Search Results (265)

A novel carbohydrazide-based ligand (L) and its binuclear Cu(II) complex were successfully synthesized and characterized. Structural analysis confirmed that the Cu(II) complex adopted a monoclinic crystal system with a distorted coordination configuration, in which the multidentate Schiff base ligand chelated and bridged two Cu(II) centers. The in vitro anti-tumor results revealed that the Cu(II) complex exhibited prominent cytotoxicity against five human cancer cell lines with much lower IC₅₀ values than the free ligand, copper chloride and cisplatin. Mechanistic studies demonstrated that the Cu(II) complex significantly increased intracellular ROS and MDA levels, decreased the GSH/GSSG ratio, and reduced ATP content, thereby disrupting cellular redox balance and bioenergetic metabolism. In addition, flow cytometry analysis verified that the complex effectively triggered tumor cell apoptosis. In contrast, free CuCl₂ showed almost no anticancer activity, indicating that the synergistic effect between the Schiff base ligand and copper ions contributed to the excellent anti-tumor performance. This work suggests that the prepared binuclear Cu(II) complex can serve as a promising candidate for developing metal-based anticancer agents. Full article

Mitochondria-targeting metal complexes (MTMCs) are a mechanistically distinct class of metallopharmaceuticals. Unlike first-generation platinum drugs that form nuclear DNA adducts, MTMCs exploit organelle-specific vulnerabilities such as hyperpolarised mitochondrial membrane potential (ΔΨm), elevated reactive oxygen species (ROS), limited mitochondrial DNA (mtDNA) repair capacity, and redox-dependent enzymes such as thioredoxin reductase (TrxR). We systematically searched PubMed, Web of Science, Scopus, and Google Scholar databases for studies published between 2016 and 2026, applying predefined inclusion criteria that included subcellular localization evidence and functional bioenergetic endpoints. The search identified 147 studies covering Pt(II/IV), Ru(II/III), Au(I/III), Ir(III), Os(II), Re(I), and V(IV/V) complexes and metal–organic framework nanoplatforms. Mechanistic evidence converges on four intramitochondrial target categories: inhibition of ETC (Electron Transport Chain) Complexes I/III with consequent ATP depletion; ROS overproduction, coupled with glutathione and TrxR depletion; outer mitochondrial membrane permeabilization and intrinsic apoptotic cascade activation; and mtDNA damage within a compartment limited to base excision repair. Multi-modal cell death—the co-occurrence of apoptosis, ferroptosis, necroptosis, and autophagic cell death—was a recurrent finding across the reviewed studies. This review thoroughly surveys the latest trends in MTMC drug design (metals, ligand structures, and mechanisms of action) and summarises analytical techniques for speciation, pharmacokinetics, safe monitoring, and resistance, while critically analysing translational barriers and clinical failures. To address the field’s inconsistent terminology, we introduce an explicit localization evidence hierarchy that distinguishes mitochondria-targeting complexes (through quantitative ICP-MS fractionation or co-localization with defined Pearson/Manders coefficients) from simply mitochondria-localising or mitochondria-perturbing agents, and we apply it throughout. We also point out that the idea of selectivity being purely driven by membrane voltage (ΔΨm) and thermodynamics is constrained by membrane and protein binding, as well as the transmembrane pH gradient, kinetic limitations, and demonstrated heterogeneity of cancer-cell membrane potential, and, as such, the functional mitochondrial effects must not be equated with mitochondrial accumulation. Since elemental quantification cannot distinguish intact complex from protein adducts and decomposition products, speciation-aware pharmacokinetics emerges as a prerequisite for a credible exposure–response interpretation. The translational progress will depend less on new chemotypes than on this analytical and pharmacokinetic rigour, together with organelle-level safety monitoring and biomarker-guided patient selection. Full article

NAD⁺ depletion is a defining feature of the aging cell, driven by a progressive decline in nicotinamide phosphoribosyltransferase (NAMPT) activity, the rate-limiting enzyme of the NAD⁺ salvage pathway. Pyrroloquinoline quinone (PQQ), a plant-derived redox-active quinone cofactor, elevates intracellular NAD⁺ by a mechanism that remains incompletely understood. We employed an integrated in silico approach combining molecular docking, density functional theory (DFT), and 100 ns molecular dynamics (MD) simulation to evaluate whether PQQ directly targets NAMPT. Docking against the NAMPT crystal structure (PDB: 7ENQ) yielded a binding free energy of −9.4 kcal/mol, with PQQ positioned in the allosteric activation site and forming hydrogen bonds at His191, Asp219, and Val242 together with π–π stacking at Tyr188, extending a known synthetic activator pharmacophore to a dietary ligand class. MM-GBSA analysis yielded binding free energy = −31.2 kcal/mol, confirming dominant electrostatic and van der Waals stabilization. In silico alanine mutagenesis of Tyr188 and Val242 reduced binding affinity to −7.2 and −7.0 kcal/mol respectively, with complete loss of allosteric-site contacts, validating the proposed mechanism computationally. DFT analysis revealed a HOMO–LUMO gap of 3.20 eV and electrophilicity index ω = 8.91 eV, consistent with non-covalent binding to nucleophilic residues. MD simulation confirmed retention of PQQ within the allosteric site over 100 ns. These data provide a structural and electronic framework for the NAD⁺-boosting activity of PQQ and a rationale for experimental validation. Full article

Cadmium (Cd) is an environmental nephrotoxicant that preferentially accumulates in the kidney and disrupts redox and energy metabolism. However, the protective effect of berberine (Ber) against Cd-induced nephrotoxicity remains insufficiently characterized. In the present study, male C57BL/6 mice were orally exposed to CdSO₄ (30 mg/kg body weight/day) for 30 days in the absence or presence of berberine (25 or 100 mg/kg/day). Renal function, histopathology, oxidative stress parameters, LC–MS/MS-based metabolomic profiling, gene and protein expression, and in silico ligand–target interactions were evaluated. Cd exposure markedly increased serum CREA, renal index, renal LDH activity, and MDA content, decreased SOD and CAT activities, and induced pronounced renal histopathological lesions. Ber significantly attenuated these abnormalities in a dose-dependent manner. Metabolomic analysis revealed that Cd broadly suppressed pyruvate metabolism, tricarboxylic acid cycle intermediates, and NAD+/NADH homeostasis, whereas berberine restored the levels of pyruvate, acetyl-CoA, oxaloacetate, citrate, isocitrate, succinate, fumarate, malate, NAD+, and NADH. In parallel, berberine normalized the expression of metabolism-related genes including the downregulation of Ldha and the upregulation of Cs, Sucnr1, G6pc, and Pfkm, with the high-dose regimen showing the most evident recovery. Western blotting further verified the lower LDHA protein expression after berberine treatment. Molecular docking demonstrated favorable potential berberine–LDHA binding, and molecular dynamics simulation supported the stability of the ligand–protein complex. Collectively, these findings indicate that berberine ameliorates Cd-induced renal injury, an effect that correlates with attenuated oxidative stress, modulation of LDHA-associated glycolytic pathways, and restoration of mitochondrial TCA-cycle activity and redox balance, highlighting berberine as a promising candidate for the prevention of heavy metal-associated nephrotoxicity. Full article

Abiotic stresses, including drought, salinity, alkalinity, temperature extremes, flooding, heavy metals, and emerging pollutants, challenge plant growth and productivity by disturbing water relations, ion balance, redox homeostasis, membrane stability, energy metabolism, and developmental progression. Although substantial progress has been made in the identification of stress-responsive hormones, second messengers, kinases, transcription factors, transporters, and metabolic regulators, plant stress adaptation cannot be fully explained by linear signaling cascades or single tolerance genes. A major unresolved question is how early molecular events are reorganized into coordinated physiological and developmental outputs that support survival, recovery, and productivity. In this review, we propose an intermolecular interaction-driven adaptive remodeling framework for plant abiotic stress responses. This framework emphasizes that stress tolerance emerges from dynamic changes in receptor–ligand recognition, protein–protein interactions, calcium decoding, redox-sensitive modification, phosphorylation networks, transcriptional regulation, chromatin-associated control, and metabolite-mediated feedback. We further emphasize ROS as integrative redox switches that connect stress sensing, defense activation, senescence-related transitions, and recovery, and chromatin-associated mechanisms as regulators that may stabilize primed or memory-like adaptive states. We discuss how these interaction networks converge on core signaling hubs, including abscisic acid, reactive oxygen species, Ca²⁺, and kinase/phosphatase systems, and how they remodel stomatal behavior, root architecture, ion and pH homeostasis, redox buffering, metabolism, development, and reproductive resilience. We further highlight how natural variation, multi-omics, genome editing, high-throughput phenotyping, and field validation can translate interaction-centered stress biology into crop resilience. This perspective provides a conceptual bridge between molecular stress perception, network behavior, physiological adaptation, and climate-resilient agriculture. Full article

Background: Ferrocene-containing compounds have gained attention in medicinal chemistry due to their unique redox and structural properties. This study investigates ferrocene-based analogues of imatinib and nilotinib to define their binding determinants within the ABL1 kinase domain using an integrated in silico approach, in relation to their previously reported cytotoxic activity. Methods: Ligand geometries were optimized at the B3LYP/def2-TZVP level with D3(BJ) dispersion and SMD solvation. Molecular docking against ABL1 (PDB ID: 2HYY) was performed using Glide SP, validated by re-docking and enrichment screening. Docked poses were refined using MM-GBSA (Prime, VSGB 2.1/OPLS4). The most active compounds (9 and 15a), together with the inactive control 15e, were subjected to three independent 500 ns molecular dynamics simulations (Desmond, OPLS4), followed by trajectory analysis including RMSD, RMSF, radius of gyration, SASA, and polar surface area. Results: Compounds 9 and 15a maintained stable binding within the ATP-binding pocket despite lacking the canonical hinge interaction with Met318, indicating hinge-independent binding. Their binding was mainly driven by interactions with Asp381 (DFG motif) and cation–π contacts with Lys271. In contrast, the compound 15e showed unstable binding, increased conformational flexibility, reduced pocket burial, and loss of key stabilizing interactions. Active compounds also preserved stable P-loop dynamics, with Tyr253 engagement suggesting a role in loop stabilization. Compound 9 exhibited the most constrained and reproducible binding mode among all analogues. Conclusions: Ferrocene-based analogues can sustain stable ABL1 binding via non-classical interaction networks independent of hinge recognition. The clear distinction between active compounds and the inactive analogue 15e supports the robustness of the proposed binding mode and provides a structural basis for their reported cytotoxic activity. These findings support further experimental evaluation of ferrocene-containing scaffolds as potential BCR-ABL1 inhibitors. Full article

Diabetic neuropathy is typically diagnosed with distal sensory and nerve conduction abnormalities. These symptoms may reflect earlier disturbances of axonal maintenance. This review examines axonal transport and cytoskeletal failure as convergent cellular mechanisms of diabetic axonopathy. Long peripheral axons are particularly vulnerable to damage because their integrity depends on continuous communication between the neuronal soma and distal terminals. This process involves the continuous renewal of cytoskeletal and functional proteins and the involvement of organelles such as mitochondria. Diabetes in experimental models disrupts this system at several levels. It slows cargo transport. The supply of neurofilaments, tubulin and retrograde signaling is reduced, and regenerative growth after injury is weakened. Carbonyl stress and AGEs cause modifications of neural proteins, the extracellular matrix, vascular barriers, and the excitability of sensory neurons. RAGE ligands, including AGEs and the proteins HMGB1 and S100, link the diabetic tissue environment to redox and inflammatory signaling. This occurs in neural and glial compartments, as well as in vascular tissue and the immune system. RAGE interacts with DIAPH1 to activate GTPase signaling and remodel the cytoskeleton. The RAGE–DIAPH1 interaction provides a plausible route from diabetic ligand accumulation to cytoskeletal remodeling. These observations provide a mechanistic context for axonal transport, although not all represent direct measurements of cargo movement. Direct evidence for transport impairment comes mainly from experimental studies showing altered slow cytoskeletal transport, impaired retrograde signaling, and weakened regenerative responses. This work highlights the possibility of developing therapies that go beyond symptomatic relief. Verifying the effectiveness of interventions in protecting axonal transport and nerve fiber integrity in diabetic neuropathy may be therapeutically beneficial. Full article

Elabela (ELA/APELA/Toddler) is an endogenous peptide ligand of the apelin receptor APLNR (also known as APJ) and, together with apelin, forms the apelinergic signalling system. Its role in embryonic development, the cardiovascular system, the kidneys and the endothelium is becoming increasingly well characterised, whilst its function in metabolic regulation remains unresolved. Elabela activates pathways essential for metabolic homeostasis—PI3K/Akt, AMPK-related pathways, redox regulation, inflammatory control and pro-survival cascades—but no study has shown that it directly regulates adipocyte lipid metabolism. This narrative review categorises the evidence at the receptor, organ, immunometabolic and intra-adipocyte levels, and also considers the adipose tissue microenvironment as a distinct level of potential relevance. The available data support a role for Elabela as a candidate mediator of lipid-related metabolic dysfunction—via anti-inflammatory, antioxidant and tissue-protective mechanisms—with macrophage lipid metabolism representing the most informative immunometabolic interface. Human studies remain scarce, heterogeneous and limited by a lack of standardisation in assay methods and the unresolved specificity of isoforms. Elabela should therefore be regarded as a candidate indirect modulator of metabolic homeostasis and a candidate biomarker of cardiometabolic stress or adaptation—not as a confirmed direct regulator of adipocyte lipid metabolism. Full article

Traditional pharmacotherapy is often constrained by suboptimal bioavailability and systemic toxicity. Biomolecularly inspired nano-drug delivery systems (nano-DDS) have emerged as precise platforms to overcome these barriers by orchestrating molecular interactions at the bio-nano interface. This review systematically evaluates the molecular recognition mechanisms and biochemical principles governing nano-DDS performance. We systematically evaluate how passive targeting relies on the EPR effect—dictated by the nanocarrier’s physicochemical properties—and how active targeting exploits ligand-receptor affinity to enhance cellular uptake. Special emphasis is placed on bioresponsive strategies that utilize pathological cues—such as pH gradients, redox potential, and enzymatic activity—for intelligent, on-demand drug release. Furthermore, we discuss structure-function relationships in lipid, polymeric, and biologically derived systems, highlighting their roles in modulating therapeutic signaling in oncology and inflammatory diseases. Finally, translational hurdles and emerging AI-driven molecular design strategies are critically examined. Full article

Background: Branch retinal vein occlusion (BRVO) represents a segmental retinal ischemic disorder characterized by localized oxidative–inflammatory activation. While redox-driven cytokine responses have been described in central retinal vein occlusion, their role in BRVO-specific macular edema and treatment responsiveness remains unclear. This study investigated whether novel redox-related inflammatory mediators in the aqueous humor are associated with disease severity and structural response to anti-vascular endothelial growth factor (VEGF) therapy in BRVO. Methods: Aqueous humor samples were collected from 30 treatment-naïve patients with BRVO and 19 control patients. Levels of VEGF and the novel redox-related inflammatory factors FMS-related tyrosine kinase 3 ligand (Flt-3L), fractalkine, CXCL-16, and endocan-1 were measured by suspension array, and the severity of macular edema was evaluated by measuring central macular thickness and neurosensory retinal thickness (TNeuro) by spectral-domain optical coherence tomography. Therapeutic response was assessed one month after intravitreal ranibizumab injection (IRI). Results: Aqueous levels of VEGF, Flt-3L, and endocan-1 were significantly higher in the BRVO group, and levels of Flt-3L, CXCL-16, and endocan-1—markers associated with oxidative endothelial damage and leukocyte recruitment—correlated significantly with each other and with aqueous flare values. Notably, baseline Flt-3L levels significantly correlated with the reduction in TNeuro, suggesting that this redox-sensitive signaling molecule is a potential biomarker for treatment sensitivity. Conclusions: These findings suggest that novel inflammatory factors, potentially driven by oxidative-nitrosative stress, play a pivotal role in the pathophysiology of BRVO. Baseline Flt-3L may serve as a predictive biomarker for structural responsiveness to anti-VEGF therapy in BRVO, suggesting that oxidative–inflammatory signaling contributes not only to disease severity but also to therapeutic heterogeneity. Full article

Over the past 20 years, the iron-activated persulfate systems have been widely used for removing pharmaceuticals and personal care products (PPCPs) from water. However, slow Fe(III)/Fe(II) redox cycling and precipitation of iron, unless in very acidic conditions, were the main limitations. Thus, two ligand-assisted Fe(III)/persulfate systems, Fe(III)-acetohydroxamic acid (AHA)/peroxydisulfate (PDS) and Fe(III)-nitrilotriacetic acid (NTA)/peroxymonosulfate (PMS), were comparatively investigated for the degradation of atenolol (ATL) in this study. The experimental results showed that the Fe(III)-NTA/PMS system worked much better than the AHA system. However, the cost of PMS is higher than that of PDS, which should be considered. The primary advantage of the NTA system was its ability to overcome the pH limitations. It worked well over a wide pH range (3.0–10.0), whereas the AHA system could only be used in a narrower pH window (pH 2.4 to 6.5). The investigation of radicals that contributed to ATL degradation revealed that sulfate radicals (SO₄^•−) were dominant in the NTA system, while hydroxyl radicals (^•OH) and SO₄^•− were the primary and secondary radicals in the AHA system. These results provided useful insight into the comparative behavior of two ligand-assisted Fe(III)/persulfate systems for ATL degradation, with the Fe(III)-NTA/PMS system showing clear potential under neutral or near-neutral conditions, while Fe(III)-AHA/PDS may still represent a lower-cost option under acidic conditions. Full article

Heat stress (HS) affects female reproductive efficiency by disrupting redox homeostasis and activating inflammatory responses in the corpus luteum (CL), a metabolically active tissue essential for pregnancy maintenance. This study reveals the protective effect of resveratrol against HS-induced luteal injury in pregnant mice through the regulation of oxidative stress and cytokine–chemokine-mediated inflammatory and immune responses. The pregnant mice were divided into three groups: control, HS, and resveratrol +HS. Heat stress was applied at 40 ± 0.5 °C for 7 days, with resveratrol (10 mg/kg) given orally 2 h before exposure to HS. The results showed that heat exposure reduced serum total superoxide dismutase activity and increased malondialdehyde level, causing significant disruption of luteal morphology with cellular disorder and vacuolization, which was partially overcome by resveratrol pretreatment. Transcriptomic profiling showed that HS induced a strong immunological and inflammatory response, involving cytokine–cytokine receptor interaction and chemokine signaling. Resveratrol significantly attenuated HS-induced transcriptional changes. The RT-qPCR results showed that HS increased chemokine ligands (Ccl11, Cxcl13, Tslp) and cytokine receptors (Ccr3, Ccr4, Ccr5), which were suppressed by resveratrol. The chemokine-based inflammatory module is one of the most important regulatory properties of the HS response, according to the network analysis. Stable binding of resveratrol with major chemokine receptors was supported by molecular docking and molecular dynamics simulations. Collectively, HS induces oxidative, structural, and inflammatory alterations in luteal tissue, while resveratrol attenuates these changes by being associated with improved antioxidant status and suppression of cytokine–chemokine-mediated responses. Full article

Ruthenocene (Rc) and its derivatives form a structurally versatile class of metallocenes with unique and multifunctional applicability. This review presents a detailed analysis of Rc chemistry including the structural comparison with ferrocene, its redox behavior, and substituent effects. We also discuss its applications in sensing, energy storage, photochemistry, and biomedicine. Rc exhibits unique conformational and adaptive electronic properties based on one and two-electron oxidation processes. Electrochemical investigations of Rc to date indicate that its redox behavior is strongly dependent on the electrolyte system, exhibiting quasi-Nernstian characteristics, the formation of stabilized dimeric species [Rc₂]²⁺, and interconversion among Ru(II), Ru(III), and Ru(IV) oxidation states. Rc-based systems exhibit superior performance as redox mediators and labels in electrochemical sensing systems in terms of electron-transfer kinetics, signal amplification, and surface immobilization. In the field of energy storage, Rc decreases the charging overpotential and increases the cycle life of Li-O₂ batteries. Rc further acts as a photoinitiator via charge-transfer-to-solvent and efficient photoinduced electron transfer in metalloporphyrin and fullerene dyads. In biomedical research, Rc derivatives as well as bioconjugates possess promising anticancer activities, displaying reactive oxygen species generation, topoisomerase inhibition, thioredoxin reductase inhibition, receptor-mediated uptake, and target peptide conjugation. Given its flexible ligand design, electrolyte driven redox behaviors, and antiproliferative properties, Rc exhibits a very adaptive molecular scaffold for next generation electrochemical technologies as well as metallodrug design. Full article

Chelating agents can extend the operational pH range of iron-based advanced oxidation processes, yet comprehensive studies on chelated Fe-activated persulfate systems for textile dye degradation remain scarce. This study establishes an integrated framework for optimizing Fe(II)/persulfate (PS) systems using chelating ligands and hybrid energy inputs under near-neutral conditions. Among the tested systems, Fe(II)/PS complexed with citric acid (CA) exhibited superior performance, achieving ~91% dye removal within 20 min at pH 6.5 under optimized conditions (1.25 mM Fe(II), 10 mM PS, 0.1 mM CA). Chelation stabilized Fe redox cycling and prevented precipitation, enabling effective catalysis across pH 3–10. Optimal CA/Fe and Fe/PS ratios (0.1:1.25 and 1.25:10) yielded ~96% decolorization and 67.65% TOC removal in 60 min, while excessive chelation reduced activity. Transition metal screening (Mn(II), Zn(II), Cu(II), Co(II), and Ni(II) confirmed Fe(II) as the most effective activator, providing removal efficiencies up to 3.2-fold higher than competing metals. Mixed-dye experiments showed competitive degradation, with >37% color removal after 60 min for ternary dye mixtures. Mineralization reached ~92% TOC reduction after 120 min, indicating deep oxidation beyond chromophore cleavage. Reactive species quenching revealed a mixed oxidation mechanism involving ^•OH radicals and high-valent Fe(IV) species. Hybrid assistance improved mineralization, with UVC increasing TOC removal by 15.6%, while solar irradiation provided moderate enhancement under low-energy input. In contrast, low-power ultrasound (40 kHz, 60 W) delivered only 17.6 W acoustic power to the solution and did not improve performance due to limited cavitation and mixing. This work thus contributes a robust platform for advancing chelated iron-persulfate oxidation systems toward practical, effective treatment of recalcitrant dye-contaminated wastewaters under near-neutral conditions. Full article

The progression of prostate cancer to castration-resistant disease (CRPC) remains a clinical challenge in which oxidative stress intersects with the PI3K/AKT–androgen receptor (AR) axis. Quercetin (QRC) is a redox-active dietary flavonol, yet its mechanistic impact on CRPC is incompletely defined. Here, we tested whether QRC suppresses AR output by directly modulating AKT. C4-2B and 22Rv1 CRPC cell lines were treated with increasing QRC concentrations, with or without enzalutamide (Enz). Proliferation and viability were monitored by IncuCyte imaging and SYTOX Green incorporation. AKT phosphorylation (S473), AR phosphorylation (S210/213), AR abundance and localization, and prostate-specific antigen (PSA) secretion were assessed by immunoblotting, immunofluorescence, and dot blot, respectively. Docking and molecular dynamic simulations were performed to identify and evaluate a putative QRC-binding site on AKT. QRC produced a dose-dependent cytostatic effect (IC₅₀ 24.37 μM in C4-2B; 21.54 μM in 22Rv1) without marked cell death, reduced pAKT(S473) by up to 80%, decreased pAR(S210/213), and diminished nuclear AR and PSA secretion. Simulations suggested a putative druggable allosteric pocket in the AKT1 N-lobe, with G159 emerging as a potential anchor residue. Enz cotreatment with QRC did not produce additive effects, consistent with a model in which QRC acts upstream of ligand-driven AR activation and thereby limits the incremental benefit of AR antagonism under these conditions. These data support QRC as an AKT–AR axis modulator in CRPC and provide a target engagement framework beyond simple ROS scavenging. Full article