Search Results (7,282)

Lipopolysaccharide (LPS) impairs the function of ovine follicular granulosa cells (GCs), representing a primary cause of follicular atresia. Selenium (Se), an essential trace element, possesses anti-inflammatory and cytoprotective properties; however, its effects on GC ultrastructure remain largely unknown. In this study, primary ovine GCs were exposed to LPS (10 µg/mL) and treated with sodium selenite (25 nM). Transmission electron microscopy (TEM), JC-1 staining, enzyme-linked immunosorbent assay (ELISA), reactive oxygen species (ROS) detection, flow cytometry, and quantitative real-time PCR (qRT-PCR) were employed to evaluate cellular ultrastructure, mitochondrial membrane potential (ΔΨm), and downstream physiological processes. LPS induced severe mitochondrial pyknosis, cristae loss, and reduced ΔΨm, accompanied by inflammation, oxidative stress, apoptosis, and impaired steroidogenesis. Se intervention markedly ameliorated these ultrastructural injuries, preserving mitochondrial morphology and ΔΨm. Functionally, Se suppressed the release of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β); enhanced the activities of antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) while attenuating ROS accumulation; inhibited apoptosis by upregulating BCL-2 and downregulating BAX and CASPASE-3; and restored E₂ and P₄ secretion via upregulation of STAR and NR5A1. This study provides direct morphological evidence that Se protects ovine GCs from LPS-induced damage by repairing mitochondrial ultrastructure. This structural restoration is central to its integrated anti-inflammatory, antioxidant, anti-apoptotic, and steroidogenic effects. These in vitro findings suggest that Se may serve as a promising nutritional strategy for mitigating inflammation-driven follicular atresia, pending further in vivo validation. Full article

Background: Head and neck squamous cell carcinoma (HNSCC) remains a highly aggressive malignancy with poor clinical outcomes. Although poly(ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in tumors with homologous recombination deficiency, their efficacy in BRCA wild-type HNSCC remains limited. Reactive oxygen species (ROS)-induced DNA damage may increase cellular dependence on DNA repair pathways and thereby enhance sensitivity to PARP inhibition. This study investigated whether ROS-mediated DNA damage could sensitize BRCA wild-type HNSCC cells to the PARP inhibitor olaparib. Methods: BRCA wild-type HSC-3 and SCC-25 HNSCC cell lines were exposed to H₂O₂ to induce oxidative stress. Intracellular ROS levels were quantified using DCFDA assays, DNA double-strand breaks were evaluated by γ-H2AX ELISA, PARP activity was assessed by ELISA, and cell viability was determined using MTT assays. Expression levels of DNA repair genes (PARP1, PARP2, BRCA1, BRCA2, RAD51, and MLH1), checkpoint kinases (ATM, ATR, and CHK1), the homologous recombination regulator FANCD2, and redox defense genes (NQO1, GPX4, and SLC7A11) were analyzed by qRT-PCR. Therapeutic selectivity was assessed using HGF-1 normal human gingival fibroblasts as a normal cell control. Apoptosis was measured through caspase-3/7 activity assays, and drug interactions were evaluated using the Chou–Talalay method. Results: H₂O₂ treatment increased intracellular ROS levels in both cell lines, accompanied by significant induction of DNA damage as demonstrated by elevated γ-H2AX levels. ROS induction markedly enhanced olaparib sensitivity, significantly reducing IC₅₀ values in both HSC-3 and SCC-25 cells. Combined H₂O₂ and olaparib treatment produced strong synergistic cytotoxicity, suppressed DNA repair, checkpoint kinase, and redox defense gene expression, and increased caspase-3/7 activity compared with control cells. Importantly, the combination demonstrated selective cytotoxicity toward cancer cells, with normal HGF-1 cells retaining significantly higher viability. Conclusions: ROS-induced DNA damage significantly enhances the anti-tumor activity of olaparib in BRCA wild-type HNSCC cells through a functional synthetic lethal-like interaction involving the simultaneous collapse of DNA repair capacity, checkpoint activation, and oxidative stress buffering, culminating in apoptosis induction. These findings support the rationale for combining ROS-generating therapies with PARP inhibitors in HNSCC treatment. Full article

Saline–alkaline aquaculture is a promising strategy to alleviate freshwater shortages; however, such environments severely impair fish growth and physiological homeostasis. Nutritional regulation has been proposed to improve stress tolerance, yet the benefits of single additives are often limited under the multifactorial challenges imposed by saline–alkaline conditions. Therefore, a compound feed additive (CFA) consisting of glutamate, cholesterol, β-glucan, myo-inositol, zinc methionine, and curcumin was developed and evaluated in Nile tilapia (Oreochromis niloticus). To assess the robustness and practical applicability of this nutritional strategy, three independent feeding trials were conducted using different commercial basal diets as validation systems. Within each dietary system, fish were reared under freshwater (FW), saline–alkaline water (SAW), or saline–alkaline water supplemented with CFA (SAW+CFA). Saline–alkaline stress significantly reduced WG and SR, increased FCR, and elevated VSI and HSI, indicating impaired growth performance and metabolic burden. These changes were accompanied by increased serum glucose and ion concentrations (Na⁺, K⁺, Cl⁻), elevated ammonia levels, and reduced crude protein content. Dietary CFA improved growth and feed utilization under saline–alkaline conditions. It enhanced hepatic glycogen content and reduced serum glucose levels. Meanwhile, it downregulated glycolysis-related genes (hk, pfk1, pk) and upregulated genes involved in gluconeogenesis and the pentose phosphate pathway (g6pase, pc, g6pdh), indicating altered glucose metabolism and improved energy homeostasis. Saline–alkaline stress induced oxidative stress, apoptosis, and histological damage in the liver, whereas CFA alleviated these alterations by reducing MDA levels, enhancing antioxidant enzyme activities (CAT, GSH-Px, T-SOD) and suppressing apoptosis-related genes (caspases, p53, c-myc). In addition, CFA alleviated saline–alkaline stress-induced gill structural damage and reduced serum ion concentrations while modulating ion transport-related gene expression, suggesting improved osmoregulatory capacity. It also enhanced ammonia metabolism and transport, as reflected by reduced serum ammonia levels and altered expression of related genes. Furthermore, Saline–alkaline stress impaired intestinal structure and function, whereas CFA improved intestinal villus structure, increased digestive enzyme activities (amylase, trypsin, lipase), and suppressed pro-inflammatory genes (il-1β, il-8). Importantly, similar beneficial response patterns were observed across the three independently analyzed dietary systems. Overall, CFA improved saline–alkaline adaptability of Nile tilapia and was associated with improvements in energy metabolism, oxidative homeostasis, osmoregulation, ammonia detoxification, and intestinal function, providing a practical nutritional strategy for saline–alkaline aquaculture. Full article

Background/Objectives: Drug repurposing has emerged as a promising strategy for identifying novel anticancer agents among clinically established drugs. Fexofenadine, a second-generation H1 antihistamine, has been proposed as a candidate for repurposing in oncology; however, the molecular mechanisms underlying its biological activity remain insufficiently characterized. This study investigated the effects of fexofenadine on oxidative stress, mitochondrial function, apoptosis, and pro-survival signaling pathways in cervical and lung cancer cells. Methods: HeLa and A549 cancer cells, as well as non-tumorigenic Beas-2B epithelial cells, were exposed to fexofenadine under in vitro conditions. Cell viability, apoptosis, reactive oxygen species generation, mitochondrial membrane potential, DNA damage, autophagy-associated responses, and PI3K/AKT and MAPK/ERK pathway activation were assessed using flow cytometry, fluorescence microscopy, electron microscopy, and biochemical assays. Three-dimensional spheroid cultures and N-acetyl-L-cysteine rescue experiments were additionally employed to evaluate biological relevance and the contribution of oxidative stress. Results: Fexofenadine induced concentration-dependent accumulation of reactive oxygen species, mitochondrial membrane depolarization, Bcl-2 inactivation, caspase-3/7 activation, DNA damage, and apoptotic cell death in HeLa and A549 cells. Antioxidant pretreatment with N-acetyl-L-cysteine significantly reduced oxidative stress, attenuated mitochondrial dysfunction, and partially suppressed apoptosis. Fexofenadine was associated with reduced PI3K/AKT and MAPK/ERK pathway activation and promoted autophagy-associated responses. In three-dimensional spheroid cultures, treatment disrupted spheroid integrity and increased apoptotic cell death. Non-tumorigenic Beas-2B cells exhibited lower sensitivity to treatment than malignant cells. Conclusions: Fexofenadine disrupts redox homeostasis and is associated with reduced activation of pro-survival signaling pathways, resulting in oxidative stress-associated mitochondrial dysfunction and apoptosis in cancer cells. These findings provide mechanistic support for further evaluation of fexofenadine as a candidate for anticancer drug repurposing, while additional pharmacokinetic and in vivo studies are required to determine its translational relevance. Full article

The formation of extracellular traps (ETs) through ETosis has emerged as a key mechanism in immunothrombosis. However, the temporal dynamics and clinical significance of ETosis in coronary thrombi of ST-elevation myocardial infarction (STEMI) patients remain incompletely understood. We investigated whether ETosis burden increases with thrombus age and is associated with DNASE1 and TREX1 genetic variants as well as impaired myocardial reperfusion. Thrombus aspirates from 81 STEMI patients undergoing primary percutaneous coronary intervention were histologically classified as fresh (n = 41) or lytic (n = 40). ETosis was quantified by citrullinated histone H3 (CitH3) immunohistochemistry and digital image analysis, complemented by multiplex staining for myeloperoxidase (MPO), CD68, caspase 3, and CD61. Plasma ET-related markers and genotyping of DNASE1 (rs1053874) and TREX1 (rs11797) were also performed. CitH3-positive cells were present in all thrombi but were more abundant in lytic (older) thrombi compared with fresh thrombi (1348 vs. 591 cells/mm², p < 0.001). Increased ETosis was associated with neutrophil and macrophage infiltration, apoptosis, prolonged ischemia time, elevated systemic inflammation (neutrophil–lymphocyte ratio and C-reactive protein), and impaired myocardial reperfusion (lower TIMI flow grades). Moreover, the DNASE1 GG genotype was associated with higher densities of MPO- and CD68-positive cells, whereas the TREX1 CC genotype was associated with increased densities of CitH3-, MPO-, and CD68-positive cells. This study demonstrates that ETosis increases with coronary thrombus maturation and is associated with local inflammation and impaired reperfusion in STEMI. Genetic variants in DNASE1 and TREX1 may modulate inflammatory cell accumulation within thrombi. These findings suggest ETosis as a potential therapeutic target, particularly in patients with delayed presentation. Full article

Background/Objectives: Malignant melanoma is characterized by constitutive PI3K/Akt/mTOR and MAPK activation, driving aggressive behavior and therapeutic resistance. Alpha-lipoic acid (αLA), a naturally occurring dithiol compound with an established clinical safety profile, has shown anticancer potential; however, its integrated molecular mechanisms in melanoma remain poorly defined. This study aimed to comprehensively evaluate the cytotoxic and mechanistic effects of αLA in B16F10 murine melanoma cells. Methods: Antiproliferative effects were assessed by MTT assay at four concentrations (250, 500, 750, 1000 µM) over 48 h. Protein levels of apoptotic markers (Bax, Bcl-2, Caspase-3, AIF), kinase signaling components (p-Akt, p-mTOR, p-ERK, p-JNK), ER stress markers (GRP78, GADD153/CHOP), and cell cycle regulator Wee1 were quantified by ELISA at a specifically selected sub-lethal concentration of 750 µM (inducing ~38% growth inhibition). Results: αLA dose-dependently inhibited B16F10 proliferation. At 750 µM, it triggered robust intrinsic apoptotic signaling, evidenced by a nearly 10-fold shift in the Bax/Bcl-2 ratio and greater than 9-fold Caspase-3 activation. Elevated AIF suggested profound mitochondrial stress and the potential priming of concurrent caspase-independent cell death mechanisms. αLA suppressed survival signaling by reducing p-Akt (44%), p-mTOR, p-ERK, and p-JNK. Treatment triggered lethal ER stress via GRP78 and GADD153/CHOP upregulation and upregulated Wee1, suggesting the induction of stress-responsive checkpoint signaling. The simultaneous CHOP upregulation and p-Akt suppression highlight a concurrent dysregulation of stress and survival pathways, suggesting a potential pro-apoptotic interplay. Conclusions: αLA exerts potent multi-target anticancer effects by inducing a broad spectrum of associated molecular changes, including the suppression of PI3K/Akt/mTOR and MAPK networks, induction of ER stress, engagement of cell cycle checkpoints, and activation of the mitochondrial Bax/Bcl-2/Caspase-3 axis. Importantly, these correlative findings do not establish proven pathway dependencies. Nevertheless, this concurrent dysregulation positions αLA as a potential disruptor of inter-pathway resilience underlying drug resistance. Full article

Redox homeostasis is the balance between oxidative processes and antioxidant defenses and is fundamental to cellular integrity. This review critically synthesizes current evidence on the phytochemical composition, redox-modulating mechanisms, and therapeutic bioactivities of Fagonia cretica L. (F. cretica), with the aim of evaluating its translational potential as a natural antioxidant and anticancer agent. F. cretica has emerged as a phytochemically rich candidate containing highly bioactive secondary metabolite for redox-targeted therapeutic applications. Its diverse secondary metabolite profile, including alkaloids, flavonoids, tannins, saponins, terpenoids, glycosides, and phenolic compounds, confers broad biological activity. Bioactive constituents, particularly kaempferol, catechin, quercetin, and arbutin, directly neutralize reactive oxygen species (ROS) and modulate inflammatory pathways through inhibition of COX-1, COX-2, and nitric oxide production. These compounds influence important major ROS-sensitive redox signaling pathways: activation of the Keap1/Nrf2/ARE axis to upregulate cytoprotective genes such as HO-1, NQO1, and GCL, suppression of the NF-κB pathway to attenuate pro-inflammatory cytokine transcription, including TNF-α, IL-1β, and IL-6, and interference with the MAPK-PI3K/Akt cascade to disrupt aberrant cancer cell survival and proliferation. Bioactive compound-rich extracts of F. cretica exhibit anticancer activity in MCF-7 breast cancer cells by inducing DNA damage, cell cycle arrest, and apoptotic signaling through the FOXO3a/p53 pathways. Similar effects have been reported in colorectal (HCT-116) and prostate (PC-3) cancer cells through DNA (cytosine-5)-methyltransferase 1 (DNMT1) downregulation, oxidative stress induction, and ER-β activation. Moreover, these extracts demonstrate cytotoxic effects in HepG2 and Caco-2 intestinal cancer cells, often associated with topoisomerase inhibition and caspase activation. Despite encouraging preclinical evidence, systematic studies encompassing pharmacokinetic profiling, toxicological characterization, and human clinical trials remain essential to translate these findings into safe, evidence-based therapeutic applications. Full article

Hepatocellular carcinoma is one of the most aggressive malignancies worldwide, with limited therapeutic options. Boswellia serrata Roxb., an Indian medicinal tree, produces a resin rich in essential oil and boswellic acids, particularly acetyl-11-keto-β-boswellic acid (AKBA), with demonstrated antiproliferative and pro-apoptotic activities. This study investigated the cytotoxic effects of B. serrata essential oil and AKBA on hepatocarcinoma Huh-7 cells in both monolayer and three-dimensional spheroid cultures and characterized the underlying molecular targets. Essential oil was extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). Cytotoxicity was assessed using the cell counting kit-8 (CCK-8). Three-dimensional spheroid cultures were also established to evaluate anti-tumoral potential. Expression of cyclin D1, cyclin-dependent of kinase 4 (CDK4) (cyclin-dependent kinase inhibitor 1A (p21), E-cadherin, (alpha fetoprotein) AFP, epithelial cell adhesion molecule (EpCAM), Myeloid cell leukemia-1 (Mcl-1), and caspase-3 was analyzed by western blot. In addition, an in silico analysis was performed on the main constituents of B. serrata essential oil targeting 5-lipoxygenase (5LO). The results showed cytotoxic effects, with AKBA exhibiting greater potency than the essential oil. Cytotoxicity was associated with caspase-3-mediated apoptosis, with minimal effects on cell cycle and epithelial–mesenchymal transition markers. The in silico analysis predicted that some compounds may act as competitive inhibitors of the 5LO at the catalytic site and partially activate pro-apoptotic pathways. These data support the potential of B. serrata-derived compounds as novel anti-hepatocarcinoma agents, with AKBA and longifolene as leads for further preclinical and clinical research. Full article

Among the non-classical platinum complexes, Pt(IV) prodrugs are most promising as versatile scaffolds for structural modification and fine tuning of their activation-by-reduction mechanism of action and the resulting anticancer activity. Herein, four new asymmetrically disubstituted pyrenebutyrate complexes of Pt(IV) (2–5) were synthesized and thoroughly studied. In this series, the second axial ligand was derived from dicarboxylic acids of different length—4 and 5 C-atoms, or replacement of the C-atom in the middle with either O- or S-atom. The structural effects on reduction kinetics, lipophilicity and cellular internalization of the complexes were monitored by NMR, HPLC, fluorescence and ICP-MS measurements. Their cytotoxicity was tested on a panel of cancer cell lines and mechanistic insights were obtained from proteome analysis and microscope imaging. The data indicate that all complexes, especially complex 3, represent a promising class of Pt(IV) prodrugs, exhibiting significantly higher cytotoxic activity than cisplatin in all tested models, including a cisplatin-resistant line. This was explained with a stronger and more integrated apoptotic response than cisplatin: pronounced Bax upregulation (3.6-fold), maximal cleaved caspase-3 (4-fold), activation of both intrinsic and extrinsic pathways, and effective p53 Ser15/Ser46 phosphorylation. The consistent rank order of potency (3 > 4 > 5 ≈ 2 ≫ cisplatin) suggests that subtle ligand modifications can substantially enhance efficacy, possibly by improving cellular uptake or altering DNA binding. Full article

The current study describes the synthesis and preliminary anticancer assessment of a novel series of C3/C28-bis-1,2,4-triazolyl-sulfanylacetate-betulin (AP1–5) derivatives to identify potent agents for clinical development. The cytotoxicity of AP1–5 was evaluated using the Alamar blue assay against MCF-7, A375, PANC-1 (cancer cells) and HaCat (human keratinocytes) cells. Moreover, the molecular mechanisms responsible for cytotoxicity were investigated through in vitro (DCFDA/H₂DCDFA assay, caspase-3/7 assay, and morphological analysis) and in silico assays (network pharmacology, molecular docking, molecular dynamics simulation, and ADMET predictions). The result highlighted AP5, containing unsubstituted 1,2,4-triazoles, as the lead derivative of the series with increased potency against MCF-7, with an IC₅₀ value of 7.41 μM compared to its phenyl-substituted analogs (AP1–4). The derivatives induced apoptosis, marked by fragmented nuclei, round cells, disorganized cytoskeletons, and activation of caspases-3/-7 through a ROS-decreasing mechanism. The network pharmacology assessment predicted AP5 may interact with key proteins in the PI3K/Akt pathway, such as MAP2K1, MDM2, IGF1, JAK2, IL2 and FGFR1, as well as ESR1, PGR and MMP2. Molecular docking suggested MMP-2 is the most favorable target for AP5 among the validated proteins, while molecular dynamics simulations supported the predicted AP5–MMP-2 interaction. Moreover, the ADMET profiling of AP5 showed acceptable intestinal absorption, non-glycoprotein-P substrate status, and reduced hepatic metabolism compared to betulin. However, the ADMET analysis also highlighted some potential toxicity risks such as DILI, genotoxicity, carcinogenicity and skin sensitization that need to be further investigated. Altogether, these promising findings support the further exploration of AP5 as a promising drug candidate for breast cancer in vivo to assess its potency and toxicity. Full article

Serotonin transporter Slc6a4a functions as a transporter in serotonin reuptake and is tightly linked with serotonergic regulation and stress responses. However, few studies have investigated its role in copper homeostasis and organogenesis in an in vivo vertebrate model. In this study, we demonstrate that slc6a4a deficiency (slc6a4a^−/−) leads to copper accumulation, retinal developmental defects, and locomotor dysfunction in zebrafish specifically. Mechanistically, slc6a4a deficiency is associated with reduced atp7b and copper accumulation, which lead to reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress, and results in Caspase-3-mediated apoptosis and retinal degeneration. Specifically, tetrathiomolybdate (TTM), a pharmacological copper chelator, partially reduces ER stress and restores retinal defects. Additionally, ectopic expression of full-length atp7b mRNA partially restores retinal defects. These findings identify serotonin transporter Slc6a4a as a novel regulator in copper homeostasis and retinal development via the regulation of Atp7b in an in vivo vertebrate model. This study supports a mechanistic link between slc6a4a deficiency, copper overload, and retinal defects and highlights copper chelation as an alternative therapeutic strategy in individuals with Slc6a4 deficiency. Full article

Pancreatic cancer remains a highly lethal malignancy, with standard therapies offering limited benefits in advanced stages; thus, novel strategies that exploit specific cancer cell vulnerabilities are urgently needed. Building on our previous findings that nanosecond pulsed electric fields (nsPEF) combined with cold atmospheric plasma (CAP) produce enhanced cytotoxicity, this study investigates the molecular mechanisms underlying this synergy. Pan02 pancreatic cancer cells were subjected to nsPEF, CAP, or a combination of both. We assessed cell viability, reactive oxygen species (ROS) production, and mitochondrial integrity using metabolic assays, flow cytometry, and fluorescence microscopy. Apoptotic markers were evaluated via Western blotting and caspase activity assays. Combined nsPEF–CAP treatment significantly outperformed either modality alone in inducing cell death. Mechanistically, dual treatment triggered a surge in intracellular ROS, particularly mitochondrial superoxide, indicating severe oxidative stress. Distinct mitochondrial responses were observed: nsPEF reduced mitochondrial membrane potential, whereas CAP alone caused a slight elevation. Notably, while CAP induced apoptosis (evidenced by increased cleaved caspase-3 and caspase-3/7 activity), lethal nsPEF (100 pulses) caused cell death without triggering apoptotic signaling. However, mild nsPEF (20 pulses) significantly potentiated CAP-induced apoptosis. These findings suggest that nsPEF sensitizes cells to CAP treatment by amplifying oxidative stress and mitochondrial dysfunction. This synergistic combination represents a promising therapeutic approach for managing pancreatic cancer cells resistant to conventional therapies. Full article

Mitochondrial diseases have traditionally been viewed as energy deficiencies, but current evidence positions mitochondria as central regulators of multiple cell death pathways. This review systematically analyzes the molecular mechanisms of apoptosis and ferroptosis in the context of both primary mitochondrial diseases—caused by mutations in mtDNA or nuclear DNA directly affecting oxidative phosphorylation—and secondary mitochondrial dysfunction associated with broader pathological conditions. Apoptosis is an energy-dependent process characterized by mitochondrial outer membrane permeabilization, cytochrome c release, and caspase cascade activation, whereas ferroptosis involves iron-dependent lipid peroxidation, glutathione depletion, and inactivation of glutathione peroxidase 4 (GPX4), leading to accumulation of oxidized phospholipids predominantly in endoplasmic reticulum and plasma membranes; mitochondrial ultrastructural changes—including volume reduction and cristae loss—represent characteristic morphological features of ferroptosis rather than its primary site of initiation. Key findings reveal that reactive oxygen species overproduction, disruption of reducing equivalent metabolism, iron dyshomeostasis, and calcium overload simultaneously prime cells for both death pathways. Cytochrome c, p53, and BCL-2 family proteins serve as integration hubs, with cardiolipin peroxidation and phospholipid composition influencing pathway switching. Tissue specificity is pronounced in primary mitochondrial diseases: retinal ganglion cells in Leber’s hereditary optic neuropathy, cardiomyocytes in mtDNA-associated cardiomyopathies, and hepatocytes in mtDNA depletion syndromes exhibit distinct dominant death pathways. It should be noted, however, that for many conditions discussed, the evidence for ferroptosis involvement relies on indirect markers—such as lipid peroxidation products, decreased GPX4, and iron deposition—rather than on pharmacological rescue with ferrostatin-1 or liproxstatin-1 and rigorous exclusion of alternative death modalities; this limitation is discussed critically throughout the review. Diagnostic criteria combining morphological, biochemical, and pharmacological tools enable differentiation of death pathways. The review concludes that combined inhibition—using mitochondria-targeted antioxidants, GPX4 modulators, iron chelators, and mPTP blockers—together with personalized diagnostic algorithms offers the most promising therapeutic strategy. Understanding the apoptosis–ferroptosis crosstalk is essential for developing targeted interventions in mitochondrial diseases. Full article

Background: Cisplatin-induced cardiotoxicity is associated with oxidative stress, inflammation, and apoptosis; however, the role of CD38-Sirt3 signaling remains unclear. This study investigated whether apigenin protects against cisplatin-induced cardiac injury via modulation of CD38-Sirt3 signaling. Methods: Male Sprague Dawley rats were assigned to three groups, (1) Control, (2) Cisplatin (5 mg/kg), and (3) Pretreatment with apigenin (50 mg/kg/day) plus cisplatin groups. Then, left ventricular (LV) function, cardiac injury, oxidative stress, inflammation, apoptosis, and CD38-Sirt3 signaling-related proteins were assessed. Results: Cisplatin impaired LV function and induced cardiac injury, oxidative stress, inflammation, and apoptosis in rats. These changes were accompanied by increased cardiac CD38 and decreased cardiac Sirt3 and SOD2 expression. Apigenin significantly improved LV function (%LVEF and %LVFS), reduced cardiac injury (LDH, CK-MB), attenuated oxidative stress, suppressed inflammatory responses (TNF-α, IL-1β, p-NF-κB, TLR-4), and inhibited apoptosis (Bax/Bcl-2, cleaved caspase-3). Notably, apigenin improved cardiac SOD2 expression and reversed the alteration of CD38-Sirt3 signaling in cisplatin-treated rats. Conclusions: This study provides evidence that cisplatin-induced cardiotoxicity is associated with alterations in CD38-Sirt3 signaling. Apigenin attenuated LV dysfunction and cardiac injury, reduced oxidative stress, inflammation, and apoptosis, potentially through CD38-Sirt3 signaling. These findings highlight the cardioprotective potential of apigenin against cisplatin-induced cardiotoxicity. Full article

Background: Obesity is associated with aggressive prostate cancer, but the links between metabolic dysregulation, inflammation, adipocyte-associated signaling, and tumor growth remain incompletely defined. This study examined whether high-fat diet (HFD)-associated systemic changes and adipocyte-derived paracrine interactions are linked to prostate cancer growth in preclinical models. Methods: An HFD xenograft model and adipocyte co-culture systems were used to evaluate systemic and local tumor-supportive features. Pharmacologic/nutritional modulation was tested using green tea or EGCG, arctigenin, and the CCR2 antagonist RS 504393, alone or in combination. Tumor growth, cell proliferation, angiogenesis-related features, circulating metabolic and cytokine levels, and selected tumor-associated signaling proteins were analyzed. Results: HFD feeding was associated with increased circulating free fatty acids, IGF-1, MCP-1, IL-6, and VEGF, together with increased tumor growth, Ki67 staining, and CD31-positive microvessel density. Adipocyte co-culture systems were used to evaluate treatment-associated changes in prostate cancer cell proliferation under adipocyte-associated conditions. Combined modulation with green tea/EGCG, arctigenin, and RS 504393 was associated with greater reductions in adipocyte-associated proliferation, tumor growth, Ki67 staining, and CD31-positive microvessel density than single or dual interventions. Antibody array analysis showed treatment-associated changes in selected stress- and apoptosis-related proteins, including cleaved caspase-7 and phosphorylated Chk1. Conclusions: HFD-associated metabolic and inflammatory alterations, adipocyte-associated interactions, proliferative activity, angiogenesis-related features, and stress/apoptosis-related signaling changes were linked within a tumor-supportive framework in preclinical prostate cancer models. Combined pharmacologic/nutritional modulation was associated with reduced tumor-supportive features under HFD conditions. Further mechanistic and translational validation is needed. Full article