Search Results (2,369)

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

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic triglyceride accumulation in the setting of obesity and insulin resistance. Although apolipoprotein C-III (APOC3) is a well-established regulator of plasma triglyceride metabolism, its hepatocyte-intrinsic role in intracellular lipid accumulation remains unclear. In this study, we investigated whether APOC3 contributes to hepatocellular triglyceride synthesis during early metabolic dysfunction. In 6-week-old db/db mice, early hepatic lipid accumulation was observed without detectable fibrosis. Transcriptomic profiling identified APOC3 as an upregulated gene associated with lipid metabolic pathways, and its hepatic upregulation was confirmed at both mRNA and protein levels. Gain- and loss-of-function experiments in HepG2 cells demonstrated that APOC3 overexpression significantly increased intracellular triglyceride content, whereas APOC3 knockdown reduced triglyceride accumulation. Mechanistically, APOC3 selectively regulated diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step of triglyceride synthesis, without significantly affecting major lipogenic transcription factors. Furthermore, under de novo lipogenesis-inducing conditions triggered by the liver X receptor agonist T0901317 and insulin, APOC3 markedly amplified DGAT2 expression and triglyceride accumulation. Collectively, these findings suggest a hepatocyte-intrinsic role for APOC3 in promoting triglyceride accumulation through DGAT2-dependent mechanisms. The APOC3–DGAT2 axis may represent a relevant pathway contributing to hepatic lipid accumulation in metabolic liver disease. 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

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

The degradation of plastic waste leads to the release of numerous chemical additives, including phthalate plasticizers, which have been implicated in the pathogenesis of metabolic disorders. Di (2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer whose primary metabolite, mono (2-ethyl-5-carboxypentyl) phthalate (MECPP), has been associated with multiple metabolic diseases. In this study, we applied an integrated approach combining network toxicology and molecular docking to systematically investigate the potential mechanistic role of MECPP in metabolic dysregulation. Our strategy included multi-platform target prediction, disease gene association analysis, functional enrichment, protein–protein interaction network construction, and molecular docking analysis. The results suggested that MECPP may be associated with six common core targets, including BCL2, BCL2L1, MAPK14, MMP2, MMP9, and TNFRSF1A, which are mainly involved in apoptosis, inflammatory regulation, and extracellular matrix remodeling. Pathway enrichment analysis further indicated the potential involvement of several disease-overlapping pathways, including insulin resistance, neuroactive ligand–receptor interaction, efferocytosis, advanced glycation end product–receptor for advanced glycation end product (AGE–RAGE) signaling, phospholipase D signaling, and renin secretion. Overall, these findings suggest that MECPP may contribute to metabolic dysregulation through overlapping molecular mechanisms across multiple diseases. This study provides a computational basis for future experimental validation and environmental risk assessment. Full article

Leucine-rich repeat kinase 2 (LRRK2) is a multidomain serine/threonine kinase and a major genetic contributor to Parkinson’s disease (PD). Although LRRK2 has been extensively studied in neurodegeneration, emerging evidence indicates that it also plays a critical role in systemic metabolism. LRRK2 regulates glucose homeostasis through modulation of insulin signaling, vesicle trafficking, mitochondrial function, and inflammatory responses. Studies using LRRK2 knockout and knock-in models, including the pathogenic G2019S mutation, have revealed abnormalities in insulin sensitivity, adipose tissue inflammation, hepatic glucose production, and skeletal muscle metabolism. Mechanistically, LRRK2 phosphorylates Rab GTPases, thereby controlling insulin receptor trafficking and GLUT4 translocation. In addition, LRRK2 influences mitochondrial dynamics and reactive oxygen species production, linking metabolic stress to inflammatory signaling. Importantly, LRRK2 also regulates innate immune pathways, including TLR4–NFκB signaling and inflammasome activation, thereby connecting peripheral metabolic dysfunction to neuroinflammation. Here, we propose an integrated metabolic–neuroinflammatory crosstalk model in which LRRK2 functions as a molecular coordinator linking peripheral metabolic dysfunction to central neurodegeneration. In this framework, systemic metabolic stress—characterized by insulin resistance, chronic inflammation, advanced glycation end product (AGE) accumulation, and blood–brain barrier disruption—drives microglial activation and neurodegenerative processes. Understanding this systemic axis may provide new therapeutic opportunities targeting both metabolic dysfunction and neurodegeneration in PD. Full article

Background/Objectives: Carbohydrate-restricted diets (CHRs) are increasingly employed in the treatment of obesity. We aimed to investigate the effects of a CHR on hepatic lipid anabolism and its association with changes in the proinflammatory environment and insulin signaling. Methods: Forty-eight C57BL/6J female mice were used in this study. We aimed to analyze the impact of a CHR on the hepatic proinflammatory profile and its relationship with changes in insulin signaling and fatty acid anabolism in obese female mice after two months on a high-fat diet. We also examined the impact of a one-month chow diet after CHR. Blood samples were collected, and the liver was processed during all-time study periods for analyses of biochemical, hormonal, and inflammatory markers, as well as possible changes in leptin and insulin signaling pathways. Results: Compared with chow-fed mice, CHR mice showed increased interleukin (IL)-1β and IL-2 levels, as well as leptin-related signaling in the liver. There was also a decrease in the expression of fatty acid synthase and the phosphorylation of ATP-citrate lyase, which was associated with a reduction in the activation of the insulin receptor, Akt, the mammalian target of rapamycin, cAMP-response element-binding protein, and glycogen synthase kinase 3β. The subsequent reintroduction of a chow diet after CHR resulted in lower hepatic free fatty acid and triglyceride levels than in obese mice without previous CH restriction. Conclusions: This study suggests that CHR inhibits de novo hepatic lipogenesis in obese mice by attenuating insulin signaling in a low-grade proinflammatory state. Full article

Chronic kidney disease (CKD), especially diabetic kidney disease (DKD), is characterized not only by progressive loss of renal function but also by profound metabolic disturbances, including insulin resistance (IR). Emerging evidence implicates gut-derived uremic toxins as mediators linking intestinal dysbiosis to metabolic and renal injury. Several microbial metabolites, for example, indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide, are known to accumulate in CKD due to decreased renal excretion and altered tubular secretion. In vitro and in vivo experiments indicate that these gut-derived nephrotoxins impair insulin signaling pathways in cells. This results in increased production of reactive oxygen species, activation of stress kinases, higher levels of inflammatory cytokines, and inhibitory serine phosphorylation of insulin receptor substrates. Consequently, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling is impaired, reducing cellular glucose uptake. At the same time, these toxins induce endothelial dysfunction and mitochondrial damage, not only causing systemic IR but also contributing to the progression of kidney disease. Observational data link higher plasma toxin levels with components of IR, rapid loss of renal function as measured by estimated glomerular filtration rate, and a high risk of cardiovascular events in CKD patients. Although causality in humans remains unproven, interventions targeting the microbiota, toxin binding, and oxidative stress pathways show promise. We propose an integrated gut–kidney–metabolic framework in which dysbiosis-driven toxin production may amplify IR and DKD progression. Full article

Diabetes mellitus (DM) is a complex metabolic disorder associated with a heightened risk of cardiovascular events, largely driven by a hypercoagulable and hypofibrinolytic state. The pathophysiological interplay between chronic hyperglycemia, oxidative stress, insulin resistance, and systemic inflammation fosters profound alterations in the coagulation cascade, endothelial function, and platelet activity. This narrative review synthesizes evidence from studies published between 2008 and 2026, focusing on coagulation and platelet-related biomarkers selected based on their biological relevance to thrombosis, endothelial dysfunction, and inflammation, as well as the availability of clinical and interventional data across different forms of DM. Although there are numerous biomarkers involved in the pathogenesis of various forms of diabetes, this narrative review critically examines key coagulation biomarkers—including D-dimer, fibrinogen, prothrombin, tissue thromboplastin or tissue factor, P-selectin, soluble urokinase plasminogen activator receptor, thrombomodulin, plasminogen activator inhibitor-1, von Willebrand factor, and β-thromboglobulin—across distinct diabetes subtypes, including type 1, type 2, gestational, and secondary forms linked to endocrinopathies and pancreatic diseases. The literature reveals substantial subtype-specific heterogeneity in hemostatic alterations. For instance, Type 1 DM is characterized by early endothelial dysfunction and platelet activation, while Type 2 DM presents with elevated coagulation factors, impaired fibrinolysis, and a proinflammatory milieu. Gestational DM exhibits pregnancy-specific changes in coagulation, yet distinguishing them from obesity-related effects remains challenging. Secondary diabetes forms, such as those associated with Cushing’s syndrome or pancreatitis, further underscore the diversity in thrombotic risk profiles. Among the coagulation and platelet activation biomarkers reviewed, fibrinogen, P-selectin, and plasminogen activator inhibitor-1 demonstrate the most consistent associations with glycemic control, vascular dysfunction, and therapeutic modulation, particularly in type 2 diabetes, suggesting greater potential for clinical translation. In contrast, evidence for markers such as D-dimer, tissue factor or tissue thromboplastin, and soluble urokinase plasminogen activator receptor remains heterogeneous and insufficient for routine clinical application. By synthesizing mechanistic insights and clinical data, this review highlights the urgent need for subtype-tailored coagulation assessment in diabetes management. A better understanding of the dynamic alterations in coagulation pathways may facilitate earlier detection of vascular complications and inform personalized antithrombotic strategies. 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

The tomato hind (Cephalopholis sonnerati) is a marine aquaculture fish species with high economic value. Elucidating the mechanisms underlying its growth regulation is crucial for the development of the aquaculture industry. To analyze the biological mechanisms underlying growth differences, individuals with extreme body sizes at 8 months of age from the same batch were selected in this study. A combined experiment of “body size × feeding status” was constructed, and transcriptome sequencing and weighted gene co-expression network analysis (WGCNA) were performed on brain and muscle tissues. The results showed that 2553 differentially expressed genes (DEGs) were identified between individuals with distinct body sizes, which were significantly enriched in growth regulation pathways such as PI3K–Akt, MAPK, and FoxO. Feeding differences affected 4480 genes, which were significantly enriched in signaling pathways including the insulin signaling pathway. WGCNA further identified co-expression modules (brown4, blue, coral1) significantly correlated with growth, as well as hub genes including pik3r1 and eif4ebp2. Comprehensive analysis demonstrated that the growth regulation of C. sonnerati operates as a cascade network. Brain tissues perceive signals through neuroactive ligand–receptor interactions and integrate and transduce these signals via core pathways including Ras–MAPK and PI3K–Akt. Finally, growth processes are executed in muscle tissues by regulating glycogen metabolism, protein synthesis, and other processes, which are precisely regulated by terminal processes such as cellular senescence. Among them, pik3r1 and eif4ebp2, as key molecular switches, play a central role in integrating upstream signals and precisely regulating downstream growth programs. This study preliminarily clarifies the molecular mechanism network of growth differences in C. sonnerati, providing a theoretical basis and candidate genes for the genetic improvement of its growth traits. Full article

Metabolic syndrome (MetS) is a multifactorial cardiometabolic condition characterized by insulin resistance, visceral adiposity, dyslipidemia, hypertension, and chronic low-grade inflammation, collectively increasing the risk of type 2 diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular disease. Growing interest has focused on plant-derived dietary strategies capable of targeting multiple pathogenic pathways simultaneously. Opuntia ficus-indica fruits (OFIF) represent a complex food matrix containing betalains, polyphenols, carotenoids, soluble fiber, functional amino acids, vitamins, and minerals. Experimental evidence suggests that these constituents interact with key molecular networks implicated in MetS pathophysiology, including redox-sensitive pathways (NRF2), inflammatory signaling (NF-κB), energy-sensing regulators (AMPK), and lipid metabolism proliferator-activated receptor alpha (PPAR-α) dependent mechanisms. Preclinical studies consistently report associations with improvements in oxidative stress, inflammatory markers, hepatic steatosis, and glucose homeostasis following OFIF supplementation. However, human evidence remains limited by small sample size, short intervention duration, and variability in compositional standardization. This narrative review adopts a systems-level perspective to integrate mechanistic, preclinical, and early clinical evidence in the context of metabolic syndrome pathophysiology, while critically addressing translational gaps, compositional variability, and current limitations in human validation. Full article

This experiment investigated the effects of dietary Artemisia ordosica Krasch. (AOK) supplementation on the n3-polyunsaturated fatty acid (n3-PUFA) profile of subcutaneous adipose tissue (SADT) in Arbas cashmere goats and explored the underlying transcriptional mechanisms. Forty healthy, weaned kids (120 ± 10 days of age; similar body weight) were randomly allocated to two groups (n = 20): a control group (CON, basal diet) and an AOK group (AOK, basal diet with 3% of the roughage replaced by AOK). The feeding trial spanned 104 days, consisting of a 14-day adaptation period and 90 days of data acquisition. Compared with the CON group, AOK significantly reduced the content of saturated fatty acids (SFAs) and n6-polyunsaturated fatty acids (n6-PUFAs)/n3-PUFAs (n6/n3). In contrast, the levels of n3-PUFAs in the SADT of cashmere goats increased markedly (p < 0.05). Compared with the CON group, AOK exhibited significantly higher activities of hormone-sensitive lipase (HSL) (p = 0.027), adenylyl cyclase 2 (ADCY2) (p = 0.010), adenylyl cyclase 5 (ADCY5) (p = 0.046), cluster of differentiation 36 (CD36) (p = 0.013), solute carrier family 27 member 4 (SLC27A4) (p = 0.021), and fatty acid binding protein 4 (FABP4) (p = 0.040), along with significantly lower activities of fatty acid synthase (FAS) (p = 0.002), lipoprotein lipase (LPL) (p = 0.048), and stearoyl-coa desaturase (SCD) (p = 0.026) in SADT. Compared with the CON group, the activities of superoxide dismutase (SOD) (p = 0.032), catalase (CAT) (p = 0.010), glutathione peroxidase (GSH-PX) (p = 0.029), and total antioxidant capacity (T-AOC) (p = 0.002) were significantly increased in the AOK group. Transcriptomic profiling revealed that AOK supplementation downregulated mRNA levels of ADCY2, ADCY5, LPL, FAS, SCD, stearoyl-CoA desaturase 1 (SCD1), stearoyl-CoA desaturase 2 (SCD2), glycogen synthase 1 (GYS1), acyl-CoA oxidase 1 (ACOX1), acetyl-CoA carboxylase (ACC), diacylglycerol acyltransferase 1 (DGAT1), fatty acid desaturase 1 (FADS1), solute carrier family 27 member 2 (SLC27A2), erythroblastic leukemia viral oncogene homolog 4 (ERBB4), and carnitine palmitoyltransferase 1B (CPT1B) (p < 0.05). It also markedly induced acyl-CoA synthetase long-chain family member 4 (ACSL4) (p < 0.01) in SADT. Genes significantly enriched in the adenosine-monophosphate-activated protein kinase (AMPK) signaling pathway included LPL, SCD1, CPT1B, and GYS1 (p = 0.010). Genes significantly enriched in the phosphatidylinositol 3-kinase-akt (PI3K-Akt) signaling pathway included GYS1 and ERBB4 (p = 0.015). CPT1B, ADCY2, and GYS1 were identified as the genes significantly enriched in the insulin resistance signaling pathway (p = 0.048). LPL was the only gene significantly enriched in the cholesterol metabolism pathway (p = 0.049). Genes showing a tendency toward significant enrichment in the peroxisome-proliferator-activated receptor (PPAR) signaling pathway included ACSL4, CPT1B, SCD1, and LPL (p = 0.051). These interconnected cascades improve insulin sensitivity, stimulate triglyceride (TG) hydrolysis, and modulate n3-PUFA levels. Supplementation with AOK enhances n3-PUFA content by accelerating TG breakdown while simultaneously restraining FA oxidation in SADT. Consequently, AOK supplementation can be effectively used to enhance the nutritional value of cashmere goat meat through improved n3-PUFA deposition in SADT. Full article

Diabetes Mellitus is a chronic metabolic disorder characterized by impaired insulin production and/or action, leading to persistent hyperglycemia and insulin resistance. It has been associated with several comorbidities, including cognitive dysfunction, affecting functions such as attention, memory, and processing speed. Mounting evidence indicates a complex relationship between type 2 Diabetes Mellitus (DM2) and neurodegenerative disorders such as mild cognitive impairment and Alzheimer’s disease (AD). Beyond the conventional hallmarks of each pathology, patients with DM2 face an increased risk of neuronal degeneration, while AD is characterized by a marked reduction in insulin receptor density. Although aging, neuroinflammation, and vascular dysfunction have been recognized as key risk factors in AD, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. Various studies have been conducted to identify reliable biomarkers that elucidate the connection between DM2 and AD, including insulin dysregulation, neuroinflammation, amyloid-β aggregation, and tau hyperphosphorylation. Investigation of these biomarkers is still ongoing, and they may serve not only as diagnostic tools but also as therapeutic targets. Here, we review the current evidence supporting a convergent biological framework between DM2 and AD. Clarifying these shared pathways may improve early detection and guide the development of targeted therapeutic strategies aimed at reducing neurodegeneration in metabolically vulnerable populations. Full article