Introduction The immunoproteasome is integral to endothelial redox homeostasis and protein quality control; however, its modulation by cigarette smoke remains unclear. We investigated whether cigarette smoke extract (CSE) suppresses immunoproteasome expression and promotes oxidative and inflammatory activation in vascular endothelial cells (VECs). Methods Mouse VECs were exposed to 1.0% CSE for 16 h or treated with the β5i-selective inhibitor ONX-0914 (0.5–1.0 μM, 24–36 h). mRNA expression levels of proteasome subunits, NADPH oxidase 4 (NOX4), and inflammatory mediators were assessed by quantitative PCR. Proteasomal activity and intracellular reactive oxygen species (ROS) were quantified using luminescent assays. β5i expression in small pulmonary arterioles (≤0.5 mm) from smokers (n = 10) and nonsmokers (n = 10) was analyzed by immunohistochemistry. Results CSE significantly suppressed immunoproteasome expression, reducing β5i mRNA by 66% ± 4% ( p = 0.0037) and decreasing proteasomal activity. Treatment with ONX-0914 increased intracellular ROS and upregulated NOX4 and inflammatory mediators, including monocyte chemoattractant protein-1 (approximately 6- to 7-fold at 0.5 μM for 36 h). Reduced endothelial β5i expression was more frequent in smokers than in nonsmokers. Discussion Cigarette smoke-associated β5i suppression is linked to endothelial oxidative stress and inflammation, suggesting a potential mechanism underlying smoking-related vascular dysfunction.
Purpose To identify clinical markers associated with hemodialysis in patients with severe lactic acidosis and concurrent ethanol intoxication. Methods A retrospective study of 22 adults (pH < 7.20, lactate > 5.0 mmol/L). We compared hemodialyzed (n=6) and non-hemodialyzed (n=16) patients. Results Hemodialysis was associated with higher peak lactate (24.4 vs 13.7 mmol/L), lower lactate clearance (4.5% vs 7.9%/h), and more profound acidemia (pH 6.7 vs 6.94). Vasopressor use was exclusive to the hemodialysis group. Conclusion Hemodialysis may serves as a physiological rescue therapy for metabolic collapse in this population.
Introduction A new Bayesian framework for dose-response modelling and benchmark dose determination is introduced, following guidelines from the World Health Organization and the European Food Safety Authority. It incorporates model averaging across a family of candidate models and defines prior distributions at the level of response distributions, dose-response median models, and model parameters. In addition to providing a fully probabilistic inferential framework, the Bayesian paradigm offers some methodological advantages over frequentist approaches. Methods The proposed framework employs regularising default priors that are adaptive to study design and biologically plausible constraints. Informative priors can also be incorporated. The performance was evaluated against frequentist model averaging across four case studies using both real and simulated datasets. Results In simulations based on the Bisphenol A study, only 3% of BMD estimates obtained using frequentist inference met the EFSA accuracy criterion (BMDU/BMDL < 50), compared with 83% obtained using Bayesian inference. Other analyses showed that design-adaptive and biology-respecting regularising priors improved estimation relative to frequentist hard constraints. In a small-sample case study with poorly informative experimental design, frequentist quantile bootstrap confidence intervals for the BMD were highly sensitive to the number of bootstrap replicates, whereas Bayesian MCMC-based inference remained stable and reliable. A final case study demonstrated that constructing an informative overarching BMD prior from multiple historical studies improved estimation performance. Discussion The case studies illustrate improved estimation and the ability to incorporate historical information. These findings support the use of Bayesian methods as a powerful alternative for regulatory toxicology and risk assessment applications.
Introduction Sulfur mustard (SM) as a potent alkylating chemical warfare agent, results in long-lasting health issues. This study aims to evaluate the associations among polymorphisms, the expression levels of DNA repair-related genes, oxidative stress, and the severity of sulfur mustard toxicity. Methods XPC (Xeroderma pigmentosum group C) rs2228001 and XRCC1 (X-ray repair cross-complementing protein 1) rs25487 were genotyped in three subgroups of 545 SM-exposed participants (asymptomatic, mild, and moderate-severe). Also, their transcriptional changes were evaluated. Results In the codominant model (AA reference), the GG genotype showed a negative association with the moderate-severe subgroup when compared to the mild subgroup. The AG genotype showed negative associations with the moderate-severe subgroup compared to both the asymptomatic and mild subgroups. In the recessive model (AA reference), the combined GG + AG genotypes only showed a negative association for the moderate-severe subgroup compared to the mild subgroup, suggesting that these genotypes may be associated with a lower risk of severe clinical signs. The XPC transcript decreased in the SM-exposed group and moderate-severe subgroup compared to the non-exposed group, while the XRCC1 transcript increased, especially in the mild and moderate-severe subgroups. This increase in XRCC1 transcript was only in the individuals with GG and AG genotypes. There was a negative correlation between XPC transcript and malondialdehyde (indicator of lipid peroxidation) levels. Discussion Variations in XRCC1 genotypes and expression of XRCC1/XPC gene are associated with responses to SM exposure and the risk of developing moderate-severe clinical signs, highlighting the complex interplay between oxidative stress and DNA repair.
Introduction: Doxorubicin (DOX) is an anthracycline anticancer agent whose clinical utility is constrained by dose-dependent cardiotoxicity. This exploratory experimental-focused study evaluated HM12, a 1,4-dihydropyridine calcium channel blocker (CCB) derivative, for protective effects against DOX-induced toxicity. Methods: Eight groups of adult male Wistarrats received saline, DOX (20 mg/kg, i.p.), lowerand upper HM12 doses (5or20 mg/kg,p.o.), nifedipine (NFD, 20 mg/kg, p.o.), or combinations of DOX with HM12 or NFD. Assessments included blood biochemistry, cardiac biomarkers, oxidative-antioxidant indices, renal and hepatic function tests, and organ histology. In silico docking was performed using the human topoisomerase II beta (PDBID: 3QX3). Results: DOX induced marked cardiotoxicity, evidenced by elevated tumor necrosis factor-alpha, C-reactive protein, lactate dehydrogenase, interleukin-6 and malondialdehyde. Renal and hepatic toxicity were also observed. However, HM12 improved heart weight, selectively reduced cardiac biomarkers, and improved antioxidant defenses. The HM12 doses mitigated cardiac damage, but offered limited protection to renal and hepatic tissues. Notably, in silico HM12 exhibited greater binding affinity than NFD and engaged in distinct interaction patterns with 3QX3. Discussion: HM12 exhibits cardioprotective effects against DOX-induced toxicity through antioxidant enhancement and modulation of inflammatory markers, although its protection of renal and hepatic tissues is limited.
Background: The rising consumption of herbal alcoholic beverages in Nigeria, driven by unverified health claims, poses growing public health risks and adds to the global disease burden.Aim: To evaluate the effects of ascorbate and alpha-tocopherol supplementation on hepatorenal biochemical parameters, histopathology, and expression of oxidative stress-related genes (Nrf2 and CYP2E1) in rats exposed to a herbal-based alcoholic beverage. Methods: Twenty-eight adult male Wistar rats were randomly assigned into four groups (n=7 per group) using a computer-generated randomisation, with all outcome assessments performed under blinded conditions. Group I consisted of the unexposed control rats. Group II rats received a daily oral dose of alcohol at 0.2 mL/kg/bw. Groups III and IV were also administered alcohol daily at 0.2 mL/kg/bw but were additionally treated with ascorbate (500 mg/kg) and alpha-tocopherol (300 mg/kg), respectively, for 28 days. Hepatorenal biochemical parameters, hepatic and renal Nrf2 and CYP2E1 expression, and histopathological changes were subsequently evaluated. Results: Supplementation with ascorbate (500 mg/kg) or alpha-tocopherol (300 mg/kg) was associated with significantly lower (p < 0.05) ALP, ALT, AST, creatinine, and urea levels compared with alcohol-exposed untreated rats. Vitamin supplementation was associated with the modulation of alcohol-induced overexpression of CYP2E1 and Nrf2, and partially restored the altered biochemical parameters. Histopathological examination further revealed mitigated alcohol-induced architectural disruptions in the liver and kidney, suggestive of the protective effects of antioxidant supplementation. Conclusion: Ascorbate and alpha-tocopherol supplementation were associated with attenuation of alcohol-induced hepatorenal biochemical alterations, partial normalisation of liver and kidney function parameters, and modulation of oxidative stress-related gene expression (CYP2E1, Nrf2), findings consistent with a potential adjunctive role of these vitamins in mitigating alcohol-related organ toxicity rather than indicating definitive therapeutic effects. Mechanistic conclusions are limited by the absence of direct oxidative stress marker measurements (lipid peroxidation, glutathione status, antioxidant enzyme activities), and interpretation is limited by the absence of pure ethanol and vitamin-only control groups and the lack of independent chemical verification of the test beverage.
Background: Atonal bHLH transcription factor 8 (ATOHB) plays heterogenous roles in different types of cancer, but its function and molecular mechanism in esophageal squamous cell carcinoma (ESCC) remain to be clarified. Methods: ATOH8 expression was analyzed using TCGA data and experimental assays. Its functional impact was assessed through in vitro assays (CCK-8, transwell) and in vivo mouse models (xenograft, lung metastasis). Molecular interactions between ATOH8, OCT4, and TFAP2A were characterized using co-immunoprecipitation (Co-IP), ubiquitination, lucif-erase, and chromatin immunoprecipitation (ChIP) assays. Results: Our results revealed that ATOH8 was significantly downregulated in ESCC. ATOH8 overexpression effectively inhibited the viability, mobility, and epithelial-mesenchymal transition (EMT) and promoted apoptosis of ESCC cells in vitro. Similarly, in vivo experiments suggested that the growth of xenograft tumors and lung metastasis were substantially suppressed by overexpressing ATOH8. Mechanistically, ATOH8 was confirmed to negatively regulate the protein stability of OCT4 by promoting its ubiquitination. The inhibitory effect of ATOH8 on ESCC aggressiveness was partially abrogated when OCT4 was overexpressed. Moreover, we found that ATOH8 deficiency in ESCC was caused by TFAP2A-induced transcriptional suppression. Conclusion: Our results demonstrated a critical role of the TFAP2A-ATOH8-OCT4 signaling axis in the aggressiveness of ESCC. Specifically, TFAP2A-mediated suppression of ATOH8 expression facilitated OCT4-induced EMT and tumor progression. These findings offer insights to identify ATOHB as a novel biomarker for ESCC management.
IntroductionPodocyte loss or functional impairment is a key event in the pathophysiology of nephrotic syndrome (NS). NS can further progress to chronic kidney disease (CKD) and/or end-stage renal disease (ESRD). This study aimed to explore the potential role and underlying mechanism of TRIM37 in NS.MethodsBioinformatics analysis was performed on the GEO dataset GSE97709 to analyze the association between TRIM37 expression and CKD. Adriamycin (ADR)-induced nephropathy models in mice and ADR-exposed human podocytes were used to investigate the function of TRIM37. TRIM37 overexpression experiments were conducted in vivo and in vitro. The binding interaction between TRIM37 and PTEN was verified and the ubiquitination and degradation of PTEN. The activation of the Akt pathway were detected. PTEN overexpression was used to confirm the regulatory relationship with TRIM37.ResultsBoth ADR-treated mice and ADR-exposed podocytes showed decreased TRIM37 expression. In vivo, ADR-induced mice exhibited elevated proteinuria, renal dysfunction, and structural damage, which were significantly ameliorated by TRIM37 overexpression. TRIM37 also inhibited ADR-induced cell apoptosis. In vitro, ADR exposure caused podocyte injury, reduced cell viability, and altered mitochondrial membrane potential, while these effects were partially reversed by TRIM37 overexpression. Mechanistically, TRIM37 directly bound to PTEN, promoting its ubiquitination and subsequent degradation, thereby activating the Akt pathway. Furthermore, PTEN overexpression counteracted the protective effects of TRIM37.DiscussionThe findings demonstrate that TRIM37 attenuates ADR-induced nephropathy by inhibiting mitochondrial apoptosis and podocyte injury through the PTEN/Akt signaling pathway. Collectively, these results suggest that TRIM37 may serve as a potential therapeutic target for NS.
PurposeThe cardiotoxic effects of anti-cancer agents on cardiomyocytes are a significant challenge for physicians. The current experiment aims to explore the potential cardioprotective effects of cardiovascular agents, i.e., eplerenone, empagliflozin, and colchicine by restoring mitochondrial fusion, reducing fission and mitigating the severity of fibrosis in doxorubicin-treated H9c2 cells.Materials and MethodsThe viability of H9c2 cells are assessed using the MTT assay. Additionally, the underlying mechanisms in H9c2 cells subject to treatment with eplerenone, empagliflozin, colchicine and doxorubicin were explored through a combination of techniques, including fluorescence microscopy, siRNA transfection, flow cytometry, and western blot analysis.ResultsAfter exposure to doxorubicin, H9c2 cells exhibit a decrease of mitochondrial fusion, an increase in myocardial fibrosis, and perturbed mitochondrial fission. However, treatment with these cardiovascular agents have effectively counteracted these doxorubicin-induced alterations with the restoration of mitochondrial dynamics and the alleviation myocardial fibrosis.ConclusionThis study suggests that eplerenone, empagliflozin, and colchicine possess direct cytoprotective actions in an in vitro model of H9c2 cells with the potential to serve as therapeutic agents of doxorubicin-induced myocardial fibrosis.
BackgroundWith the increasing aging population and the development of surgical procedures, the proportion of older adults undergoing surgical procedures is on the rise. Postoperative cognitive dysfunction (POCD) often occurs as a postoperative complication in older adults. POCD may result from neuroinflammatory and oxidative mechanisms triggered by surgical and anesthetic exposures; MiR-29a-3p may reflect or modulate these neurotoxic pathways. This study analyzed whether miR-29a-3p is associated with POCD by detecting its expression level and evaluating its diagnostic value in POCD.MethodsA total of 160 older patients participated in this study, divided into a non-POCD group and a POCD group. We used RT-qPCR to detect the expression level of miR-29a-3p in the study subjects and ROC to analyze the diagnostic value of miR-29a-3p in POCD. Pearson correlation analysis was used to assess the association of miR-29a-3p level with MOCA score and MMSE score, and Logistic regression was used to analyze the risk factors of POCD in older adults.ResultCompared with the non-POCD group, the expression level of miR-29a-3p was reduced in the POCD group. The miR-29a-3p level is positively correlated with MOCA score and MMSE score, and has high diagnostic value in POCD. In addition, miR-29a-3p was a risk factor for POCD in older adults.ConclusionMiR-29a-3p is associated with POCD and may serve as a potential diagnostic marker of POCD, but the signaling pathway needs further study.
ObjectiveCerebral ischemia-reperfusion injury (CIRI) remains a major challenge in clinical practice, without effective and targeted approaches to address it. Curculigoside has been reported to exert beneficial effects in CIRI, yet the underlying novel mechanisms remain unclear. In this work, we aimed to explore whether Curculigoside exerted its protective role by regulating transient receptor potential melastatin 2 (TRPM2)-mediated microglial polarization.MethodsA well-established middle cerebral artery occlusion (MCAO) model was constructed in Sprague-Dawley rats, with Curculigoside administrated via the caudal vein. In vitro, LPS/IFN-gamma-stimulated BV2 microglial cells were used to investigate the effects of Curculigoside on polarization and neuroinflammation. High-throughput mRNA sequencing was used to predict key targets of Curculigoside. TRPM2 overexpression and autophagy inhibition assays were conducted to verify the underlying mechanism.ResultsCurculigoside treatment significantly alleviated neurological deficits, reduced cerebral infarction volume, and decreased brain edema, accompanied by inhibited M1 polarization of microglia and mitigated inflammatory injury during CIRI. Curculigoside reduced pro-inflammatory M1 polarization in LPS/IFN-gamma-stimulated BV2 microglia, thereby reducing neuronal apoptosis. RNA-seq functional enrichment analysis identified TRPM2 as a key target, and Curculigoside was found to downregulate TRPM2 expression and regulate the mTOR-mediated autophagy pathway. Notably, the protective effects of Curculigoside on microglial polarization were reversed by TRPM2 overexpression or autophagy inhibition.ConclusionCurculigoside mitigates CIRI by promoting beneficial microglial polarization through the TRPM2/mTOR-autophagy axis, supporting its potential as a therapeutic agent for CIRI.
Background: The rapid advancement of nanotechnology has led to a wide use of engineered nanomaterials (ENMs). Ensuring their safety remains critical for successful clinical translation. It was previously reported that administration of ferumoxytol (an FDA-approved iron oxide nanoparticle formulation) resulted in fatal anaphylactic reactions. Importantly, previous studies demonstrated that ENMs can induce mast cell early-phase activation, with 20 nm citrate-coated silver nanoparticles (AgNPs) producing a robust response. Purpose: This study investigated late-phase activation of mast cells following exposure to AgNPs in comparison to a classical IgE activation. Research Design: The study used murine bone marrow-derived mast cells (BMMCs) exposed to 20 nm citrate-coated AgNPs (25 mu g/mL). Results: AgNP exposure induced late-phase BMMC activation, though this response was delayed and lower in magnitude compared to IgE activation. Specifically, exposure to AgNPs induced lipid mediator release (1h), and in some cases, showed differential regulation, with an overall lower magnitude of lipid release compared to IgE activation. Furthermore, AgNP exposure activated several inflammatory genes, with a delayed onset and reduced intensity relative to IgE stimulation. These data were reflected in the activation of mitogen-activated protein kinases (MAPKs) with significant changes occurring at later time points (24h). Importantly, no cytotoxicity or elevated levels of intracellular reactive oxygen species were observed, although Lamp-2 expression remained upregulated compared to IgE stimulation. Conclusion: The results suggest that AgNPs induce late-phase BMMC activation, potentially via a non-IgE-mediated mechanism characterized by a delayed and overall attenuated response. These findings underscore the importance of understanding ENM-bio interaction, not only for nanosafety, but also for unraveling novel therapeutic applications.
IntroductionHeated tobacco products (HTPs) are increasingly used among young people and adolescents, while their long-term toxicological effects remain insufficiently characterized. In parallel, frequent use of electronic devices has led to prolonged exposure to blue light (BL), a visible radiation that penetrates deeply into the skin and may exert phototoxic effects. Although the individual impact of these exposures has been studied, their combined effects on human skin are poorly understood.MethodsIn this study, we investigated the dual toxicity of HTP-derived total particulate matter (TPM) and BL irradiation (4.32 and 17.28 J/cm2, respectively) in HaCaT human keratinocyte cell line. Cell viability via MTT test, intracellular reactive oxygen species (ROS), inflammatory markers, and matrix remodeling factors via ELISA, and autophagosome formation via western blotting were assessed following single and combined exposures.ResultsOur findings demonstrated that BL and TPM co-exposure significantly reduced cell viability in a time-dependent manner and augmented intracellular ROS production. Co-exposure also up-regulated MMP-1 and IL-6 levels while increasing LC3 beta-II expression in human keratinocytes, suggesting the implication of oxidative stress, inflammatory signaling, and autophagy in the observed dual cytotoxicity.DiscussionThese findings indicate that concurrent exposure to BL and HTPs may exacerbate epidermal damage beyond the effects of each stressor alone. The results highlight potential health concerns associated with modern lifestyle habits, particularly regarding skin toxicity, and support the need for further toxicological evaluation of combined environmental exposures.
ObjectiveBronchopulmonary dysplasia (BPD), a common chronic lung disease in premature infants, is frequently complicated by pulmonary hypertension (PH), a dangerous condition characterized by elevated pulmonary vascular pressure. At present, the most classic and commonly used animal model for BPD involves exposure to high oxygen concentrations, but existing studies based on this model have seldom addressed whether it recapitulates the pathological features of PH.MethodsIn the present study, we established a rat model of BPD complicated with PH (BPD-PH). Histological hematoxylin and eosin (H&E) staining, enzyme-linked immunosorbent assay (ELISA), flowcytometry, reverse transcription-quantitative PCR (RT-qPCR), wound healing assay, transwell migration and invasion assays, transcriptome RNA-sequencing and GO analysis were performed to evaluate this BPD-PH model.ResultsOur study demonstrated that rats with BPD-PH exhibited characteristic alveolar simplification and features of pulmonary hypertension, including increased mRVP, RV/LV + S and RV/WT. BPD-PH rats had enhanced inflammatory response and increased accumulation of immune cells in lung. Moreover, differentially expressed genes in the BPD-PH rat model were depicted and we found Leucine-rich alpha-2-glycoprotein 1 (Lrg1) was significantly upregulated by 19.32 fold (p < 0.001). LRG1 affected migration, invasion and transforming growth factor-β (TGF-β) signaling activation in primary alveolar epithelial cells and pulmonary endothelial cells. Finally, our BPD-PH model was used for the evaluation of two commonly used drugs for BPD and PH, Dexamethasone and Sildenafil. These two drugs were effective in alleviating lung injury, inflammatory response and hypoxia-induced PH in the rat model of BPD-PH.ConclusionOur data indicate that we established a novel BPD-PH model in rats, and it provided a new choice for the future research for BPD complicated with PH.
IntroductionAging and metabolic disease enhance inhaled particulate toxicity. Nanoparticles (NPs) are rapidly coated with biomolecules forming a biocorona (BC), upon entering the body and may contribute to the susceptibility. Aging and metabolic syndrome (MetS) are progressive conditions resulting in biomolecule alterations over time potentially influencing susceptibility. We hypothesize NP-biomolecule interactions are altered during aging and throughout MetS progression.MethodsC57BL/6J mice at 6 weeks of age were fed a healthy diet or a high-fat western diet. BALF was collected after 2, 4, 8, 12, 16, 20 or 24 weeks on diets. NP-biomolecules interactions were compared between healthy and MetS to determine age- and disease progression-related BC variations (proteins and lipids).ResultsUnique BCs were determined to form at each time point indicative of aging for the healthy and aging and disease progression for the MetS. Comparisons between healthy and MetS BCs at each time demonstrated distinct biomolecule interactions attributable to disease. Comparisons determined both unique protein and lipid content as well as quantitative differences. Proteins such as apolipoprotein A-IV, complement C3 and lipids such as PE (37:5), PE (O-38:5), PE (P-38:4), PC(40:7), PC(39:0), and PC(O-40:0) were identified on the MetS BC suggesting disease progression modifications. Proteins such as pulmonary surfactant protein A, fibrinogen alpha-chain and lipids such as CE (19:0)-NH4, DG (36:7), and DG (35:0)_C18:0 were increasingly present in the healthy BC over time, suggesting age-related interactions.DiscussionOverall, unique BCs were identified demonstrating the impact of age and disease progression on BC formation which will aid in understanding initial pulmonary NP-biomolecular interactions potentially contributing to susceptibility.
IntroductionHepatotoxicity can arise secondary to several medical conditions, including inflammation, sepsis, and therapy. Lipopolysaccharide (LPS) can activate diverse inflammatory pathways and has been implicated in hepatotoxicity. The store-operated calcium entry (SOCE), a key process for maintaining cellular calcium homeostasis, was shown to modulate inflammatory signaling. Reactive oxygen species, which serve a significant role in maintaining cellular function and homeostasis, are often elevated during inflammation, contributing to tissue injury. Therefore, we hypothesized that blocking the SOCE pathway would inhibit LPS-induced hepatotoxicity by suppressing inflammation and oxidative stress.MethodsTo test this, female BALB/c mice were randomly divided into the following experimental groups: control, LPS, LPS + SOCE inhibitor 2-aminoethoxy diphenyl borate (2APB), and 2APB alone. After 24 h of treatment, serum and liver samples were collected from the mice for histopathological, biochemical, and molecular analyses.ResultsInhibition of SOCE led to a decrease in the elevated liver function enzymes (ALT and AST) and protected the liver parenchymal cells as observed by histopathological assessment. Furthermore, blockade of SOCE significantly suppressed the level of il-1b, il-6, and cox2 genes in the liver tissues of mice treated with LPS. The expression of antioxidant genes (gsta1 and gpx1) was also significantly reduced by LPS treatment, while SOCE inhibition only restored the gpx1 expression. Additionally, treatment with 2APB attenuated LPS-induced oxidative stress in the liver of mice.ConclusionCollectively, our work demonstrated the critical involvement of SOCE in regulating inflammation and oxidative stress associated with LPS treatment, thereby reducing hepatotoxicity.
ObjectiveThe study aimed to explore the inhibitory effect of stevioside on colorectal cancer and its molecular mechanism.MethodsColorectal cancer cells were selected for functional testing, including the following groups: 0 μM stevioside, 1 μM stevioside, 2.5 μM stevioside and 5 μM stevioside. CCK-8 kit and EdU staining were employed to assess the cell viability. Cell apoptosis was deterred by flow cytometry. Western blot assay was utilized to detect the protein expressions of cleaved-caspase-3, Bax, Bcl-2, E-cadherin and Vimentin. The polarization of macrophage was evaluated through flow cytometry, western blot and immunofluorescence staining. The effect of stevioside on the proliferation of tumor tissue was detected by tumor formation and immunohistochemical staining in nude mice.ResultsStevioside exhibited a significant concentration-dependent inhibitory effect on the proliferation, migration, and invasion of colorectal cancer cells, while promoting apoptosis in vitro. Following stevioside treatment, there was a notable reduction in tumor volume and weight observed. Flow cytometry and immunohistochemical staining results showed that compared with control group, CD86+ cell ratio was increased in stevioside treatment group, while the CD206+ cell ratio was decreased in stevioside treatment group. RT-qPCR analysis revealed that, compared to the control group, stevioside treatment significantly reduced the mRNA expressions of Arg-1 and IL-10, while concomitantly increasing the mRNA expressions of IL-12 and TNF-α in a concentration-dependent manner.ConclusionStevioside possesses the ability to significantly hinder the proliferation of colorectal cancer cells and induce apoptosis, the mechanism of which may be closely related to the regulation of macrophage M1 polarization.
BackgroundGlufosinate ammonium (GLA) is a widely used herbicide in rural Vietnam, often associated with severe toxicity. Given the limited diagnostic resources at primary care levels, identifying simple and effective predictors of severity is critical for early triage and intervention.ObjectiveTo identify clinical and biochemical predictors of severe outcomes in patients with glufosinate ammonium poisoning using multivariable logistic regression.MethodsWe conducted a retrospective study of 83 patients with confirmed glufosinate ammonium poisoning admitted to our poison control center at Bach Mai hospital between March 2023 and October 2024. Demographic, clinical, and laboratory data were collected. Severe outcomes were defined as the need for mechanical ventilation, inotropic support, Glasgow Coma Score ≤8, or in-hospital mortality. Logistic regression was used to identify significant predictors and evaluate model performance.ResultsThe mean age was 48.6 ± 17.3 years; 62.7% were male; 88% of cases resulted from intentional ingestion; six patients died (7.2% mortality). Significant predictors of severe outcomes included glufosinate ammonium ingestion >100 ml, (Odds Ratio (OR) 4.5, p < 0.001), time to hospital >6 h (OR 3.2, p = 0.004), pH < 7.35 (OR 5.7, p < 0.001), lactate >4.0 mmol/L (OR 6.2, p < 0.001), creatinine >110 µmol/L (OR 4.3, p = 0.005), and NH3(ammonia) > 100 µmol/L (OR 5.4, p = 0.002). The final logistic regression model including pH < 7.35, time to hospital >6 h, NH3 > 100 µmol/L, and ingested volume >100 mL demonstrated good discrimination (AUC = 0.84, 95% CI 0.74-0.93; p < 0.001) and acceptable calibration by the Hosmer-Lemeshow test (p = 0.47).ConclusionReadily available clinical and laboratory indicators, such as pH < 7.35, delayed hospital arrival, high ammonia levels, and large ingested volume, were strong predictors of severe outcomes in glufosinate ammonium poisoning. The simple logistic model (AUC = 0.84) may support early triage in low-resource settings, but prospective validation is needed.
IntroductionDue to its silent clinical progression and diagnosis often occurring at advanced stages, ovarian cancer continues to be a major contributor to gynecological cancer-related mortality worldwide. Recent evidence underscores the critical therapeutic value of targeting the interplay between DNA damage response pathways, particularly poly (ADP-ribose) polymerase 1 (PARP1), and mitogen-activated protein kinase (MAPK) signaling cascades.MethodsIn this study, we investigated the anti-cancer potential of the naturally derived small molecule usnic acid in a chemotherapy-resistant epithelial ovarian cancer model (SKOV-3 cells) at the cellular and molecular levels.ResultsOur findings demonstrate for the first time that usnic acid exerts a dual-pathway apoptotic mechanism by simultaneously inhibiting PARP1 and activating the MAPK signaling pathway. Remarkably, usnic acid mimics the gene-silencing action of siRNA on PARP1, suggesting a highly specific and potent inhibitory effect at the molecular level. Although ROS involvement and pathway causality were not directly tested, this dual-action profile enhances DNA damage-induced apoptosis and highlights usnic acid as a promising therapeutic candidate.ConclusionThe study presents a novel molecular framework in which a single small molecule can coordinate apoptosis through parallel regulatory pathways, demonstrating the potential for innovative therapeutic approaches in the treatment of aggressive and treatment-resistant ovarian cancers.
Background and ObjectiveNi is an important metal found in the human environment, including air, water, soil, food, kitchenware, and jewelry. It is widely used in electrical engineering, medicine, and industry. Ni compounds, whether insoluble (such as oxides and sulfides) or soluble (such as sulfates, chlorides, and acetates), pose serious risks to the environment, ecosystems, and human health. Such contamination can lead to harmful effects, especially on the respiratory, digestive, and skin systems. This study aims to emphasize the importance of early detection and diagnosis of Ni poisoning, as well as urgent measures and treatments, especially the use of chelators, in addition to the use of nanoparticles to remove nickel compounds from the environment.Methods and ResultThis review article draws on sources from PubMed, Scopus, various citations, and the Toxicologic Emergencies reference book spanning 1996-2025. The findings indicate that high-level exposure to nickel compounds leads to the formation of reactive oxygen species, suppression of DNA repair mechanisms, and disruption of signal transduction pathways. These effects result in genotoxicity, carcinogenicity, immunotoxicity, and poisoning across different species.ConclusionA thorough history and examination are essential for evaluating blood and urine nickel levels, as they directly relate to the severity of poisoning. Preventive measures involve avoiding nickel compounds and facilitating removal from the body. Allergic contact dermatitis is treated with antihistamines, corticosteroids, and calcineurin inhibitors like tacrolimus. For nickel poisoning treatment, chelators such as diethyl-dithiocarbamate (DDC) and disulfiram are prescribed based on urine concentration. Recently, nanoparticles have been used to remove nickel compounds from the environment.
