Search Results (505)

Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) constitute two major superfamilies of signaling enzymes in mammals, displaying comparable genomic representation (~100 genes each) and numbers of catalytically active proteins (~80 enzymes each). Both families include receptor and non-receptor forms; however, their distributions differ substantially. PTKs comprise 58 receptor tyrosine kinases (RTKs), whereas PTPs include only 21 receptor protein tyrosine phosphatases (RPTPs). Despite these differences, RTKs and RPTPs share a common structural organization consisting of (i) an extracellular domain responsible for ligand recognition; (ii) a single-pass transmembrane domain anchoring the receptor to the plasma membrane; and (iii) an intracellular catalytic domain containing either kinase or phosphatase activity. Signal transduction mediated by RTKs and RPTPs generally depends on ligand binding and receptor dimerization. Remarkably, although these receptor families regulate signaling through fundamentally opposite molecular mechanisms, both are essential for controlling cell proliferation, adhesion, migration, differentiation, development, and survival. RTKs have been more extensively characterized than RPTPs; nevertheless, both receptor classes function as critical regulators of intercellular and intracellular communication pathways. Moreover, their membrane-associated localization makes them attractive targets for therapy in multiple human diseases, particularly cancer and neurological disorders. Full article

The swimming crab, Portunus trituberculatus, holds significant economic value in aquaculture, and marker-assisted selection (MAS) offers a powerful strategy to accelerate genetic improvement of growth-related traits. In this study, we performed an association analysis between 40 SSR markers and growth traits in 244 P. trituberculatus individuals. High genetic diversity was observed, with mean Shannon’s diversity index (SI) = 1.970, expected heterozygosity (He) = 0.773, and polymorphism information content (PIC) = 0.747. Linkage disequilibrium (LD) analysis revealed that all 485 marker pairs were in linkage equilibrium (r² < 0.33), validating the suitability of these markers for association mapping. A total of eight SSR markers were identified as significantly associated with growth traits (p < 0.05, FDR < 0.05). Notably, marker PrMa04 was associated with six traits (FCW, CW, CL, MLC, BH, BW), suggesting pleiotropic effects. Marker TRAN20 explained the highest phenotypic variance (PVE = 17.06%) for CL. Sequence analysis revealed that PrMa01, PrMa05, and ZL06 are located near genes encoding zinc finger protein, receptor-type tyrosine-protein phosphatase, and mucin-2, respectively, which are known to be involved in growth and development. The eight candidate markers identified in the discovery population were not replicated in an independent cohort after FDR correction, suggesting that their effects may be population-specific. These findings provide valuable SSR markers and genetic insights for MAS programs in P. trituberculatus, while also highlighting the critical importance of cross-population validation before routine application. Full article

Arthrobotrys oligospora is a widely distributed nematode-trapping (NT) fungus that captures nematodes by developing flexible traps. In fungi, protein tyrosine phosphatases (PTPs) are crucial for intracellular signaling, governing processes such as cell growth, proliferation, and differentiation in filamentous species. In this study, we characterized the functions of AoPtp (an orthologous PTP) through gene knockout, phenotypic, multi-omics, and yeast two-hybrid (Y2H) analyses. Inactivation of Aoptp caused a marked increase in trap number and nematode predation ability. The ΔAoptp mutants exhibited enhanced mycelial growth on TYGA and TG media, but showed no significant growth difference on PDA medium, together with reduced spore yield, and altered stress responses. In addition, phenotypic and transcriptomic analyses suggested that AoPtp is associated with lipid droplet accumulation and autophagy-related processes. Metabolomic analysis revealed extensive changes in metabolic profiles, including an approximately six-fold reduction in arthrobotrisin abundance. Furthermore, AoPtp interacts with AoFus3 and AoSlt2 in a Y2H assay, suggesting its potential involvement in the mitogen-activated protein kinase signaling pathway. In summary, we demonstrated that AoPtp is a pleiotropic regulator of sporulation, trap development, stress tolerance, and metabolic process in A. oligospora. These findings provide a basis for probing the regulatory mechanism of PTPs underlying trap formation in NT fungi, as well as for exploring their potential applications in biocontrol of nematode-associated diseases. Full article

Ficus deltoidea Jack (Moraceae), locally known as Mas Cotek, is a medicinal plant traditionally used throughout Southeast Asia for the management of diabetes mellitus. This review summarises the available evidence on the antidiabetic properties of F. deltoidea based on eleven in vitro, nine in vivo and one clinical study identified through a structured literature search. In vitro investigations show that F. deltoidea inhibits α-glucosidase and α-amylase, stimulates insulin secretion in pancreatic β-cells via both K⁺-ATP channel-dependent and -independent pathways, enhances glucose uptake in hepatocytes and adipocytes, promotes adiponectin secretion and inhibits protein tyrosine phosphatase 1B (PTP1B). Vitexin and isovitexin, the predominant C-glycosyl flavonoids in F. deltoidea leaves, appear to be the main bioactive compounds responsible for these effects. Meanwhile, in vivo studies in streptozotocin-induced diabetic rodents report dose-dependent reductions in fasting blood glucose, improved glucose tolerance, restoration of pancreatic islet architecture, modulation of hepatic gluconeogenic and glucose-metabolic genes, and protection against diabetic nephropathy and bone loss. Inter-varietal differences in chemical composition and biological activity were observed, with var. trengganuensis and var. intermedia reported as the most active. The only available clinical trial in adults with prediabetes (1000 mg/day for 8 weeks) showed a reduction in LDL and total cholesterol but no significant change in fasting blood glucose or insulin. The discrepancy between preclinical and clinical findings highlights the need for standardised extracts, pharmacokinetic studies and adequately powered clinical trials in patients with established type 2 diabetes mellitus. Full article

The skipjack tuna (Katsuwonus pelamis) is one of the least commercially exploited tuna globally. The possible medicinal benefits of K. pelamis extract have not been explored. We investigated the 70% ethanol (EtOH) soluble fractions of skipjack tuna heart for the inhibition of protein-tyrosine phosphatase 1B (PTP1B) and α-glucosidase. The dichloromethane (CH₂Cl₂) fraction significantly inhibited the activities of PTP1B and α-glucosidase. Repeated column chromatography of the active CH₂Cl₂ fraction based on bioactivity-guided fractionation yielded cholesterol, cholesteryl myristate, and sn-1,3-dipalmitoyl-2-oleoylglycerol; the latter significantly inhibited PTP1B and α-glucosidase. Kinetic study revealed that sn-1,3-dipalmitoyl-2-oleoylglycerol showed mixed-type inhibition against PTP1B. Docking simulations showed that sn-1,3-dipalmitoyl-2-oleoylglycerol selectively inhibited PTP1B and α-glucosidase by targeting its active site and exhibited good binding affinity, with a docking score of −7.4 and −7.1 kcal/mol, respectively. Moreover, 70% EtOH, CH₂Cl₂ and EtOAc fractions, and sn-1,3-dipalmitoyl-2-oleoyl glycerol significantly inhibited ONOO−mediated albumin nitration. These results implicate tuna heart extract as a potential functional food ingredient for the prevention and treatment of diabetes and its associated complications. Full article

Genome mining of the marine-derived Streptomyces sp. S42 uncovered a type II polyketide synthetase (T2 PKS) biosynthetic gene cluster (BGC) harboring a gene for 3-ketoacyl-ACP synthase III (KAS III), a hallmark of non-acetate starter unit incorporation, suggesting that the BGC may produce previously unidentified aromatic polyketides. Heterologous expression and promoter engineering of this prioritized BGC in host Streptomyces albus J1074 activated the biosynthetic pathway, leading to the isolation of eight new polycyclic aromatic derivatives, verrucones A–H (1–8). Comprehensive structural elucidation via NMR and HRESIMS revealed that these compounds feature either a 2-methylbutyryl or an isobutyryl starter unit and can be classified into three distinct skeletal types. Based on these findings and bioinformatic analysis, a plausible biosynthetic pathway for 1–8 involving divergent spontaneous cyclization from a common nascent polyketide intermediate was proposed. Among the isolated compounds, 1–5 exhibited inhibitory activity against several protein tyrosine phosphatases (PTPs) with IC₅₀ values ranging from 1.84 μM to 24.82 μM. This study presents a successful case study demonstrating that combining KAS III-targeted genome mining with heterologous expression is a viable approach for discovering non-acetate-primed aromatic polyketides. Full article

A plethora of studies have demonstrated the bioactive properties of collagen peptides, including the promotion of wound healing and bone health. Research has demonstrated that these effects are attributable to their elevated biocompatibility and signaling capabilities. The present study investigated the effects of collagen peptides produced by enzymatic hydrolysis of perch scales on the induction of extracellular matrix formation and osteogenesis. The findings demonstrated that a combination of pre-heating and enzymatic hydrolysis resulted in the optimal peptide yield, with 94.9% of the peptides exhibiting a molecular weight below 1200 Daltons and containing elevated levels of hydroxyproline. The addition of perch scale collagen peptides to fibroblasts 890510-01F ATIT has been demonstrated to effectively induce the production of type I procollagen and fibronectin, a protein associated with the osteoblast phenotype and osteoblast differentiation. It is also worthy of note that experiments conducted using MC3T3-E1 osteoblasts indicate that collagen peptides significantly increased alkaline phosphatase activity by a factor of 1.46. This study demonstrates that collagen peptides derived from perch scales are enriched in bioactive peptides containing C-terminal tyrosine residues, including DYPRNHY and DPYNRHY. These findings provide a scientific basis for the future development of perch scale-derived collagen peptides as dietary supplements or functional food ingredients for promoting bone health. Full article

The review covers research on dual-target antitumor agents over the past five years. One of the targets is histone deacetylases (HDACs), while the second potential target is a protein group located both on the membrane surface (phosphatidylinositol 3-kinase (PI3K), anaplastic lymphoma kinase (ALK), receptor tyrosine kinase (AXL), tyrosine protein kinase (HER2), FMS-like tyrosine kinase (FLT3), and vascular endothelial growth factor receptor (VEGFR2)) and in the nucleus (serine/threonine protein kinase Wee1, DNA methyltransferase (DNMT), dual-specificity phosphatase (CDC25A), an enzyme from the cyclin-dependent kinase family (CDK9), dual-specificity tyrosine-serine/threonine kinase (DYRK2), and BET family proteins (BRD4, BD1, and BD2)). This review presents the results of studies on the inhibitory activity of various HDAC isoforms and other enzymes, as well as in vitro cytotoxicity studies on both neoplastic and healthy cells. It also includes selectivity studies, in vivo experiments (changes in tumor volume in mice) and oral bioavailability assessments. The review also describes the chemical structures of several dual-target agents and identifies the molecular fragments responsible for inhibiting different targets. Based on the studies reviewed in this paper, it can be concluded that some dual inhibitors have superior in vitro cytotoxicity and exhibit selectivity towards some tumor cells compared to monofunctional reference compounds. These findings may be useful for molecular design in the field of polypharmacology, with the aim of developing new dual-target molecules that exhibit improved antitumor activity and selectivity towards neoplastic cells. Full article

Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), represents a major global health challenge, driven by the increasing prevalence of obesity and sedentary lifestyles. T2DM is characterized by insulin resistance and progressive β-cell dysfunction, leading to chronic hyperglycemia and multiple complications. Among the molecular targets investigated for therapeutic intervention, protein tyrosine phosphatase 1B (PTP1B) has emerged as a key negative regulator of insulin signaling. By dephosphorylating the insulin receptor and its downstream substrates, PTP1B attenuates insulin action and contributes to metabolic dysfunction. In addition to its role in glucose homeostasis, PTP1B is implicated in obesity, diabetic complications, neurodegenerative disorders, and cancer, highlighting its relevance as a multifunctional therapeutic target. However, the development of PTP1B inhibitors remains challenging due to the highly conserved and polar nature of its catalytic site, which limits selectivity and cell permeability. Recent research has focused on alternative strategies, including allosteric modulation and multi-site inhibition, to overcome these limitations. This review provides a comprehensive overview of PTP1B inhibitors from both synthetic (2019–2025) and natural sources, with particular emphasis on natural products reported from 2022 onwards, while including selected earlier studies to provide historical context and illustrate representative structural classes and inhibition mechanisms. Although PTP1B remains an attractive therapeutic target, its clinical validation for diabetes treatment has yet to be achieved. Continued advances in medicinal chemistry and allosteric modulation may help overcome the current translational barriers. Full article

Metabolic disorders encompass a spectrum of pathologies driven by the dysregulation of systemic metabolic homeostasis. Their escalating global prevalence has positioned these conditions at the forefront of contemporary biomedical research. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) regulates cellular tyrosine phosphorylation and links metabolic perturbations to altered signal transduction. Functionally, PTPN2 modulates immune responses, cellular proliferation, and metabolic signaling pathways. Consequently, it influences immunological tolerance, glucose and lipid metabolism, and insulin sensitivity in a context-dependent manner. To facilitate the identification of novel therapeutic targets, this review systematically delineates the molecular mechanisms underlying PTPN2 function across diverse metabolic pathologies. Specifically, we examine its involvement in type 1 diabetes, type 2 diabetes, diabetic complications, and metabolic dysfunction-associated steatohepatitis. Furthermore, we highlight recent advances in PTPN2-targeted interventions, with a particular emphasis on type 2 diabetes research, while critically evaluating existing clinical challenges and future translational prospects. Ultimately, this synthesis provides an integrated perspective for the development of precision medicine strategies in the management of metabolic diseases. Full article

A chemical study of the fungus Aspergillus fumigatus F15ZA56 resulted in the elucidation of eight previously undescribed cyclohexenols, aspergienynes R-Y (1, 5–11), and three new benzopyran derivatives (2–4), together with two known analogues (12–13). The structures were determined based on HRESIMS and extensive NMR data. The absolute configurations of the chiral carbons in the new compounds were ultimately confirmed by ECD analysis. Bioactivity assays showed that compounds 4, 12 and 13 had significant inhibitory activities against TCPTP, PTP1B, and MEG2 (IC₅₀ 12.20–62.19 nM). Notably, compound 12 exhibited notable selectivity towards PTP1B (IC₅₀ 12.20 nM) over the tested phosphatases, comparable to the reference inhibitor AC484 (9.12 nM). Full article

Marine rest raw materials are often undervalued or wasted despite their nutrient and bioactive composition. Calanus finmarchicus, harvested primarily for its omega-3-rich oil, yields a side-stream protein hydrolysate, C. finmarchicus hydrolysate (CFH), during commercial enzyme-assisted extraction. Although currently used as a feed ingredient, CFH contains low-molecular-weight peptides and free amino acids with potential for human health applications. This study evaluated the gastrointestinal stability of CFH and the impact of digestion on bioactivity using a static in vitro gastrointestinal digestion model. Fresh-frozen and freeze-dried C. finmarchicus were included to provide comparative data. Antioxidant capacity was measured by ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays, and antidiabetic activity by dipeptidyl peptidase-IV (DPP-IV) and protein tyrosine phosphatase 1B (PTP1B) inhibition assays. The hydrolysate maintained its antioxidant capacity throughout digestion (at 165 min: FRAP: 27.5 ± 0.6 µmol TE/g dry weight (DW); ORAC: 411 ± 37 µmol TE/g DW). Digestion increased its DPP-IV inhibitory activity, with the inhibitory concentration (IC₅₀) decreased from 3.73 to 1.96 mg/mL (p ≥ 0.05). PTP1B inhibitors were nonselective and detected only at 0 and 30 min. These findings support our hypothesis that CFH may serve as a nutraceutical for humans and provide a rationale for subsequent in vivo studies. However, further identification of bioactive components and in vivo validation are warranted. Full article

Ebola virus disease (EVD) is characterized by immune dysregulation and damaging hyperinflammation. We aimed to characterize the signaling pathways and regulatory mechanisms dysregulated during EVD. To avoid hyperinflammation, innate immune signaling is regulated by post-translational modifications (PTMs), including protein phosphorylation. Here, we show that the protein tyrosine phosphatase nonreceptor type 13 (PTPN13) negatively regulates Interferon (IFN)-β while also positively regulating the neutrophil chemoattractant CXCL1. Using vectors encoding IRF3 with mutations on phosphorylation sites, we identified Y292 on IRF3 as a PTPN13 target of dephosphorylation. Knockout of PTPN13 increased IRF3 phosphorylation and expression of IFNβ and IFN-stimulated genes (ISGs) following poly(I:C) stimulation. Intriguingly, depletion of PTPN13 during Ebola virus (EBOV) infection resulted in decreased IFNβ and ISG induction at later time points post-infection, which correlated with increased viral titers. We identified PTPN13-mediated dephosphorylation of the viral protein VP35 as one potential mechanism inhibiting virus replication. Additionally, the induction of inflammatory chemokines, including CXCL1, decreased in PTPN13 knockout cells late during EBOV infection. These effects could be explained by increased phosphorylation of the regulatory p85 subunit of PI3K. Dephosphorylation of p85 promotes its degradation, subsequently enhancing PI3K kinase activity and downstream signaling via AKT. Together, our study suggests that PTPN13 is involved in immune regulation and efficient antiviral responses by dephosphorylation of IRF3, EBOV-VP35 and PI3K-p85. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, which has recently been found to be closely associated with neuroinflammation. As an anti-inflammatory drug, triptolide (TP), a natural diterpenoid from Tripterygium wilfordii, was selected in the current study for treating PS19 (tau^P301S transgenic) mice, tauopathy AD mice. In addition, we have previously found that TP had the ability to reduce the level of cholesterol. However, the roles and mechanisms of TP in the above processes are not clear. To this end, we found that elevated cholesterol in serum and brain tissues upregulated the expression of apolipoprotein E (APOE) and sialic acid-binding Ig-like lectin 3 (CD33), leading to the activation of SH2-containing protein tyrosine phosphatase 1 (SHP-1). The activation of SHP-1 inhibits the signaling pathways of Janus kinase 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6), which results in inhibition of the M2 polarization of microglia, which exacerbates neuroinflammation and cognitive decline in high-cholesterol diet (HCD)-fed mice. Conversely, TP treatment significantly inhibited the hepatic sterol regulatory element-binding protein 2 (SREBP2)/3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) pathway, which reduced the cholesterol levels in the serum and brain. By depressing the levels of cholesterol, the axis of CD33 and SHP-1 was suppressed, which resulted in restoration of the activity of JAK1 and STAT6 pathways, leading to the transition of microglia from the M1 to the M2 phenotype. Of note, these observations demonstrate that TP alleviates the cognitive impairment of PS19 mice via depressing neuroinflammation. Altogether, our results revealed the mechanisms of TP in treating AD via CD33/SHP-1/JAK1/STAT6 pathways in a cholesterol-dependent manner. Full article

Diabetes mellitus is a chronic and increasingly prevalent metabolic disorder characterized by persistent hyperglycemia, resulting from defects in insulin secretion, insulin action, or both. Despite the availability of pharmacological agents that effectively manage blood glucose levels, many are associated with adverse effects, limited efficacy over time, and high costs. Consequently, there is growing interest in alternative therapies, especially those derived from traditional medicinal plants, that have long been employed in various cultures for managing diabetes. Recent advances in phytochemistry have identified bioactive plant secondary metabolites with promising antidiabetic properties. This review aims to provide a comprehensive overview of plant-derived compounds that exhibit inhibitory activity against key diabetes-related enzymes, including α-glucosidase, α-amylase, protein tyrosine phosphatase 1B (PTP1B) and dipeptidyl peptidase-4 (DPP-4). These enzymes play critical roles in glucose metabolism and insulin signaling pathways. The review highlights the structural diversity of these natural inhibitors, their mechanisms of action, and their effectiveness in preclinical models. Understanding the molecular interactions and pharmacological profiles of these metabolites may facilitate the development of safer and more effective antidiabetic agents. Full article