Journal of physiology and biochemistry最新文献

Emerging research on microRNA has decoded its crucial role in gene regulation, development and diseases. Skeletal muscle atrophy is reported in several chronic diseases as well as prolonged stay at high altitude. miR-320-3p is reported to be upregulated in various chronic diseases including cancer, heart diseases, diabetes, and chronic kidney diseases. The present study evaluates the role of miR-320-3p expression in regulating apelin and its downstream signaling under hypobaric hypoxia (HH) at high altitude. The expression of miR-320-3p was found to be upregulated during 7days HH (7DHH) exposure at 25,000 ft as compared to control group. The targets for miR-320-3p were retrieved from miRWalk 3.0, TargetScan 8.0, miRTarBase 10.0 databases in Rattus norvegicus. Using in silico approach, 26 myokines were screened out of total 14,435 targets of rno-miR-320-3p and levels of few myokines were experimentally validated. The expression of apelin, decorin, osteocrin, meteorin-like myokines were found to be significantly decreased while myostatin was significantly increased during HH exposure as compared to control rats. Enhanced expression of Tgfb and p-Smad3 under 7DHH indicated activation of protein degradation pathways. Expression of Pgc1a and Nrf2, the critical regulators of mitochondrial biogenesis, were significantly decreased under HH. Thus, increased expression of miR-320-3p regulate apelin and modulate downstream signaling via attenuation of mitochondrial biogenesis and myogenesis. Hence, miR-320-3p and myokines play pivotal role to regulate skeletal muscle atrophy. Further research on potential targets of miR-320-3p regulating the muscle mass may lead to the development of novel therapeutics in personalized medicine to combat skeletal muscle diseases.

Women with polycystic ovary syndrome (PCOS) has high incidence of metabolic dysfunction-associated steatotic liver disease (MASLD). The development of PCOS-associated MASLD is accelerated by prepubertal obesity, therefore, we analyzed the impact of postnatal overfeeding-induced obesity on the gut microbiota and hepatic lipid metabolism in the PCOS rat model. Wistar rats were divided into 4 groups, where treatment with 5α-dihydrotestosterone (5α-DHT) stimulated hyperandrogenemia (DHT groups), whereas litter size reduction induced early postnatal overfeeding and obesity (SL groups). The fecal microbiota composition and diversity was analyzed by 16S rRNA sequencing. The bacterial metabolites level was measured by mass spectrometry. Hematoxylin-eosin staining, Western blots, and qRT-PCR were used to analyze hepatic lipid metabolism. Our results show that postnatal overfeeding shifted the microbiota composition towards obesity-associated genera, while hyperandrogenemia led to reduced β-diversity and increased abundance of androgen-regulated genera. Interaction of treatments reduced α- and β-diversity and decreased the abundance of beneficial butyrate-producing genera Roseburia, Oscillospira, and Ruminococcus and butyric acid plasma level. Shift in microbiota composition and activity was accompanied by decreased expression of G-protein coupled receptor (GPR) 43, fasting-induced adipocyte factor (FIAF) and increased expression of lipoprotein lipase (LPL). In accordance with altered GPR43 and FIAF/LPL pathway, increased expression of lipogenic transcription factors was observed in SL-DHT animals, but this did not result in hepatic lipid deposition. Our results demonstrated that postnatal overfeeding contributes to decreased richness and changes in gut microbiota composition in the PCOS animal model that is associated with impaired hepatic lipid metabolism, which may accelerate development of MASLD.

Intermittent fasting (IF), Time-Restricted Intermittent Fasting (TRIF), and fasting-mimicking diets have gained popularity among weight loss programs. The body efficiently utilizes its energy reserves to activate metabolic processes in response to food intake. Modifying food regimens can alter/extend life span and promote healthy aging by activating specific metabolic processes. However, changes in general lipid metabolism, especially the alteration in N-acylethanolamide (NAE) regulation and their role in promoting lipolysis and extending life span during TRIF, are still inadequately explored. To bridge the knowledge gap, this study focuses on enhancing Oleoylethanolamine (OEA), a precursor molecule that instigates satiety, promotes lipolysis and extends the life span of model system, Caenorhabditis elegans. TRIF regimen in C. elegans induces OEA, which in turn lead to satiety followed by lipolysis and ATP synthesis. Lipolysis is stimulated by the increase in Adipose Tissue Triglyceride Lipase-1 (ATGL-1) activity that results from the enrichment in OEA precursor. In addition, the TRIF regimen induces oxidative stress resistance in C. elegans. Subsequently, this promotes longevity and slow aging in C. elegans by altering the insulin/ insulin-like growth factor signaling (IIS) pathway. The present study suggested the beneficial effects of time-restricted fasting in the eukaryotic model nematodes through the activation of lipid metabolism that involves enhanced production of OEA precursors which promotes lipolysis. In addition, the data revealed that the increased ATP production resulted in oxidative stress tolerance that promoted longevity and slow aging processes.

Adipose tissue thermogenesis has emerged as a prominent research focus for the treatment of metabolic diseases, particularly through mitochondrial uncoupling, which oxidizes nutrients to produce heat rather than synthesizing ATP. Uncoupling protein 1 (UCP1) has garnered significant attention as a core protein mediating non-shivering thermogenesis(NST). However, recent studies indicate that energy dissipation can also occur via UCP1-independent thermogenesis, partially driven by futile metabolic cycles. These cycles involve ATP depletion coupled with reversible energy reactions, resulting in futile energy expenditure. Unlike classical UCP1-mediated thermogenesis, futile cycling is not confined to brown and beige adipose tissue, suggesting a broader range of therapeutic targets. These findings open new avenues for targeting these pathways to enhance metabolic health. This review explores the characteristics and distinctions of the primary metabolic organs (adipose tissue, liver, and skeletal muscle) involved in the futile cycles of thermogenesis. It further elaborates on the cellular and molecular mechanisms underlying calcium, creatine, and lipid cycling, emphasizing their strengths, limitations, and roles beyond thermogenesis.

Hepatocellular carcinoma (HCC) is the most common primary liver tumor, often arising in the context of chronic liver disease. Despite recent advances in systemic therapies, including the use of immune checkpoint inhibitors (ICIs), clinical outcomes remain suboptimal, with many patients exhibiting primary or acquired resistance. Accumulating evidence indicates that the dysregulation of epigenetic mechanisms contributes to HCC development, and may also play a crucial role in shaping the tumor immune microenvironment, influencing responses to treatments. In this study, we analyzed the expression profiles of a comprehensive set of epigenetic regulators across publicly available transcriptomic datasets of HCC and non-tumoral liver tissues. Our findings reveal a consistent dysregulation of key epigenetic modifiers, particularly those involved in DNA methylation and histone modification. Furthermore, our analysis underscores the need for a deeper understanding of the epigenetic landscape of HCC, as specific epigenetic patterns are directly associated with disease development, the major mutational, immune, and transcriptional subclasses of HCC, and patient clinical outcomes. Our study provides a foundation for integrating epigenetic biomarkers into patient stratification and therapeutic decision-making. A more comprehensive analysis of epigenetic alterations could pave the way for novel predictive markers and combination strategies that could enhance the efficacy of ICIs in HCC.

Acute pancreatitis represents a severe health problem, not only because of the number of people affected but also because of the severity of its clinical presentation that can eventually lead to the death of patients. The study of the disease is complex, and we lack optimized models that can approach the clinical presentation in patients, in addition to the significant vulnerability of the organ itself. In the present work, we undertook the task of reviewing and analyzing the experimental methods most currently used for the induction of acute pancreatitis, emphasizing the advantages and disadvantages of each model and their delimitation based on experimental objectives. We aimed to provide an actual and quick-access guide for researchers interested in experimental acute pancreatitis.

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly NAFLD, includes a range of conditions from steatosis to hepatocellular carcinoma and poses a significant health and economic burden. Circulating microRNAs (miRNAs) are key regulators of metabolic and inflammatory pathways involved in MASLD. However, their clinical utility as non-invasive biomarkers remain unclear. This review aims to clarify their diagnostic, prognostic, and therapeutic potential, addressing current gaps in the literature.

Methods: Following PRISMA guidelines, we conducted a systematic review of 1149 studies from the PubMed and Scopus databases up to 2024, focused on circulating miRNAs in MASLD.

Results: The most frequently studied miRNAs included miR-122 (35.56% of studies), miR-21 (18.89%), miR-34 (14.44%), and miR-192-5p (13.33%). Diagnostic accuracy varied among miRNAs, with miR-200 and miR-298 demonstrating AUROCs of 0.96 and 0.98, respectively, for MASLD detection. In MASH, miR-200, miR-298, and miR-342 exhibited near-perfect AUROCs of 0.99, while miR-122 showed values between 0.81 and 1.0. For HCC, miR-214 achieved an AUROC of 0.88, and miR-34a ranged from 0.73 to 0.76. Several miRNA panels demonstrated high diagnostic accuracy, with AUROCs up to 0.99, particularly in distinguishing HCC from other liver conditions. Prognostically, elevated miR-122 levels correlated with disease severity and fibrosis progression, while miR-21 and miR-223 were linked to obesity-associated MASH. Therapeutic interventions, including surgery, dietary modifications, and supplementation, were found to modulate miRNA profiles.

Conclusions: MiRNAs exhibit strong potential as minimally invasive biomarkers for MASLD, contributing to improved diagnosis, prognosis, and therapeutic decision-making. Their stability and role in personalized medicine underscore their clinical relevance.

Eccentric exercise is known to induce more pronounced muscle damage associated with delayed-onset muscle soreness than concentric exercise. This study aimed to investigate whether AMP-activated protein kinase (AMPK) pathway participates in control of mitophagy in rat skeletal muscle in response to downhill running. Eighty-eight male Sprague-Dawley rats were exercised on a treadmill tilted at 16° decline at 16 m·min^- 1 for 90 min, with the soleus muscle sampled at 0 h, 12 h, 24 h, 48 h and 72 h after exercise. The AMPK inhibitor compound C or AMPK activator AICAR or saline was injected intraperitoneally 20 min before exercise. After downhill treadmill running, the skeletal muscle mitochondrial structure appeared to be abnormal and contained mitophagosomes; the expression levels of AMPK phosphorylation, cyclophilin D (CypD), cytochrome C (CytC), mitochondrial FK506-binding protein 8 (FKBP8), microtubule-associated protein 1 light chain 3 (LC3), and the co-localization of FKBP8 with LC3 and mitochondria with dynamin-related protein 1 (Drp1), lysosomal-associated membrane protein 2 (LAMP2) were significantly higher; the expression levels of mechanistic target of rapamycin (mTOR Ser2448) phosphorylation and heat shock protein 60 (HSP60), mitochondrial respiratory complex I (NDUFB8) and complex III (UQCRC2), and adenosine triphosphate (ATP) content were significantly lower than those in the C group. Further study showed that the effect of downhill treadmill running was partly blocked by compound C and strengthened by AICAR. A session of downhill treadmill running activated the AMPK pathway and promoted LC3 co-localizations with mitochondria and FKBP8, and induced mitophagy and mitochondrial damage within rat skeletal muscle.