitive setups developed in collaboration between the National Laboratories of Frascati (LNF-INFN) and the University of Rome II Tor Vergata. The statistical analyses of the collected data revealed a clear separation between cellular signals and dark noise, confirming the high sensitivity of the apparatus. The Diffusion Entropy Analysis (DEA) was applied to the data to uncover dynamic patterns, revealing anomalous diffusion and long-range memory effects that may be related to intercellular signaling and cellular communication. These findings support the hypothesis that biophoton emissions encode rich information beyond intensity, reflecting metabolic and pathological states. The differences revealed by applying the Diffusion Entropy Analysis to the biophotonic signals of Astrocytes and Glioblastoma are highlighted and discussed in the paper. This work lays the groundwork for future studies on neuronal cultures and proposes biophoton dynamics as a promising tool for non-invasive diagnostics and the study of cellular communication. Full article

Parkinson’s disease is the second leading neurodegenerative disease of aging. For over five decades, oral levodopa has been used to manage the progressive motor deficits that are the hallmark of the disease. However, individual dose requirements are highly variable, and patients typically require increased levodopa dosage as the disease progresses, which can cause undesirable side effects. It has become increasingly apparent that the gut microbiome can have a major impact on the metabolism and efficacy of therapeutic drugs. In this Perspective, we examine recent studies highlighting the impact of metabolism by Enterococcus faecalis, a common commensal gut bacterium, on levodopa bioavailability. E. faecalis expresses a highly conserved tyrosine decarboxylase that promiscuously converts levodopa to dopamine in the gut, resulting in decreased neuronal uptake of levodopa and reduced dopamine formation in the brain. Mitochondria-targeted antioxidants conjugated to a triphenylphosphonium moiety have shown promise in transiently suppressing the growth of E. faecalis and decreasing microbial levodopa metabolism, providing an approach to modulating the microbiome that is less perturbing than conventional antibiotics. Thus, mitigating metabolism by the gut microbiota is an attractive therapeutic target to preserve and potentiate the efficacy of oral levodopa therapy in Parkinson’s disease. Full article

Non-alcoholic fatty liver disease (NAFLD) is a major metabolic disorder characterized by hepatic lipid accumulation, oxidative stress, and disturbance of lysosomal degradation. Central to these processes is glutathione (GSH), a key antioxidant regulating redox balance and cellular homeostasis. This study aimed to evaluate the therapeutic potential of two dietary antioxidants—astaxanthin and Garcinia indica (kokum)—in modulating hepatic redox status, lysosomal function, and metabolic gene expression in a murine model of diet-induced NAFLD. A total of 120 male Swiss Webster mice were allocated into control and steatotic groups, followed by a 90-day supplementation period with astaxanthin, kokum, or their combination. Liver tissue was collected post-supplementation for biochemical, antioxidant, and qRT-PCR analyses. Outcomes included lysosomal enzymes activities, superoxide dismutase (SOD), GSH, vitamin C, total polyphenols, DPPH radical-scavenging activity, and total antioxidant capacity (TAC). NAFLD induced marked oxidative stress, lysosomal overactivation, and alteration of antioxidant-related gene expression. Combined supplementation restored GSH, enhanced TAC, reduced lysosomal stress markers, and significantly upregulated nuclear factor erythroid 2-related factor 2 (Nfe2l2) while downregulating fatty acid synthase (FASN) and partially rescuing lipoprotein lipase (LpL). Correlation analyses revealed strong associations between antioxidant capacity, lysosomal function, and transcriptional regulation, supporting the therapeutic relevance of combined antioxidant therapy for concurrent redox and lysosomal dysregulation in NAFLD. These findings underscore the therapeutic potential of targeting redox and cellular degradation pathways with antioxidant-based interventions to re-establish hepatic metabolic balance in NAFLD and related disorders. Full article

Adipose tissue thermogenesis is a promising strategy to counter obesity and metabolic disease, but sustained activation of thermogenic adipocytes elevates oxidative and lipid-peroxidation stress, increasing susceptibility to ferroptotic cell death. Existing models often treat redox buffering, hypoxia signaling and ferroptosis as separate processes, which cannot explain why similar interventions—such as antioxidants, β-adrenergic agonists or iron modulators—alternately enhance thermogenesis or precipitate tissue failure. Here, we propose the Redox–Thermogenesis–Ferroptosis Compass (RTF-Compass) as a framework that maps adipose depots within a space defined by ferroptosis resistance capacity (FRC), ferroptosis signaling intensity (FSI) and HIF-1α-dependent hypoxic tone. Within this space, thermogenic output follows a hormetic, inverted-U trajectory, with a Thermogenic Ferroptosis Window (TFW) bounded by two failure states: a Reductive-Blunted state with excessive antioxidant buffering and weak signaling, and a Cytotoxic state with high ferroptotic pressure and inadequate defense. We use this model to reinterpret genetic, nutritional and pharmacological studies as state-dependent vectors that move depots through FRC–FSI–HIF space and to outline principles for precision redox medicine. Although the TFW is represented as coordinates in FRC–FSI–HIF space, we use ‘Compass’ to denote a coordinate framework in which perturbations act as vectors that orient depots toward thermogenic or cytotoxic outcomes. Finally, we highlight priorities for testing the model in vivo, including defining lipid species that encode ferroptotic tone, resolving spatial heterogeneity within depots and determining how metabolic memory constrains reversibility of pathological states. Full article

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002–2012) estimated ~99.6% attrition, while PD programs (1999–2019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons/glia, neuron–glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood–brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK/PD-driven development for brain-directed degraders. Full article

Background: Advanced glycation end products (AGEs) play a pivotal role in various human pathologies, including aging and metabolic diseases, and their formation may have significant physiological consequences for human health. Fructoselysine (FL) is an intermediate in the formation of AGEs, and its accumulation has been associated with detrimental health effects. Although several chromatographic methods have been developed for AGEs detection and quantification, no mass spectrometry-based approach has previously been established to quantify FL in different human biological matrices. Methods: In this study, we present a novel UHPLC-HRMS/MS method for the identification and quantification of this compound in various biological matrices, including plasma, feces, and urine. Results: The method demonstrates excellent linearity, accuracy, and precision, with limit of detection (LOD) of 0.02 µM and limit of quantification (LOQ) of 0.06 µM. Recovery rates ranged from 95% to 109% and intra- and inter-day relative standard deviations (RSDs) were below 10%, indicating robust analytical performance. The validated method was successfully applied to quantify FL in plasma, feces, and urine samples from healthy individuals. Additionally, given the known association between AGEs and diabetes, we analyzed a small cohort of prediabetic patients and observed elevated circulating levels of FL compared to healthy controls. Conclusions: This study introduces a sensitive and reliable method for the specific detection and quantification of FL in biological samples and provides new insights into early molecular changes associated with prediabetic condition to improve early diagnosis in aging related diseases. Full article

Background/Objectives: We investigated the association between leisure-time physical activity (LTPA) and liver fibrosis, and whether this relationship differs by obesity and diabetes status. Methods: We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) 2017–March 2020 cycle. LTPA was assessed using the Global Physical Activity Questionnaire (GPAQ) and classified as physically active if engaging in ≥600 metabolic equivalent (MET)-minutes per week of moderate-to-vigorous activity, or inactive. Clinically significant liver fibrosis was defined as liver stiffness measurement (LSM) ≥ 8.0 kPa on transient elastography. Multivariable logistic and linear regression models estimated adjusted odds ratios (ORs) for significant liver fibrosis, with additional subgroup analyses according to obesity and diabetes status. Results: In 7662 U.S. adults, physically active participants (n = 2721) had a lower prevalence of significant fibrosis than inactive individuals (5.4% vs. 11.4%, p < 0.001). In multivariable analysis, Participants who were physically active were associated with 42% lower odds of having fibrosis (OR 0.58, 95% confidence interval [CI] 0.41–0.82; p = 0.004). This association remained consistent in subgroup analyses stratified by obesity and diabetes status, even in the non-obese subgroup with body mass index (BMI) < 30 kg/m² (OR 0.54, 95% CI 0.32–0.91; p = 0.022) and the non-diabetic subgroup (OR 0.59, 95% CI 0.39–0.90; p = 0.016). Conclusions: Regular moderate-to-vigorous LTPA was independently associated with lower likelihood of clinically significant liver fibrosis. This beneficial association was significant regardless of obesity or diabetes status, suggesting that LTPA may play a clinically meaningful role in populations at high risk for progressive liver disease. Full article

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality, despite advances in pharmacological prevention and treatment. The burden of CVD necessitates implementing the treatment of risk factors including dyslipidemia. Pharmaceutical advancements and in depth understanding of pathophysiology have enabled innovative therapies targeting pathways underlying lipoprotein metabolism disorders. Angiopoietin protein-like 3 (ANGPTL3) plays a crucial role in the regulation of lipoprotein metabolism, therefore being a potential therapeutic target. Inhibition of ANGPTL3 has emerged as a new therapeutic strategy to reduce LDL-cholesterol levels independent of the LDL receptor function. Therapeutic approaches for ANGPTL3 inhibition range from monoclonal antibodies to nucleic acid therapeutics including antisense oligonucleotides and small interfering RNAs. In this review, we briefly explain the structure and mechanism of action of ANGPTL3 and discuss the therapeutic approaches for targeting ANGPTL3 in the clinical setting. We also discuss Evinacumab, a monoclonal antibody, its structure, mechanism of action, safety, tolerability, pharmacokinetics, and pharmacodynamics, as well as its clinical trial-derived results. The antisense oligonucleotides modify ANGPTL3 mRNA to inhibit protein production, and small interfering RNAs induce mRNA degradation; results from clinical trials were reviewed in detail. Finally, we discuss promising gene editing approaches including clustered regularly interspaced short palindromic repeats (CRISPR)/Cas systems. Full article

Lignans are naturally occurring compounds found in a wide variety of plant species, including flaxseed, soybean, pumpkin seed, broccoli, sesame seed, and some berries. Lignans have been used for centuries in both food and traditional herbal medicine. Recently, numerous new lignans and lignan derivatives with diverse biological properties have been identified. Lignans are considered promising for human health due to their hydrogen-donating antioxidant activity together with their ability to complex divalent transition metal cations. They have demonstrated beneficial effects for cardiovascular disease, as well as in maintaining blood glucose levels, supporting cardiac health, promoting anti-obesity effects, decreasing the risk of renal diseases, enhancing brain function, improving skin and gut health, among others. This review explores the biosynthesis and biological effects of lignans, with a particular focus on their antihypertensive and anti-obesity properties, as well as the molecular mechanisms involved. It also highlights recent advances in sustainable lignan extraction techniques that are suitable for human use. The mechanisms underlying these bioactivities are thought to involve hormonal metabolism and availability, antioxidant action, modulation of angiogenesis, and more. However, further research is needed to fully elucidate the molecular pathways through which lignans exert their therapeutic effects. Overall, lignans from various plant sources hold significant potential for application in functional foods, dietary supplements, and pharmaceutical products aimed at preventing and managing a range of health conditions, including hypertension and obesity. Full article