Toxicology and applied pharmacology最新文献_第7页

Neuregulin 1 improved gastric motility and reduced gastric inflammation by activating the α7nAChR through the cholinergic anti-inflammatory pathway in diabetic rats Neuregulin 1通过胆碱能抗炎途径激活α7nAChR，从而改善糖尿病大鼠的胃肠蠕动并减轻胃部炎症。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117205

Weigang Cui , Yuqi Ma , Libin Zhang , Lei Zhang , Qianyin Yao , Jie Zhang , Yatao Cheng , Wenqin Zeng , Qin Liu , Fengyun Liu , Chunyan Liang

Diabetic gastroparesis (DGP), a prevalent complication of diabetes, is characterized by delayed gastric emptying and inflammation. The dorsal motor nucleus of the vagus (DMV) plays a crucial role in modulating gastric function via the vagus nerve. Neuregulin 1 (NRG1), which is present in the DMV and influences the autonomic nervous system, has an unclear role in DGP. This study aimed to investigate the expression of NRG1 in the DMV of Zucker diabetic fatty (ZDF) rats and to evaluate the impact of centrally administered NRG1 on gastric motility and inflammation, as well as the underlying mechanisms. Our findings revealed a decrease in NRG1 and choline acetyltransferase (ChAT) expression in the DMV of ZDF rats, corresponding to weakened gastric motility. Microinjection of AAV-NRG1 (overexpressed NRG1 by means of an adeno-associated viral vector delivery of NRG1) into the DMV enhanced gastric motility and increased vagal nerve discharge frequency. Moreover, AAV-NRG1 upregulated acetylcholine (Ach) and α7 nicotinic acetylcholine receptor (α7nAChR) expression in the gastric body, mitigating gastric inflammation. The beneficial effects of AAV-NRG1 were partially reversed by vagotomy or α7nAChR antagonism. These findings provide novel evidence that NRG1 in the DMV can stimulate Ach release and activate α7nAChRs, thereby reducing inflammation and restoring gastric motility via the vagus nerve. This implicates the NRG1 as a potential therapeutic target for DGP.

糖尿病性胃轻瘫（DGP）是糖尿病的一种常见并发症，其特征是胃排空延迟和炎症。迷走神经背运动核（DMV）在通过迷走神经调节胃功能中起着至关重要的作用。神经调节蛋白1 （NRG1）存在于DMV中并影响自主神经系统，其在DGP中的作用尚不清楚。本研究旨在研究NRG1在Zucker糖尿病脂肪（ZDF）大鼠DMV中的表达，并评价NRG1对胃运动和炎症的影响及其机制。我们的研究结果显示，NRG1和胆碱乙酰转移酶（ChAT）在ZDF大鼠DMV中的表达降低，与胃动力减弱相对应。将AAV-NRG1（通过腺相关病毒载体递送NRG1过表达NRG1）显微注射到DMV中，胃动力增强，迷走神经放电频率增加。此外，AAV-NRG1上调胃体乙酰胆碱（Ach）和α7烟碱乙酰胆碱受体（α7nAChR）的表达，减轻胃炎症。迷走神经切开术或α7nAChR拮抗剂可部分逆转AAV-NRG1的有益作用。这些发现提供了新的证据，证明DMV中的NRG1可以刺激Ach释放并激活α 7nachr，从而通过迷走神经减少炎症并恢复胃运动。这表明NRG1是DGP的潜在治疗靶点。

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引用次数: 0

Embryonic exposure to acetamiprid insecticide induces CD68-positive microglia and Purkinje cell arrangement abnormalities in the cerebellum of neonatal rats 胚胎暴露于对乙酰脒杀虫剂可诱导新生大鼠小脑cd68阳性小胶质细胞和浦肯野细胞排列异常。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117215

Christine Li Mei Lee , Claire J. Brabander , Yoko Nomura , Yasunari Kanda , Sachiko Yoshida

Concerns have been raised regarding acetamiprid (ACE), a neonicotinoid insecticide, due to its potential neurodevelopmental toxicity. ACE, which is structurally similar to nicotine, acts as an agonist of nicotinic acetylcholine receptors (nAChRs) and resists degradation by acetylcholinesterase. Furthermore, ACE has been reported to disrupt neuronal transmission and induce developmental neurotoxicity and ataxia in animal models. However, the prenatal ACE exposure and its pathological changes, including impacts on motor control, remains unclear. In this study, we investigated the effects of ACE exposure, focusing on the development of cerebellar neurons and glia, which are linked to motor impairment. ACE at doses of 20, 40-, and 60 mg/kg body weight was administered to Pregnant Wistar rats via feed on gestational day (G) 15. The developing cerebellum of the pups was examined on postnatal days (P) 7, 14, and 18, corresponding to the critical periods of cerebellar maturation in rodents. Our data revealed that ACE exposure at 40 and 60 mg/kg induced abnormal neuronal alignment on P14, and neuronal cell loss on P18. Additionally, ACE altered microglial behavior, with an increase in the number of CD68-positive microglia, suggesting that the exposure results in an increase in phagocytic microglia in response to neuronal abnormalities, ultimately leading to neuronal cell loss. Pups exposed to 60 mg/kg ACE exhibited hindlimb clasping during the hindlimb suspension test, indicating motor impairment. These findings suggest that ACE exposure causes neuronal cell loss of developing Purkinje cells and promotes a phase shift to the activate mode of microglia. This study further highlights the crucial role of neuron-glia interactions in ACE-induced motor impairment, thus contributing to our understanding of the potential risks associated with prenatal ACE exposure.

乙酰氨脒（ACE）是一种新烟碱类杀虫剂，因其潜在的神经发育毒性而引起人们的关注。ACE在结构上与尼古丁相似，是尼古丁乙酰胆碱受体（nAChRs）的激动剂，抗乙酰胆碱酯酶降解。此外，据报道，ACE在动物模型中破坏神经元传递并诱导发育性神经毒性和共济失调。然而，产前ACE暴露及其病理变化，包括对运动控制的影响，仍不清楚。在这项研究中，我们研究了ACE暴露的影响，重点关注与运动障碍有关的小脑神经元和胶质细胞的发育。在妊娠第15天(G)通过饲料给予妊娠Wistar大鼠20、40和60 mg/kg体重剂量的ACE。在出生后7、14和18天（对应于啮齿动物小脑成熟的关键时期）检查幼鼠小脑的发育情况。我们的数据显示，40和60 mg/kg的ACE暴露会导致P14上异常的神经元排列，以及P18上的神经元细胞损失。此外，ACE改变了小胶质细胞的行为，cd68阳性的小胶质细胞数量增加，表明暴露导致吞噬性小胶质细胞增加，以应对神经元异常，最终导致神经元细胞损失。暴露于60 mg/kg ACE的幼鼠在后肢悬吊试验中出现后肢扣合现象，提示运动障碍。这些发现表明，ACE暴露会导致发育中的浦肯野细胞的神经元细胞丢失，并促进小胶质细胞向激活模式相转移。这项研究进一步强调了神经元-胶质细胞相互作用在ACE诱导的运动障碍中的关键作用，从而有助于我们了解产前ACE暴露的潜在风险。

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引用次数: 0

Resveratrol alleviates reactive oxygen species and inflammation in diabetic retinopathy via SIRT1/HMGB1 pathway-mediated ferroptosis 白藜芦醇通过SIRT1/HMGB1通路介导的铁下垂减轻糖尿病视网膜病变中的活性氧和炎症。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117214

Ye Peng , Long Hu , Huilei Xu , Jian Fang , Hongliang Zhong

This study aims to explore the potential of using resveratrol (RES) to treat diabetic retinopathy (DR), as well as the involved molecular mechanisms underlying RES-mediated protection against DR. High concentration of glucose (HG)-induced Human retinal capillary endothelial cells (HRCECs) cell model and streptozotocin (STZ)-induced DR mice model were established. Then, cell viability, apoptosis, reactive oxygen species (ROS) levels, pro-inflammatory factors, and expression of the related proteins SIRT1, HMGB1, VEGF, and CD31 were assayed by a series of cell biology methods. Also, the ferroptosis-related indicators were also explored, including contents of Fe²⁺, glutathione (GSH), malondialdehyde (MDA), SLC7A11 and GPX4 protein expression. Results showed that RES could alleviate inflammation and oxidative stress in HG-induced HRCECs. In addition, the mRNA and protein expression of SIRT1 and HMGB1 were significantly changed in HG-induced HRCECs and STZ-induced DR mice, while RES treatment could reverse this alteration. In addition, the HMGB1 acetylation level was enhanced after downregulation of SIRT1. Moreover, the ROS generation, expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α), CD31, and VEGF changed by RES administration were reversed by SIRT1-silence. Besides, HG implement could dramatically up-regulated the Fe²⁺ and MDA contents, and down-regulated the content of GSH and SLC7A11 and GPX4 protein expression in HRCECs, as well as STZ-induced DR mice. RES implement could reverse the above alterations, while SIRT1-silence dramatically reversed these alterations changed by RES treatment. In conclusion, RES suppresses inflammation in DR, as well as inhibit retinal angiogenesis and oxidative stress, and inhibits ferroptosis to alleviate DR via SIRT1/HMGB1 pathway.

本研究旨在探讨白藜芦醇（resveratrol， RES）对糖尿病视网膜病变（diabetic retinopathy， DR）的治疗作用及其保护作用的分子机制。建立了高浓度葡萄糖（HG）诱导的人视网膜毛细血管内皮细胞（HRCECs）细胞模型和链脲佐菌素（STZ）诱导的DR小鼠模型。然后，通过一系列细胞生物学方法检测细胞活力、凋亡、活性氧（ROS）水平、促炎因子以及相关蛋白SIRT1、HMGB1、VEGF和CD31的表达。此外，我们还探讨了与铁中毒相关的指标，包括铁离子含量、谷胱甘肽（GSH）、丙二醛（MDA）、SLC7A11和GPX4蛋白表达。结果表明，RES可减轻hg诱导的HRCECs的炎症和氧化应激。此外，hg诱导的HRCECs和stz诱导的DR小鼠中SIRT1和HMGB1的mRNA和蛋白表达发生了显著变化，而RES处理可以逆转这种变化。此外，下调SIRT1后，HMGB1乙酰化水平增强。此外，sirt1沉默可逆转RES引起的ROS生成、炎症细胞因子（IL-1β、IL-6和TNF-α）、CD31和VEGF表达的变化。HG可显著上调HRCECs和stz诱导的DR小鼠的Fe2+和MDA含量，下调GSH含量、SLC7A11和GPX4蛋白表达。RES可逆转上述改变，而sirt1沉默可显著逆转RES治疗改变的这些改变。综上所述，RES通过SIRT1/HMGB1通路抑制DR炎症，抑制视网膜血管生成和氧化应激，抑制铁下沉，减轻DR。

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引用次数: 0

Corrigendum to “Differentiation of sow and mouse ovarian granulosa cells exposed to zearalenone in vitro using RNA-seq gene expression” [Toxicology and Applied Pharmacology, 350 (2018) 78–90] “使用RNA-seq基因表达暴露于玉米霉烯酮的母猪和小鼠卵巢颗粒细胞的体外分化”[毒理学与应用药理学，350(2018)78-90]。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117189

Guo-Liang Zhang , Jun-Lin Song , Yi Zhou , Rui-Qian Zhang , Shun-Feng Cheng , Xiao-Feng Sun , Guo-Qing Qin , Wei Shen , Lan Li

引用次数: 0

Electronic cigarettes alter cardiac rhythm and heart rate variability hyperacutely in mice 电子烟会剧烈改变小鼠的心律和心率变异性。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117174

Jocelyn A. Castellanos , Carson G. Cornett , David H. Gonzalez , Liqiao Li , Karla Luna , Holly R. Middlekauff , Rajat Gupta , Maria C. Jordan , Dennis Rünger , Yifang Zhu , Xuesi M. Shao , Kenneth P. Roos , Jesus A. Araujo

Aims

There has been an unprecedented rise in electronic cigarette (EC) usage likely because of its perception of being safer than smoking. Recent studies show that EC exposures impact heart rate (HR) and heart rate variability (HRV), but how they are affected by the timing and frequency of exposures remain unclear. We examined the electrocardiographic (EKG) effects induced by brief EC exposures over time, their relation to EC aerosol particle and mass concentrations, and potential to promote prooxidative effects in the lungs.

Methods & results

Six 10-week-old C57BL/6J mice, implanted with telemetry devices to monitor EKG activity continuously, were exposed once per week for three weeks to two EC exposures, each lasting 15-min followed by 45-min post-exposure periods. Filtered air (primary) and PBS aerosol (secondary) were used as controls. After combining weeks, EC aerosol induced bradycardia and increased time domain parameters during EC exposures with significant reductions in the post-exposure periods. Log-transformed frequency domain parameters were significantly elevated during and after exposures (p < 0.001). HRV changes occurred within minutes with similar trends observed in particle number and mass concentrations of EC aerosol. HR and HRV varied by week and parameter, with Week 2 and 3 effects overshadowing those in Week 1. ECs induced prooxidative effects in the lungs as evidenced by elevated potential for hydroxyl radical generation in bronchoalveolar lavage fluid of exposed mice (p = 0.003).

Conclusion

Short-term EC exposures altered murine HR and HRV within minutes during and after exposures, effects that were modulated by the timing and frequency of EC exposures.

目的：电子烟（EC）的使用出现了前所未有的增长，可能是因为人们认为电子烟比吸烟更安全。最近的研究表明，EC暴露会影响心率（HR）和心率变异性（HRV），但它们如何受到暴露时间和频率的影响尚不清楚。我们研究了短时间暴露于EC引起的心电图（EKG）影响，它们与EC气溶胶颗粒和质量浓度的关系，以及促进肺部促氧化作用的可能性。方法与结果：6只10周龄C57BL/6小鼠，植入遥测装置连续监测心电图活动，每周暴露1次，连续暴露3周至2次EC暴露，每次持续15分钟，暴露后45分钟。过滤空气（一次）和PBS（二次）作为对照。EC气溶胶在暴露期间引起心动过缓和时域参数增加，暴露后显著减少。在暴露期间和暴露后，对数变换频域参数显著升高（p ）。结论：在暴露期间和暴露后的几分钟内，短期EC暴露改变了小鼠的HR和HRV，这种影响受到EC暴露的时间和频率的调节。

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引用次数: 0

Dysregulation of mRNA expression by hsa-miR-186 overexpression in arsenic-induced skin carcinogenesis 砷诱导皮肤癌中hsa-miR-186过表达导致mRNA表达异常。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117209

Mayukh Banerjee , Angeliki Lykoudi , Jae Y. Hwang , Jianmin Pan , Shesh N. Rai , Juw W. Park , J. Christopher States

Dysregulated miRNA expression contributes to development of arsenic-induced cutaneous squamous cell carcinoma (cSCC). hsa-miR-186 (miR-186) is overexpressed in arsenical cSCC tissues as well as in preclinical cell line model of arsenical cSCC. Simultaneous miR-186 overexpression and chronic inorganic trivalent arsenite (iAs; 100 nM) exposure transformed human HaCaT cell line preferentially over miR-186 overexpression or iAs exposure alone. Both iAs and miR-186 regulate the expression of wide range of mRNA targets. However, how their interaction impacts the transcriptome-wide mRNA expression landscape ushering in cancer is unknown. We performed longitudinal RNA-seq analysis in passage-matched HaCaT cell clones (±miR-186 overexpression) with simultaneous chronic iAs exposure (0/100 nM) at 12 and 29 weeks. We determined the impact of each factor and their interaction towards differential gene expression and pathway dysregulation employing two different statistical approaches (t-statistic and 2-factor ANOVA). We show that a core set of pathways are dysregulated deterministically irrespective of the statistical approach chosen, possibly representing necessary changes for transformation. The data suggest that each clonal line could take a unique route to dysregulate this core set of pathways necessary for transformation, highlighting the possible role of stochasticity in cancer development. Evidence is presented to sift the strengths and weaknesses of each statistical methodology in providing biological understanding of events that play crucial roles in carcinogenesis in large datasets with multiple contributing variables.

在砷诱导的皮肤鳞状细胞癌（cSCC）组织以及砷诱导的 cSCC 临床前细胞系模型中，hsa-miR-186（miR-186）表达过高。同时过表达 miR-186 和长期暴露于无机三价亚砷酸盐（iAs；100 nM）比单独过表达 miR-186 或单独暴露 iAs 更能转化人类 HaCaT 细胞系。iAs 和 miR-186 都能调节多种 mRNA 靶标的表达。然而，它们之间的相互作用如何影响整个转录组的 mRNA 表达，从而导致癌症的发生，目前尚不清楚。我们对同时长期暴露于 iAs（0/100 nM）12 周和 29 周的经过匹配的 HaCaT 细胞克隆（±miR-186 过表达）进行了纵向 RNA-seq 分析。我们采用两种不同的统计方法（t 统计和双因素方差分析）确定了各因素及其相互作用对不同基因表达和通路失调的影响。我们发现，无论选择哪种统计方法，一组核心通路都会发生确定性的失调，这可能代表了转化过程中的必要变化。数据表明，每个克隆系都可能采取独特的途径来失调转化所必需的这组核心通路，这突出了随机性在癌症发展中可能扮演的角色。本文提出了一些证据，以筛选每种统计方法的优缺点，从而从生物学角度理解在具有多种变量的大型数据集中对致癌起关键作用的事件。

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引用次数: 0

Female rat liver after sub-acute dibutyl phthalate treatment: Histological, stereological, biochemical, and global gene expression study 亚急性邻苯二甲酸二丁酯处理后的雌性大鼠肝脏：组织学、体视学、生化和整体基因表达研究。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117182

Ivana Ivelja, Jelena Vukcevic, Bojana Stanic, Danijela Kojic, Kristina Pogrmic-Majkic, Nebojsa Andric, Jelena Markovic Filipovic

Although it has been recognized that females are more susceptible to chemical-induced liver injury, the effects of dibutyl phthalate (DBP), a widely used synthetic chemical, on female liver structure and function are under-researched. Here, we sought to investigate the effects of DBP on histological, stereological, and biochemical parameters, as well as global gene expression in female rat liver. Female Wistar rats were exposed to 100, 500, and 5000 mg DBP/kg diet for 28 days, corresponding to 8.6, 41.43, and 447.33 mg DBP/kg body weight (B.W.)/day, respectively. The highest dose (447.33 mg DBP/kg B.W./day) was between the no-observed-adverse-effect level (NOAEL) and the lowest-observed-adverse-effect level for liver toxicity, whereas two lower doses (8.6 and 41.43 mg DBP/kg B.W./day) were below the NOAEL. Analysis of hematoxylin and eosin-stained sections revealed an increased volume of hepatocytes, their nuclei and cytoplasm, while the volume of sinusoids decreased in DBP-exposed groups compared to the control. Examination of Periodic acid-Schiff-stained sections showed reduced glycogen content, which was the most prominent in the highest dose group. Increased glutathione S-transferase and catalase activities, and decreased GSH content and superoxide dismutase activity were observed in DBP-exposed groups. The mRNA sequencing revealed DBP-induced dose-specific changes in various genes and biological functions in female rat liver. The highest number of deregulated genes was observed in the 500 mg DBP/kg diet group. In summary, exposure to DBP caused significant liver microstructural changes, decreased glycogen content, disturbed the redox status, and affected global gene expression in female rat liver.

虽然人们已经认识到女性更容易受到化学物质引起的肝损伤，但广泛使用的合成化学品邻苯二甲酸二丁酯（DBP）对女性肝脏结构和功能的影响尚不清楚。在这里，我们试图研究DBP对雌性大鼠肝脏的组织学、体视学和生化参数以及整体基因表达的影响。雌性Wistar大鼠分别饲喂100、500和5000 mg DBP/kg饲粮28 d，分别为8.6、41.43和447.33 mg DBP/kg体重/d。最高剂量（447.33 mg DBP/kg体重/天）介于无观察到的肝毒性不良反应水平（NOAEL）和最低观察到的肝毒性不良反应水平之间，而两个较低剂量（8.6和41.43 mg DBP/kg体重/天）低于NOAEL。苏木精和伊红染色切片分析显示，与对照组相比，dbp暴露组肝细胞、细胞核和细胞质体积增加，而窦状体体积减少。周期性酸-希夫染色切片显示糖原含量降低，以高剂量组最为明显。dbp暴露组小鼠谷胱甘肽s转移酶和过氧化氢酶活性升高，谷胱甘肽含量和超氧化物歧化酶活性降低。mRNA测序结果显示，dbp诱导雌性大鼠肝脏多种基因和生物学功能发生剂量特异性变化。在500 mg DBP/kg日粮组，脱调控基因数量最多。综上所述，DBP暴露导致雌性大鼠肝脏微结构发生明显变化，糖原含量降低，氧化还原状态紊乱，并影响肝脏整体基因表达。

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引用次数: 0

Preclinical safety and efficacy of the recombinant CR1 drug product CSL040 in rats and cynomolgus monkeys 重组CR1药物CSL040在大鼠和食蟹猴中的临床前安全性和有效性。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117191

Tanja Ruthsatz , Sandra Wymann , Elena Velkoska , Mariam Mansour , Daniel Schu , Marit Lichtfuss , Paolo Rossato , Meaghan FitzPatrick , Sarah Hosback , Allison Dyson , Eva Herzog , Kirstee Martin , Barbara Dietrich , Matthew P. Hardy

CSL040 is a soluble, recombinant fragment of the complement receptor 1 (CR1) extracellular domain that acts as an inhibitor of all three pathways of the complement system. Systemic toxicity, toxicokinetics (TK), and pharmacodynamics (PD) of CSL040 were assessed in two-week intravenous (IV) bolus studies in Han Wistar rats and cynomolgus monkeys. Recovery from any effects was evaluated during a four-week recovery period. Daily repeat-dose administration for 2 weeks at doses of up to 500 mg/kg CSL040 IV was well tolerated in rats and cynomolgus monkeys, leading to a no observed adverse effect level (NOAEL) of 500 mg/kg for both species. Safety pharmacology parameters such as electrophysiology of the heart, blood pressure, heart rate, and respiratory rate measurements, and general toxicological readouts were considered unaffected by CSL040 treatment. Anti-drug antibodies (ADAs) were observed in all cynomolgus monkeys and in some rats at the highest dose of CSL040, but with no effect on pharmacokinetics (PK), supportive of adequate exposure levels as required for a safety assessment. All three complement pathways were inhibited dose-dependently by CSL040. Additionally, no effect on cytokine levels by CSL040 was detected in vitro using a cytokine release assay. These non-clinical studies with CSL040 demonstrated PD activity consistent with its mode of action, adequate PK properties, and a safety profile supporting a phase 1 clinical strategy. A small follow-up study comparing the PK/PD effects of CSL040 following IV and subcutaneous (SC) administration also suggested that the latter route of administration might be a viable alternative to IV administration.

CSL040是补体受体1 （CR1）胞外结构域的可溶性重组片段，可作为补体系统所有三种途径的抑制剂。采用两周静脉给药的方法，对大鼠和食蟹猴进行了CSL040的全身毒性、毒代动力学（TK）和药效学（PD）研究。在四周的恢复期内评估任何影响的恢复情况。每天重复给药2 周，剂量高达500 mg/kg的CSL040 IV在大鼠和食蟹猴中耐受良好，导致两种物种的未观察到的不良反应水平（NOAEL）为500 mg/kg。安全药理学参数，如心脏电生理、血压、心率和呼吸频率测量，以及一般毒理学读数被认为不受CSL040治疗的影响。在所有食蟹猴和一些大鼠中观察到最高剂量CSL040的抗药物抗体（ADAs），但对药代动力学（PK）没有影响，支持安全性评估所需的适当暴露水平。这三种补体途径均被CSL040剂量依赖性地抑制。此外，体外细胞因子释放试验未检测到CSL040对细胞因子水平的影响。这些CSL040的非临床研究表明，其PD活性与其作用模式一致，具有足够的PK特性，并且具有支持i期临床策略的安全性。一项比较静脉给药和皮下给药CSL040的PK/PD效应的小型随访研究也表明，后者可能是静脉给药的可行选择。

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引用次数: 0

Epigallocatechin gallate ameliorates retinal pigment epithelial cell damage via the CYFIP2 /AKT pathway 表没食子儿茶素没食子酸酯通过CYFIP2 /AKT通路改善视网膜色素上皮细胞损伤。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117124

Sijia Li , Dongmei Su , Shanshan Hu , Qiang Hu , Dawei Sun

Age-related macular degeneration (AMD) is a representative age-related ophthalmic disease, and the pathogenesis of AMD remains unclear. This research intended to determine whether epigallocatechin gallate (EGCG) could alleviate the progression of AMD and the possible mechanism. We constructed three groups of mice (young, aged, and EGCG), and HE and TUNEL staining of retinal tissues was performed to observe the structural changes in the retinal pigment epithelial (RPE) layer and the level of apoptosis, respectively. Through RNA-Sequencing analysis of retinal tissues and by RT-qPCR, GO, KEGG, and literature analyses, we identified cytoplasmic fragile X mental retardation 1-interacting protein 2 (CYFIP2) as a possible effector gene for EGCG action and validated its role by immunofluorescent and western blotting experiments. The CCK-8 and Hoechst 33342 apoptosis assays, and western blotting and qRT-PCR assays showed that EGCG reduced hydrogen peroxide (H₂O₂)-induced apoptosis in adult human RPE (ARPE-19) cells, and the expression of Cyfip2 was changed accordingly. RNA interference analysis indicated that Cyfip2 knockdown alleviated H₂O₂-induced ARPE apoptosis, while its overexpression weakened EGCG's protective effect. Western blot analysis showed that Cyfip2 mediated the anti-apoptotic effect of EGCG by modulating the level of protein kinase B (Akt) phosphorylation in ARPE cells, and the activation level of phosphorylated AKT (p-AKT Ser473) in retinal tissue of the EGCG-fed group was higher than that of the aged group. Taken together, this study suggests that EGCG plays a protective role in the development of AMD and the apoptosis of ARPE cells through the Cyfip2/AKT pathway.

老年性黄斑变性（Age-related macular degeneration， AMD）是一种典型的老年性眼科疾病，其发病机制尚不清楚。本研究旨在确定表没食子儿茶素没食子酸酯（EGCG）是否能缓解AMD的进展及其可能的机制。我们构建三组小鼠（年轻、年老和EGCG），分别对视网膜组织进行HE和TUNEL染色，观察视网膜色素上皮（RPE）层结构变化和细胞凋亡水平。通过视网膜组织rna测序分析、RT-qPCR、GO、KEGG和文献分析，我们确定细胞质脆性X智力迟钝1-相互作用蛋白2 （CYFIP2）可能是EGCG作用的效应基因，并通过免疫荧光和western blotting实验验证了其作用。CCK-8和Hoechst 33342细胞凋亡实验以及western blotting和qRT-PCR检测显示，EGCG可降低过氧化氢（H2O2）诱导的成人RPE （ARPE-19）细胞的凋亡，Cyfip2的表达也随之改变。RNA干扰分析表明，Cyfip2敲低可减轻h2o2诱导的ARPE细胞凋亡，而其过表达可减弱EGCG的保护作用。Western blot分析显示，Cyfip2通过调节ARPE细胞中蛋白激酶B （Akt）磷酸化水平介导EGCG的抗凋亡作用，且EGCG喂养组视网膜组织中磷酸化Akt （p-AKT Ser473）的激活水平高于老龄组。综上所述，本研究提示EGCG通过Cyfip2/AKT通路在AMD的发生和ARPE细胞的凋亡中发挥保护作用。

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引用次数: 0

The effects of UGT1A4 and ABCB1 polymorphisms on clozapine and N- desmethyl clozapine plasma levels in Turkish schizophrenia patients UGT1A4和ABCB1多态性对土耳其精神分裂症患者氯氮平和N-去甲基氯氮平血浆水平的影响

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117219

Fezile Ozdemir , Merve Demirbugen Oz , Kenan Can Tok , Emrah Dural , Yagmur Kır , Mehmet Gumustas , Bora Baskak , H. Sinan Suzen

Clozapine (CLZ) is an antipsychotic which is particularly used in treatment resistant schizophrenia patients who do not respond to other agents. It is preferred because it reduces suicidal behaviours and attempts, reducing aggression and violent behaviour. The aim of the study is to evaluate the effects of ABCB1 rs1045642 and UGT1A4 rs2011425 polymorphisms on CLZ and its major metabolite N- desmethly clozapine (DCLZ) plasma concentrations in patients with schizophrenia. A total 109 of Turkish patients with schizophrenia on continually administered CLZ monotherapy were included. The plasma concentrations of CLZ and DCLZ were measured using an HPLC after liquid-liquid extraction while, transporter gene ABCB1 and phase two enzyme UGT1A4 polymorphisms were identified using PCR- RFLP method. Results showed that UGT1A4*3 polymorphism has statistically significant effects on CLZ C/D and DCLZ C/D levels in patients with sub/supra therapeutic levels while ABCB1 C3435T polymorphism has a significant effect on CLZ/DCLZ ratio among patients who have subtherapeutic levels. This study indicates the influence of genetic differences on plasma levels and highlights the importance of pharmacogenetic studies in clinic. Using the obtained results as pharmacogenetic biomarkers will help clinicians provide effective treatment in individual patients and reduce the undesirable side effects.

氯氮平（CLZ）是一种抗精神病药物，特别用于对其他药物无反应的治疗抵抗性精神分裂症患者。这是首选，因为它减少自杀行为和企图，减少侵略和暴力行为。本研究旨在评估ABCB1 rs1045642和UGT1A4 rs2011425多态性对精神分裂症患者CLZ及其主要代谢物N-地甲基氯氮平（DCLZ）血药浓度的影响。共纳入109名持续给予CLZ单药治疗的土耳其精神分裂症患者。液液萃取后，采用高效液相色谱法检测血浆中CLZ和DCLZ的浓度，采用PCR- RFLP法检测转运体基因ABCB1和二相酶UGT1A4的多态性。结果显示，UGT1A4*3多态性对亚治疗水平/上治疗水平患者的CLZ C/D和DCLZ C/D水平有统计学意义，而ABCB1 C3435T多态性对亚治疗水平患者的CLZ/DCLZ比值有统计学意义。本研究提示了遗传差异对血浆水平的影响，强调了药物遗传学研究在临床中的重要性。使用获得的结果作为药物遗传生物标志物将帮助临床医生为个别患者提供有效的治疗，并减少不良的副作用。

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