Toxicology and applied pharmacology最新文献

Corrigendum to "Toxicokinetics and in vivo genotoxicity after single dose oral gavage and intravenous administration of N-Nitrosonornicotine in Sprague Dawley rats" [Toxicology and Applied Pharmacology 505 (2025), 117572]. “单次灌胃和静脉给药n -亚硝基索烟碱对大鼠体内的毒性动力学和遗传毒性”[毒理学与应用药理学505(2025),117572]。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-12 DOI: 10.1016/j.taap.2025.117689

Mamata De, Ashley Fields, Guy Lagaud

引用次数: 0

Mechanistic insights into trimetazidine's protection against bladder ischemia-reperfusion injury via mirR-211/CHOP modulation and SIRT1/AMPK/PGC1α-mediated mitochondrial biogenesis 曲美他嗪通过mir -211/CHOP调节和SIRT1/AMPK/ pgc1 α-介导的线粒体生物发生对膀胱缺血-再灌注损伤的保护机制

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-11 DOI: 10.1016/j.taap.2025.117687

Sultan Alrashdi , Shimaa K. Mohamed , Mohamad Elbaz , Elsayed K. El-Sayed

Bladder ischemia, frequently associated with vascular insufficiency, contributes to lower urinary tract symptoms via oxidative stress, inflammation, endoplasmic reticulum (ER) stress, mitochondrial defect, and apoptosis. Ischemia-reperfusion (I/R) injury exacerbates these effects by generating excessive reactive oxygen species. Trimetazidine (TMZ), an anti-ischemic agent, has shown protective effects in several I/R models; however, its role in bladder injury remains insufficiently characterized. This study investigated the protective effect of TMZ against bladder I/R injury in rats, focusing on oxidative stress, inflammation, ER stress, mitochondrial biogenesis, microRNA regulation, and apoptosis. Forty rats were allocated into four groups: sham control, I/R, and two TMZ-pretreated groups (10 or 20 mg/kg/day, p.o., for 14 days) prior to I/R induction. Controls received Tween 80 vehicle. Bladder tissues were collected for biochemical, molecular, and histopathological analyses. TMZ showed protection by lowering MDA (∼43.5–60.8 %) and enhancing GSH (∼2–2.6 fold) and SOD activity (∼2–3.2 fold). ER stress was attenuated, with reduced p-PERK (∼29.4–63 %) and CHOP (∼29.1–60 %), alongside upregulation of mirR-211 (∼1.4–1.9 fold). TMZ restored mitochondrial biogenesis through increased SIRT1 (∼1.9–2.4 fold), PGC1α (∼2.1–4.3 fold), p-AMPK (∼3–6.3 fold), and ATP (∼2–2.8 fold). It also downregulated pro-apoptotic (Bax, Caspase 3) and pro-inflammatory (TNF-α, IL-1β) mediators. Histopathology revealed marked preservation of bladder architecture, particularly at 20 mg/kg. TMZ exerts strong antioxidant, anti-inflammatory, anti-apoptotic, and cytoprotective effects in bladder I/R injury via modulation of oxidative stress, ER stress, mitochondrial pathways, and the mirR-211/CHOP axis. These findings suggest that TMZ may represent a promising therapeutic candidate for ischemia-associated bladder dysfunction, providing a mechanistic basis for future translational and clinical investigation.

膀胱缺血常伴有血管功能不全，可通过氧化应激、炎症、内质网应激、线粒体缺陷和细胞凋亡等途径引起下尿路症状。缺血再灌注（I/R）损伤通过产生过多的活性氧而加剧了这些影响。曲美他嗪（TMZ）是一种抗缺血性药物，在几种I/R模型中显示出保护作用；然而，其在膀胱损伤中的作用尚未得到充分的研究。本研究主要从氧化应激、炎症、内质网应激、线粒体生物发生、microRNA调控和细胞凋亡等方面探讨TMZ对大鼠膀胱I/R损伤的保护作用。将40只大鼠分为4组：假对照组、I/R组和2个tmz预处理组（10或20 mg/kg/d， p.o，连续14 d）。控制室收到80辆车。收集膀胱组织进行生化、分子和组织病理学分析。TMZ通过降低MDA（~ 43.5 - 60.8%）、提高GSH（~ 2-2.6倍）和SOD活性（~ 2-3.2倍）显示出保护作用。内质网应激减弱，p-PERK（~ 29.4 - 63%）和CHOP（~ 29.1 - 60%）降低，同时mir -211上调（~ 1.4-1.9倍）。TMZ通过增加SIRT1（~ 1.9-2.4倍）、PGC1α（~ 2.1-4.3倍）、p-AMPK（~ 3-6.3倍）和ATP（~ 2-2.8倍）来恢复线粒体的生物发生。它还下调促凋亡（Bax, Caspase 3）和促炎症（TNF-α, IL-1β）介质。组织病理学显示膀胱结构明显保留，特别是在20mg /kg剂量下。TMZ通过调节氧化应激、内质网应激、线粒体通路和mir -211/CHOP轴，在膀胱I/R损伤中发挥强大的抗氧化、抗炎、抗凋亡和细胞保护作用。这些发现表明TMZ可能是一种有希望的治疗缺血性相关性膀胱功能障碍的候选药物，为未来的转化和临床研究提供了机制基础。

{"title":"Mechanistic insights into trimetazidine's protection against bladder ischemia-reperfusion injury via mirR-211/CHOP modulation and SIRT1/AMPK/PGC1α-mediated mitochondrial biogenesis","authors":"Sultan Alrashdi , Shimaa K. Mohamed , Mohamad Elbaz , Elsayed K. El-Sayed","doi":"10.1016/j.taap.2025.117687","DOIUrl":"10.1016/j.taap.2025.117687","url":null,"abstract":"<div><div>Bladder ischemia, frequently associated with vascular insufficiency, contributes to lower urinary tract symptoms via oxidative stress, inflammation, endoplasmic reticulum (ER) stress, mitochondrial defect, and apoptosis. Ischemia-reperfusion (I/R) injury exacerbates these effects by generating excessive reactive oxygen species. Trimetazidine (TMZ), an anti-ischemic agent, has shown protective effects in several I/R models; however, its role in bladder injury remains insufficiently characterized. This study investigated the protective effect of TMZ against bladder I/R injury in rats, focusing on oxidative stress, inflammation, ER stress, mitochondrial biogenesis, microRNA regulation, and apoptosis. Forty rats were allocated into four groups: sham control, I/R, and two TMZ-pretreated groups (10 or 20 mg/kg/day, p.o., for 14 days) prior to I/R induction. Controls received Tween 80 vehicle. Bladder tissues were collected for biochemical, molecular, and histopathological analyses. TMZ showed protection by lowering MDA (∼43.5–60.8 %) and enhancing GSH (∼2–2.6 fold) and SOD activity (∼2–3.2 fold). ER stress was attenuated, with reduced p-PERK (∼29.4–63 %) and CHOP (∼29.1–60 %), alongside upregulation of mirR-211 (∼1.4–1.9 fold). TMZ restored mitochondrial biogenesis through increased SIRT1 (∼1.9–2.4 fold), PGC1α (∼2.1–4.3 fold), p-AMPK (∼3–6.3 fold), and ATP (∼2–2.8 fold). It also downregulated pro-apoptotic (Bax, Caspase 3) and pro-inflammatory (TNF-α, IL-1β) mediators. Histopathology revealed marked preservation of bladder architecture, particularly at 20 mg/kg. TMZ exerts strong antioxidant, anti-inflammatory, anti-apoptotic, and cytoprotective effects in bladder I/R injury via modulation of oxidative stress, ER stress, mitochondrial pathways, and the mirR-211/CHOP axis. These findings suggest that TMZ may represent a promising therapeutic candidate for ischemia-associated bladder dysfunction, providing a mechanistic basis for future translational and clinical investigation.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117687"},"PeriodicalIF":3.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145737639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rupestonic acid targets ENO1 to exert antitumor activity and synergizes with paclitaxel in hepatocellular carcinoma. 鲁丙酮酸在肝细胞癌中靶向en1发挥抗肿瘤活性，并与紫杉醇协同作用。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-10 DOI: 10.1016/j.taap.2025.117688

Shulipan Mulati, Maierdan Maimaitiming, Jianing Ma, Miaomiao Zhang, Rongsong Jiang, Silafu Aibai, Xieraili Tuerxun

Rupestonic acid, a sesquiterpene, has protective properties against liver damage, inflammation, and tumor formation. Despite these known effects, its specific role and mechanism of action in combating hepatocellular carcinoma (HCC) remain insufficiently understood. This study aimed to investigate the anti-HCC effects of rupestonic acid and to identify its potential molecular targets. We employed cell counting kit-8 (CCK-8), colony formation, and flow cytometry assays to assess its impact on cell viability, proliferation, and apoptosis in HCC cell lines. Additionally, target fishing, cellular thermal shift assays (CETSA), ribonucleic acid interference, and Western blot (WB) were employed to identify rupestonic acid's protein targets in HCC cells. Our results showed that rupestonic acid significantly inhibited HCC cell proliferation, induced G0/G1 phase cell cycle arrest, and promoted apoptosis through the mitochondrial pathway. Target engagement studies employing an alkyne-rupestonic acid probe combined with mass spectrometry identified enolase 1 (ENO1) as a direct binding target, with CETSA confirming its destabilization. Furthermore, rupestonic acid inhibited the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box protein O (FOXO) signaling pathway, and rupestonic acid demonstrated a synergistic cytotoxic effect with paclitaxel (PTX). These findings suggest that rupestonic acid is a promising candidate for HCC treatment. They also underscore the potential of rupestonic acid in the design and development of lead compounds for HCC treatment and identify ENO1 as a viable therapeutic target.

鲁丙酮酸是一种倍半萜，具有防止肝损伤、炎症和肿瘤形成的保护作用。尽管有这些已知的作用，但其在对抗肝细胞癌（HCC）中的具体作用和作用机制尚不清楚。本研究旨在探讨鲁丙酮酸的抗hcc作用，并确定其潜在的分子靶点。我们采用细胞计数试剂盒-8 （CCK-8）、集落形成和流式细胞术检测来评估其对HCC细胞系细胞活力、增殖和凋亡的影响。此外，我们还利用靶捞、细胞热移法（CETSA）、核糖核酸干扰和Western blot （WB）等方法鉴定了肝细胞癌细胞中丙酮酸的蛋白靶点。我们的研究结果表明，丙酮酸通过线粒体途径显著抑制HCC细胞增殖，诱导G0/G1期细胞周期阻滞，促进细胞凋亡。采用炔-鲁丙酮酸探针结合质谱法进行靶结合研究，确定烯醇化酶1 （ENO1）为直接结合靶，CETSA证实了其不稳定性。鲁派通酸抑制磷酸肌醇3-激酶(PI3K)/蛋白激酶B (Akt)/叉头盒蛋白O （FOXO）信号通路，鲁派通酸与紫杉醇（PTX）具有协同细胞毒作用。这些发现表明鲁丙酮酸是一种很有希望的HCC治疗候选药物。他们还强调了丙酮酸在HCC治疗先导化合物的设计和开发中的潜力，并确定了ENO1作为可行的治疗靶点。

{"title":"Rupestonic acid targets ENO1 to exert antitumor activity and synergizes with paclitaxel in hepatocellular carcinoma.","authors":"Shulipan Mulati, Maierdan Maimaitiming, Jianing Ma, Miaomiao Zhang, Rongsong Jiang, Silafu Aibai, Xieraili Tuerxun","doi":"10.1016/j.taap.2025.117688","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117688","url":null,"abstract":"<p><p>Rupestonic acid, a sesquiterpene, has protective properties against liver damage, inflammation, and tumor formation. Despite these known effects, its specific role and mechanism of action in combating hepatocellular carcinoma (HCC) remain insufficiently understood. This study aimed to investigate the anti-HCC effects of rupestonic acid and to identify its potential molecular targets. We employed cell counting kit-8 (CCK-8), colony formation, and flow cytometry assays to assess its impact on cell viability, proliferation, and apoptosis in HCC cell lines. Additionally, target fishing, cellular thermal shift assays (CETSA), ribonucleic acid interference, and Western blot (WB) were employed to identify rupestonic acid's protein targets in HCC cells. Our results showed that rupestonic acid significantly inhibited HCC cell proliferation, induced G0/G1 phase cell cycle arrest, and promoted apoptosis through the mitochondrial pathway. Target engagement studies employing an alkyne-rupestonic acid probe combined with mass spectrometry identified enolase 1 (ENO1) as a direct binding target, with CETSA confirming its destabilization. Furthermore, rupestonic acid inhibited the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box protein O (FOXO) signaling pathway, and rupestonic acid demonstrated a synergistic cytotoxic effect with paclitaxel (PTX). These findings suggest that rupestonic acid is a promising candidate for HCC treatment. They also underscore the potential of rupestonic acid in the design and development of lead compounds for HCC treatment and identify ENO1 as a viable therapeutic target.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117688"},"PeriodicalIF":3.4,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of 2-isopropyl-N-2,3-trimethylbutyramide by a comprehensive toxicity study using gpt delta rats. 2-异丙基- n -2,3-三甲基丁胺在gpt三角洲大鼠的综合毒性研究中的评价。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-09 DOI: 10.1016/j.taap.2025.117686

Tatsuya Mitsumoto, Yuji Ishii, Norifumi Takimoto, Shinji Takasu, Moeka Namiki, Takeshi Toyoda, Kumiko Ogawa

2-Isopropyl-N-2,3-trimethylbutyramide (ITB) is a food-flavoring agent classified as an aliphatic amide. In 2016, the Joint FAO/WHO Expert Committee on Food Additives evaluated ITB and concluded that additional data on toxicity and in vivo genotoxicity are required for its safety evaluation. In this study, we comprehensively investigated ITB toxicity using reporter gene transgenic animals. Male F344 gpt delta rats were administered ITB by oral gavage at doses of 0, 5, 50, or 500 mg/kg/day for 13 weeks. Neurological symptoms were observed in the early phase of treatment at doses ≥50 mg/kg. Periportal hepatocellular vacuolation was observed histopathologically at doses ≥50 mg/kg, along with increased liver weight and serum alanine aminotransferase levels. Kidney weight increased and serum chloride levels decreased at doses ≥5 mg/kg, indicating that ITB exerted potential nephrotoxic effects at lower doses. Accordingly, the lowest observed adverse effect level in the present study was at 5 mg/kg/day. No significant changes in gpt and red/gam mutant frequencies were detected in the liver or kidney, demonstrating a lack of ITB genotoxicity. Immunohistochemical analysis of GST-P-positive foci also suggested that ITB showed no hepatocarcinogenic potential. Overall, our findings demonstrate that ITB induces hepatic and renal toxicity but shows no evidence of in vivo genotoxicity or hepatocarcinogenic potential, providing essential information for safety assessment.

2-异丙基- n -2,3-三甲基丁胺（ITB）是一种脂肪族酰胺类食品调味剂。2016年，粮农组织/世卫组织食品添加剂联合专家委员会对ITB进行了评估，并得出结论认为，需要更多的毒性和体内遗传毒性数据来进行安全性评估。在本研究中，我们利用报告基因转基因动物对ITB毒性进行了全面的研究。雄性F344 gpt delta大鼠分别以0、5、50或500 mg/kg/天灌胃给药，持续13 周。在剂量≥50 mg/kg的治疗早期观察到神经系统症状。当剂量≥50 mg/kg时，组织病理学观察到门静脉周围肝细胞空泡化，同时肝脏重量和血清丙氨酸转氨酶水平升高。剂量≥5 mg/kg时，肾脏重量增加，血清氯化物水平下降，表明低剂量ITB具有潜在的肾毒性作用。因此，在本研究中观察到的最低不良反应水平为5 mg/kg/天。在肝脏或肾脏中未检测到gpt和red/gam突变频率的显著变化，表明缺乏ITB遗传毒性。gst -p阳性灶的免疫组化分析也提示ITB无致肝癌潜能。总的来说，我们的研究结果表明，ITB诱导肝和肾毒性，但没有证据表明其体内遗传毒性或肝癌潜力，为安全性评估提供了必要的信息。

{"title":"Evaluation of 2-isopropyl-N-2,3-trimethylbutyramide by a comprehensive toxicity study using gpt delta rats.","authors":"Tatsuya Mitsumoto, Yuji Ishii, Norifumi Takimoto, Shinji Takasu, Moeka Namiki, Takeshi Toyoda, Kumiko Ogawa","doi":"10.1016/j.taap.2025.117686","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117686","url":null,"abstract":"<p><p>2-Isopropyl-N-2,3-trimethylbutyramide (ITB) is a food-flavoring agent classified as an aliphatic amide. In 2016, the Joint FAO/WHO Expert Committee on Food Additives evaluated ITB and concluded that additional data on toxicity and in vivo genotoxicity are required for its safety evaluation. In this study, we comprehensively investigated ITB toxicity using reporter gene transgenic animals. Male F344 gpt delta rats were administered ITB by oral gavage at doses of 0, 5, 50, or 500 mg/kg/day for 13 weeks. Neurological symptoms were observed in the early phase of treatment at doses ≥50 mg/kg. Periportal hepatocellular vacuolation was observed histopathologically at doses ≥50 mg/kg, along with increased liver weight and serum alanine aminotransferase levels. Kidney weight increased and serum chloride levels decreased at doses ≥5 mg/kg, indicating that ITB exerted potential nephrotoxic effects at lower doses. Accordingly, the lowest observed adverse effect level in the present study was at 5 mg/kg/day. No significant changes in gpt and red/gam mutant frequencies were detected in the liver or kidney, demonstrating a lack of ITB genotoxicity. Immunohistochemical analysis of GST-P-positive foci also suggested that ITB showed no hepatocarcinogenic potential. Overall, our findings demonstrate that ITB induces hepatic and renal toxicity but shows no evidence of in vivo genotoxicity or hepatocarcinogenic potential, providing essential information for safety assessment.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117686"},"PeriodicalIF":3.4,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Duloxetine-induced inhibition of voltage-gated K⁺ 3.1 (Kv3.1) channels and underlying electrophysiological mechanisms. 度洛西汀诱导的电压门控K+ 3.1 （Kv3.1）通道抑制及其电生理机制

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-08 DOI: 10.1016/j.taap.2025.117685

Jin Ryeol An, Junsu Jeong, Hye Ryung Kim, Sooa Lee, Armin Sultana, Raju Das, Joohan Woo, Seong Woo Choi, Young Min Bae, Yeji Lim, Hongzoo Park, Mi Seon Seo, Won Sun Park

Duloxetine is a serotonin-norepinephrine reuptake inhibitor that has been widely used to treat major depression; however, it has also been associated with severe neuropsychiatric side effects, including hallucinations, confusion, and suicide attempts. Nevertheless, the electrophysiological mechanisms underlying these adverse effects remain poorly understood. In this study, we investigated the effect of duloxetine on cloned neuronal rat voltage-gated K⁺ (Kv) channel subunit Kv3.1, stably expressed in Chinese hamster ovary (CHO) cells. Duloxetine inhibited the Kv3.1 current in a concentration-dependent manner with a half-maximal inhibitory concentration (IC₅₀) of 2.04 ± 0.27 μM (approximately 5-fold higher than the peak therapeutic plasma concentration of 0.4 μM) and a Hill coefficient of 0.94 ± 0.08. This inhibitory effect was associated with accelerated current inactivation. The association and dissociation rate constants for duloxetine were 43.43 ± 4.57 μM^-1·s^-1 and 122.12 ± 68.2 s^-1, respectively. In addition, duloxetine shifted the voltage dependence of Kv3.1 steady-state inactivation toward a more negative direction and led to use-dependent inhibition upon repetitive stimulation (1 and 2 Hz). Duloxetine also slowed recovery from inactivation. Docking analysis predicted that duloxetine binds to the central pore and interface between the voltage-sensing and pore domains on Kv3.1 channel, supporting the inhibitory mechanisms of duloxetine. Furthermore, duloxetine inhibited Kv3.1-mediated currents in SH-SY5Y human neuroblastoma cells. Taken together, our results indicate that duloxetine inhibits Kv3.1 expressed in CHO cells in concentration-, time-, and use (open and inactivated states)-dependent manners, independently of its anti-depressive effects.

度洛西汀是一种血清素-去甲肾上腺素再摄取抑制剂，已被广泛用于治疗重度抑郁症；然而，它也与严重的神经精神副作用有关，包括幻觉、精神错乱和自杀企图。然而，这些不良反应背后的电生理机制仍然知之甚少。本研究研究了度洛西汀对在中国仓鼠卵巢（CHO）细胞中稳定表达的克隆神经元型电压门控K+ (Kv)通道亚基Kv3.1的影响。度洛西汀抑制Kv3.1电流呈浓度依赖性，半最大抑制浓度（IC50）为2.04 ± 0.27 μM（约为治疗血药浓度峰值0.4 μM的5倍），Hill系数为0.94 ± 0.08。这种抑制作用与加速电流失活有关。度洛西汀的缔合速率常数为43.43 ± 4.57 μM-1·s-1，解离速率常数为122.12 ± 68.2 s-1。此外，度洛西汀将Kv3.1稳态失活的电压依赖性向更负的方向转移，并在重复刺激（1和2 Hz）时导致使用依赖性抑制。度洛西汀也减缓了失活后的恢复。对接分析预测，度洛西汀结合在Kv3.1通道的中心孔和电压感应与孔域之间的界面，支持度洛西汀的抑制机制。此外，度洛西汀抑制了SH-SY5Y人神经母细胞瘤细胞中kv3.1介导的电流。综上所述，我们的研究结果表明，度洛西汀以浓度、时间和使用（开放和失活状态）依赖的方式抑制CHO细胞中Kv3.1的表达，而不依赖于其抗抑郁作用。

{"title":"Duloxetine-induced inhibition of voltage-gated K<sup>+</sup> 3.1 (Kv3.1) channels and underlying electrophysiological mechanisms.","authors":"Jin Ryeol An, Junsu Jeong, Hye Ryung Kim, Sooa Lee, Armin Sultana, Raju Das, Joohan Woo, Seong Woo Choi, Young Min Bae, Yeji Lim, Hongzoo Park, Mi Seon Seo, Won Sun Park","doi":"10.1016/j.taap.2025.117685","DOIUrl":"https://doi.org/10.1016/j.taap.2025.117685","url":null,"abstract":"<p><p>Duloxetine is a serotonin-norepinephrine reuptake inhibitor that has been widely used to treat major depression; however, it has also been associated with severe neuropsychiatric side effects, including hallucinations, confusion, and suicide attempts. Nevertheless, the electrophysiological mechanisms underlying these adverse effects remain poorly understood. In this study, we investigated the effect of duloxetine on cloned neuronal rat voltage-gated K<sup>+</sup> (Kv) channel subunit Kv3.1, stably expressed in Chinese hamster ovary (CHO) cells. Duloxetine inhibited the Kv3.1 current in a concentration-dependent manner with a half-maximal inhibitory concentration (IC<sub>50</sub>) of 2.04 ± 0.27 μM (approximately 5-fold higher than the peak therapeutic plasma concentration of 0.4 μM) and a Hill coefficient of 0.94 ± 0.08. This inhibitory effect was associated with accelerated current inactivation. The association and dissociation rate constants for duloxetine were 43.43 ± 4.57 μM<sup>-1</sup>·s<sup>-1</sup> and 122.12 ± 68.2 s<sup>-1</sup>, respectively. In addition, duloxetine shifted the voltage dependence of Kv3.1 steady-state inactivation toward a more negative direction and led to use-dependent inhibition upon repetitive stimulation (1 and 2 Hz). Duloxetine also slowed recovery from inactivation. Docking analysis predicted that duloxetine binds to the central pore and interface between the voltage-sensing and pore domains on Kv3.1 channel, supporting the inhibitory mechanisms of duloxetine. Furthermore, duloxetine inhibited Kv3.1-mediated currents in SH-SY5Y human neuroblastoma cells. Taken together, our results indicate that duloxetine inhibits Kv3.1 expressed in CHO cells in concentration-, time-, and use (open and inactivated states)-dependent manners, independently of its anti-depressive effects.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":" ","pages":"117685"},"PeriodicalIF":3.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting sonic hedgehog (shh) signaling pathways by the concentration–dependent topical resveratrol for protection from cyclophosphamide-induced alopecia in a mouse model 通过浓度依赖性外用白藜芦醇靶向sonic hedgehog （shh）信号通路，保护小鼠模型免受环磷酰胺诱导的脱发。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-08 DOI: 10.1016/j.taap.2025.117681

Aml A. El-Din, Dina M. Tahoon, Maaly A. Abd Elmaaboud, Fleur F. Abd Elmoniem, Amany A. Abdin

Background

Chemotherapy-induced alopecia (CIA) is a common and inevitable side effect of systemic cancer treatment. There is an urgent need for novel therapies for cancer patients suffering from hair loss to improve their quality of life. This study aimed to investigate the potential protective effect of concentration-dependent topical resveratrol on hair follicles via targeting sonic hedgehog (Shh) signaling and its related downstream regulatory (Sirt-1), proliferative (Ki-67), and apoptotic status (caspase-3 and Bcl-2) pathways in cyclophosphamide-induced alopecia in female C57BL/6 mice model. Methods: All animals were subjected to depilation at the start of the experiment, then mice were divided into 5 equal groups as follows: Control group, cyclophosphamide (CPA)-untreated alopecia group, minoxidil (MXL) + CPA-alopecia, Resveratrol low concentration (RSV L10) + CPA-alopecia, Resveratrol high concentration (RSV H80) + CPA-alopecia. The effects of these drugs on hair coverage score, Shh signaling, Sirt-1, proliferation, and apoptosis were assessed. Results: Low concentration of topical RSV showed a significant increase in hair coverage score. Shh, Sirt-1, immunohistochemical expression levels of Ki-67, and Bcl-2 were significantly elevated, significantly decreasing caspase-3 expression in skin tissue. Moreover, the superiority extended to include histopathological findings and dermatoscopic skin monitoring compared to the groups that received either topical minoxidil 2 % or RSV at high concentration. Conclusion: Topical low-dose resveratrol protects against CIA by activating Shh signaling and modulating follicular proliferative and apoptotic pathways.

背景：化疗性脱发（CIA）是全身性癌症治疗中常见且不可避免的副作用。目前迫切需要一种新的治疗脱发癌症患者的方法来改善他们的生活质量。本研究旨在探讨浓度依赖性外用白藜芦醇在雌性C57BL/6小鼠模型中，通过靶向sonic hedgehog （Shh）信号通路及其相关的下游调控（Sirt-1）、增殖（Ki-67）和凋亡状态（caspase-3和Bcl-2）通路对雌性C57BL/6小鼠模型中毛囊的潜在保护作用。方法：所有动物在实验开始时进行脱毛，然后将小鼠分为5组：对照组，环磷酰胺(CPA)-未处理的脱发组，米诺地尔（MXL） + CPA-脱发，白藜芦醇低浓度（RSV L10） + CPA-脱发，白藜芦醇高浓度（RSV H80） + CPA-脱发。评估这些药物对毛发覆盖评分、Shh信号、Sirt-1、增殖和凋亡的影响。结果：局部低浓度RSV可显著提高毛发覆盖评分。皮肤组织中Shh、Sirt-1、Ki-67、Bcl-2免疫组化表达水平显著升高，caspase-3表达显著降低。此外，与外用米诺地尔2 %或高浓度RSV组相比，优势扩展到包括组织病理学结果和皮肤镜下皮肤监测。结论：局部低剂量白藜芦醇通过激活Shh信号和调节滤泡增殖和凋亡途径来预防CIA。

{"title":"Targeting sonic hedgehog (shh) signaling pathways by the concentration–dependent topical resveratrol for protection from cyclophosphamide-induced alopecia in a mouse model","authors":"Aml A. El-Din, Dina M. Tahoon, Maaly A. Abd Elmaaboud, Fleur F. Abd Elmoniem, Amany A. Abdin","doi":"10.1016/j.taap.2025.117681","DOIUrl":"10.1016/j.taap.2025.117681","url":null,"abstract":"<div><h3>Background</h3><div>Chemotherapy-induced alopecia (CIA) is a common and inevitable side effect of systemic cancer treatment. There is an urgent need for novel therapies for cancer patients suffering from hair loss to improve their quality of life. This study aimed to investigate the potential protective effect of concentration-dependent topical resveratrol on hair follicles via targeting sonic hedgehog (Shh) signaling and its related downstream regulatory (Sirt-1), proliferative (Ki-67), and apoptotic status (caspase-3 and Bcl-2) pathways in cyclophosphamide-induced alopecia in female C57BL/6 mice model. Methods: All animals were subjected to depilation at the start of the experiment, then mice were divided into 5 equal groups as follows: Control group, cyclophosphamide (CPA)-untreated alopecia group, minoxidil (MXL) + CPA-alopecia, Resveratrol low concentration (RSV L10) + CPA-alopecia, Resveratrol high concentration (RSV H80) + CPA-alopecia. The effects of these drugs on hair coverage score, Shh signaling, Sirt-1, proliferation, and apoptosis were assessed. Results: Low concentration of topical RSV showed a significant increase in hair coverage score. Shh, Sirt-1, immunohistochemical expression levels of Ki-67, and Bcl-2 were significantly elevated, significantly decreasing caspase-3 expression in skin tissue. Moreover, the superiority extended to include histopathological findings and dermatoscopic skin monitoring compared to the groups that received either topical minoxidil 2 % or RSV at high concentration. Conclusion: Topical low-dose resveratrol protects against CIA by activating Shh signaling and modulating follicular proliferative and apoptotic pathways.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117681"},"PeriodicalIF":3.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Andrographolide-induced PANoptosis underlies its multiple organ toxicity in mice 穿心莲内酯诱导的PANoptosis是其对小鼠多器官毒性的基础。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-08 DOI: 10.1016/j.taap.2025.117682

Na Lu , Yuan-wen Cai , Qi-hai Cai , Xiu-wen Liang , Nuo Sun , On-kei Chan , Zi-jian Shi , Bo Hu , Xian-hui He , Qing-bing Zha , Dong-yun Ouyang

Andrographolide (Andro), the major bioactive component of Andrographis paniculata, exhibits potent anti-inflammatory properties but has raised safety concerns due to reported organ toxicity. This study aimed to investigate the mechanisms underlying Andro's in vitro and in vivo toxicity. In mice, single dose (≤100 mg/kg) Andro administration showed no acute toxicity, with no overt histopathological organ injury. But repeated administration of the same dose of Andro triggered damage in lung, liver, uterus, and kidney, characterized by pulmonary alveolar disruption, renal tubular edema, and elevated serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT). Concurrent with systemic injury, PANoptosis was induced by Andro in these organs, as evidenced by the activation of caspase-1/−8/−3 (apoptosis), gasdermin D/E (GSDMD/E, pyroptosis), and MLKL (necroptosis), indicating the correlation between PANoptosis and organ toxicity. In vitro, Andro caused lytic cell death in macrophages and other cells in a time- and dose-dependent manner. During this process, Andro induced rapid activation of caspase-8, followed by caspase-1/−3 and GSDME cleavage and phosphorylation of MLKL (p-MLKL), indicative of the activation of the PANoptosis signaling pathway. Consistent with this, Andro induced lytic cell death was markedly attenuated by caspase-1 inhibitor VX-765, pan-caspase inhibitors (IDN-6556, Z-VAD-FMK) and GSDMD/E inhibitor (disulfiram). In addition, RIPK1 inhibition (by Nec-1) partially reduced cell death, confirming RIPK1-dependent necroptosis as a minor contributor. In conclusion, our data establish PANoptosis as an important mechanism of Andro-induced organ injury, providing a mechanistic framework for Andro's dichotomous bioactivity, informing evidence-based dosing strategies to maximize therapeutic efficacy while mitigating toxicity risks in clinical practice.

穿心莲内酯（Andrographolide, Andro）是穿心莲的主要生物活性成分，具有有效的抗炎特性，但由于器官毒性的报道而引起了安全性问题。本研究旨在探讨安德罗的体外和体内毒性机制。小鼠单次给药（≤100 mg/kg）无急性毒性，无明显的组织病理学器官损伤。但重复给药相同剂量的安卓可引起肺、肝、子宫和肾脏损伤，表现为肺泡破裂、肾小管水肿和血清谷草转氨酶(AST)/丙氨酸转氨酶（ALT）升高。在系统性损伤的同时，Andro在这些器官中诱导PANoptosis，通过激活caspase-1/-8/-3（凋亡），gasdermin D/E （GSDMD/E，焦亡）和MLKL（坏死）证明，PANoptosis与器官毒性相关。在体外，安德罗引起巨噬细胞和其他细胞的溶解性细胞死亡，并呈时间和剂量依赖性。在这个过程中，Andro诱导了caspase-8的快速激活，随后caspase-1/-3和GSDME的裂解和MLKL （p-MLKL）的磷酸化，表明PANoptosis信号通路的激活。与此一致的是，caspase-1抑制剂VX-765、泛caspase抑制剂（IDN-6556、Z-VAD-FMK）和GSDMD/E抑制剂（双硫仑）显著减轻了Andro诱导的裂解细胞死亡。此外，RIPK1抑制（通过Nec-1）部分减少了细胞死亡，证实RIPK1依赖性坏死下垂是一个次要因素。总之，我们的数据表明PANoptosis是android诱导的器官损伤的重要机制，为android的二分生物活性提供了一个机制框架，为临床实践中提供了基于证据的剂量策略，以最大限度地提高治疗效果，同时降低毒性风险。

{"title":"Andrographolide-induced PANoptosis underlies its multiple organ toxicity in mice","authors":"Na Lu , Yuan-wen Cai , Qi-hai Cai , Xiu-wen Liang , Nuo Sun , On-kei Chan , Zi-jian Shi , Bo Hu , Xian-hui He , Qing-bing Zha , Dong-yun Ouyang","doi":"10.1016/j.taap.2025.117682","DOIUrl":"10.1016/j.taap.2025.117682","url":null,"abstract":"<div><div>Andrographolide (Andro), the major bioactive component of <em>Andrographis paniculata</em>, exhibits potent anti-inflammatory properties but has raised safety concerns due to reported organ toxicity. This study aimed to investigate the mechanisms underlying Andro's <em>in vitro</em> and <em>in vivo</em> toxicity. In mice, single dose (≤100 mg/kg) Andro administration showed no acute toxicity, with no overt histopathological organ injury. But repeated administration of the same dose of Andro triggered damage in lung, liver, uterus, and kidney, characterized by pulmonary alveolar disruption, renal tubular edema, and elevated serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT). Concurrent with systemic injury, PANoptosis was induced by Andro in these organs, as evidenced by the activation of caspase-1/−8/−3 (apoptosis), gasdermin D/E (GSDMD/E, pyroptosis), and MLKL (necroptosis), indicating the correlation between PANoptosis and organ toxicity. <em>In vitro</em>, Andro caused lytic cell death in macrophages and other cells in a time- and dose-dependent manner. During this process, Andro induced rapid activation of caspase-8, followed by caspase-1/−3 and GSDME cleavage and phosphorylation of MLKL (p-MLKL), indicative of the activation of the PANoptosis signaling pathway. Consistent with this, Andro induced lytic cell death was markedly attenuated by caspase-1 inhibitor VX-765, pan-caspase inhibitors (IDN-6556, <em>Z</em>-VAD-FMK) and GSDMD/E inhibitor (disulfiram). In addition, RIPK1 inhibition (by Nec-1) partially reduced cell death, confirming RIPK1-dependent necroptosis as a minor contributor. In conclusion, our data establish PANoptosis as an important mechanism of Andro-induced organ injury, providing a mechanistic framework for Andro's dichotomous bioactivity, informing evidence-based dosing strategies to maximize therapeutic efficacy while mitigating toxicity risks in clinical practice.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117682"},"PeriodicalIF":3.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gastrodin alleviates alcohol-induced developmental and neurotoxic effects in zebrafish larvae by suppressing ferroptosis via regulating the Nrf2/GPX4 signaling pathway 天麻素通过调节Nrf2/GPX4信号通路抑制铁下垂，减轻酒精诱导的斑马鱼幼鱼发育和神经毒性作用。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-08 DOI: 10.1016/j.taap.2025.117684

Ruijing Li , Weili Yang , Lijuan Zheng , Xingxue Yan , Cuihua Liu , Yaodong Zhang , Jitong Li

Prenatal alcohol exposure is a leading cause of developmental abnormalities and neurobehavioral deficits, collectively known as fetal alcohol spectrum disorder (FASD). The underlying molecular mechanisms, however, are not fully elucidated, hindering the development of effective therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key pathological process in various diseases. Gastrodin (GAS), the primary bioactive component of Gastrodia elata, has demonstrated potent antioxidant and neuroprotective properties. This study aimed to investigate the protective effects of GAS against alcohol-induced developmental and neurotoxic damage and to elucidate the underlying molecular mechanisms. Using a zebrafish larval model, we found that exposure to 200 mM alcohol from 2 to 24 hours post-fertilization (hpf) induced significant developmental toxicity, including a decreased hatching rate, body length and eye diameter, and increased morphological malformations in larvae. Alcohol-exposed larvae also exhibited severe neurobehavioral deficits, characterized by a reduction in movement distance and average velocity in dark conditions. Mechanistically, alcohol exposure triggered ferroptosis, evidenced by an increase in intracellular Fe²⁺, malondialdehyde (MDA), and reactive oxygen species (ROS) levels, alongside a decrease in the levels of glutathione (GSH) and reduced glutathione peroxidase 4 (GPX4) and the nuclear factor erythroid 2-related factor 2 (Nrf2) activities. Co-treatment with GAS (200 mg/L) significantly ameliorated these alcohol-induced developmental and neurobehavioral defects. GAS administration effectively suppressed the hallmarks of ferroptosis by restoring the ROS level and altering the expression of genes related to oxidative stress. In addition, GAS suppressed alcohol-induced cell apoptosis, downregulated caspase3b, bax, caspase8, and upregulated bcl2 in mRNA levels. Molecular analysis revealed that GAS exerts its anti-ferroptotic effect by activating Nrf2/GPX4 signaling pathway, which was suppressed by alcohol. Our findings indicate that ferroptosis plays a key role in alcohol-induced developmental neurotoxicity, and GAS provides protection by activating the Nrf2/GPX4 axis. This suggests that GAS could be a potential therapeutic option for reducing the negative effects of prenatal alcohol exposure.

产前酒精暴露是发育异常和神经行为缺陷的主要原因，统称为胎儿酒精谱系障碍（FASD）。然而，潜在的分子机制尚未完全阐明，阻碍了有效治疗策略的发展。铁死亡是一种由脂质过氧化驱动的铁依赖性细胞死亡形式，已成为多种疾病的关键病理过程。天麻素（GAS）是天麻的主要生物活性成分，具有有效的抗氧化和神经保护作用。本研究旨在探讨GAS对酒精诱导的发育和神经毒性损伤的保护作用，并阐明其潜在的分子机制。利用斑马鱼幼虫模型，我们发现在受精后2至24 h暴露于200 mM酒精（hpf）会引起显著的发育毒性，包括孵化率、体长和眼直径降低，以及幼虫形态畸形增加。暴露于酒精的幼虫也表现出严重的神经行为缺陷，其特征是在黑暗条件下移动距离和平均速度减少。从机制上说，酒精暴露引发铁死亡，细胞内Fe2+、丙二醛（MDA）和活性氧（ROS）水平升高，谷胱甘肽（GSH）水平降低，谷胱甘肽过氧化物酶4 （GPX4）水平降低，核因子红细胞2相关因子2 （Nrf2）活性降低。与GAS（200 mg/L）联合治疗可显著改善这些酒精诱导的发育和神经行为缺陷。通过恢复ROS水平和改变与氧化应激相关的基因表达，GAS管理有效地抑制了铁下垂的标志。此外，GAS抑制酒精诱导的细胞凋亡，下调caspase3b、bax、caspase8 mRNA水平，上调bcl2 mRNA水平。分子分析表明，GAS通过激活Nrf2/GPX4信号通路发挥其抗铁腐作用，而该信号通路被酒精抑制。我们的研究结果表明，铁ptosis在酒精诱导的发育性神经毒性中起关键作用，而GAS通过激活Nrf2/GPX4轴提供保护。这表明GAS可能是一种潜在的治疗选择，可以减少产前酒精暴露的负面影响。

{"title":"Gastrodin alleviates alcohol-induced developmental and neurotoxic effects in zebrafish larvae by suppressing ferroptosis via regulating the Nrf2/GPX4 signaling pathway","authors":"Ruijing Li , Weili Yang , Lijuan Zheng , Xingxue Yan , Cuihua Liu , Yaodong Zhang , Jitong Li","doi":"10.1016/j.taap.2025.117684","DOIUrl":"10.1016/j.taap.2025.117684","url":null,"abstract":"<div><div>Prenatal alcohol exposure is a leading cause of developmental abnormalities and neurobehavioral deficits, collectively known as fetal alcohol spectrum disorder (FASD). The underlying molecular mechanisms, however, are not fully elucidated, hindering the development of effective therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key pathological process in various diseases. Gastrodin (GAS), the primary bioactive component of <em>Gastrodia elata</em>, has demonstrated potent antioxidant and neuroprotective properties. This study aimed to investigate the protective effects of GAS against alcohol-induced developmental and neurotoxic damage and to elucidate the underlying molecular mechanisms. Using a zebrafish larval model, we found that exposure to 200 mM alcohol from 2 to 24 hours post-fertilization (hpf) induced significant developmental toxicity, including a decreased hatching rate, body length and eye diameter, and increased morphological malformations in larvae. Alcohol-exposed larvae also exhibited severe neurobehavioral deficits, characterized by a reduction in movement distance and average velocity in dark conditions. Mechanistically, alcohol exposure triggered ferroptosis, evidenced by an increase in intracellular Fe<sup>2+</sup>, malondialdehyde (MDA), and reactive oxygen species (ROS) levels, alongside a decrease in the levels of glutathione (GSH) and reduced glutathione peroxidase 4 (GPX4) and the nuclear factor erythroid 2-related factor 2 (Nrf2) activities. Co-treatment with GAS (200 mg/L) significantly ameliorated these alcohol-induced developmental and neurobehavioral defects. GAS administration effectively suppressed the hallmarks of ferroptosis by restoring the ROS level and altering the expression of genes related to oxidative stress. In addition, GAS suppressed alcohol-induced cell apoptosis, downregulated <em>caspase3b</em>, <em>bax</em>, <em>caspase8</em>, and upregulated <em>bcl2</em> in mRNA levels. Molecular analysis revealed that GAS exerts its anti-ferroptotic effect by activating Nrf2/GPX4 signaling pathway, which was suppressed by alcohol. Our findings indicate that ferroptosis plays a key role in alcohol-induced developmental neurotoxicity, and GAS provides protection by activating the Nrf2/GPX4 axis. This suggests that GAS could be a potential therapeutic option for reducing the negative effects of prenatal alcohol exposure.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117684"},"PeriodicalIF":3.4,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exposure to a PFAS mixture alters cholesterol lipoprotein subfractions and induces a foam cell-like aortic macrophage expression profile in hyperlipidemic LDLr−/− mice 暴露于PFAS混合物可改变高脂血症LDLr-/-小鼠的胆固醇脂蛋白亚组分并诱导泡沫细胞样主动脉巨噬细胞表达谱。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-07 DOI: 10.1016/j.taap.2025.117683

Katherine Roth , Zhao Yang , Manisha Agarwal , Katherine Gurdziel , Michael C. Petriello

Per- and polyfluoroalkyl substances (PFAS) have been associated with elevated cholesterol, a clinically-relevant risk factor for atherosclerosis. Macrophages are key mediators of atherosclerosis progression through their polarization to various subsets including inflammatory macrophages and foam cells. However, studies examining impacts of PFAS on macrophages in the context of atherosclerosis are lacking. Here, we investigate the impact of PFAS mixtures on cholesterol subfractions and transcriptional profiling of aortic macrophages during early atherosclerosis. Male low density lipoprotein receptor (Ldlr) deficient mice were fed an atherogenic diet and exposed via their drinking water to a mixture of 5 PFAS (i.e., PFOA, PFOS, PFNA, PFHxS, and GenX), each at a concentration of 2 mg/L, for 7 weeks. Circulating cholesterol subfractions and subclasses were analyzed, and aortic macrophages were isolated using immuno-magnetic beads for RNA-sequencing. Total circulating cholesterol was significantly elevated by 10 % following PFAS exposure which was predominately due to a 25 % increase in intermediate-density lipoprotein (IDL). The densest subfraction of low-density lipoprotein, LDL7, also increased by 206 %. RNA sequencing of aortic macrophages revealed PFAS downregulated 389 and upregulated 593 genes; many related to lipid metabolism and foam cell development. Specifically, expression of inflammatory mediators chemokine (C-X-C motif) ligand 2 (Cxcl2) and chemokine (C-X-C motif) ligand 17 (Cxcl17) were significantly increased due to PFAS (2.4 log2 fold change and 10.4 log2 FC respectively) and levels of lipid metabolism and transport genes fatty acid binding protein 4 (Fabp4) and fatty acid synthase (Fasn) were similarly increased (3 log2 FC and 5.2 log2 FC respectively). This work provides additional mechanistic information related to PFAS-mediated acceleration of atherosclerosis.

全氟和多氟烷基物质（PFAS）与胆固醇升高有关，胆固醇升高是动脉粥样硬化的临床相关危险因素。巨噬细胞是动脉粥样硬化进展的关键介质，通过其分化为各种亚群，包括炎性巨噬细胞和泡沫细胞。然而，在动脉粥样硬化的背景下，研究PFAS对巨噬细胞的影响是缺乏的。在这里，我们研究了PFAS混合物对动脉粥样硬化早期主动脉巨噬细胞胆固醇亚组分和转录谱的影响。雄性低密度脂蛋白受体（Ldlr）缺陷小鼠喂食致动脉粥样硬化饮食，并通过饮用水暴露于5种PFAS（即PFOA， PFOS， PFNA， PFHxS和GenX）的混合物中，每种浓度为2 mg/L，持续7 周。分析循环胆固醇亚组分和亚类，并利用免疫磁珠分离主动脉巨噬细胞进行rna测序。暴露于PFAS后，总循环胆固醇显著升高了10 %，这主要是由于中密度脂蛋白（IDL）增加了25 %。低密度脂蛋白中密度最大的亚段LDL7也增加了206% %。主动脉巨噬细胞RNA测序结果显示，PFAS下调389个基因，上调593个基因；许多与脂质代谢和泡沫细胞发育有关。其中，炎症介质趋化因子（C-X-C基序）配体2 （Cxcl2）和趋化因子（C-X-C基序）配体17 （Cxcl17）的表达因PFAS而显著升高（分别为2.4 log2倍和10.4 log2 FC），脂质代谢和转运基因脂肪酸结合蛋白4 （Fabp4）和脂肪酸合成酶（Fasn）水平同样升高（分别为3 log2 FC和5.2 log2 FC）。这项工作提供了与pfas介导的动脉粥样硬化加速相关的额外机制信息。

{"title":"Exposure to a PFAS mixture alters cholesterol lipoprotein subfractions and induces a foam cell-like aortic macrophage expression profile in hyperlipidemic LDLr−/− mice","authors":"Katherine Roth , Zhao Yang , Manisha Agarwal , Katherine Gurdziel , Michael C. Petriello","doi":"10.1016/j.taap.2025.117683","DOIUrl":"10.1016/j.taap.2025.117683","url":null,"abstract":"<div><div><em>Per</em>- and polyfluoroalkyl substances (PFAS) have been associated with elevated cholesterol, a clinically-relevant risk factor for atherosclerosis. Macrophages are key mediators of atherosclerosis progression through their polarization to various subsets including inflammatory macrophages and foam cells. However, studies examining impacts of PFAS on macrophages in the context of atherosclerosis are lacking. Here, we investigate the impact of PFAS mixtures on cholesterol subfractions and transcriptional profiling of aortic macrophages during early atherosclerosis. Male low density lipoprotein receptor (Ldlr) deficient mice were fed an atherogenic diet and exposed via their drinking water to a mixture of 5 PFAS (i.e., PFOA, PFOS, PFNA, PFHxS, and GenX), each at a concentration of 2 mg/L, for 7 weeks. Circulating cholesterol subfractions and subclasses were analyzed, and aortic macrophages were isolated using immuno-magnetic beads for RNA-sequencing. Total circulating cholesterol was significantly elevated by 10 % following PFAS exposure which was predominately due to a 25 % increase in intermediate-density lipoprotein (IDL). The densest subfraction of low-density lipoprotein, LDL7, also increased by 206 %. RNA sequencing of aortic macrophages revealed PFAS downregulated 389 and upregulated 593 genes; many related to lipid metabolism and foam cell development. Specifically, expression of inflammatory mediators chemokine (C-X-C motif) ligand 2 (<em>Cxcl2</em>) and chemokine (C-X-C motif) ligand 17 (<em>Cxcl17</em>) were significantly increased due to PFAS (2.4 log2 fold change and 10.4 log2 FC respectively) and levels of lipid metabolism and transport genes fatty acid binding protein 4 (<em>Fabp4</em>) and fatty acid synthase (<em>Fasn</em>) were similarly increased (3 log2 FC and 5.2 log2 FC respectively). This work provides additional mechanistic information related to PFAS-mediated acceleration of atherosclerosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117683"},"PeriodicalIF":3.4,"publicationDate":"2025-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145715979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to "Arsenic exposure affects Pdgfrα stromal cells in the ileum of the small intestine" [Toxicology and Applied Pharmacology Volume 505, December 2025, 117582]. “砷暴露影响小肠回肠中Pdgfrα基质细胞”的更正[毒理学和应用药理学卷505，十二月2025,117582]。

IF 3.4 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-12-06 DOI: 10.1016/j.taap.2025.117677

Scott W Ventrello, Kayla A Lea, Lisa J Bain

引用次数: 0