Search Results (506)

Background: Chronic inflammation and the development of cancer are closely linked, with components that comprise the tumour microenvironment—including proinflammatory cytokines—exerting essential tumourigenic effects. These proinflammatory cytokines include IL-1β, which has been reported to be overexpressed in several cancers and shown to activate several signalling pathways. These pathways may involve kinases such as AKT (serine/threonine kinase) and Src (Proto-oncogene tyrosine-protein kinase), and have a broad capacity to activate nuclear factors, including NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells), which can regulate the transcription of genes encoding proteins such as cIAP1 (Cellular Inhibitor of Apoptosis Protein 1), Bcl-2 (B-cell lymphoma 2), and cyclin D1, thereby regulating processes like apoptosis and cell cycle inhibition. Objectives: The aim of this study was to investigate the role of IL-1β (Interleukin-1 beta) in regulating cell death and proliferation in RS4:11 leukaemic lymphoblasts via the PI3K (Phosphoinositide 3-kinase)/AKT/Src/NF-κB pathway using an in vitro experimental approach. Methods: We employed flow cytometry to determine the expression levels and phosphorylation status of various proteins; proliferation was assessed using the CCK-8 kit, and apoptosis was evaluated with the Annexin V kit. Results: Our findings indicate that the IL-1β-activated signalling pathway modulates these cellular processes in leukaemic lymphoblasts. Conclusions: We therefore conclude that IL-1β exerts significant effects on cell death and proliferation in leukaemic lymphoblasts through the PI3K/AKT/NF-κB pathway, with the study’s findings indicating that an inflammatory environment may promote such lymphoblasts to acquire neoplastic characteristics. As such, the proteins involved in the effects evaluated in this work could be considered as potential therapeutic targets for the treatment of Acute Lymphoblastic Leukaemia (ALL). Full article

The Xenopus oocyte has long served as a versatile and powerful model for dissecting the molecular underpinnings of reproductive and developmental processes. Its large size, manipulability, and well-characterized cell cycle states have enabled generations of researchers to illuminate key aspects of oocyte maturation, fertilization, and early embryogenesis. This review provides an integrated overview of the cellular and molecular events that define the Xenopus oocyte’s transition from meiotic arrest to embryonic activation—or alternatively, to programmed demise if fertilization fails. We begin by exploring the architectural and biochemical landscape of the oocyte, including polarity, cytoskeletal organization, and nuclear dynamics. The regulatory networks governing meiotic resumption are then examined, with a focus on MPF (Cdk1/Cyclin B), MAPK cascades, and translational control via CPEB-mediated cytoplasmic polyadenylation. Fertilization is highlighted as a calcium-dependent trigger for oocyte activation. During fertilization in vertebrates, sperm-delivered phospholipase C zeta (PLCζ) is a key activator of Ca²⁺ signaling in mammals. In contrast, amphibian species such as Xenopus lack a PLCZ1 ortholog and instead appear to rely on alternative protease-mediated signaling mechanisms, including the uroplakin III–Src tyrosine kinase pathway and matrix metalloproteinase (MMP)-2 activity, to achieve egg activation. The review also addresses the molecular fate of unfertilized eggs, comparing apoptotic and necrotic mechanisms and their relevance to reproductive health. Finally, we discuss recent innovations in Xenopus-based technologies such as mRNA microinjection, genome editing, and in vitro ovulation systems, which are opening new avenues in developmental biology and translational medicine. By integrating classic findings with emerging frontiers, this review underscores the continued value of the Xenopus model in elucidating the fundamental processes of life’s origin. We conclude with perspectives on unresolved questions and future directions in oocyte and early embryonic research. Full article

Tyrosine phosphorylation has emerged as a central regulatory mechanism in innate immunity. Building on our recent studies that Syk and EGFR sequentially phosphorylate TLR9 to fully activate it, we discuss how similar mechanisms operate across other Toll-like receptors and the cytosolic DNA sensor STING. Evidence from complementary systems reveals that receptor and nonreceptor tyrosine kinases, including Src-family kinases, Syk, BTK, and EGFR, form an integrated signaling network that triggers receptor activation, trafficking, and downstream gene expression. Scavenger receptors such as SR-A further drive this kinase cascade by coordinating viral recognition to TLR activation. These observations reveal a novel ‘tyrosine kinase axis’ that connects nucleic acid sensing to spatially controlled innate immune signaling and highlight new opportunities to modulate innate immunity through tyrosine kinase regulation. Full article

Chronic atrophic gastritis (CAG) is a precancerous gastric condition with limited therapeutic interventions, and the mechanisms underlying the benefits of Coptis chinensis Franch. (CCF) remain insufficiently defined. This study employed an integrated computational strategy to clarify the molecular basis of CCF activity against CAG. Network pharmacology was used to identify potential targets of the major CCF constituents berberine, coptisine, and palmatine, followed by molecular docking, machine learning-based IC₅₀ prediction, and molecular dynamics simulations. Fifty-eight overlapping targets between CCF compounds and CAG-related genes were identified, highlighting SRC, STAT3, MAPK1, and NFKB1 as central nodes enriched in inflammatory and immune pathways, including TNF and MAPK signaling. Docking analyses revealed strong interactions between all three compounds and SRC kinase, and machine learning models predicted IC₅₀ values in the low micromolar range (1.38–1.82 μM). Molecular dynamics simulations further suggest that berberine may stabilize the crucial regulatory regions of SRC, specifically the activation loop. It is hypothesized that this stabilization maintains the inactive conformation of the kinase domain and potentially shields Tyr416 from phosphorylation, thus potentially influencing kinase activation. These findings suggest that CCF may modulate key inflammatory and immune pathways implicated in CAG progression, with SRC emerging as a central node for further investigation. Full article

Background: Cholangiocarcinoma (CCA) is an aggressive cancer of biliary tract with poor prognosis and limited therapeutic alternatives. While targeted medicines only benefit a small subset of patients with specific genetic modifications, conventional chemotherapy offers negligible survival advantages. There is an urgent need for novel medicines with multi-target action to combat the diverse and treatment-resistant characteristics of CCA. Methods: An integrative computational strategy combining drug-likeness evaluation, target prediction, network pharmacology, Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analyses, and molecular docking was employed to elucidate the pharmacological profile of medicarpin, a natural pterocarpan derived from Dalbergia species. Overlapping targets between medicarpin and CCA-related genes were analysed to construct a protein–protein interaction (PPI) network and identify hub genes. Results: Forty-four overlapping targets were identified, with mTOR, SRC, PIK3CA, and CCND1 emerging as central nodes within the network. Enrichment analyses revealed significant involvement in carcinogenic pathways, including PI3K–Akt/mTOR, ErbB signalling, apoptosis regulation, and drug resistance. Molecular docking demonstrated a stable binding of medicarpin within the catalytic pocket of mTOR (binding energy −9.6 kcal/mol), supported by multiple hydrogen bonds and hydrophobic interactions with key residues essential for kinase activation. Conclusions: This study provides systems-level evidence that medicarpin exerts polypharmacological activity against CCA, with mTOR indicated as a possible mechanistic hub. These findings highlight medicarpin’s potential as a promising multi-target therapeutic candidate and underscore the value of natural compounds in expanding treatment strategies for cholangiocarcinoma. Full article

Mammalian sperm cells must undergo several processes collectively called capacitation before carrying out the acrosome reaction (AR), which is required for sperm penetration into the oocyte. The spontaneous acrosomal reaction (SAR), which can occur before the sperm cell reaches the vicinity of the oocyte, impairs the fertilizing ability of the sperm. This study examined the role of the Fer tyrosine kinase in sperm fertilizing activity. Inhibition of the Fer activity led to a 75% reduction in IVF rates in mice, indicating a critical role for Fer in fertilization. Further investigation of Fer’s role during sperm capacitation focused on its potential interaction with the epidermal growth factor receptor (EGFR). Inhibition of Fer during capacitation significantly decreased the EGFR activation state and increased the incidence of SAR, whereas inhibition of Fer during the acrosome reaction step had no effect on the EGF-induced AR. The effects of Fer inhibition on EGFR activation and SAR enhancement are mediated by the Ca²⁺ channel, CatSper. Notably, reduction in Ca²⁺ influx by CatSper inhibition revealed a significant increase in Fer phosphorylation/activation, while increasing intracellular Ca²⁺ concentrations completely inhibited this effect. Additionally, we show that Fer activation depends on a signaling cascade involving protein kinase A (PKA) that leads to EGFR activation through the following pathway: HCO₃⁻ → SAC → cAMP → PKA → Src → Fer → EGFR. Collectively, we decipher in this work a new regulatory cascade that leads to the Fer-directed activation of EGFR in sperm capacitation. Full article

Cholangiocarcinoma (CCA), an aggressive biliary tract cancer whose prevalence is rising, particularly in Thailand, is marked by elevated oxidative stress driven by chronic inflammation, parasitic infections, and dysregulated redox signaling. This study investigates the anticancer potential of tiliacorinine using a silico approach, including drug-likeness, ADMET, network pharmacology, molecular docking, and dynamics simulations. Tiliacorinine and 216 predicted targets were identified, with 79 overlapping CCA-related genes from GeneCards. GO and KEGG analyses revealed involvement in cell migration, membrane structure, kinase activity, and cancer-associated pathways. Network and PPI analyses identified ten key targets, including SRC, HIF1A, HSP90AA1, NFKB1, MTOR, MMP9, MMP2, PIK3CA, ICAM1, and MAPK1. Tiliacorinine showed the strongest affinity for MTOR (−10.78 kcal/mol, K_i = 12.62 nM), binding at the same site as known inhibitors with superior energy and specificity, supported by hydrogen bonding at ASP950 and hydrophobic interactions. Tiliacorinine also demonstrated strong binding to SRC, MMP9, and MAPK1. Molecular dynamics simulations revealed stable binding of tiliacorinine to MTOR, particularly at residues ASP950, TRP1086, and PHE1087. Comparative analysis with the MTOR–GDC-0980 complex confirmed consistent interaction patterns, reinforcing the structural stability and specificity of tiliacorinine. These results highlight its strong pharmacological potential and support its candidacy as a promising lead compound for cholangiocarcinoma therapy. Full article

Background/Objective: Oncogenic tyrosine kinases (TKs) such as ALK and SRC promote cancer progression, but their effects on metabolic enzymes are still not well understood. This study examines how TK signaling regulates inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, and assesses its potential as a therapeutic target. Methods: Phosphoproteomic screening and in vitro kinase assays were used to identify phosphorylation sites on IMPDH2. Lipid-binding assays explored the role of phosphatidylinositol 3-phosphate (PI3P) in IMPDH2 regulation. Structure-based virtual screening discovered small-molecule allosteric inhibitors, which were tested in lymphoma cell models, including ALK and BTK-inhibitor resistant lines. Results: Here, we identify Inosine monophosphate dehydrogenase-2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, as a novel substrate of ALK and SRC. We show that phosphorylation at the conserved Y233 residue within the allosteric domain enhances IMPDH2 activity, linking TK signaling to metabolic reprogramming in cancer cells. We further identify PI3P as a natural lipid inhibitor that binds IMPDH2 and suppresses its enzymatic function. Using structure-based virtual screening, we developed Comp-10, a first-in-class allosteric IMPDH inhibitor. Unlike classical active-site inhibitors such as mycophenolic acid (MPA), Comp-10 decreases IMPDH1/2 protein levels, blocks filament (rod/ring) formation, and inhibits the growth of ALK and BTK inhibitor-resistant lymphoma cells. Comp-10 acts post-transcriptionally and avoids compensatory IMPDH upregulation observed with MPA (rod/ring) formation, and inhibited growth in TKI-resistant lymphoma cells. Notably, Comp-10 avoided the compensatory IMPDH upregulation observed with MPA. Conclusion: These findings uncover a novel TK–IMPDH2 signaling axis and provide mechanistic and therapeutic insight into the allosteric regulation of IMPDH2. Comp-10 represents a promising therapeutic candidate for targeting metabolic vulnerabilities in tyrosine kinase driven cancers. Full article

The heparan sulfate proteoglycan syndecan-3 (SDC3) is a critical regulator of cell–matrix interactions. While other syndecan family members contribute to the progression of multiple cancers, SDC3’s functional contributions to tumor biology remain largely unexplored. This study investigates the potential role of SDC3 in the pathogenesis of breast cancer. By conducting an in-silico analysis of publicly available datasets, including TNM-plot, The Human Protein Atlas, and Kaplan–Meier Plotter, we observed that SDC3 is upregulated in breast cancer tissue. Notably, high SDC3 expression correlates with improved relapse-free survival in breast cancer patients. In vitro experiments revealed that SDC3 depletion significantly impairs cell viability, cell-cycle progression, cell migration, and 3D-spheroid-formation in MDA-MB-231 and MCF-7 breast cancer cells. Furthermore, SDC3 depletion results in dysregulated gene expression of matrix metalloproteinases (MMP1, MMP2, MMP9) in MDA-MB-231 cells, and upregulation of E-cadherin (CDH1) and vascular endothelial growth factor A (VEGFA) in MCF-7 cells. Activation of proto-oncogene tyrosine-protein kinase Src was inhibited when SDC3 depletion was combined with tissue factor pathway inhibitor treatment. These findings demonstrate that breast cancer cell-derived SDC3 plays a pivotal role in tumor progression. Full article

Background: Over the last years, the phenomenon of entosis, a form of cell-in-cell structure, has been highlighted in various tumors, including poorly treatable breast or pancreatic cancers. Nevertheless, not only the biological properties, but also the molecular drivers of entosis remain unclear. Here, we evaluated SRC tyrosine kinase, a key proto-oncogene, and podoplanin (PDPN), a membrane glycoprotein, as potential regulators of entotic cell formation. Methods: In the study, two entosis-competent cell lines, BxPC-3 and MFC-7, originating from pancreatic and breast cancers, respectively, were used. SRC or PDPN genes were silenced using dedicated siRNA and the frequency of entotic structure formation was assessed using fluorescent staining and confocal imaging. Results: It was found that BxPC-3 cells deficient in PDPN are more prone to form entotic structures and that over 90% of all entotic figures formed by mixed PDPN⁺ and PDPN^- BxPC-3 cells involved PDPN-silenced cells. The SRC data supports this observation, as the suppressed entotic formation ability presented by SRC-deficient cells was linked with increased expression of PDPN. Even though the observed effects were mainly limited to BxPC-3 cells, as PDPN expression in MCF-7 cells is restricted, overall, the obtained data suggest a strong anti-entotic function of PDPN. Additionally, the performed Western blotting indicated the activation of ezrin-radixin-moesin (ERM) proteins in PDPN-deficient cells. Conclusions: Taken together, these data suggest that the negatively controlled PDPN-ERM axis may act as a molecular factor controlling the development of entotic structures and cells with naturally low PDPN expression may be more liable to form entoses. Full article

Personalized medicine has gained an important relevance over the years with the development of targeted therapies, especially in cancer, adapted to the individual molecular tumour profiles. Accordingly, drug repurposing arises as a powerful strategy to identify and use drugs already approved for other conditions, offering advantages in terms of cost, development time, and safety. Src and Abl tyrosine kinases have been investigated as potential targets in oncology, being frequently implicated in tumour development and progression by promoting cell proliferation, migration, and angiogenesis. This review aims to provide a comprehensive overview of five tyrosine kinase inhibitors—saracatinib, imatinib, PP2, nilotinib and, tirbanibulin—that act on Src and/or Abl. Their mechanisms of action, original therapeutic indications, and potential for repurposing in other diseases, such as lung cancer, will be discussed. Although clinical data for these drugs in lung cancer remain limited, preclinical and clinical studies suggest promising therapeutic potential, particularly in specific molecular subtypes. Overall, this review highlights the therapeutic potential of Src and Abl inhibitors beyond their original contexts and supports their possible role in lung cancer therapy, considering the disease’s high heterogeneity and the growing applicability of personalized medicine. Full article

Introduction: The ability of salt-processed Alismatis Rhizoma (SAR) (Alisma plantago-aquqtica L.) to nourish Yin and promote urination is stronger than that of Alismatis Rhizoma (AR). However, there are few studies focused on evaluating the quality of its medicinal materials. Objectives: This study aimed to identify potential quality markers (Q-markers) for SAR, thereby providing a more reliable basis for its quality control and clinical application. Methods: Q-markers were identified through fingerprinting and chemical pattern recognition analysis of 15 batches of SAR. The diuretic effects of these markers were then verified by network analysis and molecular docking. Results: HPLC fingerprints of 15 SAR batches were established, with similarity analysis showing values > 0.85 (0.852–0.990). Chemical pattern recognition identified six critical compounds contributing to SAR quality: alisol F, alisol C 23-acetate, alisol A, alisol A 24-acetate, alisol B 23-acetate, and an alisol O isomer (VIP > 1.0). Network analysis revealed 76 overlapping targets between these compounds and diuretic-related diseases, with core targets including non-receptor tyrosine kinase (SRC), epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 1 (MAPK1), which were identified through protein–protein interaction (PPI) network analysis, with degrees of 27, 24, and 22, respectively. Key pathways involved were the EGFR tyrosine kinase inhibitor resistance pathway, calcium signaling pathway, tumor necrosis factor signaling pathway, etc. Molecular docking confirmed strong binding interactions between the Q-markers and the hub targets, particularly alisol B 23-acetate with MAPK1 (−60.10 kcal·mol⁻¹) and alisol A 24-acetate with EGFR (−46.14 kcal·mol⁻¹) and SRC (−48.86 kcal·mol⁻¹). The diuretic effects of SAR are likely mediated through anti-inflammatory actions and regulation of water–sodium balance via multi-target and multi-pathway mechanisms. Conclusion: This study provides a robust foundation for quality control and clinical application of SAR, though further in vivo validation is warranted. Full article

Endothelial hyperpermeability is a hallmark of diverse inflammatory and vascular pathologies, including sepsis, acute respiratory distress syndrome (ARDS), ischemia–reperfusion injury, and atherosclerosis. Traditionally considered a passive return to baseline following stimulus withdrawal, barrier recovery is now recognized as an active, endothelial-driven process. Earlier work identified individual components of this restorative phase, such as cyclic adenosine monophosphate (cAMP)/exchange protein directly activated by cAMP 1 (Epac1) signaling, Rap1/Rac1 activation, vasodilator-stimulated phosphoprotein (VASP) phosphorylation, and targeted cytoskeletal remodeling, as well as kinase pathways involving PKA, PKG, and Src. However, these were often regarded as discrete events lacking a unifying framework. Recent integrative analyses, combining mechanistic insights from multiple groups, reveal that nitric oxide (NO) generated early during hyperpermeability can initiate a delayed cAMP/Epac1 cascade. This axis coordinates Rap1/Rac1-mediated cortical actin polymerization, VASP-driven junctional anchoring, retro-translocation of endothelial nitric oxide synthase (eNOS) to caveolar domains, PP2A-dependent suppression of actomyosin tension, and Krüppel-like factor 2 (KLF2)-driven transcriptional programs that sustain endothelial quiescence. Together, these pathways form a temporally orchestrated, multi-tiered “inactivation” program capable of restoring barrier integrity even in the continued presence of inflammatory stimuli. This conceptual shift reframes NO from solely a barrier-disruptive mediator to the initiating trigger of a coordinated, pro-resolution mechanism. The unified framework integrates cytoskeletal dynamics, junctional reassembly, focal adhesion turnover, and redox/transcriptional control, providing multiple potential intervention points. Therapeutically, Epac1 activation, Rap1/Rac1 enhancement, RhoA/ROCK inhibition, PP2A activation, and KLF2 induction represent strategies to accelerate endothelial sealing in acute microvascular syndromes. Moreover, applying these mechanisms to arterial endothelium could limit low-density lipoprotein (LDL) entry and foam cell formation, offering a novel adjunctive approach for atherosclerosis prevention. In this review, we will discuss both the current understanding of endothelial hyperpermeability mechanisms and the emerging pathways of its active inactivation, integrating molecular, structural, and translational perspectives. Full article

Background and Objectives: Atrial fibrillation (AF) is a common complication of cardiac surgery. c-Src has been implicated in atrial remodeling in chronic AF, but its role in the early postoperative setting remains unclear. We, therefore, investigated whether baseline c-Src expression in atrial tissue is associated with the subsequent development of postoperative AF (PoAF). The aim of the present work was the evaluation of atrial c-Src expression and activity in patients subjected to open heart surgery who were previously free from AF and to check if changes to the initial level of this protein predispose to the development of postoperative AF (PoAF). Materials and Methods: Forty-two patients without previous AF history we enrolled. Patients with an AF episode during postoperative in-hospital follow-up were assigned to the PoAF group, while the rest (in sinus rhythm—SR) constituted the control group. Samples of the right atrial appendage were harvested before the introduction of the extracorporeal circulation. The expression of c-Src and phospho-c-Src(Tyr416), as well as upstream regulators of c-Src kinase, STAT3, ERK1/2, PDGFRα, and PDGFRβ, was assessed using Western blot. Results: AF occurred in 14 subjects. Expression of c-Src and phospho-c-Src was significantly higher in the PoAF group than in the SR group (c-Src: 1.65×, p = 0.037, and phospho-c-Src: 2.75×, p = 0.003). In addition, in the right atrium of PoAF patients, there was significantly elevated expression of STAT3, ERK1/2, and PDGF receptors, which may facilitate activation of c-Src kinase in patients with PoAF. Conclusions: Our preliminary findings suggest that c-Src expression and activity may contribute to atrial vulnerability and could represent a molecular target for future therapeutic interventions to prevent PoAF. Full article

Osteosarcoma (OS), the most common primary malignant bone tumor, arises in highly mechanosensitive tissue and exhibits marked heterogeneity and resistance to conventional therapies. While molecular drivers have been extensively characterized, the role of mechanical stimuli in OS progression remains underexplored. Here, we identify the transient receptor potential vanilloid 1 (TRPV1) channel as a key regulator of mechanotransduction and drug responsiveness in OS cells. Using uniaxial cyclic stretch, we show that aggressive U-2 OS cells undergo TRPV1-dependent perpendicular reorientation, unlike the inert SAOS-2 cells. Confocal microscopy, immunohistochemistry, and atomic force microscopy reveal that nanomolar concentrations of capsaicin—a well-characterized TRPV1 agonist—chemically mimic this mechanical phenotype, altering metastatic traits including adhesion, edge architecture, migration, nuclear-to-cytoplasmic ratio, and sensitivity to doxorubicin and cisplatin. TRPV1 activation, whether mechanical or chemical, induces subtype-specific effects absent in healthy hFOB osteoblasts. Notably, it differentially regulates nuclear localization of the proto-oncogene Src in U-2 OS versus SAOS-2 cells. Corresponding changes in Src and acetylated histone H3 (acH3) levels support a role for TRPV1 in modulating the Src–acH3 mechanosignaling axis. These effects are tumor-specific, positioning TRPV1 as a mechanosensitive signaling hub that integrates mechanical and chemical cues to drive epigenetic remodeling and phenotypic plasticity in OS, with potential as a therapeutic target in aggressive, drug-resistant subtypes Full article