Search Results (2,259)

Arterial Tortuosity Syndrome (ATS) is a rare autosomal recessive connective tissue disorder caused by pathogenic variants in SLC2A10, which encodes the facilitative glucose transporter GLUT10. Although its vascular features are well recognized, the molecular consequences of many truncating variants remain poorly understood. We report a patient with ATS carrying a homozygous nonsense variant, c.485G > A (p.Trp162Ter), identified by whole-exome sequencing. Quantitative real-time PCR assessed SLC2A10 expression, and integrated bioinformatic analyses (structural modeling, druggability prediction, transmembrane topology, molecular docking, and molecular dynamics) explored its structural impact. The patient presented with severe systemic arterial tortuosity, congenital cardiovascular anomalies, hernias, connective tissue abnormalities, and neurovascular involvement involving cerebral tortuosity and distal intracranial narrowing. Structural modeling revealed extensive truncation of GLUT10 and loss of multiple α-helical domains, with transmembrane helices reduced from twelve to five. Docking of nine known ligands showed weaker binding to the mutant, and Compound 892 bound most strongly to the wild type (−7.469 kcal/mol). Across 300 ns simulations, the mutant complex proved markedly less stable. qRT-PCR showed no significant transcript differences among patient, carriers, and controls. Our findings broaden the neurovascular spectrum of SLC2A10-related ATS and demonstrate that p.(Trp162Ter) severely disrupts GLUT10 architecture, topology, and ligand binding. Full article

The heart is a highly energy-demanding organ that depends on metabolic flexibility to adjust substrate utilization in response to changes in nutrient availability, endocrine signals, and energetic demands. Accumulating evidence demonstrates that dietary patterns are key determinants of myocardial metabolic homeostasis, affecting substrate selection, mitochondrial function, nutrient-sensing pathways, and long-term transcriptional and epigenetic regulation. This review analyzes the molecular mechanisms through which diet regulates cardiac metabolism and explores how chronic nutritional exposures influence the myocardial energetic phenotype. The physiological regulation of cardiac substrate utilization is described, with emphasis on fatty acids, glucose, ketone bodies, and branched-chain amino acids, underscoring the importance of metabolic flexibility in sustaining cardiac efficiency. The regulation of substrate transport and oxidation is examined, including the roles of the carnitine shuttle, insulin signaling, AMPK, mTOR, PPARα–PGC-1α, SIRT3, and other nutrient-sensing networks that coordinate mitochondrial ATP production. The effects of dietary composition and meal timing, such as caloric restriction and intermittent fasting, are discussed as modulators of myocardial metabolism. The adverse effects of chronic nutrient excess are reviewed, including lipotoxicity, glucotoxicity, insulin resistance, mitochondrial dysfunction, oxidative stress, pseudo-hypoxia, fetal metabolic reprogramming, and maladaptive cardiac remodeling. Recent findings on the gut–heart axis, microbiota-derived metabolites, circadian regulation, and metabolic–epigenetic interactions are also considered. Overall, current evidence supports the view that diet is an important and potentially modifiable regulator of the cardiac metabolic phenotype. Advancing the understanding of diet–metabolism interactions may enable the development of targeted nutritional strategies to maintain metabolic flexibility, enhance cardiac bioenergetics, and prevent the progression of heart failure and other cardiometabolic diseases. Full article

Excessive fructose consumption is associated with metabolic syndrome (MS). This study evaluated the effect of two coffee by-products, coffee pulp (CP) and coffee silverskin (SK), on fructose-induced intestinal changes. Sprague–Dawley rats were assigned to six groups (n = 6/group) for 10 weeks: Control, Fructose (FRU; 20% fructose in drinking water), CP, CP + FRU, SK, and SK + FRU. CP and SK were administered by oral gavage (250 mg/kg/day) using corn oil as vehicle. Intestinal morphology, gene expression (RT-qPCR), and gut microbiota composition (16S rRNA sequencing) were assessed. Fructose significantly increased jejunal expression of the glucose transporters SGLT1 and GLUT2. CP and SK reversed SGLT1 and GLUT2 overexpression and reduced GLUT5 expression relative to the FRU group. Fructose also markedly increased expression of sweet taste receptors TAS1R2 and TAS1R3 and the transcription factors SREBP-1c and ChREBP. Both CP and SK normalized TAS1R2 and TAS1R3 expression, whereas SK additionally prevented SREBP-1c and ChREBP overexpression. Both by-products restored fructose-induced reductions in microbial richness and alpha diversity. CP also modified beta diversity and increased the abundance of the genus Blautia compared with FRU. In conclusion, CP and SK reversed several fructose-induced intestinal alterations, namely in the jejunal expression of sugar-sensing and absorption-related genes. Additionally, CP showed microbiota-modulating effects, whereas SK modulated the jejunal expression of key transcription factors (SREBP-1c and ChREBP) involved in carbohydrate and lipid metabolism. Overall, these findings suggest that CP and SK may represent promising candidates for mitigating fructose-induced intestinal alterations. Full article

Sodium–glucose co-transporter 2 (SGLT2) inhibitors confer cardioprotection in patients with and without diabetes; however, whether SGLT2 is expressed in cardiac tissue and how these drugs act locally in the heart remains unclear. We investigated SGLT2 expression and the effects of empagliflozin in human iPSC-derived cardiac cells exposed to diabetogenic conditions. SGLT2 expression and the effects of empagliflozin were assessed in iPSC-derived cardiomyocytes, endothelial cells, and cardiac fibroblasts under acute diabetogenic conditions using protein expression and metabolic activity assays, and in a multicellular 3D cardiac microtissue model using metabolic activity and contraction analyses. SGLT2 was detected in all three iPSC-derived cardiac cell types with nuclear and perinuclear localisation; no membrane-bound expression was observed. Endothelial cell SGLT2 expression was elevated under diabetogenic conditions. Diabetogenic stress reduced metabolic activity in both cardiomyocytes and endothelial cells; empagliflozin partially rescued endothelial cell metabolic activity but had no effect in cardiomyocytes. Empagliflozin reversed diabetogenic stress-induced cardiac fibroblast activation. 3D cardiac microtissues under diabetogenic conditions exhibited prolonged relaxation time, reduced beat rate variability, and reduced metabolic activity. Empagliflozin maintained metabolic activity at levels comparable to those of the control but did not rescue relaxation time or beat rate variability. The responsiveness of non-myocytes (endothelial cells and cardiac fibroblasts) to empagliflozin, in the absence of any effect on cardiomyocytes, suggests that non-myocyte-mediated mechanisms may contribute to the clinically observed cardioprotection of SGLT2 inhibitors. Full article

Morinda citrifolia (Noni) is well known as a plant with therapeutic potential and is also attractive to the food and cosmetic industries. Traditional medicine supports its use, mainly for the treatment of metabolic disorders and chronic inflammation but also for certain types of cancer. Noni has been the subject of considerable interest within the scientific community due to its purported health benefits. However, despite its growing popularity and extensive traditional use, significant gaps remain in the empirical understanding of its properties, mechanisms, and potential applications. To understand its biological activity, particular attention has been given to several chemical compounds present in its leaves and fruits, as they have been identified as bioactive agents. Moreover, several studies support the idea that specific flavonoids and anthraquinones from noni act on enzymes and transporters associated with glucose and lipid metabolism in humans. Its involvement in cardiovascular, neurological, metabolic, and inflammatory regulation across several high-burden diseases expands the potential medical applications of noni. This narrative review presents the current state of knowledge, highlighting preclinical studies that suggest the mechanisms of action underlying the observed effects, including theoretical approaches proposing specific interactions between noni compounds and proteins associated with human diseases as potential therapeutic targets. It also identifies areas where information remains insufficient and proposes future research directions for pharmacological applications, including the need for additional clinical studies and more comprehensive pharmacokinetic and toxicological evaluations. Full article

Peritoneal ultrafiltration failure is a major complication of peritoneal dialysis and a common cause of technique failure often leading to hemodialysis. Chronic exposure to glucose-based dialysate contributes to inflammation, fibrosis, and peritoneal membrane dysfunction. This study evaluated the effects of dapagliflozin on peritoneal membrane function in patients with ultrafiltration failure undergoing continuous ambulatory peritoneal dialysis. In our pre–post observational study, 32 patients with high/high–average peritoneal transport status and ultrafiltration failure received dapagliflozin 10 mg daily for six months. Peritoneal equilibration tests using a 4.25% dextrose solution were performed during early peritoneal dialysis, at ultrafiltration failure, and after treatment. Ultrafiltration volume, dialysate-to-plasma creatinine ratio, dialysate glucose ratio, sodium dip, and clinical/biochemical parameters were assessed. Dapagliflozin treatment was found to be associated with higher ultrafiltration volume (480 mL vs. 90 mL at ultrafiltration failure, p < 0.001), preservation of the intraperitoneal glucose gradient, changes in the dialysate-to-plasma creatinine ratio, and altered sodium dip parameters. Favorable changes were also observed in blood pressure, body mass index, inflammatory markers, hemoglobin, albumin, sodium, bicarbonate, and glycemic indices. No serious adverse events were reported. These findings suggest that dapagliflozin may improve ultrafiltration efficiency and peritoneal membrane function in peritoneal dialysis patients with ultrafiltration failure. Further randomized controlled trials are warranted. Full article

Hedgehog (Hh) signaling regulates cell survival and microenvironmental responses in various cancers, but its role in metabolic adaptation to the hypoxic bone marrow microenvironment in myeloid malignancies remains insufficiently defined. K562, KU812, and U937 cells were cultured under normoxic or hypoxic conditions and treated with the Smoothened (Smo) antagonist Cyclopamine or the agonist SAG (Smoothened Agonist). Cell proliferation, apoptosis- and autophagy-related markers, glycolysis-associated proteins, and metabolic parameters were assessed by viability assays, Western blotting, immunofluorescence, and biochemical assays. Selected findings were further evaluated in CRISPR/Cas9-mediated Smo knockout cells. Smo inhibition reduced cell proliferation, increased PARP cleavage, and decreased BNIP3 expression under both oxygen conditions. It also downregulated glucose transporter 1 (GLUT1), hexokinase 2 (HK2), lactate dehydrogenase (LDH), monocarboxylate transporter 1 (MCT1), carbonic anhydrases IX and XII (CAIX and CAXII), and was associated with reduced glucose consumption, lactate production, and ATP levels. These changes were associated with modulation of the AMPK–mTOR axis and with reduced phosphorylation of mTOR downstream effectors. These findings support a role for Hh signaling in hypoxia-driven metabolic adaptation in myeloid malignancy cell models and suggest a functional link between Smo activity, glycolytic remodeling, and AMPK-mTOR-related signaling. Full article

Background: MASLD is a disorder linked to lipid metabolism and obesity, increasingly prevalent among sedentary people and leading to hepatic fibrosis. Cyclodipeptides (CDPs) have promising anti-obesogenic and liver-protective potential. Methods: CDP treatment was evaluated in a chronic MASLD model using female Wistar rats fed an obesogenic diet, with assessments of insulin resistance, glucose tolerance, liver damage, oxidative stress, and the expression of genes related to metabolic function. Results: MASLD CDP-treated rats showed low visceral adipose tissue (VAT) content, improved insulin responsiveness and glucose tolerance, reduced steatosis, and reversed oxidant stress and the NRF2, GPX1, and GCLC expression. Furthermore, MASLD-related dysregulation of genes involved in lipid metabolism was restored, including vLDL transport (MTTP, APOB, and RASAL2), β-oxidation (PPAR-α, ACOX1, and FOXO1), lipogenesis (ACC1 and SREBP 1C), and fatty acid transport (PSD3 and CD36). In accordance, genes of key signaling pathways were also restored, including mTOR, TSC1, and TSC2, along with fibrosis and inflammation TGF-β, Fas, NF-κB, and IL-6. In VAT of MASLD animals, crown-like structures and adiposity density were diminished by CDP treatment, with increased expression of genes associated with beige-like adipose tissue remodeling, including PGC-1α, UCP1, NRF1, ATP6v1, CEBP-α, COX4i1, PPARγ, and CS. Consistently, the UCP1 and PGC-1α protein expression was increased in the VAT of MASLD animals treated with CDPs. Conclusions: The anti-MASLD effects of CDPs were associated with reversal of key pathogenic markers in the liver and VAT, suggesting remodeling of white adipose tissue (WAT) toward a beige-like adipose tissue phenotype. The findings suggest that CDPs may modulate adipose tissue structure and adipogenesis, underscoring their therapeutic relevance for MASLD. Full article

Ethanol consumption can modify both drug exposure and drug response. However, the clinical relevance of these interactions depends strongly on the timing and pattern of alcohol intake, the affected pharmacological pathway, the dosage form and organ reserve. This review summarizes current evidence on ethanol–drug interactions, particularly human crossover studies, phenotyping studies, cohort analyses and appropriate case reports. It distinguishes acute ethanol–drug co-exposure, chronic alcohol exposure, drug use during early abstinence after chronic drinking, and pharmacotherapy in alcohol-associated liver disease. Key mechanisms include ADH- and ALDH-dependent ethanol oxidation, acetaldehyde formation, NADH/NAD⁺ redox shift, CYP2E1 induction, carboxylesterase 1 (CES1) modulation, altered intestinal and hepatic first-pass handling, dose dumping from susceptible modified-release products, changes in protein binding in alcohol-associated liver disease, and ALDH inhibition with acetaldehyde accumulation in disulfiram-like reactions. At the molecular level, ethanol may promote acetaldehyde adduct formation with proteins and DNA, CYP2E1-driven reactive oxygen species generation, redox stress, intestinal barrier injury, and CES1-dependent transesterification of selected ester drugs. Acute ethanol intake mainly increases pharmacodynamic toxicity and causes short-term pharmacokinetic disturbances, including enhanced central nervous system depression, delayed gastric emptying, impaired glucose and lactate handling and altered hemodynamic responses. In contrast, chronic exposure, early abstinence and alcohol-associated liver disease are more often associated with hepatic enzyme and transporter remodeling, altered protein binding, reduced hepatic or renal reserve, and greater susceptibility to drug-related organ injury. The highest-risk scenarios involve older adults, polypharmacy, alcohol-associated liver disease, dehydration or acute illness, early abstinence, and the concurrent use of central nervous system depressants, glucose-lowering drugs, NSAIDs, antihypertensives, renally eliminated drugs or warfarin. Hence, ethanol exposure should be treated as a dynamic, context-dependent modifier factor that can acutely exacerbate pharmacodynamic toxicity, alter selected pharmacokinetic pathways and lower organ tolerance to drug-related injury. Full article

Conventional in vitro assays and many microphysiological systems struggle to generate time-dependent drug exposure profiles because medium replacement simultaneously removes or re-adds drugs in the culture compartment. Here, we developed an Open-access Dialysis Membrane-integrated Microfluidic Device (O-DMiMD) that uses molecular weight-dependent transport across a dialysis membrane to decouple nutrient supply from drug exposure control. The device comprises a cell culture compartment (CCC) and a donor compartment (DC) separated by a dialysis membrane. Transport functions were evaluated using Lucifer Yellow, FITC-dextran, and glucose, followed by drug-response studies using SN-38 and T-DM1 under different medium change conditions. Lucifer Yellow and glucose permeated through the dialysis membrane, whereas FITC-dextran was retained. DC medium change supplied glucose to the CCC and maintained A549/HepG2 co-culture proliferation comparably to direct CCC medium replacement. For SN-38, partial transport to the DC and retention in the CCC generated time-dependent exposure profiles; in A549/HepaRG co-culture, medium change conditions altered A549 viability. For T-DM1, conditions with or without re-addition to the CCC produced different SK-BR-3 responses, suggesting exposure-dependent effects for high-molecular-weight drugs. The O-DMiMD provides an open-access in vitro platform for evaluating drug responses under exposure profiles governed by molecular weights, protein binding, medium changes, and metabolic cell contexts. Full article

Saccharomyces cerevisiae, widely used in industrial fermentation, still suffers from inherent problems in the efficient utilization of carbon sources. Here, a strategy for alleviating glucose effect and improving S-adenosyl-L-methionine (SAM) production by deleting Mig1 combined with introducing MetK1 from Leishmania infantum was applied in S. cerevisiae. The deletion of Mig1 improved glucose utilization by increasing the expression levels of genes related to glucose transport and glycolysis, thereby increasing the levels of glycolytic intermediates and increasing both the transcriptional levels of ACS1 and ALD6 and the activity of ADH2, which promotes the conversion of ethanol into acetyl-CoA. The deletion of Mig1 also upregulated the transcripts of genes involved in the metabolism of precursor amino acids of SAM and ultimately responsible for the improvement in SAM synthesis. Finally, MetK1 was introduced into yeast to redirect carbon flux toward SAM biosynthesis. As expected, the SAM production of the mutant YMig1ΔPMetK1 reached 8.91 g/L in a 10 L fermenter, which was 72.3% higher than that of the parent strain S. cerevisiae CGMCC 2842 (5.17 g/L) reported in our previous studies. This study revealed that the strategy of alleviating glucose effect and redirecting carbon flux to nonethanol products by Mig1 deletion combined with heterologous MetK1 introduction possesses great potential for improving SAM synthesis in yeast cells. Full article

Functional imaging has become an important approach for evaluating tumor physiology in vivo beyond morphologic assessment. Radiotracers used for cancer imaging are designed to mimic endogenous substrates or substrate analogues, and their accumulation can depend on membrane transport, intracellular metabolism, and clearance from normal tissues. Specifically, SLC transporters contribute to tracer uptake and signal formation, linking transporter activity with measurable imaging signals in cancer. While [¹⁸F]FDG PET/CT remains the most widely used example of transporter-associated metabolic imaging, SLC transporter-mediated imaging strategies have been developed to assess amino acid transport, sodium-dependent glucose uptake, redox metabolism, lactate exchange, nucleoside metabolism, choline metabolism, and iodide accumulation. Herein, we provide an overview of current applications of SLC transporter-mediated functional imaging in cancer diagnosis, with an emphasis on glucose and amino acid systems. Special attention is given to the relationship between transporter physiology, tracer uptake, tumor type, and diagnostic application. Full article

Ferroptosis is an iron-dependent regulated form of cell death characterized by lethal lipid peroxidation and is increasingly implicated in cancer, neurodegenerative diseases, cardiovascular injury, and metabolic disorders. Metformin, a widely prescribed antidiabetic biguanide, exerts pleiotropic effects beyond glucose lowering and has emerged as a context-dependent regulator of ferroptosis. In malignant cells, metformin may enhance ferroptotic susceptibility through activation of AMP-activated protein kinase (AMPK), suppression of mechanistic target of rapamycin (mTOR) signaling and SLC7A11, induction of ferritinophagy, mitochondrial complex I stress, and promotion of lipid peroxidation. Conversely, in normal or stressed non-malignant tissues, metformin may limit ferroptotic injury by activating nuclear factor erythroid 2-related factor 2 (NRF2), supporting glutathione peroxidase 4 (GPX4) and SLC7A11-dependent antioxidant defenses, improving mitochondrial quality control, and stabilizing iron homeostasis. This review synthesizes the molecular basis of this duality, evaluates therapeutic opportunities in oncology and cytoprotection, and outlines biomarker-driven and clinical trial strategies required for translation. Overall, metformin should not be regarded as a universal ferroptosis inducer or inhibitor, but rather as a context-dependent metabolic regulator whose effects are shaped by cell type, dose, exposure duration, transporter expression, iron status, and antioxidant capacity. Full article

Cashmere production declines with age in Inner Mongolian cashmere goats, but the molecular mechanisms are unknown. This study employed a transcriptome-wide RNA-seq analysis to compare age-associated and breed-related gene expression profiles in goat skin, with particular emphasis on age-dependent AKT1 expression and its associated signaling pathways. Skin tissues from cashmere goats at 12 and 15 months and age-matched non-cashmere controls were analyzed by RNA-seq (BGIDNBSEQ platform). Differential expression and functional enrichment analyses were performed on skin transcriptomes of cashmere and control goats at 12 and 15 months. Age-specific functional profiles emerged: 12-month cashmere goats showed enrichment in GTPase activity, glucose transport, and ribosomal assembly, whereas 15-month goats were enriched for autophagosome assembly and apoptosis. FoxO signaling was commonly enriched across both ages, while the Hepatitis B pathway was unique to 12 months. AKT1 was significantly upregulated at 12 months coinciding with peak cashmere production with reduced expression at 15 months. This age-dependent pattern was supported by coordinated regulation of downstream effectors, including TSC2, PIK3R2, MAPK9, and FOXO3. Collectively, these transcriptomic data provide a mechanistic framework linking age-dependent AKT1 regulation to the decline in cashmere fiber production. Full article

Anesthetic agents are widely used in aquaculture to facilitate handling, transport, surgery, vaccination, tagging, and other husbandry procedures. However, most previous reviews have primarily focused on induction time, recovery duration, and welfare outcomes, with comparatively limited emphasis on blood physiology as an indicator of systemic anesthetic safety. The present review synthesizes current evidence regarding hematological, hemato-biochemical, blood gas, and immunohematological alterations induced by major anesthetic classes in aquaculture species. Literature published between 2000 and 2026 was retrieved from Scopus, Web of Science, Google Scholar, PubMed, ScienceDirect, and Springer Nature databases, with approximately 150 studies included following structured screening. Available evidence indicates that anesthetic exposure frequently alters erythrocyte and leukocyte profiles, cortisol secretion, glucose and lactate metabolism, hepatic enzyme activity, electrolyte balance, acid–base regulation, and blood oxygen transport. Respiratory depression, hypercapnia, hypoxemia, and transient metabolic acidosis were recurrent consequences of deep anesthesia, particularly during prolonged exposure or unfavorable environmental conditions. Several anesthetics also modulated innate immune responses through alterations in complement activity, respiratory burst function, cytokine signaling, and leukocyte redistribution. Collectively, the review highlights blood physiology as an essential framework for evaluating anesthetic safety and improving welfare-oriented aquaculture practices. Full article