Drug Design, Development and Therapy最新文献

{"title":"Jujuboside A Regulates Calcium Homeostasis and Structural Plasticity to Alleviate Depression-Like Behavior via Shh Signaling in Immature Neurons.","authors":"Ziyan Zhong, Jian Liu, Yan Luo, Mei Wu, Feng Qiu, Hongqing Zhao, Yang Liu, Yajing Wang, Hongping Long, Lei Zhao, Yuhong Wang, Yuanshan Han, Pan Meng","doi":"10.2147/DDDT.S479055","DOIUrl":"10.2147/DDDT.S479055","url":null,"abstract":"<p><strong>Background: </strong>Depression, a leading cause of disability worldwide, is characterized by dysfunction of immature neurons, resulting in dysregulated calcium homeostasis and impaired structural plasticity. Jujuboside A (JuA), a biologically active compound derived from <i>Semen Ziziphi Spinosae</i>, has demonstrated anti-anxiety and anti-insomnia properties. Recent studies suggest that JuA may be a promising antidepressant, but its underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>Sprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS) to induce a depression model. JuA (12.5 mg/kg, 25 mg/kg, 50 mg/kg) was administered orally for 4 weeks. Emotional and cognitive function were assessed. Monoamine neurotransmitter levels were measured using enzyme-linked immunosorbent assay (ELISA). The number of immature neurons and calcium homeostasis were evaluated by immunofluorescence. Western blotting and immunofluorescence were employed to detect the expression of Sonic hedgehog (Shh) signaling proteins. Additionally, lentiviral vector expressing Shh shRNA (LV-Shh-RNAi) were infused intracerebrally to investigate the role of Shh in JuA's antidepressant effects.</p><p><strong>Results: </strong>JuA significantly ameliorated depressive-like behavior and cognitive dysfunction in CUMS rats, increased monoamine neurotransmitter levels in serum and hippocampal tissue, reduced the number of BrdU/DCX (bromodeoxyuridine/doublecortin)-positive immature neurons, and attenuated calcium ion (Ca²⁺) concentration and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) levels in immature neurons. JuA also markedly elevated synaptic density and prominence complexity, upregulated Shh, Gli family zinc finger 1 and 2 (Gli1/2), synaptophysin (Syn) and postsynaptic density protein-95 (PSD-95) expression in the ventral dentate gyrus (vDG). However, knockdown of Shh in the vDG counteracted JuA's therapeutic effects.</p><p><strong>Conclusion: </strong>These findings collectively suggest that JuA improves depressive-like behavior in CUMS rats by modulating calcium homeostasis and synaptic structural plasticity in immature neurons through the Shh signaling pathway.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4565-4584"},"PeriodicalIF":4.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460437","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 Comparative Discussion on the Selection of Cardiac Hypertrophy Models: TAC Surgery Vs Ang II Infusion [Letter].","authors":"Huiye Yang, Xiaotao Wang","doi":"10.2147/DDDT.S497043","DOIUrl":"https://doi.org/10.2147/DDDT.S497043","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4563-4564"},"PeriodicalIF":4.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460431","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":"Addition of Dexmedetomidine to the Anesthesia Regimen Attenuates Pain and Improves Early Recovery After Esophageal Endoscopic Submucosal Dissection: A Randomized Controlled Trial.","authors":"Xin Luo, Hai-Jun Hou, Pei-Shan Chen, Xin-Lu Chang, Yang Li, Li-Xin An, Fu-Kun Liu, Fu-Shan Xue","doi":"10.2147/DDDT.S475749","DOIUrl":"10.2147/DDDT.S475749","url":null,"abstract":"<p><strong>Objective: </strong>Postoperative pain is a common yet often underestimated complication following esophageal endoscopic submucosal dissection (ESD), with limited strategies for effective management. This prospective, double-blind, randomized controlled trial assessed the effects of adding dexmedetomidine (DEX) to the anesthesia regimen on postoperative pain and early recovery in patients undergoing esophageal ESD.</p><p><strong>Methods: </strong>In total, 60 patients scheduled for elective esophageal ESD under general anesthesia were randomly assigned to the DEX or control group. The DEX group received an intravenous loading dose of DEX at 1 μg/kg for 10 min, followed by a continuous intravenous infusion of 0.6 µg/kg/h, which was stopped 30 min before the end of the procedure. The control group received normal saline as a placebo. The study's primary outcome was the incidence of moderate-to-severe postoperative pain. Secondary outcomes included postoperative pain scores, hemodynamic parameters, the occurrence of postoperative nausea and vomiting (PONV), patient satisfaction, and lengths of stay in the post-anesthesia care unit (PACU) and hospital.</p><p><strong>Results: </strong>The incidence of moderate-to-severe postoperative pain in the DEX group was significantly lower than that in the control group (absolute difference: -33.4%; OR: 0.250; 95% CI: 0.085-0.731, <i>P</i> = 0.01). Pain scores at 1 h postoperatively (0.5[2.0] <i>vs</i> 3.0[1.3], <i>P</i> = 0.003) were significantly lower in the DEX group. Additionally, morphine dosage in the PACU (0[0] <i>vs</i> 1.0[2.0] <i>P</i> = 0.004) was significantly reduced in the DEX group compared with the control group. In the DEX group, the incidence and severity of PONV were significantly decreased and the length of PACU stay was shorter than in the control group (<i>P <</i> 0.01). However, the rates of intraoperative hypotension, tachycardia, and bradycardia were similar between the two groups. Patient satisfaction and length of hospital stay were also comparable.</p><p><strong>Conclusion: </strong>Adding DEX to the anesthesia regimen for esophageal ESD significantly attenuates postoperative pain and improves early recovery outcomes.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4551-4562"},"PeriodicalIF":4.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460432","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 Efficacy of Chaihu-Guizhi-Ganjiang Decoction on Chronic Non-Atrophic Gastritis with Gallbladder Heat and Spleen Cold Syndrome and Its Metabolomic Analysis: An Observational Controlled Before-After Clinical Trial [Letter].","authors":"Ying Zhu, Shiyu Geng, Feiye Zhu","doi":"10.2147/DDDT.S497570","DOIUrl":"https://doi.org/10.2147/DDDT.S497570","url":null,"abstract":"","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4527-4528"},"PeriodicalIF":4.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460442","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":"Aqueous Extract of Rhubarb Promotes Hepatotoxicity via Facilitating PKM2-Mediated Aerobic Glycolysis in a Rat Model of Diethylnitrosamine-Induced Liver Cancer.","authors":"Anni Zhao, Xiaomei Liu, Xiping Chen, Sha Na, Hui Wang, Xuan Peng, Peizhong Kong, Lu Li","doi":"10.2147/DDDT.S476273","DOIUrl":"https://doi.org/10.2147/DDDT.S476273","url":null,"abstract":"<p><strong>Objective: </strong>To identify the polar parts in Rhubarb that cause hepatotoxicity and explore the underlying mechanisms.</p><p><strong>Methods: </strong>The rat model of liver cancer was established by gavage of diethylnitrosamine (DEN; 0.002 g/rat) for 14 weeks. Starting from the 11th week, Rhubarb granule (4 g/kg), aqueous, ethyl acetate and n-butanol extract of Rhubarb or Rhein equivalent to a dose of 4 g/kg Rhubarb granule were administered intragastrically for 4 consecutive weeks. Liver tissues from rats treated with DEN and Rhubarb granules were used for non-targeted metabolomics analysis. The correlation between pyruvate kinase isozyme type M2 (PKM2) expression level and the progress and prognosis of hepatocellular carcinoma (HCC) was evaluated through bioinformatics analysis based on TCGA database. Liver tissues and blood samples from rats treated with DEN and aqueous, ethyl acetate and n-butanol extract of Rhubarb were used for the screening of hepatotoxic polar parts of Rhubarb. The liver injuries were evaluated by the changes in pathology, liver function, and the expression levels of proliferating cell nuclear antigen (PCNA) and transforming growth factor beta1 (TGF-β1). The mechanism studies focus on PKM2 expression, and the metabolic reprogramming via detecting the activities of lactate dehydrogenase A (LDHA) and isocitrate dehydrogenase (ICDH). Furthermore, molecular docking analysis was performed to validate the target interaction between Rhein and PKM2, and the hepatotoxicity of Rhein was evaluated by testing liver function in the DEN-induced liver cancer model.</p><p><strong>Results: </strong>The non-targeted metabolomics analysis revealed that Rhubarb promoted aerobic glycolysis in the rat model of DEN-induced liver cancer. And bioinformatics analysis revealed that high PKM2 expression was closely related to the progression and poor prognosis of HCC. In vivo studies indicated that the aqueous extract of Rhubarb, but not ethyl acetate and n-butanol extract, promoted the liver injuries induced by DEN. The mechanism study showed that the aqueous extract of Rhubarb increased the expression of PKM2 and promoted aerobic glycolysis. Moreover, Rhein had a strong binding affinity for PKM2 and aggravated liver injury in the DEN-induced liver cancer model.</p><p><strong>Conclusion: </strong>Aqueous extract of Rhubarb promoted hepatotoxicity via facilitating PKM2-mediated aerobic glycolysis in the rat model of DEN-induced liver cancer.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4497-4510"},"PeriodicalIF":4.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460433","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":"Network Pharmacology and Experimental Verification: SanQi-DanShen Treats Coronary Heart Disease by Inhibiting the PI3K/AKT Signaling Pathway.","authors":"Min Zhao, Liuxiang Feng, Wenhua Li","doi":"10.2147/DDDT.S480248","DOIUrl":"https://doi.org/10.2147/DDDT.S480248","url":null,"abstract":"<p><strong>Objective: </strong>To employee network pharmacology to predict the components and pathways of SanQi-DanShen (SQDS) in treating coronary heart disease, followed by in vitro experiments to validate the molecular mechanism of SQDS in treating coronary heart disease.</p><p><strong>Methods: </strong>We sourced the active ingredients and targets of Panax notoginseng and Danshen from the Traditional Chinese Medicine Systems Pharmacology database. Coronary heart disease related genes were retrieved from the OMIM, Genecards, and Therapeutic Target databases. Using Cytoscape 3.7.2 software, we constructed a network diagram illustrating the components and targets of SQDS. The associated targets were then imported into the STRING database to build a protein-protein interaction network. The Metascape database and WeChat software were utilized for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Lastly, we performed molecular docking between the key components and related targets using AutoDock Vina. To validate the potential mechanism of SQDS in treating coronary heart disease, we established an acute coronary heart disease rat model via tail vein injection of pituitrin.</p><p><strong>Results: </strong>Network pharmacology analysis revealed that 65 active ingredients and 167 targets of SQDS are implicated in the treatment of coronary heart disease. The key targets identified include AKT1, TNF, TP53, IL6, and VEGFA. Notably, the PI3K/AKT signaling pathway emerged as the primary pathway. Furthermore, animal experiments showed that, compared to the model group, SQDS significantly reduced levels of TNF-α, IL-6, Bax, and cardiac troponin I, while increasing Bcl-2 content. It also notably suppressed the expression of p-PI3K and p-AKT, thereby offering protection to myocardial tissue.</p><p><strong>Conclusion: </strong>Through the integrated approach of network pharmacology and molecular docking, we have established that SQDS exerts a multi-component, multi-target, and multi-pathway synergistic therapeutic effect on coronary heart disease. Its mechanism may involve the inhibition of the PI3K/AKT signaling pathway and the reduction of inflammatory factor expression.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4529-4550"},"PeriodicalIF":4.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460438","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":"Investigation of a Radio-Iodinated Alpha-Mangostin for Targeting Estrogen Receptor Alpha (ERα) in Breast Cancer: In Silico Design, Synthesis, and Biological Evaluation.","authors":"Muchtaridi Muchtaridi, Wiwit Nurhidayah, Taufik Muhammad Fakih, Kento Kannaka, Hiroyuki Suzuki, Toto Subroto, Tomoya Uehara","doi":"10.2147/DDDT.S479447","DOIUrl":"https://doi.org/10.2147/DDDT.S479447","url":null,"abstract":"<p><strong>Introduction: </strong>Alpha-mangostin (AM), the most representative xanthone derivative isolated from the rind of the Purple Mangosteen (Garcinia mangostana Linn), has been reported pharmacologically to be associated with breast cancer in silico, in vitro, and in vivo. Although the pharmacological effects of AM are believed to involve the estrogen receptor alpha (ERα), there are no reports available in the literature describing the binding of AM to ERα.</p><p><strong>Methods: </strong>In this study, iodine-125 (¹²⁵I)-labeled AM ([¹²⁵I]I-AM) was prepared, and its binding to ERα was investigated in vitro using MCF-7 cell lines. To investigate the applicability of radioiodine-labeled AM as a radiopharmaceutical for breast cancer, [¹²⁵I]I-AM was injected into nude mice bearing MCF-7.</p><p><strong>Results: </strong>The results obtained showed that the uptake of [¹²⁵I]I-AM into MCF-7 cells was found to be inhibited by AM and tamoxifen, suggesting that its uptake is partially mediated by ERα. In addition, the biodistribution studies using MCF-7 bearing nude mice showed that [¹²⁵I]I-AM accumulated in tumor tissues, although deiodination did occur, reducing the concentration of iodine-125 (¹²⁵I) in the targeted cells.</p><p><strong>Conclusion: </strong>These results suggested that AM would be a useful platform for the development of a new radiopharmaceutical targeting ERα. Further studies are, however, required to reduce deiodination of [¹²⁵I]I-AM in vivo.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4511-4526"},"PeriodicalIF":4.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460436","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":"Dexmedetomidine and Dexamethasone as Adjuvants to the Local Anesthetic Mixture in Rhomboid Intercostal and Sub-Serratus Block for Video-Assisted Thoracoscopic Surgery: A Randomized, Double-Blind, Controlled Trial.","authors":"Quan-Fang Liu, Cui-Na Shi, Jian-Hua Tong, Kun-Peng Li, Jian-Jun Yang, Mu-Huo Ji, Qing-Ren Liu","doi":"10.2147/DDDT.S476929","DOIUrl":"https://doi.org/10.2147/DDDT.S476929","url":null,"abstract":"<p><strong>Background: </strong>The utilization of adjuvants such as dexamethasone and dexmedetomidine in combination with local anesthetics has proven effective in extending analgesia duration. We aimed to investigate the potential efficacy of combining dexmedetomidine and dexamethasone in rhomboid intercostal and sub-serratus (RISS) block for prolonging postoperative analgesia in patients undergoing video-assisted thoracoscopic surgery (VATS).</p><p><strong>Methods: </strong>We did this randomized, double-blind, controlled trial in two tertiary-care hospitals. A total of eighty-eight patients undergoing VATS under general anesthesia were enrolled in this study. They were randomly assigned into four groups: ropivacaine (R) group, ropivacaine + dexmedetomidine (RM) group, ropivacaine + dexamethasone (RS) group, or ropivacaine + dexmedetomidine + dexamethasone (RSM) group. The primary outcome measure was the duration of analgesia. Secondary outcomes included Numeric Rating Scale (NRS) scores, cumulative oxycodone consumption, and adverse effects.</p><p><strong>Results: </strong>The RSM group exhibited a significantly prolonged duration of analgesia at 1073.5 min (932.0-1283.3) compared to the R group with a duration of 154.5 min (80.5-199.3) and the <i>RS</i> group with a duration of 282.0 min (195.3-350.0, <i>P</i> < 0 0.001). The cumulative oxycodone consumption during the 0-12 hours and 0-24-hours period was significantly reduced in the RSM group compared to the R group (<i>P</i> < 0.05). There was also a lower incidence of nausea at 48 hours postoperatively in the RSM group compared to the RM group. However, there were no significant differences between the four groups regarding NRS pain scores.</p><p><strong>Conclusion: </strong>The combination of ropivacaine, dexmedetomidine, and dexamethasone in RISS block significantly prolongs the duration of postoperative analgesia following VATS.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4485-4496"},"PeriodicalIF":4.7,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11468391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460434","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: Mesenchymal Stem Cell-Based <i>NK4</i> Gene Therapy in Nude Mice Bearing Gastric Cancer Xenografts [Corrigendum].","authors":"","doi":"10.2147/DDDT.S493671","DOIUrl":"https://doi.org/10.2147/DDDT.S493671","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.2147/DDDT.S71466.].</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4481-4483"},"PeriodicalIF":4.7,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460435","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":"Sivelestat Sodium Alleviates Ischemia-Reperfusion-Induced Acute Kidney Injury via Suppressing TLR4/Myd88/NF-κB Signaling Pathway in Mice.","authors":"Jie Wang, Yuanbo Wu, Meng Mao, Hailong Bing, Liwei Sun, Wei Xu, Wangli Tian, Zhengyuan Xia, Xiaogao Jin, Qinjun Chu","doi":"10.2147/DDDT.S480148","DOIUrl":"https://doi.org/10.2147/DDDT.S480148","url":null,"abstract":"<p><strong>Purpose: </strong>We aim to detect the effects of sivelestat on renal ischemia-reperfusion associated with AKI and also explore the underlying mechanism.</p><p><strong>Materials and methods: </strong>Mice, aged between 8 and 12 weeks, were randomly allocated among four distinct groups, respectively normal saline sham group(C), normal saline surgery group(I), sivelestat (50 mg/kg) sham group(S), sivelestat (50 mg/kg) surgery group(SI) (n=6, each group). In the surgical groups, the renal pedicles of mice were clamped with non-traumatic micro-aneurysm clamps, resulting in ischemia of the kidneys for 45 minutes. This was followed by a period of reperfusion lasting 24 hours. Sham group mice underwent the identical surgery produced without clamping renal pedicles. Mice blood was obtained from eyeballs, and Serum creatinine and blood urea nitrogen levels were measured. After a 24-hour period of reperfusion, the mice were euthanized, and their kidneys were gathered for various analyses, including Western Blot (WB) analysis, RT-PCR, immunofluorescence (IF), hematoxylin and eosin (H&E) staining, and Tunel assay.</p><p><strong>Results: </strong>Pretreatments with sivelestat decreased renal Neutrophil elastase (NE), serum creatinine, and blood urea nitrogen levels after renal ischemia-reperfusion. Sivelestat also reduced histological damage and cell apoptosis in kidneys following ischemia-reperfusion injury (IRI). In addition, the sivelestat administration diminished the levels of mRNA expression of interleukin 6 (IL-6), Macrophage inflammatory protein-2 (MIP-2), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF)-α in the kidneys during IRI. The kidney tissues of the SI group had significantly mitigated TLR4, Myd88, and NF-κB p-p65 protein expression levels compared to the I group (all P<0.05).</p><p><strong>Conclusion: </strong>We demonstrated a previously unidentified mechanism that sivelestat effectively attenuates AKI-induced renal dysfunction, possibly through suppressing the TLR4/Myd88/ NF-κB pathway.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"18 ","pages":"4449-4458"},"PeriodicalIF":4.7,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11466837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142460441","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}