With the advances in molecular diagnostics and newer treatment approaches, the overall survival and quality of life of patients have increased significantly. However, many anticancer drugs often cause ovarian damage or toxicity, leading to premature ovarian insufficiency, infertility, and serious long-term psychosocial issues, making oncofertility an unmet need in current oncology practice. This manuscript addresses questions such as, "What are the molecular pathways of anticancer drug-induced ovarian toxicity in reproductive-aged females and their clinical applications?" and "How do oncofertility care models and regulation frameworks support fertility preservation in clinical oncology?" Our goal is to provide a clear, comprehensive understanding of how major classes of anticancer drugs cause ovarian damage and to identify potential interventions to improve overall quality of life. From 2770 records, 52 studies were included. Mechanistic evidence shows distinct pathways: alkylating agents trigger oocyte apoptosis through TAp63α activation; platinum drugs and anthracyclines cause mitochondrial dysfunction and oxidative stress; and taxanes interfere with oocyte meiotic spindles. Clinically, this results in measurable loss of ovarian reserves like anti-Mullerian hormone (AMH) and antral follicle count (AFC), and decreased oocyte quality. Existing fertility preservation strategies, such as oocyte/embryo and ovarian tissue cryopreservation, are effective, and gonadotropin-releasing hormone (GnRH) agonists may offer additional protection. Ovarian toxicity from anticancer drugs represents a significant, drug-specific survivorship challenge. Understanding these mechanisms is crucial for risk assessment. To minimize the long-term impact on patients' quality of life, it is essential to incorporate proven fertility-preservation techniques into routine oncology care.
Human exposure to environmental pollutants is multi-variant with resultant interactive effects such as oxidative stress, and it's associated with several disease pathogenesis. This study aimed to assess the effects on behavioural pattern, redox status, mitochondrial metabolic rate, and possible alterations in the gut, fat body, and ovary tissues in Drosophila melanogaster exposed to N-methyl-N-nitrosourea (NMU) and Benzo[a]pyrene (BaP). The fruit flies, 1-3 days old, were distributed into the Control group, which received a [methanol and ethanol mixture (1:7)]-containing diet, and other groups received diets containing NMU (1 and 2 mM) and BaP (0.4 and 0.8 mM) for 5 days. Results showed that NMU and BaP exposure caused a significant decrease in the rate of survival of the flies. Altered behavioral pattern was observed as an eclosion rate (78%,) and the locomotor capacity was decreased. NMU and BaP caused a reduction in mitochondrial metabolic rate, and levels of total H2O2, NO, lipid peroxidation, and protein carbonyl content were observed to increase significantly; however, the total sulfhydryl and Non-protein thiols, as well as the activities of catalase, glutathione-s-transferase, and acetylcholinesterase, were decreased relative to control. Histo-architecture of gut, fat body, and ovarian tissues was negatively altered, alongside phenotypic changes such as enlargement of the eyes and abnormal morphology of the ovaries. Taken together, NMU and BaP induced toxicity via oxidative stress and disruption of redox status, behavioural deficits, and developmental abnormalities, suggesting Drosophila melanogaster as a suitable organism for assessing the toxicity of environmental carcinogens.
This study was carried out to evaluate the therapeutic efficacy of Neocuproine/Trolox treatment on chronic neuropathy induced by Chronic Constriction Injury (CCI). Rats (n = 40) were grouped as Sham, CCI, CCI+Trolox, and CCI+Neocuproine. Rats with proven neuropathy were given 80 mg/kg/day (i.p.) Trolox and 100 μM/day (i.p.) Neocuproine for 7 days. Open field and tail withdrawal tests were conducted at baseline and on days 7 and 14. ELISA test was employed in analyzing IL 1β, IL 10, TNF-α, and TGF-β levels in spinal cord and cortex tissues of rats. To explore potential mechanistic interactions, molecular docking was conducted with the key cytokine receptor. On day 14, a significant decrease in total path taken, number of frames entered, and delay values were observed in CCI group compared to the control, whereas significant increases were observed in total path taken, number of frames entered, and delay values in the CCI+Neocuproine/Trolox treatment groups compared to CCI group (p < 0.05 for all). Docking analyses were performed for Neocuproine/Trolox. In comparison to the sham group, IL‑1β and TNF-α levels in spinal cord and cortex tissues were higher, while IL‑10 and TGF-β levels were lower (p < 0.05). Neocuproine/Trolox treatments reduced proinflammatory cytokine levels and elevated anti-inflammatory cytokine levels in CCI rats on day 14 (p < 0.05 for all). Considering the docking score of Neocuproine/Trolox, high scores were observed, especially with TNF-α and TGF-β receptor. The results suggest that Neocuproine/Trolox treatments induce thermal anti-hyperalgesic behaviors in CCI-induced pain, showing significant improvements in locomotor activity, and achieve these by reducing the production of proinflammatory cytokines and elevating that of anti-inflammatory cytokines.
Nephrotoxicity is a major clinical challenge, often triggered by chemotherapeutic agents, environmental toxins, and metabolic imbalances. Its underlying mechanisms-oxidative stress, inflammation, mitochondrial dysfunction, and apoptosis-can lead to irreversible kidney damage. Current treatments offer limited molecular protection, underscoring the need for novel strategies. Quercetin, a bioactive flavonoid abundant in fruits and vegetables, has demonstrated promising nephroprotective properties due to its antioxidant, anti-inflammatory, and anti-apoptotic activities. This review aims to synthesize recent findings on therapeutic role of quercetin in preventing or mitigating nephrotoxicity. A literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar to identify in vitro, in vivo, and clinical studies published between 2021 and 2025 that explored the effects of quercetin on nephrotoxicity. Quercetin enhances renal function by lowering serum creatinine and urea, restoring antioxidant enzymes (SOD, CAT, GPx), and reducing lipid peroxidation. It activates the Sirt1/Nrf2/HO-1 axis to stabilize mitochondria and redox balance, while suppressing NF-κB and pro-inflammatory cytokines (TNF-α, IL-6). Quercetin also engages MAPK/ERK and AKT1 pathways to support cell survival, regulates apoptosis via Bax/Bcl-2 and caspase inhibition, and promotes autophagy through Beclin 1, LC3β, and TFEB activation. These combined effects preserve renal architecture, reduce fibrosis, and improve histological outcomes. Quercetin offers a multi-targeted approach to renal protection, integrating antioxidant, anti-inflammatory, anti-apoptotic, and autophagic mechanisms. Its modulation of key signaling pathways positions it as a strong candidate for adjunctive nephroprotective therapy. Future studies should focus on improving its bioavailability, assessing long-term safety, and exploring synergistic applications in clinical settings.
This study investigated the neurobehavioral toxicity of Acetamiprid (ACP), a neonicotinoid insecticide, in male rats and evaluated the potential neuroprotective effects of Resveratrol (RSV), a natural antioxidant found in grapes and peanuts. Forty rats were divided into four groups (Control, ACP 25 mg/kg, RSV 20 mg/kg, and ACP + RSV) and treated orally for 90 days. Assessments included behavioral testing for anxiety and cognition, biochemical analysis of oxidative stress and inflammatory markers (GSH, CAT, MDA, TNF-α), and gene expression profiling of the Pi3k/Akt/BDNF pathway and p38 Mapk and Nbn genes. Histopathological and Tau immunostaining examinations were also conducted. ACP exposure significantly induced anxiety-like behavior and cognitive impairment. The ACP group exhibited marked oxidative stress, apoptosis, and elevated inflammatory marker. ACP altered the expression of genes associated with neuronal survival and repair. Histology confirmed neurodegeneration, necrosis, and gliosis across various brain regions. While ACP causes neurological and oxidative damage, co-treatment with RSV maintains neurobehavioral function and mitigates cellular injury, suggesting its efficacy as a protective agent against ACP-induced neurotoxicity.
Sepsis is characterized as an aberrant and dysregulated physiological reaction to infection, resulting in severe and potentially fatal organ impairment. Globally, it poses a substantial public health burden, with nearly 48.9 million incidents and 11 million deaths annually. The core mechanisms of sepsis involve a cascade of systemic inflammation and dysregulation of the immune response, initiated by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Critical signaling pathways, such as TLR4, NF-κB, MAPK, JAK/STAT, and PI3K/Akt, drive the overproduction of inflammation-promoting molecules, oxidative damage, and organ harm. To obtain the necessary information, we searched the PubMed and Web of Science databases using the keywords sepsis, signal transduction pathway, and NF-κB-MAPK-PI3K/Akt-JAK/STAT-TLR-4. We primarily used articles published in the last 5 years. Focusing on these pathways offers potential treatment options to reduce the exaggerated inflammatory reaction and restore balanced immune function. Timely identification, tailored strategies, and the discovery of innovative biomarkers are essential for managing sepsis. This review explores the molecular pathways underlying the development and progression of sepsis.
Zingerone (Zin) exhibits multiple pharmacological properties, including anti-inflammatory, immunomodulatory, anxiolytic, anti-thrombotic, radioprotective, and antimicrobial activities. However, the therapeutic potential of Zin in coronary artery atherosclerotic heart disease (CHD) remains unexplored. This study aims to elucidate the role and underlying molecular mechanisms of Zin in CHD treatment. Putative Zin targets associated with CHD were identified through online database screening followed by functional enrichment analysis. Core target genes were screened using Protein-protein interaction (PPI) Network analysis, machine learning algorithms, molecular docking, and molecular dynamics simulations. Protein expression was examined using western blot. The levels of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) were detected using detection kits. The senescence of cells was analyzed using senescence-associated β-galactosidase (SA-β-gal) staining kits. Zin was predicted to target several core genes, including v-akt murine thymoma viral oncogene homolog 2 (AKT2), heat shock protein 90α family class B member 1 (HSP90AB1), nuclear receptor subfamily 3 group C member 1 (NR3C1), forkhead box O1 (FOXO1), and toll-like receptor 4 (TLR4), potentially contributing to the alleviation of CHD. Furthermore, molecular docking and molecular dynamics simulation predicted a stable binding interaction between Zin and HSP90AB1. Zin ameliorated ox-LDL-stimulated inflammation, an effect that was associated with downregulation of HSP90AB1. Furthermore, Zin alleviated ox-LDL-induced senescence and apoptosis in a manner correlated with reduced HSP90AB1 levels in vitro. Zin suppresses inflammation, senescence, and apoptosis of oxidized low-density lipoprotein-induced primary human coronary artery endothelial cells in a manner associated with HSP90AB1 silencing. These findings provide a foundation for the further development of Zin-based treatment strategies for CHD.
The present investigation evaluated the liver-protective effect of apigenin encapsulated in PEGylated chitosan nanoparticles (APG-PCHNPs) against hepatotoxicity induced by pesticide deltamethrin (DLM) in rats. Sixty rats were randomly allocated into six groups: a control group, groups treated with APG (20 mg/kg BW) or APG-PCHNPs (20 mg/kg BW), a group exposed to DLM (5 mg/kg BW), and two combination treatment groups receiving DLM (5 mg/kg BW) plus either APG or APG-PCHNPs at 20 mg/kg BW for 35 days. DLM administration significantly decreased serum total protein and its fractions. Simultaneously, hepatic enzyme activities, C-reactive protein, and total bilirubin concentrations were significantly elevated. DLM exposure induced oxidative damage by lowering the activity of vital antioxidant enzymes, including catalase, superoxide dismutase, and glutathione peroxidase, reducing levels of reduced glutathione, and elevating malondialdehyde as a marker of lipid peroxidation. The observed biochemical alterations coincided with a significant increase in the expression of the apoptotic genes Bax and caspase-3, while the expression of the anti-apoptotic gene Bcl-2 was markedly reduced. Additionally, the pro-inflammatory mediators nuclear factor kappa B, tumor necrosis factor alpha, interleukin-6, and DNA oxidative damage biomarkers (8-OHdG) were significantly elevated in the liver following exposure to DLM. APG-PCHNPs provided markedly better protection than crude APG against DLM-induced hepatic damage (p < 0.05). This was evidenced by restored liver enzyme levels, improved antioxidant enzyme activities, reduced liver inflammation, decreased oxidative stress-induced apoptosis, and the reversal of histological and ultra-structural damage, with outcomes nearly comparable to controls. Docking studies revealed a high affinity of APG for key proteins regulating antioxidant activity, apoptotic pathways, and inflammatory responses. In conclusion, APG-PCHNPs provided superior protection against DLM-induced liver injury by enhancing antioxidant defenses, suppressing NF-κB-mediated inflammation, and modulating Bcl-2/Bax/Caspase-3 signaling to prevent apoptosis, outperforming crude APG due to improved stability, solubility, and bioavailability.
Cyclophosphamide, a commonly used alkylating chemotherapeutic, induces acute multiple organ injury through oxidative stress, inflammation, and redox imbalance. The present study identifies oxidative signalling as a key mechanism of cyclophosphamide-mediated liver, kidney, and brain injury and evaluates dose-dependent protective effects of ellagic acid, a natural dietary polyphenol. Male Wistar rats were orally pretreated with ellagic acid (10, 20, 30, and 40 mg/kg) for 6 days before receiving a single intraperitoneal dose of cyclophosphamide (200 mg/kg) on Day 6 to reliably induce multiple organ injury within 24 h. Animals were euthanized 24 h after administration of the last dose of cyclophosphamide for serological, tissue biochemical, and histological assessments. Cyclophosphamide significantly altered liver and kidney function markers, increased lipid peroxidation, and depleted antioxidant enzyme activities, confirming oxidative stress-driven injury. Severe deformities in the tissue architecture of liver, kidney, and brain were also evident after exposure to cyclophosphamide. Ellagic acid markedly restored antioxidant defense system, normalized biochemical indices, and preserved tissue integrity in a dose-dependent manner. These findings revealed mechanistic interplay between oxidative stress and systemic injury and demonstrated that ellagic acid effectively mitigates adverse effects of cyclophosphamide-induced multiple organ injury.
The myocardial protective effect of sevoflurane (Sev) has been confirmed, but its potential molecular mechanism remains not fully elucidated. To unravel the functional contribution and mechanistic basis of miR-300, its involvement in sevoflurane-elicited cardioprotection against myocardial hypoxia/reoxygenation (H/R) injury was probed in the present investigation. AC16 cardiomyocytes were preconditioned with Sev at concentrations of 0.5%, 1.0%, and 1.5%, followed by H/R treatment. miR‑300 and HMGB1 expression were quantified by qRT‑PCR. CCK-8 and flow cytometry were employed to evaluate cell proliferation and apoptosis, respectively. ELISA was used to quantify the expression of myocardial injury-related markers and inflammatory cytokine profiles. Commercial kits were applied to detect oxidative stress indicators (MDA, SOD, and CAT). miR‑300 directly targets HMGB1, as confirmed using dual‑luciferase reporter analysis. With the extension of hypoxia time, miR-300 expression in cardiomyocytes gradually decreased, and Sev preconditioning could inhibit this downregulation trend. Sev preconditioning significantly attenuated H/R-elicited loss of cellular viability, elevation of apoptotic levels, myocardial injury exacerbation, alongside inflammatory response generation and oxidative stress induction. Downregulation of miR-300 significantly weakened the myocardial protective effect of Sev. miR-300 could directly target HMGB1. HMGB1 knockdown abolished the impairment of Sev‑mediated cardioprotection caused by miR‑300 downregulation. miR-300 modulates the cardioprotective effect of sevoflurane preconditioning on myocardial injury by regulating HMGB1 expression, which may provide a new theoretical reference for the research of cardiovascular ischemia/reperfusion injury.
Oxaliplatin (OXI), a platinum-based chemotherapeutic agent commonly used in colorectal Cancer treatment, has been linked to significant nephrotoxicity involving apoptosis, endoplasmic reticulum (ER) stress, inflammation, oxidative stress, and autophagy. This study investigated the potential mechanisms involved in kidney damage caused by OXI and explored the renoprotective effects of lycopene (LP) in renal tissues of rats. Biochemical analyses revealed that OXI administration led to elevated serum urea and creatinine levels, increased lipid peroxidation (MDA), and decreased antioxidant defense (SOD, CAT, GPx, GSH), accompanied by suppression of the Nrf-2/HO-1 pathway. Inflammatory markers such as NF-κB, IL-1β, COX-2, TNF-α, and iNOS were significantly upregulated, along with ER stress-related genes (GRP78, ATF6), apoptotic markers (p53, Bax, Bcl-2), and key mediators of autophagy (Beclin-1, JNK). Additionally, Western blot and immunohistochemistry results indicated increased expression of AKT, mTOR, and PI3K proteins in the OXI group, suggesting altered survival signaling. LP treatment ameliorated these pathological alterations by restoring antioxidant enzyme activities, downregulating proinflammatory and proapoptotic signals, mitigating ER stress and autophagy activation, and reducing PI3K/AKT/mTOR protein expression. These findings demonstrate that LP exerts a renoprotective effect against OXI-induced kidney injury through multi-targeted molecular mechanisms, including modulation of inflammation, oxidative stress, autophagy, apoptosis, and survival signaling pathways.
Acrolein (AC) is a potential environmental contaminant that poses a serious threat to human health and the environment. Studies on human diseases that can result from AC have rapidly increased in recent years. Pycnogenol (PYC), a natural phenolic compound, has therapeutic and protective potential against some cancers. Currently, there is insufficient data on the potential effects of AC and PYC on pancreatic cells or on their interaction. Because toxicological effects of AC and interactions between AC and PYC in human pancreatic cells have not yet been investigated, we evaluated the toxicological profile of AC and possible protective effect of PYC on healthy human pancreatic cells (hTERT-HPNE). Our results showed that AC (25, 50, and 100 µM) increased cytotoxicity and oxidative stress, induced apoptosis and DNA single- and double-strand breaks, whereas it decreased mitochondrial membrane potential and antioxidant parameters in human pancreatic cells. Combined treatments with AC and PYC (100 µg/mL) improved these parameters compared to AC treatment alone. Therefore, our results suggest that PYC may have a protective effect against AC-induced damage. Our results may also be particularly important for identifying the factors involved in the pathogenesis of mitochondrial diseases, which have rapidly increased in recent years, and for providing preventive solutions.
Renal failure emerges as a more often cause and concern of chronic kidney disease (CKD), throughout the world. Glycogen synthase kinase-3β (GSK-3β) is the most important regulatory protein in CKD. It is a regulator of the main signaling pathways of fibrosis, inflammation, oxidative stress and apoptosis. These are the common pathways for CKD progression. Therefore, GSK-3β is a potential therapeutic target. This review explores and examines the important role of GSK-3β in CKD. It highlights the influence of numerous phytocompounds, usually possessed by medicinal plants as secondary metabolites, on CKD. The main aim primarily lies on pathways associated with antioxidative, anti-inflammatory, antiapoptotic, and antifibrotic actions, specifically exploring how they are interconnected with GSK-3β. Furthermore, it explores numerous downstream signaling molecules of GSK-3β, which play a substantial role in the aforementioned pathways. In conclusion, the GSK-3β pathway displayed its potential role in nephrotoxicity and CKD progression. Phytocompounds inhibiting the GSK-3β pathway downstream could offer the nephroprotection.
Diabetes mellitus exerts a deleterious effect on the male reproductive system, manifesting as a metabolic disease. Recent research has indicated that the ingestion of dietary supplements rich in natural antioxidants may reduce or prevent damage to the male reproductive system in cases of diabetes-induced infertility. This study investigated the effects of zingerone on diabetes-induced reproductive damage in male rats by analyzing the Sirt1/Nrf2/HO-1 signaling pathway, apoptosis, sperm quality, and histopathological changes. Seventy-five male Sprague Dawley rats, weighing between 250 and 300 g and aged 10 to 12 weeks, were divided into six groups. These included: control; zingerone (50 mg/kg); zingerone (100 mg/kg); diabetes; diabetes with zingerone (50 mg/kg); and diabetes with zingerone (100 mg/kg). Diabetes was induced via a single intraperitoneal injection of 55 mg/kg streptozotocin. Zingerone was given daily by oral gavage for a duration of 8 weeks. Results showed that zingerone significantly reduced glucose, MDA levels, and the Bax/Bcl-2 ratio, while markedly enhancing body weight, testosterone, GSH content, GSH-Px and CAT enzyme activity, and the expression of Sirt1, Nrf2, and HO-1. Additionally, it had a beneficial impact on spermatological parameters and histopathological findings in diabetic rats. The findings from this study, obtained from both healthy and diabetic rats, are consistent with each other, thereby providing a reliable basis for the conclusions drawn. Thus, incorporating zingerone into prophylactic regimens for healthy rats and therapeutic interventions for diabetic conditions may be advisable. Furthermore, combination drug therapies including zingerone may offer a viable approach to mitigating the toxic effects associated with certain drugs and to combating diabetes-related infertility. Consequently, it was concluded that zingerone ameliorates diabetes-induced damage to the male reproductive system, with 100 mg/kg zingerone demonstrating superior efficacy.
Atherosclerosis, a major complication of diabetes mellitus, involves complex metabolic and inflammatory disruptions that remain inadequately addressed by current therapies. Ferulic acid (FA), a plant-derived polyphenol, possesses antioxidant and anti-inflammatory characteristics, yet its role in diabetic atherosclerosis remains underexplored. In the current study, we explore the anti-atherosclerosis effects of FA against diabetes-induced atherosclerosis in rats. Forty male Wistar rats received a high-fat diet, streptozotocin, and vitamin D3 to induce atherosclerosis. Rats were divided into control, atherosclerotic, and treated with FA (50 mg/kg, daily for 7 weeks as preventive and 3 weeks as therapeutic) or rosuvastatin (5 mg/kg, daily for 7 weeks). Body weight, biochemical, molecular, and histopathological analyses were conducted. Atherosclerotic rats exhibited significant hyperglycemia, dyslipidemia, inflammation, and vascular injury. FA administration obviously improved body weight, fasting and postprandial glucose levels, lipid profile, and cardiovascular indices. Moreover, FA significantly reduced serum oxLDL, MDA, and NO levels, while it significantly increased serum activities of both SOD and GPX, besides GSH levels. FA treatment significantly downregulated NF-κB p65, iNOS, and MMP-9 aortic protein levels. Additionally, serum pro-inflammatory cytokines (TNF-α and MCP-1) were reduced, while serum levels of anti-inflammatory IL-10 were improved in FA-treated atherosclerotic rats. Serum miR-27 and miR-29 expression levels were significantly modulated after treatment with FA. The overall results suggested that FA confers multi-targeted protection against diabetic atherosclerosis through modulation of metabolic, oxidative stress, inflammatory, and epigenetic pathways. These findings highlight its potential as a complementary or preventative approach in the management of vascular diseases associated with diabetes.
Oral cancer still poses a serious threat to world health and has limited feasible remedies. Recently, Alpha-tomatine (AT), a naturally occurring glycoalkaloid, has attracted attention due to its possible anticancer effects. The study investigates its cytotoxic and apoptotic impact of AT against KB human oral carcinoma cells and examine its role in regulating molecular mechanism, with an emphasis on oxidative stress and DNA damage-mediated apoptosis. The MTT assay for cytotoxicity of AT against KB cells showed an IC50 of 11.8 µM. The DCFH-DA staining technique was used to measure ROS formation, and the results indicated a notable, concentration-dependent rise in ROS levels. AO/EtBr and DAPI staining determined the apoptotic morphological alterations, and the comet assay measured the DNA damage of treated cells. Western blot analysis showed a significant downregulation of the anti-apoptotic protein Bcl-2 and an elevation of pro-apoptotic markers include p53, Bax, caspase-3, and caspase-9. Overall, the data indicates that AT triggers apoptosis in KB cell lines by promoting ROS production, p53 activation, and mitochondrial-mediated pathways, leading to DNA fragmentation and caspase-dependent apoptosis. According to these results, AT could serve as a promising candidate or anticancer agent for oral cancer.
2-Ethylhexyl diphenyl phosphate (EHDPHP) is a widely used organophosphorus flame retardant frequently detected in environmental matrices and poses potential health risks. However, its cardiotoxic effects on mammalian cardiomyocytes and the underlying molecular mechanisms remain largely unclear. Niacin (NIA), an essential water-soluble vitamin, exhibits potent antioxidant, anti-inflammatory, and mitochondrial-protective activities. In this study, we investigated EHDPHP-induced toxicity in H9C2 cardiomyocytes and the protective effects of NIA. Cells were exposed to 100 μM EHDPHP alone or in combination with 400, 600, and 800 μM NIA. EHDPHP exposure significantly reduced cell viability, disrupted the balance between pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-18) and the anti-inflammatory cytokine IL-10, and induced oxidative stress, as evidenced by elevated ROS, MitoSOX, and MDA levels alongside decreased activities of antioxidant enzymes (SOD, GSH, GSH-Px, and CAT). Additionally, EHDPHP disturbed mitochondrial dynamics by promoting fission and inhibiting fusion, impaired mitochondrial biogenesis via downregulation of AMPK and PGC-1α, triggered excessive mitophagy through PINK1, PRKN, and LC3 upregulation, and activated pyroptosis via GSDMD, NLRP3, and Caspase-1. Bioinformatics analyses confirmed the interconnected regulatory network among mitochondrial dynamics, mitophagy, pyroptosis, and inflammatory signaling in EHDPHP-induced cardiomyocyte injury. Notably, NIA intervention dose-dependently mitigated these detrimental effects, restoring cell viability, alleviating inflammation and oxidative stress, rebalancing mitochondrial fusion and fission, rescuing biogenesis, normalizing mitophagy, and inhibiting pyroptosis. These findings reveal a pathological cascade through which EHDPHP induces cardiomyocyte injury and demonstrate that NIA confers cardioprotection by targeting multiple pathological pathways. This study provides novel mechanistic insights into EHDPHP-induced cardiotoxicity and highlights NIA as a promising nutritional intervention for reducing cardiovascular risks associated with environmental pollutants.
Endometriosis is an estrogen-dependent disorder characterized by ectopic growth of endometrial tissue. There is a lack of effective biomarkers for early detection and revealing mechanisms of endometriosis. CSNK2A1 is a compositionally active serine/threonine protein kinase that exerts its role by phosphorylating a variety of substrates, however, the role and mechanism of CSNK2A1 in endometriosis progression is still unclear. The aim of this study was to uncover the role of CSNK2A1 in endometriosis and elucidate the relevant mechanisms. Herein, we found CSNK2A1 is highly expressed in endometriosis. Its depletion inhibited the activity of ectopic endometrial stromal (ESC) cells. Further, knocking down of CSNK2A1 restrained the motility of ESC cells, and its ablation contributed to the autophagy of ESC cells. Mechanically, the depletion of CSNK2A1 blocked the PI3K/Akt/mTOR pathway in ESC cells. In summary, CSNK2A ablation inhibited the viability, autophagy, proliferation and invasion of ectopic endometrial stromal cells via targeting PI3K/Akt/mTOR pathway.
Diphtheria toxin (DT) has been reported to exhibit cytotoxic effects in several cancer models; however, the molecular mechanisms underlying its apoptotic activity remain incompletely understood. In our previous study, DT was shown to induce cytotoxic and apoptotic responses in HT-29 colorectal cancer cells, characterized by the upregulation of pro-apoptotic genes and suppression of anti-apoptotic signaling. Building on these findings, the present study aimed to explore the potential molecular context underlying DT-induced transcriptional alterations using computational and bioinformatic approaches. Molecular protein-protein docking was performed to evaluate the possible interaction between DT and the anti-apoptotic protein Bcl-2. In parallel, previously obtained qRT-PCR gene expression data from HT-29 cells were reanalyzed to assess coordinated transcriptional responses associated with DT exposure. Network analysis using the STRING database indicated that DT-responsive genes form a functionally connected interaction network associated with apoptosis, cellular stress responses, and cell-cycle regulation. Principal component analysis and hierarchical clustering confirmed consistent differences in gene expression patterns between treated and control samples. Docking results suggested a potential interaction between DT and the BH3-binding groove of Bcl-2, supported by hydrogen bonding and hydrophobic contacts. Pathway enrichment analyses further linked the analyzed genes to apoptosis-related pathways, including FoxO and p53 signaling. Collectively, these findings provide an integrated framework suggesting that DT-induced cytotoxicity in HT-29 cells may involve coordinated transcriptional responses and potential structural interaction with Bcl-2, highlighting regulatory networks associated with apoptosis, cellular stress, and cell-cycle control.
Occupational exposure to chemical solvents and heavy metals among workers in textile-related industries has emerged as a significant risk factor for male reproductive dysfunction; however, the underlying biological mechanisms remain incompletely understood. Oxidative stress has been proposed as a key mediator linking occupational exposure to impaired sperm morphology and function. This study aimed to evaluate the association between occupational exposure to chemical solvents and toxic metals and alterations in sperm function, with particular emphasis on oxidative stress-mediated pathways. In this case-control study, semen samples were collected from teratozoospermic men occupationally exposed to chemical solvents and heavy metals (n = 60) and from age-matched normozoospermic controls without known occupational exposure (n = 30). Standard seminal parameters were assessed according to WHO guidelines. Oxidative stress status was evaluated by measuring reactive oxygen species (ROS) and malondialdehyde (MDA) levels, along with antioxidant defense markers, including superoxide dismutase (SOD), catalase, and reduced glutathione (GSH). Sperm functional integrity was assessed through acrosome integrity assays and sperm DNA fragmentation (SDF), evaluated using the comet assay and flow cytometry. Levels of toxic metals (cadmium, lead, and chromium) were quantified using atomic absorption spectrophotometry. Occupationally exposed teratozoospermic men exhibited significantly elevated oxidative stress markers, with increased ROS levels (32.0 ± 9.0 vs. 15.0 ± 5.0) and MDA concentrations (4.8 ± 1.1 vs. 2.1 ± 0.6 nmol/mL), accompanied by a marked reduction in antioxidant defense markers (SOD, catalase, and GSH; p < 0.05) compared with controls. The proportion of acrosome-intact spermatozoa was significantly lower in exposed men (38.3% ± 9.2% vs. 62.4% ± 10.1%). Both comet assay and flow cytometric analyses demonstrated significantly higher levels of sperm DNA fragmentation in the exposed group. Furthermore, quantitative analysis revealed significantly elevated body burdens of cadmium, lead, and chromium among occupationally exposed individuals. These findings indicate that oxidative stress represents a central pathophysiological mechanism linking occupational exposure to chemical solvents and heavy metals with sperm functional impairment and teratozoospermia. The results underscore the importance of routine reproductive health surveillance and oxidative stress monitoring among workers in high-risk occupational settings.