Search Results (1,001)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with metabolic abnormalities, shares pathophysiological pathways with metabolic syndrome, and has become a leading cause of chronic liver disease in industrialized nations. In the absence of approved pharmacological treatments and due to its high risk of progression to advanced fibrosis, MASLD represents a significant clinical challenge. Incretin-based therapies, originally developed for the treatment of type 2 diabetes mellitus and obesity, have recently gained attention as promising therapeutic strategies in hepatology. Among them, GLP-1 receptor agonists have shown efficacy in reducing hepatic steatosis, inflammation, and fibrosis-related biomarkers, primarily through weight loss and enhanced insulin sensitivity. Dual agonists targeting both GLP-1 and GIP receptors, such as tirzepatide, have demonstrated superior outcomes in improving hepatic and metabolic parameters. Emerging agents like cotadutide (a GLP-1/glucagon receptor agonist) and retatrutide (a GLP-1/GIP/glucagon triagonist) represent a novel therapeutic frontier, with early clinical data indicating potent hepatoprotective effects and favorable metabolic remodeling. This narrative review examines the hepatoprotective potential of incretin-based therapies, highlighting how targeted intervention on the underlying metabolic dysfunction may lead to significant improvements in MASLD. These therapies may also exert beneficial effects on fibrosis progression; however, the currently available evidence remains limited. Full article

Background: Postmenopausal women are at high risk of Alzheimer’s disease (AD) incidence and progression. Irisin, an exercise-induced myokine, has neuroprotective and antiaging effects against AD, especially in menopausal women suffering from insulin resistance (IR). For the first time, the novel role of irisin induced by melatonin (MTN) or/and physical exercise (PHE) was investigated in the current ovariectomized (OVX)/AD rat model by modulating brain neuroinflammation and IR-related markers. Methods: Fifty female Wistar rats were divided into five groups, with one representing a sham group. AD was induced in the other four bilateral OVX rat groups by daily intraperitoneal injection of D-galactose/AlCl₃ (60 and 10 mg/kg, respectively) for 42 days. Group III–V: Animals were exposed to MTN (10 mg/kg/day; i.p.), PHE, and a combination of these, respectively, in the final 14 days of the experiment. Results: The OVX/AD rats showed significant deterioration in learning, memory, neurochemical, and histopathological examinations, while the MTN or/and PHE treatments significantly increased serum and brain irisin, improving memory in a Y-maze assessment. Thus, hippocampal histopathological alterations and IR-related markers decreased. In addition, suppressed hippocampal amyloid-beta protein expression and neuroinflammatory content of tumor necrosis factor-alpha (TNF-α), p38 mitogen-activated protein kinase (p38 MAPK), and NOD-like receptor protein-3 (NLRP3) were associated with an increase in peroxisome proliferator-activated receptor-gamma (PPAR-γ) protein expression and insulin-like growth factor-1 content in hippocampal tissues, collectively suppressing glial fibrillary acidic protein (GFAP) content, leading to an increase in brain-derived neurotrophic factor expression. Conclusions: Irisin induction may serve as a novel avenue in AD/menopause treatment and prevention via modulating the TNF-α/p38 MAPK/PPAR-γ/NLRP3/GFAP pathway. Full article

This study explored the regulatory role of nuclear factor E2-related factor 2 (Nrf2) in aerobic exercise improving oxidative stress and inflammatory responses in mice with insulin resistance (IR) induced by a high-fat diet. We established an IR mouse model through a high-fat diet, then subjected the IR mice to aerobic exercise, intraperitoneal injection of luteolin, or a combined intervention. After 6 weeks of intervention, we measured serum lipid and glucose profiles; evaluated skeletal muscle morphology by H&E staining; quantified mRNA expression levels of Nrf2 and its downstream targets in the skeletal muscle by RT-qPCR; and determined protein abundance, localization, and expression patterns of Nrf2 and NOD-like receptor protein 3 (NLRP3) inflammasome by Western blotting and immunohistochemistry, respectively. In the skeletal muscle of IR mice, Nrf2 and its downstream targets were significantly down-regulated, whereas NLRP3 inflammasome was markedly up-regulated (p < 0.05 or p < 0.01). IR mice subjected to aerobic exercise exhibited reduced serum glucose and lipid levels together with a lower insulin-resistance index (p < 0.05 or p < 0.01); morphologically, inter-myofibrillar spaces were narrowed, intrafiber vacuoles diminished, and cellular integrity restored. Concomitantly, Nrf2 and its downstream targets were up-regulated, whereas NLRP3 inflammasome components were down-regulated in the skeletal muscle (p < 0.05 or p < 0.01). Intraperitoneal administration of luteolin during exercise, however, partially attenuated or reversed these exercise-induced improvements by inhibiting the activation of Nrf2 (p < 0.05 or p < 0.01). These results indicate that aerobic exercise confers protective effects against IR by activating the Nrf2 signaling pathway, thereby attenuating oxidative stress and inflammation; these benefits are markedly attenuated when Nrf2 activity is pharmacologically inhibited. Full article

Background: Obesity is a major driver of obstructive sleep apnea (OSA), traditionally managed as a mechanical disorder of upper airway collapse. However, growing evidence supports a broader pathophysiological model involving metabolic dysfunction, systemic inflammation, and ventilatory instability. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated substantial weight loss and cardiometabolic benefits, raising the possibility of a paradigm shift in OSA management. Objective: To critically evaluate whether tirzepatide may act as a disease-modifying therapy in obesity-related OSA beyond its effects on weight reduction. Methods: A narrative review was conducted using PubMed, Scopus, and Web of Science up to January 2026. Evidence from randomized controlled trials, meta-analyses, and mechanistic studies on incretin-based therapies in obesity and OSA was synthesized, with emphasis on clinical outcomes and underlying biological pathways. Results: Tirzepatide is associated with significant reductions in apnea–hypopnea index (AHI), accompanied by substantial weight loss. However, emerging data suggest that improvements in OSA severity may not be entirely explained by weight reduction alone. Potential weight-independent mechanisms include modulation of systemic inflammation, improvements in insulin sensitivity, alterations in adipokine profiles, and effects on autonomic regulation and ventilatory control. These pleiotropic effects may influence key components of OSA pathophysiology, including upper airway stability and chemosensitivity. Despite these findings, current evidence remains insufficient to definitively distinguish weight-dependent from weight-independent effects. Conclusions: Tirzepatide represents a promising therapeutic advance in obesity-related OSA, with potential implications extending beyond weight loss toward disease modification. While current data support a substantial role in reducing OSA severity, definitive confirmation of disease-modifying effects requires further mechanistic and long-term clinical studies. This emerging paradigm points to a shift from purely device-based management toward integrated, pathophysiology-driven treatment strategies. Full article

This study investigated the role of microglia-derived insulin-like growth factor 1 (IGF-1) in modulating host defense and disease progression in a viral model of neuroinflammation and demyelination. Intracranial infection of susceptible mice with the glial-tropic JHM strain of mouse hepatitis virus (JHMV) induces acute encephalomyelitis, followed by an immune-mediated demyelinating disease that mimics many clinical and histologic features of multiple sclerosis (MS). Utilizing an inducible fractalkine receptor (Cx3cr1) promoter-driven Cre-loxP recombinant system, we performed timed ablation of Igf1 in microglia to assess its impact on the central nervous system (CNS) response to JHMV. While the loss of microglial IGF-1 did not impair the control of viral replication, it significantly exacerbated spinal cord demyelination. CyTOF and imaging mass cytometry analysis of spinal cords indicated increased myelin damage was associated with increased accumulation of CD8⁺Ly6C⁺ effector T cells and reduced expression of TREM2 that impaired transition into a disease-associated microglia (DAM) phenotype capable of sensing and potentially mitigating myelin damage. Collectively, these findings argue that microglial IGF-1 is a non-redundant coordinator of the CNS immune responses that occur in response to CNS viral infection. Full article

The obesity–metabolic syndrome–diabetes continuum is driven by interconnected mechanisms including insulin resistance, dysfunctional adiposity, chronic inflammation and progressive cardio–renal–metabolic injury. This triggered a need for therapies that extend beyond glucose lowering alone. The benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as disease-modifying drugs include weight loss, cardiovascular risk reduction, glycemic control and renal protection. However, treatment burden, adherence issues and access restrictions may limit the long-term effects of injectable formulations. One significant translational development that aims to close this gap is oral GLP-1-based treatments. In this review, we examine the mechanistic rationale, formulation science and clinical development of oral GLP-1 RAs. Oral semaglutide is presented as the first validated proof of concept for systemic peptide delivery by the gastrointestinal route. The biological barriers to oral peptide absorption, including enzymatic degradation, low epithelial permeability, pharmacokinetic variability and epithelial safety constraints, are critically discussed. Enabling technologies such as SNAC-based gastric absorption, nanocarriers, mucoadhesive systems and stability-optimization platforms are evaluated. Evidence from the PIONEER program and related studies demonstrating meaningful glycemic and weight-loss efficacy, acceptable safety and clinical utility in patients with type 2 diabetes and chronic kidney disease is further synthesized. Beyond first-generation oral peptide platforms, we discuss the emerging landscape of non-peptide oral GLP-1 RAs, dual and triple incretin agonists, precision dosing strategies and model-informed drug development. Oral GLP-1-based therapeutics are shifting from a formulation breakthrough to a broader translational strategy for disease modification across the obesity–metabolic syndrome–diabetes continuum. Long-term renal outcomes, access and implementation barriers remain important priorities for future research. Full article

Background/Objectives: Egypt ranks among the top ten countries globally with the highest burden of type 2 diabetes mellitus (T2DM), with prevalence projected to rise significantly by 2050. Despite multiple therapeutic options, glycemic control remains suboptimal due to therapeutic inertia, treatment complexity, and healthcare system limitations. Fixed-ratio combinations (FRCs) of basal insulin and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) offer a simplified injectable strategy addressing complementary pathophysiological defects in T2DM. This study aims to develop expert consensus recommendations for the use of FRCs in Egyptian adults with T2DM, integrating international evidence with local practice. Methods: A modified Delphi technique was employed to achieve consensus among 9 diabetes experts across Egypt. Statements were formulated based on a targeted literature review and voted on using a structured Likert scale. Consensus was defined as ≥70% agreement. Results: Twenty-nine statements were endorsed with strong to very strong consensus. Recommendations covered patient selection, initiation after oral therapy or GLP-1 RA, switching from premixed or complex insulin regimens, dosing strategies, safety considerations, and intensification options. FRCs were favored for early injectable use, regimen simplification, and improved adherence, with liraglutide-based FRCs preferred for cardiovascular and renal benefits. Digital health integration was strongly recommended to enhance glycemic control and patient engagement. Conclusions: FRCs offer a simple and effective treatment simplification option for patients with uncontrolled T2DM on premix insulin, complex insulin regimens, or oral therapy. FRCs may improve glycemic control with generally favorable effects on hypoglycemia risk and body weight across many randomized and real-world studies, while reducing injection burden, simplifying the treatment regimen, and supporting patient adherence and satisfaction. Full article

The insulin-like androgenic gland (IAG) gene is considered a crucial factor in the process of sexual differentiation in decapod crustaceans. In this study, we characterized the structural features and ontogenetic expression profile of the IAG gene in the swimming crab P. trituberculatus (Pt-IAG). To further elucidate its biological roles, we performed long-term RNA interference (RNAi) to evaluate the physiological impacts of sustained Pt-IAG suppression. Results showed that the gene structure of Pt-IAG is conserved with the characteristic B-C-A polypeptide arrangement that is representative of decapod IAGs. Transcripts of Pt-IAG were detectable as early as the zygote stage, which may imply its potential role during early-stage development. Although no completesex reversal was observed, continuous knockdown of Pt-IAG resulted in a decrease in body weight and a delay in gonad development in both sexes, underscoring its pleiotropic role in coordinating growth and maturation. Furthermore, the silencing of Pt-IAG led to a significant downregulation of insulin-like growth factor-binding protein (Pt-IGFBP), and a decrease in insulin-receptor (Pt-IR) expression was observed in males. Notably, the Pt-IR gene was not detected in female ovaries. These findings suggest that IAG may modulate male development through an insulin-like signaling axis; however, the absence of ovarian Pt-IR expression implies the potential existence of alternative regulatory pathways in females. Collectively, this study identifies a dual regulatory role of IAG in both growth and reproduction, providing a specific theoretical basis for developing sex-control and growth-optimization strategies in crab aquaculture. Full article

Type 1 diabetes (T1DM) is associated with elevated cardiovascular (CV) risk, often exacerbated by the rising prevalence of obesity. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce CV risk in type 2 diabetes, but their role in T1DM is less well-defined. This umbrella review synthesizes evidence from systematic reviews, meta-analyses, and Mendelian Randomization (MR) studies to evaluate the metabolic efficacy and safety of GLP-1 RAs in T1DM. Adjunctive therapy, particularly with liraglutide and exenatide, was associated with clinically meaningful weight reduction (mean difference: −4.35 kg to −5.1 kg) and lower total daily insulin doses. HbA1c reductions were statistically significant but modest (0.2–0.3%), with no improvement in Time in Range. Secondary benefits included lower systolic blood pressure. Safety data were mixed: the risk of severe hypoglycemia was not increased, whereas Time Below Range and gastrointestinal adverse events were more frequent. Evidence on diabetic ketoacidosis (DKA) was inconsistent across studies. Overall, GLP-1 RAs improve weight and reduce insulin requirements in T1DM, potentially mitigating indirect CV risk factors; however their direct cardiovascular benefits remain unproven in the absence of dedicated outcome trials. Full article

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age, characterized by hyperandrogenism, insulin resistance, and ovarian dysfunction. Current therapies are often associated with adverse effects, highlighting the need for safer therapeutic alternatives. Peganum harmala (P. harmala), a medicinal plant rich in bioactive metabolites, was investigated through in silico approaches to identify compounds with predicted binding affinity for the androgen receptor (AR), steroid 17α-hydroxylase/17,20-lyase (CYP17A1), and glycogen synthase kinase-3 beta (GSK-3β). GC-MS analysis of P. harmala leaf essential oil collected in Riyadh, Saudi Arabia, identified 109 compounds, with terpenoids as the dominant class (21.89%). The major constituents were cis-chrysanthenyl acetate (3.48%), cis-β-damascenone (3.06%), farnesylacetone (1.44%), β-calacorene (1.36%), dihydroedulan II (1.04%), and trans-calamenene (0.46%). In silico ADMET evaluation indicated that most compounds complied with Lipinski’s rule of five and showed favorable predicted pharmacokinetic properties. Safety profiling suggested an overall acceptable toxicity profile, with minimal predicted CYP450 inhibition, except for L11, which showed broader inhibitory potential. Molecular docking showed that L15 (trans-calamenene), L14 (dihydroedulan II), L6 (β-calacorene), L3 (farnesylacetone), and L8 exhibited higher predicted binding affinity toward the androgen receptor; L3, L10 (cis-β-damascenone), and L16 (cis-chrysanthenyl acetate) interacted with CYP17A1, while L3, L9, and L6 exhibited higher affinity toward GSK-3β. Overall, these findings provide hypothesis-generating in silico predictions of ligand–target binding affinities and drug-likeness profiles. These computational findings highlight the importance of future experimental investigations to substantiate the biological activity, pharmacokinetic behavior, and safety profile of P. harmala constituents. Full article

Trastuzumab is the first humanised monoclonal antibody (Mab) developed for breast cancer (BC) therapy. The high affinity of Trastuzumab Fab-domain binding to the human epidermal growth factor receptor 2 (HER2) receptor, with a K_d value of <1 nM, is also accompanied by Fc domain interaction with Fc-receptors in natural killer cells and leukocytes, enabling the killing of tumour cells through antibody-directed cellular cytotoxicity (ADCC). Trastuzumab blocks the over-expressed HER2 receptor-mediated dimerization and consequent intracellular signalling, leading to cancerous growth. However, the trastuzumab resistance (TR) became the major problem within 1 year of treatment. The mutation in phosphatidylinositol 3′-kinase (PI3K) pathway, cross-talk with estrogen receptors, over-expression of Mucin 1 (MUC1) protein, insulin-like growth factor I receptor, etc., are key pathways involved in TR. In this review, we have provided a molecular view of TR and the possible remedies for overcoming TR using BC stem cell (BCSC)-based therapy, PI3K pathway inhibitors, MUC1-based treatment, etc. We have also analysed the patents and clinical trials from the pre-TR and post-TR era to rationalise the possible steps to overcome TR. Our analysis implies that Trastuzumab monotherapy no longer applies to HER2+ BC treatment. Further, combination therapy using other antibodies like pertuzumab and protein kinase inhibitors and targeting pathways like the ubiquitin proteasome pathway will be the future option for BC Treatment. Overall, this review provides a detailed summary of the molecular mechanisms involving TR and its potential ways of evasion, based on updated information from published research articles, clinical trial outcomes, and patent data. Full article

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy worldwide, with molecular heterogeneity complicating early detection and treatment stratification. The insulin-like growth factor (IGF) axis interacts bidirectionally with immune regulatory mechanisms in ways that shape tumor phenotype and therapeutic vulnerability. This review synthesizes evidence on how IGF signaling orchestrates immunosuppression through effects on tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, while inflammatory cytokines reciprocally modulate IGF bioavailability. Three mechanistic principles emerge: IGF binding protein 2 (IGFBP-2) functions as a central coordinator linking growth factor signaling to immune evasion through STAT3-dependent pathways driving M2 macrophage polarization and regulatory T cell differentiation; IGF–immune crosstalk varies considerably across molecular subtypes, with microsatellite-stable tumors exhibiting high reliance on IGF-I receptor-mediated immune silencing; and local paracrine IGF production increasingly dominates over systemic regulation as disease progresses. These bidirectional connections establish self-reinforcing circuits that determine whether tumors remain immunologically responsive or develop immune exclusion. Multi-marker panels incorporating IGFBP-2 alongside complementary biomarkers have shown improved diagnostic performances for early CRC detection, underscoring the need for the large-scale prospective clinical evaluation of IGF network components as biomarkers for CRC in diverse populations. The convergence of IGF signaling with checkpoint regulation suggests that combined targeting warrants investigation for resistance in tumors lacking effective immunotherapy options. Full article

Glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists, originally introduced for the management of type 2 diabetes mellitus and obesity, are increasingly recognized for their broader actions within the central nervous system, with emerging implications in neuropsychiatry and neurodegeneration. This review integrates current preclinical and clinical evidence, emphasizing their pharmacodynamic profile, central receptor distribution, and the molecular pathways linking metabolic signaling to neural function. Evidence suggests that GLP-1 receptor activation across key brain regions involved in energy balance and reward modulates multiple neurotransmitter systems, including dopamine and serotonin, as well as glutamatergic and GABAergic transmission, thereby influencing behavior, affective processes, and cognitive function. In parallel, these agents exhibit neuroprotective properties through improved neuronal insulin sensitivity, attenuation of neuroinflammatory pathways, and support of neuroplasticity, alongside effects on limiting pathological protein aggregation. Dual GIP/GLP-1 agonism may further potentiate these central actions through complementary metabolic and synaptic mechanisms. Although pharmacovigilance data have identified isolated neuropsychiatric adverse events, current clinical evidence does not support a consistent causal association. Collectively, incretin-based therapies represent a promising translational approach at the interface of metabolic and neuropsychiatric disorders, warranting further investigation into their long-term central safety, therapeutic efficacy, and clinical relevance. Full article

Insulin-like growth factor 2 (IGF2) plays a pivotal role in regulating growth and development; however, its functional involvement in skeletal muscle satellite cells (SMSCs) remains incompletely understood. To elucidate the regulatory role of IGF2, goose SMSCs were engineered to overexpress IGF2 via lentiviral transduction, followed by comprehensive transcriptomic profiling. Comparative analysis revealed 2802 differentially expressed genes (DEGs) in IGF2-overexpressing cells relative to controls, comprising 1202 upregulated and 1600 downregulated genes. IGF2 overexpression markedly activated fibrogenic programs, as evidenced by the upregulation of AP-1 complex components (FOS, JUN), extracellular matrix-related genes (COL1A1, COL5A3), and Wnt signaling receptors (FZD1, FZD7). In contrast, genes involved in myogenic differentiation and contractile function were broadly suppressed, including key myogenic transcription factors (MEF2C, MEF2D), sarcomeric structural proteins (MYBPC1, ACTN2, MYOM3), and metabolic enzymes. Through the construction of protein–protein interaction networks coupled with functional enrichment analysis, we observed a concerted suppression of myogenic regulatory networks critical for myofiber formation. Quantitative real-time PCR validation further confirmed the reliability of the transcriptomic data. Collectively, these findings suggest that overexpression of IGF2 induces a phenotypic shift from myoblasts toward a fibroblast-like state, uncoupling proliferation from differentiation while enhancing fibrogenic identity. This study provides novel insights into IGF2-mediated regulatory mechanisms underlying skeletal muscle development and fibrotic processes. Full article

Thyroid eye disease (TED) is an autoimmune inflammatory disorder primarily affecting orbital tissues, but ocular surface and adnexal involvement represent a frequent and clinically significant component of disease burden. Beyond mechanical exposure resulting from eyelid retraction and proptosis, TED-associated ocular surface disease arises from complex interactions between immune activation, epithelial stress, glandular dysfunction, and altered neuro-epithelial signaling. Increasing use of systemic immunomodulatory therapies, biologics, and orbital radiotherapy has improved control of orbital inflammation; however, their molecular and cellular effects on ocular surface homeostasis remain incompletely defined. This review summarizes current evidence on the cellular and molecular mechanisms underlying ocular surface dysfunction in TED and examines how disease-modifying therapies influence epithelial integrity, tear film stability, meibomian and lacrimal gland function, and local immune signaling. Key pathways discussed include cytokine-mediated inflammation, thyroid-stimulating hormone receptor and insulin-like growth factor-1 receptor crosstalk, pro-fibrotic signaling, neuro-inflammatory mechanisms, and epithelial stress responses involving mitogen-activated protein kinase and nuclear factor kappa B pathways. We further highlight the challenge of disentangling therapy-induced molecular effects from persistent exposure-related mechanical stress. Understanding how TED therapies modulate ocular surface and adnexal homeostasis is essential for optimizing integrated management strategies that address both orbital inflammation and long-term ocular surface stability. Full article