Toxicology and applied pharmacology最新文献_第8页

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 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2025.117237

Rong Zou , Zhaoxia Liu , Peng Wang , Ying Liu

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.

{"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

An oat fiber intervention for reducing PFAS body burden: A pilot study in male C57Bl/6 J mice 燕麦纤维干预减轻PFAS身体负担：雄性C57Bl/6 J小鼠的初步研究。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117188

Jennifer J. Schlezinger , Kushal Biswas , Audrey Garcia , Wendy J. Heiger-Bernays , Dhimiter Bello

Perfluoroalkyl substances (PFAS) are a major public health concern, in part because several PFAS have elimination half-lives on the order of years and are associated with adverse health outcomes. While PFAS can be transported into bile, their efficient reuptake by intestinal transporter proteins results in minimal fecal elimination. Here, we tested the hypothesis that consumption of oat β-glucan, a dietary supplement known to disrupt the enterohepatic recirculation of bile acids, will reduce PFAS body burdens. Male C57Bl/6 J mice were fed diets based on the “What we eat in America” analysis that were supplemented with inulin or oat β-glucan and exposed via drinking water to a seven PFAS mixture (PFHpA, PFOA, PFNA, Nafion Byproduct-2, PFHxS and PFOS) for 6 weeks. One cohort of mice was euthanized at the end of the exposure, and one cohort continued on the experimental diets for 4 more weeks without additional PFAS exposure. The β-glucan fed mice drank significantly more water than the inulin fed mice, resulting in a significantly higher dose of PFAS. Relative to overall exposure, we observed lower serum concentration trends (p < 0.1) in β-glucan fed mice for PFHpA, PFOA and PFOS. Additionally, β-glucan fed mice had lower adipose:body weight ratios and liver and jejunum triglyceride concentrations. Hepatic mRNA expression of Cyp4a10, Cyp2b10 and Cyp3a11 were elevated in PFAS exposed mice, with only the expression of Cyp3a11 decreasing following depuration. This pilot study generates support for the hypothesis that oat β-glucan supplementation can reduce PFAS body burdens and stimulate healthful effects on lipid homeostasis.

全氟烷基物质（PFAS）是一个主要的公共卫生问题，部分原因是几种PFAS的消除半衰期约为数年，并与不良健康后果有关。虽然PFAS可以运输到胆汁中，但它们被肠道转运蛋白有效地再吸收导致粪便消除最少。在这里，我们测试了燕麦β-葡聚糖（一种已知会破坏胆汁酸的肠肝再循环的膳食补充剂）的消耗将减少PFAS的身体负担的假设。雄性C57Bl/6 J小鼠根据“What we eat in America”分析，在饲料中添加菊粉或燕麦β-葡聚糖，并通过饮用水暴露于七种PFAS混合物（PFHpA， PFOA， PFNA， Nafion副产品-2，PFHxS和PFOS） 6 周。一组小鼠在暴露结束时被安乐死，另一组小鼠在没有额外PFAS暴露的情况下继续实验饮食4周。β-葡聚糖喂养的小鼠比菊粉喂养的小鼠喝更多的水，导致PFAS剂量显著增加。相对于总体暴露，我们观察到较低的血清浓度趋势(p

{"title":"An oat fiber intervention for reducing PFAS body burden: A pilot study in male C57Bl/6 J mice","authors":"Jennifer J. Schlezinger , Kushal Biswas , Audrey Garcia , Wendy J. Heiger-Bernays , Dhimiter Bello","doi":"10.1016/j.taap.2024.117188","DOIUrl":"10.1016/j.taap.2024.117188","url":null,"abstract":"<div><div>Perfluoroalkyl substances (PFAS) are a major public health concern, in part because several PFAS have elimination half-lives on the order of years and are associated with adverse health outcomes. While PFAS can be transported into bile, their efficient reuptake by intestinal transporter proteins results in minimal fecal elimination. Here, we tested the hypothesis that consumption of oat β-glucan, a dietary supplement known to disrupt the enterohepatic recirculation of bile acids, will reduce PFAS body burdens. Male C57Bl/6 J mice were fed diets based on the “What we eat in America” analysis that were supplemented with inulin or oat β-glucan and exposed via drinking water to a seven PFAS mixture (PFHpA, PFOA, PFNA, Nafion Byproduct-2, PFHxS and PFOS) for 6 weeks. One cohort of mice was euthanized at the end of the exposure, and one cohort continued on the experimental diets for 4 more weeks without additional PFAS exposure. The β-glucan fed mice drank significantly more water than the inulin fed mice, resulting in a significantly higher dose of PFAS. Relative to overall exposure, we observed lower serum concentration trends (<em>p</em> < 0.1) in β-glucan fed mice for PFHpA, PFOA and PFOS. Additionally, β-glucan fed mice had lower adipose:body weight ratios and liver and jejunum triglyceride concentrations. Hepatic mRNA expression of <em>Cyp4a10</em>, <em>Cyp2b10</em> and <em>Cyp3a11</em> were elevated in PFAS exposed mice, with only the expression of <em>Cyp3a11</em> decreasing following depuration. <em>This pilot study generates support for the hypothesis that oat β-glucan supplementation can reduce PFAS body burdens and stimulate healthful effects on lipid homeostasis.</em></div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117188"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142795133","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

Didecyldimethylammonium chloride-induced lung fibrosis may be associated with phospholipidosis 二烷基二甲基氯化铵诱导的肺纤维化可能与磷脂沉积症有关。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.taap.2024.117211

Wonkyun Jung , Mi-Jin Yang , Min-Sung Kang , Jiyun Lim , Hyosun Choi , Ji Ae Lee , Kyung-Sik Yoon , Jin-Bae Kim , Eun-Jung Park

In the current study, we dosed didecyldimethylammonium chloride (DDAC) in mice by pharyngeal aspiration for 28 days or 90 days (weekly) and tried to elucidate the relationship between lamellar body formation and the lesions. When exposed for 28 days (0, 5, 10, 50, and 100 μg/head), all the mice in the 50 and 100 μg/head groups died since Day 2 after the third dosing (Day 16 after the first dosing). Edema, necrosis of bronchiolar and alveolar epithelium, and fibrinous exudate were observed in the lungs of all the dead mice, and chronic inflammatory lesions were observed in the lung tissues of alive mice. When dosed with DDAC of 0, 1, 4, and 8 μg/head for 13 weeks, the total number of pulmonary cells and the pulmonary levels of pro- and anti-inflammatory cytokines significantly increased, and chronic inflammatory lesions were detected with the production of collagen, collagen fibers, and lamellar body-like structures. Swelling of the nuclear envelope and nucleoplasmic components and generation of lipid droplets were also notably observed in the lung tissues of DDAC (8 μg/head)-treated mice. Furthermore, transcriptomic analysis performed using human bronchial epithelial cells showed that DDAC affected the expression of DNA damage, ER stress, lipid metabolism, and transcription regulation-related genes at 6 h after treatment, as it did 24 h treatment and that early growth response factor 1 gene was added to a list of the most up-regulated genes. Meanwhile, cytokines that are associated with the pathology of chronic lung diseases (IL-11, IL-24, and TGF-β) were slightly increased in the lung of DDAC-treated mice, and only the pulmonary level of CCL-2, but not CXCL-1 and CCL-3, increased in both sexes of mice. More importantly, the GM-CSF level increased dose-dependently in the lungs of both sexes of mice exposed to DDAC. Considering that the wound-healing process can take several weeks to complete, we suggest that DDAC-induced pulmonary fibrosis may be attributable to disruption of the wound-healing process due to continuous exposure to DDAC. We also hypothesize that the formation of lamellar bodies may be attributable to lysosomal accumulation of phospholipids separated from the destroyed lung tissue membrane.

在本研究中，我们通过咽部滴入给药小鼠28 天或90 天（每周），试图阐明板层体形成与病变之间的关系。暴露28 天（0、5、10、50和100 μg/头）后，50和100 μg/头组小鼠自第三次给药后第2天（第一次给药后第16天）全部死亡。所有死亡小鼠肺组织均可见细支气管、肺泡上皮水肿、坏死、纤维性渗出，活鼠肺组织可见慢性炎性病变。DDAC浓度分别为0、1、4和8 μg/头，持续13 周后，肺细胞总数和肺中促炎性和抗炎性细胞因子水平显著升高，慢性炎性病变出现胶原蛋白、胶原纤维和板层状体样结构的生成。DDAC（8 μg/头）处理小鼠肺组织中核膜和核质成分明显肿胀，脂滴产生明显。此外，利用人支气管上皮细胞进行的转录组学分析显示，DDAC在治疗后6 h影响DNA损伤、内质网应激、脂质代谢和转录调控相关基因的表达，就像24 h一样，并且早期生长反应因子1基因被添加到上调最多的基因列表中。与此同时，与慢性肺部疾病病理相关的细胞因子（IL-11、IL-24、TGF-β）在ddac处理小鼠肺中略有升高，两性小鼠肺中只有CCL-2水平升高，而CXCL-1和CCL-3水平未升高。更重要的是，暴露于DDAC的雌雄小鼠肺中GM-CSF水平呈剂量依赖性增加。考虑到伤口愈合过程可能需要数周才能完成，我们认为DDAC诱导的肺纤维化可能是由于持续暴露于DDAC而破坏了伤口愈合过程。我们还假设片层体的形成可能归因于从被破坏的肺组织膜分离的磷脂的溶酶体积累。

{"title":"Didecyldimethylammonium chloride-induced lung fibrosis may be associated with phospholipidosis","authors":"Wonkyun Jung , Mi-Jin Yang , Min-Sung Kang , Jiyun Lim , Hyosun Choi , Ji Ae Lee , Kyung-Sik Yoon , Jin-Bae Kim , Eun-Jung Park","doi":"10.1016/j.taap.2024.117211","DOIUrl":"10.1016/j.taap.2024.117211","url":null,"abstract":"<div><div>In the current study, we dosed didecyldimethylammonium chloride (DDAC) in mice by pharyngeal aspiration for 28 days or 90 days (weekly) and tried to elucidate the relationship between lamellar body formation and the lesions. When exposed for 28 days (0, 5, 10, 50, and 100 μg/head), all the mice in the 50 and 100 μg/head groups died since Day 2 after the third dosing (Day 16 after the first dosing). Edema, necrosis of bronchiolar and alveolar epithelium, and fibrinous exudate were observed in the lungs of all the dead mice, and chronic inflammatory lesions were observed in the lung tissues of alive mice. When dosed with DDAC of 0, 1, 4, and 8 μg/head for 13 weeks, the total number of pulmonary cells and the pulmonary levels of pro- and anti-inflammatory cytokines significantly increased, and chronic inflammatory lesions were detected with the production of collagen, collagen fibers, and lamellar body-like structures. Swelling of the nuclear envelope and nucleoplasmic components and generation of lipid droplets were also notably observed in the lung tissues of DDAC (8 μg/head)-treated mice. Furthermore, transcriptomic analysis performed using human bronchial epithelial cells showed that DDAC affected the expression of DNA damage, ER stress, lipid metabolism, and transcription regulation-related genes at 6 h after treatment, as it did 24 h treatment and that early growth response factor 1 gene was added to a list of the most up-regulated genes. Meanwhile, cytokines that are associated with the pathology of chronic lung diseases (IL-11, IL-24, and TGF-β) were slightly increased in the lung of DDAC-treated mice, and only the pulmonary level of CCL-2, but not CXCL-1 and CCL-3, increased in both sexes of mice. More importantly, the GM-CSF level increased dose-dependently in the lungs of both sexes of mice exposed to DDAC. Considering that the wound-healing process can take several weeks to complete, we suggest that DDAC-induced pulmonary fibrosis may be attributable to disruption of the wound-healing process due to continuous exposure to DDAC. We also hypothesize that the formation of lamellar bodies may be attributable to lysosomal accumulation of phospholipids separated from the destroyed lung tissue membrane.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117211"},"PeriodicalIF":3.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142877922","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

Toxic effects of prenatal azithromycin exposure on fetal adrenal gland in mice: The role of stage, dose and course of treatment

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-01-29 DOI: 10.1016/j.taap.2025.117244

Xiaomin Li , Ying Xiong , Aihemaitijiang Ailikaiti , Ying Ao , Hao Kou , Hui Wang

Azithromycin is widely used in treating bacterial infections during pregnancy. Previous studies suggest prenatal exposure (PAzE) induces embryonic developmental toxicity. However, the influence of PAzE on fetal adrenal gland development is unknown. Pregnant mice received azithromycin in varying ways: different stages (mid- and late-pregnancy), doses (50, 100, and 200 mg/kg d), and courses (single- and multi-course). Adrenal gland morphology, cell proliferation, apoptosis, steroid synthesis, and expression of key transcriptional factors were examined. PAzE predominantly affected fetal adrenal gland development in males, characterized by obvious pathological changes (irregular arrangement and decreased density of adrenocortical cells, aggravated cytoplasmic vacuolization), weakened cell proliferation (decreased Pcna but increased Caspase3 expression), and inhibited steroidogenesis (reduced expression of Star, 3β-hsd, P450c21, and P450c11). The most significant damage occurred with multi-course high-dose (clinical dose) azithromycin treatment in late-pregnancy, possibly linked to inhibited Cited2 expression. This study delineated the sex-specific toxic effects of PAzE on fetal adrenal gland development, influenced by various stages, doses, and courses of azithromycin treatment. These findings contribute to a better understanding of azithromycin's safe use during pregnancy and offer a crucial theoretical and experimental foundation for future research.

{"title":"Toxic effects of prenatal azithromycin exposure on fetal adrenal gland in mice: The role of stage, dose and course of treatment","authors":"Xiaomin Li , Ying Xiong , Aihemaitijiang Ailikaiti , Ying Ao , Hao Kou , Hui Wang","doi":"10.1016/j.taap.2025.117244","DOIUrl":"10.1016/j.taap.2025.117244","url":null,"abstract":"<div><div>Azithromycin is widely used in treating bacterial infections during pregnancy. Previous studies suggest prenatal exposure (PAzE) induces embryonic developmental toxicity. However, the influence of PAzE on fetal adrenal gland development is unknown. Pregnant mice received azithromycin in varying ways: different stages (mid- and late-pregnancy), doses (50, 100, and 200 mg/kg d), and courses (single- and multi-course). Adrenal gland morphology, cell proliferation, apoptosis, steroid synthesis, and expression of key transcriptional factors were examined. PAzE predominantly affected fetal adrenal gland development in males, characterized by obvious pathological changes (irregular arrangement and decreased density of adrenocortical cells, aggravated cytoplasmic vacuolization), weakened cell proliferation (decreased <em>Pcna</em> but increased <em>Caspase3</em> expression), and inhibited steroidogenesis (reduced expression of <em>Star, 3β-hsd, P450c21,</em> and <em>P450c11</em>). The most significant damage occurred with multi-course high-dose (clinical dose) azithromycin treatment in late-pregnancy, possibly linked to inhibited Cited2 expression. This study delineated the sex-specific toxic effects of PAzE on fetal adrenal gland development, influenced by various stages, doses, and courses of azithromycin treatment. These findings contribute to a better understanding of azithromycin's safe use during pregnancy and offer a crucial theoretical and experimental foundation for future research.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117244"},"PeriodicalIF":3.3,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075593","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

Zebrafish Cyp1b1 knockout alters eye and brain metabolomic profiles, affecting ocular and neurobehavioral function

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-01-29 DOI: 10.1016/j.taap.2025.117246

Dante M. Perone , Andrew J. Annalora , Jared V. Goldstone , Allison N. Dickey , Matthew C. Salanga , Rene D. Francolini , Fred A. Wright , Craig B. Marcus , Robyn L. Tanguay , Manuel Garcia-Jaramillo

Cytochrome P450 1B1 (CYP1B1) metabolizes endogenous and xenobiotic substrates, including steroids and fatty acids. It is implicated in the metabolism of compounds essential for eye development and is a causative gene in primary congenital glaucoma (PCG). However, CYP1B1's role in PCG and related eye disorders and neurobehavioral function is poorly understood. To investigate the role of Cyp1b1 this study used a novel CRISPR-Cas9 generated Cyp1b1 mutant zebrafish (Danio rerio) line. Behavioral, metabolomic, and transcriptomic analyses were performed to determine the molecular and behavioral consequences of the mutant Cyp1b1. Further we aimed to distinguish a visual defect from other neurological effects. Larval mutant zebrafish were hyperactive during the vision-based larval photomotor response assay but behaved normally in the sound-based larval startle response assay. Adult mutants exhibited normal locomotion but altered interactions with other fish. In vision and hearing-based assays, mutant fish showed altered behavior to visual stimuli and reduced auditory responses. Mass spectrometry-based metabolomics analysis revealed 26 differentially abundant metabolites in the eye and 49 in the brain between the genotypes, with perturbed KEGG pathways related to lipid, nucleotide, and amino acid metabolism. RNA sequencing identified 95 differentially expressed genes in the eye and 45 in the brain. Changes in arachidonic and retinoic acid abundance were observed and potentially modulated by altered expression of CYP 1, 2, and 3 family enzymes. While these findings could not point to specific ocular defects over other neurobehavioral phenotypes, behavioral assays and omics analyses highlighted the role of Cyp1b1 in maintaining metabolic homeostasis and the behavioral consequences due to its loss.

{"title":"Zebrafish Cyp1b1 knockout alters eye and brain metabolomic profiles, affecting ocular and neurobehavioral function","authors":"Dante M. Perone , Andrew J. Annalora , Jared V. Goldstone , Allison N. Dickey , Matthew C. Salanga , Rene D. Francolini , Fred A. Wright , Craig B. Marcus , Robyn L. Tanguay , Manuel Garcia-Jaramillo","doi":"10.1016/j.taap.2025.117246","DOIUrl":"10.1016/j.taap.2025.117246","url":null,"abstract":"<div><div>Cytochrome P450 1B1 (CYP1B1) metabolizes endogenous and xenobiotic substrates, including steroids and fatty acids. It is implicated in the metabolism of compounds essential for eye development and is a causative gene in primary congenital glaucoma (PCG). However, CYP1B1's role in PCG and related eye disorders and neurobehavioral function is poorly understood. To investigate the role of Cyp1b1 this study used a novel CRISPR-Cas9 generated Cyp1b1 mutant zebrafish (<em>Danio rerio</em>) line. Behavioral, metabolomic, and transcriptomic analyses were performed to determine the molecular and behavioral consequences of the mutant Cyp1b1. Further we aimed to distinguish a visual defect from other neurological effects. Larval mutant zebrafish were hyperactive during the vision-based larval photomotor response assay but behaved normally in the sound-based larval startle response assay. Adult mutants exhibited normal locomotion but altered interactions with other fish. In vision and hearing-based assays, mutant fish showed altered behavior to visual stimuli and reduced auditory responses. Mass spectrometry-based metabolomics analysis revealed 26 differentially abundant metabolites in the eye and 49 in the brain between the genotypes, with perturbed KEGG pathways related to lipid, nucleotide, and amino acid metabolism. RNA sequencing identified 95 differentially expressed genes in the eye and 45 in the brain. Changes in arachidonic and retinoic acid abundance were observed and potentially modulated by altered expression of CYP 1, 2, and 3 family enzymes. While these findings could not point to specific ocular defects over other neurobehavioral phenotypes, behavioral assays and omics analyses highlighted the role of Cyp1b1 in maintaining metabolic homeostasis and the behavioral consequences due to its loss.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117246"},"PeriodicalIF":3.3,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075595","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

Effects of melatonin on the pharmacokinetics and amino acid metabolism profile of vigabatrin in rats

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-01-28 DOI: 10.1016/j.taap.2025.117247

Qiang Zheng , Song-Lin Xu , Xin-Lin Guo , Chuan-Yu Wang , Meng-Die Ma , Jin-Fang Ge

Objectives

Investigating the effect of melatonin (MLT) on the pharmacokinetics and related neurotransmitter and amino acid metabolism of vigabatrin (VGB) in epileptic rats in vivo.

Methods

High performance liquid chromatography was used to examine the pharmacokinetics and tissue distribution of VGB after intragastric administration dosing (50，100，200) mg/kg singly or in combination with melatonin (20 mg/kg) in rats. The single-compartment model of first-order elimination was fitted with the nonlinear mixed-effect model of first-order estimation. Targeting metabolomics were used to measure and analyze the amino acid levels in the hippocampus of kainic acid (KA)-induced epileptic rats treated with VGB alone or coupled melatonin.

Results

Melatonin significantly alters the pharmacokinetics of VGB, primarily by lengthening the elimination t_1/2, Tmax, MRT and Vz/F, and decreasing the Cmax of both vigabatrin R(−) enantiomer (R-VGB) and vigabatrin S(+) enantiomer (S-VGB). Moreover, the concentrations of R-VGB and S-VGB were increased significantly in the lung and spleen of VGB + MLT group at 15 min compared with that of the VGB group. At 1 h, S-VGB levels increased significantly in spleen. At 4 h, the levels of S-VGB in the hippocampus and R-VGB in the prefrontal cortex increased significantly. Results of targeted metabolomics experiment showed that compared with control group, the level of aminobutyric acid/glutamate (GABA/Glu) in hippocampus of KA-induced epileptic rats was decreased, while glutamate/glutamine (Glu/Gln), tyrosine, dopamine, 3-methoxytyramine, tryptophan, 5-hydroxytryptamine, arginine and phenylalanine were significantly increased. These elevated levels of neurotransmitters and amino acids were decreased in VGB- and VGB + MLT treated group.

Conclusions

MLT affected the pharmacokinetics and tissue distribution of VGB in rats, prolonging its elimination time and improving the tissue distribution. Moreover, it might help VGB improve the imbalance of neurotransmitters and amino acids in the hippocampus of epileptic rats.

研究目的方法：采用高效液相色谱法检测大鼠胃内给药（50、100、200）mg/kg单独或与褪黑素（20 mg/kg）联合给药后VGB的药代动力学和组织分布。一阶消除的单室模型与一阶估计的非线性混合效应模型相拟合。采用靶向代谢组学测量和分析了单独或联合使用 VGB 的凯尼酸（KA）诱导癫痫大鼠海马中的氨基酸水平：结果：褪黑素明显改变了VGB的药代动力学，主要是延长了消除t1/2、Tmax、MRT和Vz/F，降低了维格巴曲林R（-）对映体（R-VGB）和维格巴曲林S（+）对映体（S-VGB）的Cmax。此外，与 VGB 组相比，15 分钟后 VGB + MLT 组肺部和脾脏中 R-VGB 和 S-VGB 的浓度显著增加。1 小时后，脾脏中的 S-VGB 水平明显升高。4 小时后，海马中的 S-VGB 和前额叶皮层中的 R-VGB 水平明显升高。靶向代谢组学实验结果显示，与对照组相比，KA 诱导的癫痫大鼠海马中氨基丁酸/谷氨酸（GABA/Glu）的水平降低，而谷氨酸/谷氨酰胺（Glu/Gln）、酪氨酸、多巴胺、3-甲氧基酪胺、色氨酸、5-羟色胺、精氨酸和苯丙氨酸的水平明显升高。在 VGB 和 VGB + MLT 治疗组中，这些升高的神经递质和氨基酸水平有所下降：结论：MLT 影响了 VGB 在大鼠体内的药代动力学和组织分布，延长了其消除时间并改善了组织分布。结论：MLT 影响了 VGB 大鼠的药代动力学和组织分布，延长了 VGB 的消除时间，改善了组织分布，并有助于 VGB 改善癫痫大鼠海马中神经递质和氨基酸的失衡。

{"title":"Effects of melatonin on the pharmacokinetics and amino acid metabolism profile of vigabatrin in rats","authors":"Qiang Zheng , Song-Lin Xu , Xin-Lin Guo , Chuan-Yu Wang , Meng-Die Ma , Jin-Fang Ge","doi":"10.1016/j.taap.2025.117247","DOIUrl":"10.1016/j.taap.2025.117247","url":null,"abstract":"<div><h3>Objectives</h3><div>Investigating the effect of melatonin (MLT) on the pharmacokinetics and related neurotransmitter and amino acid metabolism of vigabatrin (VGB) in epileptic rats in vivo.</div></div><div><h3>Methods</h3><div>High performance liquid chromatography was used to examine the pharmacokinetics and tissue distribution of VGB after intragastric administration dosing (50，100，200) mg/kg singly or in combination with melatonin (20 mg/kg) in rats. The single-compartment model of first-order elimination was fitted with the nonlinear mixed-effect model of first-order estimation. Targeting metabolomics were used to measure and analyze the amino acid levels in the hippocampus of kainic acid (KA)-induced epileptic rats treated with VGB alone or coupled melatonin.</div></div><div><h3>Results</h3><div>Melatonin significantly alters the pharmacokinetics of VGB, primarily by lengthening the elimination t<sub>1/2</sub>, Tmax, MRT and Vz/F, and decreasing the Cmax of both vigabatrin R(−) enantiomer (R-VGB) and vigabatrin S(+) enantiomer (S-VGB). Moreover, the concentrations of R-VGB and S-VGB were increased significantly in the lung and spleen of VGB + MLT group at 15 min compared with that of the VGB group. At 1 h, S-VGB levels increased significantly in spleen. At 4 h, the levels of S-VGB in the hippocampus and R-VGB in the prefrontal cortex increased significantly. Results of targeted metabolomics experiment showed that compared with control group, the level of aminobutyric acid/glutamate (GABA/Glu) in hippocampus of KA-induced epileptic rats was decreased, while glutamate/glutamine (Glu/Gln), tyrosine, dopamine, 3-methoxytyramine, tryptophan, 5-hydroxytryptamine, arginine and phenylalanine were significantly increased. These elevated levels of neurotransmitters and amino acids were decreased in VGB- and VGB + MLT treated group.</div></div><div><h3>Conclusions</h3><div>MLT affected the pharmacokinetics and tissue distribution of VGB in rats, prolonging its elimination time and improving the tissue distribution. Moreover, it might help VGB improve the imbalance of neurotransmitters and amino acids in the hippocampus of epileptic rats.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117247"},"PeriodicalIF":3.3,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143068276","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

Bisphenol F (BPF) exposure impairs sperm quality and offspring development in male zebrafish

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-01-26 DOI: 10.1016/j.taap.2025.117245

Wenying Wu , Zhongjing Su , Congying Luo , Jiejie Li , Xinle Yu , Han Xie , Ganglong Wu , Dinghui Wang , Kusheng Wu

Background

Bisphenol F (BPF), a substitute for bisphenol A (BPA), is widely used in consumer products, increasing the potential for environmental exposure. Our study investigated the reproductive effects of BPF on adult male zebrafish and explored its toxicological mechanisms, as well as its intergenerational effects.

Methods

Adult male zebrafish were exposed to BPF concentrations of 0, 50, 500, 2500, and 5000 nM for 21 days. We evaluated sperm cell quantity and quality, hormonal markers testosterone (T) and vitellogenin (VTG), gene expression profiles related to hormone synthesis, metabolism, apoptosis, cell cycle, sexual behavior, and offspring health metrics including survival, development and locomotion.

Results

BPF exposure did not significantly affect body weight or gonadal index. However, at 500 and 2500 nM, a significant reduction in sperm count was observed. BPF exposure led to decreased serum T and increased hepatic VTG levels, indicating hormonal disruption. At 50 nM, BPF initiated sperm apoptosis, and at higher doses, it disrupted sperm meiosis, affecting cell distribution. This exposure negatively impacted sperm quality, reduced offspring survival rates, and altered sperm motility in adult fish. Offspring from BPF-exposed groups showed developmental issues, including increased mortality, delayed developmental stages, abnormal tail coiling and heart rate, which correlated with paternal sperm count and quality changes, alterations in T and VTG levels, and cell cycle phase distributions.

Conclusions

Our study demonstrated that BPF exposure significantly impacted sperm quality, characterized by reduced sperm count and altered motility patterns, leading to developmental anomalies in offspring. These novel findings highlight the need for further research into BPF's reproductive and developmental toxicity, emphasizing the potential risks to aquatic ecosystems and human health. The observed effects on sperm quality, hormonal balance, and offspring development provide new insights into the reproductive toxicity profile of BPF.

{"title":"Bisphenol F (BPF) exposure impairs sperm quality and offspring development in male zebrafish","authors":"Wenying Wu , Zhongjing Su , Congying Luo , Jiejie Li , Xinle Yu , Han Xie , Ganglong Wu , Dinghui Wang , Kusheng Wu","doi":"10.1016/j.taap.2025.117245","DOIUrl":"10.1016/j.taap.2025.117245","url":null,"abstract":"<div><h3>Background</h3><div>Bisphenol F (BPF), a substitute for bisphenol A (BPA), is widely used in consumer products, increasing the potential for environmental exposure. Our study investigated the reproductive effects of BPF on adult male zebrafish and explored its toxicological mechanisms, as well as its intergenerational effects.</div></div><div><h3>Methods</h3><div>Adult male zebrafish were exposed to BPF concentrations of 0, 50, 500, 2500, and 5000 nM for 21 days. We evaluated sperm cell quantity and quality, hormonal markers testosterone (T) and vitellogenin (VTG), gene expression profiles related to hormone synthesis, metabolism, apoptosis, cell cycle, sexual behavior, and offspring health metrics including survival, development and locomotion.</div></div><div><h3>Results</h3><div>BPF exposure did not significantly affect body weight or gonadal index. However, at 500 and 2500 nM, a significant reduction in sperm count was observed. BPF exposure led to decreased serum T and increased hepatic VTG levels, indicating hormonal disruption. At 50 nM, BPF initiated sperm apoptosis, and at higher doses, it disrupted sperm meiosis, affecting cell distribution. This exposure negatively impacted sperm quality, reduced offspring survival rates, and altered sperm motility in adult fish. Offspring from BPF-exposed groups showed developmental issues, including increased mortality, delayed developmental stages, abnormal tail coiling and heart rate, which correlated with paternal sperm count and quality changes, alterations in T and VTG levels, and cell cycle phase distributions.</div></div><div><h3>Conclusions</h3><div>Our study demonstrated that BPF exposure significantly impacted sperm quality, characterized by reduced sperm count and altered motility patterns, leading to developmental anomalies in offspring. These novel findings highlight the need for further research into BPF's reproductive and developmental toxicity, emphasizing the potential risks to aquatic ecosystems and human health. The observed effects on sperm quality, hormonal balance, and offspring development provide new insights into the reproductive toxicity profile of BPF.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117245"},"PeriodicalIF":3.3,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059111","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

Sex differences in aristolochic acid I-induced nephrotoxicity in mice and the effect of estradiol

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-01-26 DOI: 10.1016/j.taap.2025.117240

Qianru Wang , Jiuwen Hou , Fan Shui , Jia Tang , Jianjun Du , Cheng Chen , Wenjing Zhang , Maggie Shiliu Tu , Chunhui Li , Qibing Mei

Aristolochic acid I (AAI), the most prominent component of aristolochic acids and found in nearly all aristolochic herbs, has been demonstrated significant nephrotoxicity. In this study, an acute nephrotoxicity model of AAI mice was established by a single dose injection of AAI. It was observed that there are differences of the sensitivity to AAI nephrotoxicity in female and male mice, with male mice exhibiting nephrotoxic effects even at lower doses. After the administration of estradiol (E2), serum levels of creatinine and urea nitrogen in male mice were observed to decrease. We used UPLC-MS/MS to determine the pharmacokinetics and renal tissue distribution of AAI and its metabolite aristololactam I (ALI). It was found that AAI had a longer plasma half-life in female mice, while the content of ALI in renal tissue of male mice was much higher than that in female. The administration of E2 was found to extend the half-life of AAI and reduce the levels of ALI in the kidneys of male mice. The proposed mechanism may involve the reduction of renal OATs transporter activity by E2, leading to decreased concentrations of ALI in the renal tubules. This reduction may mitigate its toxic effects on epithelial cells and diminish the production of its harmful metabolites, thereby alleviating AAI-induced nephrotoxicity.

{"title":"Sex differences in aristolochic acid I-induced nephrotoxicity in mice and the effect of estradiol","authors":"Qianru Wang , Jiuwen Hou , Fan Shui , Jia Tang , Jianjun Du , Cheng Chen , Wenjing Zhang , Maggie Shiliu Tu , Chunhui Li , Qibing Mei","doi":"10.1016/j.taap.2025.117240","DOIUrl":"10.1016/j.taap.2025.117240","url":null,"abstract":"<div><div>Aristolochic acid I (AAI), the most prominent component of aristolochic acids and found in nearly all aristolochic herbs, has been demonstrated significant nephrotoxicity. In this study, an acute nephrotoxicity model of AAI mice was established by a single dose injection of AAI. It was observed that there are differences of the sensitivity to AAI nephrotoxicity in female and male mice, with male mice exhibiting nephrotoxic effects even at lower doses. After the administration of estradiol (E2), serum levels of creatinine and urea nitrogen in male mice were observed to decrease. We used UPLC-MS/MS to determine the pharmacokinetics and renal tissue distribution of AAI and its metabolite aristololactam I (ALI). It was found that AAI had a longer plasma half-life in female mice, while the content of ALI in renal tissue of male mice was much higher than that in female. The administration of E2 was found to extend the half-life of AAI and reduce the levels of ALI in the kidneys of male mice. The proposed mechanism may involve the reduction of renal OATs transporter activity by E2, leading to decreased concentrations of ALI in the renal tubules. This reduction may mitigate its toxic effects on epithelial cells and diminish the production of its harmful metabolites, thereby alleviating AAI-induced nephrotoxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117240"},"PeriodicalIF":3.3,"publicationDate":"2025-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059414","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

Involvement of nuclear atrophy of binucleated hepatocytes in the large micronucleus formation induced by rat hepatocarcinogen acetamide

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-01-25 DOI: 10.1016/j.taap.2025.117243

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

Acetamide is a hepatocarcinogen in rats. We previously revealed that acetamide induces characteristic large micronuclei in rat liver, suggesting the possible involvement of chromosome aberrations in acetamide-induced hepatocarcinogenesis. To elucidate the mechanism of large micronuclei formation, in this study we examined time-dependent changes in rat hepatocytes after administration of acetamide. Male 6-week-old F344 rats were gavaged with a single-dose administration of acetamide. A liver micronucleus test showed large micronuclei formation 48 and 72 h after acetamide administration. Histopathological analysis showed binucleated hepatocytes with a unilateral atrophic nucleus beginning 6 h after acetamide administration, and the number reached a maximum at 24 h. At 48 h, the number of binucleated hepatocytes with an atrophic nucleus decreased, and apoptotic hepatocytes and large micronucleated hepatocytes appeared. The changes in the frequency of these abnormal binucleated hepatocytes demonstrated a transition from atrophic nuclei to large micronuclei. Immunohistopathological examinations of binucleated hepatocytes showed loss of nuclear lamina, accumulation of barrier-to-autointegration factor (BAF) and chromatin condensation with heterochromatinization at the atrophic site of nuclei. Results of a BrdU-labeling assay were negative. The abnormal expression of BAF in morphologically normal nuclei suggested that nuclear envelope aberration in hepatocytes was an initial event of the nuclear atrophy. In addition, lack of involvement of cell division in the nuclear atrophy and large micronucleus formation was also demonstrated by BrdU-labeling assay. Overall, our data suggest that large micronuclei induced by acetamide are formed in binucleated hepatocytes through nuclear atrophy.

{"title":"Involvement of nuclear atrophy of binucleated hepatocytes in the large micronucleus formation induced by rat hepatocarcinogen acetamide","authors":"Norifumi Takimoto , Yuji Ishii , Tatsuya Mitsumoto , Shinji Takasu , Moeka Namiki , Takeshi Toyoda , Makoto Shibutani , Kumiko Ogawa","doi":"10.1016/j.taap.2025.117243","DOIUrl":"10.1016/j.taap.2025.117243","url":null,"abstract":"<div><div>Acetamide is a hepatocarcinogen in rats. We previously revealed that acetamide induces characteristic large micronuclei in rat liver, suggesting the possible involvement of chromosome aberrations in acetamide-induced hepatocarcinogenesis. To elucidate the mechanism of large micronuclei formation, in this study we examined time-dependent changes in rat hepatocytes after administration of acetamide. Male 6-week-old F344 rats were gavaged with a single-dose administration of acetamide. A liver micronucleus test showed large micronuclei formation 48 and 72 h after acetamide administration. Histopathological analysis showed binucleated hepatocytes with a unilateral atrophic nucleus beginning 6 h after acetamide administration, and the number reached a maximum at 24 h. At 48 h, the number of binucleated hepatocytes with an atrophic nucleus decreased, and apoptotic hepatocytes and large micronucleated hepatocytes appeared. The changes in the frequency of these abnormal binucleated hepatocytes demonstrated a transition from atrophic nuclei to large micronuclei. Immunohistopathological examinations of binucleated hepatocytes showed loss of nuclear lamina, accumulation of barrier-to-autointegration factor (BAF) and chromatin condensation with heterochromatinization at the atrophic site of nuclei. Results of a BrdU-labeling assay were negative. The abnormal expression of BAF in morphologically normal nuclei suggested that nuclear envelope aberration in hepatocytes was an initial event of the nuclear atrophy. In addition, lack of involvement of cell division in the nuclear atrophy and large micronucleus formation was also demonstrated by BrdU-labeling assay. Overall, our data suggest that large micronuclei induced by acetamide are formed in binucleated hepatocytes through nuclear atrophy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117243"},"PeriodicalIF":3.3,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053777","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

Formononetin ameliorates DSS-induced colitis by inhibiting the MAPK/PPAR-γ/NF-κB/ROS signaling pathways

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology

Pub Date : 2025-01-23 DOI: 10.1016/j.taap.2025.117239

Shen Cao , Baojiang Lv , Yi Tai , Hong Xiang Zuo , Yue Xing , Young-Joon Surh , Ming Yue Li , Juan Ma , Xuejun Jin

Background and aim

Formononetin (FMN) is a compound isolated from Astragalus membranaceus, that exhibits a range of pharmacological activities, including antitumor, anti-inflammatory, hypolipidemic, and antioxidant effects. Although preliminary study suggests that FMN have a therapeutic role in Inflammatory Bowel Disease (IBD), its specific mechanism of action requires further investigation. This study aimed to investigate the mechanism by which FMN treats DSS-induced colitis in mice.

Methods

RAW264.7 and Bone marrow-derived macrophages (BMDMs) were treated with LPS to establish an inflammatory cell model. Biochemical parameters and morphological characteristics were assessed in the present or absent of FMN. 4 % solution of DSS was administered to C57BL/6 mice to induce IBD, which served as an animal model for investigating the pharmacodynamics of FMN.

Results

FMN significantly reduced colitis-associated injury, as evidenced by a decrease in the disease activity index (DAI), weight gain, and restoration of colon length. Furthermore, FMN inhibits protein expression of NLRP3 inflammasome, suppressed the nuclear translocation of NF-κB/p65, and prevented mitochondrial damage, this process results in a reduction in the accumulation of reactive oxygen species (ROS). Additionally, FMN inhibited the mitogen-activated protein kinase (MAPK) signaling pathway, upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) in the nucleus, and decreased the release of inflammatory factors, thereby exerting anti-inflammatory effects.

Conclusion

By inhibiting mitochondrial damage, activating the MAPK/PPAR-γ/ROS signaling pathway, reducing the nuclear translocation of NF-κB, and suppressing the expression of NLRP3 inflammasome-associated proteins, FMN exerts anti-inflammatory effects.

{"title":"Formononetin ameliorates DSS-induced colitis by inhibiting the MAPK/PPAR-γ/NF-κB/ROS signaling pathways","authors":"Shen Cao , Baojiang Lv , Yi Tai , Hong Xiang Zuo , Yue Xing , Young-Joon Surh , Ming Yue Li , Juan Ma , Xuejun Jin","doi":"10.1016/j.taap.2025.117239","DOIUrl":"10.1016/j.taap.2025.117239","url":null,"abstract":"<div><h3>Background and aim</h3><div>Formononetin (FMN) is a compound isolated from <em>Astragalus membranaceus</em>, that exhibits a range of pharmacological activities, including antitumor, anti-inflammatory, hypolipidemic, and antioxidant effects. Although preliminary study suggests that FMN have a therapeutic role in Inflammatory Bowel Disease (IBD), its specific mechanism of action requires further investigation. This study aimed to investigate the mechanism by which FMN treats DSS-induced colitis in mice.</div></div><div><h3>Methods</h3><div>RAW264.7 and Bone marrow-derived macrophages (BMDMs) were treated with LPS to establish an inflammatory cell model. Biochemical parameters and morphological characteristics were assessed in the present or absent of FMN. 4 % solution of DSS was administered to C57BL/6 mice to induce IBD, which served as an animal model for investigating the pharmacodynamics of FMN.</div></div><div><h3>Results</h3><div>FMN significantly reduced colitis-associated injury, as evidenced by a decrease in the disease activity index (DAI), weight gain, and restoration of colon length. Furthermore, FMN inhibits protein expression of NLRP3 inflammasome, suppressed the nuclear translocation of NF-κB/p65, and prevented mitochondrial damage, this process results in a reduction in the accumulation of reactive oxygen species (ROS). Additionally, FMN inhibited the mitogen-activated protein kinase (MAPK) signaling pathway, upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) in the nucleus, and decreased the release of inflammatory factors, thereby exerting anti-inflammatory effects.</div></div><div><h3>Conclusion</h3><div>By inhibiting mitochondrial damage, activating the MAPK/PPAR-γ/ROS signaling pathway, reducing the nuclear translocation of NF-κB, and suppressing the expression of NLRP3 inflammasome-associated proteins, FMN exerts anti-inflammatory effects.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117239"},"PeriodicalIF":3.3,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143041941","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