Drug Design, Development and Therapy最新文献

{"title":"ShenQi ShenKang Granule Alleviates Chronic Kidney Disease by Inhibiting the PI3K/AKT/mTOR Pathway and Restoring Autophagy Flux and Mitochondrial Integrity.","authors":"Chenhui Xia, Jiale Zhang, Huixi Chen, Shaofeng Zhou, Weimin Jiang, Huijuan Zheng, Zaoqiang Lin, Qinxiang Tan, Weiwei Sun","doi":"10.2147/DDDT.S513824","DOIUrl":"10.2147/DDDT.S513824","url":null,"abstract":"<p><strong>Purpose: </strong>This study investigates the effect of Shenqi Shenkang granule (SQSKG) on chronic kidney disease (CKD), focusing on regulating the PI3K/AKT/mTOR pathway, autophagy, and mitochondrial homeostasis.</p><p><strong>Methods: </strong>The compounds and targets of SQSKG on CKD were identified by network pharmacology and validated by molecular docking. LC-MS/MS was used to verify the compounds screened by network pharmacology. In vitro experiments based on HK-2 cells were used to assess its impact on cell migration, viability, oxidative stress, and key proteins of the PI3K/AKT/mTOR pathway, autophagy, and fibrosis. Mitochondrial function and autophagic flux were evaluated via JC-1, Mito-Tracker, and Ad-mCherry-GFP-LC3B assays. In vivo, an adenine-induced CKD rat model was used to analyze renal function, fibrosis, and autophagy through serum/urine tests, histology, and immunofluorescence.</p><p><strong>Results: </strong>Network pharmacology identified 49 compounds and 149 targets associated with SQSKG's therapeutic effects on CKD, highlighting critical targets such as AKT1, MAPK1, EGFR, HSP90AA, and IGF1R. The primary mechanism involves the PI3K/AKT pathway. In vitro experiments demonstrated that SQSKG significantly enhanced cell migration, colony formation, viability in AGEs-treated HK-2 cells, and exhibited robust antioxidant properties by increasing SOD levels and reducing MDA and ROS production. SQSKG effectively inhibited the phosphorylation of PI3K, AKT, and mTOR, and reduced TGF-β fluorescence intensity in kidney tissue. Autophagic flux analysis showed that SQSKG increased autophagic activity and reduced p62 accumulation. Additionally, JC-1 and Mito-Tracker Green assays demonstrated that SQSKG improved mitochondrial membrane potential and morphology. In vivo, SQSKG significantly improved renal function and alleviated renal fibrosis in a dose-dependent manner, reversing fibrosis marker overexpression (Col-I, α-SMA, TGF-β) and activating autophagy.</p><p><strong>Conclusion: </strong>Our findings provide novel insights into the therapeutic potential of SQSKG in CKD management, highlighting its ability to modulate PI3K/AKT/mTOR pathway, activating autophagy flux, and restoring mitochondrial integrity, thereby offering a promising complementary or alternative treatment option for patients with CKD.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3925-3947"},"PeriodicalIF":4.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12089262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110065","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":"Biochemical and Molecular Studies on the Role of Celecoxib and Some Related Bipyrazoles in Mitigating Induced Liver Injury in Experimental Animals.","authors":"Maram Marei, Nefertiti El-Nikhely, Eman Sheta, Hanan Ragab, Ahmed Wahid, Hesham Saeed, Sherif A F Rostom","doi":"10.2147/DDDT.S512058","DOIUrl":"10.2147/DDDT.S512058","url":null,"abstract":"<p><strong>Introduction: </strong>Liver fibrosis is a life-threatening disease that greatly impacts the morbidity and mortality of hepatic patients worldwide, resulting mainly as a consequence of hepatitis C, alcoholic and non-alcoholic fatty liver. COX-1 and COX-2 isozymes catalyze the synthesis of prostaglandins (PGs) and thromboxanes (TXs) from arachidonic acid causing inflammation. Owing to the scarcity of approved fibrolytic drugs available for human use, celecoxib (a selective COX-2 inhibitor) has been repurposed as a potential antifibrotic and fibrolytic agent in some chronic liver fibrosis models.</p><p><strong>Methods: </strong>The present study aims to discover a non-invasive treatment for liver fibrosis through investigating the possible ability of three celecoxib-related bipyrazole compounds <b>HR1-3</b> to reverse chemically induced liver fibrosis in rats using CCl₄. This fibrolytic effect was verified by histopathological, immunohistochemical, biochemical and biomolecular assays. In addition, in silico computer-aided evaluation of the compounds' binding mode to certain molecular targets was performed, and the in silico physicochemical properties, drug likeness and pharmacokinetic parameters were predicted using web-based applications.</p><p><strong>Results: </strong>The analogs <b>HR1-3</b> could serve as novel therapeutic candidates for the mitigation of liver fibrosis that deserves further derivatizations and investigations. In particular, the fluorinated analog <b>HR3</b> proved to be the most active member in this study when compared to celecoxib due to its distinguished histopathological and immunohistochemical investigation results, beside its antioxidant potential, as well as its reliable effects against some biomarkers, namely, MMP-9, TGF-β1, TIMP-1, IL-6 and TNF-α.</p><p><strong>Conclusion: </strong>Based on the obtained results, the fluorinated analog <b>HR3</b> could serve as a novel therapeutic candidate for the amelioration of liver fibrosis that deserves further derivatizations and investigations.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3857-3882"},"PeriodicalIF":4.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101644","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":"Inhibition of Dormant Lung Cancer Cell Reactivation by <i>Punica Granatum Peel</i> and <i>Dioscorea Nipponica</i>: Involving MYC, SKP2 and p27.","authors":"Su Su Thae Hnit, Ling Bi, Chanlu Xie, Ling Xu, Yi Zhong, Ming Yang, Yan Wang, Qihan Dong","doi":"10.2147/DDDT.S494168","DOIUrl":"10.2147/DDDT.S494168","url":null,"abstract":"<p><strong>Introduction: </strong>Dormant cancer cells, capable of reactivating from the G₀ phase, drive tumor recurrence and therapy resistance. Current clinical strategies targeting dormancy remain limited. This study evaluates Punica granatum peel (PGP) and Dioscorea Nipponica (DN) for their ability to sustain dormancy in lung cancer cells and inhibit reactivation.</p><p><strong>Methods: </strong>Dormancy was induced in A549 and H460 lung cancer cells via contact inhibition or serum deprivation. Subcutaneous and orthotopic xenograft mouse models were employed. Cells and mice were treated with PGP, DN, or their combination. SYBR Green assays, flow cytometry, and immunoblotting assessed DNA synthesis, cell cycle phases, and protein expression (p27, SKP2, cMYC, AURORA A, SUPT16H, SSRP1).</p><p><strong>Results: </strong>Both PGP and DN significantly inhibited DNA synthesis and cell cycle re-entry (G₀-to-G₁ transition) in vitro. In vivo, tumor volume and weight decreased by 26-50% (p < 0.05) in treated mice. Treatments upregulated p27 while downregulating SKP2, cMYC, AURORA A, SUPT16H, and SSRP1. No synergistic effect was observed, but additive efficacy (Combination Index ≈1) was noted at a 10:1 PGP:DN ratio.</p><p><strong>Discussion: </strong>PGP and DN sustain dormancy by modulating key cell cycle regulators, highlighting their potential to reduce recurrence and combat drug resistance. These findings underscore the therapeutic promise of traditional Chinese medicines in managing dormant cancer cells. Future studies should identify active compounds and validate mechanisms in advanced models.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3997-4010"},"PeriodicalIF":4.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101557","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":"Huashi Jiedu Decoction Enhances 5-Fluorouracil Efficacy in Gastric Cancer via miRNA-21-3p/p53 Pathway.","authors":"Qianran Hong, Weiye Lin, Yici Yan, Shuangyu Chen, Jiayang Li, Jieru Yu, Ying Zhu, Shengliang Qiu","doi":"10.2147/DDDT.S513371","DOIUrl":"10.2147/DDDT.S513371","url":null,"abstract":"<p><strong>Purpose: </strong>To explore the mechanism of Huashi Jiedu Decoction (HJD) synergizing with 5-fluorouracil (5-Fu) in gastric cancer (GC) therapy.</p><p><strong>Methods: </strong>MicroRNAs (miRNAs) and genes involved in HJD-mediated GC treatment were identified using ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry, network pharmacology, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and molecular docking. The effects of HJD on 5-Fu sensitivity in BGC-823 cells were evaluated with 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and Western blotting. Synergistic effects in vector-transfected and miRNA-21-3p knockdown cells were assessed by colony formation, wound healing, transwell assays, and flow cytometry (FCM). An in vivo study evaluated the impact of HJD on 5-Fu sensitivity, measuring miRNA-21-3p, tumor protein p53 (p53), N-cadherin, vimentin, and E-cadherin in tumors, along with tumor volume and weight.</p><p><strong>Results: </strong>miRNA-21-3p and p53 were key targets in HJD's therapeutic effect on GC. RT-qPCR showed that HJD combined with 5-Fu reduced miRNA-21-3p and upregulated p53 in vector cells and increased p53 mRNA (<i>p</i> < 0.01) and protein (<i>p</i> < 0.05) compared to 5-Fu alone. These effects were abolished in miRNA-21-3p knockdown cells. The combination reduced colony formation by 48.92% (<i>p</i> < 0.01), suppressed transwell migration by 28.5% (<i>p</i> < 0.01), and inhibited wound healing by 81.9% compared to 5-Fu monotherapy (<i>p</i> < 0.001), with no effects in knockdown cells. FCM showed a 15.1% increase in G₀/G₁ phase arrest (<i>p</i> < 0.05). In vivo, the combination significantly reduced tumor volume (<i>p</i> < 0.05) and weight by 18.7%, with concomitant miRNA-21-3p downregulation (<i>p</i> < 0.0001), EMT marker suppression (N-cadherin, vimentin), and tumor suppressor activation (p53, E-cadherin) versus 5-Fu alone.</p><p><strong>Conclusion: </strong>HJD enhances 5-Fu's effects on GC by regulating the miRNA-21-3p/p53 pathway and modulating cadherin expression, supporting its potential as an adjunctive treatment in GC.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3883-3906"},"PeriodicalIF":4.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101556","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":"Computational and Experimental Investigation of Antidiabetic Drugs on Tofacitinib Metabolism: Molecular Docking, in vitro, and in vivo Studies.","authors":"Junxi Zhou, Qinglian Zhang, Jingjing Guan, Xiuyun Peng, Zebei Lu, Quan Zhou, Abdullah Al Mamun, Shuanghu Wang","doi":"10.2147/DDDT.S507141","DOIUrl":"10.2147/DDDT.S507141","url":null,"abstract":"<p><strong>Background: </strong>Tofacitinib is an orally administered Janus kinase (JAK) inhibitor that has demonstrated significant efficacy in the treatment of rheumatoid arthritis. This study aimed to investigate the effects of gliquidone and linagliptin, two hypoglycemic agents on the pharmacokinetics of tofacitinib in vitro and in vivo.</p><p><strong>Methods: </strong>The mechanism of drug-drug interaction was studied in vitro using a murine liver microsome incubation system and in vivo by administering gliquidone and linagliptin orally to rats pretreated with various concentrations of tofacitinib. This study used waters ACQUITY UPLC I-Class/Xevo TQD ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometer. Furthermore, molecular docking was performed to simulate the interaction using computer simulations.</p><p><strong>Results: </strong>Gliquidone and linagliptin inhibited the metabolism of tofacitinib by heparanase in vitro with IC₅₀ values of 1.140 μM and 4.064 μM, respectively. Co-administration of gliquidone significantly increased the AUC_(0-t) of tofacitinib by approximately 43.3%, accompanied by a 45.1% increase in C_max and a 27.5% reduction in clearance (CLz/F). In contrast, linagliptin exhibited a more potent inhibitory effect, raising the AUC_(0-t) approximately 4.4-fold, enhancing the C_max by 2.86-fold, and decreasing clearance to 25.8% of the control level. These findings suggest that while both gliquidone and linagliptin significantly enhance the systemic exposure of tofacitinib, linagliptin demonstrates a markedly more significant inhibitory effect on tofacitinib's metabolism and elimination.</p><p><strong>Conclusion: </strong>Gliquidone and linagliptin significantly altered the pharmacokinetics of tofacitinib in vitro and in vivo. This study demonstrated the drug-drug interactions between linagliptin, gliquidone, and tofacitinib, highlighting the need for clinical attention to this possibility.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3845-3856"},"PeriodicalIF":4.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093163","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":"Enhancing Cartilage Repair in Osteoarthritis Using Platelet Lysates and Arthroscopic Microfracture.","authors":"Haiyan Zhang, Dipeng Li, Wei Zheng, Jiaqing Hua, Zuxiang Chen, Wenting Xu, Jianing Zhu, Yue Wang, Xiaotian Chen, Huixin Chen, Le Guo, Qiang Yuan, Li Zhou, Letian Shan","doi":"10.2147/DDDT.S502935","DOIUrl":"10.2147/DDDT.S502935","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) is the most prevalent joint degenerative disease. MF is considered as a first-line treatment for OA. In the long term, the cartilage tissue regenerated after MF is fibrocartilage. In this study, we examine whether combined treatment of MF and Platelet lysate (PL) can inhibit promotion of cartilage repair and antifibrosis.</p><p><strong>Methods: </strong>OA rat model established by the modified Hulth method. Rat PL injected into treated knee joints after MF surgery. The expression levels of metabolic and fibrosis molecules (Col2, Mmp13, Col1, Col3, α-SMA, and Ctgf) of chondrocytes were examined by immunohistochemistry. Cell immunofluorescence was used to assess bone marrow MSCs (BMSCs) proliferation. Transwell assays evaluated BMSCs migration, and qPCR and Western blot analyzed the mechanisms of PL. Moreover, a retrospective analysis was conducted to determine the clinical efficacy and safety of the combined treatment of MF and PL on OA patients.</p><p><strong>Results: </strong>In vivo data showed that the combined treatment of MF and PL significantly alleviated joint pain, protected chondrocytes and inhibited synovial fibrosis on OA rats, as was confirmed by upregulation of Collagen II and downregulation of Mmp13, Col1, Col3, α-SMA, and Ctgf. Such anti-OA and antifibrosis effects of the combined treatment of MF and PL were superior to MF alone. In vitro data showed that PL induced cellular chondrogenic differentiation and migration of BMSCs, suggesting that PL facilitated stem cell homing to the cartilage injury sites and promoted cartilage repair and regeneration. Furthermore, the clinical data showed significant improvements of pain reduction and cartilage repair in OA patients.</p><p><strong>Conclusion: </strong>This study demonstrated the anti-OA and antifibrosis effects of the combination of MF and PL, providing a promising synergistic therapeutic option for the treatment of OA.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3827-3843"},"PeriodicalIF":4.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093164","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":"A Bibliometric Analysis of Microneedle-Mediated Drug Delivery: Trends, Hotspots, and Future Directions.","authors":"Weiyi Xiang, Xian Jiang, Linghong Guo","doi":"10.2147/DDDT.S519048","DOIUrl":"10.2147/DDDT.S519048","url":null,"abstract":"<p><strong>Purpose: </strong>Microneedles can physically penetrate the stratum corneum, creating micropores on the skin, and allowing for drug delivery through direct diffusion, injection, or other methods. As a novel drug delivery method, it possesses significant application potential. This study uses bibliometric analysis to explore the research hotspots and development trends of microneedle-mediated drug delivery.</p><p><strong>Methods: </strong>Relevant research articles on microneedle-mediated drug delivery published between 1998 and 2024 in the Web of Science Core Collection (WoSCC) database were retrieved. Data analysis and visualization were performed using VOSviewer, CiteSpace, Scimago Graphica, and Pajek, enabling the prediction of research trends in microneedle-mediated drug delivery.</p><p><strong>Results: </strong>In general, research on microneedle-mediated drug delivery has shown a continuous increase. China and the United States are the leading countries in this field of study. Notably, Ryan F. Donnelly (n=224) is the most prominent contributor to this field. The current core research directions include: disease treatment, enhancement of transdermal absorption performance of microneedles, vaccine delivery, and new materials and technologies for microneedle manufacturing.</p><p><strong>Conclusion: </strong>Microneedle-mediated drug delivery, as a novel technology and method, holds significant research value and application potential. However, further strengthening of international collaboration and the clinical translation of research findings are needed.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3805-3825"},"PeriodicalIF":4.7,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076572","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":"Ethnobotanical Use, Phytochemistry, Pharmacology, and Toxicity of <i>Canavalia gladiata</i>.","authors":"Huiqin Qian, Di Meng, Lu Yue, Haibo Xu, Kun Feng, Jianan Wang","doi":"10.2147/DDDT.S519102","DOIUrl":"https://doi.org/10.2147/DDDT.S519102","url":null,"abstract":"<p><p><i>Canavalia gladiata</i> (<i>C. gladiata</i>) is a significant traditional Chinese medicine that has been used to treat hiccups, vomiting, nausea, amenorrhea, chronic dysentery, larynx arthralgia, lumbago, and inflammatory diseases in Asia for a long history. Although the chemical composition of <i>C. gladiata</i> has been reported, no thorough review of <i>C. gladiata</i> has been published. Therefore, the present study aimed to comprehensively analyze the ethnobotanical use, phytochemistry, pharmacology, and toxicity of <i>C. gladiata</i>. All the available information on <i>C. gladiata</i> was actualized by systematically searching scientific databases including Web of Science, ScienceDirect, PubMed, Google Scholar, Springer, Wiley, CNKI, CSPD, and Baidu Scholar between 1967 and up-to-date. Based on the reported information, more than 231 components have been identified in <i>C. gladiata</i>, including flavonoids, terpenes, steroids, organic acids, nitrogenous compounds, amino acids, proteins, etc. Crude extracts, fractions, and constituents from <i>C. gladiata</i> show various pharmacological activities, including antioxidant, antitumor, antimicrobial, anti-inflammatory, antiallergic, immunomodulatory, antiobesity, hepatoprotective, antidiabetic, etc. Notably, the immature seeds are poisonous. Besides, modern research reveals that <i>C. gladiata</i> is rich in chemical constituents and pharmacological activities, which are of great research value. However, more in-depth studies including chemical composition, pharmacological mechanism, quality standardisation, toxicology, and clinical research trials are needed for <i>C. gladiata</i> as a new candidate for future drug development.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3779-3803"},"PeriodicalIF":4.7,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12075509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076574","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":"Pharmacokinetics and Safety of HRS-1780 in Renal Impaired Subjects: A Multicenter, Non-Randomized, Open-Label Study.","authors":"Yue Fei, Zhihong Xie, Yuanyuan Luo, Xiaolan Yong, Na Li, Rong Huang, Xiaolin Du, Yijing Zhu, Dongmei Lan, Yang Qi, Gang Cheng, Quanren Wang, Kai Shen","doi":"10.2147/DDDT.S500384","DOIUrl":"10.2147/DDDT.S500384","url":null,"abstract":"<p><strong>Purpose: </strong>HRS-1780 is a selective non-steroidal mineralocorticoid receptor antagonist developed for the treatment of chronic kidney disease. This study aimed to assess the pharmacokinetics (PK) and safety profiles of HRS-1780 in subjects with renal impairment.</p><p><strong>Patients and methods: </strong>Eligible participants were enrolled in the healthy (glomerular filtration rate [GFR] of ≥90 mL/min), mild (GFR of 60-89 mL/min), and moderate renal impairment (GFR of 30-59 mL/min) groups with 9 subjects each and orally received 20 mg HRS-1780. Concentrations of HRS-1780 and its main metabolites were measured in plasma and urine. PK profiles between healthy and renal impairment subjects were compared using analysis of variance.</p><p><strong>Results: </strong>A total of 27 subjects completed the study. HRS-1780 was rapidly absorbed and eliminated, with T_max of 0.50-0.52 hour and t_1/2 of 2.06-2.56 hours. Exposure (AUC_0-inf) to HRS-1780 was comparable between mildly and moderately renal impaired subjects, while higher, but not significantly than that in healthy subjects. Similar plasma protein binding among different renal function groups suggested a consistent effect of renal function on total and unbound HRS-1780. Renal clearance of HRS-1780 decreased with severity of renal impairment, but renal elimination of HRS-1780 was minimal. Exposure to SX2183-M3 was significantly increased in the moderate renal impairment subjects. Renal impairment did not appear to be associated with an increased risk of adverse events.</p><p><strong>Conclusion: </strong>HRS-1780 PK and safety profiles did not differ significantly between healthy and renal impairment subjects. This supports the drug dose regimen for renal impairment patients in clinical practice.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3751-3761"},"PeriodicalIF":4.7,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987957","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":"A Natural Compound Methylnissolin: Physicochemical Properties, Pharmacological Activities, Pharmacokinetics and Resource Development.","authors":"Ziyang Lin, Mingjie Liang, Xianlong Zhang, Zhuo Cen, Fengxin Kang, Baien Liang, Ying Lai, Minyi Li, Tingting Duan, Junzheng Yang, Bo Liu","doi":"10.2147/DDDT.S518508","DOIUrl":"https://doi.org/10.2147/DDDT.S518508","url":null,"abstract":"<p><p>Methylnissolin (also known as Astrapterocarpan) is an isoflavonoid compound featuring a pterocarpan core structure. To date, leguminous plants of the genus <i>Astragalus</i> remain the exclusive natural source of Methylnissolin and its glycoside derivative, Methylnissolin-3-O-glucoside. Upon oral administration, Methylnissolin and its glycosides enter systemic circulation and modulate signaling pathways such as RIPK2/ASK1, PI3K/AKT, IκB/NF-κB, MAPK, and Nrf2/HO-1. Their pharmacological activities span anti-inflammatory, antioxidant, glucose-lipid metabolism regulation, and antitumor effects, underscoring their broad potential for drug development. This review comprehensively evaluates the physicochemical properties, pharmacological activities, mechanisms of action, pharmacokinetic characteristics, and toxicological profile of Methylnissolin and its glycoside derivatives. Notably, we systematically elucidate the metabolic fate of methylnissolin, identifying hydroxylation, demethylation, dimerization, hydration, and dehydrogenation as predominant biotransformation pathways. Furthermore, the influence of factors such as plant variety, geographical origin, and processing methods on Methylnissolin and its glycoside content in <i>Astragalus membranaceus</i> is analyzed, providing crucial insights for drug development and resource utilization.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3763-3777"},"PeriodicalIF":4.7,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12068406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969687","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}