Toxicology and applied pharmacology最新文献

{"title":"Toxicokinetic insights into distinct mechanisms of action of two thyroid toxicants: Propylthiouracil and pregnenolone 16α‑carbonitrile","authors":"Naïs Clavel Rolland ,&nbsp;Bénédicte Kiehr ,&nbsp;Meiling Zhu ,&nbsp;Chun Chen ,&nbsp;Peng Gao ,&nbsp;Thierry Pourcher ,&nbsp;Olivier Blanck","doi":"10.1016/j.taap.2025.117282","DOIUrl":"10.1016/j.taap.2025.117282","url":null,"abstract":"<div><div>Thyroid hormones (THs) are critical for metabolic regulation and brain development. Disruptions in TH homeostasis, especially during fetal development, can lead to irreversible neurodevelopmental impairments. Thyroid hormone system-disrupting chemicals (THSDCs), are of growing concern for human health due to their potential to interfere with TH signaling. This study investigates the toxicokinetic properties of two THSDCs: propylthiouracil (PTU), which inhibits TH synthesis, and pregnenolone-16α‑carbonitrile (PCN), which enhances the TH hepatic metabolism. Using <em>in vitro</em> approaches and <em>in vivo</em> models involving pregnant, fetal, and neonatal rats, we aimed to characterize the absorption, distribution, metabolism, and excretion (ADME) profiles of these compounds. Liver metabolism, fraction unbound, plasma concentrations, and tissue distribution of PTU and PCN were assessed. Our investigation demonstrated that PCN underwent quick liver metabolism, resulting in undetectable PCN levels in adult and newborn rat tissues as well as in maternal milk. In contrast, PTU exhibited high permeability through the intestinal barrier and was slowly metabolized by the liver, leading to high PTU concentrations in the maternal milk, thyroid gland, and the brain of fetuses and newborns. These latter results raise concerns regarding the potential direct effect of PTU on neonatal brain development. Especially, the hypothesis that PTU can interact with brain peroxidases involved in detoxification processes warrants further investigation. These findings highlight the intricate relationship between THSDC exposure, altered TH synthesis and metabolism, and subsequent impacts on neurodevelopment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"498 ","pages":"Article 117282"},"PeriodicalIF":3.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537649","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":"Mitochondrial iron deficiency mediated inhibition of ecdysone synthesis underlies lead (Pb) induced developmental toxicity in Drosophila melanogaster","authors":"Zhi-Hua Liu ,&nbsp;YuYin Zhai ,&nbsp;Jiakai Zhang ,&nbsp;Wei Huang ,&nbsp;Wanrong Li ,&nbsp;Wenting Qin","doi":"10.1016/j.taap.2025.117283","DOIUrl":"10.1016/j.taap.2025.117283","url":null,"abstract":"<div><div>Lead (Pb) is a pervasive heavy metal possessing developmental toxicity, at least in part, by disrupting iron homeostasis. In this study, we aimed to elucidate the underlying mechanism of iron deficiency mediated developmental defects in Pb exposed <em>Drosophila melanogaster</em>, mainly focusing on iron-dependent synthesis of ecdysone signaling, which plays a key role in the development of insects. Herein, we found Pb exposure resulted in iron deficiency in mitochondria by inhibiting expression of mitoferrin (evidenced by qPCR assay), the mitochondrial iron importer. Further study demonstrated that biosynthesis of ecdysone, a hormone synthesized with the help of iron-containing cytochrome P450s in mitochondria, was inhibited following Pb exposure. Ecdysone supplementation, to some extent, rescued Pb induced developmental delay and reproductive defects in <em>Drosophila melanogaster.</em> Furthermore, we found that disruption of mitoferrin and ecdysone synthesis was restored by NAC (N-Acetylcysteine, a well-known ROS scavenger), suggesting that oxidative stress plays a key role in Pb mediated mitochondrial iron dys-homeostasis and developmental toxicity. This study therefore revealed that mitochondrial iron deficiency mediated inhibition of ecdysone synthesis is a key event associated with iron dys-homeostasis mediated developmental defects caused by Pb exposure. Meanwhile, our study indicated that mitochondria may act as an important target of Pb, thus providing potential protective strategies against Pb toxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117283"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143512441","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":"Role of activating transcription factor 3 as a mediator of the protective effects of berberine against lipopolysaccharide-stimulated SW982 cells and in rheumatoid arthritis animal models","authors":"Kwan Yong Yeon ,&nbsp;Seongmi Ji ,&nbsp;Hyae Gyeong Cheon","doi":"10.1016/j.taap.2025.117279","DOIUrl":"10.1016/j.taap.2025.117279","url":null,"abstract":"<div><div>This study aimed to explore the protective effects of berberine against rheumatoid arthritis (RA) and clarify the role of activating transcription factor 3 (ATF3) in the mechanism of action of berberine, using a lipopolysaccharide (LPS)-stimulated SW982 human synovial cell line. Berberine treatment resulted in a concentration-dependent reduction in LPS-induced proinflammatory cytokines and matrix metalloproteinases (MMPs) in SW982 cells. These inhibitory effects were associated with increased ATF3 expression, reduced nuclear translocation of nuclear factor-κB (NF-κB), and diminished phosphorylation of mitogen-activated protein kinase (MAPK). In contrast, ATF3 knockdown reversed the suppressive effects of berberine on proinflammatory cytokines and MMP production, leading to enhanced MAPK phosphorylation; however, it had minimal impact on adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Furthermore, AMPK knockdown negated the protective effects of berberine and reduced ATF3 levels, whereas treatment with 5-aminoimidazole-4-carboxamide ribonucleotide, an AMPK activator, replicated the beneficial effects of berberine. In an in vivo collagen-induced arthritis (CIA) mouse model, intraperitoneal administration of berberine significantly reduced paw edema and arthritis severity, accompanied by ATF3 induction and increased AMPK phosphorylation in the synovial tissue. These findings highlighted the pivotal role of ATF3 in mediating the protective effects of berberine in RA- and LPS-activated synoviocytes, suggesting its potential as a therapeutic agent for RA management.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117279"},"PeriodicalIF":3.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511194","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":"EGFR tyrosine kinase inhibitor ZZC4 overcomes acquired resistance to gefitinib","authors":"Mawusse K.I. Attiogbe ,&nbsp;Ting-ting Huang ,&nbsp;Hong-yi Zhao ,&nbsp;Hong-ying Wang ,&nbsp;Lei Cao ,&nbsp;Ping-ping Yan ,&nbsp;San-qi Zhang ,&nbsp;Yong-xiao Cao","doi":"10.1016/j.taap.2025.117280","DOIUrl":"10.1016/j.taap.2025.117280","url":null,"abstract":"<div><div>Despite the tremendous progress of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) development, acquired resistance mechanisms have limited their efficacy in treating non-small cell lung cancer (NSCLC). To overcome these limitations, novel EGFR-TKIs are needed. In our previous study, we presented ZZC4 as a potent EGFR-TKI. In this study, we developed NSCLC cells resistant to EGFR-TKI gefitinib and osimertinib and assessed the effect and mechanism of action of ZZC4 on those cells. HCC827 cells were cultured with gefitinib in a concentration-escalation manner to achieve HCC827 gefitinib-resistant (HCC827-GR) cells after 6 months of treatment. Then, the effect of ZZC4 was assessed at the cellular and animal levels. To understand ZZC4's mechanism of action, the proteome alteration induced by ZZC4 on the resistant cell line was compared to the parental HCC827 cells using comparative proteomics. The result showed that gefitinib's IC₅₀ on HCC827 was 533 nM, approximately 80 times its IC₅₀ on normal cells (7.6 nM), confirming its resistance to HCC827 cells. The obtained resistant cells were treated with ZZC4, which potently suppressed the resistant cells' proliferation with an IC₅₀ of 0.1 nM. In tumor-bearing mice, ZZC4 also suppressed the growth of HCC827-GR cell tumors with an inhibition ratio of 82 % at ZZC4 4 mg/kg. Further, the proteomic analysis revealed that ZZC4 inhibited HCC827-GR cell growth by upregulating CDKN1B and downregulating CCNA2 and CHEK1. In conclusion, ZZC4 overcomes resistance to gefitinib by altering the cell cycle pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117280"},"PeriodicalIF":3.3,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143504330","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":"Misrepresentation of mouse genotypes: A call for precision","authors":"Wei Li","doi":"10.1016/j.taap.2025.117276","DOIUrl":"10.1016/j.taap.2025.117276","url":null,"abstract":"","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117276"},"PeriodicalIF":3.3,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143479843","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":"Analysis of accumulation of DNA double-strand breaks in mouse tissues by pulsed-field gel electrophoresis","authors":"Takeshi Terabayashi ,&nbsp;Takako Sasaki ,&nbsp;Toshimasa Ishizaki ,&nbsp;Tadashi Tomo ,&nbsp;Yoshihiro Nishida ,&nbsp;Katsuhiro Hanada","doi":"10.1016/j.taap.2025.117278","DOIUrl":"10.1016/j.taap.2025.117278","url":null,"abstract":"<div><div>Double-strand DNA breaks (DSBs) are among the most cytotoxic DNA lesions, which can lead to chromosomal instability and eventually cell death. The substances that can potentially induce DSB formation are thus regarded as genotoxic. To date, many genotoxicity tests for detecting DNA breaks have been designed. However, there are limited options available for measuring the accumulation of DSBs in vivo. In this study, we aimed to evaluate a method of detecting the DSBs formed by the direct action of genotoxic substances using pulsed-field gel electrophoresis (PFGE). This approach has the advantage of making it easier to distinguish between DSBs and single-strand DNA breaks (SSBs) induced by the direct action of genotoxic substances. To confirm the detection of DSBs using PFGE, we investigated their accumulation after treatment with <em>cis</em>-diamminedichloroplatinum(II) (cisplatin) or γ-rays in mouse organs. The results revealed the successful detection of cisplatin-induced DSB formation in mouse kidney and thymus and γ-ray-induced DSB formation in all organs. We also discuss the advantages of PFGE-based detection of DSBs in vivo.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117278"},"PeriodicalIF":3.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473909","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":"Hepatotoxicity from long-term administration of hepatoprotective low doses of oleanolic acid in mice","authors":"Yasha Xu ,&nbsp;Xi Yang ,&nbsp;Yuanfu Lu ,&nbsp;Jie Liu","doi":"10.1016/j.taap.2025.117277","DOIUrl":"10.1016/j.taap.2025.117277","url":null,"abstract":"<div><div>Oleanolic acid is a triterpenoid existed in many medicinal herbs/plants. Oleanolic acid at low doses are hepatoprotective but at high doses produce cholestasis. This study examined hepatotoxicity potential of low doses of oleanolic acid after log-term administration. Male Kunming mice were orally given oleanolic acid at 100, 200 and 300 μmol/kg daily for 14 weeks. Body weights were monitored, and liver injury was determined via blood biochemistry. Histopathology was examined via H&amp;E, Masson, and Sirius red stains. Oleanolic acid accumulation in plasma and liver was determined by LC-MS and hepatic gene expression by qPCR. Oleanolic acid at low doses did not affect animal body weights, but increased liver index. Serum alanine aminotransferase and alkaline phosphatase were increased, while total bilirubin was unchanged. Chronic oleanolic acid produced hepatocyte degeneration, spot necrosis, and fibrosis. Plasma oleanolic acid was increased more than that in the liver. Oleanolic acid increased hepatic expression of Nrf2, Nqo1, Gclc and Mgst1; Expression of bile acid synthesis genes (Cyp7a1, Cyp8b1, Cyp27a1, Cyp7b1, FXR, SHP) was also suppressed at higher doses. The expression of TGF-β1 and Smad3 was increased, while Smad7 decreased, suggesting the progression to liver fibrosis. High dose of oleanolic acid was less effective in producing these changes, probably due to increased liver injury. Overall, oral administration of low doses of oleanolic acid for 14 weeks produced liver injury and fibrosis. These harmful effects were associated with increased oleanolic acid in plasma and liver, and the disruptions of bile acid metabolism, the Nrf2 and TGF-β/Smad signaling pathways.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117277"},"PeriodicalIF":3.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454308","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":"Afzelechin alleviates deltamethrin induced hepatic dysfunction via regulating TLR4/MyD88, HMGB1/RAGE and NF-κB pathway","authors":"Fuad M. Alzahrani ,&nbsp;Khalid J. Alzahrani ,&nbsp;Khalaf F. Alsharif ,&nbsp;Muhammad Faisal Hayat ,&nbsp;Ahmed Al-Emam","doi":"10.1016/j.taap.2025.117275","DOIUrl":"10.1016/j.taap.2025.117275","url":null,"abstract":"<div><div>Deltamethrin (DMN) is a type-II pyrethroid that has been documented to instigate numerous organ toxicities. Afzelechin (ALN) is a plant based polyphenolic compound that exhibits marvelous biological properties. The present research was conducted to assess the alleviative potential of ALN against DMN induced hepatic dysregulations. Thirty-six male albino (Sprague Dawley) rats were apportioned into four random groups including the control, DMN (5mgkg⁻¹), DMN (5mgkg⁻¹) + ALN (2mgkg⁻¹), and ALN (2mgkg⁻¹) alone administrated group. ALN protected hepatic tissues against DMN induced oxidative stress, inflammation and apoptosis. ALN supplementation donwregulated the gene expression of <em>receptor for advanced glycation end products (RAGE), high mobility group box1 (HMGB1), tumor necrosis factor- α (TNF-α), Myeloid differentiation primary response 88 (MyD88), nuclear factor- kappa B (NF-κB), interleukin-6 (IL-6), toll-like receptor 4 (TLR4), cyclooxygenase-2 (COX-2)</em>, and <em>interleukin-1β (IL-1β)</em>. Besides, ALN administration reduced the levels of reactive oxygen species (ROS) and malondialdehyde while increasing the activities of glutathione peroxidase (GPx), catalase (CAT), glutathione reductase (GSR), heme oxygenase-1 (HO-1), superoxide dismutase (SOD) and glutathione (GSH). The levels of hepatic function markers including GGT, ALT, ALP, and AST were lowered while the concentrations of albumin and total proteins were promoted following the ALN treatment. The levels of Bax, Caspase-9 and Caspase-3 were suppressed while the levels of Bcl-2 were escalated after ALN therapy. Moreover, ALN treatment remarkably mitigated DMN induced histological impairments. These findings highlight the hepatoprotective efficacy of ALN against DMN induced liver toxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117275"},"PeriodicalIF":3.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459405","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":"Cyanidin-3-O-glucoside inhibits the malignant progression of colorectal cancer by regulating Kruppel-like factor 4-mediated ERK/p38 signaling pathway","authors":"Jian Chang,&nbsp;Geqiong Xiao","doi":"10.1016/j.taap.2025.117268","DOIUrl":"10.1016/j.taap.2025.117268","url":null,"abstract":"<div><h3>Background</h3><div>Cyanidin-3-<em>O</em>-glucoside (Cy3g) is a natural anthocyanin, showing favorable anti-cancer efficacy in colorectal cancer (CRC). However, its specific mechanism in CRC remains largely unexplored.</div></div><div><h3>Objective</h3><div>This study aimed to investigate the underlying mechanisms of Cy3g on CRC.</div></div><div><h3>Methods</h3><div>Cell viability of human CRC cell lines (SW620, HT29, LS174T, and HCT116) and normal colon fibroblast cell line (CCD-18Co) treated with Cy3g was detected by CCK-8. Effects of Cy3g on malignant characteristics of SW620 cells were determined by CCK-8, EdU, colony formation, wound healing, Transwell, and flow cytometry assays. To further elucidate Cy3g's mechanism in CRC, KLF4 expression was detected by RT-qPCR, and expression of the extracellular signal-related kinase (ERK) and p38 was examined by western blotting. The effects and mechanisms of Cy3g on CRC progression were further validated in a xenograft mouse model.</div></div><div><h3>Results</h3><div>Cy3g significantly inhibited the cell viability of human CRC cell lines but rarely affected the cell viability of normal colon fibroblast. Cy3g dose-dependently inhibited proliferation, migration, and invasion and promoted apoptosis of SW620 cells. Moreover, Cy3g upregulated KLF4 expression and inactivated the ERK/p38 pathway in a concentration-dependent manner. KLF4 knockdown reversed the inhibitory effects of Cy3g on the malignant characteristics of SW620 and expression of ERK and p38. Animal experiments further validated that Cy3g inhibited tumor growth without altering body weight, activated KLF4, and suppressed the ERK/p38 pathway in CRC model mice.</div></div><div><h3>Conclusion</h3><div>Cy3g inhibits CRC progression by suppressing the KLF4-mediated ERK/p38 pathway, offering new insights into CRC prevention and treatment.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117268"},"PeriodicalIF":3.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143445800","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":"Isonardosinone attenuates osteoclastogenesis and OVX-induced bone loss via the MAPK/NF-κB pathway","authors":"Guangwei Wen ,&nbsp;Haishan Li ,&nbsp;Jiasheng Yang ,&nbsp;Bin Mai ,&nbsp;Tengpeng Zhou ,&nbsp;GuoYe Mo ,&nbsp;Yongxian Li ,&nbsp;Yiyi Lai","doi":"10.1016/j.taap.2025.117267","DOIUrl":"10.1016/j.taap.2025.117267","url":null,"abstract":"<div><div>Osteoporosis is a globally prevalent metabolic bone disease that manifests itself as a decrease in bone mineral density and deterioration of bone structure, which reduces overall bone strength and increases fracture risk. However, the effect of anti-inflammatory isonardosinone (the active ingredient in <em>Nardostachys chinensis</em>) on osteoclastogenesis is unknown. We first predicted the main pathways and targets of ISO action in osteoporosis by network pharmacology. CCK-8 was used to test whether ISO affects cell proliferation of BMMs (osteoclast precursor cells) and to determine the safe action concentration. TRAcP and F-actin staining were used to characterise the inhibitory effect on osteoclast differentiation. RT-PCR and WB were used to examine changes in the relative expression of genes and proteins generated by osteoclasts under isopinacolone treatment, and we examined its effects on the RANKL-activated MAPK and NF-κB signaling pathways. An ovariectomy-induced osteoporosis model was constructed to assess the <em>in vivo</em> therapeutic effects of ISO. CCK-8 results showed that ISO had no cytotoxic or proliferative effects on BMMs at concentrations below 30 μM; TRAcP staining showed that ISO suppressed osteoclastogenesis in a concentration- and time-gradient-dependent manner; and F-actin staining showed that ISO suppressed osteoblast skeleton formation and expansion; RT-PCR and Western Blot assays showed that ISO suppressed the expression of CTSK, NFATC1, MMP9, C-Fos, and ACP5, inhibited the phosphorylation of JNK, P38, and ERK, and reversed the degradation of IκB-α, especially within 15 min. The <em>in vivo</em> results indicated that ISO has therapeutic effects on osteoporosis by improving bone microstructure to rescue bone loss. Taken together, these results lead to the conclusion that ISO is an attractive drug development strategy for the treatment of osteoporosis by effectively suppressing osteoclastogenesis through the MAPK/NF-κB signaling pathway, thereby reversing the bone loss associated with ovariectomy <em>in vivo</em>.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"497 ","pages":"Article 117267"},"PeriodicalIF":3.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427685","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}