Search Results (550)

The kallikrein–kinin system (KKS) and the kallikrein-related peptidase (KLK) family are interconnected proteolytic networks that regulate inflammatory signaling, vascular permeability, extracellular matrix remodeling, and tissue barrier dynamics. Beyond their classical vasoactive and inflammatory functions, accumulating evidence indicates that kinin peptides, including bradykinin, Lys-bradykinin, and their des-Arg⁹ metabolites, together with selected KLKs, modulate cell–cell and cell–extracellular matrix adhesion. Through B1 and B2 kinin receptor activation, the KKS influences endothelial adhesion molecule expression, leukocyte integrin activation, neutrophil trafficking, focal adhesion kinase/Src signaling, cytoskeletal remodeling, and matrix metalloproteinase activity. In parallel, KLKs directly reshape the adhesive microenvironment by cleaving junctional proteins, including E-cadherin and desmosomal components, and extracellular matrix substrates such as fibronectin, laminin, vitronectin, fibrinogen, and collagens. These coordinated actions affect epithelial and endothelial barrier integrity, leukocyte transmigration, angiogenesis, fibrosis, epithelial–mesenchymal transition, tumor cell migration, invasion, and metastatic dissemination. This review critically summarizes current evidence linking KKS and KLK activity to adhesion-dependent processes in inflammation and cancer, emphasizing how proteolytic signaling may either preserve tissue homeostasis or promote pathological barrier disruption depending on cellular context, receptor expression, protease activity, and microenvironmental cues. Understanding these mechanisms may refine the identification of adhesion-related biomarkers and support the development of targeted therapeutic strategies for inflammatory disorders, fibrotic remodeling, and cancer progression. Full article

The epidermal growth factor receptor (EGFR) was the first receptor tyrosine kinase identified soon after v-Src was recognized as a tyrosine kinase. EGFR signaling begins when EGF binds to EGFR at the cell surface, inducing receptor dimerization, activation, and autophosphorylation. The resulting phosphotyrosine sites recruit downstream effectors that activate signaling cascades such as the RAS-RAF-MEK-ERK and PI3K-Akt pathways, thereby regulating cell growth, proliferation, and survival. EGF binding also promotes EGFR endocytosis, which can direct the receptor to lysosomal degradation. Aberrant EGFR activity is associated with many cancers, and the receptor has been therapeutically targeted using small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Furthermore, EGFR endocytosis has been exploited for the targeted delivery of anticancer agents into EGFR-expressing cancer cells through antibody–drug conjugates (ADCs) and antibody–nanoparticle conjugates (ANCs). Although ADCs and ANCs both utilize mAbs as homing mechanisms to recognize cancer-associated antigens, they further harness EGFR endocytosis to deliver therapeutic payloads directly into target cells. In this review, we briefly discuss EGFR structure, activation, signaling, and endocytosis, as well as the mechanisms underlying EGFR function in cancer development. We then focus on current advances and future perspectives in using EGFR endocytosis pathways to improve targeted cancer drug delivery and therapy, particularly in the context of ANCs. Full article

Extracellular traps (ETs) are a novel host defense mechanism used to immobilize and eliminate invading microorganisms, and their formation depends on the recognition of foreign pathogens by membrane receptors. Previous studies have demonstrated that Vibrio splendidus flagellin can induce the release of ETs in coelomocytes of the sea cucumber Apostichopus japonicus, yet the underlying regulatory mechanism remains unclear. Here, we identify another Toll-like receptor (TLR) homolog, AjTLR2, in Apostichopus japonicus, which is composed of an extracellular LRR domain, a transmembrane domain, and an intracellular TIR domain. As a membrane receptor, AjTLR2 is upregulated upon infection with Vibrio splendidus AJ01, which is isolated from diseased Apostichopus japonicus. The extracellular LRR domain exhibits binding activity toward LPS, PGN, and MAN. In addition to these ligands, AjTLR2 recognizes flagellin C of AJ01 (AJ01-FliC), whereas other AjTLRs, such as AjToll and AjTLR3, do not. Further functional analysis reveals that knockdown of AjTLR2 results in a reduction in the typical weblike DNA structures of ETs, accompanied by a significant decrease in the expression of the ET-associated antimicrobial proteins H2A, H2B, and lysozyme. Furthermore, AjTLR2 knockdown similarly inhibits ET formation induced by recombinant AJ01-FliC protein. Mechanistically, the Apostichopus japonicus proto-oncogene tyrosine-protein kinase Src homolog (AjSRC), previously identified in our laboratory, is a downstream signaling molecule of AjTLR2 and is recruited via the TIR domain of AjTLR2. Knockdown of AjSRC also suppresses AJ01-FliC-induced ET formation. Collectively, our results indicate that the recruitment of AjSRC by AjTLR2 represents a potential regulatory pathway for AJ01-FliC induced ET generation. Full article

Background/Objectives: In obese skeletal muscle, impaired insulin signalling and persistent low-grade inflammation frequently arise together, jointly driving metabolic dysfunction; yet a single intracellular node capable of simultaneously correcting both defects has not been identified. Curcumol is the principal active sesquiterpene of the traditional Chinese herb Curcuma zedoaria (Christm.) Rosc. We therefore sought to determine whether curcumol modulates obesity-driven insulin resistance and inflammatory activation in skeletal muscle, and to delineate the responsible molecular pathway. Methods: The study combined in vivo and in vitro experiments with network pharmacology, molecular docking, pharmacological inhibition, and cellular thermal shift assay (CETSA). In vivo experiments used mice rendered obese by prolonged high-fat diet (HFD) feeding; in vitro, insulin resistance was modelled in C2C12 myotubes via palmitate challenge. Network pharmacology implicated SRC as a principal candidate target, and molecular docking assigned SRC kinase the highest binding affinity for curcumol. Selective blockade of SRC (PP2) and PI3K (LY294002) was used to delineate the signalling hierarchy. Results: Network pharmacology and molecular docking identified SRC kinase as the highest-ranked candidate target of curcumol. In both HFD-induced obese mice and palmitate-challenged C2C12 myotubes, curcumol restored SRC phosphorylation and activated the downstream PI3K/AKT axis, concurrently improving insulin sensitivity and attenuating NF-kB-driven inflammatory responses. Selective PI3K inhibition abolished all functional benefits of curcumol without altering SRC phosphorylation, whereas SRC blockade with PP2 prevented both PI3K/AKT activation and the downstream recovery of insulin sensitivity and inflammatory suppression, placing SRC upstream of PI3K/AKT in the signalling order. Direct binding of curcumol to SRC protein was confirmed by a cellular thermal shift assay. Conclusions: Curcumol directly engages SRC kinase and, through subsequent PI3K/AKT axis activation, concurrently rescues skeletal muscle insulin sensitivity and suppresses metabolic inflammation. These findings provide mechanistic justification for developing curcumol as a candidate dietary bioactive compound toward preventing and treating obesity-related metabolic disturbances. Full article

Cancer progression is driven by dysregulated kinase signaling and apoptotic evasion across multiple malignancies. Although targeted kinase inhibitors have improved outcomes, resistance and toxicity remain major challenges. Natural phytochemicals offer promising multi-target therapeutic potential. Persea americana contains diverse bioactive compounds; however, its role in multi-cancer kinase targeting remains underexplored. This study aimed to identify and validate anti-cancer kinase targets of Persea americana phytoconstituents across five cancers: lung, breast, cervical, colorectal, and prostate, using integrated network pharmacology and molecular simulation approaches. Cancer-associated genes were retrieved from the Open Targets Platform and prioritized through Gene Ontology analysis. Overlapping targets with 208 predicted human targets of Persea americana were identified. Protein–protein interaction networks revealed hub genes, followed by TCGA-based validation. Twenty-five phytoconstituents were docked against SRC and GSK3β, and top complexes underwent 100 ns molecular dynamics simulations. Enrichment highlighted kinase activity and apoptosis. SRC emerged as a pan-cancer hub, while GSK3β was prominent in breast cancer. Luteolin showed strongest binding to SRC (−11.9 kcal/mol), outperforming the co-crystal inhibitor, while valencene showed affinity toward GSK3β (−8.8 kcal/mol). Simulations confirmed stable interactions. Luteolin exhibits strong multi-target kinase inhibition, particularly against SRC, supporting its potential as a pan-cancer therapeutic candidate. Full article

Brain-derived neurotrophic factor (BDNF) is a key mediator of central sensitization and chronic pain through activation of TrkB receptors. Although the Pannexin 1 (Panx1) channel has been implicated in chronic pain, its involvement in BDNF-TrkB signaling remains unclear. Here, we investigated the functional relationship between TrkB activation and Panx1 using a BDNF-induced pain model in rats. Animals received a single intrathecal administration of BDNF, and mechanical nociception was assessed using the Randall–Selitto test. Behavioral analyses were combined with pharmacological interventions, Western blotting, confocal microscopy, YOPRO-1 uptake assays, and ATP quantification in spinal cord tissue. Intrathecal BDNF induced a robust mechanical hyperalgesia that persisted for up to 10 days. Blockade of Panx1 with 10Panx significantly attenuated BDNF-induced hyperalgesia. BDNF increased Src416 phosphorylation, Panx1 phosphorylation, and YOPRO-1 uptake in dorsal horn neurons, indicating enhanced channel activation. These effects were prevented by the TrkB antagonist ANA12, demonstrating that Panx1 acts downstream of BDNF-TrkB signaling. Inhibition of Src-family kinases with PP2 reduced both hyperalgesia and Panx1 activation, supporting a TrkB-Src-Panx1 signaling cascade. Furthermore, BDNF enhanced ATP release from spinal cord slices, an effect abolished by ANA12, PP2, and 10Panx. Together, these findings identify Panx1 as a downstream effector engaged by BDNF-TrkB signaling during the onset of mechanical hyperalgesia. While persistent TrkB activation appears to be required for the prolonged nociceptive state, the Src family kinase-Panx1 pathway contributes primarily to the early phase of BDNF-induced sensitization. Full article

Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), limiting the durability of targeted therapy. Bardoxolone methyl (CDDO-Me) has been reported to exert anti-inflammatory and anti-cancer activities. However, its role in acquired EGFR-TKI resistance remains unclear. Here, we found that CDDO-Me significantly enhanced sensitivity of resistant NSCLC cells to gefitinib, with combination index analysis confirming a synergistic interaction between CDDO-Me and gefitinib. Mechanistically, CDDO-Me induced mitochondrial dysfunction and reactive oxygen species (ROS) accumulation, thereby activating Caspase-3 mediated apoptosis and GSDME-dependent pyroptosis, as evidenced by increased lactate dehydrogenase (LDH) release. Network pharmacology and molecular docking analyses identified Src as a potential target of CDDO-Me. Cellular thermal shift assay (CETSA) confirmed cellular engagement between CDDO-Me and Src, and Western blot analysis showed that CDDO-Me suppressed Src/STAT3 signaling. Consistently, Src knockdown reduced the inhibitory effect of combined CDDO-Me and gefitinib treatment on colony formation and attenuated changes in apoptosis and pyroptosis regulatory proteins induced by the combination treatment. Collectively, these findings suggest that CDDO-Me enhances gefitinib sensitivity by targeting Src and suppressing Src/STAT3 signaling, leading to apoptosis and pyroptosis in gefitinib-resistant NSCLC cells. This study provides mechanistic evidence for further investigation of CDDO-Me-based combination strategies for gefitinib-resistant NSCLC. Full article

Mitochondria coordinate cellular energy production, metabolism, and signalling through the organization of the electron transport chain (ETC) and formation of respiratory supercomplexes. These structures facilitate efficient electron transfer and enable coenzyme Q (CoQ) channelling, allowing differential regulation of NADH- and succinate-driven respiration while modulating reactive oxygen species (ROS) production. Beyond their damaging potential, ROS act as key signalling molecules that regulate mitochondrial function through redox-sensitive modifications. Mitochondrial protein kinases add an additional layer of control, with Src-family kinases playing a central role. In particular, the mitochondrial tyrosine-kinase Fgr is activated by H₂O₂ and promotes phosphorylation of succinate dehydrogenase, boosting complex II activity, delivering more electrons to CoQ and inducing reverse electron transfer (RET) through CI, in a ROS-induced ROS generation amplification cycle. This induces a metabolic rewiring aimed at supporting stress adaptation, immune cell activation, and macrophage polarization. Overall, the interplay between supercomplex organization, ROS signalling, and kinase activity is critical for metabolic flexibility and represents a promising target for therapeutic intervention. Full article

Lung cancer is the most common malignant tumor worldwide in terms of both incidence and mortality, and the development of highly effective, low-toxicity therapeutic strategies remains an urgent clinical challenge. Here, we report that Salvianolic acid A (SAA), a natural compound extracted from Salvia miltiorrhiza Bunge, inhibits the proliferation of non-small cell lung cancer (NSCLC) cells and induces ferroptosis. Mechanistically, SAA acts as an SRC kinase inhibitor, blocking SRC autophosphorylation at Tyr416, thereby disrupting the SRC-YAP interaction and preventing YAP nuclear translocation. This leads to GPX4 downregulation and subsequently triggers ferroptosis, characterized by increased reactive oxygen species (ROS), Fe²⁺ accumulation, and lipid peroxidation. Overexpression of YAP abrogates the effects of SAA, while inhibiting SRC or YAP enhances its activity. SAA inhibits tumor growth and downregulates key effector molecules in vivo. In summary, this study reveals a novel mechanism by which SAA induces ferroptosis via the SRC/YAP/GPX4 axis, supporting its further development as a candidate therapeutic agent for NSCLC. Full article

CD36 is a multifunctional scavenger receptor involved in long-chain fatty acid (LCFA) uptake, binding of oxidized lipids, and interactions with extracellular matrix proteins such as thrombospondin-1. Through association with Src family kinases, integrins, and adaptor proteins, it also modulates signaling, migration, inflammation, angiogenesis, and phagocytosis. Hypoxia, a common feature of solid tumors, inflamed tissues, and ischemic organs, remodels CD36 expression, localization, and function through hypoxia-inducible factor (HIF) signaling and stress-activated kinases. These effects change cellular metabolism, intercellular lipid trafficking, and cell behavior (migration, phagocytosis, angiogenesis, immune phenotype) in a manner that is highly dependent on tissue type, duration of hypoxia, and metabolic context, with important implications for disease progression. In acute hypoxia, CD36 regulation often contributes to rapid metabolic adaptation, whereas in chronic hypoxia, it may promote sustained lipid accumulation, inflammation, maladaptive remodeling, or tumor progression. In this review, we aim to highlight the regulation and function of CD36 in hypoxia in different tissues, conditions, and metabolic states, emphasizing the distinct roles of CD36 in acute versus chronic hypoxia and its potential therapeutic implications. For example, hypoxia typically downregulates CD36 in ischemic cardiomyocytes to limit lipotoxic fatty acid influx, whereas in hepatocytes, adipocytes, and tumor-associated macrophages, it upregulates CD36-mediated lipid uptake to sustain steatotic, inflammatory, or protumorigenic metabolism, illustrating the tissue-specific nature of this regulation. Full article

Sickle cell disease (SCD) is an autosomal recessive hemoglobin disorder that is mainly characterized by the presence of hemoglobin S (HbS; point mutation [Glu6Val] in the beta-globin gene). Under deoxygenated conditions, HbS polymerizes and serves as the primary trigger of oxidative stress in red blood cells (RBCs), promoting polymerization of Band 3, a major membrane scaffold protein that links the lipid bilayer to the spectrin–ankyrin cytoskeletal network. Phosphorylation at key residues within the cytosolic domain of Band 3 induces conformational changes that weaken ankyrin binding and enhance lateral mobility and clustering of Band 3. These effects are mediated through a coordinated network of erythrocyte tyrosine kinases, primarily spleen tyrosine kinase (SYK) and sarcoma (Src) family kinases, which act sequentially to modify distinct tyrosine residues. Structural features of these kinases, including tandem SH2 domains in SYK and conserved SH2–SH3–kinase domain architecture of Src family members, enable precise recognition of phosphotyrosine motifs and propagation of phosphorylation cascades. Sequence alignment and structural superimposition of SH2 domains across studied kinases demonstrate a highly conserved fold that is critical for phosphotyrosine recognition, suggesting potential overlap in substrate engagement. Therapeutically, targeting these kinases has shown considerable promise, as tyrosine kinase inhibitors (TKIs) reduce Band 3 phosphorylation, restore RBC deformability, and decrease hemolysis and vaso-occlusive interactions in vitro. Thus, in this narrative review, we focus on the regulation of Band 3 by the above-mentioned tyrosine kinases, as well as the therapeutic potential of TKIs in SCD. Full article

Litchi chinensis seeds are rich in flavonoids and exhibit potent antioxidant activity. This study constructed a D-galactose-induced oxidative stress model in mice and applied ultra-high performance liquid chromatography–mass spectrometry (UHPLC-MS), network pharmacology, and molecular docking to clarify the antioxidant activity and material basis of ethanolic litchi seed extract. Litchi seed extract was orally given by gavage at 100 and 200 mg/kg in antioxidant tests, whereas a dosage of 500 mg/kg was adopted for the detection of absorbed constituents in plasma. The results showed that the total flavonoid content of litchi seed extract reached 68.37%. The extract could markedly reduce malondialdehyde (MDA) levels and elevate superoxide dismutase (SOD) activity in the serum, liver and kidney tissues of model mice, thereby mitigating oxidative damage. Thirteen prototype compounds absorbed into blood were characterized by UHPLC-MS. Most of these substances were flavonoids, with isorhamnetin, quercetin and naringenin as the major representatives. Core targets including IGF1R, PIK3R1, EGFR, PIK3CA, ERBB2 and proto-oncogene tyrosine-protein kinase Src (SRC) were screened using network pharmacology, among which SRC was identified as the pivotal hub target. Molecular docking results revealed that isorhamnetin, quercetin, naringenin, and diosmetin were able to bind stably to the SRC protein. The present study demonstrated that litchi seed extract exhibits remarkable antioxidant activity, with isorhamnetin, quercetin, naringenin, and diosmetin as the main bioactive antioxidant components. Full article

Retroviruses, after their genomes are integrated into the host genome, replicate through host cell replication. In this hitchhiking phase, their only way of increasing their fitness is to encourage the host cell to have unregulated, rapid cell replication. The v-Src gene in avian sarcoma virus and the v-sis gene in the simian sarcoma virus were originally mined from the host genome by the virus to increase host cell replication rate, with the corresponding host cellular counterparts c-Src (non-receptor tyrosine kinase) and c-sis (platelet-derived growth factor). The resulting out-of-control replication ultimately would lead to cancer. The battle between the host and the retroviruses left many retroviral corpses known as endogenous retroviruses, and the host occasionally domesticates retroviral genes. The syncytins (whose fusogenic function is crucial for the trophoblast fusion and the formation of a syncytium during placenta morphogenesis) and suppressyn (which serves the dual function of regulating syncytialization and host resistance against retroviruses) are examples of successful domestication. Syncytin-1 and suppressyn have each been “domesticated” independently multiple times by different mammalian lineages. Molecular phylogenetics is an essential tool for tracing the evolutionary trajectories of such genetic exchanges between retroviruses and their hosts and for determining the direction of the genetic exchange. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) has traditionally been framed as a Kelch-like ECH-associated protein 1 (KEAP1)-regulated stress-response transcription factor, but three observations now require a broader framework: NRF2 turnover is controlled by parallel E3 ligase systems; transcriptional output can be limited by coactivator assembly despite unchanged NRF2 abundance; and NRF2 activation can be beneficial or harmful depending on disease context, as illustrated by lung cancer models in which NRF2 paradoxically promotes metastasis through BTB and CNC homology 1 (BACH1) stabilization. We synthesize these observations into an NRF2 partner-code framework in which NRF2 acts as a context-dependent transcriptional platform assembled through four partly independent modules: a degradation module (KEAP1; β-transducin repeat-containing protein, β-TrCP; HMG-CoA reductase degradation protein 1/synoviolin 1, Hrd1/SYVN1; WD repeat-containing protein 23/DDB1- and CUL4-associated factor 11, WDR23/DCAF11); a cytoplasmic scaffold module (p62/sequestosome 1, p62/SQSTM1; IQ motif-containing GTPase-activating protein 1, IQGAP1; type I phosphatidylinositol 4-phosphate 5-kinase γ/heat shock protein 27, PIPKIγ–HSP27; peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, PIN1; peptidyl-prolyl isomerase A/cyclophilin A, PPIA); a nuclear coactivator module at Neh4/5 (CREB-binding protein/p300, CBP/p300; receptor-associated coactivator 3/steroid receptor coactivator 3, RAC3/SRC-3; protein arginine methyltransferase 1/coactivator-associated arginine methyltransferase 1, PRMT1/CARM1; Mediator complex subunit 16, MED16); and a DNA/chromatin module at Neh1 (small musculoaponeurotic fibrosarcoma [Maf] proteins, BACH1, and chromodomain helicase DNA-binding protein 6, CHD6). Mapping 22 partners onto the Neh-domain architecture identifies approximately 25 pharmacologically addressable interfaces, stratified into four translational tiers. The framework reframes NRF2 pharmacology around one principle: the most actionable target is often a partner rather than NRF2 itself, with disease context dictating the direction of modulation. We close with five testable hypotheses and a partner-code decision matrix linking disease, biomarker, and candidate target. Full article

Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are major global health burdens that share interconnected pathological mechanisms involving impaired insulin signaling, metabolic stress, and chronic neuroinflammation. This study applied an integrative systems biology and atomistic simulation framework to investigate bioactive compounds from Caesalpinia sappan L. targeting shared molecular regulators linking AD and T2DM. Network topology analysis identified four central hub genes, STAT3, SRC, HSP90AA1, and TP53, representing key regulatory nodes involved in inflammatory signaling, kinase regulation, proteostasis, and cellular stress responses. Compound-specific interaction analysis revealed distinct target preferences among phytochemical subclasses. Protosappanin B showed strong binding toward both STAT3 and HSP90α, whereas flavonols including quercetin and rhamnetin exhibited high affinity for SRC, and the chalcone derivative sappanchalcone preferentially interacted with TP53. Atomistic molecular dynamics simulations and MM-PBSA calculations supported stable protein ligand interactions and favorable binding energetics, while density functional theory analysis indicated electronic properties consistent with sustained intermolecular interactions. Collectively, these findings suggest that structurally distinct subclasses of C. sappan phytochemicals converge on complementary regulatory hubs within the shared AD and T2DM molecular network, supporting coordinated multi-target modulation of interconnected inflammatory, kinase signaling, proteostasis, and cellular stress pathways underlying AD–T2DM comorbidity. Full article