Search Results (6,127)

Background/Objectives: Triosephosphate Isomerase (TPI) is a glycolytic enzyme known to be associated with TPI deficiency, a severe form of childhood-onset glycolytic enzymopathy associated with hemolytic anemia, neuromuscular impairment and early death. Most often the disease results from the common TPI1^E105D mutation, which can be either homozygous or compound heterozygous with another allele. Methods: We purified TPI^R5G protein, studied mutant protein biochemistry, established and characterized TPI^R5G/f.s.patient cells, and investigated newly identified compounds for their efficacy in vitro using Western blot and TPI activity assays. Results: We identified novel TPI1 alleles that result in TPI Deficiency with an atypical presentation lacking anemia and with more slowly developing neurologic and locomotor impairment. The patient was found to be compound heterozygous with a missense mutation resulting in an R5G amino acid substitution and a frameshift mutation that is a predicted null allele. To better understand disease pathogenesis in this patient, we expressed and purified the TPI^R5G human protein and studied it biochemically in addition to studying TPI^R5G/f.s.patient cells. We discovered that purified TPI^R5G protein has wildtype activity with modestly increased dimer stability. We also discovered that steady-state TPI protein levels were markedly reduced, suggesting that the instability of the mutant protein underlies disease pathogenesis. We tested compounds recently identified in a screen for novel TPI Df therapies for their efficacy in TPI^R5G/f.s.patient cells. All three compounds significantly increased TPI protein levels in patient cells. As expected, since the mutant protein retains essentially wild type activity, the increase in TPI protein levels also resulted in a significant increase in TPI activity. Conclusions: These results establish TPI^R5G as a TPI Df allele, demonstrate that reduced stability of the mutant protein underlies pathogenesis akin to other disease-causing alleles, and suggest that recently discovered developing therapies will likely function broadly and should be developed as potential TPI Df therapies. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the hepatic manifestation of systemic metabolic dysregulation, strongly linked to type 2 diabetes, cardiovascular diseases, liver-related complications, and different types of malignancies. Although MASLD is associated with obesity and insulin resistance, it is increasingly recognized that the liver engages in complex crosstalk with several endocrine pathways, including thyroid function, sex and steroid hormone regulation, and growth hormone signaling. The pathophysiology of MASLD is multifactorial and complex, as reflected by its clinical range—from simple steatosis to cirrhosis. MASLD now affects about one-quarter of the global population, with its prevalence rising due to sedentary lifestyles, chronic caloric excess, and endocrine disturbances contributing to disease progression. Given the escalating prevalence of MASLD and its frequent concurrence with various endocrinopathies, understanding this relationship is critical for refining diagnostic accuracy and optimizing therapeutic strategies. This review aims to synthesize contemporary insights into the complex interactions between MASLD and selected endocrine disorders, elucidate underlying pathophysiological mechanisms, and underscore novel treatment paradigms. As MASLD remains a significant clinical challenge worldwide, its intersection with endocrine dysfunctions represents a vital and promising domain for future research and clinical management. Full article

High-fat (HF) diets are widely used in aquaculture to reduce feed costs, but they often lead to hepatic steatosis, oxidative stress, and reduced environmental tolerance in carnivorous fish. This study evaluated whether dietary rosiglitazone (RO; 10 mg·kg⁻¹) alleviates HF (18% fat) diet-induced metabolic dysfunctions in juvenile largemouth bass (Micropterus salmoides). Fish were fed a control diet (10% fat), an HF diet (18% fat), or an HF + RO diet for 8 weeks. RO supplementation reversed HF-induced dyslipidemia by lowering plasma triglyceride (TG) and total cholesterol (T-CHO) while elevating high-density lipoprotein cholesterol (HDL-c), and it reduced intraperitoneal fat and whole-body lipid (p < 0.05). RO also mitigated hepatic vacuolization and decreased plasma alanine aminotransferase (ALT) (p < 0.05) and aspartate aminotransferase (AST) (p > 0.05) activities. Antioxidant capacity was enhanced by RO, as indicated by increased glutathione (GSH), catalase (CAT), and total antioxidant capacity (T-AOC), together with reduced malondialdehyde (MDA), and accompanied by upregulation of nrf2, downstream antioxidant genes, and downregulation of keap1 (p < 0.05). Moreover, RO suppressed HF-induced endoplasmic reticulum (ER) stress (grp78, eif2α, chop) and pro-inflammatory genes (tnfα, il-1β, nf-κb), while upregulating il-10 (p < 0.05). Gut microbiota analysis showed RO-mediated enrichment of Firmicutes and short-chain fatty acid-producing genera (Faecalibaculum, Dubosiella). Importantly, RO significantly reduced mortality during a 96 h acute ammonia challenge (p < 0.05). Collectively, these results demonstrate that dietary rosiglitazone mitigates HF diet-induced hepatic oxidative stress and metabolic dysregulation through Nrf2 activation, anti-inflammatory effects, and microbiota modulation, providing a potential strategy to enhance HF feed utilization and environmental stress resilience in carnivorous fish. Further studies on dose optimization and residue safety are warranted. Full article

Background/Objectives: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms such as tremor, bradykinesia, rigidity, and postural instability. In the absence of disease-modifying therapies, exercise remains one of the few interventions shown to effectively reduce fall risk and improve mobility. However, it remains unclear whether skeletal muscle ATP metabolism is impaired in PD, and whether the benefits of exercise arise primarily from improvements in central motor control or peripheral metabolic adaptations. Methods: Fourteen individuals with PD and five healthy controls underwent kinetic ³¹P Magnetic Resonance Spectroscopy (MRS) to assess resting muscle ATP synthesis and dynamic ³¹P MRS during in-magnet exercise to evaluate oxidative phosphorylation in active muscle. Results: At rest, ATP synthesis rates mediated by ATPase and creatine kinase (CK) were on average 46 ± 23% and 24 ± 9% lower, respectively, in the PD group compared to controls (p < 0.005), suggesting peripheral mitochondrial dysfunction. During plantar flexion exercise at 15% of lean body mass, range of motion (ROM) was reduced by 22 ± 5% in PD participants (p = 0.01). Despite this, post-exercise recovery of phosphocreatine (PCr) and inorganic phosphate (Pi) was similar between groups. Recovery time constants for PCr and Pi correlated with participants’ total weekly exercise time, indicating a metabolic adaptation to regular physical activity. Modest ROM improvements were observed in both groups following calf-raise exercise training. Conclusions: Reduced skeletal muscle ATP metabolism may contribute to peripheral weakness in PD. Regular exercise appears to promote adaptive metabolic responses, highlighting the need for therapeutic strategies targeting both central and peripheral components of PD. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and climate change are major global health challenges. Aim: Our aim was to assess the relationship between intrahepatic fat content (IFC) and diet-related environmental impact in a Mediterranean diet (MD)-based intervention. Design: The design included a six-month longitudinal analysis within the frame of a FLIPAN randomized controlled trial, including 60 participants aged 40–60 years with MASLD, metabolic syndrome and obesity. Methods: IFC expressed as a percentage (%IFC) was measured by magnetic resonance imaging, and dietary intake was assessed via a validated food frequency questionnaire (FFQ). Environmental impacts of diets were estimated using life cycle assessment data from the Agribalyse^® database, focusing on greenhouse gas (GHG) emissions, water use, energy use and land use. A composite sustainability score was also calculated. Changes in liver fat and environmental footprints were analyzed using a general linear model (GLM) adjusted for within-subject variability and partial correlation analysis adjusted for energy intake, MD adherence and body weight. Results: The participants with the highest %IFC reduction group in the GLM showed the highest decreases in GHG emissions and land use. Water use increased in this same group. Energy use and the composite sustainability score did not differ significantly between groups. Higher %IFC reductions were also associated with higher MD adherence and lower visceral fat. When the adjusted partial correlation analysis for the environmental parameters was performed, only water use remained significant. Conclusions: Higher reductions in %IFC were linked to dietary patterns with lower GHG emissions and land use and higher water use. However, when adjusted by energy intake, MD adherence and body weight in continuous modeling, only higher water use was related to lower %IFC. These findings highlight the complexity of achieving environmentally sustainable and health-promoting diets. Full article

Acute pancreatitis (AP) and chronic pancreatitis (CP) are distinct inflammatory conditions with significant clinical burden, including associated complications and mortality. These pancreatic conditions share overlapping pathophysiologic features. Although AP can be followed by recurrent episodes (recurrent acute pancreatitis, RAP), most CP does not follow a simple linear progression from AP; rather, CP reflects sustained processes causing injury to the pancreas (e.g., toxic-metabolic, genetic, obstructive), leading to fibrosis and organ dysfunction. Lipidomics and metabolomics can provide insights into the pathophysiology of the disease. Although researchers have extensively explored lipids and metabolites to better understand disease mechanisms, comprehensive detailed insights into the pathways and intricate roles these molecules play in pancreatitis remain unidentified. This gap can be partially attributed to limited availability of human samples from disease subgroups in pancreatitis, and current technological constraints in analytical methods, particularly regarding complete lipid and metabolite detection, identification, and quantification. In this review, we summarize lipidomic and metabolomic workflows in the context of understanding pancreatitis pathophysiology, including their design and analytical strategies. We also highlight clinical studies on pancreatitis, utilizing lipidomics and metabolomics as a tool to identify altered or dysregulated lipids or metabolites, and their association with the disease state and its progression. Full article

Cold stress poses a critical threat to fish survival by triggering metabolic dysfunction, oxidative damage, immune suppression, and apoptosis. However, hybrid polyploid fish triploid crucian carp (3nRCR, 3n = 150) demonstrate superior stress tolerance. In this study, we investigated the cold adaptation mechanisms in different ploidy cyprinid fishes: triploid crucian carp compared to its diploid improved red crucian carp (Carassius auratus red var., RCC, 2n = 100, ♀) and improved allotetraploid (4nAT, 4n = 200, ♂) progenitors. Under controlled cooling, 3nRCR lost equilibrium at a significantly lower temperature (3.2 °C) than RCC (4.0 °C) and 4nAT (4.5 °C), confirming its superior enhanced cold resistance. Histological examination revealed minimal tissue damage in 3nRCR, characterized by reduced gill inflammation and cellular apoptosis. Transcriptomics revealed triploid-specific molecular strategies: 3nRCR uniquely activated retinol metabolism and metabolic rewiring (arginine/proline metabolism, oxidative phosphorylation). Notably, in the immune-related NLR signaling pathway, both nlrp1 and nlrp3 (key inflammasome components) were significantly downregulated in 3nRCR (p < 0.01). In contrast, genes involved in endoplasmic reticulum (ER) stress response, including chop and nrf2, were markedly upregulated, indicating a reinforced cellular stress resolution mechanism absent in both RCC and 4nAT. Our results demonstrate that triploid cold adaptation is orchestrated through a balanced interaction among mitochondrial apoptosis, ER stress, and inflammasome pathways. These findings provide novel insights into hybrid polyploid adaptation mechanisms and targets for cold-resilient aquaculture breeding. Full article

Polycystic ovary syndrome (PCOS) is a systemic metabolic and endocrine disorder that significantly disrupts reproductive physiology and endometrial function. In this narrative review, we examine the molecular impact of metabolic and hormonal imbalances on the endometrium of women with PCOS. We investigate the specific mechanisms that delineate how hyperinsulinemia and insulin resistance, chronic low-grade inflammation, and estrogen/progesterone/androgen imbalance contribute to altered epigenetic, transcriptomic, metabolomic, and signaling profiles in a wide array of different cell types within endometrial tissues. The synergistic interplay between upregulated inflammatory cytokines (e.g., IL-1,2,6,8,17,18, and TNF-α), along with key changes in critical molecular pathways associated with hyperinsulinemia and insulin resistance (e.g., PI3K/AKT/MAPK, and Wnt/β-catenin), in addition to aberrant sex steroid hormone signaling (e.g., CYP19A1, COX-2, PGE₂, HOXA10, 11βHSD2), promotes deleterious changes within the endometrial microenvironment. These anomalies underpin a spectrum of clinical manifestations observed in women with PCOS at each stage of the life course, including abnormal uterine bleeding in reproductive-age women, impaired decidualization in pregnancy, and altered postmenopausal endometrial physiology. Clinically, these alterations are associated with abnormal uterine bleeding, subfertility, implantation failure, miscarriage, pregnancy complications, and postmenopausal endometrial hyperplasia and cancer. Overall, our review provides novel insights into the molecular mechanisms linking systemic metabolic and endocrine dysfunction with endometrial pathology in PCOS and has broader implications that apply to all women. Full article

Type 2 diabetes is a major global health burden, causing approximately 2 million deaths annually. Recent studies have revealed a strong positive correlation between elevated triglyceride levels and plasma glucose, as well as increased prevalence, incidence, and mortality of type 2 diabetes, suggesting a potential causal link. This review explores the metabolic interconversion between triglycerides and glucose, emphasizing how excess carbohydrate intake leads to ectopic triglyceride accumulation, which in turn enhances hepatic gluconeogenesis. It highlights key signaling pathways through which ectopic triglyceride deposition drives insulin resistance, hyperinsulinemia, β-cell dysfunction and apoptosis, and increased glucose production—central mechanisms in diabetes pathogenesis. Evidence from clinical interventions, such as the reversal of type 2 diabetes through bariatric surgery and dietary energy restriction, supports the hypothesis that ectopic triglyceride accumulation is a driving factor. Furthermore, this review explains why omega-3 fatty acids and niacin, in contrast to fibrates, do not protect against type 2 diabetes, despite lowering triglycerides. Overall, this review emphasizes the contribution of ectopic triglyceride accumulation—driven by obesity, hypertriglyceridemia, excessive consumption of carbohydrates and fats, and physical inactivity—to the onset and progression of type 2 diabetes, offering valuable insights into potential therapeutic strategies. Full article

Asthma is a chronic respiratory disease affecting over 262 million people worldwide, with obesity-associated asthma emerging as a distinct endotype of increasing prevalence characterized by metabolic inflammation and airway remodeling. Unlike allergic asthma, this phenotype is driven by chronic low-grade inflammation, originating from hypertrophic and hypoxic adipose tissue. This dysregulated state leads to the activation of pro-inflammatory pathways and the secretion of cytokines, contributing to airway dysfunction and remodeling. Recent evidence highlights non-coding RNAs (ncRNAs) as key regulators of these processes. MicroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) influence inflammation and remodeling by modulating immune cell polarization, cytokine secretion, extracellular matrix composition, and airway smooth muscle cell (ASMC) proliferation. Notably, H19, MEG3, GAS5, miR-26a-1-3p, and miR-376a-3p have been implicated in both asthma and obesity, suggesting their role in linking metabolic dysfunction with airway pathology. Moreover, ncRNAs regulate Treg/Th17 balance, fibroblast activation, and autophagy-related pathways, further influencing airway remodeling. Our in silico analysis highlighted the IGF1R signaling pathway as a key enriched mechanism, linking selected ncRNAs with metabolic dysregulation and inflammation in obesity-related asthma. This paper reviews how ncRNAs regulate inflammation and airway remodeling in obesity-associated asthma, emphasizing their potential molecular links between metabolic dysfunction and airway pathology. Full article

The parallel global increase in obesity and Alzheimer’s disease (AD) underscores an urgent public health challenge, with converging evidence indicating that metabolic dysfunction strongly contributes to neurodegeneration. Obesity is now recognized not only as a systemic metabolic condition but also as a modifiable risk factor for AD, acting through mechanisms such as chronic low-grade inflammation, insulin resistance, and adipose tissue dysfunction. Among the molecular mediators at this interface, adipokines have emerged as pivotal regulators linking metabolic imbalance to cognitive decline. Adipokines are hormone-like proteins secreted by adipose tissue, including adiponectin, leptin, and resistin, that regulate metabolism, inflammation and can influence brain function. Resistin, frequently elevated in obesity, promotes neuroinflammation, disrupts insulin signaling, and accelerates β-amyloid (Aβ) deposition and tau pathology. Conversely, adiponectin enhances insulin sensitivity, suppresses oxidative stress, and supports mitochondrial and endothelial function, thereby exerting neuroprotective actions. The imbalance between resistin and adiponectin may shift the central nervous system toward a pro-inflammatory and metabolically compromised state that predisposes to neurodegeneration. Beyond their mechanistic relevance, adipokines hold translational promise as biomarkers for early risk stratification and therapeutic monitoring. Importantly, natural compounds, including polyphenols, alkaloids, and terpenoids, have shown the capacity to modulate adipokine signaling, restore metabolic homeostasis, and attenuate AD-related pathology in preclinical models. This positions adipokines not only as pathogenic mediators but also as therapeutic targets at the intersection of diabetes, obesity, and dementia. By integrating mechanistic, clinical, and pharmacological evidence, this review emphasizes adipokine signaling as a novel axis for intervention and highlights natural compound-based strategies as emerging therapeutic approaches in obesity-associated AD. Beyond nutraceuticals, antidiabetic agents also modulate adipokines and AD-relevant pathways. GLP-1 receptor agonists, metformin, and thiazolidinediones tend to increase adiponectin and reduce inflammatory tone, while SGLT2 and DPP-4 inhibitors exert systemic anti-inflammatory and hemodynamic benefits with emerging but still limited cognitive evidence. Together, these drug classes offer mechanistically grounded strategies to target the adipokine–inflammation–metabolism axis in obesity-associated AD. Full article

Background: Phelan–McDermid syndrome (PMS), caused by SHANK3 variants or 22q13.3 deletions, often includes systemic features such as gastrointestinal and hepatic abnormalities. This study highlights the overlap between PMS and metabolic-associated steatotic liver disease (MASLD), focusing on PNPLA3 variants and underscoring the need for structured metabolic monitoring. Methods: We describe a 25-year-old male with PMS due to a 22q13.33 microdeletion involving SHANK3. He exhibited developmental delay, seizures, and hypotonia. Genetic testing revealed homozygosity for the PNPLA3 p.I148M variant. Clinical, anthropometric, biochemical, imaging, and metabolic investigations were performed, including liver ultrasound and metabolic profiling of lymphoblastoid cell lines. Results: Ultrasound revealed moderate hepatic steatosis consistent with MASLD. After ursodeoxycholic acid treatment and a Mediterranean-style diet, steatosis improved to mild. Metabolic profiling demonstrated increased nicotinamide adenine dinucleotide generation under metabolic stimuli, suggesting altered energy homeostasis. Conclusions: We highlight the contribution of PNPLA3 to MASLD in PMS and support systematic hepatic monitoring. Genotype–phenotype associations in PMS may provide insights relevant to MASLD research and clinical management. Full article

Background/Objectives: Malnutrition, systemic inflammation, and immune dysfunction are key determinants of adverse outcomes in older adults following acute illness. Composite biomarkers integrating these domains could enhance early risk stratification. This study investigates, for the first time in acute geriatric care, the prognostic value of the C-reactive protein–albumin–lymphocyte (CALLY) index—a composite marker of nutritional, inflammatory, and immune status—in predicting short-term survival. Methods: We retrospectively analyzed 264 patients admitted to the acute geriatrics ward of Santa Maria della Misericordia Hospital in Perugia. The CALLY index was calculated as: (Albumin × Lymphocytes)/(CRP × 10⁴). The optimal prognostic cut-off was determined using receiver operating characteristic (ROC) curve analysis. Three-month survival was assessed by Kaplan–Meier analysis. Results: The cohort included 167 women (63.3%) and 97 men (36.7%), with a mean age of 88.0 ± 6.4 years. At 3-month follow-up, 80 patients (30.3%) had died. The CALLY index showed an area under the ROC curve of 0.647 (95% CI: 0.576–0.718; p < 0.001), with a cut-off of 0.055 (sensitivity: 68.5%, specificity: 46.3%). Among deceased patients, 42.5% had a CALLY index <0.055. After multivariable adjustment, a lower CALLY index remained independently associated with increased mortality (B = −0.805; OR = 0.45; 95% CI: 0.215–0.930; p = 0.031). Kaplan–Meier analysis demonstrated significantly higher survival in patients with a CALLY index ≥ 0.055 (Log-rank test: 13.71; p < 0.001). Conclusions: The CALLY index shows a modest but statistically significant discriminative ability for predicting short-term mortality in acutely ill older adults. As a simple, low-cost marker derived from routine laboratory tests, it holds potential for integration into clinical workflows to guide nutritional, metabolic, and prognostic management strategies in geriatric acute care. Full article

Background: Uric acid (UA) is linked to gout, renal dysfunction, and cardiovascular disease. Prior studies often assume linear relationships, potentially oversimplifying physiological complexity. Methods: We analyzed data from 5200 healthy Taiwanese men. Demographic, biochemical, lifestyle, and inflammatory variables were assessed using Pearson correlation, multiple linear regression (MLR), and multivariate adaptive regression splines (MARS), an interpretable machine learning method for detecting nonlinear, threshold-based effects. Results: Pearson correlation showed broad linear associations, whereas MARS identified fewer but more physiologically meaningful predictors. Waist-to-hip ratio (WHR) had a strong threshold effect, influencing UA only below 0.969. Creatinine showed a nonlinear impact, becoming substantial above 0.97 mg/dL, suggesting a renal threshold within the “normal” range. Calcium and high-sensitivity C-reactive protein (hs-CRP) each displayed inflection points (9.5 mg/dL and 3.38 mg/L, respectively), indicating range-specific effects. Notably, betel nut exposure, nonsignificant in linear models, emerged in MARS as a predictor with a complex, non-binary association with UA metabolism. Predictive performance was comparable (RMSE: 1.6694 for MARS vs. 1.6666 for MLR), but MARS offered superior interpretability by highlighting localized nonlinear effects. Conclusions: MARS modeling revealed critical nonlinear, threshold-dependent associations between UA and WHR, creatinine, calcium, hs-CRP, and betel nut exposure, which were not captured by conventional methods. These findings underscore the value of interpretable machine learning in metabolic research and suggest precise thresholds for clinical risk stratification. Full article

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving the progressive degeneration of upper and lower motor neurons. While oxidative stress, RNA-binding protein (RBP) pathology, mitochondrial dysfunction, and glial–neuronal dysregulation is involved in ALS pathogenesis, current therapies provide limited benefit, underscoring the need for multi-target disease-modifying strategies. Nuclear factor erythroid 2-related factor 2 (Nrf2), classically regarded as a master regulator of redox homeostasis, has recently emerged as a central integrator of cellular stress responses relevant to ALS. Beyond its canonical antioxidant function, Nrf2 regulates critical pathways involved in mitochondrial quality control, proteostasis, nucleocytoplasmic transport, RNA surveillance, and glial reactivity. Experimental models demonstrate that astrocyte-specific Nrf2 activation enhances glutathione metabolism, suppresses neuroinflammation, promotes stress granule disassembly, and reduces RBP aggregation. In C9orf72-linked ALS, Nrf2 activation mitigates dipeptide repeat protein toxicity and restores RNA processing fidelity via modulation of nonsense-mediated decay and R-loop resolution. Recent advances in Nrf2-targeted interventions including Keap1–Nrf2 protein–protein interaction inhibitors, dual Nrf2/HSF1 activators, and cell-type-selective Adeno-associated virus 9 (AAV9) vectors show promise in preclinical ALS models. These multimodal approaches highlight Nrf2’s therapeutic versatility and potential to address the upstream convergence points of ALS pathogenesis. Taken together, positioning Nrf2 as a systems-level regulator offers a novel framework for developing precision-based therapies in ALS. Integrating Nrf2 activation with RNA- and glia-directed strategies may enable comprehensive modulation of disease progression at its molecular roots. Full article