Journal of physiology and biochemistry最新文献

The study aims to characterize the secretion dynamics of glucagon-related peptides, including GLP-1, GIP, and GLP-2, across different stages of metabolic-associated steatotic liver disease (MASLD), while evaluating the impact of type 2 diabetes (T2D) on these hormonal responses. Thirty-four MASLD subjects were stratified according with the liver transient elastography (TE ≥ 9 kPa) and T2D in NF (no fibrosis, without T2D; n = 12), NFD (no fibrosis, with T2D; n = 8), F (fibrosis, without T2D; n = 5), and FD (fibrosis, with T2D; n = 9) and completed a standardized 3-h meal tolerance test (MTT). The presence of liver fibrosis, regardless of diabetes status, was associated with hyperglycemia, hyperinsulinemia, and greater insulin resistance compared to the non-fibrosis (NF) group. Significant differences in glucagon and GLP-1 response curves were observed across groups. People with T2D showed an elevated peak of glucagon and increased glucagon exposure, as indicated by both the 60-min area under the curve (AUC60') and total AUC during the MTT. In the FD group, fasting and peak GLP-1 levels, as well as AUC60' and total AUC GLP-1, were 1.9-, 1.8-, and 1.9-fold higher, respectively, compared to the NF group. GIP responses were similar across groups, except for elevated fasting levels in NFD (p = 0.002). GLP-2 mirrored GLP-1, with FD showing the highest fasting and postprandial levels. Stepwise regression identified fibrosis and FPG as the main predictors of GLP-1, while glucagon was linked to FPG, HbA1c, and BMI. Liver fibrosis and T2D impact glucagon-related peptides responses in MASLD, revealing important metabolic alterations that may guide therapeutic approaches.

The interplay between systolic and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF) progression is unclear. First-phase ejection fraction (EF1), a sensitive marker of early systolic function, aids in assessing systolic-diastolic relationships in human hypertension and aortic stenosis. This study examines temporal changes in these relationships in mouse models of HFpEF and elevated afterload. Mouse models of abdominal aortic banding (AAB) and HFpEF (induced by hypertension and high fat feeding) underwent comprehensive serial echocardiography. In AAB, EF1 significantly decreased at week 1 post-surgery (18.8 ± 1.2 vs 24.3 ± 0.8%, p<0.001) compared to controls, with further reduction at week 3 (16.8 ± 0.6%) and week 6 (13.9 ± 0.9%, both p<0.001). EF, global longitudinal strain (GLS) and longitudinal strain rate (LSR) remained unchanged until week 3. Isovolumic relaxation time (IVRT) was the only abnormal index of diastolic function at week 1. In the HFpEF model, EF1 significantly decreased at week 2 (19.1 ± 1.1 vs 25.8 ± 1.0%, p<0.001) compared to controls, while EF, GLS, and LSR were unaltered. At week 3, EF1 decreased further (18.1 ± 0.7%) alongside a significant reduction in GLS (p<0.01), while EF and LSR remained unchanged. IVRT increased early in the HFpEF model, followed by later left atrial (LA) enlargement. EF1, an early marker of systolic impairment, decreases early in HFpEF and afterload-induced dysfunction, accompanied by IVRT prolongation. LA dilatation appears later. These findings highlight the interplay between systolic and diastolic dysfunction in HFpEF progression.

Calsequestrin 2 (CASQ2) has emerged as a central sensor and modulator of calcium (Ca²⁺) dynamics in sarcoplasmic reticulum (SR), influencing both health and disease. This review explores the molecular architecture and multifunctional roles of CASQ2, beginning with its domain organization and Ca²⁺-binding properties and detecting how its folding and supramolecular assembly modulate Ca²⁺ storage and release within cardiac muscle. Post-translational modifications, genetic regulatory mechanisms and CASQ2's multipartner interactome; including Ryanodine receptor 2 (RyR2), triadin and junctin are also discussed to highlight potential models in which complex stoichiometry and luminal Ca²⁺ dictate channel refractoriness and excitation-contraction coupling. Disruption of CASQ2 function is increasingly recognized as a driver of certain types of arrhythmias, notably catecholaminergic polymorphic ventricular tachycardia (CPVT) and heightened risk of sudden cardiac death. This review appraises contemporary therapies that focus on pharmacological and device-based interventions and surveys next-generation strategies that aim to directly stabilize CASQ2 or target its gene expression. Despite therapeutic advances, the challenges remain; and a translational agenda aligning mechanism with therapy is proposed. By integrating recent structural, functional, regulatory and pathological insights, this review provides a conceptual framework for the pivotal role of CASQ2 in arrhythmogenesis and positions CASQ2 biology at the center of precision cardiology.

Telomere shortening is a key marker of cellular aging and linked to pathologies such as liver disease. Oxidative stress and inflammation (hallmarks of obesity) contribute to telomere shortening, while omega-3 (DHA) and exercise may counteract these effects by enhancing cellular homeostasis. This study aims to analyze the influence of DHA supplementation and/or exercise over one year on liver telomere length in obese aged mice. Two-month-old female mice were fed either a control or high-fat diet (HFD) for four months. Diet-induced obese (DIO) mice were then assigned to one of four groups: (1) DIO, maintained on an HFD; (2) DIO + EX, subjected to exercise; (3) DIO + DHA, fed an HFD supplemented with DHA; and (4) DIO + DHA + EX, subjected to both exercise and DHA supplementation. The intervention continued until the mice reached 18 months of age. The DIO group showed significant telomere attrition, which was prevented only when omega-3 and exercise were combined. Additionally, only the combined DHA and exercise group improved the expression of genes related to oxidative stress (Sirt3, Foxo3, Sod1, Cat). Interestingly, DHA and exercise separately reduced pro-inflammatory cytokine Il-1b expression compared to the control group, but not when combined. These results indicate that DHA combined with physical exercise could be an effective strategy to maintain telomere integrity in aged obese female mice, due to their antioxidant properties.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis alongside metabolic comorbidities like type 2 diabetes mellitus (T2DM), dyslipidaemia, overweight, or obesity. Liver damage could be prevented promoting consumption of fruits and vegetables, the main source of phenolic compounds. These molecules have been previously related with antioxidant and anti-obesity properties. Therefore, the objective of this study is to determine the antioxidant capacity and potential preventive activity of an autochthonous apple pulp extract, Amarilla de Octubre, and its main phenolic compound, procyanidin B2 (PB2), in an in vitro model of liver steatosis. Antioxidant activity was assessed by xanthine/xanthine oxidase (X/XO) system and nitric oxide scavenging production. Monoamine oxidase A (MAO-A) inhibition was also determined due to its implication in detoxification processes in liver. Human hepatocytes (HepG2 cell line) were selected to test their potential cytotoxicity, oxidative stress situations (ROS production) and the potential effect in lipid metabolism by overloading cells with oleic acid. Fat accumulation and gene expression related to lipid metabolism (PPARγ, CD36 and FAS) were also analysed by Oil Red O and qPCR respectively. PB2 showed promising results as an antioxidant compound in scavenging and enzymatic inhibition-related experiments. However, Amarilla de Octubre not only reduce fat accumulation, but also modulates the expression of PPARγ, CD36, and FAS and demonstrates slightly lower efficacy than PB2 in scavenging and enzymatic inhibition-related experiments. These results highlight the potential of apples to mitigate pathogenic conditions associated with metabolic disorders such as obesity, emphasizing the role of dietary polyphenols in this protective effect.

Chronic stress disrupts homeostasis, leading to major health problems such as liver damage, intestinal barrier dysfunction, and impaired glucose metabolism. Although current treatments, including anxiolytics, sedatives, antidepressants, and beta blockers, are effective, their adverse effects emphasize the need for safer alternatives. Nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), plays a central role in energy metabolism and oxidative stress regulation; elevated NAD + levels have been associated with reduced risk of chronic diseases such as obesity and type 2 diabetes. However, the effects of NR on liver metabolism, intestinal barrier integrity, and related protein pathways remain unclear. This study investigated the effects of NR supplementation in rats exposed to chronic variable stress (CVS). Fifty-six male Sprague Dawley rats were divided into normal and CVS groups and treated in a 2 × 4 factorial design with 0, 150, 300, or 600 mg/kg NR. Under CVS conditions, serum glucose, corticosterone, ACTH, and insulin levels increased, whereas NAD+, NADPH, nicotinamide (NAM), and nicotinic acid (NA) decreased significantly (p < 0.001). NR supplementation effectively corrected these biochemical imbalances and upregulated hepatic markers, including PPARγ, SIRT1, GLUT2, IRS1, and FASN (p < 0.001). Furthermore, the increased expression of key transport proteins such as PepT1, LAT2, EAAT3, FABP2, and FATP4 contributed to maintaining intestinal barrier integrity and improving gut health. NR also promoted the recovery of tight and adherens junction proteins. Notably, high-dose NR (600 mg/kg) markedly alleviated liver fibrosis, improved glucose metabolism, and strengthened intestinal barrier function, demonstrating its therapeutic potential as an alternative strategy against stress-induced metabolic disorders. KEY POINTS: • NR mitigated chronic stress-induced liver, intestinal, and glucose dysregulation. • NR improved glycemia and NAD⁺-related biomarkers under stress. • NR reduced hepatic fibrosis markers. • NR strengthened TJ/AJ proteins, supporting intestinal barrier integrity. • Findings support NR's therapeutic potential in stress-related metabolism.

Overweight impacts over 390 million children and adolescents worldwide, of whom around 160 million are living with obesity. Adipose tissue biology in pediatric obesity is still relatively unknown. Adaptations to obesity including fat mobilization and remodeling are being investigated. The objective was to examine the lipidomic profile of subcutaneous and visceral adipose tissue (sWAT and vWAT, respectively) in children with obesity compared to those with normal weight, in order to identify novel lipid species modulated by obesity. Thirty pediatric patients with and without obesity were prospectively recruited at a referral single center and clinical data were reported. sWAT and vWAT samples were obtained for lipidomic analysis. Novel lipid species, including ether-linked triglycerides, ether-linked phosphatidylethanolamine, and oxidized triglycerides, were identified as altered in the sWAT from children with obesity compared with normal-weight children. These species are involved in beige adipose tissue development, energy metabolism, mitochondrial function, and oxidative stress. Compared with normal-weight children, the vWAT lipidome from children with obesity showed significant changes in some glycerophosphocholines, ceramides, and diglycerides, with accumulation of lipid species involved in inflammation, insulin resistance, and cardiovascular risk. The observed lipid correlations between vWAT and sWAT highlighted systemic dysregulation of lipid storage in childhood obesity, identifying both shared and depot-specific mechanisms of lipid handling. Our study reveals several critical lipid species that are modulated across both WAT depots, with notable implications for oxidative stress, lipid storage, and adipose tissue dysfunction. Key Points • The adipose lipidome of children with obesity showed specific alterations. • Lipid correlations revealed shared and depot-specific lipid handling mechanisms. • The altered lipid species had an impact on oxidative stress and insulin resistance.

Opuntia ficus-indica exhibits antioxidant, anti-inflammatory and anti-hyperglycemic properties, making it a promising candidate for the prevention and treatment of metabolic dysfunction-associated fatty liver disease. However, its effects on triglyceride accumulation remain largely unexplored. The aim of the present study is to evaluate the anti-steatotic effect of peel and pulp extracts from different varieties of Opuntia ficus-indica fruits (Pelota, Colorada and Sanguinos) in hepatic murine in vitro models, using both AML12 hepatocytes and hepatic organoids. The pulp extracts of Pelota and Colorada varieties, as well as both peel and pulp extracts of Sanguinos, were effective in reducing palmitic acid-induced triglyceride accumulation in AML12 hepatocytes. The doses that caused the greatest triglyceride reduction were 50 µg/mL of the pulp of Pelota and 100 µg/mL for the other extracts. The potential mechanisms underlying these effects seem to be associated, at least in part, with the inhibition of fatty acid uptake and triglyceride assembly. The pulp extract of the Colorada variety was able to prevent triglyceride accumulation also in hepatic organoids, likely due to downregulation of fatty acid transporters. These findings underscore the value of employing diverse in vitro models (e.g., 2D, 3D) to investigate the potential effects of these extracts, and suggest that the pulp extract of the Colorada variety may be effective in preventing steatosis.

Aerobic training (beneficial for type 1 diabetes mellitus (T1DM) patients) could result boring, leading to inactivity or suboptimal performance. Therefore, High-Intensity Interval Training (HIIT) could be an appealing alternative. The present study aimed to compare modulation of certain inflammatory cytokines in T1DM participants performing aerobic vs. HIIT routines. We recruited 26 T1DM male subjects: ages 18-40, T1DM ≥ 2 years, glycated hemoglobin < 8.5%, stable insulin regimen for 6 months, minimum 90 min weekly physical activity and completion of International Physical Activity Questionnaire (IPAQ). IPAQ:2 corresponds to moderate activity and IPAQ:3 to intense physical activity. Participants performed a single aerobic or HIIT session separated by at least 72 h. Blood plasma samples were collected 20 min before and after each session. Cytokines were measured using LUMINEX technique. After aerobic exercise, pro-inflammatory cytokines interleukin (IL)-1β, IL-6, IL-7, IL-8, IL-17 A, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) showed no significant differences in participants (IPAQ:2 and 3). Only anti-inflammatory cytokine IL-2 increased significantly in IPAQ:3 participants. Compared to pre-exercise, post-exercise HIIT situation presented a similar pattern. The 4 participants (IPAQ:3) that voluntarily followed a 12-week HIIT routine, showed significant increases in IL-7, IL-8, and TNF- α, and the detection of the anti-inflammatory cytokine IL-22. Altogether, these results suggest that HIIT favors the presence of some pro-inflammatory cytokines. The anti-inflammatory action of certain cytokines, such as IL-22, should be considered for a possible compensatory action. Nevertheless, programs of interval exercises at moderate intensity could be at the moment a safe option for T1DM patients.