Toxicology and applied pharmacology最新文献

{"title":"Zebrafish Cyp1b1 knockout alters eye and brain metabolomic profiles, affecting ocular and neurobehavioral function","authors":"Dante M. Perone ,&nbsp;Andrew J. Annalora ,&nbsp;Jared V. Goldstone ,&nbsp;Allison N. Dickey ,&nbsp;Matthew C. Salanga ,&nbsp;Rene D. Francolini ,&nbsp;Fred A. Wright ,&nbsp;Craig B. Marcus ,&nbsp;Robyn L. Tanguay ,&nbsp;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}

{"title":"Effects of melatonin on the pharmacokinetics and amino acid metabolism profile of vigabatrin in rats","authors":"Qiang Zheng ,&nbsp;Song-Lin Xu ,&nbsp;Xin-Lin Guo ,&nbsp;Chuan-Yu Wang ,&nbsp;Meng-Die Ma ,&nbsp;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_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.</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}

{"title":"Bisphenol F (BPF) exposure impairs sperm quality and offspring development in male zebrafish","authors":"Wenying Wu ,&nbsp;Zhongjing Su ,&nbsp;Congying Luo ,&nbsp;Jiejie Li ,&nbsp;Xinle Yu ,&nbsp;Han Xie ,&nbsp;Ganglong Wu ,&nbsp;Dinghui Wang ,&nbsp;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}

{"title":"Sex differences in aristolochic acid I-induced nephrotoxicity in mice and the effect of estradiol","authors":"Qianru Wang ,&nbsp;Jiuwen Hou ,&nbsp;Fan Shui ,&nbsp;Jia Tang ,&nbsp;Jianjun Du ,&nbsp;Cheng Chen ,&nbsp;Wenjing Zhang ,&nbsp;Maggie Shiliu Tu ,&nbsp;Chunhui Li ,&nbsp;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}

{"title":"Involvement of nuclear atrophy of binucleated hepatocytes in the large micronucleus formation induced by rat hepatocarcinogen acetamide","authors":"Norifumi Takimoto ,&nbsp;Yuji Ishii ,&nbsp;Tatsuya Mitsumoto ,&nbsp;Shinji Takasu ,&nbsp;Moeka Namiki ,&nbsp;Takeshi Toyoda ,&nbsp;Makoto Shibutani ,&nbsp;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}

{"title":"Formononetin ameliorates DSS-induced colitis by inhibiting the MAPK/PPAR-γ/NF-κB/ROS signaling pathways","authors":"Shen Cao ,&nbsp;Baojiang Lv ,&nbsp;Yi Tai ,&nbsp;Hong Xiang Zuo ,&nbsp;Yue Xing ,&nbsp;Young-Joon Surh ,&nbsp;Ming Yue Li ,&nbsp;Juan Ma ,&nbsp;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}

{"title":"Engineering human cerebral organoids to explore mechanisms of arsenic-induced developmental neurotoxicity","authors":"Xian Wu ,&nbsp;Anna Kreutz ,&nbsp;Darlene Dixon,&nbsp;Erik J. Tokar","doi":"10.1016/j.taap.2025.117230","DOIUrl":"10.1016/j.taap.2025.117230","url":null,"abstract":"<div><div>Modeling brain development and function is challenging due to complexity of the organ. Human pluripotent stem cell (PSC)-derived brain-like organoids provide new tools to study the human brain. Compared with traditional <em>in vivo</em> toxicological studies, these 3D models, together with 2D cellular assays, enhance our understanding of the mechanisms of developmental neurotoxicity (DNT) during the early stages of neurogenesis and offer numerous advantages including a rapid, cost-effective approach for understanding compound mechanisms and assessing chemical safety. Arsenic (As) exposure is associated with DNT, although the mechanisms involved are not well-defined. Here, we used 3D PSC-derived embryoid bodies (EBs) to recapitulate events involved in embryogenesis and neurogenesis before neural induction, and EB-derived cerebral organoids to mimic neural development <em>in vivo</em>. As (0.5 μM; 35 ppb) increased ectoderm differentiation within the EBs by upregulating genes (<em>PAX6</em>, <em>SOX1)</em> critical for embryonic development. Histological staining of EBs showed As disrupted neural rosette structures. qPCR and RNA-seq showed As inhibited expression of markers of mature neural cells (<em>MAP2+/vGLUT2+</em>) and astrocytes (<em>GFAP+</em>). In organoids, Ingenuity Pathway Analysis was used to identify the top 5 pathways affected by As exposure, and Gene Ontology enrichment analysis found several key signaling pathways to be inhibited by As exposure. These data provide insights into pathways contributing to As-induced inhibition of neurite outgrowth and disrupted neural rosette structures in the 2D neurite outgrowth assay and in organoids, respectively. Results herein show this multipronged 2D/3D approach can provide valuable insights into cellular events and molecular mechanisms of As-induced DNT.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"496 ","pages":"Article 117230"},"PeriodicalIF":3.3,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143024803","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}

{"title":"PPARβ/δ agonist GW0742 mitigates acute liver damage induced by acetaminophen overdose in mice","authors":"Lin Wang ,&nbsp;Jing-Hui Chen ,&nbsp;Yan-Jing Zhang ,&nbsp;Ming-Bao Zhang ,&nbsp;Tao Zeng","doi":"10.1016/j.taap.2024.117180","DOIUrl":"10.1016/j.taap.2024.117180","url":null,"abstract":"<div><div>Liver damage caused by acetaminophen (APAP) overdose remains a worldwide medical problem. New therapeutic medicines for APAP poisoning are needed as the efficacy of the only antidote, <em>N</em>-acetyl-cysteine (NAC), significantly decreases if administered after 8 h of APAP intake and massive APAP overdose remains to induce hepatotoxicity despite the timely administration of NAC. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) possesses versatile roles including regulation of lipid homeostasis and anti-inflammation in the liver. This study aimed to investigate the effects of GW0742, one specific PPARβ/δ agonist, on APAP-caused liver damage in mice. We found that GW0742 (40 mg/kg, i.p.) pretreatment completely blocked the increase of serum aminotransferase activities, hepatocyte necrosis, oxidative stress, and liver inflammation in mice exposed to 300 mg/kg APAP (i.p.). Mechanistically, GW0742 pretreatment significantly suppressed the M1 polarization of liver Kupffer cells and activation of NLRP3 inflammasome. Interestingly, GW0742 remained effective when administered 6 h after APAP exposure, although its efficacy was less pronounced than that administered 6 h before the APAP challenge. Notably, GW0742 exhibited a more profound effect than NAC evidenced by the lower serum alanine transaminase (ALT) level and the improved histopathological manifestation. Furthermore, exposure to APAP for 6 h had resulted in dramatic liver inflammation, while pretreatment with GW0742 prior to APAP exposure did not influence the increase in serum aminotransferase activity and oxidative stress at 2 h after APAP exposure. These results highlight that PPARβ/δ may be a promising therapeutic target for treating APAP-caused acute liver damage probably acting on liver macrophages.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117180"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772649","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}

{"title":"Salidroside exerts neuroprotective effects on retrograde neuronal death following neonatal axotomy via activation of PI3K/Akt pathway and deactivation of p38 MAPK pathway","authors":"Shengtao Ji ,&nbsp;Daiyue Chen ,&nbsp;Fei Ding ,&nbsp;Xiaosong Gu ,&nbsp;Qiu Xue ,&nbsp;Chun Zhou ,&nbsp;Maohong Cao ,&nbsp;Shu Yu","doi":"10.1016/j.taap.2024.117178","DOIUrl":"10.1016/j.taap.2024.117178","url":null,"abstract":"<div><div>Salidroside, a glucoside of tyrosol, is a powerful active ingredient extracted from the Chinese herb medicine <em>Rhodiola rosea</em> L.. As a neuroprotective agent, the application of salidroside in combination with neural tissue engineering has recently attracted much attention in peripheral nerve repair and reconstruction. However, the cellular and molecular mechanisms by which salidroside promotes nerve regeneration remain to be elucidated. We aim to evaluate the long-term neuroprotective potential of salidroside in an experimental rat model of neonatal sciatic nerve crush injury, with a focus on target-deprived neuronal death and the mechanisms involved. Behavioral analysis showed that salidroside dose-dependently improved voluntary hindlimb behavior and rod rotation ability following neonatal axotomy during an 8-week observation period. According to electrophysiology, Fluoro-Gold retrograde tracing, histological and immunohistochemical analyses, salidroside significantly improved nerve regeneration and reinnervation. Nissle and TUNEL staining, as well as caspase-3 activation assay indicated a beneficial effect of salidroside on retrograde loss and apoptosis of motoneurons within 2 weeks after axotomy. qPCR, ELISA and oxidative stress experiments revealed that salidroside improved the imbalance of spinal microenvironment, including oxidative stress and down-regulation of neurotrophic factors. Western blotting analysis showed that salidroside enhanced the activation of PI3K/Akt and inhibited the p38 MAPK signaling pathway following axotomy. The oxidative stress and axonal disconnection/regeneration models of primary motoneurons in vitro further confirmed the involvement of these two pathways in the neuroprotective effects of salidroside. These data provide a theoretical basis for the application of salidroside in peripheral nerve repair and reconstruction.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117178"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772651","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}

{"title":"Centromere protein K enhances the activation of YAP1/TAZ signal cascade to drive the progression of clear cell renal cell carcinoma","authors":"Ning Nan","doi":"10.1016/j.taap.2024.117181","DOIUrl":"10.1016/j.taap.2024.117181","url":null,"abstract":"<div><div>Centromere protein K (CENPK) is a newly identified malignancy-related gene that exhibits differential expression in various cancers and plays a crucial role in carcinogenesis. However, it remains uncertain whether CENPK is involved in clear cell renal cell carcinoma (ccRCC). This work aimed to unveil the expression, clinical significance, biological functions, and regulatory mechanisms of CENPK in ccRCC. Through analysis of RNA-seq data obtained from TCGA, a high expression pattern of CENPK was identified in ccRCC, which was found to be associated with pathologic stage, histologic grade, and clinical outcome. The enrichment of CENPK in ccRCC was further verified through the analysis of clinical samples. By conducting cellular functional experiments, we showed an inhibitory effect of CENPK knockdown on the malignant behavior of ccRCC cells. GSEA revealed a close relationship between CENPK and the Hippo–YAP1/TAZ signal cascade. The following experiments demonstrated that the activation of YAP1/TAZ was strongly inhibited by CENPK knockdown, and this change was accompanied by a decrease in the levels of CTGF and CYR61. Blockade of the MST1/2-LATS1/2 axis reversed the suppressive impact of CENPK knockdown on YAP1/TAZ. The tumor-promoting impact observed upon CENPK overexpression was diminished in YAP1 knockout cells. Notably, ccRCC cells with reduced CENPK expression exhibited a diminished capability to form tumors in nude mice. This report highlights the importance of CENPK in ccRCC and sheds new light on the underlying mechanism of this cancer type. Therefore, CENPK has the potential to serve as a viable candidate target for treating ccRCC.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117181"},"PeriodicalIF":3.3,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142772647","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}