Toxicology and applied pharmacology最新文献_第9页

Engineering human cerebral organoids to explore mechanisms of arsenic-induced developmental neurotoxicity

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-01-20 DOI: 10.1016/j.taap.2025.117230

Xian Wu , Anna Kreutz , Darlene Dixon, Erik J. Tokar

Modeling brain development and function is challenging due to complexity of the organ. Human pluripotent stem cell (PSC)-derived brain-like organoids provide new tools to study the human brain. Compared with traditional in vivo toxicological studies, these 3D models, together with 2D cellular assays, enhance our understanding of the mechanisms of developmental neurotoxicity (DNT) during the early stages of neurogenesis and offer numerous advantages including a rapid, cost-effective approach for understanding compound mechanisms and assessing chemical safety. Arsenic (As) exposure is associated with DNT, although the mechanisms involved are not well-defined. Here, we used 3D PSC-derived embryoid bodies (EBs) to recapitulate events involved in embryogenesis and neurogenesis before neural induction, and EB-derived cerebral organoids to mimic neural development in vivo. As (0.5 μM; 35 ppb) increased ectoderm differentiation within the EBs by upregulating genes (PAX6, SOX1) critical for embryonic development. Histological staining of EBs showed As disrupted neural rosette structures. qPCR and RNA-seq showed As inhibited expression of markers of mature neural cells (MAP2+/vGLUT2+) and astrocytes (GFAP+). In organoids, Ingenuity Pathway Analysis was used to identify the top 5 pathways affected by As exposure, and Gene Ontology enrichment analysis found several key signaling pathways to be inhibited by As exposure. These data provide insights into pathways contributing to As-induced inhibition of neurite outgrowth and disrupted neural rosette structures in the 2D neurite outgrowth assay and in organoids, respectively. Results herein show this multipronged 2D/3D approach can provide valuable insights into cellular events and molecular mechanisms of As-induced DNT.

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引用次数: 0

PPARβ/δ agonist GW0742 mitigates acute liver damage induced by acetaminophen overdose in mice PPARβ/δ激动剂GW0742减轻对乙酰氨基酚过量引起的小鼠急性肝损伤。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-01-01 DOI: 10.1016/j.taap.2024.117180

Lin Wang , Jing-Hui Chen , Yan-Jing Zhang , Ming-Bao Zhang , Tao Zeng

Liver damage caused by acetaminophen (APAP) overdose remains a worldwide medical problem. New therapeutic medicines for APAP poisoning are needed as the efficacy of the only antidote, N-acetyl-cysteine (NAC), significantly decreases if administered after 8 h of APAP intake and massive APAP overdose remains to induce hepatotoxicity despite the timely administration of NAC. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) possesses versatile roles including regulation of lipid homeostasis and anti-inflammation in the liver. This study aimed to investigate the effects of GW0742, one specific PPARβ/δ agonist, on APAP-caused liver damage in mice. We found that GW0742 (40 mg/kg, i.p.) pretreatment completely blocked the increase of serum aminotransferase activities, hepatocyte necrosis, oxidative stress, and liver inflammation in mice exposed to 300 mg/kg APAP (i.p.). Mechanistically, GW0742 pretreatment significantly suppressed the M1 polarization of liver Kupffer cells and activation of NLRP3 inflammasome. Interestingly, GW0742 remained effective when administered 6 h after APAP exposure, although its efficacy was less pronounced than that administered 6 h before the APAP challenge. Notably, GW0742 exhibited a more profound effect than NAC evidenced by the lower serum alanine transaminase (ALT) level and the improved histopathological manifestation. Furthermore, exposure to APAP for 6 h had resulted in dramatic liver inflammation, while pretreatment with GW0742 prior to APAP exposure did not influence the increase in serum aminotransferase activity and oxidative stress at 2 h after APAP exposure. These results highlight that PPARβ/δ may be a promising therapeutic target for treating APAP-caused acute liver damage probably acting on liver macrophages.

对乙酰氨基酚（APAP）过量引起的肝损伤仍然是一个世界性的医学问题。由于唯一的解药n -乙酰半胱氨酸（NAC）在APAP摄入8小时后服用，其疗效显著下降，且尽管及时给药，仍存在大量过量的APAP，导致肝毒性，因此需要新的治疗APAP中毒的药物。过氧化物酶体增殖物激活受体β/δ (PPARβ/δ)具有多种作用，包括调节肝脏脂质稳态和抗炎症。本研究旨在探讨一种特异性的PPARβ/δ激动剂GW0742对apap引起的小鼠肝损伤的影响。我们发现GW0742 （40 mg/kg, i.p.）预处理完全阻断300 mg/kg APAP暴露小鼠血清转氨酶活性升高、肝细胞坏死、氧化应激和肝脏炎症。机制上，GW0742预处理显著抑制肝库普弗细胞的M1极化和NLRP3炎性体的活化。有趣的是，GW0742在APAP暴露6小时后仍然有效，尽管其效果不如APAP攻击前6小时施用的效果明显。值得注意的是，GW0742比NAC表现出更深远的作用，这可以从降低血清丙氨酸转氨酶（ALT）水平和改善的组织病理学表现中得到证明。此外，暴露于APAP 6小时会导致严重的肝脏炎症，而在APAP暴露前用GW0742预处理不影响APAP暴露后2小时血清转氨酶活性和氧化应激的增加。这些结果表明，PPARβ/δ可能是治疗apap引起的急性肝损伤的一个有希望的治疗靶点，可能作用于肝巨噬细胞。

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引用次数: 0

Salidroside exerts neuroprotective effects on retrograde neuronal death following neonatal axotomy via activation of PI3K/Akt pathway and deactivation of p38 MAPK pathway 红红草苷通过激活PI3K/Akt通路和使p38 MAPK通路失活，对新生儿轴切术后逆行性神经元死亡具有神经保护作用。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-01-01 DOI: 10.1016/j.taap.2024.117178

Shengtao Ji , Daiyue Chen , Fei Ding , Xiaosong Gu , Qiu Xue , Chun Zhou , Maohong Cao , Shu Yu

Salidroside, a glucoside of tyrosol, is a powerful active ingredient extracted from the Chinese herb medicine Rhodiola rosea L.. As a neuroprotective agent, the application of salidroside in combination with neural tissue engineering has recently attracted much attention in peripheral nerve repair and reconstruction. However, the cellular and molecular mechanisms by which salidroside promotes nerve regeneration remain to be elucidated. We aim to evaluate the long-term neuroprotective potential of salidroside in an experimental rat model of neonatal sciatic nerve crush injury, with a focus on target-deprived neuronal death and the mechanisms involved. Behavioral analysis showed that salidroside dose-dependently improved voluntary hindlimb behavior and rod rotation ability following neonatal axotomy during an 8-week observation period. According to electrophysiology, Fluoro-Gold retrograde tracing, histological and immunohistochemical analyses, salidroside significantly improved nerve regeneration and reinnervation. Nissle and TUNEL staining, as well as caspase-3 activation assay indicated a beneficial effect of salidroside on retrograde loss and apoptosis of motoneurons within 2 weeks after axotomy. qPCR, ELISA and oxidative stress experiments revealed that salidroside improved the imbalance of spinal microenvironment, including oxidative stress and down-regulation of neurotrophic factors. Western blotting analysis showed that salidroside enhanced the activation of PI3K/Akt and inhibited the p38 MAPK signaling pathway following axotomy. The oxidative stress and axonal disconnection/regeneration models of primary motoneurons in vitro further confirmed the involvement of these two pathways in the neuroprotective effects of salidroside. These data provide a theoretical basis for the application of salidroside in peripheral nerve repair and reconstruction.

红景天苷，酪醇的一种糖苷，是从中草药红景天中提取的一种强效活性成分。红景天苷作为一种神经保护剂，结合神经组织工程技术在周围神经修复与重建中的应用近年来备受关注。然而，红景天苷促进神经再生的细胞和分子机制仍有待阐明。我们的目的是评估红景天苷在新生儿坐骨神经挤压损伤的实验大鼠模型中的长期神经保护潜力，重点关注目标剥夺神经元死亡及其机制。行为学分析显示，在8周的观察期内，红景天苷剂量依赖性地改善了新生儿肛切开术后的自主后肢行为和杆旋转能力。根据电生理、氟金逆行示踪、组织学和免疫组织化学分析，红景天苷显著改善神经再生和神经再生。Nissle和TUNEL染色以及caspase-3激活实验表明，红红草苷对轴切术后2周内运动神经元的逆行丧失和凋亡有有益作用。qPCR、ELISA和氧化应激实验显示，红红草苷改善了脊髓微环境失衡，包括氧化应激和神经营养因子的下调。Western blotting分析显示，红红草苷增强了轴切开术后PI3K/Akt的激活，抑制了p38 MAPK信号通路。体外原代运动神经元氧化应激和轴突断裂/再生模型进一步证实了这两条通路参与红柳苷的神经保护作用。这些数据为红景天苷在周围神经修复重建中的应用提供了理论依据。

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引用次数: 0

Centromere protein K enhances the activation of YAP1/TAZ signal cascade to drive the progression of clear cell renal cell carcinoma 着丝粒蛋白K增强YAP1/TAZ信号级联的激活，驱动透明细胞肾细胞癌的进展。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-01-01 DOI: 10.1016/j.taap.2024.117181

Ning Nan

Centromere protein K (CENPK) is a newly identified malignancy-related gene that exhibits differential expression in various cancers and plays a crucial role in carcinogenesis. However, it remains uncertain whether CENPK is involved in clear cell renal cell carcinoma (ccRCC). This work aimed to unveil the expression, clinical significance, biological functions, and regulatory mechanisms of CENPK in ccRCC. Through analysis of RNA-seq data obtained from TCGA, a high expression pattern of CENPK was identified in ccRCC, which was found to be associated with pathologic stage, histologic grade, and clinical outcome. The enrichment of CENPK in ccRCC was further verified through the analysis of clinical samples. By conducting cellular functional experiments, we showed an inhibitory effect of CENPK knockdown on the malignant behavior of ccRCC cells. GSEA revealed a close relationship between CENPK and the Hippo–YAP1/TAZ signal cascade. The following experiments demonstrated that the activation of YAP1/TAZ was strongly inhibited by CENPK knockdown, and this change was accompanied by a decrease in the levels of CTGF and CYR61. Blockade of the MST1/2-LATS1/2 axis reversed the suppressive impact of CENPK knockdown on YAP1/TAZ. The tumor-promoting impact observed upon CENPK overexpression was diminished in YAP1 knockout cells. Notably, ccRCC cells with reduced CENPK expression exhibited a diminished capability to form tumors in nude mice. This report highlights the importance of CENPK in ccRCC and sheds new light on the underlying mechanism of this cancer type. Therefore, CENPK has the potential to serve as a viable candidate target for treating ccRCC.

着丝粒蛋白K （CENPK）是一种新发现的恶性肿瘤相关基因，在各种癌症中表现出差异表达，在癌变过程中起着至关重要的作用。然而，CENPK是否参与透明细胞肾细胞癌（ccRCC）仍不确定。本研究旨在揭示CENPK在ccRCC中的表达、临床意义、生物学功能及调控机制。通过TCGA获得的RNA-seq数据分析，在ccRCC中发现了CENPK的高表达模式，并发现其与病理分期、组织学分级和临床结局相关。通过临床样品分析进一步验证了ccRCC中CENPK的富集。通过细胞功能实验，我们发现CENPK敲低对ccRCC细胞的恶性行为有抑制作用。GSEA揭示了CENPK与hpo - yap1 /TAZ信号级联之间的密切关系。接下来的实验表明，CENPK敲低会强烈抑制YAP1/TAZ的激活，这种变化伴随着CTGF和CYR61水平的降低。阻断MST1/2-LATS1/2轴逆转了CENPK敲低对YAP1/TAZ的抑制作用。在YAP1敲除细胞中，对CENPK过表达的促瘤作用减弱。值得注意的是，CENPK表达降低的ccRCC细胞在裸鼠体内形成肿瘤的能力降低。本报告强调了CENPK在ccRCC中的重要性，并揭示了这种癌症类型的潜在机制。因此，CENPK有可能作为治疗ccRCC的可行候选靶点。

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引用次数: 0

Model-based analysis for investigating the impact of tumor size, lymphocyte and neutrophil on the survival of breast cancer 4T1 tumor-bearing mice 基于模型的分析研究肿瘤大小、淋巴细胞和中性粒细胞对乳腺癌4T1荷瘤小鼠存活的影响

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-11-28 DOI: 10.1016/j.taap.2024.117176

Qing-yu Yao , Xin-yu Hou , Wei-zhe Jian , Tian-yu Wang , Ping-yao Luo , Jun-sheng Xue , Rong Chen , Tian-yan Zhou

Survival is one of the foremost endpoints in cancer therapy, and parametric survival analysis could comprehensively demonstrate the overall result of various different baseline and longitudinal factors. In this study, the survival of triple negative breast cancer 4T1 tumor-bearing mice treated by gemcitabine (GEM) and dexamethasone (DEX) was investigated with model-based analysis. The tumor size, lymphocyte (LY) and neutrophil (NE) of 4T1 tumor-bearing BALB/c mice were collected, and the PK/PD models of these longitudinal data were established in a sequential manner, respectively. The parametric time-to-event (TTE) model of survival was developed and the PK/PD models were tested and integrated as time-varying prognostic factors. The final model was evaluated and externally validated. LY and NE influence the survival directly, while tumor size showed its indirect impact on survival by affecting LY. The exposure of GEM significantly improved the survival results but DEX did not bring extra benefit. The models established in this study quantitatively characterized the abnormal increasing of LY and NE due to tumor progression in T1 tumor-bearing mice and also demonstrate their relationship with survival outcomes, and further provide a modeling framework to demonstrate potential prognostic factors of survival and evaluate the efficacy of different therapies.

生存期是癌症治疗中最重要的终点之一，参数生存期分析可以综合反映各种不同基线和纵向因素的总体结果。本研究采用基于模型的分析方法，研究吉西他滨（GEM）和地塞米松（DEX）联合治疗的三阴性乳腺癌4T1荷瘤小鼠的生存情况。收集4T1荷瘤BALB/c小鼠的肿瘤大小、淋巴细胞（LY）和中性粒细胞（NE），依次建立这些纵向数据的PK/PD模型。建立了参数化的生存时间-事件（TTE）模型，并对PK/PD模型进行了测试，并将其作为时变预后因素进行了整合。最后的模型进行了评估和外部验证。LY和NE直接影响生存，而肿瘤大小通过影响LY间接影响生存。暴露于GEM显著改善了生存结果，但DEX没有带来额外的益处。本研究建立的模型定量表征了T1荷瘤小鼠肿瘤进展过程中LY和NE的异常升高及其与生存结局的关系，为揭示潜在的生存预后因素和评价不同治疗方法的疗效提供了模型框架。

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引用次数: 0

Curcumin alleviated dextran sulfate sodium-induced ulcerative colitis via inhibition of the Wnt/β-catenin signaling pathway and regulation of the differentiation of intestinal stem cells 姜黄素通过抑制Wnt/β-catenin信号通路和调节肠道干细胞分化，减轻葡聚糖硫酸钠诱导的溃疡性结肠炎

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-11-26 DOI: 10.1016/j.taap.2024.117175

Shaojie Liang , Kun Wang , Dabin Mao , Qianqian Ouyang , Xiaoping Lv , Liwei Xie , Dajian Zhu

In this study, we investigated the regulatory role of curcumin in the differentiation of intestinal stem cells (ISCs) in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) model mice and explored whether this effect was mediated by the Wnt/β-catenin signaling pathway. We conducted experiments in DSS-induced UC model mice to observe changes in intestinal morphology through HE staining and detect the expression of key proteins in the Wnt/β-catenin signaling pathway. According to these findings, curcumin was found to have a significant impact on the differentiation of ISCs. These results indicated that curcumin inhibited the Wnt/β-catenin signaling pathway and restored ISC differentiation. The effects of curcumin on the Wnt/β-catenin signaling pathway were further confirmed using Wnt/β-catenin agonists. These findings provide a new perspective for understanding the behavior of ISCs in the context of inflammation and offer new insights into the development of novel therapeutic strategies and drugs for UC.

在本研究中，我们研究了姜黄素在葡聚糖硫酸钠（DSS）诱导的溃疡性结肠炎（UC）模型小鼠肠道干细胞（ISCs）分化中的调节作用，并探讨了这种作用是否通过Wnt/β-catenin信号通路介导。我们对dss诱导的UC模型小鼠进行实验，通过HE染色观察肠道形态学的变化，检测Wnt/β-catenin信号通路关键蛋白的表达。根据这些发现，姜黄素对ISCs的分化有显著影响。这些结果表明姜黄素抑制Wnt/β-catenin信号通路，恢复ISC分化。使用Wnt/β-catenin激动剂进一步证实姜黄素对Wnt/β-catenin信号通路的影响。这些发现为理解炎症背景下ISCs的行为提供了新的视角，并为UC的新治疗策略和药物的开发提供了新的见解。

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引用次数: 0

Synthesis and evaluation of novel ethyl ferulate derivatives as potent Keap1 inhibitors to activate the Nrf2/ARE pathway in Parkinson's disease 合成和评估新型阿魏酸乙酯衍生物作为强效 Keap1 抑制剂，以激活帕金森病的 Nrf2/ARE 通路。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-11-26 DOI: 10.1016/j.taap.2024.117172

Amritha Chakkittukandiyil , Deepak Vasudevan Sajini , Emdormi Rymbai , Deepa Sugumar , Jinu Mathew , Suresh Arumugam , Vadivelan Ramachandran , Divakar Selvaraj

The Kelch-like ECH-associated protein 1/Nuclear factor erythroid 2 related factor 2/Antioxidant Response Elements (Keap1/Nrf2/ARE) pathway is essential for neuronal resilience against the complex pathogenesis of Parkinson's disease (PD). Activating this pathway by covalently modifying Keap1 cysteine residues is a promising strategy for regulating neuroprotective gene expression. Our study aimed to identify phytochemicals that could irreversibly inhibit Keap1. A preliminary docking analysis revealed that ethyl ferulate could covalently bind with Cys151 of Keap1 by Michael's addition reaction. Further, we designed several ethyl ferulate derivatives with improved lipophilicity and assessed their binding affinity with Keap1. The molecules with good binding scores were synthesized and structures were confirmed through ¹H NMR, ¹³C NMR, FT-IR, and mass spectroscopy. Neuroprotection screening was conducted in all-trans retinoic acid differentiated SH-SY5Y cells using rotenone as a disease-inducing agent. Pre-treatment with compounds C2 and C4 significantly mitigated rotenone toxicity. Additionally, C2 and C4 decreased rotenone-induced ROS production and mitochondrial membrane potential loss. C2 and C4 also induced Nrf2 nuclear translocation in SH-SY5Y cells and increased mRNA expression of heme oxygenase-1, an Nrf2-regulated antioxidant response element. In vivo, pretreatment with C2 (50, 100 mg/kg, p.o.) and C4 (50, 100 mg/kg, p.o.) protected against neurodegenerative phenotypes associated with rotenone (1.5 mg/kg, s.c.) induction in Wistar rats. Results indicate, C2 and C4 dose-dependently improved muscle rigidity, catalepsy, and cognitive deficits in rotenone-induced Wistar rats, and mitigated dopaminergic neurodegeneration in the substantia nigra. These findings highlight the potential of ethyl ferulate derivatives in modulating oxidative stress and neurodegeneration in PD via activation of Nrf2.

Kelch-like ECH-associated protein 1/Nuclear factor erythroid 2 related factor 2/Antioxidant Response Elements（Keap1/Nrf2/ARE）通路对于神经元抵御帕金森病（PD）复杂的发病机制至关重要。通过共价修饰 Keap1 半胱氨酸残基来激活该通路是一种很有前景的神经保护基因表达调控策略。我们的研究旨在找出能不可逆地抑制 Keap1 的植物化学物质。初步的对接分析表明，阿魏酸乙酯可通过迈克尔加成反应与 Keap1 的 Cys151 共价结合。此外，我们还设计了几种亲油性更好的阿魏酸乙酯衍生物，并评估了它们与 Keap1 的结合亲和力。我们合成了具有良好结合力的分子，并通过 1H NMR、13C NMR、傅立叶变换红外光谱和质谱确认了它们的结构。以鱼藤酮作为疾病诱导剂，在全反式维甲酸分化的 SH-SY5Y 细胞中进行了神经保护筛选。使用化合物 C2 和 C4 进行预处理可明显减轻鱼藤酮的毒性。此外，C2 和 C4 还能减少鱼藤酮诱导的 ROS 生成和线粒体膜电位丧失。C2 和 C4 还能诱导 SH-SY5Y 细胞中的 Nrf2 核转位，并增加血红素加氧酶-1（一种由 Nrf2 调控的抗氧化反应元件）的 mRNA 表达。在体内，C2（50、100 毫克/千克，口服）和 C4（50、100 毫克/千克，口服）可保护 Wistar 大鼠免受与鱼藤酮（1.5 毫克/千克，静脉注射）诱导相关的神经退行性表型的影响。结果表明，C2 和 C4 可剂量依赖性地改善鱼藤酮诱导的 Wistar 大鼠的肌肉僵硬、催眠和认知障碍，并减轻黑质的多巴胺能神经退行性变。这些发现凸显了阿魏酸乙酯衍生物通过激活 Nrf2 调节氧化应激和帕金森病神经退行性变的潜力。

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引用次数: 0

Cisplatin caused highly delayed cytotoxicity in the immortalized cells derived from S3 segment of mouse kidney proximal tubules 顺铂对源自小鼠肾近曲小管 S3 段的永生细胞产生高度延迟的细胞毒性

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-11-24 DOI: 10.1016/j.taap.2024.117171

Hiroki Taguchi, Daigo Sumi, Ayumi Uemura, Kanako Matsumoto, Hitomi Fujishiro

Anti-cancer drug cisplatin (CDDP) causes severe acute kidney injury (AKI). CDDP-induced AKI does not occur immediately after administration, but rather 6 to 10 days after administration. However, the mechanism underling the delayed renal injury by CDDP is not well understood. In a previous investigation using immortalized cells derived from the S1, S2, and S3 segments of the proximal tubules, we found that S3 cells were more sensitive to CDDP than S1 and S2 cells. In this study, we examined whether S1, S2, and S3 cells would be useful in elucidating the mechanism of CDDP-induced delayed renal injury and whether the high sensitivity of S3 cells contributes to CDDP-induced delayed renal injury. Measurement of platinum (Pt) content by ICP-MS showed that Pt accumulation peaked at 15 min after CDDP exposure in each cell type. Even when the medium was replaced with CDDP-free medium after the 15-min CDDP exposure and the cells were further incubated, delayed cytotoxicity was still observed. The S3 cells exhibited greater sensitivity to CCDP than the S1 and S2 cells at all time points after the medium change. To investigate the mechanism of the CDDP-induced delayed cytotoxicity, we examined the cell cycle distribution of cells after CDDP exposure. The results showed that CDDP-induced perturbation of cell cycle was greater in S3 than in S1 and S2 cells. These results suggest that perturbation of the cell cycle in S3 cells due to enhanced CDDP–DNA adduct formation contributes to the high susceptibility of S3 cells to CDDP-induced delayed cytotoxicity.

抗癌药物顺铂（CDDP）会导致严重的急性肾损伤（AKI）。CDDP 引起的急性肾损伤不会在用药后立即发生，而是会在用药后 6 到 10 天发生。然而，CDDP导致延迟性肾损伤的机制尚不十分清楚。在之前的一项使用源自近端肾小管 S1、S2 和 S3 区段的永生化细胞的研究中，我们发现 S3 细胞比 S1 和 S2 细胞对 CDDP 更敏感。在本研究中，我们考察了 S1、S2 和 S3 细胞是否有助于阐明 CDDP 诱导的延迟性肾损伤的机制，以及 S3 细胞的高敏感性是否是 CDDP 诱导的延迟性肾损伤的原因。通过ICP-MS测量铂（Pt）含量显示，铂的积累在CDDP暴露后15分钟在每种细胞中达到峰值。即使在 15 分钟的 CDDP 暴露后将培养基更换为不含 CDDP 的培养基并继续培养细胞，仍可观察到延迟细胞毒性。在更换培养基后的所有时间点，S3 细胞都比 S1 和 S2 细胞对 CCDP 更敏感。为了研究 CDDP 诱导延迟细胞毒性的机制，我们检测了 CDDP 暴露后细胞的细胞周期分布。结果显示，CDDP 诱导的细胞周期扰动在 S3 细胞中比在 S1 和 S2 细胞中更大。这些结果表明，由于 CDDP-DNA 加合物形成的增强，S3 细胞的细胞周期发生了扰动，从而导致 S3 细胞对 CDDP 诱导的延迟细胞毒性高度敏感。

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引用次数: 0

Curcumin ameliorates astrocyte inflammation through AXL in cuprizone-induced mice 姜黄素通过 AXL 改善铜绿素诱导的小鼠星形胶质细胞炎症。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-11-23 DOI: 10.1016/j.taap.2024.117170

Wenjing Zhang, Mengjiao Sun, Ning Liu, Xiaoling Li, Jing Sun, Manxia Wang

Curcumin has gained global attention owning to its anti-inflammatory, antioxidant, anticancer, and antimicrobial activities. Curcumin has recently been shown to have well-documented effects on neuroinflammation in multiple sclerosis (MS). Astrocytes, the most widely distributed glial cells in the brain, have a significant influence on the regulation of neuroinflammation in MS. However, it is unknown how curcumin exerts neuroprotective effects in astrocytes. To elucidate the mechanism underlying the effects of curcumin on astrocytes, we explored the effect of curcumin on cuprizone (CPZ)-induced mice in vivo and on primary astrocytes in vitro. In this study, we observed that curcumin significantly ameliorated myelin loss and reduced astrocyte activation in the corpus callosum (CC) region in mice induced with CPZ, and in primary astrocytes stimulated with lipopolysaccharide (LPS). Meanwhile, our research indicated that curcumin may exert neuroprotective effects in CPZ-induced mice by downregulating astrocyte-mediated inflammation by AXL. This study provides new insights into possible targeted therapies for MS.

姜黄素因其抗炎、抗氧化、抗癌和抗菌活性而受到全球关注。姜黄素最近被证实对多发性硬化症（MS）的神经炎症有显著效果。星形胶质细胞是大脑中分布最广的胶质细胞，对多发性硬化症的神经炎症调节有重要影响。然而，姜黄素如何在星形胶质细胞中发挥神经保护作用尚不清楚。为了阐明姜黄素对星形胶质细胞的作用机制，我们探讨了姜黄素对体内铜绿素（CPZ）诱导的小鼠和体外原发性星形胶质细胞的影响。在这项研究中，我们观察到姜黄素能明显改善CPZ诱导的小鼠胼胝体（CC）区域的髓鞘脱失，并降低用脂多糖（LPS）刺激的原代星形胶质细胞的活化。同时，我们的研究还表明，姜黄素可以通过AXL下调星形胶质细胞介导的炎症，从而对CPZ诱导的小鼠发挥神经保护作用。这项研究为多发性硬化症的靶向疗法提供了新的视角。

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引用次数: 0

Epigenetic modifications control CYP1A1 Inducibility in human and rat keratinocytes 表观遗传修饰控制人和大鼠角质细胞中 CYP1A1 的诱导性

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-11-22 DOI: 10.1016/j.taap.2024.117163

Lo-Wei Lin, Allison K. Ehrlich, Robert H. Rice

Serially passaged rat keratinocytes exhibit dramatically attenuated induction of Cyp1a1 by aryl hydrocarbon receptor ligands such as TCDD. However, the sensitivity to induction can be restored by protein synthesis inhibition. Previous work revealed that the functionality of the receptor was not affected by passaging. The present work explored the possibility of epigenetic silencing on CYP1A1 inducibility in both rat and human cells. Use of an array of small molecule epigenetic modulators demonstrated that inhibition of histone deacetylases mimicked the effect of protein synthesis inhibition. Consistent with this finding, cycloheximide treatment also reduced histone deacetylase activity. More importantly, when compared to human CYP1A1, rat Cyp1a1 exhibited much greater sensitivity toward epigenetic modulators, particularly inhibitors of histone deacetylases. Other genes in the aryl hydrocarbon receptor domain showed variable and less dramatic responses to histone deacetylase inhibitors. These findings highlight a potential species difference in epigenetics that must be considered when extrapolating results from rodent models to humans and has implications for xenobiotic- or drug-drug interactions where CYP1A1 activity plays an important role.

芳基烃受体配体（如 TCDD）对大鼠角质形成细胞 Cyp1a1 的诱导作用显著减弱。然而，通过抑制蛋白质合成可以恢复对诱导的敏感性。以前的工作表明，受体的功能不受传代的影响。本研究探讨了表观遗传沉默对大鼠和人类细胞中 CYP1A1 诱导性的影响。一系列小分子表观遗传调节剂的使用表明，组蛋白去乙酰化酶的抑制模拟了蛋白质合成抑制的效果。与这一发现相一致的是，环己亚胺也能降低组蛋白去乙酰化酶的活性。更重要的是，与人类 CYP1A1 相比，大鼠 Cyp1a1 对表观遗传调节剂（尤其是组蛋白去乙酰化酶抑制剂）的敏感性要高得多。芳基烃受体域中的其他基因对组蛋白去乙酰化酶抑制剂的反应各不相同，且不太明显。这些发现凸显了表观遗传学中潜在的物种差异，在将啮齿类动物模型的结果推断到人类时必须考虑到这一点，并且对 CYP1A1 活性发挥重要作用的异生物或药物相互作用具有影响。

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