Drug Design, Development and Therapy最新文献

{"title":"Specnuezhenide Alleviates Senile Osteoporosis by Activating TGR5/FXR Signaling in Bone Marrow Mesenchymal Stem Cells and RANKL-Induced Osteoclasts.","authors":"Xuehui Deng, Bingfeng Lin, Wenlong Xiao, Fang Wang, Pingcui Xu, Nani Wang","doi":"10.2147/DDDT.S493711","DOIUrl":"10.2147/DDDT.S493711","url":null,"abstract":"<p><strong>Background: </strong>Specnuezhenide (SPN) is an iridoid glycoside isolated from <i>Fructus Ligustri Lucidi</i>, an herb prescribed for the treatment of senile osteoporosis. However, the direct role of SPN on bone metabolism remains unclear. In this study, the effects of SPN on d-galactose (d-gal)-induced mice, bone marrow mesenchymal stem cells (BMSCs), and nuclear factor-κB ligand-induced osteoclasts were examined.</p><p><strong>Methods: </strong>Micro-computed tomography was used to observe the bone microstructure. Osteogenesis was examined using Western blotting and alkaline phosphatase staining. Osteoclastogenesis was examined using Western blotting and F-actin ring staining. Senescence-associated β-galactosidase was used to detect cell senescence. In addition, the expression of Takeda G protein-coupled receptor 5 (TGR5)/farnesoid X receptor (FXR) signaling pathway-related genes and proteins was determined through quantitative real-time polymerase chain reaction and immunofluorescence.</p><p><strong>Results: </strong>Oral administration of SPN improved the bone microstructure in d-gal-induced mice and increased bone mineral density, bone volume, trabecular thickness, and trabecular number. SPN also upregulated the expression of the osteogenesis markers osteocalcin, bone morphogenetic protein 2, and runt-related transcription factor 2 and downregulated the expression of the osteoclasis markers tartrate-resistant acid phosphatase, nuclear factor-κB, and nuclear factor of activated T-cells in the d-gal-induced bone. Furthermore, SPN increased alkaline phosphatase staining, inhibited F-actin ring formation, and reduced the activity of senescence-associated β-galactosidase in vitro. Mechanistically, SPN activated the TGR5/FXR pathway in d-gal-induced BMSCs and osteoclasts. The protective effects of SPN were abolished after addition of the TGR5 inhibitor SBI-115 or FXR inhibitor DY268. Moreover, SPN could elevate the protein and mRNA levels of TGR5, FXR, and the downstream small heterodimer partner in d-gal-induced bone.</p><p><strong>Conclusion: </strong>SPN alleviated senile osteoporosis and cell senescence by activating the TGR5/FXR pathway.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1595-1608"},"PeriodicalIF":4.7,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11892377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596521","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":"Dose-Response Study of Remimazolam Combined With Remifentanil for Attenuating Stress Response During Laryngeal Mask Airway Insertion in Elderly Female Patients: A Prospective Double-Blinded Study.","authors":"Qiang Xu, Jing Qian, Su-Qin Zhang, Feng Xia, Hui-Jing Hu, Fei Xiao","doi":"10.2147/DDDT.S494426","DOIUrl":"10.2147/DDDT.S494426","url":null,"abstract":"<p><strong>Background: </strong>Optimum dose of remimazolam for inducing loss of consciousness in elderly patients has been suggested by prior studies. Opioids can enhance their sedative effects, thereby permitting dose reduction. However, the dose-response of remimazolam when combined remifentanil for attenuating stress response during laryngeal mask airway (LMA) insertion in elderly female patients is still unknown. Moreover, the ideal dose of medications is especially critical in elderly patients due to their compromised cardiopulmonary function. The objective of this study was to determine the median effective dose (ED50) and ED95 of remimazolam in inhibiting the stress response associated with LMA insertion.</p><p><strong>Methods: </strong>Sixty aged ≥ 65 and < 80 years old female patients were randomized allocated into 1 of 4 groups receiving doses of 0.2, 0.25, 0.3, and 0.35 mg/kg remimazolam. Following a dosage of 2.0 ng/mL of remifentanil, patients received different doses of remimazolam. Effective dose is defined as the prevention of stress response associated with LMA insertion, characterized by a post-sedation induction SBP variation < 20% of baseline value, jaw relaxation and absence of patient body motion during the initial 2 minutes following LMA insertion. Probit regression analysis was utilized to estimate the ED50 and ED90 values.</p><p><strong>Results: </strong>The ED50 and ED95 of effective remimazolam of general induction for elderly female patients not suffer intubation stress response were 0.24 mg/kg (95% CI 0.20-0.27 mg/kg) and 0.37 mg/kg (95% CI 0.32-0.49 mg/kg), respectively. The incidence of hypotension was 33.3% (5/15), 46.7% (7/15), 73.3% (11/15), and 80% (12/15) in the four groups, respectively.</p><p><strong>Conclusion: </strong>The ED50 and ED95 values of intravenous remimazolam for preventing stress response during LMA insertion were 0.24 and 0.37 mg/kg, respectively in elderly female.</p><p><strong>Trial number and registry url: </strong>Registration number, ChiCTR2400083990, https://www.chictr.org.cn/showproj.html?proj=229006.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1575-1583"},"PeriodicalIF":4.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11891449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596465","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":"FoxO1 as a Hub in Immunosenescence Induced by Hepatocellular Carcinoma and the Effect of Yangyin Fuzheng Jiedu Prescription.","authors":"Yuqing Xie, Fengna Yan, Xiaoli Liu, Lihua Yu, Huiwen Yan, Zimeng Shang, Yaxian Kong, Zhiyun Yang","doi":"10.2147/DDDT.S492576","DOIUrl":"10.2147/DDDT.S492576","url":null,"abstract":"<p><strong>Purpose: </strong>Yangyin Fuzheng Jiedu Prescription (YFJP) is a traditional Chinese medicine (TCM) used for the treatment of hepatocellular carcinoma (HCC). However, the potential mechanisms remain unclear. The objective of this study is to clarify the mechanism of action of YFJP in treating HCC.</p><p><strong>Methods: </strong>By constructing networks, the active components and molecular targets of YFJP in the treatment of HCC were explored. The TCGA database was utilized to analyze the correlation between the core target and the overall survival (OS) of patients with HCC. The regulatory effect of YFJP on T cell was evaluated by detecting samples from patients with HCC. The molecular mechanism of YFJP in treating HCC was validated through in vivo and in vitro experiments.</p><p><strong>Results: </strong>Constructing networks and analyse indicated that the key targets of YFJP in the treatment of HCC is FoxO1. Analysis of the HCC patient cohort in the TCGA database demonstrated that FoxO1 is an independent protective factor for overall survival in patients with HCC. Pathway enrichment analysis enriched FoxO signaling pathway and Cellular senescence pathway. Prospectively collecting samples from patients with HCC suggested that YFJP treatment increased the proportion of CD8⁺ T cells. In vivo experiments showed that YFJP treatment ameliorated CD8⁺ T cell senescence in tumor-bearing mice. Western blot, flow cytometry and multi-color immunofluorescence co-staining showed that YFJP treatment increased the expression of FoxO1 in CD8⁺ T cells. The primary CD8⁺ T cells were sorted and co-cultured with an HCC cell line in vitro. Inhibiting the expression of FoxO1 in CD8⁺T cells confirmed that FoxO1 is a key target for YFJP to improve the senescence of CD8⁺ T cell.</p><p><strong>Conclusion: </strong>FoxO1 is the key molecular target of YFJP in improving CD8⁺ T cell senescence in HCC. This study preliminarily clarified the mechanism of YFJP in regulating immunosenescence of HCC.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1543-1560"},"PeriodicalIF":4.7,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11890352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585025","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":"Association of NR1I2 Polymorphism with Midazolam Clearance in Mechanically Ventilated ICU Patients: A Population Pharmacokinetic and Pharmacogenetic Study.","authors":"Helin Xie, You Zheng, Hui Zhang, Yanmei Guo, Maobai Liu, Qinyong Weng, Xuemei Wu","doi":"10.2147/DDDT.S495647","DOIUrl":"10.2147/DDDT.S495647","url":null,"abstract":"<p><strong>Background: </strong>Significant variability in the metabolism of midazolam (MDZ) exists among mechanically ventilated (MV) patients in the intensive care unit (ICU) due to complex clinical conditions and genetic factors. The NR1I2 gene (PXR), which encodes a nuclear receptor that regulates drug-metabolizing enzymes like CYP3A4, plays a critical role in MDZ metabolism. Polymorphisms in NR1I2, along with variations in genes such as CYP3A4, CYP3A5, and ABCB1, may influence enzyme activity and MDZ pharmacokinetics (PK). Understanding these factors is essential for optimizing MDZ dosing in high-risk patient populations.</p><p><strong>Methods: </strong>We studied 61 MV ICU patients receiving continuous MDZ infusion. A population pharmacokinetic (PopPK) model was used to assess MDZ PK, with genetic factors (NR1I2 rs2461817, CYP3A4, CYP3A5, ABCB1, and other PXR polymorphisms) and clinical covariates (body weight (BW), aspartate aminotransferase (AST) levels) evaluated for their impact on MDZ clearance (CL).</p><p><strong>Results: </strong>The PK of MDZ and its metabolite, 1-hydroxymidazolam (1-OH-MDZ), were accurately described using a one-compartment model. The estimated population means for MDZ and 1-OH-MDZ CL were 22.6 L/h (inter-individual variability [IIV] 59.4%) and 67.1 L/h (IIV 57.7%), respectively. MDZ CL was significantly associated with the NR1I2 rs2461817 polymorphism and AST levels, accounting for 11.3% of the variability. MDZ CL decreased by 32.7% as AST increased from 22 IU/L to 60 IU/L, and by 40.7% in patients homozygous for the NR1I2 rs2461817 variant. BW also influenced the CL of 1-OH-MDZ, demonstrating a 34.2% increase as weight increased from 54 kg to 65 kg. Simulations confirmed the significant impact of NR1I2 rs2461817 on MDZ CL.</p><p><strong>Conclusion: </strong>The PopPK model highlights the significant impact of NR1I2 rs2461817 polymorphism on MDZ CL in Chinese MV patients, emphasizing the need to consider genetic and clinical factors for optimizing MDZ dosing in ICU settings.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1527-1541"},"PeriodicalIF":4.7,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11891766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596445","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":"Crop Wild Relatives (CWRs) in the United Arab Emirates: Resources for Climate Resilience and Their Potential Medicinal Applications.","authors":"Ramya Manoharan, Chythra Somanathan Nair, Drishya Nishanth, Radhakrishnan Subramanian, Xiulan Xie, Maozhi Ren, Abdul Jaleel","doi":"10.2147/DDDT.S497800","DOIUrl":"10.2147/DDDT.S497800","url":null,"abstract":"<p><p>Global climate change threatens the production, growth, and sustainability of plants. Crop wild relatives (CWRs) offer a practical and sustainable solution to these climatic issues by boosting genetic diversity and crop resilience. Even though CWRs are wild relatives of domesticated plants, they are nevertheless mostly neglected. This review focuses on the possible application of CWRs, which are found in the United Arab Emirates (UAE) and are known for their abiotic stress tolerance and potential medicinal properties. In olden days, traditionally, CWRs has been used as medicine for various ailments as they are rich in phytochemical compounds. However, the medicinal potential of these wild plant species is decreasing at an alarming rate due to climate change stress factors. The medicinal potential of these native crop wild plant species must be investigated because they could be a useful asset in the healthcare sector. Research on pangenomics studies of certain CWRs is also highlighted in the review, which reveals genetic variability caused due to climate change stress factors and how these genetic variability changes affect the production of secondary metabolites that have potent medicinal value. This provides insights into developing personalized medicine, in which particular CWRs plant species can be chosen or modified to generate medicinal compounds. Despite their superior medicinal properties, many CWRs in the UAE are still not well understood. Finding the desired genes coding for the biosynthesis of specific phytochemicals or secondary metabolites may help us better understand how these substances are synthesized and how to increase their production for a range of treatments.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1515-1525"},"PeriodicalIF":4.7,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11887499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143585023","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":"Mogrol Regulates the Expression of ATPase Na+/K+ Transport Subunit 3, Inhibits Cardiomyocyte Apoptosis, and Plays a Protective Role Against Myocardial Infarction.","authors":"Feng Wang, Jinling Zhou, Weiwei Liu, Wei Wang, Boyan Tian, Jinyu Liu, Han Zhang, Peina He, Xiaoyun Yang, Li Yang, Yueheng Wang","doi":"10.2147/DDDT.S490484","DOIUrl":"10.2147/DDDT.S490484","url":null,"abstract":"<p><strong>Background: </strong>With the advancements in medical technology, the death rate from myocardial infarction (MI), a prevalent heart illness, has gradually decreased; however, treatment hurdles and diagnostic issues remain. Mogrol is a naturally occurring plant extract with specific biological activities such as antioxidant, anti-inflammatory, antitumor, and hypoglycemic effects. These biological activities make it a potential therapeutic drug or research subject; however, its function in MI remains unclear.</p><p><strong>Methods: </strong>Potential targets of mogrol were searched using the MI Disease Database through online databases. Among the three intersecting genes, we focused on ATPase Na+/K+ transporting subunit 3A3, which is expressed at low levels in patients with MI. The preventive effect of mogrol against MI was investigated using cardiac ultrasonography, Western blotting, qPCR assay, Cell counting kit-8, Ca2+ concentration measurement, Na+/K+-ATPase, and flow cytometry.</p><p><strong>Results: </strong>The findings demonstrated that mogrol upregulated Ca2+ concentration and ATPase Na+/K+ transporting subunit 3 protein levels in cardiomyocytes and tissues, downregulated the apoptosis-related proteins B-cell lymphoma 2-like protein 4, cleaved-caspase-3, and upregulated B-cell lymphoma 2. These effects enhanced cardiac function, prevented cardiomyocyte apoptosis, encouraged cardiomyocyte proliferation, and protected mice from MI. Knocking down ATP1A3 can reverse the protective effect of Mogrol.</p><p><strong>Conclusion: </strong>Mogrol may have a protective effect on myocardial infarction by regulating Ca2+ concentration and the level of the ATPase Na+/K+ transport subunit 3 protein, as well as by regulating apoptosis-related proteins. Further revealing the pharmacokinetics of mogrol in vivo is expected to make it a subsequent drug for the treatment of cardiac infarction.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1489-1502"},"PeriodicalIF":4.7,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11884411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572493","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, Pharmacodynamics, Safety, and Tolerability of Milvexian in Healthy Chinese Adults.","authors":"Zhu Luo, Jie Wang, Zhuolu Niu, Cuili Hu, Madhu Chintala, Xinchao Luo, Tsung-I Lee, Alexei N Plotnikov, Peter Zannikos","doi":"10.2147/DDDT.S488414","DOIUrl":"10.2147/DDDT.S488414","url":null,"abstract":"<p><strong>Background: </strong>Milvexian is a small molecule, selective factor XIa (FXIa) inhibitor being developed as an oral anticoagulant. This study assessed the pharmacokinetics, pharmacodynamics (activated partial thromboplastin time [aPTT]), and safety of milvexian in healthy Chinese subjects.</p><p><strong>Methods: </strong>Part 1: Thirty subjects were randomly assigned 1:1:1 to receive milvexian 25 mg on Day 1 followed by 25 mg once daily (QD) on Days 5-12; milvexian 25 mg twice daily at 12-hour intervals (BID) on Days 1-8; or milvexian 100 mg BID on Days 1-8. Part 2: Ten subjects received milvexian 200 mg on Day 1 followed by 200 mg BID on Days 5-12. Plasma samples were collected for pharmacokinetics and aPTT assessments. Safety and tolerability were assessed.</p><p><strong>Results: </strong>Milvexian was rapidly absorbed (median t_max of 3-4 hours after a single dose and repeated administration). Mean maximum concentrations or area under the concentration-time curve values of milvexian in plasma after single doses or BID administration of 25 mg, 100 mg, or 200 mg increased in a dose-dependent manner. Steady state conditions were achieved within 6 days of repeated administration based on milvexian trough concentration values. Mean terminal half-life values (9-10 hours) were independent of the dose. Milvexian reversibly prolonged aPTT in a manner that was directly related to milvexian dose and exposure. All milvexian regimens were safe and well tolerated, with only mild treatment-emergent adverse events and no clinically significant bleeding events. No new safety signals were identified.</p><p><strong>Conclusion: </strong>The pharmacokinetic, pharmacodynamic, and safety profiles of milvexian demonstrate suitability for further clinical development in Chinese participants.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1503-1514"},"PeriodicalIF":4.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566387","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":"Tempol Mitigates Methotrexate-Induced Osteotoxicity via Oxidative Stress Modulation and MAPK Pathway Inhibition.","authors":"Fariz Selimli, Meryem Taş Reyhanioğlu, Ahmet Can Haskan, Muhammed Said Altun, Soner Mete, Halil Mahir Kaplan","doi":"10.2147/DDDT.S510206","DOIUrl":"10.2147/DDDT.S510206","url":null,"abstract":"<p><strong>Purpose: </strong>Osteotoxicity, a common consequence of Methotrexate (MTX) therapy, significantly compromises bone health by inducing oxidative stress and disrupting bone remodeling. This study examines the protective effects of Tempol, a nitroxide compound with antioxidant properties, against MTX-induced osteotoxicity.</p><p><strong>Methods: </strong>Osteocyte-like MLO-Y4 cells were cultured and treated with Tempol and MTX to evaluate changes in apoptotic mediators, MAPK signaling pathways, and oxidative stress parameters.</p><p><strong>Results: </strong>MTX treatment significantly increased caspase-3 activity and Bax expression while decreasing Bcl-2 levels, thereby creating a pro-apoptotic environment. It also activated stress-related pathways by elevating JNK and ERK activities. Conversely, Tempol effectively countered these effects by restoring the balance of apoptotic mediators, downregulating MAPK activation, and enhancing Total Antioxidant Status (TAS). Additionally, Tempol reduced Total Oxidant Status (TOS) and improved the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx).</p><p><strong>Conclusion: </strong>These findings highlight Tempol's potential to mitigate oxidative stress and apoptosis linked to MTX therapy, supporting its use as an adjunctive treatment to protect bone health in patients undergoing MTX therapy. Emphasizing Tempol's clinical implications as a protective agent reinforces the urgency for further research into its long-term effects on cellular viability and bone integrity in the context of chemotherapy.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1441-1449"},"PeriodicalIF":4.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11881157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566391","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":"Efficacy and Safety of Colquhounia Root Tablet for Chronic Glomerulopathy: A Real-World Survey With Bioinformatics Insights.","authors":"Huixia Liu, Hao Yan, Yujuan Li, Ye Yao, Chun Zhang, Jing Xiong","doi":"10.2147/DDDT.S488557","DOIUrl":"10.2147/DDDT.S488557","url":null,"abstract":"<p><strong>Background: </strong>Colquhounia root tablet (CRT) has been in treatment of autoimmune and inflammatory diseases for decades, but large-scale clinical observations are lacking. The novelty of this study lies in providing the first large-scale real-world clinical data to evaluate the effectiveness and safety of CRT on chronic glomerulopathy and to explore potential molecular mechanisms.</p><p><strong>Methods: </strong>This is a single-arm retrospective study in the real-world. Data analysis included descriptive statistics, <i>t</i>-tests, non-parametric tests, and analysis of variance, with <i>P</i> < 0.05 considered as the standard for statistical significance. Predicting molecular targets and pathways of CRT through network pharmacology and validating through molecular docking.</p><p><strong>Results: </strong>(1) Among 317 patients, 74.8% experienced a significant decrease in proteinuria (<i>P</i> < 0.001), particularly in IgA nephropathy (IgAN), type 2 diabetes mellitus-related chronic kidney disease (T2DM related-CKD) and membranous nephropathy (MN). (2) CRT works quickly in reducing proteinuria. 76.7% patients had obvious effect at first visit (<i>P</i> < 0.001). (3) CRT had no obvious effect on creatinine and albumin. (4) Subgroup analysis showed regardless of level of proteinuria and eGFR, CRT had significant efficacy. (5) CRT has good security and low incidence of adverse reactions. (6) Bioinformatics analysis suggested that CRT acts on chronic glomerulopathy by infections, metabolism, Th17 cell differentiation and C-type lectin signaling pathways. The core targets are IL-6, TNF, AKT1, IL-1β and ALB.</p><p><strong>Conclusion: </strong>CRT treatment for chronic glomerulopathy is safe and effective, which can significantly reduce proteinuria. Network pharmacology results suggest the mechanism of CRT in chronic glomerulopathy may involve Th17 cell differentiation and CLR signaling pathway.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1421-1440"},"PeriodicalIF":4.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556124","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":"LncRNA MALAT1/Calpain-1 Axis in ATO Induced hERG Channel Deficiency.","authors":"Caichuan Yan, Yuexin Li, Xiaoxu Li, Yang Li, Yuhao Zhang, Jinyang Sun, Qirui Ding, Xin Zhao, Baoxin Li","doi":"10.2147/DDDT.S502776","DOIUrl":"10.2147/DDDT.S502776","url":null,"abstract":"<p><strong>Background: </strong>KCNH2 encodes the hERG potassium channel, which is associated with drug-induced long QT syndrome. Arsenic trioxide (ATO) is an effective therapeutic agent for acute promyelocytic leukemia; however, its long-term use can lead to cardiotoxicity, particularly in cases of acquired long QT syndrome (acLQTS), which may result in torsade de pointes (TdP). Therefore, it is essential to comprehend the mechanisms behind acLQTS and to develop effective preventive and therapeutic strategies.</p><p><strong>Aim: </strong>This study sought to investigate the role and molecular mechanism of MALAT1 in ATO-induced acLQTS. Furthermore, it sought to identify pharmacological agents that could mitigate the cardiotoxic effects of ATO and establish viable intervention targets for the prevention and management of acLQTS.</p><p><strong>Methods: </strong>First, we employed gene chip arrays to identify target long noncoding RNAs (lncRNAs). Subsequently, we performed quantitative qRT-PCR and RNA-binding protein immunoprecipitation (RIP) to assess lncRNA levels. Next, we utilized Western blotting for protein expression analysis, and finally, we conducted whole-cell patch-clamp recordings to evaluate hERG currents.</p><p><strong>Results: </strong>Our results revealed a significant upregulation of lncRNA MALAT1 expression in HEK293-hERG cells treated with ATO. Mechanistically, MALAT1 interacts with calpain-1, inhibiting its ubiquitin-mediated degradation and enhancing the cleavage activity of calpain-1 on the hERG channel. FEX and TAN were found to mitigate the effects of ATO on the MALAT1/calpain-1 pathway, ultimately restoring hERG protein levels.</p><p><strong>Conclusion: </strong>This study demonstrated that ATO-induced enhancement of calpain-1 and reduction of hERG may be linked to the aberrant overexpression of lncRNA MALAT1. Tanshinone IIA and fexofenadine restored the hERG protein levels potentially by decreasing MALAT1 expression and counteracting ATO's effects on the MALAT1/calpain-1 pathway. Collectively, our research uncovers a previously unreported regulatory mechanism underlying ATO-induced acLQTS. Moreover, it identifies potential molecular targets and intervention strategies for acLQTS therapy.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1475-1487"},"PeriodicalIF":4.7,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556126","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}