Drug Development Research最新文献

{"title":"KLF2 Inhibits Ferroptosis and Improves Mitochondrial Dysfunction in Chondrocyte Through SIRT1/GPX4 Signaling to Improve Osteoarthritis","authors":"Jiaqi Shi,&nbsp;Li Chen,&nbsp;Xu Wang,&nbsp;Xin Ma","doi":"10.1002/ddr.70015","DOIUrl":"10.1002/ddr.70015","url":null,"abstract":"<div>\u0000 \u0000 <p>Osteoarthritis (OA), a disease of articular joints, is the leading cause of disability in the elderly. Repressing ferroptosis and improving mitochondrial function can delay the progression of OA. Kruppel-like factor 2 (KLF2) exerts a protective effect on OA. However, whether KLF2 affects ferroptosis and mitochondrial function during OA remains unknown. The OA in vivo and in vitro models were constructed in this work. The structural damage of knee joint in OA mice was evaluated through Micro-CT scanning. H&amp;E, SOFG, TB, and TUNEL staining were applied for pathological examination of cartilage tissues. ELISA was employed to examine the contents of inflammatory factors. Additionally, iron deposition in cartilage tissues was measured by Prussian blue staining, and the levels of proteins related to ferroptosis were assessed by immunoblotting. Besides, mitochondrial morphology and function were estimated using a transmission electron microscope and JC-1 staining. In interleukin (IL)-1β-treated C28/I2 cells, the levels of inflammatory factors, intracellular ROS, mitochondrial ROS, lipid ROS, and Fe²⁺ were measured. Mitochondrial function was evaluated by detecting the levels of mitochondrial membrane potential (MMP), ATP, mPTP, and OCR. KLF2 overexpression ameliorated the structural damage of knee cartilage in OA mice. KLF2 upregulation inhibited ferroptosis and alleviated mitochondrial damage in knee cartilage of OA mice and IL-1β-treated C28/I2 cells. Moreover, KLF2 overexpression activated SIRT1/GPX4 signaling in vivo and in vitro. EX527 addition blocked the influences of KLF2 upregulation on ferroptosis and mitochondrial dysfunction in IL-1β-treated C28/I2 cells. Altogether KLF2 inhibits ferroptosis and improves mitochondrial dysfunction in chondrocytes through SIRT1/GPX4 signaling to improve OA.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Fatty Acid Metabolism, the Related Potential Biomarkers, and Targeted Therapeutic Strategies in Gastrointestinal Cancers","authors":"Ruixi Xie,&nbsp;Ying Luo,&nbsp;Bowen Bao,&nbsp;Xinshu Wu,&nbsp;Jia Guo,&nbsp;Jin Wang,&nbsp;Xiujuan Qu,&nbsp;Xiaofang Che,&nbsp;Chunlei Zheng","doi":"10.1002/ddr.70014","DOIUrl":"10.1002/ddr.70014","url":null,"abstract":"<div>\u0000 \u0000 <p>Gastrointestinal cancer has emerged as a significant global health concern due to its high incidence and mortality, limited effectiveness of early detection, suboptimal treatment outcomes, and poor prognosis. Metabolic reprogramming is a prominent feature of cancer, and fatty acid metabolism assumes a pivotal role in bridging glucose metabolism and lipid metabolism. Fatty acids play important roles in cellular structural composition, energy supply, signal transduction, and other lipid-related processes. Changes in the levels of fatty acid metabolite may indicate the malignant transformation of gastrointestinal cells, which have an impact on the prognosis of patients and can be used as a marker to monitor the efficacy of anticancer therapy. Therefore, targeting key enzymes involved in fatty acid metabolism, either as monotherapy or in combination with other agents, is a promising strategy for anticancer treatment. This article reviews the potential mechanisms of fatty acid metabolism disorders in the occurrence and development of gastrointestinal tumors, and summarizes the related potential biomarkers and anticancer strategies.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown of ENO1 promotes autophagy dependent-ferroptosis and suppresses glycolysis in breast cancer cells via the regulation of CST1","authors":"Guoliang Huang,&nbsp;Lian Lu,&nbsp;Yuhong You,&nbsp;Jie Li,&nbsp;Kaixiang Zhang","doi":"10.1002/ddr.70004","DOIUrl":"10.1002/ddr.70004","url":null,"abstract":"<p>Autophagy-dependent ferroptosis and glycolysis play a significant role in tumor development. α-Enolase (ENO1), a glycolytic enzyme, has been demonstrated to function as a crucial modulator in breast cancer (BC). However, the specific mechanism by which ENO1 influences the ferroptosis and glycolysis of BC remains unclear. qRT-PCR, along with western blot analysis was applied to investigate ENO1 and cystatin SN (CST1) expression in BC cells. Glycolysis level was measured by extracellular acidification rate (ECAR), lactate production, glucose consumption, and western blot analysis. Ferroptosis was evaluated by iron and lipid peroxidation assay, DCFH-DA staining, and western blot analysis. Immunofluorescence, together with western blot analysis was adopted for assessing cell autophagy and mTOR signaling pathway. Cell apoptosis and Ki67 level were measured by TUNEL and immunohistochemistry, respectively. ENO1 had abundant existence in BC cell lines. ENO1 silencing inhibited glycolysis but promoted ferroptosis and autophagy. In addition, autophagy inhibitor 3-MA reversed the impacts of ENO1 silencing on glycolysis and ferroptosis. Meanwhile, mTOR activator MHY1485 demonstrated opposing effects on autophagy. Moreover, CST1 could be extensively found in BC cell lines, and its overexpression reversed the effects of ENO1 silencing on glycolysis and ferroptosis. In vivo experiments illustrated that ENO1 deletion suppressed BC tumor growth, increased the apoptosis rate, restrained cell proliferation, and glycolysis, but promoted ferroptosis and autophagy, as well as reducing CST1 and mTOR signaling. To sum up, ENO1 silencing mediated a utophagy-dependent ferroptosis and glycolysis in BC cells by regulating CST1.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PARP7i Clinical Candidate RBN-2397 Exerts Antiviral Activity by Modulating Interferon-β Associated Innate Immune Response in Macrophages","authors":"Xiaoli Du,&nbsp;Jiawei Zhou,&nbsp;Yi Zhou,&nbsp;Yulong Chen,&nbsp;Yanhua Kang,&nbsp;Dongjiu Zhao,&nbsp;Xiang-Yang Ye,&nbsp;Liwei Wang,&nbsp;Tian Xie,&nbsp;Hang Zhang","doi":"10.1002/ddr.70013","DOIUrl":"10.1002/ddr.70013","url":null,"abstract":"<div>\u0000 \u0000 <p>Polyadenosine diphosphate-ribose polymerase 7 (PARP7) acts as a suppressor of the type I interferon (IFN) signaling pathway via suppressing TANK-binding protein 1 (TBK1). Research study indicates that inhibition of PARP7 could potentially regulate tumor immunity. However, the effect of PARP7 inhibition on innate antiviral immunity in macrophages as well as the underlying mechanism have not been demonstrated else well. We report herein that PARP7 inhibitor clinical candidate RBN-2397 could augment type I interferon (IFN-I) production in macrophages by elevating retinoic acid-inducible gene I (RIG-I) and stimulator of interferon genes (STING) signaling pathways. Treatment with RBN-2397 leads to increased pattern recognition ligands-induced interferon-β production in primary bone marrow-derived macrophages (BMDM) and RAW264.7 cells. Additionally, RBN-2397 suppresses viral replication efficiency in macrophages infected by vesicular stomatitis virus (VSV) and amplifies the expression of interferon-stimulated chemokine genes (ISGs). Mechanistically, RBN-2397 promotes TBK1 phosphorylation, consequently leading to the amplified activation of RIG-I and STING signaling pathways. Furthermore, RBN-2397 enhances the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2 induced by IFN-α/β and the expression of chemokine genes in macrophages in response to IFN stimulation. In vivo experiments demonstrated that RBN-2397 enhances innate antiviral immunity in mice infected with VSV, resulting in increased serum IFN-β levels, reduced viral loads, and alleviated pulmonary inflammatory responses of the VSV-infected mice. In conclusion, our findings highlight the potential of RBN-2397 as a promising antiviral therapeutic agent for enhancing the IFN-relative antiviral immune defense in host.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MLLT3 knockdown suppresses proliferation and cell mobility in human lung adenocarcinoma","authors":"Wenbo Shi,&nbsp;Tongyangzi Zhang,&nbsp;Li Zhang,&nbsp;Wanzhen Li,&nbsp;Zhiwei Chen,&nbsp;Xianghuai Xu","doi":"10.1002/ddr.70010","DOIUrl":"10.1002/ddr.70010","url":null,"abstract":"<p>Lung cancer is emerging as one of the most frequently encountered malignancies around the world that carries high morbidity and mortality. Lung adenocarcinoma (LUAD) has become the most common subtype of lung cancer. MLLT3 or named AF9 was first characterized in acute myeloid leukemia and can downregulate the expression of several critical genes. The aim of this study was to explore the function of MLLT3 in the progression of LUAD and related molecular mechanisms. Immunohistochemistry was employed to assess MLLT3 expression in LUAD tissues, while quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were utilized to detect MLLT3 expression levels in lung adenocarcinoma cell lines. These results revealed a significant overexpression of MLLT3 in LUAD cell lines and tissues. We further uncovered an association between MLLT3 expression profiles in LUAD tissues and metastasis, as well as TNM stage. Survival analysis showed that elevated MLLT3 correlated with a poorer survival rate. We also found that MLLT3 knockdown repressed LUAD cells invasion, migration, and proliferation in vitro, while inducing cell cycle arrest and apoptosis of LUAD cells. Moreover, knocking down MLLT3 inhibited tumor growth in vivo. Specific markers of apoptosis, cell cycle, epithelial-mesenchymal transition (EMT), and MLLT3-induced signaling were examined by Western blot. We demonstrated that MLLT3 knockdown inhibited the activity of the EGFR-MAPK/ERK signaling pathway, and MLLT3 might be a novel diagnostic biomarker and therapeutic target in lung adenocarcinomas.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted therapies for Glioblastoma multiforme (GBM): State-of-the-art and future prospects","authors":"Smera Satish,&nbsp;Maithili Athavale,&nbsp;Prashant S. Kharkar","doi":"10.1002/ddr.22261","DOIUrl":"10.1002/ddr.22261","url":null,"abstract":"<p>Glioblastoma multiforme (GBM) remains one of the most aggressive and lethal forms of brain cancer, characterized by rapid growth and resistance to conventional therapies. The present review explores the latest advancements in targeted therapies for GBM, emphasizing the critical role of the blood-brain barrier (BBB), blood-brain-tumor barrier, tumor microenvironment, and genetic mutations in influencing treatment outcomes. The impact of the key hallmarks of GBM, for example, chemoresistance, hypoxia, and the presence of glioma stem cells on the disease progression and multidrug resistance are discussed in detail. The major focus is on the innovative strategies aimed at overcoming these challenges, such as the use of monoclonal antibodies, small-molecule inhibitors, and novel drug delivery systems designed to enhance drug penetration across the BBB. Additionally, the potential of immunotherapy, specifically immune checkpoint inhibitors and vaccine-based approaches, to improve patient prognosis was explored. Recent clinical trials and preclinical studies are reviewed to provide a comprehensive overview of the current landscape and future prospects in GBM treatment. The integration of advanced computational models and personalized medicine approaches is also considered, aiming to tailor therapies to individual patient profiles for better efficacy. Overall, while significant progress has been made in understanding and targeting the complex biology of GBM, continued research and clinical innovation are imperative to develop more effective and sustainable therapeutic options for patients battling this formidable disease.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Agmatine: An Emerging Approach for Neuroprotection in Recurrent Ischemic Stroke Events in a Murine Model","authors":"M. L. Miranda-Mosqueda,&nbsp;S. Y. Ruiz-Oropeza,&nbsp;J. A. González-Barrios,&nbsp;R. Jaimez,&nbsp;Fernando Peña-Ortega,&nbsp;C. Gómez-Acevedo","doi":"10.1002/ddr.70012","DOIUrl":"10.1002/ddr.70012","url":null,"abstract":"<p>This study investigates the effect of agmatine on reducing mortality, neurobehavioral alterations, infarct size, and expression of pro-inflammatory cytokines in mice subjected to bilateral carotid thrombosis. Under pentobarbital anesthesia, the left common carotid artery was exposed to 6% FeCl₃. Thirty-two days later, the same procedure was performed on the right common carotid artery. Subsequently, Agmatine (100 mg/kg) was administered 15 min after the second procedure, and in another experimental group, the dose of Agmatine was repeated at 72 h. Administration of agmatine extended survival in ischemic animals up to 72 h for the single-dose group and up to 96 h for the repeated-dose group, without significant increases in neurological deficits or infarct area size. This neurobehavioral effect was also observed in sham animals treated with agmatine. In ischemic animals, agmatine administration improved digging behavior and reduced recovery times, consistently shorter in those animals treated with repeated doses. RT-PCR analyses revealed a positive regulation of the cytokine IL-1β in agmatine-treated animals, which has been associated with recovery stages. The results suggest that the observed effect may be attributed to the multiple interactions of agmatine with ischemic cascade events, highlighting its anti-inflammatory role.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular docking, DFT and antiproliferative properties of 4-(3,4-dimethoxyphenyl)−3-(4-methoxyphenyl)−1-phenyl-1H-pyrazolo[3,4-b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency","authors":"Faizah A. Binjubair,&nbsp;Basma S. Almansour,&nbsp;Noha I. Ziedan,&nbsp;Alaa A.-M. Abdel-Aziz,&nbsp;Sara T. Al-Rashood,&nbsp;Mohamed K. Elgohary,&nbsp;Mahmoud S. Elkotamy,&nbsp;Hatem A. Abdel-Aziz","doi":"10.1002/ddr.70009","DOIUrl":"10.1002/ddr.70009","url":null,"abstract":"<p>Due to the limited effeteness and safety concerns associated with current cancer treatments, there is a pressing need to develop novel therapeutic agents. 4-(3,4-Dimethoxyphenyl)−3-(4-methoxyphenyl)−1-phenyl-1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridine (<b>3</b>) was synthesized and Initially screened on 59 cancer cell lines showed promising anticancer activity, so, it was chosen for a 5-dose experiment by the NCI/USA. The GI₅₀ values ranged from 1.04 to 8.02 μM on the entire nine panels (57 cell lines), with a GI₅₀ of 2.70 μM for (MG-MID) panel, indicating an encouraging action. To further explore the molecular attributes of compound <b>3</b>, we optimized its structure using DFT with the B3LYP/6-31 + + G(d,p) basis set. We have considered vibrational analysis, bond lengths and angles, FMOs, and MEP for the structure. Additionally, pharmacokinetic assessments were conducted using various in-silico platforms to evaluate the compound safety. A molecular modeling study created a kinase profile on 44 different kinases. This allowed us to study our compound's binding affinity to these kinases and compare it to the co-crystallized one. Our findings revealed compound <b>3</b> exhibited better binding for half of the tested kinases, suggesting its potential as a multi-kinase inhibitor. To further validate our computational results, we tested compound <b>3</b> for its inhibitory effects on CDK2 and PIM1. Compound <b>3</b> exhibited an IC₅₀ of 0.30 µM for CDK2 inhibition, making it five times less active than Roscovitine, which has an IC₅₀ of 0.06 µM. However, compound <b>3</b> demonstrated slightly better inhibition of PIM1 compared to Staurosporine. These findings suggest that compound <b>3</b> is a promising anticancer agent with the potential for further development into a highly active compound.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA sequencing comparing centenarian and middle-aged women lymphoblastoid cell lines identifies age-related dysregulated expression of genes encoding selenoproteins, heat shock proteins, CD99, and BID","authors":"Irena Voinsky,&nbsp;Ofir Goldenberg-Bogner,&nbsp;Ifat Israel-Elgali,&nbsp;Hadas Volkov,&nbsp;Monika Puzianowska-Kuźnicka,&nbsp;Noam Shomron,&nbsp;David Gurwitz","doi":"10.1002/ddr.70011","DOIUrl":"10.1002/ddr.70011","url":null,"abstract":"<p>Women typically live longer than men, and constitute the majority of centenarians. We applied RNA-sequencing (RNA-seq) of blood-derived lymphoblastoid cell lines (LCLs) from women aged 60-80 years and centenarians (100-105 years), validated the RNA-seq findings by real-time PCR, and additionally measured the differentially expressed genes in LCLs from young women aged 20-35 years. Top RNA-seq genes with differential expression between the age groups included three selenoproteins (<i>GPX1, SELENOW, SELENOH</i>) and three heat shock proteins (<i>HSPA6, HSPA1A, HSPA1B</i>), with the highest expression in LCLs from young women, indicating that young women are better protected from oxidative stress. The expression of two additional genes, <i>BID</i> encoding BH3-interacting domain death agonist and <i>CD99</i> encoding CD99 antigen, showed unique age dependence, with similar expression levels in young and centenarian women while exhibiting higher and lower expression levels, respectively, in LCLs from women aged 60-80 years compared with the two other age groups. This age-related differential expression of <i>BID</i> and <i>CD99</i> suggests elevated inflammation susceptibility in middle-aged women compared with either young or centenarian women. Our findings, once validated with human peripheral blood mononuclear cells and further cell types, may lead to novel healthy aging diagnostics and therapeutics.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of BIX01294 in the intracranial inhibition of H3K9 methylation lessens neuronal loss in vascular dementia model","authors":"Fardin Sehati,&nbsp;Saereh Hosseindoost,&nbsp;Mina Ranjbaran,&nbsp;Fatemeh Nabavizadeh,&nbsp;Seyed-Morteza Karimian,&nbsp;Soheila Adeli,&nbsp;Elham Zahedi,&nbsp;Leila Chodari,&nbsp;Ghorbangol Ashabi","doi":"10.1002/ddr.70001","DOIUrl":"10.1002/ddr.70001","url":null,"abstract":"<p>Dementia develops as a result of multiple factors, including cerebrovascular disease which is called vascular dementia (VD). Histone-3 lysine-9 dimethylation (H3K9me2) broadly increases during VD and inhibits neuroprotective gene expressions. So, we aimed to determine how H3K9me2 inhibitor (BIX01294) affects neuronal damage in VD. An in vivo model of VD was used followed by BIX01294 treatment. Behavioral tests, hematoxylin, and eosin (H&amp;E), Congo red, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were carried out. Hippocampal phosphorylated cyclic-AMP responsive element binding protein (p-CREB), c-fos, brain-derived neurotrophic factor (BDNF), and H3K9me2, were detected by western blot analysis technique. Neurological deficit and anxiety-related behavior significantly reduced in the treatment group compared to the VD group (<i>p</i> &lt; 0.05). BIX01294 improved spatial and passive avoidance memory (<i>p</i> &lt; 0.01 and <i>p</i> &lt; 0.05, respectively) compared to the VD group. Treatment with BIX01294 restored the level of p-CREB/CREB ratio (<i>p</i> &lt; 0.05), cfos (<i>p</i> &lt; 0.01), BDNF (<i>p</i> &lt; 0.01), and suppressed H3K9me2 (<i>p</i> &lt; 0.001) when compared to the VD group. BIX01294 microinjection reduced the apoptosis level in TUNEL staining (<i>p</i> &lt; 0.05), and raised neural cell count in H&amp;E staining (<i>p</i> &lt; 0.01); amyloid beta accumulation significantly decreased in the treatment group (<i>p</i> &lt; 0.05) compared to the VD group. In conclusion, long-term treatment with a low dose of BIX01294 can prevent the progression of neuronal loss in VD model by raising the expression of neurotrophic factors, and reducing the apoptosis level.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 7","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}