Search Results (1,232)

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) are a cell model now widely used to investigate pathophysiological features of cardiac tissue. Given the invaluable contribution hiPSC-CM could make for studies on cardio-metabolic disorders by defining a postnatal metabolic phenotype, our work herein focused on monitoring the insulin response in CM derived from the hiPSC line UKBi015-B. Western blot analysis on total cell lysates obtained from hiPSC-CM showed increased phosphorylation of both AKT and AS160 following insulin treatment, but failed to highlight any changes in the expression dynamics of the glucose transporter GLUT4. By contrast, the Western blot analysis of membrane fractions, rather than total lysates, revealed insulin-induced plasma membrane translocation of GLUT4, which is known to also occur in postnatal CM. Thus, these findings suggest that hiPSC-derived CMs exhibit an insulin response reminiscent to that of adult CMs regarding intracellular signaling and GLUT4 translocation to the plasma membrane, representing a suitable cellular model in the cardio-metabolic research field. Moreover, our studies also demonstrate the relevance of analyzing membrane fractions rather than total lysates in order to monitor GLUT4 dynamics in response to metabolic regulators in hiPSC-CMs. Full article

Preserving the function and survival of pancreatic beta-cells, in order to achieve long-term glycemic control and prevent complications, is an essential feature for an innovative drug to have clinical value in the treatment of diabetes. Innovative research is developing therapeutic strategies to prevent pathogenic mechanisms and protect beta-cells from the deleterious effects of inflammation and/or chronic hyperglycemia over time. A better understanding of receptors and signaling pathways, and of how they interact with each other in beta-cells, remains crucial and is a prerequisite for any strategy to develop therapeutic tools aimed at modulating beta-cell function and/or mass. Here, we present a comprehensive review of our knowledge on membrane and intracellular receptors and signaling pathways as targets of interest to protect beta-cells from dysfunction and apoptotic death, which opens or could open the way to the development of innovative therapies for diabetes. Full article

The impaired function of the serotonin transporter (SERT) in humans has been linked to a higher risk of obesity and type 2 diabetes, especially as people age. Consuming a “Western diet” (WD), which is high in saturated fats, cholesterol, and sugars, can induce metabolic syndrome. Previous research indicated that mice carrying a targeted inactivation of the Sert gene (knockout, KO) and fed a WD display significant metabolic disturbances and behaviors reminiscent of ADHD. These abnormalities might be mediated via a dysfunction in insulin receptor (IR) signaling, which is also associated with adult ADHD. However, the impact of Sert deficiency on IR signaling and systemic metabolic changes has not been thoroughly explored. In this study, we conducted a detailed analysis of locomotor behavior in wild-type (WT) and KO mice fed a WD or control diet. We investigated changes in the blood metabolome and examined, via PCR, the expression of insulin receptor A and B isoforms and key regulators of their function in the brain. Twelve-month-old KO mice and their WT littermates were fed a WD for three weeks. Nuclear magnetic resonance spectroscopy analysis of plasma samples showed that KO mice on a WD had higher levels of lipids and lipoproteins and lower levels of glucose, lactate, alanine, valine, and isoleucine compared to other groups. SERT-KO mice on the control diet exhibited increased brain levels of both IR A and B isoforms, accompanied by a modest increase in the negative regulator ENPP. The KO mice also displayed anxiety-like behavior and reduced exploratory activity in an open field test. However, when the KO animals were fed a WD, the aberrant expression levels of IR isoforms in the KO mice and locomotor behavior were ameliorated indicating a complex interaction between genetic and dietary factors that might contribute to ADHD-like symptoms. Overall, our findings suggest that the lack of Sert leads to a unique metabolic phenotype in aged mice, characterized by dysregulated IR-related pathways. These changes are exacerbated by WD in the blood metabolome and are associated with behavioral abnormalities. Full article

This narrative review explores the pathophysiology of obesity, cellular senescence, and exosome release. When exposed to excessive nutrients, adipocytes develop mitochondrial dysfunction and generate reactive oxygen species with DNA damage. This triggers adipocyte hypertrophy and hypoxia, inhibition of adiponectin secretion and adipogenesis, increased endoplasmic reticulum stress and maladaptive unfolded protein response, metaflammation, and polarization of macrophages. Such feed-forward cycles are not resolved by antioxidant systems, heat shock response pathways, or DNA repair mechanisms, resulting in transmissible cellular senescence via autocrine, paracrine, and endocrine signaling. Senescence can thus affect preadipocytes, mature adipocytes, tissue macrophages and lymphocytes, hepatocytes, vascular endothelium, pancreatic β cells, myocytes, hypothalamic nuclei, and renal podocytes. The senescence-associated secretory phenotype is closely related to visceral adipose tissue expansion and metaflammation; inhibition of SIRT-1, adiponectin, and autophagy; and increased release of exosomes, exosomal micro-RNAs, pro-inflammatory adipokines, and saturated free fatty acids. The resulting hypernefemia, insulin resistance, and diminished fatty acid β-oxidation lead to lipotoxicity and progressive obesity, metabolic syndrome, and physical and cognitive functional decline. Weight cycling is related to continuing immunosenescence and exposure to palmitate. Cellular senescence, exosome release, and the transmissible senescence-associated secretory phenotype contribute to obesity and metabolic syndrome. Targeted therapies have interrelated and synergistic effects on cellular senescence, obesity, and premature aging. Full article

The most widely used synthetic glucocorticoid, dexamethasone (DEX), causes stunted growth in children when used excessively or for long periods of time; however, there are still plenty of pediatric patients require long-term treatment with DEX. As an alternative, growth hormone is used in combination, but it has side effects, a high cost, and psychological factors, and it is not satisfactory in terms of effectiveness. It is necessary to develop a safe and affordable treatment that can replace it. The Korean Food and Drug Administration approved HT042, a standardized functional food ingredient, with the claim that it can help height growth of children. In this study, it was found that HT042 activated the Indian hedgehog/parathyroid hormone-related protein signaling pathway and enhanced the number of growth hormone receptors and insulin-like growth factor-1 receptors on the growth plate surface, which were reduced by DEX treatment, and restored growth retardation. In metatarsal bone and primary chondrocyte models, it was found that HT042 can promote the length of growth plate and recover DEX-induced growth retardation. It was also found that HT042 promotes cell proliferation using bromodeoxyuridine and terminal deoxynucleotidyl transferase dUTP nick end labeling assays; moreover, we verified increased expression of GHR/IGF-1R and Ihh/PTHrP pathway activity using qRT-PCR, western blotting, and siRNA analyses to verify its direct action on the growth plate. The anti-apoptotic effect of HT042 was identified by regulating the expression of apoptotic factors such as caspase-3, Bcl2, Bclx, and Bax. These results were identified using both ex vivo and in vitro models. Our study verified that co-administration of HT042 could recover the DEX induced growth retardation Full article

Diabetes mellitus type 2 (T2DM) is a common chronic condition that presents as unsettled hyperglycemia (HG) and results from insulin resistance (IR) and β-cell dysfunction. T2DM is marked by an increased risk of microvascular and macrovascular complications, all of which can be the cause of increasing mortality. Diabetic nephropathy (DNE), neuropathy (DNU), and retinopathy (DR) are the most common complications of diabetic microangiopathy, while diabetic cardiomyopathy (DCM) and peripheral vascular diseases are the major diabetic macroangiopathy complications. Chalcones (CHs) are in the flavonoid family and are commonly found in certain plant species as intermediate metabolites in the biosynthesis of flavonoids and their derivatives. Natural CHs with different substituents exert diverse therapeutic activities, including antidiabetic ones. However, the therapeutic mechanisms of natural CHs through influencing genes and/or signaling pathways in T2DM complications remain unknown. Therefore, this review summarizes the existing results from experimental models which highlight the mechanisms of natural CHs as therapeutic agents for T2DM complications. Full article

Blue gourami (gourami, Trichogaster trichopterus) is a model for labyrinth fishes (Anabantoidei) adapted to partial air breathing. Its reproductive endocrinology has been extensively studied, and transcriptomic sex differences in the gonads were described. Nevertheless, sex differences in gene expression in non-gonadal tissues ostensibly affected by the sex-specific hormonal balance, e.g., the brain, are unknown. To assess such differences, we used bulk RNA-seq to assemble and compare polyA+ transcriptomes between whole brains of four adult male and five adult female gourami, in addition to other tissues (three dorsal fin and five ovary samples) from the same female group. While all nine brain transcriptomes clustered together relative to the other tissues, they showed separation according to sex. A total of 3568 genes were differentially expressed between male and female brains; of these, 1962 and 1606 showed lower and higher expression in males, respectively. Male brains showed stronger down-regulation of specific genes, which included hormone receptors, e.g., pituitary adenylate cyclase-activating polypeptide receptor (pacap-r1). Among the genes with lower expression in male brains, multiple pathways essential to brain function were over-represented, including GABA, acetylcholine and glutamate receptor signaling, calcium and potassium transmembrane transport, and neurogenesis. In contrast, genes with higher expression in male brains showed no significant over-representation of brain-specific functions. To measure the mRNA levels of specific hormone receptors known from prior studies to regulate reproductive function and behavior in gourami and to validate RNA-seq results for these specific genes, we performed RT-qPCR for five receptors, pacap-r1, gonadotropin-releasing hormone 2 receptor (gnrh2r), kisspeptin receptor 1 (gpαr1/kiss1), insulin-like growth factor 1 receptor (igf1r), and membrane progesterone receptor 1 (mpr1), in the brain RNA sample groups. Of these, pacap-r1 showed a significant, three-fold down-regulation, while gpαr1/kiss1 showed a significant two-fold down-regulation in male vs. female gourami brains. Our results are novel in describing the suppression of brain function-related gene expression in male, as compared to female, gourami brains. Further research is needed to assess the behavioral significance of this effect and its prevalence in other vertebrate groups. Full article

Poplar buds are characterized by a high content of phenolic compounds, which exhibit a broad spectrum of biological activities. However, the relationship between Chinese propolis and poplar buds based on their antioxidant capacities and underlying mechanisms remains unclear. This study aimed to investigate the antioxidant properties of poplar bud (Populus) extract (PBE) and Chinese propolis (CP) and to elucidate the mechanisms behind their activity. High-performance liquid chromatography (HPLC) analysis revealed that both PBE and CP contain a significant amount of phenolic acids and flavonoids. 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and ferric-reducing antioxidant power (FRAP) assays demonstrated that PBE and CP possess excellent antioxidant activity. Furthermore, administration of PBE and CP improved the survival rate of C. elegans under oxidative stress. They also decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while enhancing the activity of antioxidant enzymes (SOD, CAT). PBE and CP intervention upregulated the expression of key genes daf-16, sod-3, hsp-16.2, and skn-1 in nematodes. This suggests that the antioxidant activity of PBE and CP is dependent on daf-16 and skn-1 signaling pathways. In conclusion, poplar bud extracts ha have the potential to become a substitute for propolis and a potential therapeutic agent for treating diseases associated with oxidative damage. Full article

Imiqualines are analogues of the immunomodulatory drug imiquimod. EAPB02303, the lead of the second-generation imiqualines, is characterized by significant anti-tumor effects with IC50s in the nanomolar range. We used Caenorhabditis elegans transgenic and mutant strains of two key signaling pathways (PI3K-Akt and Ras-MAPK) disrupted in human cancers to investigate the mode of action of EAPB02303. The ability of this imiqualine to inhibit the insulin/IGF1 signaling (IIS) pathway via the PI3K-Akt kinase cascade was explored through assessing the lifespan of wild-type worms. Micromolar doses of EAPB02303 significantly enhanced longevity of N2 strain and led to the nuclear translocation and subsequent activation of transcription factor DAF-16, the only forkhead box transcription factor class O (Fox O) homolog in C. elegans. Moreover, EAPB02303 significantly reduced the multivulva phenotype in let-60/Ras mutant strains MT2124 and MT4698, indicative of its mode of action through the Ras pathway. In summary, we showed that EAPB02303 potently reduced the activity of IIS and Ras-MAPK signaling in C. elegans. Our results revealed the mechanism of action of EAPB02303 against human cancers associated with hyperactivated IIS pathway and oncogenic Ras mutations. Full article

Glycolipid metabolic disorders (GLMDs) are various metabolic disorders resulting from dysregulation in glycolipid levels, consequently leading to an increased risk of obesity, diabetes, liver dysfunction, neuromuscular complications, and cardiorenal vascular diseases (CRVDs). In patients with GLMDs, excess caloric intake and a lack of physical activity may contribute to oxidative stress (OxS) and systemic inflammation. This study aimed to review the connection between GLMD, OxS, metainflammation, and the onset of CRVD. GLMD is due to various metabolic disorders causing dysfunction in the synthesis, breakdown, and absorption of glucose and lipids in the body, resulting in excessive ectopic accumulation of these molecules. This is mainly due to neuroendocrine dysregulation, insulin resistance, OxS, and metainflammation. In GLMD, many inflammatory markers and defense cells play a vital role in related tissues and organs, such as blood vessels, pancreatic islets, the liver, muscle, the kidneys, and adipocytes, promoting inflammatory lesions that affect various interconnected organs through their signaling pathways. Advanced glycation end products, ATP-binding cassette transporter 1, Glucagon-like peptide-1, Toll-like receptor-4, and sphingosine-1-phosphate (S1P) play a crucial role in GLMD since they are related to glucolipid metabolism. The consequences of this is system organ damage and increased morbidity and mortality. Full article

Affecting approximately 25% of the global population, steatotic liver disease (SLD) poses a significant health concern. SLD ranges from simple steatosis to metabolic dysfunction-associated steatohepatitis and fibrosis with a risk of severe liver complications such as cirrhosis and hepatocellular carcinoma. SLD is associated with obesity, atherogenic dyslipidaemia, and insulin resistance, increasing cardiovascular risks. As such, identifying SLD is vital for cardiovascular disease (CVD) prevention and treatment. Bile acids (BAs) have critical roles in lipid digestion and are signalling molecules regulating glucose and lipid metabolism and influencing gut microbiota balance. BAs have been identified as critical mediators in cardiovascular health, influencing vascular tone, cholesterol homeostasis, and inflammatory responses. The cardio-protective or harmful effects of BAs depend on their concentration and composition in circulation. The effects of certain BAs occur through the activation of a group of receptors, which reduce atherosclerosis and modulate cardiac functions. Thus, manipulating BA receptors could offer new avenues for treating not only liver diseases but also CVDs linked to metabolic dysfunctions. In conclusion, this review discusses the intricate interplay between BAs, metabolic pathways, and hepatic and extrahepatic diseases. We also highlight the necessity for further research to improve our understanding of how modifying BA characteristics affects or ameliorates disease. Full article

Previous studies have demonstrated that enzymatically prepared coix seed prolamin hydrolysates (CHPs) contain several bioactive peptides that efficiently inhibit the activity of target enzymes (α-glucosidase and dipeptidyl kinase-IV) in type 2 diabetes mellitus (T2DM). However, the anti-T2DM effects and potential mechanisms of CHPs as a whole in vivo have not yet been systematically explored. Therefore, we evaluated the preventive, therapeutic, and modifying effects of CHPs on T2DM by combining physiological and liver transcriptomics with a T2DM mouse model. The results showed that sustained high-fructose intake led to prediabetic symptoms in mice, with abnormal fluctuations in blood glucose and blood lipid levels. Intervention with CPHs effectively prevented weight loss; regulated abnormal changes in blood glucose; improved impaired glucose tolerance; inhibited the abnormal expression of total cholesterol, triglycerides, and low-density lipoproteins; alleviated insulin resistance; and restored pancreatic islet tissue function in mice fed a high-fructose diet. In addition, we found that CHPs also play a palliative role in the loss of liver function and protect various organ tissues (including the liver, kidneys, pancreas, and heart), and are effective in preventing damage to the liver and pancreatic islet cells. We also found that the intake of CHPs reversed the abnormally altered hepatic gene profile in model mice and identified 381 differentially expressed genes that could serve as key genes for preventing the development of T2DM, which are highly correlated with multiple glycolipid metabolic pathways. We demonstrated that CHPs play a positive role in the normal functioning of the insulin signalling pathway dominated by the IRS-1/PI3K/AKT (insulin receptor substrates-1/phosphoinositide 3-kinase/protein kinase B) pathway. In summary, CHPs can be used as effective food-borne glucose-modifying components of healthy foods. Full article

While obesity-related nonalcoholic fatty liver disease (NAFLD) is linked with metabolic dysfunctions such as insulin resistance and adipose tissue inflammation, lean NAFLD more often progresses to liver fibrosis even in the absence of metabolic syndrome. This review aims to summarize the current knowledge regarding the mechanisms of liver fibrosis in lean NAFLD. The most commonly used lean NAFLD models include a methionine/choline-deficient (MCD) diet, a high-fat diet with carbon tetrachloride (CCl₄), and a high-fructose and high-cholesterol diet. The major pro-fibrogenic mechanisms in lean NAFLD models include increased activation of the extracellular signal-regulated kinase (ERK) pathway, elevated expression of α-smooth muscle actin (α-SMA), collagen type I, and TGF-β, and modulation of fibrogenic markers such as tenascin-X and metalloproteinase inhibitors. Additionally, activation of macrophage signaling pathways promoting hepatic stellate cell (HSC) activation further contributes to fibrosis development. Animal models cannot cover all clinical features that are evident in patients with lean or obese NAFLD, implicating the need for novel models, as well as for deeper comparisons of clinical and experimental studies. Having in mind the prevalence of fibrosis in lean NAFLD patients, by addressing specific pathways, clinical studies can reveal new targeted therapies along with novel biomarkers for early detection and enhancement of clinical management for lean NAFLD patients. Full article

This study explored the potential of saponins from Korean Red Ginseng to target the PINK1/Parkin mitophagy pathway, aiming to enhance insulin sensitivity in hepatocytes—a key factor in metabolic disorders like metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes. Results from both in vitro and in vivo experiments showed increased expression of PINK1 and Parkin, activating mitophagy and reducing oxidative stress through reduction in mitochondrial and total reactive oxygen species. Additionally, improvements in insulin signaling were observed, including the upregulation of phosphorylated IRS and AKT, and downregulation of gluconeogenic enzymes, underscoring the saponins’ efficacy in boosting insulin sensitivity. The findings highlighted Korean Red Ginseng-derived saponins as potential treatments for insulin resistance and related metabolic conditions. Full article

Protein tyrosine phosphatase 1B (PTP1B) is a non-receptor tyrosine phosphatase best known for its role in regulating insulin and leptin signalling. Recently, knowledge on the role of PTP1B as a major regulator of multiple signalling pathways involved in cell growth, proliferation, viability and metabolism has expanded, and PTP1B is recognised as a therapeutic target in several human disorders, including diabetes, obesity, cardiovascular diseases and hematopoietic malignancies. The function of PTP1B in the immune system was largely overlooked until it was discovered that PTP1B negatively regulates the Janus kinase—a signal transducer and activator of the transcription (JAK/STAT) signalling pathway, which plays a significant role in modulating immune responses. PTP1B is now known to determine the magnitude of many signalling pathways that drive immune cell activation and function. As such, PTP1B inhibitors are being developed and tested in the context of inflammation and autoimmune diseases. Here, we provide an up-to-date summary of the molecular role of PTP1B in regulating immune cell function and how targeting its expression and/or activity has the potential to change the outcomes of immune-mediated and inflammatory disorders. Full article