Toxicology and applied pharmacology最新文献_第2页

Intranasal exposure of poly (I:C) exacerbates OVA-induced allergic asthma by causing a major shift in the immune response 鼻内暴露聚（I:C）通过引起免疫反应的重大转变而加剧ova诱导的过敏性哮喘。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-02-06 DOI: 10.1016/j.taap.2026.117747

Ayushi Sandhu, Amarjit S. Naura

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 exaggerated 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.

病毒性呼吸道感染是过敏性哮喘恶化的主要原因，往往导致急诊和住院人数增加。然而，在这种情况下，对细胞/分子水平上的免疫途径的理解是缺乏的。因此，本研究旨在利用小鼠模型阐明在模拟变应性哮喘病毒感染加重的情况下免疫反应的复杂相互作用。用卵清蛋白（OVA）致敏并刺激小鼠诱导过敏性哮喘，随后鼻内给予病毒模拟物poly（I:C）。给药200 μg的Poly（I:C）使OVA致敏和攻毒小鼠的气道炎症从嗜酸性粒细胞转变为中性粒细胞，并伴有气道高反应性增强。有趣的是，过敏小鼠在poly（I:C）暴露后Th2细胞因子（IL-4/IL-5/IL-13）的下调和促炎细胞因子（TNF-α/IL-6/KC/MCP-1）的急剧产生表明免疫反应从适应性型转变为先天型。此外，poly（I:C）暴露会加剧OVA诱导的氧化应激，并伴有肺组织中MAPK/NF-κB的过度激活。这些变化伴随着Th17/Treg失衡。尽管皮质类固醇在控制ova诱导的过敏性哮喘中嗜酸性粒细胞炎症方面已被证实有效，但地塞米松（一种类固醇类药物，可减轻过敏小鼠暴露于Poly（I:C）时中性粒细胞驱动的炎症）的失败表明，先天免疫介质可能在病毒感染介导的过敏性哮喘恶化过程中发挥了重要作用。总的来说，我们的研究强调了病毒诱导的过敏性哮喘加重期间免疫反应的复杂性，并可能为解决此类类固醇不敏感疾病提供新的见解。

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引用次数: 0

Iatrogenic plasticizer Di(2-ethylhexyl) phthalate (DEHP) exposure increases Sepsis mortality risk: Machine learning implicates monocyte-driven immune dysregulation 医源性增塑剂邻苯二甲酸二（2-乙基己基）酯（DEHP）暴露增加败血症死亡风险：机器学习涉及单核细胞驱动的免疫失调

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-02-04 DOI: 10.1016/j.taap.2026.117752

Jun-jie Gao , Li-zhu Huang , Tao Wang , Yun-long Zhang , Kai Ye , Wei-hua Lu , Pu-hong Zhang

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.

脓毒症构成了重大的全球健康负担，ICU患者不成比例地暴露于邻苯二甲酸二（2-乙基己基）酯（DEHP），这是一种从PVC医疗器械中浸出的免疫毒性增塑剂；然而，这种暴露是否会导致败血症的结果尚不清楚。为了研究这种关系，我们进行了一项前瞻性队列研究，比较了90名ICU脓毒症患者和50名对照组，使用LC-MS/MS量化尿DEHP代谢物。脓毒症患者DEHP代谢物水平显著升高(p

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引用次数: 0

Multi-omics reveal the key role of gut microbiota metabolism in adenine-induced chronic kidney disease 多组学揭示了肠道微生物群代谢在腺嘌呤诱导的慢性肾脏疾病中的关键作用。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-02-04 DOI: 10.1016/j.taap.2026.117754

Yijing Xin , Hui Ma , Xiang Li , Ruiyang Sun , Luo Fang , Libin Pan

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.

肠道微生物群在慢性肾脏疾病（CKD）的进展中起着至关重要的作用。腺嘌呤诱导的CKD小鼠模型广泛用于临床前研究，但腺嘌呤对肠道微生物群组成和代谢功能的影响仍有待阐明。本研究旨在验证腺嘌呤诱导的肠道微生物群结构和功能的改变与CKD的发生和进展显著相关的假设。为此，采用0.15%和0.20%腺嘌呤交替喂养7 周的方法建立小鼠CKD模型。采用多组学分析（非靶向代谢组学、宏基因组学和空间代谢组学）将腺嘌呤诱导的CKD组与标准饮食喂养的正常对照组进行比较。血浆代谢组学和肠道内容代谢组学的综合分析鉴定出94种差异共调节代谢物：其中吲哚乳酸显著上调，而吲哚-3-丙酸显著下调。胆汁酸代谢途径也发生了明显的扰动：牛磺酸-去氧胆酸和牛磺酸-β-胆酸（两种牛磺酸偶联胆汁酸）显著升高，而去氧胆酸和去胆酸显著降低。综合代谢组学-宏基因组学分析进一步表明，乳酸菌与一部分上调代谢物（包括吲哚乳酸）呈显著正相关，而牛磺酸偶联胆汁酸与牛磺酸偶联胆汁酸呈强烈负相关。此外，肾脏空间代谢组学显示，腺嘌呤诱导的CKD组的磷脂代谢紊乱直接导致肾脏炎症反应的加重。总的来说，这些发现揭示了受腺嘌呤干扰的肠道微生物群-代谢-肾轴，为CKD的发病机制和代谢干预的潜在靶点提供了新的见解。

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引用次数: 0

Targeting aryl hydrocarbon receptor signaling attenuates hypertension programmed by maternal Di-2-ethylhexylphthalate exposure 靶向芳基烃受体信号可减轻母体暴露于邻苯二甲酸二乙己基酯所致的高血压。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-02-03 DOI: 10.1016/j.taap.2026.117751

Chien-Ning Hsu , Hsi-Yun Liu , Chih-Yao Hou , Yu-Wei Chen , Guo-Ping Chang-Chien , Shu-Fen Lin , You-Lin Tain

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.

不良的早期生活条件可使后代易受长期健康风险的影响。孕期和哺乳期暴露于邻苯二甲酸酯，特别是暴露于邻苯二甲酸二乙己基酯（DEHP），通过芳烃受体（AHR）激活、肾素-血管紧张素系统（RAS）失调、一氧化氮（NO）缺乏和肠道微生物群改变与后代高血压有关。利用母体DEHP暴露大鼠模型，我们研究了AHR信号的阻断（直接使用AHR抑制剂CH223191或间接使用吲哚胺2,3-双加氧酶（IDO）抑制剂incn -024360）是否可以预防后代高血压。妊娠大鼠在妊娠和哺乳期均给予DEHP(10 mg/kg/day)，同时给予或不给予CH223191（10 mg/kg/day）或INCN-024360（50 mg/kg/day）。母体DEHP暴露诱导成年雄性后代持续收缩期高血压，并伴有肾AHR信号和RAS成分的上调。IDO抑制剂减弱了这种作用（收缩压降低约10 mmHg）， AHR抑制剂更有效（降低约16 mmHg）。在机制上，IDO抑制剂降低了不对称二甲基精氨酸（一种内源性一氧化氮合酶抑制剂）、肾素和CYP1A1的表达，同时增加了血管紧张素转换酶2 (ACE2)，而AHR抑制剂抑制了肾脏AHR、肾素、血管紧张素转换酶（ACE）和血管紧张素II型1受体（AT1R）的表达，并显著增强了短链脂肪酸受体的表达。两种干预措施都与肠道菌群组成的明显改变有关。这些发现确定了AHR是生命早期环境邻苯二甲酸盐暴露与程序性高血压之间的关键机制联系，并支持早期AHR阻断作为后代心脏代谢-肾脏风险的潜在预防策略。

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引用次数: 0

Thiophene-based styrene derivative improves colitis symptoms in DSS-induced BALB/C mice through AhR-mediated gut barrier function and inflammatory responses 噻吩基苯乙烯衍生物通过ahr介导的肠道屏障功能和炎症反应改善dss诱导的BALB/C小鼠结肠炎症状。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-02-02 DOI: 10.1016/j.taap.2026.117748

Ang-Kun Yang , Yong-Liang Li , Yan-Ying Chen , Yan Liu , Zhi-Yun Du , Chang-Zhi Dong , Bernard Meunier , Hui-Xiong Chen

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.

近年来，世界范围内溃疡性结肠炎（UC）的发病率和流行率一直在上升，它可以发生在任何年龄，在幼儿和40至50岁的人群中发病率很高。芳烃受体（AhR）激活轴在调节肠道炎症、肠道稳态、肠道免疫系统和改善结肠炎结局中发挥着重要作用。本文研究了新型AhR激动剂噻吩基苯乙烯衍生物（TBSD）在体外和体内对UC的治疗效果。TBSD降低Caco-2/RAW264.7共培养体系和dss诱导的uc样小鼠中fitc -葡聚糖高通透性，上调紧密连接（TJ）相关蛋白表达水平，调节肿瘤坏死因子-α (TNF-α)、白细胞介素(IL)-6、IL-22和环氧化酶2 （COX-2）等炎症介质。综上所述，TBSD可能被认为是一种很有前景的治疗药物，可以通过减轻炎症、维持肠黏膜稳态和增强肠屏障完整性来改善UC的严重程度。

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引用次数: 0

Human umbilical cord mesenchymal stem cells-derived exosomes restore lung architecture and reduce the susceptibility to asthma of offspring in maternal asthma 人脐带间充质干细胞来源的外泌体恢复肺结构并降低母亲哮喘的后代对哮喘的易感性。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-02-02 DOI: 10.1016/j.taap.2026.117746

Xin Li , Yueting Wu , Min Mao , Hong Xu , Caijun Liu , Yang Liu , Haiyang Zhang , Hanmin Liu

Asthma is a heterogeneous disorder driven by inflammatory processes that promote pathogenic airway remodeling. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) emerge as a compelling therapeutic candidate to disrupt this disease cycle, with potential intergenerational benefits. In a chronic OVA-induced asthma model using C57BL/6 mice, hucMSC-Exos were delivered via serial injections during the sensitization phase. Airway structural changes were evaluated through histological analysis (H&E staining, Masson's trichrome) and immunofluorescence for key remodeling markers including α-SMA, CC-10, and the proliferation marker Ki67. Molecular pathway analyses specifically targeted the TGF-β/Smad and STAT6 signaling cascades. We found that hucMSC-Exos intervention effectively ameliorated the core pathological features of asthma-induced lung injury and significantly reduced the levels of IL-6 and TNF-α in bronchoalveolar lavage fluid (BALF) in a dose-dependent manner. Additionally, this treatment reduced asthma susceptibility in offspring of mothers with chronic asthma. Compared to the OVA group, the Exos group showed restored CC-10 expression and decreased pulmonary Ki67 levels. In offspring, Hopx (but not SPC) expression was significantly elevated at PN1 and PN4 relative to the OVA group, though these differences lost statistical significance at PN14, consistent with Western blotting (WB) validation. Notably, unlike maternal findings, both CC-10 and Ki67 expression in the lungs of treated offspring were lower than in controls. Furthermore, we observed that OVA-induced activation of PECAM-1, α-SMA, p-ROCK1, and Caspase-8 was attenuated by hucMSC-Exos treatment. RNA sequencing of hucMSC-Exos identified asthma-associated miRNAs, including let7a-5p and miR-125a-5p. The therapeutic efficacy of hucMSC-Exos against asthma was partially abolished when these miRNA inhibitors were applied, underscoring their critical regulatory role in exosome-based asthma therapy. In conclusion, hucMSC-Exos have demonstrated significant efficacy in the treatment of asthma, capable of alleviating airway remodeling and related symptoms. What is particularly important is that they have a cross-generational protective effect, which can reduce the asthma susceptibility of children born to asthmatic mothers. Mechanistically, this benefit may be achieved through the transfer of asthma-related miRNAs. These findings elucidate the key molecular pathways of the cross-generational therapeutic effect mediated by hucMSC-Exos, providing a scientific basis for their clinical application in the management of maternal and offspring asthma.

哮喘是一种异质性疾病，由促进致病性气道重塑的炎症过程驱动。人脐带间充质干细胞衍生的外泌体（hucMSC-Exos）作为一种引人注目的治疗候选体出现，可以破坏这种疾病周期，并具有潜在的代际益处。在C57BL/6小鼠慢性ova诱导哮喘模型中，在致敏期连续注射humsc - exos。通过组织学分析（H&E染色、马松三色）和免疫荧光检测关键重塑标志物α-SMA、CC-10和增殖标志物Ki67评估气道结构变化。分子通路分析专门针对TGF-β/Smad和STAT6信号级联。我们发现，hucMSC-Exos干预可有效改善哮喘性肺损伤的核心病理特征，并显著降低支气管肺泡灌洗液（BALF）中IL-6和TNF-α的水平，且呈剂量依赖性。此外，这种治疗降低了慢性哮喘母亲的后代的哮喘易感性。与OVA组相比，Exos组CC-10表达恢复，肺Ki67水平降低。在子代中，Hopx（而非SPC）的表达在PN1和PN4组相对于OVA组显著升高，尽管这些差异在PN14组没有统计学意义，与Western blotting （WB）验证一致。值得注意的是，与母体的发现不同，CC-10和Ki67在治疗后代肺部的表达均低于对照组。此外，我们观察到ova诱导的PECAM-1、α-SMA、p-ROCK1和Caspase-8的活化被hucMSC-Exos处理减弱。hucMSC-Exos的RNA测序鉴定出哮喘相关的mirna，包括let7a-5p和miR-125a-5p。当使用这些miRNA抑制剂时，hucMSC-Exos对哮喘的治疗效果部分被取消，强调了它们在基于外泌体的哮喘治疗中的关键调节作用。综上所述，hucMSC-Exos在哮喘治疗中表现出显著的疗效，能够缓解气道重塑及相关症状。特别重要的是，它们具有跨代保护作用，可以降低哮喘母亲所生孩子的哮喘易感性。从机制上讲，这种益处可能通过哮喘相关mirna的转移来实现。这些发现阐明了hucMSC-Exos介导的跨代治疗作用的关键分子通路，为其在母婴哮喘治疗中的临床应用提供了科学依据。

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引用次数: 0

Long-term exposure to Di(2-ethylhexyl) phthalate induced uterine histopathologic alterations in female mice 长期暴露于邻苯二甲酸二（2-乙基己基）酯诱导雌性小鼠子宫组织病理改变。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-29 DOI: 10.1016/j.taap.2026.117738

Je Yeon Lee , Jin Su Kim , Javeria Zaheer , Sun Hee Chang , Kyungho Choi , Dong Won Hwang , Jisun Lee , Young Ah. Kim , Yoon Hee Cho

Objective

To investigate the effects of long-term Di(2-ethylhexyl) phthalate (DEHP) exposure on the female reproductive system, employing different dosages and durations of exposure.

Methods

Pregnant female CD-1 mice (F0) were orally exposed to DEHP at doses of 0, 100, and 500 mg/kg/day during gestation. Following birth, the female offspring (F1) were allocated into three groups as F0 mice. Both F0 and F1 mice were consequently subjected to ongoing DEHP exposure until they were sacrificed. Body weight, anogenital distance, anogenital index (AGI), and histopathologic outcomes of the uterus were examined at 21 and 35 weeks for F0 mice and at 10 and 24 weeks for F1 mice.

Results

Both low and high DEHP exposures significantly decreased body weight in F0 at 21 weeks and in F1 at 10 and 24 weeks, while AGI was not significantly changed in response to DEHP exposure in both F0 and F1 mice. DEHP exposure induced endometrial stromal fibrosis, endometrial hyperplasia, and myometrial atrophy in the uterus of F1mice, while cystic hyperplasia and endometrial stromal sarcoma (ESS) were seen in the F0 after DEHP exposure at 35 weeks.

Conclusions

Long-term Exposure to DEHP significantly reduced body weight and induced pathological alterations in the uterus of both F0 and F1 mice. Dams exposed to high doses of DEHP developed ESS, suggesting that DEHP may have carcinogenic potential in the uterus. However, further research is necessary to confirm this finding.

目的：探讨长期暴露于邻苯二甲酸二（2-乙基己基）酯（DEHP）对女性生殖系统的影响。方法：妊娠期雌性CD-1小鼠（F0）口服0、100、500 mg/kg/d剂量的DEHP。出生后，将雌性后代（F1）分为三组，作为F0小鼠。因此，F0和F1小鼠都持续暴露于DEHP，直到它们被处死。F0小鼠在21和35 周以及F1小鼠在10和24 周时检测体重、肛门生殖器距离、肛门生殖器指数（AGI）和子宫组织病理学结果。结果：低DEHP和高DEHP暴露均显著降低F0在21 周的体重，F1在10和24 周的体重，而F0和F1小鼠的AGI对DEHP暴露均无显著变化。DEHP暴露诱导f1小鼠子宫间质纤维化、囊性增生和子宫肌瘤萎缩，DEHP暴露35 周后，F0出现囊性增生和子宫内膜间质肉瘤（ESS）。结论：长期暴露于DEHP可显著降低F0和F1小鼠的体重，并引起子宫病理改变。暴露于高剂量DEHP的母鼠出现ESS，提示DEHP可能在子宫中具有致癌潜力。然而，需要进一步的研究来证实这一发现。

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引用次数: 0

Angelicin attenuates sepsis-associated splenic injury by targeting NF-κB/JAK2/STAT3 and PI3K/Akt pathways to inhibit inflammation and apoptosis 当归素通过NF-κB/JAK2/STAT3和PI3K/Akt通路抑制炎症和细胞凋亡，减轻败血症相关脾损伤

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-26 DOI: 10.1016/j.taap.2026.117737

Enzhuang Pan , Huilin Sun , Zhihao Ma , Shasha Zhang , Yedan Liu , Zihan Xu , Yusa Li , Xiaomin Jin , Heng Wang , Jingquan Dong

Sepsis represents a clinical syndrome characterized by maladaptive host immune dysregulation in response to infection, leading to potentially fatal multiorgan dysfunction. As the largest secondary lymphoid organ in mammals, spleen tissue plays a fundamental role in immune defense. Angelicin (ANG), the main active ingredient in the traditional Chinese medicine Psoralea corylifolia Linn., possesses biological activities such as anti-inflammation and anti-apoptosis. This study established a mouse sepsis-associated splenic injury model using cecal ligation and puncture (CLP) to systematically analyze the protective effects of ANG and its underlying mechanisms. Additionally, the J774A.1 cell model stimulated with lipopolysaccharide (LPS) was used to further validate the pathway regulation phenomena observed in vivo. The results showed that ANG treatment significantly attenuated sepsis-associated splenic injury in mice. qPCR results showed that ANG downregulated pro-inflammatory and upregulated anti-inflammatory cytokine transcripts. TUNEL results showed that ANG treatment inhibited the ratio of TUNEL-positive cells. Further studies demonstrated that ANG suppressed inflammatory responses by inhibiting the NF-κB and JAK2/STAT3 pathways, and alleviate apoptosis by activating the PI3K/Akt pathway. Notably, the suppressive effect of ANG on JAK2/STAT3 pathway was dependent on the inhibition of the NF-κB pathway.

脓毒症是一种临床综合征，其特征是宿主对感染的免疫失调，导致可能致命的多器官功能障碍。脾组织作为哺乳动物最大的次级淋巴器官，在免疫防御中起着重要作用。当归素是中药补骨脂的主要活性成分。具有抗炎症、抗细胞凋亡等生物活性。本研究采用盲肠结扎穿刺法（CLP）建立小鼠败血症相关脾损伤模型，系统分析ANG的保护作用及其机制。此外，通过脂多糖（LPS）刺激的J774A.1细胞模型进一步验证在体内观察到的通路调节现象。结果表明，ANG治疗可显著减轻小鼠败血症相关脾损伤。qPCR结果显示，ANG下调促炎细胞因子转录，上调抗炎细胞因子转录。TUNEL结果显示，ANG处理抑制了TUNEL阳性细胞比例。进一步研究表明，ANG通过抑制NF-κB和JAK2/STAT3通路抑制炎症反应，通过激活PI3K/Akt通路减轻细胞凋亡。值得注意的是，ANG对JAK2/STAT3通路的抑制作用依赖于对NF-κB通路的抑制。

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引用次数: 0

Transcription factor TFAP2A drives EMT progress by activating BDKRB1 transcription: The potential mechanism by which TFAP2A promotes idiopathic pulmonary fibrosis 转录因子TFAP2A通过激活BDKRB1转录驱动EMT进展：TFAP2A促进特发性肺纤维化的潜在机制

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-24 DOI: 10.1016/j.taap.2026.117736

Jingwen Zhang , Xin Jin , Yajiao Sun , Rongyao Xia , Fuhui Chen

Epithelial-mesenchymal transition (EMT)-inducing signals trigger the accumulation of extracellular matrix, thereby contributing to organ pathology, including idiopathic pulmonary fibrosis (IPF). Transcription factor AP-2 alpha (TFAP2A) has been reported to facilitate the EMT process, but its function in IPF remain unknown. A mouse IPF model was established via single intratracheal instillation of bleomycin (BLM). Adenovirus carrying shRNA specifically targeting TFAP2A was administered 24 h prior to BLM challenge to achieve TFAP2A silencing. For in vitro studies, human bronchial epithelial cells (BEAS-2B) underwent lentivirus infection for 48 h to achieve TFAP2A silencing, followed by BLM treatment. We found that the expression of TFAP2A at both mRNA and protein levels was significantly upregulated in fibrotic lung tissue. TFAP2A knockdown alleviated BLM-induced lung injury and fibrosis, as evidenced by reduced collagen deposition and decreased expression of the fibrotic biomarkers α-SMA and Collagen I. Furthermore, TFAP2A silencing inhibited BLM-induced EMT in in the lungs of fibrotic mice, characterized by the upregulation of epithelial markers (Cytokeratin-8 and E-cadherin) and downregulation of mesenchymal markers (Fibronectin, Vimentin, and N-cadherin). In vitro assays demonstrated that BLM exposure increased α-SMA protein expression and promoted the EMT process in BEAS-2B cells, which were reversed by TFAP2A knockdown. Interestingly, TFAP2A significantly upregulated the RNA level of bradykinin receptor B1 (BDKRB1), a fibrosis-inducing factor. Mechanistically, TFAP2A activated BDKRB1 transcription by binding to the promoter of BDKRB1. Overexpression of BDKRB1 abrogated the protective effects of TFAP2A knockdown against lung fibrosis. Overall, our findings demonstrate that TFAP2A drives EMT progression and promotes IPF development by transcriptionally activating BDKRB1, identifying the TFAP2A/BDKRB1 axis as a potential therapeutic target in IPF.

上皮-间质转化（EMT）诱导信号触发细胞外基质的积累，从而导致器官病理，包括特发性肺纤维化（IPF）。据报道，转录因子AP-2 α (TFAP2A)可促进EMT过程，但其在IPF中的功能尚不清楚。采用单次气管内滴注博来霉素建立小鼠IPF模型。在BLM攻击前24 h给药携带特异性靶向TFAP2A的shRNA的腺病毒以实现TFAP2A的沉默。在体外研究中，人支气管上皮细胞（BEAS-2B）接受慢病毒感染48 h以实现TFAP2A沉默，然后进行BLM治疗。我们发现，TFAP2A在mRNA和蛋白水平上的表达在纤维化肺组织中均显著上调。TFAP2A敲低可减轻blm诱导的肺损伤和纤维化，表现为胶原沉积减少，纤维化生物标志物α-SMA和胶原i表达降低。此外，TFAP2A沉默可抑制blm诱导的纤维化小鼠肺EMT in，表现为上皮标志物（Cytokeratin-8和E-cadherin）上调，间充质标志物（Fibronectin, Vimentin, N-cadherin）下调。体外实验表明，BLM暴露增加了BEAS-2B细胞中α-SMA蛋白的表达，促进了EMT过程，这一过程被TFAP2A敲低逆转。有趣的是，TFAP2A显著上调缓激肽受体B1 （BDKRB1）的RNA水平，这是一种纤维化诱导因子。机制上，TFAP2A通过结合BDKRB1启动子激活BDKRB1转录。BDKRB1的过表达消除了TFAP2A敲低对肺纤维化的保护作用。总体而言，我们的研究结果表明，TFAP2A通过转录激活BDKRB1驱动EMT进展并促进IPF的发展，从而确定TFAP2A/BDKRB1轴是IPF的潜在治疗靶点。

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引用次数: 0

Expression of drug transporters in human allogenic transplanted kidneys in acute rejection 急性排斥反应中药物转运体在人同种异体移植肾中的表达。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2026-01-23 DOI: 10.1016/j.taap.2026.117735

J. Łapczuk-Romańska , J. Hybiak , K. Piotrowska , M. Marchelek-Myśliwiec , A. Wilk , M. Słojewski , E. Urasińska , M. Droździk

Kidney drug transporters, primarily located in the basolateral and apical membranes of proximal tubule cells, play a key role in the secretion and reabsorption of drugs and endogenous compounds. Recent studies have demonstrated that kidney diseases can alter transporter expression; however, the expression of these transporters in human transplanted kidneys, with and without rejection, remains unclear. Therefore, the aim of this study was to investigate the mRNA expression (qRT-PCR) and immunolocalization (via immunohistochemistry) of key ABC (ATP-binding cassette) (n = 14) and SLC (solute carriers) (n = 33) transporters in glomeruli and proximal tubule cells from human normal kidney (CTRL, n = 8), non-rejected transplanted kidney (AR-0, n = 7) and transplanted kidney under rejection process (AR-I, n = 8) from patients receiving immunosuppressive drugs. Our study shows that mRNA expression level of SLC22A4, SLC22A6, SLC22A7, SLC22A8, SLC28A1, SLC47A1, SLC22A11, SLC15A2, SLC16A1, ABCC2, ABCC5 and ABCC6 are statistically significantly downregulated, while SLC22A2, SLCO4A1 and ABCB1 are statistically upregulated in proximal tubule cells from rejected transplanted kidneys compared to controls. Immunohistochemistry revealed that OAT1, OAT3, OCT2, MATE1, MRP2, MRP6 and P-gp were primarily expressed in proximal tubule cells, with significantly lower protein expression of OAT1, OAT3, P-gp in AR-I and AR-0 biopsies compared to CTRL sections. These preliminary data suggest that the expression profile of kidney transporters may be altered in transplanted kidneys from patients treated with immunosuppressive drugs.

肾脏药物转运蛋白主要位于近端小管细胞的基底外侧和根尖膜，在药物和内源性化合物的分泌和重吸收中起关键作用。最近的研究表明，肾脏疾病可以改变转运蛋白的表达；然而，这些转运蛋白在人移植肾中的表达，是否有排斥反应，尚不清楚。因此,本研究的目的是探讨mRNA表达(存在)和immunolocalization(通过免疫组织化学)关键的ABC(磷酸腺苷磁带)(n = 14)和SLC(溶质载体)(n = 33)转运蛋白在肾小球和从人类正常的肾近端小管细胞(CTRL, n = 8),non-rejected移植肾(AR-0 n = 7)和移植肾排斥的过程(AR-I n = 8)接受免疫抑制药物的病人。我们的研究表明，与对照组相比，排斥移植肾近端小管细胞SLC22A4、SLC22A6、SLC22A7、SLC22A8、SLC28A1、SLC47A1、SLC22A11、SLC15A2、SLC16A1、ABCC2、ABCC5和ABCC6的mRNA表达水平在统计学上显著下调，而SLC22A2、SLCO4A1和ABCB1的mRNA表达水平在统计学上上调。免疫组化显示，OAT1、OAT3、OCT2、MATE1、MRP2、MRP6和P-gp主要在近端小管细胞中表达，AR-I和AR-0活检组织中OAT1、OAT3、P-gp的蛋白表达明显低于CTRL切片。这些初步数据表明，在接受免疫抑制药物治疗的患者移植肾脏中，肾脏转运蛋白的表达谱可能会发生改变。

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引用次数: 0