Drug Design, Development and Therapy最新文献

{"title":"S-Ketamine Reduces the Risk of Rebound Pain in Patients Following Total Knee Arthroplasty: A Randomized Controlled Trial.","authors":"Qun Li, Shaoqi Tian, Lei Zhang, Dongyue Chai, Jia Liu, Fang Sheng, Xin Jiang, Wei Feng, Yang Zhao, Youzhuang Zhu","doi":"10.2147/DDDT.S515741","DOIUrl":"10.2147/DDDT.S515741","url":null,"abstract":"<p><strong>Purpose: </strong>Investigating the effectiveness of S-ketamine in reducing rebound pain (RP) following total knee arthroplasty.</p><p><strong>Patients and methods: </strong>This study was a randomized, double-blind, placebo-controlled trial involving 356 adult patients undergoing total knee arthroplasty. Patient enrollment occurred between April and October 2023, with in-person follow-up assessments conducted from admission to 3 days post-surgery. Participants were randomly assigned to the S-ketamine group (n = 178) and the placebo group (n = 178). In the S-ketamine group, participants received a continuous intraoperative infusion of S-ketamine at a dose of 0.30 mg/(kg·h) from the completion of spinal anesthesia until the beginning of joint cavity closure, whereas the placebo group received a continuous infusion of 0.9% saline at the same volume and duration. The primary outcome was the incidence of RP within 12 hours post-surgery. Secondary outcomes included the incidence of RP within 24 hours, time to RP onset, time to first rescue analgesia, pain scores, opioid consumption, clinical outcomes, and harms.</p><p><strong>Results: </strong>RP was observed in 21.3% of patients in the S-ketamine group compared with 34.8% in the placebo group within 12 hours post-surgery (adjusted RR, 0.62; 95% CI, 0.44 to 0.88; <i>P</i> = 0.008). The onset of RP was significantly delayed in the S-ketamine group compared with the placebo group (unadjusted HR, 0.60; 95% CI, 0.41 to 0.88; <i>P</i> = 0.009). The numerical rating scale during activity and physical therapy was lower in the S-ketamine group than in the placebo group (day 1 AM: unadjusted difference, -1; 95% CI, -1 to 0; <i>P</i> = 0.011; day 1 PM: unadjusted difference, -1; 95% CI, -1 to 0; <i>P</i> = 0.003; day 1 physical therapy: unadjusted difference, -2; 95% CI, -2 to -1; <i>P</i> < 0.001). The quality of recovery score was higher in the S-ketamine group than in the placebo group (unadjusted difference, 5; 95% CI, 5 to 5; <i>P</i> < 0.001). Patient satisfaction was higher in the S-ketamine group than in the placebo group (unadjusted difference, 1; 95% CI, 1 to 1; <i>P</i> < 0.001).</p><p><strong>Conclusions: </strong>S-ketamine effectively reduces the risk of rebound pain and delays its onset in total knee arthroplasty. Additionally, S-ketamine can reduce early pain levels, enhance recovery quality, and improve patient satisfaction.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2315-2327"},"PeriodicalIF":4.7,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751190","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":"An Open-Label, Single and Multiple Dose Study to Evaluate the Pharmacokinetics and Safety of Fezolinetant in Healthy Chinese Female Subjects.","authors":"Yang Li, Yue Liu, Megumi Iwai, Masato Takeuchi, Nan Song, Yuan Li, Aixin Shi","doi":"10.2147/DDDT.S486562","DOIUrl":"10.2147/DDDT.S486562","url":null,"abstract":"<p><strong>Purpose: </strong>To evaluate pharmacokinetics (PK) and safety of fezolinetant after single-dose and multiple-dose administration of 15, 30, and 60 mg in healthy Chinese women.</p><p><strong>Patients and methods: </strong>This was a fixed-sequence crossover study in 16 healthy Chinese female subjects, 18-45 years old. All received single doses of fezolinetant 15 mg, 30 mg or 60 mg with a 3-day washout. From Day 10, subjects received multiple doses of 30 mg fezolinetant once-daily for 7 days. PK parameters were obtained during the single- and multiple-dose periods. Safety assessments were based on adverse events, vital signs, and laboratory tests.</p><p><strong>Results: </strong>Fezolinetant exhibited rapid absorption, with median time of the maximum concentration (t_max) 1.50 to 1.75 hours after single-dose administration of fezolinetant tablets in the fasted state, followed by a decline in plasma levels, with a mean t_1/2 of 6.12-7.69 hours at dose levels of 15, 30 and 60 mg. There was a dose-proportional increase in maximum concentration and total exposure for fezolinetant across the doses studied. Mean peak concentration (C_max) values were 221, 439 and 834 ng/mL, for the 15, 30, and 60 mg doses, respectively. The drug exposure parameters had a low-to-moderate variability (21.1-39.7%). Minimum accumulation was observed after multiple doses. Metabolite ES259564 showed rapid formation following a single dose of fezolinetant, with a median t_max of 1.50-2.00 hours. Plasma levels then declined, with mean t_1/2 ranging from 5.72-6.31 hours. Dose-proportional increases in C_max and AUC_inf were observed following single-doses of fezolinetant. Steady state was achieved on the second day after starting multiple-dose administration. In total, 3 (18.8%) subjects experienced 4 drug-related treatment-emergent adverse events; all mild in severity.</p><p><strong>Conclusion: </strong>Linear PK was confirmed within the dose range of 15 to 60 mg in healthy Chinese women.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2243-2252"},"PeriodicalIF":4.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11955179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751618","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":"Screening of Covalent Kinase Inhibitors Yields Hits for Cysteine Protease USP7 / HAUSP.","authors":"Larissa N Ernst, Simon J Jaag, Valentin R Wydra, Benedikt Masberg, Cornelius Knappe, Stefan Gerstenecker, Ricardo A M Serafim, Xiaojun Julia Liang, Nico J Seidler, Michael Lämmerhofer, Matthias Gehringer, Frank M Boeckler","doi":"10.2147/DDDT.S513591","DOIUrl":"10.2147/DDDT.S513591","url":null,"abstract":"<p><strong>Purpose: </strong>The ubiquitin-specific protease 7 (USP7), also known as herpes-associated ubiquitin-specific protease (HAUSP) is an interesting target due to its role in the tumor suppressor p53 pathway. In recent years targeted covalent inhibitors have gained significant importance in pharmaceutical research. Thus, we have investigated a small library of 129 ligands bearing different types of covalent reactive groups (\"warheads\") from various kinase drug discovery projects for their reactivity towards the catalytic cysteine of USP7, as well as their influence on its melting temperature. These compounds mainly encompassed α,β-unsaturated amides specifically acrylamides, S_NAr reacting compounds, aryl fluorosulfates and sulfonyl fluorides.</p><p><strong>Methods: </strong>We analyzed an array of 129 electrophilic compounds which had been designed as covalent kinase inhibitors in a DSF-based (differential scanning fluorimetry) screen against USP7. The hits were evaluated for their ability to cause similar thermal shifts for a CYS-deficient USP7 control mutant (USP7asoc), where only the catalytic Cys223 was retained. Additionally, covalent binding was evaluated by intact protein mass spectrometry (MS).</p><p><strong>Results: </strong>The DSF screen revealed that, predominantly 18 of the 129 tested compounds decreased the melting temperature of USP7 and its mutant USP7asoc. For 8 of these, the hypothesized covalent binding mode was corroborated with native and mutant USP7 by intact protein MS. Nearly all identified hits have a covalent warhead that reacts via nucleophilic aromatic substitution (S_NAr).</p><p><strong>Conclusion: </strong>The screening and evaluation of the kinase library revealed several initial hits of interest. Seven S_NAr warheads and one acrylamide warhead compound covalently modified the target protein (USP7) and showed clear shifts in the melting temperatures ranging from -6.0 °C to +1.7 °C.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2253-2284"},"PeriodicalIF":4.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11955496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751147","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":"MK-4 Ameliorates Diabetic Osteoporosis in Angiogenesis-Dependent Bone Formation by Promoting Mitophagy in Endothelial Cells.","authors":"Fan Ding, Weidong Zhang, Ting Liu, Xing Rong, Yajun Cui, Lingxiao Meng, Luxu Wang, Bo Liu, Minqi Li","doi":"10.2147/DDDT.S503930","DOIUrl":"10.2147/DDDT.S503930","url":null,"abstract":"<p><strong>Purpose: </strong>Diabetic osteoporosis (DOP), one of the usual complications in diabetic patients, poses a significant threat to bone health. Type H vessels in metaphysis and medial cortical bone are associated with osteogenesis. As a form of Vitamin K_2, menaquinone-4 (MK-4) is a potential treatment for osteoporosis. We aimed to investigate whether MK-4 ameliorates DOP by promoting bone formation through protecting type H vessels and its associated mechanisms.</p><p><strong>Methods: </strong>High fat diet (HDF) feeding and streptozotocin (STZ) injection were applied to establish a mouse model of type 2 diabetic osteoporosis (T2DOP). Micro-CT, Masson staining, HE staining and IHC staining were applied to observe bone mass and the osteoblastic ability of osteoblasts. Tissue immunofluorescence (IF) staining and flow cytometry were employed to assess alteration of type H blood vessels. In vitro, to evaluate the functional level and mitophagy of ECs under high glucose conditions, wound healing assay, tube formation assay, EdU assay and IF were employed. Osteogenic differentiation ability in vitro was evaluated by ALP staining, AR staining, Western blot and RT-qPCR.</p><p><strong>Results: </strong>MK-4 alleviated type H vessel injury and angiogenesis-dependent osteogenesis in DOP mice, thereby maintaining the bone mass. The vitro results showed that MK-4 could mitigate the dysfunction of ECs subjected to HG treatment, and further facilitate the osteogenic differentiation of MC3T3-E1 cells. Moreover, mechanism exploration found that PINK1/Parkin-mediated mitophagy was required for the impact of MK-4 on ECs. Meanwhile, ERK signal pathway is necessary for the improvement of MK-4 in PINK1/Parkin-mediated mitophagy.</p><p><strong>Conclusion: </strong>MK-4 is capable of alleviating the PINK1/Parkin-mediated mitophagy of ECs via the ERK pathway, thereby facilitating angiogenesis-dependent bone formation and further ameliorating DOP.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2173-2188"},"PeriodicalIF":4.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11954476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751657","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":"External Validation of a Pharmacokinetic Model Developed for Vancomycin Administration via Target-Controlled Infusion.","authors":"Jung-Min Yi, Kyung Mi Kim, Hak-Jae Lee, Suk-Kyung Hong, Byung-Moon Choi","doi":"10.2147/DDDT.S507377","DOIUrl":"10.2147/DDDT.S507377","url":null,"abstract":"<p><strong>Purpose: </strong>Target-controlled infusion (TCI) could provide a patient-tailored approach for vancomycin dosing. This study aimed to externally evaluate the predictive performance of a previously constructed pharmacokinetic model of vancomycin (Choi model) specifically optimized for TCI administration of vancomycin differing from the existing model, and to assess the feasibility of administering vancomycin via TCI in clinical practice. Additionally, clinical outcomes were exploratively compared between the TCI and intermittent infusion (standard) methods for vancomycin administration.</p><p><strong>Patients and methods: </strong>Clinically ill patients were randomly assigned in a 1:1 ratio to either the TCI or standard group. In the TCI group, vancomycin was administered using the Choi model, targeting an initial concentration of 25 mg/L, adjusted to maintain therapeutic levels (20-30 mg/L). The standard group received a loading dose of 25 mg/kg, then 15 mg/kg every 12 hours. Vancomycin concentrations for analysis were obtained from three blood samples per patient at set times, along with routine therapeutic drug monitoring data. Predictive performance was assessed using four parameters: inaccuracy, divergence, bias, and wobble. The occurrence of acute kidney injury (AKI) during and up to 7 days after vancomycin was investigated.</p><p><strong>Results: </strong>The study was terminated early due to challenges in enrolling subjects (TCI: n=12, standard: n=13). Thirty-seven serum concentration measurements from the TCI group were analyzed. Pooled median bias and inaccuracy (95% confidence interval) were -2.7 (-7.3 to 1.9) and 17.0 (13.9 to 20.2), respectively. AKI incidence was similar between groups (TCI: n=0, standard: n=1) in this exploratory analysis, but caution is warranted in interpreting these outcomes as the planned sample size was not met.</p><p><strong>Conclusion: </strong>The predictive performance of the TCI system integrated with the Choi model was suitable for clinical use. Further studies with a large cohort should be performed to determine the clinical effectiveness of vancomycin administered via the TCI method.</p><p><strong>Trial registration: </strong>This study was registered at the Clinical Research Information Service of the Korean National Institute of Health (CRIS, http://cris.nih.go.kr), with registration number KCT0003462, on January 31, 2019).</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2229-2241"},"PeriodicalIF":4.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751624","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":"An Updated Review of Molecular Mechanisms Implicated with the Anticancer Potential of Diosgenin and Its Nanoformulations.","authors":"Pratibha Pandey, Seema Ramniwas, Lalji Baldaniya, Sorabh Lakhanpal, Danish Mahmood, Kamlesh Chaudhary, Shivam Pandey, Min Choi, Jinwon Choi, Hyo Jeong Kim, Chi-Hoon Ahn, Moon Nyeo Park, Fahad Khan, Bonglee Kim","doi":"10.2147/DDDT.S502322","DOIUrl":"10.2147/DDDT.S502322","url":null,"abstract":"<p><p>Dietary components have gained broader recognition in preventing and managing numerous human carcinomas. Plant-derived natural compounds offer several benefits, including their limited toxicity and multi-targeted agents in modulating deregulated oncogenic pathways, including PI3K/AKT, NF-κB/STAT3, and HIF-1α, and hence, they emerged as better chemotherapeutic alternatives. Diosgenin (phytosteroidal saponin) and its nanoformulations have been extensively reported to impact cancer progression and metastasis. Research has indicated that diosgenin and its nanoformulations possess significant anticancer potential with improved bioavailability. However, novelty of this review relies on compiling the updated anticancer role of diosgenin and its nanoformulations in modulating numerous oncogenic targets associated with carcinogenesis and metastasis. Diosgenin has also been utilized with traditional therapies to enhance the sensitivity of cancerous cells towards normal chemotherapeutic processes. More focus should be given to gain detailed insights about the mechanisms associated with the anticancer potential of diosgenin and its nanoformulations, which can further potentiate its candidature in developing efficient cancer therapies. However, more preclinical studies are warranted to exploit the anticancer efficacy of this plant-based compound in an efficient manner.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2205-2227"},"PeriodicalIF":4.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751621","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":"Quercetin Improves Hippocampal Neurogenesis in Depression by Regulating the Level of Let-7e-5p in Microglia Exosomes.","authors":"Ying Xie, Tongxuan Ouyang, Anli Xu, Qinglai Bian, Biran Zhu, Min Zhao","doi":"10.2147/DDDT.S493779","DOIUrl":"10.2147/DDDT.S493779","url":null,"abstract":"<p><strong>Background: </strong>Adult hippocampal neurogenesis plays a beneficial role in the treatment of depression. The precise mechanism by which let-7e-5p functions as a potential marker for depression remains unclear. Quercetin, a flavonoid compound, exhibits antidepressant effects; however, further investigation is needed to elucidate its regulatory effect and mechanism on hippocampal neurogenesis.</p><p><strong>Methods: </strong>Chronic unpredictable mild stress (CUMS) was employed to induce depressive-like signaling and cognitive impairment in mice, while quercetin was administered via oral gavage. The symptoms of the mice were evaluated using various signaling methods. The expression levels of microglia, neural stem cells, and let-7e-5p in the dentate gyrus (DG) area of hippocampus were assessed using pathological observation methods. The expression levels of let-7e-5p and the Wnt1/β-catenin signaling pathways in the hippocampal DG of mice were assessed using qRT-PCR and Western blotting, respectively. The exosomes from peripheral blood were isolated and identified, followed by the detection of expression levels for microglia markers CD11b and TMEM119. We isolated hippocampal neural stem cells (NSCs) and co-cultured them with exosomes secreted by BV2 cells under LPS stimulation to observe the proliferation of NSCs and the generation of new neurons. The targeting relationship between let-7e-5p and Wnt1 was ultimately confirmed through the utilization of a dual luciferase reporter assay.</p><p><strong>Results: </strong>(1) Quercetin ameliorated depression-like behaviors in mice induced by CUMS and restored neurogenesis in the DG region of the hippocampus. (2) Quercetin suppressed the secretion of microglia-derived exosomes carrying let-7e-5p in the DG, which exerted effects on NSC. (3) let-7e-5p regulates depression-related neurogenesis through targeting the Wnt1/β-catenin signaling pathway.</p><p><strong>Conclusion: </strong>The inhibitory effect of let-7e-5p in microglial exosomes on depression-associated neurogenesis is mediated through the blockade of the Wnt1/β-catenin signaling pathway, which can be effectively reversed by Quercetin treatment.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2189-2203"},"PeriodicalIF":4.7,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11951924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751658","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":"Caffeic Acid Protects Against Ulcerative Colitis via Inhibiting Mitochondrial Apoptosis and Immune Overactivation in <i>Drosophila</i>.","authors":"Minghui Xiu, Botong Li, Li He, Yan Shi, Yongxuan Zhang, Shihong Zhou, Yongqi Liu, Ningbo Wang, Jianzheng He","doi":"10.2147/DDDT.S499284","DOIUrl":"10.2147/DDDT.S499284","url":null,"abstract":"<p><strong>Background: </strong>Ulcerative colitis (UC) is a chronic intestinal inflammation that is prone to relapse and is difficult to fully recover; therefore, there is a need for safer alternative treatments. Caffeic acid (CA) is a natural polyphenolic compound that has antioxidant and anti-inflammatory properties. However, the beneficial effects and mechanisms of action of CA in UC remain unclear.</p><p><strong>Purpose: </strong>This study evaluated the protective effect of CA against dextran sulfate sodium (DSS)-induced intestinal injury in <i>Drosophila</i> melanogaster model.</p><p><strong>Results: </strong>Oral administration of CA significantly reduced body damage in UC flies, improved their survival rate, restored damaged digestion, and improved locomotion. CA supplementation significantly alleviated intestinal damage in UC flies by restoring excretion balance, repairing intestinal atrophy, improving acid-base balance imbalance, inhibiting intestinal structural destruction, inhibiting intestinal epithelial cell death and intestinal stem cell (ISC) excessive proliferation, and reducing the number of harmful bacteria. Mechanistic studies found that CA significantly reduced the expression of Toll and Imd pathway genes (including <i>Myd88, Dif, PGRP-LC, Imd, Rel</i>, and <i>Dpt</i>), reduced ROS levels and the expression of apoptosis-related genes (<i>Debcl, Cyt-c-p, DrlCE, Dronc</i>, and <i>Dark</i>), and increased ATP and MFN2 levels.</p><p><strong>Conclusion: </strong>CA alleviated intestinal damage mainly by inhibiting the Toll and Imd signaling pathways and inhibiting apoptosis mediated by mitochondrial damage. These findings suggest that CA holds promise as a potential therapeutic for UC treatment.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2157-2172"},"PeriodicalIF":4.7,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718323","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":"Unveiling the Therapeutic Potential of Banxia Xiexin Decoction in Alzheimer's Disease: Insights From Network Pharmacology and Experimental Validation.","authors":"Gaofeng Qin, Rongqiang Song, Jingyi Sun, Juanjuan Dai, Wentao Wang, Fantao Meng, Dan Wang, Zhe Liu, Baoliang Sun, Chen Li","doi":"10.2147/DDDT.S499852","DOIUrl":"10.2147/DDDT.S499852","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is associated with various pathological states for which there is no effective treatment. First documented in the Eastern Han Dynasty's medical classic, \"Treatise on Febrile and Miscellaneous Diseases\" (200-210 Anno Domini), Banxia Xiexin Decoction (BXD) stands as a quintessential approach to treating spleen ailments. Recent studies have shown BXD's effectiveness in mitigating memory impairment associated with AD. Yet, the precise mechanisms underlying BXD's action against AD require further exploration.</p><p><strong>Aim of the study: </strong>To explore the important components of BXD in exerting anti-AD effects and the underlying molecular mechanisms using network pharmacology, metabolomics analysis, and in vitro and in vivo validation strategies. Initially, candidates for BXD's application in AD therapy were identified through extensive database searches, followed by an analysis of protein-protein interactions (PPI). To elucidate BXD's therapeutic pathways in AD, we engaged in Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) assessments. Further, we delved into BXD's primary constituents through ultra-high-pressure liquid chromatography coupled with Q Exactive mass spectrometry and molecular docking techniques. Finally, AD-associated Aβ₄₂-SY5Y cells and APPswe/PS1dE9 (APP/PS1) transgenic mice models were utilized to further determine the activity and mechanisms of BXD through various molecular or phenotypic assays and metabolomics analysis.</p><p><strong>Results: </strong>Our findings identified the PI3K/Akt signaling pathways as central to BXD's effects. Using in vitro and in vivo models, we found the activity of BXD against AD to be mediated by the suppression of neuroinflammation and apoptosis, accompanied by activation of the PI3K/Akt pathway. Finally, we observed robust changes in metabolite levels in the plasma of BXD-treated APP/PS1 mice.</p><p><strong>Conclusion: </strong>Through systematic data analysis and experimental validation, the therapeutic advantages and fundamental molecular mechanisms of BXD in treating AD were revealed. These findings underscore the promising prospects and compelling potential of BXD, which targets the PI3K/Akt signaling pathway and inflammation, apoptosis, as a therapeutic strategy for improving AD.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2133-2155"},"PeriodicalIF":4.7,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708439","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":"Erratum: Population Pharmacokinetic of Epidural Sufentanil in Labouring Women: A Multicentric, Prospective, Observational Study [Corrigendum].","authors":"","doi":"10.2147/DDDT.S528296","DOIUrl":"https://doi.org/10.2147/DDDT.S528296","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.2147/DDDT.S500189.].</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2131-2132"},"PeriodicalIF":4.7,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708213","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}