Chemico-Biological Interactions最新文献

{"title":"Sevoflurane postconditioning mitigates neuronal hypoxic-ischemic injury via regulating reactive astrocytic STAT3 protein modification","authors":"Yufei Jia,&nbsp;Yanhong Song,&nbsp;Hang Xue,&nbsp;Xingyue Li,&nbsp;Yinong Zhang,&nbsp;Shiyue Fan,&nbsp;Xu Yang,&nbsp;Zixuan Ding,&nbsp;Yue Qiu,&nbsp;Ziyi Wu,&nbsp;Ping Zhao","doi":"10.1016/j.cbi.2024.111308","DOIUrl":"10.1016/j.cbi.2024.111308","url":null,"abstract":"<div><div>Astrocyte activation plays a pivotal role in accelerating the cascade of neuroinflammation associated with the development of hypoxic-ischemic brain injury. This study aimed to investigate the mechanism by which sevoflurane postconditioning mitigates neuronal damage through astrocytes by regulating reactive astrocytic Signal Transducer and Activator of Transcription 3 (STAT3) modifications. A modified Rice‒Vannucci model in rats and a conditioned culture system established by subjecting primary astrocytes to oxygen glucose deprivation, followed by using the conditioned medium to culture the neuron cell line SH-SY5Y were used to simulate HI insult in vivo and in vitro, respectively. These models were followed by 30 min of 2.5 % sevoflurane treatment. Stattic was used to inhibit STAT3 phosphorylation, and (Z)-PUGNAc or OSMI-1 was added to regulate O-linked-β-N-acetylglucosamine modification (O-GlcNAcylation) in primary astrocytes in vitro. Neurobehavioral tests, Nissl staining, CCK8 assay, and flow cytometry for apoptosis were used to assess neuronal function. Immunofluorescence staining was used to detect astrocyte reactivity and the intracellular distribution of STAT3. Immunoprecipitation combined with Western blotting was used to evaluate the O-GlcNAcylation of STAT3. Protein expression and phosphorylation levels were detected by Western blotting. ELISA was conducted to detect the detrimental cytokines IL-6 and IL-1β in astrocyte-conditioned medium. Sevoflurane postconditioning enhanced the O-GlcNAcylation of astrocytic STAT3 following HI insult via the manner of OGT. Crosstalk between O-GlcNAcylation and phosphorylation of STAT3 showed that O-GlcNAcylation inhibited STAT3 phosphorylation. The inhibitory effect on astrocytes suppressed STAT3 nuclear translocation, reduced astrocyte reactivity, decreased the release of the inflammatory cytokines IL6 and IL-1β, attenuated neuronal apoptosis following HI insult, and improved neuron viability. Sevoflurane postconditioning increased astrocytic STAT3 O-GlcNAcylation level to competitively inhibit STAT3 phosphorylation. This deactivated downstream inflammation pathways and reduced astrocyte reactivity, thereby mitigating HI insult in neurons both in vivo and in vitro.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111308"},"PeriodicalIF":4.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicological effects and potential reproductive risk of microplastic-induced molecular changes in protamine-like proteins and their DNA binding","authors":"Carmela Marinaro ,&nbsp;Giulia Scarciello ,&nbsp;Anna Rita Bianchi ,&nbsp;Bruno Berman,&nbsp;Teresa Chianese,&nbsp;Rosaria Scudiero,&nbsp;Luigi Rosati ,&nbsp;Anna De Maio ,&nbsp;Gennaro Lettieri,&nbsp;Marina Piscopo","doi":"10.1016/j.cbi.2024.111309","DOIUrl":"10.1016/j.cbi.2024.111309","url":null,"abstract":"<div><div>Today, plastic pollution is a widespread problem in all ecosystems and has a particularly severe impact on marine ecosystems and external fertilisers such as the mussel <em>Mytilus galloprovincialis</em>. The present study aims to assess the toxicological reproductive health effects in this organism following exposure to two concentrations of polystyrene microplastics (PS-MPs) (0.5 and 1 μg/L), representative of conditions in the Mediterranean Sea. After exposure, the electrophoretic pattern of protamine-like (PL) proteins, the major basic protein component of <em>Mytilus galloprovincialis</em> sperm chromatin, was analysed. Compared to the unexposed condition, differences were observed by SDS-PAGE and an increased ability of PL to bind and protect DNA from oxidative damage was then measured, particularly for PL from mussels exposed to 1 μg/L PS-MPs. At this dose of PS-MPs, a reduced release of all PLs from the sperm nuclei was also observed, whereas the digestion by micrococcal nuclease did not show any significant differences between the exposed and the unexposed conditions. Finally, the possibility of poly(ADP)-ribosylation of the PLs was investigated. PL-II showed an increase in poly(ADP)-ribosylation after PS-MPs exposure, which may account for the difference in the ability of the PLs to bind DNA. In conclusion, while all the results might suggest a molecular mechanism of gametic plasticity occurring upon exposure of mussels to PS-MPs 1 μg/L, they also indicate that this dose of exposure could be extremely detrimental to the reproductive health of <em>Mytilus galloprovincialis</em> because it could prevent the release of basic nuclear proteins from the sperm DNA at fertilisation.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111309"},"PeriodicalIF":4.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diosgenin attenuates nonalcoholic fatty liver disease through mTOR-mediated inhibition of lipid accumulation and inflammation","authors":"Guoliang Yin ,&nbsp;Hongyi Liang ,&nbsp;Yiran Cheng ,&nbsp;Suwen Chen ,&nbsp;Xin Zhang ,&nbsp;Decheng Meng ,&nbsp;Wenfei Yu ,&nbsp;Hongshuai Liu ,&nbsp;Chaoyuan Song ,&nbsp;Fengxia Zhang","doi":"10.1016/j.cbi.2024.111306","DOIUrl":"10.1016/j.cbi.2024.111306","url":null,"abstract":"<div><div>Excessive hepatic lipid accumulation and inflammatory injury are significant pathological manifestations of nonalcoholic fatty liver disease (NAFLD). Our previous research discovered that diosgenin, a natural steroidal saponin derived from Chinese herbs, can reduce hepatic lipid accumulation and steatosis; however, the exact mechanism remains unclear. This study aimed to investigate the protective mechanisms of diosgenin against NAFLD. We utilized network pharmacology and molecular docking approaches to identify the pathways through which diosgenin improves NAFLD. In high-fat diet (HFD)-fed rats, we measured biochemical markers in the serum and liver. Liver histopathology was assessed using HE and oil-red O staining. In free fatty acids (FFAs)-induced HepG2 cells, we employed the cell transfection overexpression method to verify the regulatory relationship of the identified pathways. The mechanisms <em>in vitro</em> and in vivo were examined using quantitative polymerase chain reaction and Western blot analyses. Bioinformatics analysis indicated that the mTOR-FASN/HIF-1α/RELA/VEGFA pathway may be the target pathway for diosgenin in alleviating NAFLD. Diosgenin inhibited hepatic lipid accumulation and pro-inflammatory cytokines in HFD-fed rats, and reduced intracellular lipid accumulation as well as TG, TC, IL-1β, and TNF-α levels in FFAs-induced HepG2 cells. Mechanistically, diosgenin downregulated the expression of p-mTOR, FASN, HIF-1α, RELA, and VEGFA, which are associated with lipid synthesis and inflammation. Overexpression of mTOR abolished the beneficial effects of diosgenin on lipid reduction and inflammation, as well as its inhibitory effects on the expression of FASN, HIF-1α, RELA, and VEGFA. In conclusion, diosgenin alleviates NAFLD through mTOR-mediated inhibition of lipid accumulation and inflammation.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111306"},"PeriodicalIF":4.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic investigation of NP toxicity on HepaRG spheroids","authors":"Merve Erden Tüçer ,&nbsp;Nazlıcan Tunç ,&nbsp;Suat Tüçer ,&nbsp;Rana Acar ,&nbsp;Duygu Deniz Usta ,&nbsp;Kouroush Salimi ,&nbsp;Özlen Konu ,&nbsp;Urartu Özgür Şafak Şeker","doi":"10.1016/j.cbi.2024.111303","DOIUrl":"10.1016/j.cbi.2024.111303","url":null,"abstract":"<div><div>Metal nanoparticles (NPs) are commonly used nanomaterials, however concerns have been raised about their toxicity. Although a few studies have reported the toxicity of NPs on cells, they have generally been restricted to a limited variety of NPs, inappropriate cell lines, or culture methods. Thus, the adverse effects remain inadequately understood, necessitating further analysis. This study focuses on assessing the impacts of diverse NPs of varying materials and sizes on HepaRG spheroids to determine the genes that respond to acute NP toxicity. HepaRG cells, the most appropriate alternative to primary hepatocytes, were cultured in 3D spheroids to better mimic the cellular microenvironment of the liver. To elucidate the toxicity mechanisms of NPs on HepaRG spheroids, transcriptome analysis was conducted by using RNA sequencing (RNA-seq). Among all NPs, lowest and highest numbers of differentially expressed genes (DEGs) were found for 40 nm AuNP (118 genes) and InP/ZnS (1904 genes), respectively. Remarkably, processes such as drug metabolism, sensitivity to metal ions, oxidative stress, endothelial-mesenchymal transition (EMT) and apoptosis consistently exhibited significant enrichment across all NPs of different materials. Pathways related to stress responses of the cells such as the MAPK, p53 and mTOR pathways are found to be dysregulated upon exposure to various NPs. The genes that are common and unique between DEGs of different NPs were identified. These results provide novel insights into the toxicological mechanisms of NPs on HepaRG spheroids.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111303"},"PeriodicalIF":4.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the mechanism of ursolic acid in preventing liver fibrosis and improving intestinal microbiota based on NOX2/NLRP3 inflammasome signaling pathway","authors":"Qi Liu ,&nbsp;Lin-Xiang Liu ,&nbsp;Bi-Min Li ,&nbsp;Wang Zhang ,&nbsp;Yue Zhang ,&nbsp;Peng Chen ,&nbsp;Chen-Kai Huang ,&nbsp;Yuan Nie ,&nbsp;Xuan Zhu","doi":"10.1016/j.cbi.2024.111305","DOIUrl":"10.1016/j.cbi.2024.111305","url":null,"abstract":"<div><div>Early-stage liver fibrosis can be reversed; however, the underlying mechanisms remain incompletely understood. The intestinal tract hosts a substantial and diverse microbiota involved in various physiological activities and is closely linked to chronic liver disease. Previous studies have indicated that ursolic acid (UA), derived from herbal plants, possesses anti-inflammatory and antifibrotic properties; however, its precise mechanism remains to be elucidated. Consequently, liver fibrosis models were constructed utilizing both the methionine/choline deficieny (MCD) diet and carbon tetrachloride (CCl4) intraperitoneal injections. 16S rRNA was conducted to analyze the intestinal microbiota. Results indicated that UA attenuated liver injury and fibrosis, reduced indices related to liver fibrosis, and decreased the expression levels of NADPH oxidase 2 (NOX2) and NOD like receptor protein 3 (NLRP3). Hepatic fibrosis was alleviated in post-model NOX2 and NLRP3 gene knockout (NOX2^−/− and NLRP3^−/−) mice in comparison to post-model wild-type (WT) mice. Nonetheless, neither UA treatment nor control treatment significantly improved liver fibrosis in comparison to post-model knockout mice. Furthermore, the liver of NOX2^−/− mice exhibited lower levels of NLRP3 expression. Importantly, knockout mice displayed a higher diversity of intestinal microbiota, characterized by an increased presence of beneficial bacteria and a reduced presence of harmful bacteria compared to WT mice. In conclusion, UA exerts antifibrotic effects through the inhibition of the NOX2/NLRP3 inflammasome signaling pathway. UA has the potential to reverse liver fibrosis by modulating this signaling pathway, thereby enhancing the gut microbiota.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111305"},"PeriodicalIF":4.7,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molybdenum interferes with MMPs/TIMPs expression to reduce the receptivity of porcine endometrial epithelial cells","authors":"Xiao-Ying Gao ,&nbsp;Yan Zhang ,&nbsp;Wen-Peng Zhao,&nbsp;Er-Jie Tian,&nbsp;Mohammad Mehdi Ommati,&nbsp;Ji-Cang Wang,&nbsp;Hong-Wei Wang,&nbsp;Bian-Hua Zhou","doi":"10.1016/j.cbi.2024.111304","DOIUrl":"10.1016/j.cbi.2024.111304","url":null,"abstract":"<div><div>To investigate the effect of trace element molybdenum (Mo) on the receptivity of porcine endometrial epithelial cells (PEECs) and evaluate Mo toxicity and its potential molecular mechanisms, Mo-treated PEECs models were established by incubating the cells with various concentrations of medium containing Mo (0, 0.005, 0.020, 0.200, and 5 mmol/L MoNa₂O₄·2H₂O). The results showed that Mo disrupted the morphology and ultrastructure of PEECs, triggered blurred cell edges, cell swelling, cell cycle arrest, and increased apoptosis. At the molecular level, Mo treatment activated the TGF-β1/SMAD2 and PI3K/AKT1 pathways, causing a significant increase in matrix metalloproteinase (MMP)-9 and MMP-2 protein expression. Accompanied by markedly increased tissue inhibitors matrix metalloproteinase (TIMP)-2 and decreased TIMP-1, the balance of MMP2/TIMP-2 and MMP-9/TIMP-1 were disrupted. Ultimately, the receptivity of PEECs was destroyed by excessive Mo, which is revealed by the significant decrease of receptive marker molecules, including leukemia inhibitory factor (LIF), integrins β3 (ITGβ3), heparin-binding epidermal growth factor (HB-EGF), and vascular endothelial growth factor (VEGF). To sum up, the current study demonstrated the potential toxicity of Mo to PEECs, indicating reproductive toxicity at high Mo concentrations and suggesting that the content of Mo should be evaluated as a potential risk factor.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111304"},"PeriodicalIF":4.7,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomic analysis of Lewisite exposed human dermal equivalent tissues","authors":"Elizabeth S. Dhummakupt,&nbsp;Conor C. Jenkins,&nbsp;Gabrielle M. Rizzo,&nbsp;Allison E. Clay,&nbsp;Jennifer R. Horsmon,&nbsp;Tyler D.P. Goralski,&nbsp;Julie A. Renner,&nbsp;Daniel J. Angelini","doi":"10.1016/j.cbi.2024.111295","DOIUrl":"10.1016/j.cbi.2024.111295","url":null,"abstract":"<div><div>Lewisite (Military Code: L) is an arsenical vesicant chemical warfare agent (CWA) that was developed in the United States during World War I. Even though its use has not been documented in warfare, large stockpiles were created and still exist in various locations around the world. Given that large quantities exist as well as the relative straightforward process for its creation, Lewisite still presents itself as a serious threat agent. In this study, we examined the effects of Lewisite on human dermal equivalent tissues (EpiDerm™/EpiDerm™-FT) through the evaluation of cellular viability, histology, and multiomic analysis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111295"},"PeriodicalIF":4.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of protein kinase B rescues against thapsigargin-elicited cardiac dysfunction through regulation of NADPH oxidase and ferroptosis","authors":"Xiaohu Wang ,&nbsp;Feng-Juan Li ,&nbsp;Yong Cheng ,&nbsp;Shuying Chen ,&nbsp;Shuyi Zhu ,&nbsp;Yingmei Zhang ,&nbsp;Russel J. Reiter ,&nbsp;Milad Ashrafizadeh ,&nbsp;Jie Lin ,&nbsp;Guizhen Wang ,&nbsp;Ling Lin ,&nbsp;Jun Ren","doi":"10.1016/j.cbi.2024.111292","DOIUrl":"10.1016/j.cbi.2024.111292","url":null,"abstract":"<div><div>Endoplasmic reticulum (ER) stress is a known contributor to cardiac remodeling and contractile dysfunction. Although NADPH oxidase has been implicated in ER stress-induced organ damage, its specific role in myocardial complications resulting from ER stress remains unclear. This study aimed to investigate the possible involvement of NADPH oxidase in ER stress-induced myocardial abnormalities and to evaluate the impact of Akt constitutive activation on these myocardial defects. Mice with cardiac-specific overexpression of active mutant of Akt (Myr-Akt) and their wild-type (WT) littermates were treated with ER stress instigator thapsigargin (1 mg/kg, i. p. 72 hrs) before evaluating myocardial morphology and function. Our results noted that thapsigargin significantly impaired echocardiographic parameters and cell shortening indices, including elevated LVESD, decreased ejection fraction, fractional shortening, peak shortening, electrically-stimulated intracellular Ca²⁺ release, and cardiomyocyte survival. These functional deteriorations were accompanied by upregulation of NADPH oxidase, O₂⁻ production, mitochondrial damage, carbonyl formation, lipid peroxidation, apoptosis, and interstitial fibrosis, with unchanged myocardial size. Constitutive Akt hyperactivation did not generate any response on myocardial morphology and function, although it greatly suppressed or nullified thapsigargin-induced myocardial remodeling and dysfunction. Thapsigargin also triggered dephosphorylation of Akt and its downstream signal GSK3β, along with development of ferroptosis, all of which were nullified by Akt hyperactivation. <em>In vitro</em> studies further revealed that thapsigargin provoked cardiomyocyte mechanical anomalies and lipid peroxidation, similar to <em>in vivo</em> results. These effects were reverted by inhibitors of NADPH oxidase and ferroptosis (apocynin and LIP1). Collectively, our data denote an important protective role for Akt hyperactivation in thapsigargin-evoked myocardial anomalies, likely through NADPH oxidase-mediated regulation of ferroptosis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111292"},"PeriodicalIF":4.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maackiain: A comprehensive review of its pharmacology, synthesis, pharmacokinetics and toxicity","authors":"Waqas Haider ,&nbsp;Wei Pan ,&nbsp;Dayang Wang ,&nbsp;Waqas Niaz ,&nbsp;Muhammad Kashif Zaman ,&nbsp;Raza Ullah ,&nbsp;Shakir Ullah ,&nbsp;Muhammad Rafiq ,&nbsp;Bing Yu ,&nbsp;Hailin Cong","doi":"10.1016/j.cbi.2024.111294","DOIUrl":"10.1016/j.cbi.2024.111294","url":null,"abstract":"<div><div>Maackiain is an important component of some herbs in traditional Chinese medicine (TCM), such as <em>Sophora flavescens</em> Aiton, <em>Spatholobus suberectus</em> Dunn and <em>Paeonia lactiflora</em> Pall. Maackiain belongs to the second largest group of isoflavonoids the pterocarpans that is widespread in several plant genera, for example <em>Maackia, Sophora, Caragana, Trifolium</em> and <em>Millettia</em>. Recently, maackiain has attracting more attention because of its numerous pharmacological properties. This review offers the first extensive overview of maackiain natural isolation sources, pharmacological activities, synthesis, toxicity, and pharmacokinetic properties. The literature search published between 1962 and 2023 were reported by collecting the data from Google Scholar, Science Direct, SpringerLink, Web of Science, PubMed, Wiley Online, China National Knowledge Infrastructure, Scopus and structure search in SciFinder. Finding reveals the broad range of pharmacological activities of maackiain, such as anti-inflammatory, sepsis prevention, anti-cancer, anti-allergic, anti-osteolytic, anti-obesity, nephroprotective, antifungal, neuroprotective, anti-leukemic, antimalarial and inflammasome activation. Based on findings of pharmacokinetic studies, it is observed that maackiain possesses a low level of bioavailability and absorption and a rapid rate of elimination, but maackiain absorption rates in the extract were comparatively much higher than pure forms because of higher solubility and may reduce the metabolism by other ingredients present in the extract. Toxicity investigations revealed that maackiain is non-toxic to the majority of cells and selectively cytotoxic. After witnessing the beneficial pharmacological properties of maackiain, it is believed to be an emerging drug candidate for the treatment of inflammation, allergic, nephroprotection in T2D, depression, or Alzheimer's disease and obesity. However, future research topics should likely to include that elucidates its mechanism of toxicity and in vivo proper tracking of its conducts in drug delivery system. Integrating toxicity and efficiency, as well as structure modification, are critical approaches to enhancing its pharmacological properties and oral bioavailability.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111294"},"PeriodicalIF":4.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"7-Hydroxycoumarin and its conjugated metabolites interact with organic anion transporters 1 and 3 in vitro and in vivo","authors":"Lijun Luo ,&nbsp;Yongchun Chang ,&nbsp;Weilin Zhang ,&nbsp;Xiao Liu ,&nbsp;Junpu Ge ,&nbsp;Jieyi Chen ,&nbsp;Yan Li ,&nbsp;Dan Zhang ,&nbsp;Li Sheng","doi":"10.1016/j.cbi.2024.111293","DOIUrl":"10.1016/j.cbi.2024.111293","url":null,"abstract":"<div><div>7-Hydroxycoumarin (7-HC) is a natural coumarin compound rich in Chinese herbal medicines and has various pharmacological activities. After oral administration of 7-HC in rodents, its conjugated metabolites 7-hydroxycoumarin-β-D-glucuronide (7-HCG) and 7-hydroxycoumarin sulfate (7-HCS), exhibit high systemic exposure and urinary excretion. Organic anion transporters 1 and 3 (OAT1 and OAT3), mainly expressed in the proximal renal tubules, play an important role in drug-drug interactions and drug-induced kidney injury. We aimed to explore the mechanisms of OAT-mediated drug interactions and renal protective mechanisms of 7-HC and its conjugates. OAT-overexpressing cell models revealed that 7-HC was not a substrate for OAT1 and OAT3, while 7-HCG was specifically transported by OAT3. In contrast, 7-HCS can be transported by both OATs. Besides, 7-HC significantly inhibited the activity of OAT1 and OAT3, while 7-HCS had a strong inhibitory effect on OAT1 (IC₅₀ &lt; 10 μM). After co-administration of 100 mg/kg of 7-HC to mice, systemic exposure and clearance of furosemide (a clinical substrate of OATs) were significantly increased and decreased, respectively. In addition, 7-HC decreased OAT-mediated cytotoxicity and reduced the renal distribution of adefovir in mice. Together, these findings will provide support for OAT-mediated drug interactions and the renal protection of 7-HC.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111293"},"PeriodicalIF":4.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}