Drug Design, Development and Therapy最新文献

{"title":"Saikosaponin A Mediates the Anti-Acute Myeloid Leukemia Effect via the P-JNK Signaling Pathway Induced by Endoplasmic Reticulum Stress.","authors":"Xiao-Hong Sun, Yi-Hong Chai, Xiao-Teng Bai, Hong-Xing Li, Pan-Pan Yang, Ya-Ming Xi","doi":"10.2147/DDDT.S498458","DOIUrl":"10.2147/DDDT.S498458","url":null,"abstract":"<p><strong>Objective: </strong>This study aims to investigate the antitumor effects of saikosaponin A (SSA) on acute myeloid leukemia (AML) and elucidate its underlying mechanisms, particularly focusing on the endoplasmic reticulum stress (ERS)-mediated MAPK-p-JNK signaling pathway.</p><p><strong>Methods: </strong>The inhibitory effects of SSA on the proliferation of AML cell lines K562 and HL60 were evaluated using CCK8 and EdU assays. Apoptotic effects induced by SSA were analyzed via flow cytometry. RNA sequencing was performed to identify differentially expressed genes and enriched signaling pathways. Western blot analysis was utilized to confirm the involvement of ERS and activation of the MAPK-p-JNK signaling pathway. Further validation of the potential mechanism of SSA-induced apoptosis was conducted using SP600125 and 4PBA. The in vivo anti-AML efficacy of SSA was assessed using a xenograft model.</p><p><strong>Results: </strong>SSA exhibited significant inhibitory effects on the proliferation of AML cell lines K562 and HL60, with IC50 values at 12, 24, and 48 hours demonstrating time- and dose-dependency (19.84 μM, 17.86 μM, and 15.38 μM for K562; 22.73 μM, 17.02 μM, and 15.25 μM for HL60, respectively). Western blot analysis demonstrated that SSA induces apoptosis in AML cells through the mitochondrial apoptotic pathway. Transcriptomic profiling and Western blot analyses confirmed that SSA activates the ERS-mediated p-JNK signaling pathway to induce apoptosis in AML, a process that can be reversed by the addition of 4PBA or SP600125. Furthermore, SSA significantly reduced tumor volume and weight in a NOD-SCID mouse xenograft model without causing notable toxicity to the liver, kidneys, lungs, or heart, while also activating the ERS and p-JNK signaling pathways in vivo.</p><p><strong>Conclusion: </strong>SSA induces apoptosis in AML cells by activating the ERS-mediated p-JNK signaling pathway, exhibiting significant anti-AML effects both in vitro and in vivo, accompanied by a favorable safety profile.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1983-2001"},"PeriodicalIF":4.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11928444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691513","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":"Effect of Esketamine-Based Opioid-Sparing Anesthesia Protocol on the Quality of Early Recovery After Urological Surgery: A Randomized Clinical Trial.","authors":"Yu Qi, Weihua Li, Ying Ren, Jia Sun, Yangzi Zhu, Long Wang, Meiyan Zhou, Liwei Wang","doi":"10.2147/DDDT.S511112","DOIUrl":"10.2147/DDDT.S511112","url":null,"abstract":"<p><strong>Purpose: </strong>The quality of postoperative recovery under enhanced recovery after surgery protocols has always been the focus of anesthesiologists. It has been proven that esketamine application during the perioperative period can reduce the use of opioid drugs and improve the quality of postoperative recovery. The present study explored the effect of the esketamine-based opioid-sparing anesthesia protocol on the quality of postoperative recovery in patients undergoing elective urological surgery.</p><p><strong>Patients and methods: </strong>A randomized, double-blind, controlled clinical trial was adopted. Patients aged 18-65 years, with American Society of Anesthesiologists physical status grades I-III, scheduled for elective laparoscopic partial nephrectomy or unilateral nephrectomy in urological surgery, were randomly divided into the OSA group and the control group. The OSA group received 0.25 mg/kg of esketamine for anesthesia induction during the operation, and maintenance was carried out at a rate of 0.125 mg·kg⁻¹·h⁻¹. The primary outcome measure was the Quality of Recovery Scale-15 score 24 hours after the operation.</p><p><strong>Results: </strong>The total Quality of Recovery Scale-15 score was significantly higher in the OSA than in control groups 24 hours after the operation (114 [108, 116] vs 106 [102, 109], <i>p</i> < 0.001). The anesthesia recovery level was better in the OSA than in control groups in the post-anesthesia care unit, demonstrated by shorter eye-opening time (19 [17 20] vs 22 [18, 22], <i>p</i> = 0.031) and extubation time (20 [20, 23] vs 25 [20, 25], <i>p</i> = 0.004). Additionally, the incidence of nausea and vomiting within 0-48 hours after surgery was lower in the OSA than in control groups.</p><p><strong>Conclusion: </strong>The esketamine-based opioid-sparing anesthesia protocol can improve the quality of early postoperative recovery and the level of anesthesia recovery, and accelerate rehabilitation in patients undergoing elective urological surgery.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2005-2016"},"PeriodicalIF":4.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11927495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691175","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: Dexmedetomidine Attenuated Neuron Death, Cognitive Decline, and Anxiety-Like Behavior by Inhibiting CXCL2 in CA1 Region of AD Mice [Corrigendum].","authors":"","doi":"10.2147/DDDT.S526425","DOIUrl":"https://doi.org/10.2147/DDDT.S526425","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.2147/DDDT.S489860.].</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"2003-2004"},"PeriodicalIF":4.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691180","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":"RET Inhibitor SPP86 is a Potential Candidate for the Clinical Treatment of Cutaneous Melanoma [Response to Letter].","authors":"Yuli Zhang, Haidong Liu, Kun Wang, Juan Zheng, Hong Luan, Ming Xin","doi":"10.2147/DDDT.S524526","DOIUrl":"https://doi.org/10.2147/DDDT.S524526","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1943-1944"},"PeriodicalIF":4.7,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662781","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 Opioid-Sparing Effects of Intraoperative Esketamine Combined with Dexmedetomidine During Laparoscopic Major Abdominal Surgery: A Randomized Controlled Double-Blind Trial.","authors":"Wenjun Wang, Yanxin Chen, Guanzhu Li, Ying Chen, Jianwei Wu, Yongyong Shi, Min Zhong","doi":"10.2147/DDDT.S480700","DOIUrl":"10.2147/DDDT.S480700","url":null,"abstract":"<p><strong>Background: </strong>Recently, opioid-sparing (OS) interventions have been proposed to facilitate rapid postoperative recovery for patients. However, the advantages of OS anesthesia strategy in laparoscopic abdominal major surgery are still unknown.</p><p><strong>Methods: </strong>157 patients undergoing laparoscopic major abdominal surgery were randomly assigned to two groups: Remi (77, remifentanil) and OS (80, esketamine combined with dexmedetomidine), the drugs were administered at 0.2-0.5 mg/kg/h (remifentanil or esketamine) and 0.2-0.7μg/kg/h (remifentanil or dexmedetomidine) in two syringes, respectively The primary outcome was the numeric rating scale (NRS) pain score on postoperative day (POD)1. The proportion of rescue analgesia within 48 h, extubation time, postoperative quality recover scale (PQRS), Pittsburgh Sleep Quality Index (PSQI) on POD30 were also recorded.</p><p><strong>Results: </strong>In the postanaesthesia care unit (PACU), the NRS pain score and the proportion of rescue analgesia in Remi group was significantly higher than that in OS group (3 [1 to 3] vs 1 [1 to 3], <i>P</i> = 0.001; 15.6% vs 5.0%, <i>P</i> = 0.028, respectively), although there were no statistical differences in NRS pain score on POD1, POD7 and POD30 between groups (3 [2 to 3] vs 3 [2 to 3], <i>P</i> = 0.648; 2 [1 to 2] vs 2 [1 to 2], <i>P</i> = 0.418; 0 [1 to 1] vs 0 [1 to 1], <i>P</i> = 0.656, respectively). The extubation time in the OS group was longer and the proportion of dreaminess was also higher than that in the Remi group (20 [11 to 34] vs 31 [21 to 40], <i>P</i> < 0.01; 15.6% vs 42.5%, <i>P</i> < 0.01), However, the PSQI on POD30 were similar between groups (8.27±3.94 vs 8.37±3.89, <i>P</i> = 0.870).</p><p><strong>Conclusion: </strong>In this study, OS anesthesia strategy during laparoscopic major abdominal surgery decreases the NRS pain scores in PACU and reduces the use of rescue analgesia, though it may prolong the extubation time and increase the proportion of dreaminess during hospitalization.</p><p><strong>Trial registration number: </strong>ChiCTR2200060130.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1971-1981"},"PeriodicalIF":4.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11920631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662848","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":"Effect and Mechanism of Aloin in Ameliorating Chronic Prostatitis/Chronic Pelvic Pain Syndrome: Network Pharmacology and Experimental Verification.","authors":"Rongxin Li, Yanan Wang, Yongfeng Lao, Chengyu You, Liangliang Qing, Xin Guan, Jian Wang, Xiaolong Li, Qingchao Li, Shuai Liu, Zhilong Dong","doi":"10.2147/DDDT.S473678","DOIUrl":"10.2147/DDDT.S473678","url":null,"abstract":"<p><strong>Purpose: </strong>This research aims to investigate the role and potential mechanisms of Aloin in Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) through network pharmacology and experimental approaches.</p><p><strong>Methods: </strong>Using network pharmacology methods, potential targets of Aloin and targets related to CP/CPPS were screened from public databases. The protein-protein interaction (PPI) network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to predict the core targets and pathways of Aloin against CP/CPPS. The effects of Aloin in ameliorating CP/CPPS were verified in animal experiments.</p><p><strong>Results: </strong>A total of 235 genes interacting with Aloin in CP/CPPS were identified. PPI network analysis revealed five core targets: AKT1, EGFR, ESR1, HSP90AA1, and SRC. GO analysis yielded 2916 enrichment results, with 2562 related to Biological Process (BP), 94 to Cellular Component (CC), and 260 to Molecular Function (MF). KEGG pathway analysis identified 172 pathways. Molecular docking confirmed stable binding between Aloin and core targets. Molecular dynamics simulations further validated binding stability by analyzing Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), hydrogen bonds, Solvent Accessible Surface Area (SASA), and Gibbs free energy of Aloin-target complexes. Experimental validation showed that Aloin alleviated pain, reduced inflammatory factors, and decreased oxidative stress in a rat model of CP/CPPS. The qRT-PCR results showed that Aloin intervention reduced the mRNA expression of AKT1, EGFR, HSP90AA1, and SRC, while increasing ESR1 mRNA expression. These changes may underlie its therapeutic effects in CP/CPPS.</p><p><strong>Conclusion: </strong>Our study revealed that Aloin exerts a beneficial effect on mitigating the pain symptoms associated with CP/CPPS, ameliorating inflammation, and reducing oxidative stress. Through network pharmacology, potential targets and signaling pathways were identified, suggesting the therapeutic promise of Aloin for CP/CPPS. These findings advocate for further exploration into its clinical efficacy and mechanistic underpinnings in the treatment of CP/CPPS.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1945-1969"},"PeriodicalIF":4.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11920635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662833","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 Role of Radiosensitizing Drugs in Osteosarcoma Treatment: Mechanisms and Clinical Perspectives.","authors":"Yilei Zhang, Yuhuan Xie, Yiwen Wang, Panpan Huang, Yao Lu","doi":"10.2147/DDDT.S512479","DOIUrl":"10.2147/DDDT.S512479","url":null,"abstract":"<p><p>Osteosarcoma is a highly malignant bone tumor that is resistant to radiotherapy and is associated with poor treatment outcomes and prognoses. Understanding the mechanisms of radioresistance and finding strategies to enhance the radiosensitivity is crucial for improving clinical efficacy. The aim of this review was to address the approaches for enhancing the efficacy of radiotherapy in osteosarcoma, thereby improving patient outcomes. Specifically, we have focused on the mechanisms of radiosensitization and the relationship between drugs that enhance radiosensitivity and cancer. These mechanisms involve a delay in DNA damage repair, promotion of apoptosis, inhibition of angiogenesis, and regulation of the tumor microenvironment. In addition, we have summarized the effects of these drugs on the proliferation, migration, invasion and apoptosis of osteosarcoma cell lines. Finally, we have discussed the therapeutic effects and adverse reactions of these drugs in other cancers, providing valuable guidance for clinical treatment strategies tailored to patients with osteosarcoma.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1927-1942"},"PeriodicalIF":4.7,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11920643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662887","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":"Design of a Highly Active Peptide Inhibitor of Farnesyltransferase and Its Protective Effect Against Acute Liver Failure.","authors":"Chun-Lian Huang, Hang-Shuai Qu, A-Li Li, Chen-Qian Ying, Hui Shao, Yong-Zhi Tang, Hua-Zhong Chen, Tao-Hsin Tung, Jian-Sheng Zhu","doi":"10.2147/DDDT.S505541","DOIUrl":"10.2147/DDDT.S505541","url":null,"abstract":"<p><strong>Purpose: </strong>Acute liver failure (ALF) is a fatal syndrome associated with massive hepatocyte death. Previous studies have found that Farnesyltransferase (FTase) inhibitors improve disease progression in mouse models of endotoxemia, sepsis, and autoimmune hepatitis. PANoptosis is a novel type of programmed cell death (PCD), including pyroptosis, apoptosis, and necrosis, that plays an important role in ALF. This study was designed and investigated whether the FTase inhibitor PD083176 (d2,d3,d5) could attenuate ALF progression by modulating PANoptosis.</p><p><strong>Methods: </strong>Combining the technical tools of computational biology, structural biology and pharmacology, we designed and obtained three high-affinity human FTase inhibitors of PD083176(d2,d3,d5). Then, these FTase inhibitors were investigated by animal experiments by administering PD083176(d2,d3,d5) (10 mg/kg) before modeling with LPS (100 μg/kg)/D-GalN (300 mg/kg) or TAA (800 mg/kg).</p><p><strong>Results: </strong>We found that ALF induced by LPS/D-GaIN or TAA were associated with increased farnesylated protein in the liver. PD083176(d2,d3,d5) not only inhibited hepatic farnesylated proteins but also significantly attenuated liver injury and mortality in ALF mice. Importantly, PD083176(d2,d3,d5) treatment effectively inhibited hepatocyte apoptosis (Bax, Bcl-xL and TUNEL cell counts), pyroptosis (Caspase-1 and GSDMD), and necrotic apoptosis (RIPK1 and RIPK3).</p><p><strong>Conclusion: </strong>Collectively, these findings demonstrate that PD081376(d2,d3,d5) could alleviate LPS/D-GaIN or TAA-induced ALF by regulating apoptosis, pyroptosis, and necrotizing apoptosis, which might provide a new therapeutic strategy and scalability challenge for ALF.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1909-1926"},"PeriodicalIF":4.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647651","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":"Tubeimoside I Inhibits the Proliferation of Liver Cancer Through Inactivating NF-κB Pathway by Regulating TNFAIP3 Expression.","authors":"Yajun Zhang, Mingqin Zhou, Liwen Zhu, Lichan Chen, Haohua Zhang, Zhen Huang, Hongzhong Zhou","doi":"10.2147/DDDT.S507656","DOIUrl":"10.2147/DDDT.S507656","url":null,"abstract":"<p><strong>Purpose: </strong>This study aims to evaluate the therapeutic potential of tubeimoside I (TBMS1), a monomer compound extracted from the tubers of Chinese herb <i>Bolbostemma paniculatum</i> (Maxim). Franquet (<i>Cucurbitaceae</i>), in the treatment of liver cancer. Specifically, we sought to elucidate the underlying mechanisms through which TBMS1 exerts its anticancer effects.</p><p><strong>Methods: </strong>The effects of TBMS1 on the viability, proliferation, and apoptosis of two liver cancer cell lines, MHCC97-H and SNU-449, were comprehensively assessed using Cell Counting Kit-8 (CCK-8), colony formation, 5-ethynyl-2'-deoxyuridine (EDU) assay, and flow cytometry assays. To uncover the molecular mechanisms, RNA sequencing was performed to identify the downstream targets of TBMS1. Additionally, we utilized network pharmacology to predict TBMS1 targets in liver cancer and employed Venn diagram analysis to integrate these predictions with our experimental findings. Pathway enrichment analysis was conducted using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases to elucidate the biological processes involved. Furthermore, a subcutaneous xenograft tumor model was established to investigate the in vivo antitumor efficacy of TBMS1.</p><p><strong>Results: </strong>In vitro experiments demonstrated that TBMS1 significantly enhanced cell apoptosis and inhibited the growth of liver cancer cells. Both network pharmacology predictions and RNA-seq analyses revealed that the downstream target genes of TBMS1 were highly enriched in the NF-κB signaling pathway. Notably, we observed a significant upregulation of TNFα-induced protein 3 (TNFAIP3) expression with increasing concentrations of TBMS1. In vivo studies further confirmed that TBMS1 treatment dramatically reduced the volume and weight of liver cancer tumors compared to controls.</p><p><strong>Conclusion: </strong>Our study provides compelling evidence that TBMS1 suppresses liver cancer progression by inactivating the NF-κB pathway and regulating TNFAIP3 expression. These findings offer novel insights and a theoretical basis for the development of targeted therapies for liver cancer.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1895-1908"},"PeriodicalIF":4.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647668","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":"Gut-Brain Axis-Based Polygala Tenuifolia and Magnolia Officinalis Improve D-gal-Induced Cognitive Impairment in Mice Through cAMP and NF-κB Signaling Pathways.","authors":"Dan Yang, Wen Li, Qiuping Chen, Si Liu, Chengjie Peng, Fengcheng Deng, Yingqi Meng, Yang Yang, Ping Yan, Hui Ao, Lihua Huang","doi":"10.2147/DDDT.S506545","DOIUrl":"10.2147/DDDT.S506545","url":null,"abstract":"<p><strong>Purpose: </strong><i>Polygala tenuifolia</i> Willd. (PT) is commonly used to address cognitive impairment (CI), while <i>Magnolia officinalis</i> Rehd. et Wils (MO) is often prescribed for gastrointestinal issues as well as CI. This study seeks to explore the impacts and mechanisms behind the combined therapy of PT and MO (PM) in treating CI, based on the concept of the gut-brain axis.</p><p><strong>Methods: </strong>The characteristic components of PT, MO, and PM were identified using ultra-high performance liquid chromatography-tandem triple quadrupole mass Spectrometry (UPLC-MS/MS). A mouse model was established by D-gal induction, and the effects of PT, MO, and PM on CI were evaluated through behavioral tests, pathological staining, and Enzyme-Linked Immunosorbent Assay (ELISA). Subsequently, network pharmacology was used to analyze the potential mechanisms by which PM improves CI, followed by validation through Western blotting (WB), traditional Chinese medicine (TEM), Immunofluorescence (IF), and 16S rRNA.</p><p><strong>Results: </strong>PT, MO, and PM can each alleviate cognitive decline and neuropathological damage in D-gal mice to varying degrees, reduce the expression of pro-inflammatory factors (TNF-α, IL-1β, IL-6, IFN-γ, LPS) in serum or hippocampal tissue, and increase SOD and GSH levels. Network pharmacology analysis and molecular experiments confirmed that PM upregulates the expression of tight junction s (TJs), enhances the expression of proteins in the cAMP pathway, and inhibits p-NF-κB-p65 expression. PM reverses D-gal-induced gut microbiota dysbiosis, increases the abundance of SCFA-producing bacteria, and decreases the abundance of LPS-producing bacteria.</p><p><strong>Conclusion: </strong>PM alleviates CI by reducing inflammation and oxidative stress, protecting the blood-brain barrier (BBB) and intestinal barrier, inhibiting the NF-κB pathway, activating the cAMP pathway, and regulating gut microbiota.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"1869-1894"},"PeriodicalIF":4.7,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647674","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}