Drug Design, Development and Therapy最新文献

{"title":"GA-LDV: A Promising Derivative of 18β-Glycyrrhetinic Acid with Enhanced in vitro and in vivo Anti-Cancer Properties.","authors":"Jiaying Zheng, Qiqi Feng, Qi Gao, Yaonan Wang, Shurui Zhao, Xiaoyi Zhang, Ming Zhao","doi":"10.2147/DDDT.S492303","DOIUrl":"https://doi.org/10.2147/DDDT.S492303","url":null,"abstract":"<p><strong>Purpose: </strong>The clinical translation of 18β-Glycyrrhetinic acid (GA) is impeded by its relatively low antitumor potency and poor aqueous solubility, we developed a novel derivative of GA by incorporating the Leu-Asp-Val (LDV) tripeptide to enhance its anti-tumor and anti-metastatic activities both in vitro and in vivo, thereby increasing its potential as a therapeutic agent for cancer treatment.</p><p><strong>Methods: </strong>The water solubility of GA-LDV was evaluated. The inhibitory effects of GA-LDV on cell viability were assessed in four different human cancer cell lines. In vitro assays were conducted to measure the compound's impact on tumor cell adhesion, migration, and invasion. In vivo studies were performed using S180 and LLC xenograft models to evaluate the tumor inhibition and anti-metastatic properties.</p><p><strong>Results: </strong>GA-LDV water solubility was increased 4.1 folds compared with GA. In vitro assays suggested that GA-LDV, at a concentration of 25 μM, significantly impeded the adhesion, migration, and invasion of LLC tumor cell lines, with inhibition rates of 52.7%, 55.5% (vs GA 16.9%, P < 0.05) and 35.9% (vs GA 27.5%, P < 0.05). Moreover, GA-LDV demonstrated stronger tumor inhibition ability than GA (P < 0.05), and anti-metastasis activities in a dose-dependent manner, at the concentration of 5 μmol/kg/d, 1 μmol/kg/d, 0.2 μmol/kg/d with lung metastatic nodules 7.5 (P < 0.01 compared with the control group), 9.8 (P < 0.05 compared with the control group) and 14.5. And GA-LDV had almost no systemic toxicity in S180 or LLC xenograft models.</p><p><strong>Conclusion: </strong>The newly synthesized GA-LDV derivative demonstrates superior water solubility and significantly enhanced anti-tumor and anti-metastatic activities. The in vitro and in vivo studies indicate that GA-LDV is a promising candidate for further development as a cancer therapeutic agent, with the benefit of potentially reduced systemic toxicity.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2641-2652"},"PeriodicalIF":4.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11977563/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810725","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":"Mechanism of the Traditional Chinese Medicine Simiao Biejia Decoction Improves the Diabetes Mellitus-Induced Erectile Dysfunction in Rats.","authors":"Yuanyuan Liu, Dalin Sun, Dong Xing, Yiqi Rui, Yihan Jin, Peng Wang, Bin Cai, Chuyu Li, Chao Gao, Yugui Cui, Baofang Jin","doi":"10.2147/DDDT.S495366","DOIUrl":"10.2147/DDDT.S495366","url":null,"abstract":"<p><strong>Objective: </strong>Simiao Biejia (SMBJ) granules, a traditional Chinese herbal remedy, have been used to treat erectile dysfunction caused by diabetes mellitus (DMED). However, the molecular mechanisms underlying SMBJ's therapeutic effects remain unclear. This study aimed to investigate the effects and mechanisms of SMBJ in a rat model of DMED using network pharmacology, proteomics, and molecular docking.</p><p><strong>Methods: </strong>A rat model of DMED was established, and SMBJ granules were administered (0, 7.1, 14.2, and 28.4 mg/kg/d, respectively) for 4 weeks. Erectile function was evaluated by measuring intracavernous pressure and mean arterial pressure. The active compounds in SMBJ were analyzed by gas chromatography and identified using network pharmacology and bioinformatics. Potential targets in the penile tissue was identified via proteomics and validated by Western blotting. Molecular docking was used to assess the binding affinity between bioactive compounds and primary targets.</p><p><strong>Results: </strong>SMBJ significantly improves erectile function and ameliorates DMED in rats by reducing corpus cavernosum fibrosis, decreasing eNOS and nNOS levels, alleviating oxidative stress in penile tissue, and mitigating damage to smooth muscle cells (SMCs) and vascular endothelial cells (VECs). Network pharmacology and proteomics identified 24 potential SMBJ targets in DMED. The 4 drug molecules identified were involved in the therapeutic effects of SMBJ, among which luteolin was predicted to be the core drug component. Luteolin bound directly with AKT1, a key differentially expressed protein in the penile tissue of DMED rats. Further analysis showed that luteolin in SMBJ activates the PI3K/Akt pathway and regulation of nNOS and NF-kB expression in the penile tissue of DMED rats to improve erectile function.</p><p><strong>Conclusion: </strong>SMBJ improved oxidative stress damage, vascular endothelial repair, and angiogenesis in the penile tissue of DMED rats. Luteolin is one of the core drug components of SMBJ in DMED treatment that regulates PI3K/AKT-related pathways.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2609-2628"},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974569/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802599","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":"The Changing Landscape of Heart Failure Drug Clinical Trials in China, 2013-2023.","authors":"Wenjie Zhang, Yinming Zhang, Jiawei Tang, Xuejiao Wang, Chao Meng, Ji Wu, Jun Li","doi":"10.2147/DDDT.S511608","DOIUrl":"10.2147/DDDT.S511608","url":null,"abstract":"<p><strong>Objective: </strong>This review aimed to delineate the changing landscape of heart failure (HF) drug clinical trials conducted in China during 2013<b>-</b>2023.</p><p><strong>Methods: </strong>Detailed information on HF drug trials registered on the National Medical Products Administration Clinical Trial Information Disclosure Platform from January 1, 2013, to December 31, 2023, was collected. The characteristics, drug mechanisms, data safety, participant protection, geographical locations, and scales of HF drug clinical trials were analyzed.</p><p><strong>Results: </strong>China initiated 354 hF drug clinical trials during 2013<b>-</b>2023, encompassing eight acute heart failure (AHF) trials and 346 trials for chronic heart failure (CHF). The overall number of HF trials continued to increase, whereas the number of AHF trials remained consistently low. Significant differences were observed between AHF and CHF trials regarding trial phases, drug types, trial designs, blinding methods, and geographical coverage. 85.8% CHF trials were bioequivalence studies, whereas AHF trials were exclusively Phase I<b>-</b>III studies. Most trial drugs were chemical drugs, with renin-angiotensin-aldosterone system inhibitors accounting for the highest proportion. Sixteen new drug studies involved 13 different new drugs. The proportion of studies establishing independent data monitoring committees annually remained generally low, whereas the proportion of studies purchasing clinical trial insurance for participants annually exhibited an overall upward trend. The 354 trials were led by principal investigators from 27 provinces, autonomous regions, or municipalities in China. 47.2% leading units for these studies were distributed in the eastern coastal regions of China. There were 30 drug clinical trials with more than ten participating centers and 16 drug clinical trials with a target number of participants of over 1000 individuals.</p><p><strong>Conclusion: </strong>Over the past decade, China has experienced rapid development in HF drug trials, particularly in drug consistency evaluations. All stakeholders involved in drug trials should carefully consider the inadequate innovations in first-in-class drugs.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2597-2608"},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802724","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":"Bibliometric and Visualization Analysis of DprE1 Inhibitors to Combat Tuberculosis.","authors":"Qingqing Wang, Huixiao Fu, Yining Zhang, Man Zhang, Jian Xu, Jian Fu","doi":"10.2147/DDDT.S515049","DOIUrl":"10.2147/DDDT.S515049","url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis (TB) poses a serious threat to public health, particularly owing to the increase in multidrug-resistant tuberculosis (MDR-TB) and extremely drug-resistant tuberculosis (XDR-TB); thus, there is an imperative need for novel treatments to tackle this issue. Decaprenylphosphoryl-<i>β</i>-D-ribose 2'-epimerase (DprE1) is essential for mycobacterial cell wall integrity and viability. As no relevant bibliometric study has been reported, we performed bibliometric and visual analyses to depict the knowledge framework of research related to the involvement of DprE1 in TB.</p><p><strong>Methods: </strong>Relevant studies were sourced from the Web of Science Core Collection database. VOSviewer, CiteSpace, and bibliometrics (http://bibliometric.com/) were used to construct networks based on an analysis of journals, countries, funding, institutions, authors, references, and keywords.</p><p><strong>Results: </strong>A total of 184 publications were retrieved; the total citations were 3405 times and the mean citation was 17.28 per article. The annual number of publications on DprE1 in TB has shown a significantly increasing trend. The European Journal of Medicinal Chemistry is the most published journal, with 19 articles. Lu Yu and Bin Wang contributed the most prolific authors with 18 articles. Stratified by the number of publications, India was the most prolific country that cooperated closely with the USA, UK, Japan, and United Arab Emirates. Burstness analysis of references and keywords showed that the developing research trends in this field mainly woven around \"Mtb\", \"DprE1\" and \"inhibitors\" during the past years.</p><p><strong>Conclusion: </strong>A systematic bibliometric study indicates that DprE1 remains a focal point in the anti-TB domain. These results can serve as a data-driven reference for future research and offer precise insights into the development of anti-TB agents associated with DprE1. To the best of our knowledge, this study is the first to comprehensively investigate DprE1 in TB by means of bibliometric analysis.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2577-2596"},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802731","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":"New Drug Approvals in China: An International Comparative Analysis, 2019-2023.","authors":"Yilong Yan, Xiangyu Guo, Ziming Li, Weilin Shi, Min Long, Xiaolin Yue, Fanpu Kong, Zhigang Zhao","doi":"10.2147/DDDT.S514132","DOIUrl":"10.2147/DDDT.S514132","url":null,"abstract":"<p><strong>Purpose: </strong>Over the past five years, China's pharmaceutical industry has rapidly developed but still lags behind global leaders. This study aims to analyze and compare the trends in new drug approvals in China, the United States (US), the European Union (EU), and Japan from 2019 to 2023.</p><p><strong>Methods: </strong>Data on new drug approvals were collected from the National Medical Products Administration (NMPA), Food and Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA), including information on the generic name, trade name, applicants, target, approval date, drug type, approved indications, therapeutic area, the highest R&D status in China, and special approval status. The approval time gaps between China and other regions were calculated.</p><p><strong>Results: </strong>From 2019 to 2023, China led with 256 new drug approvals, followed by the US (243 approvals), the EU (191 approvals), and Japan (187 approvals). Oncology, hematology, and infectiology were identified as the leading therapeutic areas globally and in China. Notably, PD-1 and EGFR inhibitors saw substantial approval, with 8 drugs each approved by the NMPA. China significantly reduced the approval timeline gap with the US and the EU since 2021, approving 15 first-in-class drugs during the study period.</p><p><strong>Conclusion: </strong>Despite COVID-19 challenges, China has improved in both the quantity and speed of new drug approvals, narrowing timeline gaps with major markets and enhancing its global pharmaceutical presence.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2629-2639"},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802719","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":"From Oral to Sublingual: A Redefined Avanafil Tablet with a Breakthrough in Bioavailability and First-Pass Metabolism Avoidance.","authors":"Turky Omar Asar, Omar D Al-Hejaili, Hossam S El-Sawy, Fathy I Abd-Allah, Abdelsattar M Omar, Tarek A Ahmed, Khalid M El-Say","doi":"10.2147/DDDT.S504291","DOIUrl":"10.2147/DDDT.S504291","url":null,"abstract":"<p><strong>Introduction: </strong>Avanafil (AVA) is a very efficient phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction. However, it has limited bioavailability when taken orally and considerable first-pass metabolism. Enhancing its solubility and choosing an alternative delivery route may enhance its effectiveness and duration of action.</p><p><strong>Methods: </strong>Eight complex formulations were elaborated and analyzed at various ratios using different polyethylene glycols and hydroxypropyl-beta-cyclodextrin (HP-β-CD). Sublingual tablets containing AVA were designed and optimized using the Quality-by-design approach. The tablets' pre-compression and post-compression properties were evaluated. The in-vivo pharmacokinetic behavior of the optimized tablet was assessed and compared with that of the commercial oral tablets in human volunteers.</p><p><strong>Results: </strong>The HP-β-CD-AVA inclusion complex (1:1 molar ratio) showed an optimum solubilization capacity with an amount suitable for incorporation into sublingual tablets. The total amounts of superdisintegrants and Plasdone XL and the percentage of starch significantly influenced the length of time it took for 80% of the AVA to be released from the sublingual tablets, the tablet hardness, and the length of time for tablet disintegration. The optimized AVA sublingual tablet exhibited a 5.98-fold increase in the AVA mean residence time over the commercial tablet, with greater plasma exposure over 72 hours and 1356.42% relative bioavailability.</p><p><strong>Conclusion: </strong>The sublingual tablets of the solubility-enhanced HP-β-CD-AVA inclusion complex represent a promising strategy to improve AVA bioavailability and bypass the first-pass effect. Furthermore, their extended activity offers potential clinical benefits, particularly for ED patients, such as ease of administration and reduced side effects.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2551-2576"},"PeriodicalIF":4.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11975010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802733","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":"Ginkgolide B Inhibits EMT and Promotes Pyroptosis in Gastric Cancer via AKT/mTOR Pathway.","authors":"Xinxing Lu, Yan Zhang, Ran Wang, Ziyu Li","doi":"10.2147/DDDT.S485240","DOIUrl":"10.2147/DDDT.S485240","url":null,"abstract":"<p><strong>Introduction: </strong>Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, necessitating the exploration of novel therapeutic agents to improve patient outcomes. This study elucidates the anti-cancer properties of Ginkgolide B (GGB), a diterpenoid lactone derived from Ginkgo biloba, in both in vitro and in vivo models of GC.</p><p><strong>Methods and results: </strong>Using AGS and HGC-27 cell lines, we assessed GGB's impact on cellular proliferation, colony formation, migration, invasion, apoptosis, and pyroptosis. GGB exhibited significant dose- and time-dependent inhibition of cell proliferation and colony formation, with no cytotoxicity observed in normal gastric epithelial cells. Furthermore, GGB markedly suppressed migration and invasion, and induced apoptosis and pyroptosis, as evidenced by increased Bax and GSDMD expression and decreased Bcl-2 levels. In vivo, GGB treatment significantly reduced tumor growth in a nude mouse xenograft model and modulated EMT markers, decreasing PCNA and N-cadherin levels while increasing E-cadherin expression. Mechanistically, GGB's anti-cancer effects were mediated through the deactivation of the PI3K/AKT/mTOR signaling pathway.</p><p><strong>Conclusion: </strong>These findings underscore the potential of GGB as a promising therapeutic agent for GC, warranting further clinical evaluation.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2491-2502"},"PeriodicalIF":4.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794897","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 TRPM3 by Primidone Provides a Potential Therapeutic Method for Adenomyosis Management.","authors":"Zhixing Jin, Yaoming Peng, He Zhang, Xiaoping He, Yi Zhang, Xin Pan, Min Li, Qianqian Yang","doi":"10.2147/DDDT.S494981","DOIUrl":"10.2147/DDDT.S494981","url":null,"abstract":"<p><strong>Purpose: </strong>To test the expression profile of transient receptor potential channels (TRPs) in adenomyosis patients and evaluate the effects of primidone on tamoxifen-induced adenomyosis mice.</p><p><strong>Patients and methods: </strong>This study included in vivo animal model and human tissue samples. Eutopic endometrium from adenomyosis patients (n=20) was collected and subjected to mRNA analysis of TRP channels. TRPA1, TRPV1 and TRPM3 in adenomyosis patients (n=50) and tamoxifen-induced adenomyosis mice (n=6) were examined by immunohistochemistry. From 10 weeks after birth, primidone (2 mg/kg/d) and atosiban (1 mg/kg/d) were given separately to adenomyotic mice by intraperitoneal injection for 3 weeks. The hotplate test was conducted once a week beginning at 10 weeks, and then uterine samples were harvested for HE staining and RNA-seq at 13 weeks.</p><p><strong>Results: </strong>The mRNA expression of 15 TRPs was significantly increased in the proliferative phase of the adenomyotic endometrium. TRPV1, TRPM3 or TRPA1 staining levels were positively correlated with dysmenorrhea severity, menses amount and uterine size. In tamoxifen-induced adenomyosis mice, primidone had a significant effect on both the depth of myometrial infiltration and analgesia. Forty-seven DEGSSs were identifieSd after primidone treatment, and bioinformatics analysis predicted that they were enriched in the cell cycle and cell division.</p><p><strong>Conclusion: </strong>The expression profile of TRP channels varies significantly in adenomyosis patients, and primidone may provide a potential therapeutic method for adenomyosis management.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2533-2549"},"PeriodicalIF":4.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794825","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":"Rho Kinase Inhibitors in Glaucoma Management: Current Perspectives and Future Directions.","authors":"Eleftherios Chatzimichail, Eirini Christodoulaki, Panagiotis A G Konstas, Georgios N Tsiropoulos, Efstratia Amaxilati, Konstantin Gugleta, Zisis Gatzioufas, Georgios D Panos","doi":"10.2147/DDDT.S515166","DOIUrl":"10.2147/DDDT.S515166","url":null,"abstract":"<p><p>Glaucoma is a group of eye conditions characterised by optic nerve damage and visual field loss, representing the leading cause of irreversible blindness worldwide. Glaucoma exerts substantial global impact on visual impairment and blindness. The management of glaucoma has traditionally relied on medications such as prostaglandin analogs, beta-blockers, alpha agonists, and carbonic anhydrase inhibitors, which aim to lower intraocular pressure through various mechanisms. Rho kinase (ROCK) inhibitors have recently emerged as a novel class of antiglaucoma drugs, offering an alternative approach by enhancing aqueous humour outflow through the conventional pathway. Recent clinical studies assessing the efficacy and safety of Ripasudil (K-115) and Netarsudil (AR-13324) have demonstrated promising outcomes in the treatment of various types of glaucoma. Comparative studies have shown that ROCK inhibitors are non-inferior to traditional antiglaucomatous medications, such as beta-blockers and prostaglandins. Additionally, emerging evidence suggests their neuroprotective properties, which may play a role in preserving retinal ganglion cells. Furthermore, positive outcomes have been observed when these agents are used in conjunction with glaucoma filtering surgery, potentially enhancing surgical success rates. Adverse effects, including conjunctival hyperemia, cornea verticillata, conjunctivitis, and blepharitis, have been reported following the use of ROCK inhibitors. However, those side effects appear to be subtle in most cases. This review aims to provide an overview of ROCK inhibitors, focusing on their mechanisms of action, clinical efficacy, safety profiles, and additional benefits for eye health. Furthermore, further potential applications of ROCK inhibitors in glaucoma management are going to be discussed.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2519-2531"},"PeriodicalIF":4.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794930","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":"The Jieduan-Niwan Formula Reduces Inflammatory Responses in Acute-on-Chronic Liver Failure Rats by Inhibiting HMGB1-Induced Hepatocyte Pyroptosis.","authors":"Weixin Hou, Peng Fang, Jiajun Liang, Xiaoyi Wei, Chongyang Ma, Yanbin Gao, Qiuyun Zhang, Jingnan Li","doi":"10.2147/DDDT.S488659","DOIUrl":"10.2147/DDDT.S488659","url":null,"abstract":"<p><strong>Background: </strong>Acute-on-chronic liver failure (ACLF) is a global intractable disease. HMGB1-induced hepatocyte pyroptosis expanding inflammatory responses contributes to the pathogenesis of ACLF. The JDNW formula (JDNWF) has a significant clinical effect on ACLF, but its hepatoprotective mechanisms remain elusive.</p><p><strong>Purpose: </strong>To explore the potential molecular mechanisms of the JDNWF in ACLF by HMGB1-induced hepatocyte pyroptosis.</p><p><strong>Methods: </strong>Rats were divided into normal, ACLF, Caspase-1 inhibitor, HMGB1 inhibitor, JDNW, JDNW+Caspase-1 inhibitor and JDNW+HMGB1 inhibitor groups. The ACLF rat model was established by 40% carbon tetrachloride-induced liver fibrosis, followed by intraperitoneal injection of D-galactosamine and lipopolysaccharide. The liver function, coagulation function, liver pathological damage and ultrastructural changes of hepatocytes were evaluated. Triple-immunostaining of active Caspase-1, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and albumin were performed to evaluate the percentage of pyroptotic hepatocytes. Western blot, immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and quantitative real-time PCR (RT-qPCR) were used to analyze the expressions of key genes and proteins in HMGB1-induced pyroptosis pathways and the level of inflammatory factors.</p><p><strong>Results: </strong>The JDNWF improved liver function, coagulation function and liver pathological damage, reduced the percentage of pyroptotic hepatocytes and inflammatory responses, and down-regulated the expressions of key genes and proteins in the HMGB1-induced pyroptosis pathways in ACLF rats. The effect of the JDNWF was better than those of HMGB1 inhibitor (glycyrrhizin) and Caspase-1 inhibitor (VX-765). Compared with glycyrrhizin or VX-765, there were no significant differences in the above indicators after the JDNWF in combination with glycyrrhizin or VX-765. These results indicated that the JDNWF inhibited hepatocyte pyroptosis and liver inflammation in ACLF rats through the HMGB1-induced pyroptosis pathways.</p><p><strong>Conclusion: </strong>The JDNWF protects the livers of ACLF rats by inhibiting HMGB1-induced hepatocyte pyroptosis reducing inflammatory responses, suggesting that HMGB1-induced hepatocyte pyroptosis may be a potential therapeutic target of ACLF.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2503-2517"},"PeriodicalIF":4.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794932","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}