Current drug metabolism最新文献

{"title":"Quality by Design Approach for the Development of Cariprazine Hydrochloride Loaded Lipid-Based Formulation for Brain Delivery <i>via</i> Intranasal Route.","authors":"Pallavi Chiprikar, Vinayak Mastiholimath, Prakash Biradar, Nisha Shirkoli","doi":"10.2174/0113892002327148240924071717","DOIUrl":"10.2174/0113892002327148240924071717","url":null,"abstract":"<p><strong>Background: </strong>Cariprazine (CPZ) is a third-generation antipsychotic medication that has been approved for treating schizophrenia. This study aimed to develop a cariprazine-loaded nanostructured lipid carrier (CPZ-NLCs) to prevent first-pass metabolism and improve bioavailability and site-specific delivery from nose to the brain.</p><p><strong>Methods: </strong>The CPZ-NLCs were prepared using melt emulsification. The formulation was optimized using the Box-Behnken design (BBD); where the influence of independent variables on critical quality attributes, such as particle size and entrapment efficiency was studied.</p><p><strong>Results: </strong>The optimized batch (F6) had a particle size of 173.3 ± 0.6 nm and an entrapment efficiency of 96.1 ± 0.57%, respectively. The in vitro release showed >96% release of CPZ from NLC within 30 min. The optimized formulation's ex vivo studies revealed significantly increased CPZ permeability (>75%) in sheep nasal mucosa compared to the CPZ suspension (~26%). The ciliotoxicity study of the nasal mucosa revealed that the CPZ-NLC formulation did not affect the nasal epithelium. The intranasal administration of the formulation achieved 76.14±6.23 μg/ml concentration in the brain which was significantly higher than the oral CPZ suspension administration (30.46±7.24 μg/ml). The developed formulation was stable for 3 months.</p><p><strong>Conclusion: </strong>The study concluded that the developed CPZ-NLC could significantly improve the bioavailability with quick delivery to the brain.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"523-541"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-Drug Interaction Potential of Remimazolam: CYP 450, Transporters, and Protein Binding.","authors":"Karl-Uwe Petersen, Wolfgang Schmalix, Marija Pesic, Thomas Stöhr","doi":"10.2174/0113892002300657240521094732","DOIUrl":"10.2174/0113892002300657240521094732","url":null,"abstract":"<p><strong>Background: </strong>The ultra-short-acting benzodiazepine, remimazolam, is a new treatment modality for procedural sedation and general anesthesia. Its activity is terminated by carboxylesterase 1 (CES1).</p><p><strong>Objective: </strong>The objective of this study was to determine the drug-drug interaction (DDI) potential of remimazolam through mechanisms unrelated to its metabolizing enzyme, CES1.</p><p><strong>Methods: </strong>Conventional in vitro co-exposure experiments were conducted to study possible interactions of remimazolam and its primary metabolite, CNS7054, mediated by competitive binding to plasma protein or reactions with cytochrome P450 isoforms or drug transporters.</p><p><strong>Results: </strong>No relevant interactions of remimazolam or its metabolite with cytochrome P450 (CYP) isoforms at clinically relevant concentrations were identified. Likewise, standard experiments revealed no clinically relevant interactions with drug transporters and plasma proteins.</p><p><strong>Conclusion: </strong>The present data and analyses suggest a very low potential of remimazolam for pharmacokinetic DDIs mediated by CYP isoforms, drug transporters, and protein binding.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"266-275"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Cytochrome P450 3A4 in Cancer Drug Resistance: Challenges and Opportunities.","authors":"Swaroop Kumar Pandey, Sona Verma, Shobha Upreti, Anuja Mishra, Neha Yadav, Hemlata Dwivedi-Agnihotri","doi":"10.2174/0113892002312369240703102215","DOIUrl":"10.2174/0113892002312369240703102215","url":null,"abstract":"<p><p>One of the biggest obstacles to the treatment of diseases, particularly serious conditions like cancer, is therapeutic resistance. The process of drug resistance is influenced by a number of important variables, including MDR genes, drug efflux, low-quality medications, inadequate dosage, etc. Drug resistance must be addressed, and new combinations based on the pharmacokinetics/pharmacodynamics (PK-PD) characteristics of the partner pharmaceuticals must be developed in order to extend the half-lives of already available medications. The primary mechanism of drug elimination is hepatic biotransformation of medicines by cytochrome P450 (CYP) enzymes; of these CYPs, CYP3A4 makes up 30-40% of all known cytochromes that metabolize medications. Induction or inhibition of CYP3A4-mediated metabolism affects the pharmacokinetics of most anticancer drugs, but these details are not fully understood and highlighted because of the complexity of tumor microenvironments and various influencing patient related factors. The involvement of CYPs, particularly CYP3A4 and other drug-metabolizing enzymes, in cancer medication resistance will be covered in the current review.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"235-247"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141562879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study on Cytochrome P450 Metabolic Profile of Paclitaxel on Rats using QTOF-MS.","authors":"Zhaoyang Meng, Junjun Chen, Lingyan Xu, Xiao Xiao, Ling Zong, Yonglong Han, Bo Jiang","doi":"10.2174/0113892002308509240711100502","DOIUrl":"10.2174/0113892002308509240711100502","url":null,"abstract":"<p><strong>Background: </strong>Paclitaxel (PTX) is a key drug used for chemotherapy for various cancers. The hydroxylation metabolites of paclitaxel are different between humans and rats. Currently, there is little information available on the metabolic profiles of CYP450 enzymes in rats.</p><p><strong>Objective: </strong>This study evaluated the dynamic metabolic profiles of PTX and its metabolites in rats and <i>in vitro</i>.</p><p><strong>Methods: </strong>Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) and LC-MS/MS were applied to qualitative and quantitative analysis of PTX and its metabolites in rats, liver microsomes and recombinant enzyme CYP3A1/3A2. Ten specific inhibitors [NF (CYP1A1), FFL (CYP1A2), MOP (CYP2A6), OND (CYP2B6), QCT (CYP2C8), SFP (CYP2C9), NKT (CYP2C19), QND (CYP2D6), MPZ (CYP2E1) and KTZ (CYP3A4)] were used to identify the metabolic pathway <i>in vitro</i>.</p><p><strong>Results: </strong>Four main hydroxylated metabolites of PTX were identified. Among them, 3'-p-OH PTX and 2-OH PTX were monohydroxylated metabolites identified in rats and liver microsome samples, and 6α-2-di-OH PTX and 6α-5\"-di-OH PTX were dihydroxylated metabolites identified in rats. CYP3A recombinant enzyme studies showed that the CYP3A1/3A2 in rat liver microsomes was mainly responsible for metabolizing PTX into 3'-p- OH-PTX and 2-OH-PTX. However, 6α-OH PTX was not detected in rat plasma and liver microsome samples.</p><p><strong>Conclusion: </strong>The results indicated that the CYP3A1/3A2 enzyme, metabolizing PTX into 3'-p-OH-PTX and 2- OH-PTX, is responsible for the metabolic of PTX in rats. The CYP2C8 metabolite 6α-OH PTX in humans was not detected in rat plasma in this study, which might account for the interspecies metabolic differences between rats and humans. This study will provide evidence for drug-drug interaction research in rats.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"330-339"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Avapritinib Carries the Risk of Drug Interaction <i>via</i> Inhibition of UDP-Glucuronyltransferase (UGT) 1A1.","authors":"Xin Lv, Zhen Wang, Zhe Wang, Hang Yin, Yangliu Xia, Lili Jiang, Yong Liu","doi":"10.2174/0113892002288312240521092054","DOIUrl":"10.2174/0113892002288312240521092054","url":null,"abstract":"<p><strong>Background: </strong>Avapritinib is the only drug for adult patients with PDGFRA exon 18 mutated unresectable or metastatic gastrointestinal stromal tumor (GIST). Although avapritinib has been approved by the FDA for four years, little is known about the risk of drug-drug interactions (DDIs) via UDP-glucuronyltransferases (UGTs) inhibition.</p><p><strong>Objective: </strong>The aim of the present study was to systematically evaluate the inhibitory effects of avapritinib against UGTs and to quantitatively estimate its potential DDIs risk <i>in vivo</i>.</p><p><strong>Methods: </strong>Recombinant human UGTs were employed to catalyze the glucuronidation of substrates in a range of concentrations of avapritinib. The kinetics analysis was performed to evaluate the inhibition types of avapritinib against UGTs. The quantitative prediction of DDIs was done using <i>in vitro-in vivo</i> extrapolation (IVIVE).</p><p><strong>Results: </strong>Avapritinib had a potent competitive inhibitory effect on UGT1A1. Quantitative prediction results showed that avapritinib administered at clinical doses might result in a 14.85% increase in area under the curve (AUC) of drugs primarily cleared by UGT1A1. Moreover, the Rgut value was calculated to be 18.44.</p><p><strong>Conclusion: </strong>Avapritinib has the potential to cause intestinal DDIs <i>via</i> the inhibition of UGT1A1. Additional attention should be paid when avapritinib is coadministered with UGT1A1 substrates.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"197-204"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogen Peroxide Induces Ethanol-inducible CYP2E1 <i>via</i> the NF-kB-classical Pathway: CYP2E1 mRNA Levels are not High in Alcoholic Hepatitis.","authors":"Akiyoshi Tamura, Ferbian Milas Siswanto, Takumi Yoshimura, Ami Oguro, Susumu Imaoka","doi":"10.2174/0113892002305174240805064406","DOIUrl":"10.2174/0113892002305174240805064406","url":null,"abstract":"<p><strong>Aims: </strong>The aim of the present study is to elucidate the mechanism of CYP2E1 induction as a causative factor of Alcoholic Hepatitis (AH) and its relationship with inflammation.</p><p><strong>Background: </strong>Chronic alcohol consumption induces CYP2E1, which is involved in the development of Alcoholic Hepatitis (AH). However, the mechanisms underlying the induction of CYP2E1 by alcohol remain unclear. Therefore, we herein investigated the induction of drug-metabolizing enzymes, particularly CYP2E1, by hydrogen peroxide (H₂O₂), the concentration of which is elevated under inflammatory conditions.</p><p><strong>Objective: </strong>The mechanisms underlying the induction of CYP2E1 by H₂O₂ were examined with a focus on Keap1, a target factor of H₂O₂.</p><p><strong>Methods: </strong>We assessed changes in the expression of drug-metabolizing enzymes in the human hepatoma cell line, Hep3B, following treatment with H₂O₂, and evaluated changes in the expression of the NF-kB-related factor RelA(p65) after the knockdown of Keap1, a regulator of Nrf2 expression by reactive oxygen species. We also performed a promoter analysis using the upstream region of the CYP2E1 gene. We herein used the GSE89632 series for non-alcoholic hepatitis (NASH) and the GSE28619 series for AH.</p><p><strong>Results: </strong>The induction of CYP2E1 by H₂O₂ was significantly stronger than that of other drugmetabolizing enzymes. On the other hand, the knockdown of Keap1, a target of H₂O₂, markedly increased RelA(p65), an NFkB factor. Furthermore, the overexpression of RelA(p65) strongly induced the expression of CYP2E1. Four candidate p65-binding sequences were identified upstream of the CYP2E1 gene, and promoter activity assays showed that the third sequence was responsive to the overexpression of RelA(p65). We used the GSE89632 series for NASH and the GSE28619 series for AH in the present study. The expression of CYP2E1 mRNA in the liver was significantly lower in AH patients than in HC patients, but was similar in HC patients and NASH patients.</p><p><strong>Conclusion: </strong>We herein demonstrated that the expression of CYP2E1 was induced by H₂O₂. The overexpression of RelA(p65) also induced CYP2E1 mRNA expression, whereas H₂O₂ did not after the knockdown of RelA. These results suggest that H₂O₂ acts on Keap1 to upregulate RelA (p65) in the NFkB system. One of the mechanisms underlying the induction of CYP2E1 was dependent on the H₂O₂-Keap1-RelA axis. The results of the database analysis revealed that the expression of CYP2E1 in the liver was significantly lower in AH patients than in NASH patients, suggesting that CYP2E1 is not the main cause of AH; however, CYP2E1 may exacerbate the pathogenesis of AH.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"307-316"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Advances in Hepatic Metabolic Regulation by the Nuclear Factor Rev-erbɑ.","authors":"Qi Zhang, Yutong Chen, Jingqi Li, Haishan Xia, Yongbin Tong, Yuyu Liu","doi":"10.2174/0113892002290055240212074758","DOIUrl":"10.2174/0113892002290055240212074758","url":null,"abstract":"<p><p>Rev-erbɑ (NR1D1) is a nuclear receptor superfamily member that plays a vital role in mammalian molecular clocks and metabolism. Rev-erbɑ can regulate the metabolism of drugs and the body's glucose metabolism, lipid metabolism, and adipogenesis. It is even one of the important regulatory factors regulating the occurrence of metabolic diseases (e.g., diabetes, fatty liver). Metabolic enzymes mediate most drug metabolic reactions in the body. Rev-erbɑ has been recognized to regulate drug metabolic enzymes (such as Cyp2b10 and Ugt1a9). Therefore, this paper mainly reviewed that Rev-erbɑ regulates I and II metabolic enzymes in the liver to affect drug pharmacokinetics. The expression of these drug metabolic enzymes (up-regulated or down-regulated) is related to drug exposure and effects/ toxicity. In addition, our discussion extends to Rev-erbɑ regulating some transporters (such as P-gp, Mrp2, and Bcrp), as they also play an essential role in drug metabolism. Finally, we briefly describe the role and mechanism of nuclear receptor Rev-erbɑ in lipid and glucose homeostasis, obesity, and metabolic disorders syndrome. In conclusion, this paper aims to understand better the role and mechanism of Rev-erbɑ in regulating drug metabolism, lipid, glucose homeostasis, obesity, and metabolic disorders syndrome, which explores how to target Rev-erbɑ to guide the design and development of new drugs and provide scientific reference for the molecular mechanism of new drug development, rational drug use, and drug interaction.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"2-12"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the Role of COMT Polymorphism in Dopamine-Mediated Vasopressor Effects: An Observational Cross-Sectional Study.","authors":"Kannan Sridharan, Anfal Jassim, Ali Mohammed Qader, Sheikh Abdul Azeez Pasha","doi":"10.2174/0113892002293952240315064943","DOIUrl":"10.2174/0113892002293952240315064943","url":null,"abstract":"<p><strong>Aims: </strong>To evaluate the association between rs4680 polymorphism in the COMT gene and the vasoconstrictive effects of commonly used vasopressors.</p><p><strong>Background: </strong>Dopamine is a medication that is given intravenously to critically ill patients to help increase blood pressure. Catechol O-Methyl Transferase (COMT) breaks down dopamine and other catecholamines. There is a genetic variation in the COMT gene called rs4680 that can affect how well the enzyme works. Studies have shown that people with this genetic variation may have different blood pressure levels. However, no one has looked at how this genetic variation affects the way dopamine works to increase blood pressure.</p><p><strong>Objectives: </strong>To investigate the impact of the rs4680 polymorphism in the COMT gene on the pharmacodynamic response to dopamine.</p><p><strong>Methods: </strong>Critically ill patients administered dopamine were included following the consent of their legally acceptable representatives. Details on their demographic characteristics, diagnosis, drug-related details, changes in the heart rate, blood pressure, and urinary output were obtained. The presence of rs4680 polymorphism in the COMT gene was evaluated using a validated method.</p><p><strong>Results: </strong>One hundred and seventeen patients were recruited, and we observed a prevalence of rs4680 polymorphism in 57.3% of our critically ill patients. Those with mutant genotypes were observed with an increase in the median rate of change in mean arterial pressure (mm Hg/hour) [wild: 8.9 (-22.6 to 49.1); heterozygous mutant: 5.9 (-34.1 to 61.6); and homozygous mutant: 19.5 (-2.5 to 129.2)] and lowered urine output (ml/day) [wild: 1080 (21.4 to 5900); heterozygous mutant: 380 (23.7 to 15800); and homozygous mutant: 316.7 (5.8 to 2308.3)].</p><p><strong>Conclusion: </strong>V158M (rs4680) polymorphism is widely prevalent in the population and was significantly associated with altered effects as observed clinically. This finding suggests valuable insights into the molecular basis of COMT function and its potential impact on neurotransmitter metabolism and related disorders. Large-scale studies delineating the effect of these polymorphisms on various vasopressors are the need of the hour.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"152-156"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Shenmai Injection on the Pharmacokinetics of Dasatinib: An In-Depth <i>In vivo</i> Analysis Utilizing UPLC-MS/MS Technique.","authors":"Weina Ma, Ling Li, Zhihui Li, Jungang Guo, Yifei Zhu, Liye Ge, Rong Wang, Lei Lv","doi":"10.2174/0113892002336775250108112738","DOIUrl":"10.2174/0113892002336775250108112738","url":null,"abstract":"<p><strong>Background: </strong>Dasatinib has been widely used in the treatment of a variety of cancers, such as lung cancer and acute myeloid leukemia. Shenmai injection is a traditional Chinese medicine injection that is often used in antitumor adjuvant therapy. In recent years, dasatinib combined with Shenmai injection has been increasingly used to treat tumors clinically. However, the potential risks and benefits of co-administering Shenmai injection and dasatinib are unclear.</p><p><strong>Objective: </strong>The study aimed to investigate the potential influence of Shenmai injection on dasatinib pharmacokinetics.</p><p><strong>Methods: </strong>Twelve rats were selected and randomly divided into two groups: dasatinib alone and a combination of dasatinib and Shenmai injection. To measure the concentration of dasatinib in rat plasma, blood samples were obtained from the orbital vein. Using ultra-performance liquid chromatography-tandem mass spectrometry, the concentration of dasatinib was determined to obtain pharmacokinetic parameters.</p><p><strong>Results: </strong>Compared to the dasatinib alone administration, the maximum concentration of the dasatinib plus Shenmai injection administration was decreased (355.9 ± 194.9 vs. 199.2 ± 73.8 ng·mL^-1) (P < 0.05). Moreover, the area under the moment curve (3867.0 ± 2141.9 vs. 6355.3 ± 3311.6 ng·mL^-1·h²) and mean residence time (3.7 ± 1.2 vs. 6.5 ± 3.1 h) showed a statistically significant increase (P < 0.05).</p><p><strong>Conclusion: </strong>The study revealed that Shenmai injection might have the capacity to slow down the absorption rate of dasatinib and could extend the retention period of dasatinib in the body, resulting in stabilized blood drug concentrations and a reduction in adverse drug reactions.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"670-676"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Umbelliferone Enhances Immune Function in Cyclophosphamide-Induced Immunosuppressed Mice <i>via</i> Histidine and Purine Metabolism Regulation.","authors":"Mei Li, Jing Wang, Bingjie Huo, Qianqian Wan, Liwei Xing, Yuming Wang, Huan Pei, Li Wang, Yafei Xia, Huantian Cui","doi":"10.2174/0113892002360132250122164637","DOIUrl":"10.2174/0113892002360132250122164637","url":null,"abstract":"<p><strong>Background: </strong>Chemotherapy-induced immunosuppression significantly impacts patient's quality of life. Umbelliferone (UMB) is known for its anti-inflammatory, antioxidant, and anti-apoptotic properties, but its effects on cyclophosphamide (CTX)-induced immunosuppression need further study.</p><p><strong>Methods: </strong>We established a CTX-induced immunosuppressed mouse model and administered varying doses of UMB. Immune function was assessed by evaluating white blood cells, lymphocytes, thymus and spleen indices, and CD4⁺/CD8⁺ T cell ratios. Serum levels of IL-2, IFN-γ, IgA, IgM, and IgG, along with macrophage phagocytic activity, NK cytotoxicity, and lymphocyte proliferation, were measured. Untargeted metabolomics was used to identify key pathways regulated by UMB, and RT-qPCR and Western blotting were performed to analyze the expression of related enzymes and metabolites.</p><p><strong>Results: </strong>UMB intervention increased white blood cells, lymphocytes, thymus and spleen indices, and CD4+/CD8+ T cell ratios in CTX-immunosuppressed mice. It reversed reduced levels of serum IL-2, IFN-γ, IgA, IgM, and IgG and improved macrophage phagocytic activity, NK cytotoxicity, and lymphocyte proliferation. Key pathways identified by metabolomics included histidine and purine metabolism. UMB improved levels of histamine, L-glutamate, L-aspartate, xanthine, dAMP, deoxyinosine, xanthosine, and cGMP and upregulated HDC, ASPA, and PNP while downregulating XDH, PDE5, ROS, and MDA in spleen tissue. UMB enhanced SOD activity and GSH levels and reduced apoptosis, as indicated by lower TUNEL-positive expression.</p><p><strong>Conclusion: </strong>UMB enhanced immune function in CTX-immunosuppressed mice through the regulation of histidine and purine metabolism, exhibiting antioxidant and anti-apoptotic effects. These findings highlight the potential of UMB in mitigating immunosuppression.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"695-705"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}