Search Results (129)

Corneal fibrosis is a major cause of visual impairment worldwide and is characterized by persistent stromal scarring that disrupts corneal transparency. Although transforming growth factor-β (TGF-β)-mediated myofibroblast differentiation is well established, the mechanisms that sustain myofibroblast survival and persistence remain poorly understood. In this study, we investigated the role of the insulin-like growth factor (IGF) signaling axis in corneal myofibroblast survival and evaluated the therapeutic potential of linsitinib, a dual IGF-1 receptor (IGF-1R)/insulin receptor (INSR) inhibitor. Primary corneal myofibroblasts were exposed to pro-apoptotic conditions and treated with IGF ligands in the presence or absence of linsitinib. The effects of IGF pathway inhibition were further examined in a mouse model of corneal fibrosis. IGF-1 and IGF-2 promoted myofibroblast survival under pro-apoptotic conditions, whereas pharmacologic inhibition of IGF-1R/INSR signaling with linsitinib blocked these pro-survival effects. In vivo, linsitinib treatment reduced myofibroblast persistence and attenuated corneal fibrosis. These findings identify the IGF axis as a critical regulator of corneal myofibroblast survival and suggest that persistent fibrosis is maintained, in part, by IGF-dependent resistance to apoptosis. Targeting survival pathways rather than myofibroblast differentiation may represent a novel therapeutic strategy for the treatment of corneal fibrosis. Full article

Astragalus species have long been recognized for their pharmacological relevance, yet the antidiabetic properties of Astragalus cruciatus Link (Ac) remain poorly explored. This study aimed to investigate the antidiabetic potential of A. cruciatus Link and to elucidate possible underlying mechanisms. The ethanolic extract of Ac (AcEE) was prepared and analyzed for phenolic and flavonoid content. Antioxidant activity was assessed through a series of in vitro assays. The in vitro inhibition of α-amylase and α-glucosidase was assessed, followed by molecular docking to probe ligand-enzyme interactions. LC-ESI-MS analysis revealed a polyphenol-rich profile, with rutin (953.54 µg/g extract) and quinic acid (797.18 µg/g of extract) identified as main compounds. The AcEE showed significant inhibitory activity against both α-amylase and α-glucosidase (IC₅₀ = 239.30 ± 7.40 and 192.60 ± 15.51 μg/mL, respectively). Moreover, low cytotoxic effects were observed in hepatic cell lines. Computational analysis revealed stable interactions between rutin and both enzymes (−12.935 and −8.073 Kcal/mol, respectively). Network pharmacology revealed that AcEE may modulate key targets, including IL-6, TNF-α, IL-1β, Akt-1, STAT3, EGFR, and INSR as well as pathways related to insulin resistance, AGE-RAGE, and inflammation. These findings suggest that AcEE exerts significant antidiabetic effects through multitarget modulation, highlighting its potential as a natural therapeutic agent for T2DM. Full article

High-starch diets are increasingly used in aquafeeds to reduce feed costs, but carnivorous fish such as largemouth bass (Micropterus salmoides) have limited capacity to utilize dietary starch and are prone to hepatic metabolic disorders. In the present study, we evaluated whether dietary N-carbamylglutamate (NCG) could alleviate high-starch-induced hepatic oxidative stress and liver injury in largemouth bass. Fish were fed a control diet containing 11.50% starch, a high-starch diet containing 18.00% starch, or a high-starch diet supplemented with 0.15%, 0.20%, or 0.25% NCG for 8 weeks. Compared with the high-starch group, dietary NCG supplementation significantly reduced serum glucose and triglyceride levels, decreased hepatic glycogen and malondialdehyde contents, and increased hepatic superoxide dismutase and glutathione peroxidase activities. NCG also reduced serum alanine aminotransferase and aspartate aminotransferase activities and alleviated hepatic histopathological damage. At the transcriptional level, NCG upregulated genes related to insulin signaling, glycolysis, lipid catabolism, and antioxidant regulation, including insr, irs, gk, pk, atgl, hsl, ampk, and nrf2, while downregulating the expression of keap1, nf-κB, mtor, and multiple inflammation- and apoptosis-related genes. These changes were accompanied by increased serum nitric oxide levels and improved survival and growth performance under high-starch feeding conditions. Collectively, these results indicate that dietary NCG supplementation attenuates high-starch-induced hepatic oxidative stress and redox-associated liver injury in largemouth bass, which may be associated with the transcriptional modulation of genes related to the AMPK/Nrf2/Keap1 and mTOR/NF-κB signaling pathways. Full article

Pork production is closely linked to skeletal muscle growth and anabolic processes. This study investigated the effects of dietary supplementation with a multi-strain probiotic (Lactiplantibacillus plantarum, Streptococcus thermophilus, and Bacillus subtilis) on the growth performance, carcass traits, gut microbiota, and potential signaling pathways in growing pigs. A total of 144 weaning piglets (28 days old) were randomly allocated to two groups and fed diets with or without probiotics (0.1%) for 18 weeks. Pigs fed with probiotics showed significantly improved feed efficiency (p < 0.05) and greater muscle mass in the loin eye, arm shoulder, and blade shoulder regions. Microbiome analysis revealed significant enrichment of short-chain fatty acid (SCFA)-producing taxa, including Acidaminococcus, Allisonella, Dialister, and Megasphaera, alongside an increased cecal butyrate level in pigs fed probiotics. Integrated fecal microbiome and serum metabolomics analysis demonstrated that the metabolite profile was substantially altered by the supplementation of probiotics. Additionally, serum insulin levels, expression of the bile acid receptor tgr5, and upstream genes in the PI3K/Akt/mTOR pathway (igf1r, insr, and pi3k) were significantly upregulated (p < 0.05). Collectively, these results suggest that a multi-strain probiotic supplementation may be a promising strategy for improving muscle deposition and feed efficiency in commercial pig production. Full article

Postnatal loss of cardiac regenerative capacity coincides with profound remodeling of signaling, structural, and metabolic programs in the developing heart. Here, we profiled Insulin growth factor (IGF)/Fibrobrast growth factor (FGF)/insulin receptors (InsR), Ras/Raf/MEK/ERK pathway components, cytoskeletal markers, and cell-cycle/metabolic proteins in mouse whole-heart tissue at P3, P7, P14, P28, and adulthood. IGF-1R- and IGF-2R-associated signals declined sharply during maturation, whereas InsR changed more modestly. FGFR1-derived immunoreactive species showed a transient early postnatal increase before marked reduction at later stages. These receptor-associated changes paralleled strong decreases in B-Raf, MEK1, and MEK2, together with pronounced loss of MEK1/2 activation-loop phosphorylation. MEK1 Thr292 phosphorylation also declined markedly, identifying a previously unrecognized developmental phosphorylation pattern. Structural maturation was accompanied by stable Actn2 expression, downregulation of immature cytoskeletal markers, increased cytochrome c and myoglobin, and significant loss of Aurora B and phospho-histone H3 in adult hearts. Together, these findings describe a coordinated postnatal maturation program in which signaling, cytoskeletal remodeling, metabolism, and proliferative withdrawal change in parallel. These data are consistent with reduced MAPK pathway activity during maturation and highlighting this signaling as node associated with closure of the neonatal regenerative window. Full article

This study reviews the main candidate genes involved in the pathophysiology of Polycystic Ovary Syndrome (PCOS). PCOS is a common endocrine–metabolic disorder in women of reproductive age, characterized by menstrual irregularity, hyperandrogenism, and polycystic ovarian morphology. It is associated with increased metabolic and cardiovascular risk and is a leading cause of infertility. Although its pathophysiology is not fully understood, alterations in the hypothalamic–pituitary–ovarian axis, insulin metabolism, and steroidogenesis have been described. Polymorphisms in genes encoding hormones, enzymes, and receptors in these pathways contribute to clinical variability and ethnic differences, offering potential for early diagnosis and personalized medicine. This review summarizes key candidate genes related to insulin metabolism (INS, INSR, IRS-1), the hypothalamic–pituitary–ovarian axis (LHβ, LHCGR, FSHR, GnRHR, AMH, AMHR2, KISS1, CAPN10), steroidogenesis (CYP11A, CYP17A1, CYP19A1, CYP21, 17β-HSD, SHBG, AR, STAR), and other clinically relevant mechanisms such as obesity, lipid metabolism (PPARG, VDR, FTO), and follicular development (ACE). Full article

Sequestosome 1 (SQSTM1, also known as p62) has emerged as a multifunctional signaling adaptor that bridges autophagy, proteostasis, and inflammation. In this review, we discuss the molecular mechanisms by which SQSTM1 regulates selective autophagy and immune signaling pathways, and how its dynamic modulation shapes host responses during sepsis. We highlight the tissue-specific roles of SQSTM1 in sepsis-associated injury across major organs—including the liver, kidney, heart, lung, brain, and skeletal muscle—and explore its function as a damage-associated molecular pattern (DAMP) in the extracellular milieu. Recent studies implicate extracellular SQSTM1 in metabolic reprogramming and pro-inflammatory cytokine production via INSR signaling, supporting its classification as a novel DAMP and potential therapeutic target. We conclude a stage- and compartment-specific model for SQSTM1 during sepsis: its transition from a protective intracellular autophagy mediator in the early stage to a pathological extracellular DAMP in late stage. Furthermore, we discuss the translational relevance of pharmacological agents that modulate SQSTM1 levels or activity to restore immune balance and organ homeostasis. A better understanding of SQSTM1’s dual roles in immune activation and resolution could open new avenues for precision therapies in sepsis. Full article

Aging is a multifactorial process characterized by progressive physiological changes, including cellular senescence, cellular loss, and organ decline, which collectively accelerate the development of metabolic syndrome (MetS) in older adults. MetS, in turn, not only significantly increases the risk of cardiovascular disease (CVD) but also contributes to decreased functional and cognitive capacity, partly due to diminished ability to adapt to metabolic stress. While genetic predisposition has a substantial influence on the risk of developing MetS, other intrinsic factors, including chronic inflammation, insulin resistance (InsR), and altered neurohormonal activation, also play crucial roles. Targeted therapies, lifestyle interventions, and pharmacotherapy can decelerate the progression of CVD, improving the likelihood of survival with favorable neurological and functional outcomes in older individuals with MetS. However, adverse drug reactions and the lack of adequate interventions for cognitive decline have led to the emergence of self-medication with nonprescription products. The anti-inflammatory, antioxidant, anti-channelopathy, antiaging, and neuroprotective properties of flavonoids, alkaloids, polysaccharides, and polyphenols found in key traditional medicines have shown promising potential in the treatment of MetS-induced cognitive decline. This narrative review summarizes current evidence on bioactive compounds and herbal medicines that may offer cognitive benefits in elderly patients with MetS. Full article

Insulin is an anabolic hormone involved in the regulation of several processes, such as the storage of glucose into glycogen, decrease of glucose output, stimulation of glucose transport into cells, etc. The hormone binds to its receptor, thereby activating an intracellular signaling cascade. Once activated, the insulin receptor (INSR) phosphorylates multiple intracellular substrates, which initiate the downstream signaling pathway. The nature of insulin signaling pathways may vary depending on the organ or tissue. In the central nervous system (CNS), INSRs are expressed in all cell types. This observation may suggest that insulin signaling is involved in important and diverse processes. It regulates glucose metabolism, supports cognitive functions, enhances the outgrowth of neurons, as well as plays a role in the modulation of release and uptake of catecholamine, among other roles. Importantly, insulin can freely cross the blood–brain barrier (BBB) from the circulation and is also synthesized locally within the brain. Insulin resistance (IR) impairs insulin signaling, which may accelerate brain aging, affect plasticity, and potentially contribute to neurodegeneration. Dysregulation of insulin signaling has been implicated in several diseases, including diabetes mellitus, metabolic syndrome, certain cancers, and neurodegenerative diseases, such as Alzheimer’s disease. There are two principal insulin signaling pathways: the PI3K/AKT pathway, primarily associated with metabolic effects, and the MAPK pathway, which is involved in cell growth, survival, and gene expression. Our review describes the role of insulin in the human brain, as well as the disturbances in insulin signaling resulting from brain insulin resistance, with a particular focus on its association with Alzheimer’s disease. Full article

Gut microbiota is a potential therapeutic target for type 2 diabetes (T2D), but its role remains unclear. Investigating causal associations between them could further our understanding of their biological and clinical significance. A two-sample Mendelian randomization (MR) analysis was conducted to assess the causal relationship between gut microbiota and T2D. Key genes and mechanisms were identified through the integration of Genome-Wide Association Studies (GWAS) and cis-expression quantitative trait loci (cis-eQTL) data. Network pharmacology was applied to identify potential drugs and targets. Additionally, gut microbiota community analysis and machine learning models were used to construct a diagnostic model for T2D. MR analysis identified 17 gut microbiota taxa associated with T2D, with three showing significant associations: Actinomyces (odds ratio [OR] = 1.106; 95% confidence interval [CI]: 1.06–1.15; p < 0.01; adjusted p-value [p_adj] = 0.0003), Ruminococcaceae (UCG010 group) (OR = 0.897; 95% CI: 0.85–0.95; p < 0.01; p_adj = 0.018), and Deltaproteobacteria (OR = 1.072; 95% CI: 1.03–1.12; p < 0.01; p_adj = 0.029). Ten key genes, such as EXOC4 and IGF1R, were linked to T2D risk. Network pharmacology identified INSR and ESR1 as target driver genes, with drugs like Dienestrol showing promise. Gut microbiota analysis revealed reduced α-diversity in T2D patients (p < 0.05), and β-diversity showed microbial community differences (R² = 0.012, p = 0.001). Furthermore, molecular docking confirmed the binding affinity of potential therapeutic agents to their targets. Finally, we developed a class-weight optimized Extreme Gradient Boosting (XGBoost) diagnostic model, which achieved an area under the curve (AUC) of 0.84 with balanced sensitivity (95.1%) and specificity (83.8%). Integrating machine learning predictions with MR causal inference highlighted Bacteroides as a key biomarker. Our findings elucidate the gut microbiota-T2D causal axis, identify therapeutic targets, and provide a robust tool for precision diagnosis. Full article

Buffaloes (Bubalus bubalis) are central to the dairy and agricultural economy, contributing high-quality milk, meat, draft power, and manure. Rich milk composition, the ability to utilize low-quality roughage, and strong disease resistance make buffaloes indispensable across diverse production systems. Among India’s major dairy breeds—Murrah, Nili-Ravi, Jaffarabadi, Surti, Bhadawari, Mehsana, and Nagpuri, none exhibit the distinctive trait of intermittent milking, which is uniquely observed in the Pandharpuri buffalo, a registered indigenous breed of Maharashtra. Despite coexisting with dominant dairy breeds such as Murrah, Pandharpuri buffalo is considered to possess primitive riverine ancestry and may represent one of the ancestral lineages from which several Indian breeds evolved. Its evolutionary relevance and unique intermittent milking capacity underscore the need to understand its genomic architecture. To address this, we applied whole-genome resequencing and the De-Correlated Composite of Multiple Signals (DCMS) approach to identify within-breed selection signatures. Our analyses identified 1337 candidate genes, including several linked to milk production, particularly those relevant to the physiological capacity for intermittent milking. Notable genes included ERBB4, ESR1, SYK, INSR, PTPN11, VAV3, MAPK3, and PRKG1. These signatures provide insights into genomic regions and biological pathways that may be involved in lactation-related processes relevant to intermittent milking. The identified genomic regions offer promising targets for functional validation and future genome-informed breeding strategies aimed at conserving this unique indigenous germplasm while improving lactation efficiency and resilience. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, is a highly prevalent hepatic condition closely linked to metabolic syndrome (MetS). Epigenetic regulators such as microRNAs (miRNAs) have emerged as critical modulators of the molecular pathways underlying MASLD pathogenesis, offering new perspectives for non-invasive diagnosis and targeted therapy. This study aimed to identify and characterize target genes and pathways regulated by two key hepatic miRNAs, namely miR-122 and miR-29a, through a comprehensive in silico bioinformatics approach, to better understand their functional roles in MASLD and MetS. Methods: Target genes of miR-122 and miR-29a were predicted using three databases (TargetScan, DIANA-microT-CDS, and miRWalk), and those identified by at least two databases were selected for downstream analyses. Functional enrichment was performed using Gene Ontology and KEGG pathway analysis. Gene networks and biological process maps were constructed using Metascape, clusterProfiler and Cytoscape. Results: miR-122 was found to negatively regulate genes involved in lipid metabolism, insulin signaling, and inflammatory pathways, including PPARGC1A, PPARA, LPL, TLR4, and HMGCR, contributing to insulin resistance and liver dysfunction. By contrast, miR-29a demonstrated potential hepatoprotective effects by targeting LEP, INSR, IL13, and IL18, enhancing insulin sensitivity and reducing fibrogenic activity. Enrichment analysis revealed strong associations with biological processes, such as STAT phosphorylation, lipid homeostasis, and inflammatory signaling, as well as associations with cellular components, including lipoproteins and plasma membranes. miR-122 and miR-29a exhibit opposing regulatory functions in MASLD pathogenesis. Whereas miR-122 is associated with disease progression, miR-29a acts protectively. These miRNAs may serve as promising biomarkers and therapeutic targets in MASLD and related metabolic conditions. Further validation through experimental and clinical studies is warranted. Full article

Background: Intracellular delivery of high-molecular-weight proteins is limited by the cell membrane. Cell-penetrating peptides (CPPs) offer a potential solution, but effective cytosolic delivery remains hindered by endosomal sequestration. Pas2r12, a CPP-derived peptide, facilitates cytosolic delivery of proteins including immunoglobulin G. Because Pas2r12 internalization occurs via caveolae-dependent endocytosis, we hypothesized that cell-surface receptors contribute to uptake. Methods: HEK293 cells were treated with Pas2r12 alone or complexed with enhanced green fluorescent protein (EGFP). Phosphorylation of insulin receptor (INSR), insulin-like growth factor 1 receptor (IGF1R), and extracellular signal–regulated kinase 1/2 (ERK1/2) was analyzed by Western blot. Linsitinib was used to inhibit INSR/IGF1R kinase activity. Cytosolic delivery was assessed by confocal microscopy, and receptor involvement was evaluated using siRNA-mediated knockdown and receptor overexpression. Results: Pas2r12 alone transiently increased INSR/IGF1R phosphorylation at 2 min (6.6-fold), which was suppressed by linsitinib (1.3-fold), and strongly increased ERK1/2 phosphorylation (6.2-fold), which was not inhibited by linsitinib. Pas2r12–EGFP did not induce detectable INSR/IGF1R phosphorylation in parental cells but increased ERK1/2 phosphorylation (3.4-fold). Linsitinib markedly reduced cytosolic EGFP delivery to 16% of control. INSR knockdown decreased delivery to 13–16%, and IGF1R knockdown to 19–65%. In INSR-overexpressing lines, Pas2r12–EGFP induced INSR/IGF1R phosphorylation (6.0-fold) and enhanced delivery (230–270%). In IGF1R-overexpressing lines, Pas2r12–EGFP did not induce phosphorylation, and delivery decreased to 60–69%. Conclusions: Pas2r12-mediated cytosolic delivery involves both INSR and IGF1R, with INSR contributing more prominently. These findings, including the largely INSR/IGF1R-independent ERK1/2 activation, provide mechanistic insight into Pas2r12-mediated protein delivery. Full article

This study aimed to investigate the chemical composition, antioxidant activity, and in vitro antidiabetic properties of extracts obtained from ripe, unripe, and fermented (unripe) cornelian cherry (Cornus mas L.) fruits. Polyphenols were identified using UPLC-ESI-qTOF-MS/MS and quantified by HPLC-PDA. Antioxidant activity was evaluated using ABTS, DPPH, and FRAP assays, while enzyme inhibitory activity was determined for α-glucosidase and α-amylase. Additionally, the effects of C. mas extracts on insulin sensitivity in adipocytes were investigated. The study’s results showed that each of the extracts tested contained varying proportions of substances with proven health-promoting properties. The extract from ripe fruits was characterized by the highest loganic acid content, whereas the extract from fermented unripe fruits contained a high amount of gallic acid, released through the hydrolysis of tannins during fermentation. The extract from unripe fruits exhibited the highest tannin content and the strongest antioxidant activity. All extracts inhibited α-glucosidase and α-amylase to a similar extent and improved insulin-stimulated glucose uptake in 3T3-L1 adipocytes without affecting INSR or SLC2A4 expression. In conclusion, extracts from unripe and fermented C. mas fruits may represent promising agents for alleviating insulin resistance and preventing type 2 diabetes. Full article

Dorper sheep (DOR) are a commercially important mutton breed renowned for their high growth rate, favorable carcass composition, environmental adaptability, and natural wool shedding. In China, they are widely utilized as terminal sires to enhance growth and carcass yield in local breeds. To elucidate the genetic basis of these traits, we sequenced the genomes of 20 DOR and integrated the data with whole-genome sequences from 73 individuals representing four Chinese indigenous breeds. Analyses of genetic diversity, inbreeding coefficients, and population structure revealed reduced genomic diversity, elevated inbreeding levels, and clear genetic separation for DOR from other indigenous breeds. Selective sweep scans using F_ST, pi, and XP-EHH identified candidate genes involved in five major trait categories: growth performance and development (COL2A1, DAB2IP, EPYC, TSPAN18, WNT1, CTPS1, FBXW7, INSR, S100A6, SOCS2), energy metabolism (ACSS3, ADGRE3, CPT2, GCGR, PRKAA1), fat deposition and adipocyte differentiation (EHBP1, FOXP1, KLF12, PDGFD, RALGAPA2), immune response (CXCR6, IL17RB, NFKBIZ, TMEM154), and wool traits (CERS4, MITF). These results will provide novel insights into the genomic architecture of economically important traits in DOR and support their genetic improvement through informed crossbreeding with Chinese local breeds. Full article