Journal of physiology and biochemistry最新文献

Mediated by the bitter taste receptors (TAS2R), the perception of bitter taste does not only involve the oral cavity but various physiological systems throughout the gastrointestinal tract. The relationship between stimulation and modulation is crucial for understanding the broader implications of bitter taste signalling in health and disease. In this study, we investigated how the expression of intestinal rat Tas2r (rTas2r) is affected by natural extracts containing bitter ligands, examined their association with obesity, and their effects on GLP-1 secretion. For this, we performed subchronic stimulations with a mixture of polyphenols and individual molecules in rats. Moreover, we also examined how the individual bitter molecule (epicatechin) affects the secretory profile of intestinal enteroendocrine cells. Treating rats with procyanidins up-regulated rTas2r in all the segments of the gastrointestinal tract, with the most changes observed in the duodenum and ascending colon. Epicatechin, one of the main components of the previously used extract, had a much more specific effect, as we observed mostly changes in the jejunum, where rTas2137, -139, -143 and -144 were up-regulated. In Hutu-80 cells, epicatechin downregulated TAS2R14 after 24 hours, which limited GLP-1 secretion after acute peptone stimulation. Our results support a network effect in the role of the bitter taste receptors along the intestinal areas that must be considered to address the work with bitter agonists.

Hedgehog (Hh) signaling is an important pathway involved in major biological processes such as embryonic development, adult morphogenesis, and vascular biology (i.e., vasculogenesis, angiogenesis and arterial remodeling). The latter role was more recently elucidated, occurring through regulation of angiogenic cytokines and controlling the proliferation, and migration of endothelial cells (ECs) or vascular smooth muscle cells (VSMCs), that help deliver oxygen and nutrients to tissues. Anomalous inhibition or activation of Hh signaling is therefore implicated in various pathological conditions, including vascular diseases. However, the mechanisms of Hh involvement in vascular biology have not been systematically clarified. This review covers recent research regarding the regulatory role and mechanism of Hh signaling in vasculogenesis, angiogenesis, and arterial remodeling. We conclude that the Hh signaling pathway holds great promise for treating vascular diseases and cancers. We encourage further research to develop a full understanding of the underlying mechanisms so that we can better determine the Hh pathway's therapeutic value.

Ceramides are sphingolipids formed from fatty acids linked to sphingosine and an amide, which are involved in cellular pathways such as apoptosis, fibrosis, oxidative stress, and inflammation. Six distinct fatty acyl selective ceramide synthases (CerS) produce ceramides. This specific enzymatic modulation can either increase or reduce the production of specific ceramides, which can have either adverse or protective effects, suggesting that enzymatic modulation may serve as a tool for innovative therapy. Specifically, modulation of glucosylceramide synthase, sphingomyelinase, or ceramidase can reverse the generation of potentially apoptotic ceramides, similar to how inhibition of serine palmitoyltransferase or ceramide synthases may be significant in inflammatory conditions by decreasing the generation of inflammatory ceramides. In this context, the modulation of plasma ceramides may represent a protective factor for chronic non-communicable diseases (NCDs), such as cardiovascular diseases, type 2 diabetes, and chronic kidney disease. Previous studies indicate that dietary fat and protein intake influence plasma sphingolipid levels. Therefore, this review aims to discuss the effects of ceramide on patients with NCDs, providing an overview of the influence of nutrition on ceramide levels and outlining future perspectives.

Malnutrition of protein and essential nutrients in children can lead to serious health problems. It significantly alters hepatic physiology and leads to impaired liver function. The present study investigated the underlying mechanism of malnutrition-induced steatohepatitis in a rat model. Weanling rats were divided into two groups. The control rats received a standard protein diet, while the other group was fed a low protein diet (LPD) for eight weeks. LPD significantly reduced the body and liver weights and altered the blood parameters. LPD resulted in elevated serum liver injury markers and lowered glucose, albumin, and total protein levels. The reduced levels of TIBC and TSI and upregulated expression of Hamp gene were observed in the LPD group. Histopathology revealed the severe fat accumulation in the hepatocytes, leading to inflammation and fibrognesis. LPD upregulated the de novo lipogenesis (Srebp1c, Fas, Acc, and Scd1) markers and oxidative stress in the hepatic tissue. The downregulation of Pgc1α, Tim23, and Tfam indicated mitochondrial dysfunction in the LPD group. Transcriptomic analysis revealed the upregulation of 7,545 genes in the LPD group mainly associated with metabolic dysfunction-associated steatotic liver disease (MASLD), beta-oxidation, AMPK signalling and oxidative phosphorylation. Hepatic lipidome revealed the elevated levels of various lipid species in the LPD group. Further, LPD altered the gut microbiome of rats and reduced the relative abundance of beneficial bacteria. The present study revealed that malnutrition induces hepatic steatoheptitis by altering the hepatic lipid metabolism and disrupting mitochondrial function and gut-liver axis.

Ferroptosis is a kind of programmed cell death characterized by the iron-dependent lipid peroxides accumulation, playing a pivotal role in the pathogenesis of various diseases, including neurodegenerative disorders, cardiovascular diseases, and osteoporosis. Mesenchymal stem cells (MSCs) and MSCs-derived exosomes (MSC-exos) are actively implicated in key biological processes, such as inflammatory and immune responses, tissue regeneration and repair, and aging. Emerging studies highlight the potential of MSCs and MSC-exos as effective regulators of ferroptosis, offering novel strategies for targeted therapeutic intervention in ferroptosis-related pathologies. This review comprehensively explores the precise regulatory mechanisms by which MSCs and MSC-exos modulate ferroptosis. We also evaluate the impact of ferroptosis on MSC biological functions and MSC-exos release. Furthermore, the therapeutic potentials and advantages of engineered MSCs and MSC-exos in the treatment of various diseases have also been explored, emphasizing their mechanistic roles in ferroptosis modulation across different organs and systems. This review provides insights and future directions for the development of novel MSC- or MSC-exos-based therapeutic strategies targeting ferroptosis.

Acute intermittent porphyria (AIP) is a genetic metabolic disorder characterized by neurovisceral attacks. Although high-carbohydrate diets or intravenous glucose administration can help alleviate incipient attacks in patients, these interventions may also promote insulin resistance and increase metabolic risk. This study explored targeted dietary interventions to manage hyperinsulinemia and to enhance glucose uptake in insulin-sensitive organs under high-carbohydrate diet. Body composition and fecal microbiota profile were also investigated in a murine model of the disease. Wild-type and AIP mice (n = 6/group) were supplemented with tapioca maltodextrin in drinking water for 12 weeks, alongside heat-treated Bifidobacterium animalis subsp. lactis CECT-8145 (BPL1®HT), its by-product lipoteichoic acid (LTA), or the insulin-sensitizing agent α-lipoic acid (α-LA). Liver-targeted therapies, previously assessed in AIP mice, were also included in this study. AIP mice on a high-carbohydrate diet exhibited hyperinsulinemia and tissue-specific differences in glucose uptake compared to wild-type mice. Dysbiosis, marked by reduced fecal Dorea spp. and Adlercreutzia muris, alongside higher abundance of Escherichia coli, was also showed. Supplementation with α-LA and LTA revealed superior ability to improve glucose tolerance test and skeletal muscle glucose uptake, reduce hyperinsulinemia, and enhance body composition by increasing lean mass relative to fat, compared to gene therapy or liver-targeted insulin administration. Notably, LTA restored fecal microbiota profiles resembling those of wild-type mice. In conclusion, supplementation with LTA from BPL1®HT and α-LA may represent promising dietary interventions to manage glucose tolerance, improve insulin sensitivity in muscle and adipose tissues, and potentially ameliorate body composition in AIP patients under a high-carbohydrate diet.

Myocardial infarction (MI) is characterized by sudden interruption of coronary blood flow, leading to ischemic damage and cardiomyocyte death. Evidence for new molecular targets remains limited. Here, we investigated the role of Schlafen 4 (Slfn4), identified via bioinformatic screening, in MI pathogenesis. We analyzed GSE46395 microarray data and observed elevated Slfn4 expression in ischemic cardiac tissue. An MI mouse model further confirmed Slfn4 upregulation, which was abrogated by AAV9-mediated shRNA knockdown. Silencing Slfn4 reduced inflammatory cell infiltration and cardiomyocyte apoptosis, leading to lower serum levels of ANP, BNP, cTnT, cTnI, IL-1β, and TNF-α. Notably, Slfn4 knockdown augmented BNIP3-dependent mitophagy, evidenced by upregulated LC3 I/II, decreased P62, and reduced mitochondrial proteins (COX IV, TOMM20), while also suppressing DRP1-mediated mitochondrial fission. In cultured H9C2 cells subjected to hypoxia, Slfn4 knockdown likewise diminished apoptosis and enhanced BNIP3-associated mitophagy, whereas BNIP3 silencing reversed these protective effects, underscoring the importance of BNIP3-mediated mitophagy in Slfn4-driven cardioprotection. These findings indicate that Slfn4 promotes MI-induced damage by inhibiting BNIP3-mediated mitophagy and exacerbating mitochondrial fission. By contrast, Slfn4 knockdown fosters cardiomyocyte survival, highlighting its therapeutic potential for MI. Overall, our data suggest that modulating Slfn4 expression may preserve mitochondrial quality control, attenuate inflammation and apoptosis, and improve cardiac function following ischemic injury. .

The age-related decrease in skeletal muscle mass and function, mostly known as sarcopenia, increases the risk of mobility impairments, chronic disease and early mortality. Physical activity and targeted dietary approaches are the most effective intervention to prevent or limit sarcopenia. Omega-3 polyunsaturated fatty acids (PUFA) could alleviate some aspects of age-related diseases. We investigated the effect of a chronic intake of a diet containing a high content of omega-3 PUFA in old mice exposed to a normocaloric or an obesogenic diet. Female C57BL/6J mice received a low-fat or a high-fat diet containing 5 or 6%, respectively, of camelina oil (comprising 27% omega-3 PUFA) for 18 weeks and were compared to animals receiving the similar diets containing high-oleic sunflower oil instead. Circulating parameters, calorimetry and physical performances were evaluated as well as muscle lipid content and molecular adaptations. Consumption of camelina oil increased omega-3 PUFA content in biological membranes, as well as circulating levels of anti-inflammatory oxylipin mediators. High-fat diets induced changes in body composition but these effects were not affected by the intake of camelina oil. However, camelina oil consumption increased motor coordination in the low-fat condition. Some lipidomic adaptations were observed in relation to oil intake. Variations in plasma levels of glycerol, free fatty acids and muscle gene expression suggested improved lipid homeostasis in groups receiving camelina oil. In conclusion, the consumption of an energy-balanced diet with a high content of omega-3 PUFA provided by camelina oil could provide benefits on muscle health. CLINICAL TRIAL REGISTRATION: Not applicable.

Adipose tissue browning, the conversion of white adipose tissue (WAT) into brown or beige adipose tissue, offers potential for combating obesity and metabolic disorders. This review delves in to the transcriptional and epigenetic regulation of WAT browning and how it impacts metabolic health and its significance in various disease conditions. Further the review explains how various external factors such as diet and exercise play an influential role in the regulation of WAT browning. UCP1 gene, which plays a crucial role in cellular thermogenesis is found to be the major mediator of this phenomenon along with functional dynamics of mitochondria. Gut microbiome has been another focus point in this review that highlights how alterations to the composition of different species of bacteria in gut microbiome can directly influence WAT browning. Finally the review discusses the various pharmaceutical and neutraceutical options under research that targets WAT browning to improve metabolic status of an individual. Therapeutic strategies include β3-adrenergic receptor agonists, GLP-1 receptor agonists, AMPK activators, and natural compounds such as capsaicin and resveratrol. Emerging CRISPR/Cas9 gene therapies aim to induce WAT browning. Clinical evidence to prove the significance of this phenomena is currently limited but growing rapidly as seen in the number of clinical trials that are undergoing currently, therefore the review strongly rely upon animal model and cell culture based studies to justify this area of novel research. Despite its potential, challenges like individual variability, long-term safety, and complex gut microbiome interactions remain. Future research should target novel pathways, optimize therapeutic regimens, and personalize treatments.