Chemico-Biological Interactions最新文献

{"title":"Hyperbaric oxygen rapidly produces intracellular bioenergetics dysfunction in human pulmonary cells","authors":"Tanvir Hossain ,&nbsp;Jackson T. Secor ,&nbsp;David M. Eckmann","doi":"10.1016/j.cbi.2024.111266","DOIUrl":"10.1016/j.cbi.2024.111266","url":null,"abstract":"<div><div>Hyperoxic exposure lasting days alters mitochondrial bioenergetic and dynamic functions in pulmonary cells as indices of oxygen toxicity. The aim of this study was to examine effects of short duration hyperbaric and hyperoxic exposures to induce oxygen toxicity similarly. Cultured human lung microvascular endothelial cells, human pulmonary artery endothelial cells and A549 cells were exposed to hyperoxia (∼5 % CO₂ equivalent, balance O₂) under hyperbaric conditions (4.8 ATA) for 1 and 4 h. Measures of mitochondrial dynamics, inner membrane potential, mitochondrial respiration, the intracellular distribution of bioenergetic capacity and respiration complex protein levels were then quantified. Exposures resulted in altered mitochondrial motility, presence of inhomogeneities in respiration parameters, loss of inner membrane potential, and changes in intracellular partitioning of ATP-linked respiration. Changes in the levels of respiration complex protein levels were also found. The combination of hyperoxic exposure with hyperbaric conditions rapidly produced changes in mitochondrial dynamics and bioenergetics in pulmonary cells. These changes are consistent with the onset of pulmonary oxygen toxicity previously known to result from long duration exposure to hyperoxia alone. These findings suggest health caution is warranted in environmental settings in which both hyperoxic and hyperbaric conditions are present. The synergism of hyperoxia and hyperbaria for rapid induction of oxygen toxicity in cellular models has utility for the study of mechanistic determinants of oxygen toxicity, testing of putative therapeutics, and associated investigations of mitochondrial dysfunction.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"404 ","pages":"Article 111266"},"PeriodicalIF":4.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483063","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":"Aristolochic acid I induced mitochondrial Ca2+ accumulation triggers the production of MitoROS and activates Src/FAK pathway in hepatocellular carcinoma cells","authors":"Yongkang Hu,&nbsp;Qi Zhang,&nbsp;Wenjuan Jiang,&nbsp;Xian Wang,&nbsp;Xinlong Guo,&nbsp;Langqun Chen,&nbsp;Siyu Cheng,&nbsp;Jiahui Ying,&nbsp;Jing Ye ,&nbsp;Liang Zhang","doi":"10.1016/j.cbi.2024.111269","DOIUrl":"10.1016/j.cbi.2024.111269","url":null,"abstract":"<div><div>Aristolochic acid I (AAI) is one of the nephrotoxic and carcinogenic compounds in Aristolochic acids (AAs). Recent studies have reported its promoting effect on hepatocellular carcinoma. However, the underlying mechanisms of AAI for the development of HCC is still unclear. Here, we found that AAI exposure caused alterations in mitochondrial function, which featured with increased ATP level and mitochondrial membrane potential, accumulation of mitochondrial Ca²⁺ and mitochondrial ROS (MitoROS) in Hepa1-6 and HepG2 cells. The restriction of mitochondrial Ca²⁺ uptake alleviated these effects. Our results showed that increased MitoROS was associated with AAI-induced migration and invasion in HCC cells. MitoROS/Src/FAK pathway was involved in the AAI-induced migration and invasion of HCC cells. In summary, our study showed that AAI affected mitochondrial metabolism of HCC cells by promoting the accumulation of mitochondrial Ca²⁺. These effects resulted in the activation of the MitoROS/SRC/FAK pathway in AAI-treated HCC cells, which in turn induced cell migration and invasion.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"405 ","pages":"Article 111269"},"PeriodicalIF":4.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483061","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":"Drug-induced inflammation: A review of literature","authors":"Yoshiyasu Takefuji","doi":"10.1016/j.cbi.2024.111282","DOIUrl":"10.1016/j.cbi.2024.111282","url":null,"abstract":"<div><div>This review examines how various medications can trigger inflammation throughout the body. It explores causes, ranging from common pain relievers like NSAIDs to chemotherapy drugs. The review also highlights potential treatments, including established medications and promising new therapies. Physicians and patients can work together to reduce this risk by understanding these causes and implementing preventive measures, such as monitoring for side effects and using alternative medications when possible. Drug-induced inflammation can be categorized into four types based on the immune response involved. Symptoms vary by type and affected organ. Common symptoms include fever, malaise, joint pain, rash, and swelling. Diagnosis involves blood tests, imaging, and biopsies. Treatment primarily involves discontinuing the suspected drug and providing supportive care. The development of new drugs and therapies has made diagnosis challenging. However, recent advances in biomarkers and genetic risk assessment techniques are improving diagnosis and risk assessment of drug-induced liver injury. Preventive measures for drug-induced inflammation include monitoring for side effects, using alternative medications, developing new drug delivery methods, exploring new anti-inflammatory drugs, being aware of rare side effects, and understanding the underlying mechanisms.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"404 ","pages":"Article 111282"},"PeriodicalIF":4.7,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483062","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":"Oxymatrine inhibits migration and invasion of esophageal squamous cell carcinoma cell lines via the MEK1/ERK/β-catenin pathway","authors":"Baoshi Xu ,&nbsp;Tian Qiu ,&nbsp;Rongrong Yang ,&nbsp;Jingchao Qiang ,&nbsp;Yongliang Yang ,&nbsp;Mengyuan Zhou ,&nbsp;Xing Li ,&nbsp;Jingquan Dong ,&nbsp;Yingzhi Lu ,&nbsp;Zibo Dong","doi":"10.1016/j.cbi.2024.111270","DOIUrl":"10.1016/j.cbi.2024.111270","url":null,"abstract":"<div><div>Esophageal, cancer is a prevalent malignant tumour of the digestive system in China, and esophageal squamous cell carcinoma (ESCC) accounts for 90 % of all esophageal cancer cases. Currently, the primary treatment involves surgical resection combined with postoperative radiotherapy. In this study, we used two ESCC cell lines to determine whether oxymatrine (OMT) inhibits ESCC, whether the mechanism involves the MEK1/ERK/β-catenin pathway, and how OMT modulates this pathway to affect the development of ESCC. The effects of OMT treatment were monitored with Cell Counting Kit-8 (CCK-8) assays as well as with clony formation, migration and invasion, wound healing, Hoechst 33258, and Western blot analyses. The relationship between OMT and the target was also evaluated by molecular docking and cell stability experiments. These findings suggest that ESCC development and metastasis may be inhibited by OMT and that OMT targets MEK1 through the ERK/β-catenin/EMT pathway to suppress ESCC cell migration and invasion. In addition, in vivo studies confirmed that OMT can inhibit the growth of ESCC cell lines in NOG mice without causing damage to other organs. In conclusion, in vitro experiments, revealed that OMT prevents the migration and invasiveness of ESCC cells by inhibiting the ERK/β-catenin/EMT pathway and thus targeting MAP2K1 (MEK1) in ESCC.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"404 ","pages":"Article 111270"},"PeriodicalIF":4.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446626","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":"The assessment of the phototoxic potential of drugs forming complexes with melanin - Screening in vitro studies using normal skin cells with varying pigmentation irradiated by a sunlight simulator","authors":"Jakub Rok,&nbsp;Justyna Kowalska,&nbsp;Zuzanna Rzepka,&nbsp;Klaudia Banach,&nbsp;Dorota Wrześniok","doi":"10.1016/j.cbi.2024.111268","DOIUrl":"10.1016/j.cbi.2024.111268","url":null,"abstract":"<div><div>Phototoxic reactions are among the most common skin-related adverse effects induced by drugs. It is believed that the binding of chemicals to melanin biopolymers is a significant factor influencing skin toxicity. The formation of drug-melanin complexes can lead to the accumulation of drugs or their photodegradation products in pigmented cells, potentially affecting phototoxic reactions. Current procedures for assessing the phototoxic potential of drugs are based on tests using immortalized mouse fibroblasts.</div><div>This study aimed to assess the phototoxic potential of selected drugs that form complexes with melanin (chloroquine, chlorpromazine, doxycycline) using human melanocytes with varying degrees of pigmentation. Parallel research was conducted on human dermal fibroblasts. To induce phototoxicity, cell cultures were irradiated using a sunlight simulator (5 J/cm² for UVA spectrum). To account for the process of drug accumulation, two experimental models with different incubation times of cells with drugs before irradiation were used. The photo-irritation factor (PIF) was calculated based on NRU and WST-1 screening tests. Additionally, cell viability was examined cytometrically, and analyses of the cell cycle and reduced glutathione levels were conducted.</div><div>The results indicated that drugs binding with melanin exhibited different levels of cytotoxicity and phototoxicity towards fibroblasts and melanocytes. These observed differences impact the values of PIF, potentially complicating the interpretation of the studies. Additional analyses, such as examining cell subpopulations in the sub-G1 phase and determining the level of reduced glutathione, can enhance the assessment of the phototoxicity of drugs on pigmented cells.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"404 ","pages":"Article 111268"},"PeriodicalIF":4.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441613","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":"Investigation of ponatinib metabolism and drug-drug interactions with lycopene and shikonin in vitro and in vivo","authors":"Jie Chen ,&nbsp;Fengsheng Hong ,&nbsp;Hailun Xia ,&nbsp;Yuxin Shen ,&nbsp;Xiaohai Chen ,&nbsp;Hualu Wu ,&nbsp;Guanyang Lin ,&nbsp;Ruanjuan Zhan","doi":"10.1016/j.cbi.2024.111265","DOIUrl":"10.1016/j.cbi.2024.111265","url":null,"abstract":"<div><div>Ponatinib is approved for use in patients with chronic myeloid leukemia (CML) who are resistant to or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. Given that ponatinib can induce significant cardiotoxicity when taken, and that most Chinese medicines have cardioprotective effects, it is possible to administer them in combination in clinic to alleviate adverse effects. The quantitative determination of ponatinib and its metabolite N-desmethyl ponatinib was optimized and fully verified by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). And the drug-drug interactions (DDI) of ponatinib with lycopene and shikonin, both <em>in vivo</em> and <em>in vitro</em><em>,</em> were studied. The results of bioanalytical methodology showed that ponatinib and N-desmethyl ponatinib had good linearity in plasma samples, and their selectivity, accuracy, precision, stability, matrix effect and recovery were all satisfied with the need of quantitative analysis of samples. In animal experiments, compared with the control group, lycopene and shikonin significantly changed the pharmacokinetic parameters of ponatinib, including AUC_(0-t), AUC_(0-∞) and CL_z/F, while having no effect on the pharmacokinetic parameters of N-desmethyl ponatinib. <em>In vitro</em> interaction studies indicated that lycopene showed mixed inhibition mechanism on ponatinib metabolism in both rat liver microsomes (RLM) and human liver microsomes (HLM). And, shikonin displayed mixed inhibition mechanism in RLM and competitive inhibition mechanism in HLM, respectively. In summary, the UPLC-MS/MS method can accurately and sensitively quantify ponatinib and N-desmethyl ponatinib, and provide further reference for clinical drug combination between ponatinib and lycopene or shikonin.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"404 ","pages":"Article 111265"},"PeriodicalIF":4.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483067","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":"Isavuconazonium sulfate induces heart development defects in zebrafish larvae by upregulation of oxidative stress","authors":"Qiang Yuan ,&nbsp;Li Zhang ,&nbsp;Yehao Li ,&nbsp;Zhipeng Wang ,&nbsp;Jiejun liu ,&nbsp;Weitao Hu ,&nbsp;Yihui Hu ,&nbsp;Fasheng Liu ,&nbsp;Shouhua Zhang ,&nbsp;Xinjun Liao ,&nbsp;Juhua Xiao ,&nbsp;Zigang Cao","doi":"10.1016/j.cbi.2024.111267","DOIUrl":"10.1016/j.cbi.2024.111267","url":null,"abstract":"<div><div>Environmental pollution remains a pressing global concern, with a substantial number of annual fatalities attributed to pollution-induced diseases. One emerging facet of environmental pollution is drug contamination, whereby pharmaceutical compounds can readily infiltrate water sources during manufacturing or utilization, subsequently being detected in various aquatic ecosystems. Some drugs have been detected in many watersheds at concentrations that can cause toxicity to aquatic organisms. Isavuconazonium sulfate (ISAV-SF), a prevalent antifungal medication, is no exception, warranting an exploration of its potential toxicity. However, limited research has been conducted in this domain. In this investigation, zebrafish were employed as a model organism to scrutinize the cardiotoxicity of ISAV-SF. Exposure of zebrafish embryos to concentrations of 0.5, 0.75, and 1 mg/L of ISAV-SF resulted in noteworthy cardiac developmental aberrations. These anomalies encompassed enlarged pericardial area, diminished heart rate, alterations in SV-BA distance, and the detachment of cardiomyocytes from the endocardium. Exposure to ISAV-SF caused disruption of the expression of genes related to cardiac development (<em>gata4, klf2a, nkx2.5, vmhc, tbx2b</em>), especially in the high concentration group. Moreover, the Notch signaling pathway was inhibited and oxidative stress levels were upregulated in all exposed groups. Remarkably, the administration of the antioxidant astaxanthin effectively mitigated oxidative stress levels, thus ameliorating heart developmental impairments. These results suggest that ISAV-SF may contribute to cardiac developmental defects by upregulating oxidative stress. This study serves as a pivotal reference for the utilization of ISAV-SF within the market, emphasizing the necessity to curtail its introduction into aquatic environments during production and consumption and to evaluate its repercussions on aquatic organisms.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"404 ","pages":"Article 111267"},"PeriodicalIF":4.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142483064","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":"Inhibition of protein disulfide isomerase mitigates steroid-induced osteonecrosis of the femoral head by suppressing osteoclast activity through the reduction of cellular oxidative stress","authors":"Xin Zhang ,&nbsp;Changgong Feng ,&nbsp;Tao Yuan ,&nbsp;Yi Wang ,&nbsp;Haojue Wang ,&nbsp;Qizhen Lu ,&nbsp;YongShuang Lv ,&nbsp;Ziqing Li ,&nbsp;Chuanyun Fu ,&nbsp;Shui Sun","doi":"10.1016/j.cbi.2024.111263","DOIUrl":"10.1016/j.cbi.2024.111263","url":null,"abstract":"<div><div>Osteonecrosis of the femoral head (ONFH) is a devastating and irreversible hip disease usually associated with increased oxidative stress due to the clinical application of high-dose or long-term glucocorticoids (GCs). Previous publications have demonstrated protein disulfide isomerase (PDI) plays a critical role in regulating cellular production of reactive oxygen species (ROS). We therefore ask whether interfering PDI could affect GCs-stimulated osteoclastogenesis. To test the hypothesis, we conducted bioinformatics and network analysis based on potential gene targets of steroid-induced osteonecrosis of the femoral head (SIONFH) in light of multiple databases and concomitantly verified the associated biological effect via the in vitro model of dexamethasone (DEX)-stimulated osteoclastogenesis. The results revealed 70 potential gene targets for SIONFH intervention, including the P4HB gene that encodes PDI. Further analysis based on network topology-based analysis techniques (NTA), protein-protein interaction (PPI) networks, and mouse cell atlas database identified the importance of PDI in regulating the cellular redox state of osteoclast during ONFH. Western blotting (WB) validations also indicated that PDI may be a positive regulator in the process of DEX-stimulated osteoclastogenesis. Hence, various PDI inhibitors were subjected to molecular docking with PDI and their performances were analyzed, including 3-Methyltoxoflavin (3 M) which inhibits PDI expression, and ribostamycin sulfate (RS) which represses PDI chaperone activity. The binding energies of DEX, 3 M, and RS to PDI were −5.3547, −4.2324, and −5.9917 kcal/mol, respectively. The Protein-Ligand Interaction Profiler (PLIP) analysis demonstrated that both hydrogen bonds and hydrophobic interactions were the key contributions to the DEX-PDI and 3M-PDI complexes, while only hydrogen bonds were identified as the predominant driving forces in the RS-PDI complex. Subsequent experiments showed that both 3 M and RS reduced osteoclast differentiation and bone resorption activity by stifling the expression of osteoclastic markers. This reduction was primarily due to the PDI inhibitors boosting the antioxidant system, thereby reducing the production of intracellular ROS. In conclusion, our results supported PDI's involvement in SIONFH progression by regulating ROS in osteoclasts and highlighted PDI inhibitors may serve as potential options for SIONFH treatment.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"404 ","pages":"Article 111263"},"PeriodicalIF":4.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142407366","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":"Binding characteristics of the major kratom alkaloid, mitragynine, towards serum albumin: Spectroscopic, calorimetric, microscopic, and computational investigations","authors":"Khairul Azreena Bakar ,&nbsp;Su Datt Lam ,&nbsp;Shevin Rizal Feroz","doi":"10.1016/j.cbi.2024.111264","DOIUrl":"10.1016/j.cbi.2024.111264","url":null,"abstract":"<div><div>Mitragynine (MTG) is a prominent indole alkaloid that is present abundantly in <em>Mitragyna speciosa</em>, commonly referred to as kratom. MTG has garnered significant attention due to its selective agonistic characteristics towards opioid receptors and related analgesic effects. In the circulatory system, the <em>in vivo</em> efficacy of MTG is dictated by its interaction with plasma proteins, primarily human serum albumin (HSA). In the present study, we utilized a broad methodology that included spectroscopic, calorimetric, microscopic, and <em>in silico</em> approaches to characterize the interaction between MTG and HSA. Alterations in the UV absorption spectrum of HSA by the presence of MTG demonstrated a ground-state complexation between the protein and the ligand. The <em>K</em>_a values obtained for the MTG–HSA interaction were in the range 10³–10⁴ M⁻¹ based on analysis of fluorescence and ITC data, respectively, indicating an intermediate binding affinity. The binding reaction was thermodynamically favorable as revealed by Δ<em>H</em>, Δ<em>S</em>, and Δ<em>G</em> values of −16.42 kJ mol⁻¹, 39.97 J mol⁻¹ K⁻¹, and −28.34 kJ mol⁻¹, respectively. Furthermore, CD spectroscopy results suggested MTG binding induced minimal effects on the structural integrity of HSA, supported by computational methods. Changes in the dimensions of HSA particles due to aggregation, as observed using atomic force microscopy in the presence of MTG. Competitive drug displacement results seemingly suggested site III of HSA located at subdomain IB as the preferred binding site of MTG, but were in inconclusive. However, docking results showed the clear preference of MTG to bind to site III, facilitated by hydrophobic (alkyl and pi-alkyl) and van der Waals forces, together with carbon hydrogen bonds. Additionally, the MTG–HSA complexation was demonstrated to be stable based on molecular dynamics analysis. The outcomes of this study shed light on the therapeutic potential of MTG and can help in the design of more effective derivatives of the compound.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"404 ","pages":"Article 111264"},"PeriodicalIF":4.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142407365","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":"Hinokiflavone from Platycladi cacumen as a potent broad-spectrum inhibitor of gut microbial Loop-1 β-glucuronidases: Inhibition kinetics and molecular simulation","authors":"Yue Han ,&nbsp;Yu-Tong Liu ,&nbsp;Lu Chen ,&nbsp;Hao-Fan Sun ,&nbsp;Guang-Hao Zhu ,&nbsp;Dong-Ning Kang ,&nbsp;Qi Zhou ,&nbsp;Hui Tang ,&nbsp;Yu-Ling Yin ,&nbsp;Jie Hou","doi":"10.1016/j.cbi.2024.111261","DOIUrl":"10.1016/j.cbi.2024.111261","url":null,"abstract":"<div><div>Gut microbial Loop-1 β-glucuronidases (gmGUS) played an important role in irinotecan-induced gastrointestinal toxicity by regulating the level of its active metabolite SN38 through enterohepatic recirculation. gmGUS inhibition has emerged as a promising approach to relieve its dose-limiting intestinal toxicity and improve its medication efficacy. This study aims to investigate the inhibitory effects and mechanisms of <em>Platycladi cacumen</em> and its main constituent hinokiflavone against four different types of Loop-1 gmGUS (<em>Ee</em>GUS, <em>Sa</em>GUS, <em>Cp</em>GUS and <em>Ec</em>GUS). Our results showed that the ethanol extract of <em>Platycladi cacumen</em> displayed strong broad-spectrum inhibition against four gmGUS, and hinokiflavone could potently inhibit <em>Ee</em>GUS, <em>Sa</em>GUS, <em>Cp</em>GUS and <em>Ec</em>GUS with IC₅₀ values of 0.09 ± 0.01 μM, 0.44 ± 0.01 μM, 0.20 ± 0.01 μM and 0.69 ± 0.10 μM, respectively. Inhibition kinetic analyses demonstrated that hinokiflavone acted as a strong competitive inhibitor of <em>Ee</em>GUS with <em>K</em>_<em>i</em> value of 0.13 μM, while it displayed non-competitive inhibition against <em>Sa</em>GUS, <em>Cp</em>GUS and <em>Ec</em>GUS, with the <em>K</em>_<em>i</em> values of 0.43 μM, 0.33 μM and 0.76 μM, respectively. Docking simulations revealed that hinokiflavone could tightly bind with Tyr-485 and Glu-516 in catalytic sites of <em>E</em>eGUS, as well it created strong interactions with amino acids in loop structures of <em>Sa</em>GUS (Asn-362), <em>Cp</em>GUS (Phe-363, Met-364, Ala-365 and Arg-375) and <em>Ec</em>GUS (Leu-361) to interfere the substrate entry into the catalytic pocket. Collectively, these results confirmed that hinokiflavone from <em>Platycladi cacumen</em> is a potent naturally occurring inhibitor of gmGUS with broad efficiency, suggesting hinokiflavone will be helpful for alleviating intestinal toxicity in irinotecan therapy.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"404 ","pages":"Article 111261"},"PeriodicalIF":4.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142402339","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}