Toxicology and applied pharmacology最新文献_第10页

Exploring the impact of sEH inhibition on intestinal cell differentiation and Colon Cancer: Insights from TPPU treatment 探索抑制 sEH 对肠细胞分化和结肠癌的影响：TPPU治疗的启示

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-10-15 DOI: 10.1016/j.taap.2024.117128

Katerina Koubova, Zdenek Tauber, Katerina Cizkova

Inhibition of soluble epoxide hydrolase (sEH) appears to be promising for the treatment of many diseases. Studies have focused on the beneficial effects of epoxyeicosatrienoic acids (EETs), which are sEH substrates. However, our recent studies have shown that the sEH activity is crucial for the proper intestinal cell differentiation. In this recent study, we investigated the impact of TPPU, an inhibitor of sEH, on the colon cancer cell lines Caco2 and HT-29. We analysed the changes in the expression of the cytoskeletal protein ezrin and the phosphorylated protein kinase p38 (p-p38). Our results showed a decrease in ezrin expression in differentiated cells and an increase in p-p38 expression after TPPU treatment. Immunocytochemical staining revealed a higher staining intensity of p-p38 in the nuclei of HT-29 cells following TPPU treatment. Immunohistochemical staining was performed on human samples of normal colon tissue, grade 2 tumours, and embryonal/foetal tissues. The staining intensity of ezrin in tumours was reduced in the surface area compared to the crypts. Additionally, we observed the translocation of p-p38 expression from the cytoplasm to the nucleus during differentiation. The tumour samples exhibited higher levels of p-p38 in the cytoplasm, similar to normal undifferentiated tissue. To observe the disruption of the cytoskeleton after TPPU treatment, confocal microscopy was used. It was found that β-actin associated with ezrin forms clusters under the plasma membranes. All of these results are significant because sEH inhibitors are being tested in clinical trials, but they could cause an unexpected adverse effects.

抑制可溶性环氧化物水解酶（sEH）似乎有望治疗多种疾病。研究主要集中于作为 sEH 底物的环氧二十碳三烯酸（EETs）的有益作用。然而，我们最近的研究表明，sEH 活性对肠道细胞的正常分化至关重要。在这项最新研究中，我们调查了 sEH 抑制剂 TPPU 对结肠癌细胞系 Caco2 和 HT-29 的影响。我们分析了细胞骨架蛋白 ezrin 和磷酸化蛋白激酶 p38（p-p38）的表达变化。结果显示，TPPU 处理后，分化细胞中 ezrin 的表达减少，p-p38 的表达增加。免疫细胞化学染色显示，TPPU 处理后，HT-29 细胞核中 p-p38 的染色强度更高。对人体正常结肠组织、2 级肿瘤和胚胎/胎儿组织样本进行了免疫组化染色。与隐窝相比，肿瘤表面区域的 ezrin 染色强度降低。此外，我们还观察到在分化过程中，p-p38 的表达从细胞质转位到细胞核。肿瘤样本的细胞质中 p-p38 水平较高，与正常未分化组织相似。为了观察 TPPU 处理后细胞骨架的破坏情况，使用了共聚焦显微镜。结果发现，与 ezrin 相关的 β-肌动蛋白在质膜下形成簇。所有这些结果都意义重大，因为sEH抑制剂正在进行临床试验，但它们可能会引起意想不到的不良反应。

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引用次数: 0

Impact of different gastric acid suppressants on chronic unpredictable mild stress-induced cognitive impairment in rats: A possible involvement of gut dysbiosis 不同胃酸抑制剂对慢性不可预测轻度应激诱发的大鼠认知障碍的影响：肠道菌群失调的可能参与

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-10-13 DOI: 10.1016/j.taap.2024.117126

Reem M. Eladawy , Lamiaa A. Ahmed , Maha B. Salem , Olfat A. Hammam , Ahmed F. Mohamed , Hesham A. Salem , Rehab M. El-Sayed

Recently, clinical evidence indicates that gastric acid suppressants are associated with an increased risk of the development of cognitive impairment and dementia, especially in elderly patients and those with mild cognitive impairment. Therefore, the aim of this research was to explore the impact of different gastric acid suppressants use, famotidine (Famo), esomeprazole (Esome) and vonoprazan (Vono) in the absence or the presence of chronic unpredictable mild stress (CUMS) on several memory tasks with examination of the role of gut dysbiosis. In the present study, rats received famotidine (3.7 mg/kg/day, p.o.) or esomeprazole (3.7 mg/kg/day, p.o.) or vonoprazan (1.85 mg/kg/day, p.o.) for 7 weeks with or without exposure to CUMS. Remarkably, CUMS with different acid suppressants caused a significant decrease in all memory tasks in late CUMS in the current investigation. CUMS with acid suppressants also revealed a marked alteration in the fecal Firmicutes/Bacteroidetes ratio compared to CUMS alone. This gut microbiome alteration was associated with an alteration in gut membrane integrity, as revealed by colonic histopathology and an elevation of systemic inflammatory markers. Besides, upregulation of hippocampal amyloid β and p-tau proteins and modification of brain histopathology were noticed. Our findings support the detrimental effect of gastric acid suppressants, especially proton pump inhibitors, on cognitive impairment in the presence of stress, with the possible involvement of gut dysbiosis.

最近，临床证据表明，胃酸抑制剂与认知障碍和痴呆症的发病风险增加有关，尤其是在老年患者和轻度认知障碍患者中。因此，本研究旨在探讨法莫替丁（Famo）、埃索美拉唑（Esomeprazole）和沃诺普拉赞（Vonoprazan）等不同胃酸抑制剂在没有或有慢性不可预测轻度应激（CUMS）的情况下对几种记忆任务的影响，并考察肠道菌群失调的作用。在本研究中，大鼠接受法莫替丁（3.7毫克/千克/天，口服）或埃索美拉唑（3.7毫克/千克/天，口服）或沃诺普拉赞（1.85毫克/千克/天，口服）治疗7周，同时接受或不接受CUMS治疗。值得注意的是，在本次调查中，含有不同抑酸剂的CUMS会导致晚期CUMS的所有记忆任务显著下降。与单独使用 CUMS 相比，使用抑酸剂的 CUMS 还明显改变了粪便中的固着菌/类杆菌比例。这种肠道微生物组的改变与肠道膜完整性的改变有关，结肠组织病理学和全身炎症标志物的升高都表明了这一点。此外，我们还注意到海马淀粉样蛋白β和p-tau蛋白的上调以及大脑组织病理学的改变。我们的研究结果支持胃酸抑制剂（尤其是质子泵抑制剂）在压力下对认知障碍的有害影响，这可能与肠道菌群失调有关。

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引用次数: 0

Toxicology profile of a novel GLP-1 receptor biased agonist-SAL0112 in nonhuman primates 新型 GLP-1 受体偏性激动剂--SAL0112 在非人灵长类动物中的毒理学概况。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-10-10 DOI: 10.1016/j.taap.2024.117125

Jingchao Sun , Ying Xiao , Xuefeng Hu , Shu Chen , Jing Huang , Zhiqiang Ren , Binbin Luo , Rongzhi Jiang , Hongmei Zhang , Xiaolei Shen

Oral small-molecule GLP-1 receptor biased agonists exhibit promising treatment efficacy of type 2 diabetes and obesity. SAL0112 is a novel compound that has demonstrated remarkable efficacy in preclinical animal models. Herein, both in vitro and in vivo preclinical toxicity investigations were conducted to explore the safety profile of SAL0112. The HTRF assay and TR-FRET assay were utilized for cAMP detection. Patch clamp assay was employed for hERG potassium ion channel determination. Cynomolgus monkeys were used in a cardiovascular safety pharmacology study and a 13-week repeated dose toxicity study. The telemetry system was employed to detect cardiovascular indicators such as ECG, HR, and BP. During the repeated dose toxicity study, body weight, food intake, hematology, coagulation function test, serum biochemistry tests, and urine analysis were measured. Macroscopic and microscopic observations were conducted at the end of the study. TK studies were conducted on Day 1 and Day 91. SAL0112 exhibited a high degree of potency in activating the monkey GLP-1 receptor whereas had no effect on the rodent GLP-1 receptor. In contrast to Danuglipron, which demonstrated high potency on hERG with an IC₅₀ value of 6.9 μM, the IC₅₀ of SAL0112 on hERG was greater than 100 μM. Compared to the Vehicle Control group, no significant changes in cardiovascular indicators were observed in the cardiovascular safety pharmacology study after a single dose of SAL0112 up to 250 mg/kg (P > 0.05). A repeated dose toxicity study revealed moderate anorexigenic effects and a reduction in body weight, effects that were found to be reversible and not associated with any pathological changes. The NOAEL of SAL0112 is 150 mg/kg, providing an approximate safety margin of threefold. SAL0112 demonstrated a favorable safety profile in cynomolgus monkeys, with a substantial therapeutic window that supports the progression of this compound into clinical studies.

口服小分子 GLP-1 受体偏性激动剂对 2 型糖尿病和肥胖症具有良好的治疗效果。SAL0112 是一种新型化合物，已在临床前动物模型中显示出显著疗效。在此，我们进行了体外和体内临床前毒性研究，以探索 SAL0112 的安全性。采用 HTRF 法和 TR-FRET 法检测 cAMP。采用膜片钳法测定 hERG 钾离子通道。在心血管安全性药理学研究和为期 13 周的重复剂量毒性研究中使用了眼镜猴。遥测系统用于检测心电图、心率和血压等心血管指标。在重复剂量毒性研究期间，对体重、进食量、血液学、凝血功能测试、血清生化测试和尿液分析进行了测量。研究结束时进行宏观和微观观察。在第 1 天和第 91 天进行了 TK 研究。SAL0112 在激活猴 GLP-1 受体方面表现出很高的效力，而对啮齿类动物的 GLP-1 受体则没有影响。与对 hERG 具有高效力（IC50 值为 6.9 μM）的达奴利普隆相比，SAL0112 对 hERG 的 IC50 值大于 100 μM。在心血管安全性药理学研究中，与车辆对照组相比，单次服用 SAL0112 达 250 mg/kg 后，心血管指标未见明显变化（P > 0.05）。重复剂量毒性研究显示，SAL0112 有中度的厌食作用和体重下降，但这些作用是可逆的，且与任何病理变化无关。SAL0112 的无观测不良效应水平为 150 毫克/千克，安全系数约为三倍。SAL0112 在猕猴体内表现出良好的安全性，并具有可观的治疗窗口期，支持将该化合物推向临床研究。

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引用次数: 0

Pharmacology and molecular modeling studies of sulfoxaflor, flupyradifurone and neonicotinoids on the human neuronal α7 nicotinic acetylcholine receptor 磺胺草醚、氟吡菌脲和新烟碱类药物对人类神经元α7烟碱乙酰胆碱受体的药理学和分子模型研究。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-10-10 DOI: 10.1016/j.taap.2024.117123

Alison Cartereau , Zakaria Bouchouireb , Sara Kaaki , François Héricourt , Emiliane Taillebois , Jean-Yves Le Questel , Steeve H. Thany

We conducted electrophysiological and molecular docking studies using a heterologous expression system (Xenopus oocytes) to compare the effects of four neonicotinoids (acetamiprid, imidacloprid, clothianidin and thiamethoxam), one sulfoximine, (sulfoxaflor), and one butenolide (flupyradifurone), on human α7 neuronal nicotinic acetylcholine receptors (nAChRs). All neonicotinoids (except thiamethoxam), as well as the recently introduced nAChR competitive modulators, flupyradifurone and sulfoxaflor, appear to be weaker agonists than acetylcholine. Two mutations in loop C (E211N and E211P) and one mutation in loop D (Q79K), known to be involved in the binding properties of neonicotinoids were introduced to the α7 wild type. Interestingly, the acetylcholine and nicotine-evoked activation was not modified in human α7 mutated receptors, but the net charge was enhanced for clothianidin and imidacloprid, respectively. Flupyradifurone responses strongly increased under the Q79K mutation. The molecular docking investigations demonstrated that the orientations and interactions of the ligands considered were in accordance with those observed experimentally. Specifically, the charged fragments of acetylcholine and nicotine, used as reference ligands, and their neonicotinoid homologs were found to be surrounded by aromatic residues, with key interactions with Trp171 and Y210. Furthermore, the molecular docking investigations predicted the water-mediated interaction between the carbonyl oxygen of acetylcholine and the Nsp² nitrogen of the pyridine ring for nicotine (as well as for the majority of the corresponding neonicotinoid fragments) and main chain NH of L141. The docking scores, extending over a significant range of 6 kcal/mol, showed that most neonicotinoids were poorly stabilized in the α7 nAChR compared to acetylcholine, except sulfoxaflor.

我们利用异源表达系统（爪蟾卵母细胞）进行了电生理学和分子对接研究，比较了四种新烟碱类（啶虫脒、吡虫啉、噻虫嗪和噻虫嗪）、一种亚磺酰亚胺（磺草酮）和一种丁烯内酯（氟吡嘧啶呋酮）对人类α7神经元烟碱乙酰胆碱受体（nAChRs）的影响。所有新烟碱类（噻虫嗪除外）以及最近推出的 nAChR 竞争性调节剂氟吡脲和磺胺草酮似乎都是比乙酰胆碱更弱的激动剂。在 α7 野生型中引入了 C 环的两个突变（E211N 和 E211P）和 D 环的一个突变（Q79K），已知这两个突变与新烟碱类药物的结合特性有关。有趣的是，人α7突变受体的乙酰胆碱和尼古丁诱导的活化没有改变，但对氯噻啶和吡虫啉的净电荷分别增强了。在 Q79K 突变的情况下，氟吡脲的反应强烈增加。分子对接研究表明，所考虑的配体的取向和相互作用与实验观察到的一致。具体来说，作为参考配体的乙酰胆碱和尼古丁的带电片段及其新烟碱同系物被发现被芳香残基包围，与 Trp171 和 Y210 有关键的相互作用。此外，分子对接研究还预测了尼古丁（以及大多数相应的新烟碱类药物片段）的乙酰胆碱羰基氧与吡啶环 Nsp2 氮以及 L141 主链 NH 之间由水介导的相互作用。对接得分在 6 kcal/mol 的很大范围内显示，与乙酰胆碱相比，大多数新烟碱类药物在 α7 nAChR 中的稳定性较差，磺草酮除外。

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引用次数: 0

Circ_0049979 ameliorates myocardial infarction through improving Cx43-mediated endothelial functions Circ_0049979通过改善Cx43介导的内皮功能来改善心肌梗死。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-10-09 DOI: 10.1016/j.taap.2024.117121

Meng Sun , Shaodong Zhai , Yangyang Gao , Nan Hu , Rui Wang , Ruiping Zhang

Endothelial injury is a fundamental pathogenesis of coronary atherosclerotic heart disease (CHD). Circular RNAs (circRNAs) are important post-transcriptional regulators in many human major diseases, including CHD. The aim of the present study was to explore the role of circ_0049979, a novel identified circRNA from ANO8 gene locus, in endothelial injury during CHD. We found that expression of circ_0049979 was reduced by ox-LDL treatment in HUVECs in a dose-dependent manner. Loss- and gain-of-function experiments demonstrated that knockdown of circ_0049979 decreased the capacities of proliferation, migration and tube formation in normal HUVECs. While, overexpression of circ_0049979 improved these capacities in both normal and ox-LDL-incubated HUVECs. Then, the online bioinformatic tool Circinteractome was used to predicted the target miRNAs of circ_0049979, and miR-653 was selected as the candidate. We demonstrated that miR-653 directly interacted with and was negatively regulated by circ_0049979, and played a negative role in regulating proliferation, migration and tube formation of HUVECs. In terms of the mechanism, miR-653 post-transcriptionally suppressed the expression of the gap junction protein 43 (Cx43), a key protein of endothelial tight junction. Finally, we verified that overexpression of circ_0049979 was able to alleviate plaque formation, lipid deposition, and endothelial cell apoptosis, as well as myocardial infarction, in coronary atherosclerotic mice in vivo. In conclusion, circ_0049979 plays a protective role in coronary atherosclerotic myocardial infarction by improving miR-653/Cx43-mediated endothelial functions.

内皮损伤是冠状动脉粥样硬化性心脏病（CHD）的基本发病机制。环状 RNA（circRNA）是包括冠心病在内的许多人类重大疾病的重要转录后调控因子。本研究的目的是探讨circ_0049979（一种从ANO8基因位点发现的新circRNA）在CHD过程中内皮损伤中的作用。我们发现，在 HUVECs 中，circ_0049979 的表达因 ox-LDL 处理而降低，且呈剂量依赖性。功能缺失和功能增益实验表明，敲除 circ_0049979 会降低正常 HUVECs 的增殖、迁移和管形成能力。而过表达 circ_0049979 则会提高正常 HUVEC 和氧化-LDL 诱导的 HUVEC 的上述能力。然后，我们利用在线生物信息学工具 Circinteractome 预测了 circ_0049979 的靶 miRNA，并选择 miR-653 作为候选靶。结果表明，miR-653与circ_0049979直接相互作用并受其负向调控，在调控HUVECs的增殖、迁移和管形成中发挥负向作用。在机制方面，miR-653转录后抑制了内皮紧密连接的关键蛋白--间隙连接蛋白43（Cx43）的表达。最后，我们验证了过表达 circ_0049979 能够缓解冠状动脉粥样硬化小鼠体内斑块的形成、脂质沉积、内皮细胞凋亡以及心肌梗死。总之，circ_0049979通过改善miR-653/Cx43介导的内皮功能，在冠状动脉粥样硬化性心肌梗死中发挥保护作用。

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引用次数: 0

PM10 dysregulates epithelial barrier function in human corneal epithelial cells that is restored by antioxidant SKQ1 PM10 可使人类角膜上皮细胞的上皮屏障功能失调，而抗氧化剂 SKQ1 可使其恢复正常。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-10-09 DOI: 10.1016/j.taap.2024.117122

Mallika Somayajulu , Robert Wright , Farooq Muhammed , Sharon A. McClellan , Ahmed Ibrahim , Linda D. Hazlett

Exposure to airborne particulate <10 μm (PM₁₀) adversely affects the ocular surface. This study tested PM₁₀ on epithelial barrier integrity in immortalized human corneal epithelial cells (HCE-2) and mouse cornea, and whether antioxidant SKQ1 is restorative. HCE-2 were exposed to 100 μg/ml PM₁₀ ± SKQ1 for 24 h. An Electric Cell-Substrate Impedance Sensing (ECIS) system monitored the impact of PM₁₀. RT-PCR, western blotting and immunofluorescence measured levels of barrier and associated proteins, stanniocalcin 2 (STC2), and a kit measured total calcium. In vivo, female C57BL/6 mice were exposed to either control air or PM₁₀ (±SKQ1) in a whole-body exposure chamber, and barrier associated proteins tested. Tight junction and mucins proteins in the cornea were tested. In HCE-2, PM₀ vs control significantly reduced mRNA and protein levels of tight junction and adherence proteins, and mucins. ECIS data demonstrated that PM₁₀ vs control cells exhibited a significant decrease in epithelial barrier strength at 4000 Hz indicated by reduced impedance and resistance. PM₁₀ also upregulated STC2 protein and total calcium levels. In vivo, PM₁₀ vs control reduced zonula occludens 1 and mucins. SKQ1 pre-treatment reversed PM₁₀ effects both in vitro and in vivo. In conclusion, PM₁₀ exposure reduced tight junction and mucin proteins, and compromised the seal between cells in the corneal epithelium leading to decreased epithelial barrier strength. This effect was reversed by SKQ1. Since the corneal epithelium forms the first line of defense against air pollutants, including PM₁₀, preserving its integrity using antioxidants such as SKQ1 is crucial in reducing the occurrence of ocular surface disorders.

暴露于空气中的颗粒物10）会对眼表层产生不利影响。本研究测试了 PM10 对永生人角膜上皮细胞（HCE-2）和小鼠角膜上皮屏障完整性的影响，以及抗氧化剂 SKQ1 是否具有修复作用。将 HCE-2 暴露于 100 μg/ml PM10 和 SKQ1 24 小时。电细胞-基底阻抗传感（ECIS）系统监控了PM10的影响。RT-PCR、Western印迹和免疫荧光测量了屏障和相关蛋白、Stanniocalcin 2 (STC2)的水平，一种试剂盒测量了总钙的水平。在体内，雌性 C57BL/6 小鼠在全身暴露室中暴露于对照组空气或 PM10（±SKQ1），并检测屏障相关蛋白。对角膜上的紧密连接蛋白和粘蛋白进行了检测。在 HCE-2 中，PM0 与对照组相比，明显降低了紧密连接蛋白、粘附蛋白和粘蛋白的 mRNA 和蛋白质水平。ECIS数据显示，在4000赫兹频率下，PM10与对照细胞相比，上皮屏障强度明显降低，表现为阻抗和电阻降低。PM10 还上调了 STC2 蛋白和总钙水平。在体内，PM10 与对照组相比减少了闭锁带 1 和粘蛋白。SKQ1 预处理可逆转 PM10 在体外和体内的影响。总之，接触 PM10 会减少紧密连接蛋白和粘蛋白，损害角膜上皮细胞之间的密封性，导致上皮屏障强度降低。SKQ1 可逆转这种影响。由于角膜上皮是抵御包括 PM10 在内的空气污染物的第一道防线，因此使用 SKQ1 等抗氧化剂保护角膜上皮的完整性对于减少眼表疾病的发生至关重要。

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引用次数: 0

Effects of sitagliptin and L-theanine combination therapy on testicular tissue in rats with experimental diabetes 西他列汀和左旋茶氨酸联合疗法对实验性糖尿病大鼠睾丸组织的影响

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-10-06 DOI: 10.1016/j.taap.2024.117119

Cagatay Oltulu , Onur Ersoy , Melek Akinci , Zatiye Ayca Cevikelli-Yakut , Mustafa Dasman , Elvan Bakar

This study examines the impact of the combination of sitagliptin and L-theanine on the testis tissue of rats with experimental diabetes. Diabetes mellitus, a chronic metabolic illness, significantly reduces quality of life and can cause male infertility by decreasing sperm count, motility, and testosterone levels. Rats were allocated to five separate groups: control, diabetes, L-theanine, sitagliptin, and combination therapy. The measurements encompassed blood glucose levels, body weight, serum insulin levels, and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). The histological examination of testicular tissue was conducted using H&E, PASH, caspase-12, and PCNA staining techniques, in addition to a TUNEL assay to detect apoptosis. Levels of oxidative stress indicators, including glutathione peroxidase (GPX), malondialdehyde (MDA), and catalase, were also evaluated. The results showed that the group of individuals with diabetes had significantly higher levels of blood glucose, apoptotic indices, GPX, catalase, and MDA levels and activities in comparison with the control group. Although both the L-theanine and sitagliptin groups exhibited some improvement, the combination therapy demonstrated the most significant decrease in histopathological damage and apoptotic markers. These results indicate that the combination of sitagliptin and L-theanine may significantly decrease testicular damage caused by diabetes, making it a promising therapeutic strategy.

本研究探讨了西他列汀和左旋茶氨酸联合用药对实验性糖尿病大鼠睾丸组织的影响。糖尿病是一种慢性代谢性疾病，会大大降低生活质量，并通过降低精子数量、活力和睾酮水平导致男性不育。大鼠被分配到五个不同的组别：对照组、糖尿病组、左旋茶氨酸组、西他列汀组和综合疗法组。测量包括血糖水平、体重、血清胰岛素水平和胰岛素抵抗稳态模型评估（HOMA-IR）。睾丸组织的组织学检查采用H&E、PASH、caspase-12和PCNA染色技术，此外还采用TUNEL检测法检测细胞凋亡。此外，还评估了氧化应激指标的水平，包括谷胱甘肽过氧化物酶（GPX）、丙二醛（MDA）和过氧化氢酶。结果显示，与对照组相比，糖尿病患者组的血糖水平、细胞凋亡指数、谷胱甘肽过氧化物酶、过氧化氢酶和 MDA 的水平和活性都明显较高。虽然左旋茶氨酸组和西他列汀组都有一定程度的改善，但联合治疗组的组织病理学损伤和细胞凋亡指标下降最为明显。这些结果表明，西他列汀和左旋茶氨酸联合疗法可显著减少糖尿病对睾丸的损伤，是一种很有前景的治疗策略。

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引用次数: 0

Fosaprepitant improves cyclophosphamide-induced bladder damage by alleviating inflammatory response in mice 福沙匹坦通过减轻炎症反应改善环磷酰胺诱发的小鼠膀胱损伤。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-10-06 DOI: 10.1016/j.taap.2024.117120

Yaren Yesilbas Aksel , Elif Nur Barut , Seckin Engin

Inhibition of inflammatory process is a key therapeutic target for the treatment of interstitial cystitis (IC). Recent reports indicate that neurokinin 1 receptor (NK1R) antagonists have beneficial roles in inflammatory-based diseases. Herein, we investigate the protective effects of fosaprepitant (FOS), a NK1R antagonist, in cyclophosphamide (CP)-induced cystitis. The cystitis model was established multiple CP (80 mg/kg; i.p.) injection one day apart, and mice were treated with FOS (20 and 60 mg/kg/day; i.p.) for seven consecutive days. Detrusor contractility, vesical vascular permeability, myeloperoxidase (MPO) activity and protein expression levels of the TLR4 pathway were evaluated in mice bladder. Carbachol and electric field stimulation-evoked contractions of detrusor strips were significantly increased in CP-treated mice, which was significantly attenuated by FOS (60 mg/kg/day) treatment (p<0.001, p<0.05). Notably, vesical vascular permeability was markedly impaired in CP-induced cystitis, that was restored by FOS (60 mg/kg/day) treatment (p<0.01). MPO activity was significantly increased in cystitis group whereas FOS (20 and 60 mg/kg/day) treatment remarkably suppressed MPO activity in bladder tissue (p<0.001). Although TLR4 expression increased with cystitis, MyD88 and p-NFκB^Ser536/total NFκB did not change, FOS (20 and 60 mg/kg/day) treatment caused a dramatic decrease in TLR4 expression (p<0.001), indicating the anti-inflammatory effect of FOS. In conclusion, FOS improved detrusor overactivity and inflammatory response by inhibiting MPO activity and TLR4 expression, resulting in functional and histological recovery in CP-induced cystitis.

抑制炎症过程是治疗间质性膀胱炎（IC）的关键治疗目标。最近的报道表明，神经激肽 1 受体（NK1R）拮抗剂对炎症性疾病有益。在此，我们研究了 NK1R 拮抗剂福沙匹坦（FOS）对环磷酰胺（CP）诱导的膀胱炎的保护作用。小鼠膀胱炎模型的建立是多次注射环磷酰胺（80 毫克/千克；静注），每次间隔一天，然后连续七天用 FOS（20 和 60 毫克/千克/天；静注）治疗。对小鼠膀胱的逼尿肌收缩力、膀胱血管通透性、髓过氧化物酶（MPO）活性和 TLR4 通路的蛋白表达水平进行了评估。卡巴胆碱和电场刺激诱发的小鼠逼尿肌收缩明显增加，而 FOS（60 毫克/千克/天）治疗可明显减弱（p˂0.001, p˂0.05）。值得注意的是，在 CP 诱导的膀胱炎中，膀胱血管通透性明显受损，而 FOS（60 毫克/千克/天）治疗可使其恢复（p˂0.01）。膀胱炎组的 MPO 活性明显升高，而 FOS（20 和 60 毫克/千克/天）治疗可明显抑制膀胱组织中的 MPO 活性（p˂0.001）。虽然TLR4的表达随膀胱炎而增加，但MyD88和p-NFκBSer536/总NFκB没有变化，FOS（20和60毫克/千克/天）治疗使TLR4的表达急剧下降（p˂0.001），这表明FOS具有抗炎作用。总之，FOS通过抑制MPO活性和TLR4表达，改善了逼尿肌过度活动和炎症反应，从而使CP诱导的膀胱炎患者的功能和组织学得到恢复。

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引用次数: 0

Bisphenol AP inhibits mouse oocyte maturation in vitro by disrupting cytoskeleton architecture and cell cycle processes 双酚 AP 通过破坏细胞骨架结构和细胞周期过程抑制小鼠卵母细胞的体外成熟。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-10-01 DOI: 10.1016/j.taap.2024.117118

Caiyun Wu , Zhiming Ding , Chen Yang , Cong Ma , Huilei Chen , Ping Zhou , Zuying Xu , Huifen Xiang

Bisphenol A (BPA) is among the extensively researched environmental endocrine-disrupting chemicals (EDCs), and its utilization is restricted owing to the detrimental impacts it has on human health. Bisphenol AP (BPAP) is one of the alternatives to BPA, but the influence of BPAP on human health has not been elucidated. The objective of the current research was to determine the influence of BPAP exposure on the in vitro maturation of mouse oocytes and to explore its potential reproductive toxicity. BPAP exposure was found to inhibit polar body extrusion during mouse oocyte maturation, resulting in an arrest at the metaphase I stage of meiosis. Exposure to BPAP led to sustained activation of BubR1, preventing the degradation of both Securin and Cyclin B1. Mechanistically, BPAP exposure disrupts spindle assembly and chromosome alignment. Levels of acetylated α-tubulin were significantly elevated in BPAP-treated oocytes, reflecting decreased spindle stability. Exposure to BPAP also induced DNA damage and impaired DNA damage repair. In addition, BPAP exposure altered histone modification levels. In summary, this investigation suggests that exposure to BPAP can influence cytoskeletal assembly, interfere with cell cycle progression, induce DNA damage, alter histone modifications, and ultimately impede oocyte meiotic maturation. This investigation enhances understanding of the impact of bisphenol analogs on female gametes, underscoring that BPAP cannot be considered a reliable replacement for BPA.

双酚 A（BPA）是被广泛研究的环境内分泌干扰化学品（EDCs）之一，由于其对人体健康的有害影响，其使用受到限制。双酚 AP（BPAP）是双酚 APA 的替代品之一，但 BPAP 对人体健康的影响尚未阐明。当前研究的目的是确定暴露于 BPAP 对小鼠卵母细胞体外成熟的影响，并探索其潜在的生殖毒性。研究发现，在小鼠卵母细胞成熟过程中，暴露于磷酸氢二钠会抑制极体挤出，导致其在减数分裂的分裂期 I 阶段停滞。暴露于 BPAP 会导致 BubR1 持续活化，阻止 Securin 和 Cyclin B1 的降解。从机理上讲，暴露于 BPAP 会破坏纺锤体的组装和染色体的排列。在经 BPAP 处理的卵母细胞中，乙酰化 α-微管蛋白的水平显著升高，这反映了纺锤体稳定性的降低。暴露于 BPAP 还会诱发 DNA 损伤并损害 DNA 损伤修复。此外，暴露于 BPAP 会改变组蛋白修饰水平。总之，这项研究表明，暴露于 BPAP 可影响细胞骨架的组装，干扰细胞周期的进展，诱发 DNA 损伤，改变组蛋白修饰，并最终阻碍卵母细胞减数分裂成熟。这项调查加深了人们对双酚类似物对雌配子影响的了解，同时强调了不能将双酚AP视为双酚A的可靠替代品。

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引用次数: 0

Alcohol promotes hepatocyte injury via ER stress sensor XBP1s mediated regulation of autophagy and lysosomal activity 酒精通过ER应激传感器XBP1s介导的自噬和溶酶体活性调节促进肝细胞损伤。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2024-10-01 DOI: 10.1016/j.taap.2024.117117

Yong Cheng , Peng Rao , Shuojiao Li , Wenxian Yu , Yue Tang , Ranran Wang , Wei He , Jiatao Liu

Objective

Endoplasmic reticulum stress (ERS) plays an important role in the development of Alcoholic liver injury (ALI), but the exact mechanism needs further exploration. This study aims to investigate the role of ERS-XBP1s in ALI, and providing new target for the treatment of liver injury.

Method

The ALI model was constructed using the NIAAA method and was validated by several methods. ERS was detected using western-blot, RT-qPCR and immunohistochemistry. Apoptosis was measured by TUNEL staining, Hoechst staining, western-blot and Annexin V-FITC. Lysosomal function and autophagy were measured by Lyso-Tracker Green probe, western-blot and immunofluorescence, respectively.

Results

The ALI model was successfully constructed as demonstrated by increased liver steatosis, inflammation and oxidative stress, and higher levels of serum ALT, AST and TG. Alcohol significantly increased the expression of ERS-related molecules, such as PERK, IRE1α, GRP78 and XBP1s, and promoted the nuclear translocation of XBP1s. Moreover, alcohol significantly increased apoptosis and inhibition of XBP1s could reverse this effect in vivo and in vitro. Interestingly, we found that alcohol significantly elevated hepatocyte LC3-II/I levels and concomitantly accumulation of P62, and this phenomenon was reversed by inhibiting XBP1s both in vivo and in vitro. Mechanistically, we found that alcohol activation of ER stress sensor XBP1s which promoted liver injury via inhibiting lysosomal function and autophagy activity in hepatocytes, whereas inhibition of XBP1s reduces hepatocyte apoptosis by restoring lysosomal activity and activating of autophagy.

Conclusion

Alcohol promotes hepatocytes injury via ER stress sensor XBP1s mediated inhibition of autophagy. Therefore, inhibition of XBP1 may protect the liver from alcohol-induced damage.

目的：内质网应激（ERS）在酒精性肝损伤（ALI）的发生发展中起着重要作用，但其确切机制尚需进一步探讨。本研究旨在探讨ERS-XBP1s在ALI中的作用，为治疗肝损伤提供新靶点：方法：采用 NIAAA 方法构建 ALI 模型，并通过多种方法进行验证。方法：采用 NIAAA 方法构建 ALI 模型，并通过多种方法进行验证。通过 TUNEL 染色、Hoechst 染色、Western-blot 和 Annexin V-FITC 测定细胞凋亡。溶酶体功能和自噬分别通过Lyso-Tracker Green探针、Western-blot和免疫荧光进行测定：结果：ALI 模型构建成功，表现为肝脏脂肪变性、炎症和氧化应激增加，血清 ALT、AST 和 TG 水平升高。酒精明显增加了 ERS 相关分子的表达，如 PERK、IRE1α、GRP78 和 XBP1s，并促进了 XBP1s 的核转位。此外，酒精可明显增加细胞凋亡，而抑制 XBP1s 可逆转体内和体外的这种效应。有趣的是，我们发现酒精会明显提高肝细胞 LC3-II/I 的水平，同时导致 P62 的积累，而通过抑制 XBP1s 可以逆转体内和体外的这一现象。从机理上讲，我们发现酒精激活ER应激传感器XBP1s通过抑制肝细胞溶酶体功能和自噬活性促进肝损伤，而抑制XBP1s则通过恢复溶酶体活性和激活自噬减少肝细胞凋亡：结论：酒精通过ER应激传感器XBP1s介导的自噬抑制作用促进肝细胞损伤。因此，抑制 XBP1 可保护肝脏免受酒精引起的损伤。

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引用次数: 0