Drug Design, Development and Therapy最新文献

{"title":"Safety and Pharmacokinetics of SRN001, a Novel siRNA Drug Targeting Amphiregulin via the SAMiRNA Platform.","authors":"Jiyeon Park, SeungHwan Lee, Jae-Yong Chung, Sungil Yun, Han Oh Park, June Y Park, InJin Jang","doi":"10.2147/DDDT.S589997","DOIUrl":"https://doi.org/10.2147/DDDT.S589997","url":null,"abstract":"<p><strong>Introduction: </strong>SRN001 is a small interfering RNA (siRNA) drug targeting amphiregulin. It was developed using a novel SAMiRNA^® platform, in which the siRNAs are protected within a self-assembled micelle. This platform eliminates the need for additional excipients to reduce unintended immune reactions. Amphiregulin plays a critical role in tissue repair and immune modulation. By silencing it, SRN001 is expected to be a therapeutic option for various pathologically fibrotic and cancerous diseases. This study aimed to evaluate safety and pharmacokinetics (PK) of SRN001 in humans for the first time.</p><p><strong>Methods: </strong>A randomized, double-blind, placebo-controlled, single ascending dose, Phase 1 trial was conducted (NCT05984992). Participants randomly received a single intravenous dose of SRN001 (15, 45, 135, or 210 mg) or placebo. Safety was assessed with vital signs, clinical laboratory tests, electrocardiograms, and inflammatory cytokine assays (IL-1β, IL-6, IFN-γ, and TNF-α). Serial blood samples were collected until 168 hours post-dose to quantify plasma antisense siRNA concentrations. Anti-drug antibodies (ADAs) were measured at pre-dose, 15 days, and 29 days post-dose.</p><p><strong>Results: </strong>Among 25 participants, SRN001 was generally well tolerated. Unlike other approved siRNA drugs, no systemic symptoms or cytokine elevation suggestive of infusion-related reactions (IRRs) were observed in any subjects receiving SRN001, even without premedication. SRN001 exhibited dose-proportional exposure, with the average AUC_inf of 1.35 ug·hour/mL in the 15 mg dose group, achieving the therapeutic exposure in preclinical studies. The average plasma half-life was 0.48 hours. No ADAs were detected.</p><p><strong>Conclusion: </strong>A single IV administration of SRN001 demonstrated a favorable safety profile and dose-proportional PK in this small first-in-human phase 1 clinical trial. By minimizing the need for excipients, the SAMiRNA platform is anticipated to facilitate the development of safer siRNA drugs in the future. Therapeutic potential of SRN001 will be explored in subsequent clinical trials.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"589997"},"PeriodicalIF":5.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13112037/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765402","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":"Bioengineering Applications of Chinese Herbal Medicine-Derived Exosomes in Cardiovascular Diseases: Mechanisms and Translational Prospects.","authors":"Yixin Liu, Yiru Wang, Ming Fang","doi":"10.2147/DDDT.S590015","DOIUrl":"https://doi.org/10.2147/DDDT.S590015","url":null,"abstract":"<p><p>Cardiovascular disease remains the leading cause of death worldwide, with current therapies facing limitations in efficacy and safety. Chinese Herbal Medicine-Derived Exosomes (CHM-Exos) are nano-sized membrane vesicles secreted by herbal cells, capable of cross-species delivery of bioactive substances. While plant-derived extracellular vesicles have been extensively reviewed, analyses specifically focused on CHM-Exos in cardiovascular contexts remain limited. This review systematically examines the bioengineering applications and therapeutic mechanisms of CHM-Exos in cardiovascular diseases, addressing a critical gap in translational literature. Mechanistically, CHM-Exos show potential to alleviate oxidative stress and modulate vascular cell function, though direct cardiovascular evidence remains preliminary. Key translational barriers-including standardization challenges, scalability constraints, and regulatory uncertainties-are critically discussed, alongside strategies to advance these promising nanocarriers toward clinical application.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"590015"},"PeriodicalIF":5.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110736/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765625","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":"Mechanisms and Drug-Augmenting Strategies of Mesenchymal Stem Cells for Preserving β-Cell in Type 2 Diabetes.","authors":"Kunlu Wang, Jiuwei Li, Cong Han, Jie Li","doi":"10.2147/DDDT.S586404","DOIUrl":"https://doi.org/10.2147/DDDT.S586404","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) is closely linked to β-cell dysfunction. Preserving β-cell function has emerged as a critical therapeutic strategy for T2D. Mesenchymal stem cells (MSCs) have demonstrated remarkable potential in achieving this goal. This paper systematically reviews the multifaceted mechanisms by which MSCs protect pancreatic β-cell function in T2D. It integrates eight core mechanisms: modulating the inflammatory microenvironment, regulating the immune system, counteracting oxidative stress, enhancing autophagy levels, alleviating endoplasmic reticulum stress, safeguarding mitochondrial function, promoting β-cell regeneration and repair, and inhibiting ferroptosis. Together, these form a multi-layered, networked intervention system. This framework elucidates MSC protective effects across three functional levels: eliminating injury initiators, maintaining cellular homeostasis, and intervening in cellular fate outcomes. Additionally, this review examines pharmacological strategies to enhance MSC efficacy, including hypoglycemic agents, other drugs, and natural products, with a focus on their mechanisms of action and barriers to clinical translation. Finally, based on MSC advantages and existing research limitations, we propose future research directions, including optimizing MSC source selection and engineering MSC-derived exosomes. These recommendations aim to provide theoretical foundations and strategic references for MSC-based T2D therapies.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"586404"},"PeriodicalIF":5.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765422","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":"Fermentation-Induced Changes in Phytochemical Composition and Pharmacological Activities of <i>Zingiberaceae</i> Plants: Insight from in vitro and in vivo Studies.","authors":"Suci Fitriani Sammulia, Suhaera Suhaera, Deshanda Kurniawan Prayoga, Pitriani Pitriani, Zelika Mega Ramadhania, Adryan Fristiohady, Tiana Milanda","doi":"10.2147/DDDT.S604038","DOIUrl":"https://doi.org/10.2147/DDDT.S604038","url":null,"abstract":"<p><p>The <i>Zingiberaceae</i> family has long been used in traditional medicine due to its rich array of secondary metabolites. However, its low bioavailability, limited stability in its native form, degradation during digestion, and poor solubility in water all restrict its absorption in the human body. Fermentation represents an effective biotechnological method for modifying the phytochemical composition and potentially enhancing its pharmacological effects. This study aims to explore the impact of fermentation on <i>Zingiberaceae</i>, focusing on the alteration of phytochemical profiles and the enhancement of pharmacological activities. Articles were sourced from the Scopus and PubMed databases and filtered for publications between 2015 and 2025; there were 2 articles that were electronically removed before screening due to duplication, yielding 62 articles. These articles were then further screened based on titles, abstracts, and full texts, resulting in five relevant studies. Fermentation was found to improve the phytochemical profile, influenced by the microbial strains used and the physicochemical properties of the phytochemicals. The fermentation process enhanced the stability of compounds, such as converting 6-gingerol to 6-shogaol and transforming glycosides into aglycones, which are more easily absorbed by the body. Additionally, fermentation increased phenolic and flavonoid content, accompanied by enhanced antioxidant and anti-inflammatory activities. Pharmacologically, in vitro studies showed that fermented extracts modulate cytokine signaling pathways in immune cells while enhancing anti-aging properties and skin barrier protection. Meanwhile, in vivo studies demonstrated improvements in metabolic regulation and neuroprotective effects in cognitive disorders. Further mechanistic investigations are needed to clarify the pathways through which fermentation influences the behavior of phytoconstituents and their pharmacological performance. This review provides an overview of preclinical fermentation studies on <i>Zingiberaceae</i> plants, both in vitro and in vivo, with a focus on their phytochemical composition and effectiveness in enhancing pharmacological activity.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"604038"},"PeriodicalIF":5.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765115","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":"Population Pharmacokinetics of Tiapride in Children and Adolescents with Tic Disorders: Leveraging Plasma and Saliva Concentration to Guide Individualized Dosing.","authors":"Wei Huang, Jianfeng Shen, Xin Luo, Yangrui Wu, You Zheng, Jianxing Zhou, Baohua Xu, Xiaorong Yin, Xuemei Wu","doi":"10.2147/DDDT.S587387","DOIUrl":"https://doi.org/10.2147/DDDT.S587387","url":null,"abstract":"<p><strong>Introduction: </strong>This study aimed to develop population pharmacokinetic (PopPK) models of tiapride based on plasma and saliva concentration in pediatric patients with tic disorders (TD) and evaluate the feasibility of non-invasive therapeutic drug monitoring (TDM) for precision dosing.</p><p><strong>Methods: </strong>A prospective study was conducted in 38 TD patients aged 5-15 years. PopPK models of tiapride were sequentially developed using nonlinear mixed-effects modeling. Monte Carlo simulation was employed to optimize dosing regimens, and Bayesian maximum a posteriori (MAP) was applied to facilitate model-informed precision dosing (MIPD). The predictive performance of the established model was internally evaluated using saliva concentration.</p><p><strong>Results: </strong>The PopPK model of tiapride using plasma concentration was best described by a one-compartment structure model. The typical estimates of the absorption rate constant (Ka), plasma clearance (CL/F), and volume of distribution (V/F) were 0.219 h^-1, 15.3 L/h, and 5.77 L, respectively. A plasma-saliva joint model was subsequently established, incorporating Michaelis-Menten nonlinear transport kinetics to characterize the drug distribution from plasma to saliva, with an estimated Michaelis-Menten constant (KM) of 762 ng/mL and a maximum transport rate (Vmax) of 34.7 mg/h. Saliva elimination was modeled as a first-order process. Fat-free mass (FFM) was identified as a significant covariate on both CL/F and saliva clearance (K30), scaled by power exponents of 0.553 and 0.38, respectively, relative to a reference FFM of 30.62 kg. Simulations based on the final model suggested that a dosing regimen of 75 mg administered three times daily (tid) is optimal for achieving target therapeutic concentration. MAP estimation confirmed that saliva concentration can reliably predict the systemic exposure of tiapride.</p><p><strong>Conclusion: </strong>The PopPK models of tiapride enable MIPD in children and adolescents with TD and support saliva as a non-invasive matrix for TDM. Further prospective validation in independent pediatric cohorts is warranted before routine clinical implementation.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"587387"},"PeriodicalIF":5.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13111164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765420","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 Drug-Drug Interaction of Ainuovirine with Fluconazole in Healthy Adults and Dose Optimization Informed by Pharmacokinetics Modelling.","authors":"Jianfei Huang, Yan Lei, Weiping Cai, Yu Meng, Lei Xiao, Yi Zhao, Weitong Lin, Yaozu He, Kaipeng Huang, Linghua Li","doi":"10.2147/DDDT.S597672","DOIUrl":"https://doi.org/10.2147/DDDT.S597672","url":null,"abstract":"<p><strong>Purpose: </strong>The study aimed to assess the drug-drug interaction (DDI) and safety of ainuovirine (a new-generation non-nucleoside reverse transcriptase inhibitor, primarily metabolized by CYP2C19) coadministered with fluconazole, a strong CYP2C19 inhibitor, in healthy adults.</p><p><strong>Methods: </strong>This was a multiple-dose, open-label, two-period, parallel, sequential study. In group A, 18 participants received ainuovirine (150 mg, q.d.) from day 1-7 (Period 1), followed by coadministration with fluconazole (200 mg, q.d.) from day 8-14 (Period 2). In group B, 18 participants received fluconazole (200 mg, q.d.) from day 1-7 (Period 1), followed by coadministration with ainuovirine (150 mg, q.d.) from day 8-14 (Period 2). A physiologically based pharmacokinetic (PBPK) model of ainuovirine predicted its DDI with fluconazole, incorporating population PK analysis.</p><p><strong>Results: </strong>In group A, when coadministered with fluconazole, geometric means of ainuovirine <i>C</i> _max,ss, AUC_0-24,ss increased up to 233.0% and 349.6%, respectively, versus ainuovirine alone. In group B, there were no apparent effects of ainuovirine on <i>C</i> _max,ss, AUC_0-24,ss and <i>T</i> _max,ss for fluconazole. No death or grade ≥3 serious adverse events occurred. The predictive performance of the PBPK model for the interaction scenario is excellent, because the ratios of predicted-to-observed C_max,ss and AUC_0-∞,ss are very close to 1.0, which provides high confidence in the model's simulations for dose optimization.</p><p><strong>Conclusion: </strong>Coadministration with fluconazole significantly alters the steady-state PK of ainuovirine, but not conversely. The DDI PBPK model supports that dose reduction of ainuovirine is warranted for coadministration with fluconazole.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"597672"},"PeriodicalIF":5.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765644","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":"Immunomodulatory and Anti-Inflammatory Effects of Ketotifen Versus Vitamin E in Patients with Non-Alcoholic Fatty Liver Disease: A Randomized Pilot Study.","authors":"Khlood Mohammad Aldossary, Hend Talkhan, Furqan M Abdulelah, Fedaa A Kotkata, Yasmine M Elmorsi, Eslam Habba, Nashwa Eltantawy, Shereen A Mourad, Eman Hamza, Haidy M Sami, Khaled Abo Bakr Khalaf Ali, Eman I Elberri, Mostafa M Bahaa","doi":"10.2147/DDDT.S593561","DOIUrl":"https://doi.org/10.2147/DDDT.S593561","url":null,"abstract":"<p><strong>Background: </strong>Non-alcoholic fatty liver disease (NAFLD) represents a prevalent, long-standing hepatic condition marked by the accumulation of fat in the liver and varying degrees of fibrotic changes. Ketotifen, a mast cell stabilizer, has been proposed to modulate inflammation and fibrogenesis, but clinical evidence is limited.</p><p><strong>Objective: </strong>To assess the effectiveness and safety of ketotifen vs vitamin E in individuals with NAFLD. The primary outcome was the change in hepatic steatosis, while the secondary outcomes included modifications in fibrosis-related indices and inflammatory biomarkers. In addition to other biochemical, anthropometric, and metabolic parameters.</p><p><strong>Methods: </strong>In this randomized study, 60 individuals with NAFLD were allocated in a 1:1 ratio into two groups. The vitamin E group was treated with vitamin E, and the ketotifen group received ketotifen for six months. Anthropometric parameters, liver steatosis and fibrosis, lipid profile, glycemic markers, liver enzymes, matrix metalloproteinase (MMP)-9, and tumor necrosis factor (TNF)-α were measured before and after 6 months.</p><p><strong>Results: </strong>Ketotifen treatment resulted in significant improvements in hepatic steatosis and disease activity compared with vitamin E, including lower steatosis and FibroScan-AST (FAST) score. Fibrosis severity was also reduced, with significant decreases in fibrosis score and fibrosis index (FIB-4) index, whereas Metabolic-Associated Steatosis Combined with Keratin-18 (MACK-3) score showed no significant between-group change. Glycemic outcomes improved significantly with ketotifen, including reductions in HOMA-IR, fasting blood glucose, and fasting insulin. Ketotifen also significantly reduced AST, TNF-α and MMP-9, and improved central adiposity measures (hip circumference, waist-stature ratio. No significant differences were observed for lipid profile, body weight, body mass index, or HbA1c. Ketotifen was generally well tolerated; drowsiness was the most common adverse event.</p><p><strong>Conclusion: </strong>Ketotifen exerts superior hepatoprotective, anti-inflammatory, antifibrotic, and insulin-sensitizing effects compared with vitamin E in NAFLD. These findings suggest that ketotifen may offer a promising adjunctive therapy for NAFLD.</p><p><strong>Clinical trial registration: </strong>NCT05616442.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"593561"},"PeriodicalIF":5.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13110014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765337","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":"Clarifying Baseline Cognitive Eligibility and Cross-Scale Follow-Up in a Randomized Trial of Remimazolam Tosylate for Laparoscopic Surgery [Letter].","authors":"Feng Zhou, Yuxia Jiao, Yao Yu, Zhihe Zeng","doi":"10.2147/DDDT.S615336","DOIUrl":"https://doi.org/10.2147/DDDT.S615336","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"615336"},"PeriodicalIF":5.1,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765658","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":"Defining the Therapeutic Range of Levetiracetam for Personalized Treatment in Pediatric Epilepsy: Insights from a Large Real-World Study.","authors":"Xi-Li Sun, Yuan-Yuan Zhang, Yi-Jing Liu, Hong-Li Guo, Yue Li, Xiao-Peng Lu, Chun-Feng Wu, Chao Liang, Feng Chen","doi":"10.2147/DDDT.S593587","DOIUrl":"https://doi.org/10.2147/DDDT.S593587","url":null,"abstract":"<p><strong>Background: </strong>This study sought to define the therapeutic drug monitoring (TDM) reference range and assess the efficacy-safety profile along with its determinants for levetiracetam (LEV) in Chinese children with epilepsy.</p><p><strong>Methods: </strong>We conducted a retrospective study (2021-2023) at Children's Hospital of Nanjing Medical University in children with epilepsy taking LEV therapy with routine TDM. The observational LEV reference range was defined by the generalized additive models for location, scale, and shape (GAMLSS) analysis. A linear mixed-effects model identified concentration determinants. Efficacy was assessed via propensity score matching (PSM)-adjusted logistic regression, time-to-failure via Kaplan-Meier/Cox regression (monotherapy), and adverse events (AEs) temporal patterns via Weibull distribution analysis.</p><p><strong>Results: </strong>This study (n = 1,174) proposed an observational LEV reference range of 2.82-24.37 µg/mL based on the 2.5th-97.5th percentile distribution. Predictors of LEV levels included age, body weight, oxcarbazepine (OXC)/topiramate use, and developmental delay. OXC lowered concentration-to-dose (<i>C</i> ₀/D) (β = -0.1824, <i>P</i> = 0.0012). The 12-month response rate was 81.01% (90.89% monotherapy vs 70.78% polytherapy). Concentration-response correlation was significant only in focal epilepsy. Protective factors for response were female sex, generalized epilepsy, and longer treatment; risk factors were polytherapy and infectious etiology. Comorbid attention deficit and hyperactive disorder improved, but developmental delay did not affect, response. Neuropsychiatric AEs were most frequent (median onset: 196.5 days); gastrointestinal and systemic reactions showed early failure patterns.</p><p><strong>Conclusion: </strong>This real-world study confirmed the efficacy and safety of LEV in Chinese children with epilepsy and revealed relevant drug interactions. By proposing an observational LEV reference range (2.82-24.37 µg/mL), it provides a critical evidence base for TDM and guides the personalized treatment.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"593587"},"PeriodicalIF":5.1,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765682","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":"β-Amyrin Acetate Confers Anti-Epileptic Protection via Suppression of Calcium Overload-Induced Neuroinflammation and Apoptosis.","authors":"Jiali Cai, Yaojian Zhang, Tian Zhang, Mengyi Wu, Dijun Wang, Chunyan Yin, Xueke Nie, Lan Chen, Zhihu Sun, Chanming Liu, Xiaojing Yan","doi":"10.2147/DDDT.S566649","DOIUrl":"https://doi.org/10.2147/DDDT.S566649","url":null,"abstract":"<p><strong>Purpose: </strong>β-Amyrin acetate (BAA), a natural pentacyclic triterpenoid, exhibits greater lipophilicity than its antiepileptic precursor β-amyrin, implying enhanced blood-brain barrier (BBB) permeability. This study aimed to evaluate the antiepileptic efficacy of BAA and investigate its neuroprotective mechanisms, with a focus on calcium signaling.</p><p><strong>Patients and methods: </strong>An epilepsy model was established in zebrafish using pentylenetetrazole (PTZ) to assess the effects of BAA on seizure-like behaviors, reactive oxygen species (ROS) levels, apoptosis, and inflammatory markers. Potential targets were predicted via network pharmacology and molecular docking. Furthermore, a glutamate (Glu)-induced HT-22 neuronal injury model was used to validate BAA's effects on intracellular calcium homeostasis and downstream signaling pathways.</p><p><strong>Results: </strong>BAA significantly attenuated PTZ-induced seizure-like behaviors in zebrafish, specifically reducing the frequency of clonic and tonic-clonic seizures, as well as total movement distance and velocity. Concurrently, BAA mitigated oxidative stress, apoptosis, and neuroinflammation in the zebrafish. Network pharmacology and molecular docking analyses suggested the calcium signaling pathway as a potential target, with BAA showing high binding affinity to proteins such as Bcl-2 and JAK2. In vitro experiments suggested that BAA effectively alleviated Glu-induced calcium overload in HT-22 cells. It downregulated the Bax/Bcl-2 ratio, suppressed overactivation of the JAK2/STAT3 pathway, and consequently reduced neuronal apoptosis and inflammation. The BAPTA-AM co-treatment experiment further supported that the protective effect of BAA depends on the regulation of intracellular calcium homeostasis.</p><p><strong>Conclusion: </strong>BAA exerts antiepileptic effects by inhibiting neuronal calcium overload and modulating the JAK2/STAT3 signaling pathway, thereby attenuating neuroinflammation and apoptosis. These findings provide a solid experimental foundation for developing BAA as a promising antiepileptic candidate and elucidate its multi-target mechanism of action.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"20 ","pages":"566649"},"PeriodicalIF":5.1,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765443","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}