Toxicology and applied pharmacology最新文献

Viral respiratory infections are the major cause of exacerbation of allergic asthma, often resulting in increased emergency visits and hospitalizations. However, the understanding of the immune pathways at the cellular/molecular level under the conditions is lacking. Therefore, the present work was designed to elucidate the complex interplay of immune response under the settings mimicking exacerbation of allergic asthma upon viral infection using mouse model of the condition. Mice were sensitized & challenged with Ovalbumin (OVA) to induce allergic asthma, and subsequently subjected to intranasal administration of poly(I:C), a viral mimetic. Poly(I:C) administration at a dose of 200 μg in OVA sensitized & challenged mice resulted in shift of airway inflammation from eosinophils to neutrophils and was accompanied by enhanced airway hyper-responsiveness. Interestingly, down-regulation of Th2 cytokines (IL-4/IL-5/IL-13), and steep production of pro-inflammatory cytokines (TNF-α/IL-6/KC/MCP-1) upon poly(I:C) exposure in allergic mice indicates a switch of immune response from adaptive to innate type. Further, poly(I:C) exposure exaggerates the OVA induced oxidative stress along with over-activation of MAPK/NF-κB in lung tissue. Such changes were accompanied with Th17/Treg imbalance. Despite the proven efficacy of corticosteroids in controlling eosinophilic inflammation in OVA-induced allergic asthma, failure of dexamethasone, a steroid class of drug to mitigate neutrophil-driven inflammation upon Poly(I:C) exposure in allergic mice, suggests that innate immune mediators may contribute considerably during viral infection mediated exacerbation of allergic asthma. Overall, our study highlights the complexity of the immune response during viral induced exacerbation of allergic asthma and may provide new insights to tackle such steroid insensitive conditions.

Tungsten exposure is associated with multiple cardiovascular diseases, but limited information exists on the mechanistic underpinnings of these relationships. The current study investigated the individual and combined effects of angiotensin II (AT-II) treatment, as a model of accelerated cardiovascular disease risk, and tungsten (W) exposure on cardiac function, to provide insights into potential mechanisms involved in tungsten-mediated cardiac injury. Mice received AT-II (0.73 mg/kg/d) or saline (Veh) for 24 days through osmotic mini-pumps. The final 2-weeks of treatment, mice were exposed 4 times (4 h each) to filtered air (FA) or 1.50 ± 0.22 mg/m³ W particles by whole-body inhalation. Laser ablation and bulk inductively-coupled plasma mass spectrometry (ICP-MS) of lung samples indicated an accumulation of iron in AT-II treatment groups and confirmed the deposition of W and decreases in essential elements zinc, magnesium, and molybdenum in exposure groups. Echocardiographic data showed W exposure decreased cardiac output and stroke volume; however treatment with AT-II did not further exacerbate W's effects. The A'/E' ratio was significantly elevated in the AT-II + W group compared to the W + Veh group and trending significant compared to the FA + AT-II group. Blood cardiac troponin I was elevated in the W + AT-II group compared to either FA + Veh or W + Veh groups. Results suggest an interactive effect of both W and AT-II to drive cardiac injury following exposure. However, neither W exposure nor AT-II treatment resulted in pulmonary inflammation at the terminal endpoint of the study. Data illustrate pathophysiological effects of inhaled W and AT-II that contribute to cardiac injury.

Sepsis poses a significant global health burden, and ICU patients are disproportionately exposed to di(2-ethylhexyl) phthalate (DEHP), an immunotoxic plasticizer that leaches from PVC medical devices; however, whether this exposure causally influences sepsis outcomes remains unclear. To investigate this relationship, we conducted a prospective cohort study comparing 90 ICU sepsis patients with 50 controls, quantifying urinary DEHP metabolites using LC-MS/MS. Sepsis patients demonstrated significantly elevated DEHP metabolite levels (p < 0.001), and high exposure (≥341.58 μg/g creatinine) was independently associated with reduced 28-day survival (35% vs 55%, p = 0.04; HR = 1.92, 95%CI:1.01-3.65). To identify the molecular mechanisms underlying this association, we integrated seven sepsis transcriptomic datasets with predicted DEHP targets, revealing 46 overlapping genes. Subsequently, machine learning algorithms (LASSO, SVM-RFE, and Random Forest) prioritized seven core genes, with SHAP analysis identifying MAPK14 as the predominant contributor. Molecular docking further confirmed high-affinity binding between DEHP and these target proteins. To establish causality, Mendelian randomization analysis using cis-eQTLs and FinnGen GWAS data demonstrated that genetically predicted higher MAPK14 expression increases sepsis susceptibility (OR = 1.18, p = 0.045). In conclusion, these findings provide converging evidence that high iatrogenic DEHP exposure is associated with increased sepsis mortality, potentially through MAPK14-mediated pathways, suggesting that DEHP exposure represents a modifiable risk factor in critical care settings and supporting the evaluation of DEHP-free alternatives for high-leach medical devices.

The gut microbiota plays a crucial role in the progression of chronic kidney disease (CKD). The adenine-induced CKD mouse model is widely employed in preclinical research, yet the effects of adenine on the composition and metabolic function of the gut microbiota remain to be elucidated. This study aimed to test the hypothesis that adenine-induced alterations in the structure and function of the gut microbiota are significantly associated with the onset and progression of CKD. To this end, a mouse CKD model was established by alternating feeding with 0.15% and 0.20% adenine for 7 weeks. Multi-omics analysis (untargeted metabolomics, metagenomics, and spatial metabolomics) was performed to compare the adenine-induced CKD group with a standard diet-fed normal control group. Integrated analysis of plasma metabolomics and intestinal content metabolomics identified 94 differentially co-regulated metabolites: among these, indolelactic acid was significantly upregulated, while indole-3-propionic acid was significantly downregulated. The bile acid metabolic pathway also underwent marked perturbations: taurochenodeoxycholic acid and tauro-β-muricholic acid (two taurine-conjugated bile acids) were significantly elevated, whereas nordeoxycholic acid and norcholic acid were notably reduced. Integrated metabolomics-metagenomics analysis further demonstrated that Lactobacillus exhibited a significant positive correlation with a subset of upregulated metabolites (including indolelactic acid), while Taurinivorans muris showed a strong negative correlation with the taurine-conjugated bile acids. Additionally, renal spatial metabolomics revealed that phospholipid metabolic disorders in the adenine-induced CKD group directly contributed to the aggravation of renal inflammatory responses. Collectively, these findings reveal a gut microbiota-metabolite-kidney axis perturbed by adenine, providing novel insights into the pathogenesis of CKD and potential targets for metabolic intervention.

Adverse early-life conditions can predispose offspring to long-term health risks. Phthalate exposure, particularly to di-2-ethylhexylphthalate (DEHP), during pregnancy and lactation has been implicated in programming offspring hypertension via aryl hydrocarbon receptor (AHR) activation, renin-angiotensin system (RAS) dysregulation, nitric oxide (NO) deficiency, and gut microbiota alterations. Using a maternal DEHP exposure rat model, we investigated whether blockade of AHR signaling-directly with the AHR inhibitor CH223191 or indirectly with the indoleamine 2,3-dioxygenase (IDO) inhibitor INCN-024360-prevents offspring hypertension. Pregnant rats received DEHP (10 mg/kg/day) by oral gavage throughout pregnancy and lactation, with or without CH223191 (10 mg/kg/day) or INCN-024360 (50 mg/kg/day). Maternal DEHP exposure induced sustained systolic hypertension in adult male offspring, accompanied by upregulation of renal AHR signaling and RAS components. This effect was attenuated by the IDO inhibitor (approximately 10 mmHg reduction in systolic blood pressure) and more effectively by the AHR inhibitor (approximately 16 mmHg reduction). Mechanistically, the IDO inhibitor reduced asymmetric dimethylarginine (an endogenous nitric oxide synthase inhibitor), renin, and CYP1A1 expression while increasing angiotensin-converting enzyme 2 (ACE2), whereas the AHR inhibitor suppressed renal AHR, renin, angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor (AT1R) expression and significantly enhanced short-chain fatty acid receptor expression. Both interventions were associated with distinct alterations in gut microbiota composition. These findings identify AHR as a key mechanistic link between early-life environmental phthalate exposure and programmed hypertension and support early-life AHR blockade as a potential preventive strategy for offspring cardiometabolic-kidney risk.

Worldwide incidence and prevalence of ulcerative colitis (UC) has been rising in recent years, which can occur at any age, with a high frequency seen in young children and people aged 40 to 50. The aryl hydrocarbon receptor (AhR) activation axis is well known for its important role in the regulation of intestinal inflammation, intestinal homeostasis, intestinal immune system and improvement of colitis outcomes. This study investigated the therapeutic efficacy of the thiophene-based styrene derivative (TBSD), a novel AhR agonist against UC in vitro and in vivo. TBSD decreased FITC-dextran hyperpermeability, upregulated the tight junction (TJ)-related protein expression levels and regulated the inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-22 and cyclooxygenase 2 (COX-2) in the Caco-2/RAW264.7 co-culture system and in DSS-induced UC-like mice. Overall, TBSD may be considered as a promising therapeutic agent to improve UC severity through mitigating inflammation, maintaining intestinal mucosal homeostasis and enhancing the intestinal barrier integrity.