Human & experimental toxicology最新文献

ObjectiveThe study aimed to investigate the role of luteolin in alleviating POF and its underlying molecular mechanisms.MethodsPOF model was established in rats by intraperitoneal injection of 100 mg/kg cyclophosphamide. Then, rats in the treatment group received intragastric administration of with luteolin at doses of 25 mg/kg, 50 mg/kg and 100 mg/kg, respectively. Rats in POF model group were administered the same volume of saline intragastrically. The concentrations of E2, FSH, AMH, P, LH, SOD and MDA in serum were quantified using ELISA kits. H&E and TUNEL staining were employed to assess pathological alterations and apoptosis. The cellular localizations of 4-HNE, 8-OHdG and NTY were detected by immunohistochemistry staining. The PharmMapper database and UbiBrowser prediction were used for the prediction of luteolin interaction with RNF8/HDAC2.ResultsLuteolin treatment significantly increased serum levels of estradiol (E2) (P < 0.01) and anti-Müllerian hormone (AMH) (P < 0.01) while reducing follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels (P < 0.05), restoring ovarian function. Additionally, luteolin could significantly improve ovarian tissue morphology and reduce apoptosis. ELISA kit results indicated luteolin significantly reduced the levels of SOD and MDA. Immunohistochemical staining results revealed a significant decrease in the expressions of 4-HNE, 8-OHdG and NTY in luteolin treatment group. Combining The PharmMapper database and UbiBrowser prediction, we found luteolin could bind RNF8 and inhibit HDAC2 expression.DiscussionLuteolin could mitigate cyclophosphamide-induced ovarian senescence, with its molecular mechanisms involving the regulation of RNF8/HDAC2 signaling axis and the inhibition of oxidative stress.

BackgroundLipopolysaccharide (LPS) is a glycolipid that constitutes the Gram-negative bacteria outermost membrane main portion. LPS is frequently of concern in medicine because of nearly all severe sepsis patients have elevated LPS plasma levels, which cause life-threatening organ dysfunction. Consequently, the potential protective benefit of acriflavine (Ac) in limiting LPS-induced acute inflammatory response and the possible underlying mechanisms were investigated.MethodsMale albino mice were treated with i.p. Ac 4 or 8 mg/kg/day for 2 weeks, then received a single i.p. LPS (10 mg/kg) at day 14.ResultsAc administration ameliorated hepatic, pulmonary, and testicular dysfunction, as confirmed by attenuation of pathological changes and amendment of oxidative stress parameters. This was associated with inhibition of protein kinase R-like endoplasmic reticulum kinase/phosphatidylinositol 3-kinase (PERK/PI3K) endoplasmic reticulum (ER) stress pathway; toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) and active caspase-1/gasdermin D (GSDMD)-N-terminal as well as interleukin-1 beta (IL-1β) inflammatory and pyroptotic signals.ConclusionOur results highlighted the protective potential of Ac in a mouse model of LPS-mediated systemic inflammatory response, which paves the way for its clinical application in sepsis.

IntroductionThis study investigates the skin-irritating and skin-resorptive effects of drilling fluid (DF) through acute and subacute experiments conducted on adult rabbits and sexually mature male and female rats.MethodsAcute and subacute experiments were conducted on adult rabbits and sexually mature male and female rats. The acute experiment involved a single exposure to DF, while the subacute study involved repeated dermal exposure. Various physiological, biochemical, and histopathological assessments were performed to evaluate the effects.ResultsThe results of the acute experiment demonstrated that DF exhibits a mild skin-irritating effect but causes significant irritation to the ocular mucous membranes in rabbits. In the subacute study, dermal exposure to DF led to notable alterations in the physiological and biochemical status of rats, including reduced food and water intake, decreased body weight gain, and significant changes in hematological and biochemical parameters. An increase in the relative count of certain leukocyte populations was observed, with a statistically significant elevation in absolute eosinophil counts in both sexes. Similar trends were observed for basophils and lymphocytes. Moderate elevations in serum enzyme levels (ALT, AST, ALP, GGT, and LDH) indicated systemic toxicity. Morphological and morphometric analysis of the skin further supported the dermal toxicity of DF, revealing epidermal keratinization, marked proliferation of germinative layer cells, and cellular heterotopia. In the basal layer of the epidermis, cells exhibited signs of intracellular edema. The papillary layer showed moderate focal inflammatory infiltrates, while the reticular dermis displayed edema of fibrous structures, swelling of collagen fibers, and increased fiber thickness.DiscussionThese findings collectively demonstrate that the tested drilling fluid possesses significant dermal and systemic toxicity, indicating potential health risks for mammals upon repeated exposure.

IntroductionBardoxolone methyl (Bardo), a Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 pathway activator, has demonstrated efficacy in slowing eGFR decline in diabetic kidney disease (DKD). However, its Phase 3 trial in stage 4 DKD was terminated owing to unexpected cardiovascular complications.MethodsTo explore the underlying mechanisms, the human cardiomyocyte cell line AC16 was subjected to various concentrations of Bardo. Nuclear translocation of Nrf2 and the expression of its downstream antioxidant factors, heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1), were quantified. Cell injury was assessed using microscopy, crystal violet staining, and lactate dehydrogenase release assays. The research employed ferroptosis, apoptosis, and necrosis inhibitors to identify the mechanisms of cell death. Additional analyses included measurements of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), reactive oxygen species (ROS), ferrous ions, and malondialdehyde (MDA), while mitochondrial ultrastructure was evaluated by transmission electron microscopy.ResultsBardo induced dose-dependent Nrf2 activation and increased AC16 cell death, which was attenuated by the ferroptosis inhibitor Ferrostatin-1 (Fer-1) but not by apoptosis or necrosis inhibitors. Mechanistically, Bardo suppressed SLC7A11 and GPX4 expression while elevating ROS, ferrous ions, and MDA levels. Ultrastructural analysis further revealed mitochondrial volume reduction, disrupted cristae, and increased membrane density.DiscussionThese findings establish that Bardo induces ferroptosis in cardiomyocytes, potentially explaining the cardiotoxic effects observed in clinical trials.

ObjectiveTo investigate the mechanism of tumor-associated macrophages (TAM) in the invasive migration of lung adenocarcinoma (LUAD) cells.MethodsThe single-cell sequencing data of lung adenocarcinoma (GSE131907) were initially analyzed. Kaplan-Meier curve analysis, univariate as well as multivariate Cox analysis, and immunofluorescence staining were performed. The analysis of fibroblast-macrophage interactions using Single-cell CellChat revealed their relationship. Subsequently, we screened and validated the target proteins in macrophages that interact with SEMA3C. The effects of these interactions on lung cancer cell migration and invasion were evaluated in vitro through Western blot analysis to assess phenotypic changes in macrophages, as well as through Transwell migration and invasion assays.ResultsSEMA3C was predominantly expressed in fibroblasts of patients with high-grade lung adenocarcinoma at high levels. SEMA3C exhibited independent prognostic significance in determining the overall survival outcome among individuals diagnosed with lung adenocarcinoma. Lung adenocarcinoma fibroblasts had elevated SEMA3C. CellChat demonstrated enhanced interactions between TAM as well as T cells. A high expression of vascular non-inflammatory molecule 1 (VNN1) in fibroblast macrophages during Stage II-III, and this elevated VNN1 was also an independent prognostic factor. The interaction between cancer-associated fibroblasts (CAFs) and VNN1 on macrophage membranes mediated by SEMA3C. Furthermore, these experiments demonstrated that SEMA3C regulates the polarization of TAM through VNN1, thereby influencing lung cancer.ConclusionThe phenotype of TAM is regulated by SEMA3C, which in turn influences the migration as well as invasion of lung cancer cells through VNN1.

IntroductionMethanol toxicity is a significant health concern with potentially severe outcomes. This study aimed to investigate the prognostic factors of patients with methanol toxicity referred to Tabriz Sina Hospital.MethodsA descriptive-analytical retrospective study was conducted in methanol toxicity patients admitted in Tabriz Sina Hospital since 2019 to 2021. Demographic characteristics and management methods were extracted from the patients' medical records.ResultsPatients were predominantly male (91.3%) with a median age of 30-40 years. Winter accounted for 48.7% of cases. Coma (OR = 8.0, 95% CI: 3.2-19.9) and arrhythmia (OR = 5.5, 2.0-15.1) at admission, pH <7.1 (OR = 4.2, 2.0-8.9), elevated creatinine (OR = 1.3/mg/dL, 1.1-1.6), opiate co-use (OR = 2.8, 1.2-6.5), and delayed ethanol therapy (>3 h, OR = 2.3, 1.1-4.8) independently increased mortality risk. Bicarbonate, Eprex, and methylprednisolone reduced complications. Time from ingestion to admission (48-72 h) did not affect mortality, but delayed hemodialysis initiation worsened outcomes.ConclusionEarly presentation and providing early therapeutic modalities have a significant impact on the mortality rate and the patients' outcome.

IntroductionOral carcinoma cancer exhibits high global incidence and mortality. Physalin A (PA) was reported to induce programmed cell death in cancer cells. No study has yet investigated the influence of PA in oral squamous cell carcinoma. Herein, this study aims to explore PA-induced anti-cancer effects in human oral carcinoma.MethodsThis study used DNA gel electrophoresis and Annexin V/PI staining to detect DNA fragmentation and cell apoptosis. Western blotting and immunofluorescence analyzed protein expression. Flow cytometry measured Ca²⁺ release and mitochondrial membrane potential (∆Ψm). Moreover, molecular docking models predicted the molecular binding affinity.ResultsDNA gel electrophoresis and annexin V/PI staining confirmed PA-induced DNA fragmentation and apoptosis. Flow cytometry showed PA increased Ca²⁺ release and reduced ∆Ψm levels. PA activated cleaved caspase-3, -8, and -9, upregulated Bax and Bid, and downregulated Bcl-2. PA dose-dependently increased Fas (CD95/APO-1), apoptosis-inducing factor (AIF), and cytochrome c release in western blotting analysis. Confocal microscopy confirmed increased Bax, AIF, cleaved caspase-3, and Fas, with decreased Bcl-2. Molecular docking showed strong PA binding via hydrophobic interactions with the Fas-associated death domain (FADD). Compared with cisplatin, PA inhibited HSC-3 cell xenograft tumor growth in NOD/SCID mice.DiscussionWe reveal that PA binds to the Fas-FADD complex, inducing caspase-8 activation and triggering extrinsic and intrinsic mitochondria-dependent apoptosis in HSC-3 cells. It also suppresses HSC-3 cell xenograft tumors in NOD/SCID mice. These findings suggest PA as a potential anti-oral cancer agent in the future.

Introduction: Tamoxifen (TMX) shows promise in treating breast cancer, but it faces challenges such as poor solubility, instability, and incomplete release when targeting tumors. Additionally, TMX therapy's toxicity is a critical issue in breast cancer treatment. This study aimed to assess the impact of hyaluronic acid (HA)-coated TMX-loaded solid lipid nanoparticles (HA-TMX-SLNs) on MCF7 breast cancer cells.

Methods: Solid lipid nanoparticles (SLNs) were prepared using hot homogenization. The HA-TMX-SLNs and TMX-SLNs were characterized and evaluated through transmission electron microscopy (TEM). Cytotoxicity was assessed using the MTT assay, and Western blot analysis was utilized to identify key factors in the cell cycle and apoptosis.

Results: The nanoparticles (HA-TMX-SLNs) demonstrated approximately 55% loading efficiency after 100 h. HA-TMX-SLNs exhibited lower cytotoxicity in MCF7 cells compared to other treatments. Significant decreases in expression levels of cyclin-dependent kinase (CDK) 4, Cyclin D1, CDK2, and Bcl2 were observed after treatment with HA-TMX-SLNs, along with an increase in cleaved/procaspase-7.

Discussion: The in vitro release study showed that HA-coated SLNs consistently released the drug into the media under controlled conditions. Furthermore, HA-TMX-SLNs exhibited cytotoxic effects, increasing apoptosis and inhibiting cancer cell proliferation. These findings suggest that HA-TMX-SLNs effectively deliver TMX to breast cancer cells.

IntroductionAccurate determinations of the cause of death are crucial for public health, crime investigations, and social justice. In the Netherlands, cause-of-death determinations rely heavily on external examinations, which can miss substance-related deaths. This study investigates the added value of toxicological blood testing in the determination of the cause and manner of death by forensic physicians in the Netherlands.MethodsCollected blood samples of 642 decedents that were examined by a forensic physician in Amsterdam and surrounding regions underwent toxicological testing. Findings and concluding remarks from the external examination and toxicological testing were compared using descriptive statistics.ResultsBlood samples of 69% of cases tested positive for one or more pharmaceuticals, and 36% tested positive for illicit drugs and/or alcohol. In 55% of cases, toxicological testing revealed substances that were not indicated by the external examination. Its findings also prompted a revision of the initial cause and manner of death in 18 cases (3%).DiscussionKey limitations in this study include that not all detected substances were quantified and a verification bias of the included cases, which may have led to an underrepresentation of unsuspected detections. Nonetheless, despite the constraints of (routine) screening capabilities and the effects of post-mortem degradation and redistribution, this study presented the importance of toxicological blood testing within a multifaceted approach that combines toxicological findings with scene evidence, medical history and the external examination, which is essential for improving the accuracy of cause-of-death determinations by the forensic physician.