Search Results (13,883)

Oxidative stress is a central and well-established driver of cardiovascular disease, contributing to mitochondrial dysfunction, endothelial injury, inflammatory activation, and progressive myocardial and vascular remodeling. Although the major endogenous sources of cardiovascular reactive oxygen species (ROS), including NADPH oxidases, mitochondrial electron transport chain leakage, and uncoupled nitric oxide synthase, are well characterized, an additional and underappreciated contributor has recently emerged: cytochrome P450 2D6 (CYP2D6), an enzyme classically regarded as a hepatic drug-metabolizing protein. Accumulating evidence indicates that CYP2D6 is expressed extrahepatically in cardiac, vascular, and neural tissue, where uncoupled catalytic cycling is proposed to generate ROS independently of its canonical xenobiotic-metabolizing role, although direct experimental evidence for this pathway in human cardiac and vascular tissue remains limited. CYP2D6-derived oxidative processes may interact with mitochondrial respiratory function, endothelial nitric oxide bioavailability, and redox-sensitive inflammatory pathways, potentially contributing to cardiovascular vulnerability under specific genetic or pathological conditions. Critically, the magnitude of this oxidative contribution is not fixed: it is dynamically shaped by inherited CYP2D6 genetic variation, with poor and ultra-rapid metabolizer phenotypes exhibiting divergent oxidative burden and pharmacokinetic vulnerability, and is further amplified by polypharmacy, multimorbidity, and inflammation-driven phenoconversion, whereby clinically expressed CYP2D6 activity diverges from inherited genotype in ways that intensify redox imbalance. These dynamics are particularly relevant in East Asian populations, where the decreased-function CYP2D6*10 allele is highly prevalent. In this narrative, hypothesis-generating review, we integrate evidence from pharmacogenomics, redox biology, and cardiovascular pharmacology to propose a conceptual framework that reframes CYP2D6 as a genetically and pharmacologically tunable node within cardiovascular redox biology. We further examine emerging redox biomarkers, multi-omics platforms, and AI-assisted modeling as translational strategies for capturing this dynamic oxidative risk in real time. This framework supports a shift from static genotype-guided prescribing toward oxidative-risk-informed, adaptive cardiovascular precision medicine. Importantly, our focus on CYP2D6 should not be interpreted as evidence that it is a major cardiovascular CYP isozyme or an established driver of cardiovascular pathology. Rather, CYP2D6 is examined here as a deliberately hypothesis-generating candidate whose unusually strong pharmacogenetic variability, clinically important cardiovascular drug substrates, dynamic susceptibility to phenoconversion, extrahepatic expression, and mechanistically plausible links to endogenous substrate metabolism and CYP-associated ROS generation provide a convergent rationale for focused investigation. The mechanistic framework proposed in this review has not yet been experimentally and prospectively validated and should not be applied directly to clinical decision-making without supporting clinical data. Full article

Multicomponent antibiotic–anti-inflammatory systems have recently attracted considerable attention, as this combination is becoming a standard therapy for infectious diseases. This study aimed to develop a multicomponent system comprising norfloxacin (NOR), an old fluoroquinolone antibiotic, and niflumic acid (NIF), another old, poorly soluble anti-inflammatory drug, to improve the physicochemical properties, antibiotic potency, and anti-inflammation effect, as well as their safety. First, a phase diagram was constructed to ensure solid-state reaction and to predict its stoichiometry; subsequently, the multicomponent system was prepared by solvent-drop grinding. The product was analyzed by a series of thermal analyses and powder X-ray diffraction (PXRD). Next, Fourier-transform infrared spectroscopy and nuclear magnetic resonance elucidated the molecular interactions, and the final 3D structure was determined by single-crystal X-ray diffraction, followed by Hirshfeld surface analysis. Afterward, the solubility and chemical stability were assessed using high-performance liquid chromatography, and the physical stability of the multicomponent system was evaluated by PXRD. Antimicrobial potency against Gram-negative and Gram-positive bacteria, as well as anti-inflammatory activity in vivo, were also evaluated. The results demonstrated that a newly formed antibiotic–anti-inflammatory multicomponent system, named norfloxacin–niflumate (NORNIF), in a salt dihydrate form, significantly improved the stability and antibiotic potency of NOR, including against the resistant microbe, as well as the solubility and in vivo anti-inflammatory effect of NIF simultaneously. In addition, preliminary in silico studies using Swiss-ADME and ProTox-3 predicted that the salt was well absorbed in the gastrointestinal tract and could be classified as toxicity class 4 (non-toxic). Full article

Background/Objectives: General cardio-oncology guidance describes cardiovascular toxicity from BRAF/MEK inhibitors and immune checkpoint inhibitors (ICIs), but it does not resolve how treatment decisions should change when heart failure (HF) is already present. This critical narrative review separates direct HF-specific evidence from indirect evidence and proposes an HF-centered framework for systemic melanoma. Methods: MEDLINE/PubMed, Embase, and the Cochrane Library were searched for English-language sources published from January 2015 to April 2026, with targeted guideline, prescribing-information, interaction, and geriatric-oncology updates through July 2026. Sources were classified as direct, indirect, or extrapolated. This review follows SANRA principles but does not claim systematic-review conduct, pooled estimates, formal risk-of-bias assessment, or GRADE certainty. Results: Only case-level evidence directly describes systemic melanoma treatment in established HF; most cardiotoxicity rates are derived from selected longitudinal and real-world cohorts. We therefore organize decisions across four domains: HF phenotype and current stability; oncological urgency and alternatives; treatment-specific toxicity phenotype; and detectability, reversibility, and patient priorities. Each domain is graded ordinally and generates its own decision output, and explicit precedence rules resolve situations in which several domains are simultaneously abnormal; the pathway from assessment to documented output is presented as a decision flowchart and applied to illustrative clinical cases. This approach modifies interpretation of symptoms, biomarkers, ventricular function, surveillance, drug interactions, treatment interruption, and rechallenge. Every actionable statement is labeled as guideline-supported or author-proposed, therapy-specific baseline and follow-up monitoring are tabulated separately for each treatment class, and heart failure with preserved ejection fraction is addressed as a phenotype in which clinical deterioration may occur without any change in ejection fraction. Patient-level priorities in older adults—survival, quality of life, avoidance of hospitalization, tolerance of frequent monitoring, oral versus infusion treatment, and functional expectation—are specified as items to be recorded rather than inferred. Conclusions: Stable HF is not an automatic contraindication to effective melanoma therapy, whereas recent or active decompensation requires stabilization or monitored treatment when oncological delay is unsafe. The proposed framework operationalizes guideline principles for an understudied population while making the limits of the evidence explicit. It makes a procedural rather than an empirical claim: it is a transparent structure for documenting a decision that must be made anyway, not an algorithm derived from or validated against outcome data. Full article

Background: Eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) primarily participates in protein synthesis by binding aminoacyl-tRNA complexes to facilitate peptide chain elongation on ribosomes. Its expression and functional roles exhibit significant heterogeneity across various malignancies, exerting dual regulatory effects as both an oncogene and a tumor suppressor. This study aims to investigate the potential prognostic value and tumor-suppressive role of EEF1A1 in kidney renal clear cell carcinoma (KIRC). Methods: We analyzed the differential expression of EEF1A1 in KIRC and its correlation with patient prognosis based on the TCGA, GEO, and HPA databases. The STRING and GEPIA databases were utilized to perform functional enrichment analysis of its interacting proteins and co-expressed genes. The xCell algorithm was employed to assess the correlation between EEF1A1 and immune cell infiltration, immune checkpoints, and immunomodulatory molecules. Furthermore, drug sensitivity analysis was conducted to evaluate its clinical application potential. Finally, the expression of EEF1A1 in 786-0 and A498 cell lines was validated via qRT-PCR and Western blotting. Furthermore, CCK-8, wound healing, and Transwell migration/invasion assays were performed to evaluate cell proliferation, migration, and invasion, respectively. Results: EEF1A1 may function as a negative regulator of malignant behaviors in KIRC tissues and cell lines, and its expression level was closely associated with clinicopathological features and prognosis of patients. GO, KEGG, and GSEA enrichment analyses revealed that low EEF1A1 expression is closely linked to immunosuppressive pathways. Further immunological analysis confirmed significant correlations between EEF1A1 and various immune cell infiltrates, immune checkpoints, tumor-infiltrating lymphocytes, and immunomodulatory molecules. Moreover, cells with high EEF1A1 expression exhibited increased sensitivity to anti-tumor drugs, with expression levels negatively correlated with inhibitory activity (IC50). Finally, overexpression of EEF1A1 significantly inhibited the proliferation, migration, and invasion of clear cell renal cell carcinoma cells. Conclusions: EEF1A1 serves as a potential prognostic biomarker in KIRC and is associated with clinical progression, immune-related characteristics, metabolic pathways, and drug sensitivity. Functional validation further supports its role in regulating malignant phenotypes of KIRC cells. Full article

Tannic acid grafting provides a practical strategy for introducing bioactive phenolic functionality into microbial polysaccharides for multifunctional hydrogel design. Herein, tannic acid-modified succinoglycan (SG-TA) was prepared through an ascorbic acid/ H₂O₂-mediated free-radical process. Spectroscopic, thermal, and purification-control analyses were consistent with covalent incorporation of tannic acid-derived moieties into SG, while characteristic structural features of the SG framework remained evident after modification. SG-TA exhibited tannic acid-equivalent phenolic contents of up to 321.9 mg TAE/g and markedly enhanced antioxidant and antibacterial activities compared with native SG. SG-TA was subsequently incorporated into a poly(vinyl alcohol) (PVA)/borax network to form dynamic SG-TA/PVA/borax (STPB) hydrogels based on reversible interactions. The hydrogels exhibited composition-dependent viscoelasticity, rapid rheological recovery, macroscopic self-rejoining, enhanced deformability, antioxidant and antibacterial functionality, and preliminary cytocompatibility. Time-dependent phenolic release showed that SG-TA-derived phenolic species were partially released from the network, indicating contributions from both matrix-associated and releasable functionality. The reversible network also enabled pH- and glucose-responsive release of 5-fluorouracil as a model small-molecule drug. These findings demonstrate the potential of SG-TA as an intrinsically bioactive microbial polysaccharide for multifunctional, self-healing, and stimuli-responsive drug-delivery hydrogels. Full article

Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), exposed critical gaps in global preparedness for rapidly evolving viral pandemics. Though current antiviral treatments have shown some efficacy in managing COVID-19, substantial limitations, such as inefficient targeted drug delivery, aberrant host immune responses, and inadequate preparedness for future viral pandemics, were also evident. These challenges underscore the urgent need for target-specific, precise and efficient therapeutic strategies to modulate viral entry and immune dysregulation. Extracellular vesicles (EVs), cell-released cargo-carrying nanoscale vesicles, can both facilitate and inhibit viral infection depending on their cargo composition. Thus, endogenous EVs can promote or inhibit COVID-19 pathogenesis by modulating critical pathways, including angiotensin-converting enzyme 2 (ACE2)-mediated viral entry, transmembrane protease serine 2 (TMPRSS2)- dependent spike protein activation, nuclear factor kappa B (NF-κB)-driven inflammatory signaling, and NLRP3 inflammasome activation. In contrast, engineered EVs, such as ACE2-expressing EVs, mesenchymal stem cell-derived EVs and microRNA-enriched EVs, have therapeutic potential as they can facilitate antiviral defense through immune modulation, viral neutralization and suppression of cytokine storm. Moreover, EV-associated nucleic acids, proteins and lipids can act as biomarkers for disease detection and severity stratification. A deeper understanding of EV-virus mechanistic insights can enhance preparedness for similar viral diseases. In this review, we provide a comprehensive analysis of the molecular mechanisms underlying EV-virus interactions highlighting the therapeutic and diagnostic potential of EVs in tackling COVID-19 and future viral pandemics. Full article

Zeolites are crystalline microporous aluminosilicates whose tunable porosity, ion-exchange capacity, surface charge, and chemical robustness make them versatile materials at the biointerface. This review surveys three converging domains of zeolite biomedicine. First, haemostasis and wound healing, where water adsorption and Ca²⁺ release drive procoagulant activity, from the QuikClot generation to strategies that mitigate the exothermic response and to flexible zeolite–textile dressings. Second, the separation, immobilization, and sensing of biomolecules, where external surface area, hierarchical porosity, and surface chemistry—rather than intracrystalline sieving alone—govern the interaction with proteins and nucleic acids in complex matrices. Third, the emerging design of zeolite-based theranostic platforms integrating drug delivery, imaging, and stimuli-responsive therapy, enabled by the transition from bulk crystals to surface-engineered nanozeolites. Across all three domains, a single lesson recurs: the biological behaviour of zeolites is governed by the external surface rather than by molecular sieving, and the chemical integrity of the framework under working conditions is a design parameter that is reported only sporadically. We further show that the theranostic literature reaching in vivo validation is dominated by zeolite-like imidazolate frameworks, whereas the evidence for aluminosilicate zeolites remains largely in vitro—the gap that most urgently needs closing. The successes of ZIFs should therefore be read as structural inspiration for zeolite design rather than as direct evidence for aluminosilicate clinical translation. Full article

Liquid–liquid phase separation (LLPS), especially via coacervation, offers a novel drug delivery strategy by encapsulating therapeutic agents within phase-separated droplets, thereby improving stability, solubility, and controlled release. Polypeptides and polypeptoids are ideal biomaterials for these systems due to their versatility and tunable properties. Polypeptoids are particularly advantageous, offering enhanced enzymatic resistance and greater control over molecular interactions, making them suitable for complexation studies. This research explores the binary complexation of L-, D,L-, and N-substituted (peptoid) poly-lysine with nucleic acids, specifically two lengths of salmon sperm dsDNA and baker’s yeast tRNA, and two nucleotides, adenosine triphosphate (ATP) and cytidine triphosphate (CTP). By adjusting the charge fractions, we studied the morphology of the complexes and tested their salt resistance under different ionic conditions. Results show that dsDNA forms precipitates with lysine polypeptides and polypeptoids, whereas tRNA forms coacervate droplets, likely due to differences in secondary structure. Both nucleotides formed coacervates in all systems. L-homochiral poly-lysine complexes are the most salt-stable, followed by racemic poly-lysine, with N-substituted polymers being the least stable as ionic strength rises. For all dsDNA and tRNA systems, the complexes remained under physiologically relevant salt concentrations. These results highlight the role of salt and polymer structures in modulating complexation. The study offers insights into nucleic acid complexation, with implications for nucleic acid encapsulation and stabilization. Full article

Community pharmacists play an increasingly important role in the care of transgender individuals receiving gender-affirming hormone therapy (GAHT). However, the content of structured pharmaceutical consultations tailored to this population has not yet been clearly defined. This systematic review aimed to identify therapeutic issues relevant to community pharmacy practice in order to inform the development of structured pharmaceutical consultations. A systematic literature review was conducted in accordance with the PRISMA 2020 Statement. The review question was structured using the PICo framework, with transgender individuals as the population, treatment-related issues associated with GAHT as the phenomenon of interest, and community pharmacy practice as the context. Electronic searches of Medline, Google Scholar, and APA PsycINFO were performed on 17 July 2024. Studies involving transgender adolescents or adults receiving GAHT and reporting therapeutic effects, adverse events, monitoring requirements, or medication-related issues were eligible. Two reviewers independently screened the studies and extracted data using a standardized form. Owing to the heterogeneity of study designs, the findings were synthesized narratively according to therapeutic domains relevant to community pharmacy practice. Among 755 screened records, 116 articles met the inclusion criteria. Seven therapeutic domains relevant to pharmacist-led consultations were identified: cardiovascular and cardiometabolic effects, dermatologic effects, gynecologic effects, musculoskeletal effects, biological and pharmacological effects, psychiatric effects, and other adverse effects or specific clinical situations. The evidence highlighted treatment-specific monitoring needs, medication-related risks, fertility and contraceptive considerations, laboratory monitoring requirements, drug–drug interactions, and mental health outcomes. Community pharmacists may contribute to the monitoring and optimization of GAHT, adverse effect management, patient education, fertility and contraceptive counseling, pharmacovigilance, and interdisciplinary collaboration within the scope of their professional practice. These findings provide an evidence-informed basis for the future development of structured pharmaceutical consultations tailored to transgender individuals. Full article

Background/Objectives: Electron paramagnetic resonance (EPR) spectroscopy is a direct and highly specific method for detecting paramagnetic species, including free radicals, transition-metal centers, spin labels and spin probes. In pharmaceutical research, it is particularly valuable in systems involving radical chemistry, oxidative degradation, drug–membrane interactions, drug delivery carriers, metallodrugs and oxygen-sensitive microenvironments. This review aims to summarize current applications of and emerging opportunities for EPR spectroscopy in pharmaceutical research, with primary emphasis on continuous-wave (CW) EPR, the mode most widely used for routine pharmaceutical measurements. Methods: This review is organized around the main CW-EPR approaches relevant to pharmaceutical research, including direct detection of paramagnetic species, spin trapping, spin labeling and spin-probe analysis. The discussion emphasizes how spectral parameters such as the g-value, hyperfine splitting, signal intensity and linewidth can provide structural, kinetic and microenvironmental information. Results: CW-EPR supports the study of radical-mediated drug activity and toxicity, antioxidant properties, formulation stability, membrane interactions, carrier structure, metallodrug behavior and oxygenation. Its main strength is the ability to connect molecular-level radicals and paramagnetic processes with broader pharmaceutical questions related to drug efficacy, safety, stability and delivery. Conclusions: CW-EPR is a specialized but versatile analytical tool at the interface of radical chemistry, pharmaceutical technology and biomedical research. Recent developments in compact instrumentation, selective probes and spectral simulation may further expand its use in pharmaceutical development, stability assessment and drug delivery research. Full article

Background/Objectives: Despite the clinical efficacy of cannabidiol (CBD) in treating certain epilepsies, its in vivo neuropharmacological mechanisms remain incompletely understood. This Phase 1 clinical trial aimed to evaluate the acute effects of a single oral dose of highly purified CBD (GWP42003-P) on cortical excitability. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) and electromyography (TMS-EMG) were utilized as assessment tools. Methods: In a randomized, double-blind, placebo-controlled crossover trial, 15 healthy male participants received a single 1500 mg dose of GWP42003-P or placebo. Cortical activity metrics, including resting and active motor thresholds (RMT, AMT), short intracortical inhibition (SICI), TMS-evoked potentials (TEPs), TMS-related spectral perturbations (TRSP), and inter-trial phase clustering (ITPC), were recorded pre-dose and at 1, 4, and 6 h post-dose. Results: RMT and AMT significantly decreased over time following CBD administration, though without a significant Condition × Time interaction. While primary analyses showed no condition-driven alterations for SICI, TEPs, or TRSP, secondary longitudinal modeling revealed a transient reduction in beta-band desynchronization 1 h post-dose, aligning with peak plasma concentration. The drug condition also exhibited a qualitative, non-significant trend toward increased alpha ITPC and decreased delta ITPC at 4 and 6 h post-dose compared to placebo. Conclusions: A single acute 1500 mg dose of GWP42003-P did not produce statistically significant alterations in widespread cortical excitability in healthy adult males. However, the transient blunting of beta desynchronization at peak concentration may reflect CBD’s distinct, non-classical neuromodulatory profile. Overall, these largely null findings suggest that acute CBD administration lacks a robust, direct modulatory effect on cortical networks. Capturing its precise neuropharmacological mechanisms will likely require future investigations utilizing chronic dosing paradigms or clinical patient populations. Full article

Background/Objectives: Programmed cell death protein 1 (PD-1) is a key immune checkpoint that suppresses anti-tumor T-cell responses and is an established target for cancer immunotherapy. UDIZ-007 is a fully human anti-PD-1 antibody that blocks PD-1/PD-L1 and PD-1/PD-L2 interactions and eradicates MC38-hPD-L1 colon tumors in B-hPD-1 transgenic mice. This study further characterized the pharmacokinetics (PK), immunogenicity, and safety of UDIZ-007 to support its clinical development. Methods: UDIZ-007 was produced in a stable Chinese hamster ovary (CHO) cell line, and its biophysical and in vitro functional profiles were assessed. PK, immunogenicity, and safety were evaluated in mice and cynomolgus macaques. Results: UDIZ-007 showed biophysical and in vitro functional properties consistent with therapeutic antibodies and demonstrated potent, dose-dependent anti-tumor activity against MC38-hPD-L1 colon tumors engrafted in B-hPD-1 transgenic mice. Single-dose PK studies in mice at 10 and 100 mg/kg and in cynomolgus macaques at 10, 50, and 101.2 mg/kg showed a trend toward dose-proportional exposure. In cynomolgus macaques, UDIZ-007 had a prolonged half-life of approximately 12 days. Repeated intravenous administration at 10, 50, or 101.2 mg/kg in cynomolgus macaques was generally well tolerated, with no major treatment-related toxicities. Accordingly, the no-observed-adverse-effect level (NOAEL) was established at the highest tested dose, 101.2 mg/kg. Anti-drug antibodies (ADAs) were detected in some animals and were associated with expected PK variability but not with adverse effects. Tissue cross-reactivity studies across 32 human and cynomolgus macaque tissues showed binding primarily restricted to lymphoid tissues known to express PD-1. Conclusions: UDIZ-007 demonstrated robust anti-tumor activity, favorable PK and safety profiles, as well as selective binding to PD-1-expressing tissues, supporting its clinical development as a potential cancer immunotherapy. Full article

This review systematically elucidates the rapidly evolving field of biomimetic coacervate coatings, bridging the fundamental thermodynamic principles of liquid–liquid phase separation (LLPS) with advanced biomedical translations. While conventional surface modifications for medical implants frequently fail to maintain structural and functional integrity within dynamic, wet physiological environments, biomimetic coacervation inspired by natural underwater adhesive mechanisms offers a highly versatile, conformable, and robust interfacial strategy. Here, we analyze the critical physicochemical driving forces governing coacervate formation, emphasizing the synergistic interplay of electrostatic, hydrophobic, hydrogen-bonding, and cation–$\pi$ interactions. We comprehensively discuss diverse macromolecular design principles utilizing marine-derived biopolymers, synthetic or recombinant polypeptides, and hybrid organic–inorganic condensates, alongside key architectural orchestration methodologies including direct deposition, in situ triggerable coacervation, and layer-by-layer (LbL) assembly. Furthermore, we evaluate multi-functional clinical translations, highlighting breakthroughs in wet tissue sealing, bone repair, localized stimuli-responsive drug or nucleic acid delivery, anti-biofouling medical device coatings, and regenerative cell–material interfaces. Ultimately, this review underscores the profound potential of biomimetic coacervates as a cornerstone platform for next-generation multifunctional medical devices and personalized regenerative medicine. Full article

The hepatocyte growth factor (HGF)/c-Met signaling pathway plays a central role in cellular proliferation, survival, migration, invasion, angiogenesis, and therapeutic resistance. Aberrant c-Met activation, driven by gene amplification, overexpression, activating mutations, exon 14-skipping alterations, or ligand-dependent stimulation, drives the development and progression of many solid tumors, positioning c-Met as a key target for anticancer drug development. The clinical effectiveness of c-Met-targeted treatments such as crizotinib, capmatinib, tepotinib, savolitinib, and cabozantinib has confirmed c-Met as a viable oncogenic driver for therapy, leading to the development of various next-generation inhibitors with different structures. This review provides a comprehensive perspective on small-molecule c-Met inhibitors from the perspectives of medicinal chemistry and structure-based drug design, encompassing approved drugs, investigational agents, natural-product-inspired leads, and emerging multitarget anticancer therapeutics. Particular emphasis is given to the principles of molecular recognition that govern c-Met inhibition. This includes the structure of the kinase domain, interactions at the ATP-binding site, recognition of the hinge region, and the different binding modes of Type I, Type II, and allosteric inhibitors. The design, synthesis, biological evaluation, and structure–activity relationships of diverse heterocyclic scaffolds that have shaped c-Met inhibitor discovery are critically analyzed. Key medicinal chemistry strategies, including scaffold hopping, bioisosteric replacement, conformational optimization, molecular hybridization, and multitarget pharmacophore integration, are discussed in the context of potency, selectivity, resistance management, and drug-like properties. Particular attention is given to the integration of structural biology, molecular docking, binding-mode analysis, and structure-guided optimization approaches that have enabled the development of potent c-Met-directed inhibitors. In addition, recent advances in dual- and multitarget agents that simultaneously modulate c-Met and complementary therapeutic targets, including VEGFR-2, EGFR, AXL, MER, PARP1, CDK2, and tubulin, are highlighted as promising strategies for overcoming pathway redundancy and acquired resistance. This review summarizes contemporary structure-based and medicinal chemistry principles underlying c-Met inhibitor discovery, critically evaluates the relationship between biochemical potency and therapeutic efficacy, and provides a framework for the rational design of next-generation c-Met-targeted and multitarget anticancer agents. Full article

Cervical cancer remains a major cause of cancer-related mortality worldwide, highlighting the need for strategies that may improve responses to conventional chemotherapeutics. Epigallocatechin gallate (EGCG), a green-tea polyphenol with diverse biological activities, has been investigated as a potential chemosensitizing agent. This study evaluated the interaction between EGCG and doxorubicin (DOX) in HeLa cervical cancer cells, with HaCaT keratinocytes included as a non-malignant comparator. Cell viability and drug interactions were assessed using the CCK-8 assay and Chou–Talalay combination index (CI) analysis. Complementary assays evaluated membrane integrity, wound closure, apoptosis, cell-cycle distribution, intracellular DCF-associated fluorescence with or without N-acetylcysteine (NAC) pretreatment, caspase-3 immunoreactivity, and EGFR, FOXP3, CASP3, and CASP7 mRNA expression. Network-based analyses were additionally used to identify candidate molecular associations and pathways. CI analysis demonstrated synergistic EGCG–DOX interactions in HeLa cells under the tested conditions, whereas additive or antagonistic interactions predominated in HaCaT cells. Combined treatment produced the greatest reduction in viable cells, increased apoptosis, altered cell-cycle distribution, and reduced wound closure. It also produced the highest viability-normalized DCF-associated fluorescence, which was attenuated by NAC pretreatment, indicating an antioxidant-sensitive change in intracellular oxidative status without establishing a causal role in cytotoxicity. Combined treatment was further associated with increased total caspase-3 immunoreactivity and altered EGFR, FOXP3, CASP3, and CASP7 transcript levels. Overall, EGCG and DOX exhibited synergistic interactions and multiple treatment-associated cellular and transcriptional responses in HeLa cells under the present in vitro conditions. These findings do not establish cancer-specific selectivity or a definitive molecular mechanism but provide a basis for validation in additional cervical cancer models and at clinically relevant exposures. Full article