Toxicology and applied pharmacology最新文献_第10页

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

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

{"title":"Embryonic exposure to acetamiprid insecticide induces CD68-positive microglia and Purkinje cell arrangement abnormalities in the cerebellum of neonatal rats","authors":"Christine Li Mei Lee , Claire J. Brabander , Yoko Nomura , Yasunari Kanda , Sachiko Yoshida","doi":"10.1016/j.taap.2024.117215","DOIUrl":"10.1016/j.taap.2024.117215","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117215"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

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

{"title":"Resveratrol alleviates reactive oxygen species and inflammation in diabetic retinopathy via SIRT1/HMGB1 pathway-mediated ferroptosis","authors":"Ye Peng , Long Hu , Huilei Xu , Jian Fang , Hongliang Zhong","doi":"10.1016/j.taap.2024.117214","DOIUrl":"10.1016/j.taap.2024.117214","url":null,"abstract":"<div><div>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 Fe<sup>2+</sup>, 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 Fe<sup>2+</sup> 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 <em>via</em> SIRT1/HMGB1 pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117214"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885469","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 “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

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

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

{"title":"Electronic cigarettes alter cardiac rhythm and heart rate variability hyperacutely in mice","authors":"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","doi":"10.1016/j.taap.2024.117174","DOIUrl":"10.1016/j.taap.2024.117174","url":null,"abstract":"<div><h3>Aims</h3><div>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.</div></div><div><h3>Methods & results</h3><div>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 (<em>p</em> < 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 (<em>p</em> = 0.003).</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117174"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142751682","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

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

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

{"title":"Dysregulation of mRNA expression by hsa-miR-186 overexpression in arsenic-induced skin carcinogenesis","authors":"Mayukh Banerjee , Angeliki Lykoudi , Jae Y. Hwang , Jianmin Pan , Shesh N. Rai , Juw W. Park , J. Christopher States","doi":"10.1016/j.taap.2024.117209","DOIUrl":"10.1016/j.taap.2024.117209","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117209"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142885344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

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

{"title":"Female rat liver after sub-acute dibutyl phthalate treatment: Histological, stereological, biochemical, and global gene expression study","authors":"Ivana Ivelja, Jelena Vukcevic, Bojana Stanic, Danijela Kojic, Kristina Pogrmic-Majkic, Nebojsa Andric, Jelena Markovic Filipovic","doi":"10.1016/j.taap.2024.117182","DOIUrl":"10.1016/j.taap.2024.117182","url":null,"abstract":"<div><div>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 <em>Wistar</em> 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 <em>S</em>-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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117182"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780568","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

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

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

{"title":"Preclinical safety and efficacy of the recombinant CR1 drug product CSL040 in rats and cynomolgus monkeys","authors":"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","doi":"10.1016/j.taap.2024.117191","DOIUrl":"10.1016/j.taap.2024.117191","url":null,"abstract":"<div><div>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 <em>in vitro</em> 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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117191"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

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

{"title":"Epigallocatechin gallate ameliorates retinal pigment epithelial cell damage via the CYFIP2 /AKT pathway","authors":"Sijia Li , Dongmei Su , Shanshan Hu , Qiang Hu , Dawei Sun","doi":"10.1016/j.taap.2024.117124","DOIUrl":"10.1016/j.taap.2024.117124","url":null,"abstract":"<div><div>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 (H<sub>2</sub>O<sub>2</sub>)-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 H<sub>2</sub>O<sub>2</sub>-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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117124"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819295","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

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

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

{"title":"The effects of UGT1A4 and ABCB1 polymorphisms on clozapine and N- desmethyl clozapine plasma levels in Turkish schizophrenia patients","authors":"Fezile Ozdemir , Merve Demirbugen Oz , Kenan Can Tok , Emrah Dural , Yagmur Kır , Mehmet Gumustas , Bora Baskak , H. Sinan Suzen","doi":"10.1016/j.taap.2024.117219","DOIUrl":"10.1016/j.taap.2024.117219","url":null,"abstract":"<div><div>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 <em>ABCB1</em> rs1045642 and <em>UGT1A4</em> 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 <em>ABCB1</em> and phase two enzyme <em>UGT1A4</em> polymorphisms were identified using PCR- RFLP method. Results showed that <em>UGT1A4*3</em> polymorphism has statistically significant effects on CLZ C/D and DCLZ C/D levels in patients with sub/supra therapeutic levels while <em>ABCB1</em> 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.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117219"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142955563","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

Ginkgolide B binds to GPX4 and FSP1 to alleviate cerebral ischemia/reperfusion injury in rats 银杏内酯 B 可与 GPX4 和 FSP1 结合，缓解大鼠脑缺血再灌注损伤。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2025.117237

Rong Zou , Zhaoxia Liu , Peng Wang , Ying Liu

{"title":"Ginkgolide B binds to GPX4 and FSP1 to alleviate cerebral ischemia/reperfusion injury in rats","authors":"Rong Zou , Zhaoxia Liu , Peng Wang , Ying Liu","doi":"10.1016/j.taap.2025.117237","DOIUrl":"10.1016/j.taap.2025.117237","url":null,"abstract":"<div><div>Ischemia/reperfusion (I/R) injury can increase the anomalous permeability of the blood-brain barrier and the risk of hemorrhagic conversion. Ginkgolide B (Gin B) has been recognized for its neuroprotective properties in stroke treatment. This study aimed to analyze the association of Gin B with GPX4 and FSP1 in cerebral I/R injury treatment. HT22 cells were induced by oxygen-glucose deprivation/reoxygenation (OGD/R) and treated with a series of Gin B (10, 20, 40 μM) for 24 h. It found that the Gin B treatment declined the OGD/R-induced cellular ROS and lipid ROS with increasing concentrations. Moreover, the Gin B treatment improved the OGD/R-induced ferroptotic cell death by activating the GPX4-GSH and FSP1-CoQ10-NADH pathways with increasing concentrations. Molecular docking showed there is a good binding activity of Gin B to GPX4 (score = −6.4 kcal/mol) and FSP1 (score = −6.7 kcal/mol), and the microscale thermophoresis (MST) assay confirmed that Gin B can directly bind to GPX4 and FSP1. In vivo, rats were induced by middle cerebral artery occlusion (MCAO)/R and treated with 20 mg/kg of Gin B to analyze its effects on the GPX4-GSH and FSP1-CoQ10-NADH pathways. The GPX4 inhibitor (RSL3) and the FSP1 inhibitor (iFSP1) were used to confirm the mechanism of Gin B in the MCAO/R-treated rats. It showed that the Gin B treatment alleviated the MACO/R-induced brain injury by activating the GPX4-GSH and FSP1-CoQ10-NADH pathways. This study showed that Gin B improved cerebral I/R-induced ferroptotic cell death by activating the GPX4-GSH and FSP1-CoQ10-NADH pathways, providing a new mechanism of Gin B for cerebral I/R treatment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117237"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143042035","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