Drug Development Research最新文献

{"title":"Design, Synthesis, Biological Evaluation and Molecular Docking Study of New 1,3,4-Thiadiazole-Based Compounds as EGFR Inhibitors","authors":"Marwa I. Serag,&nbsp;Samar S. Tawfik,&nbsp;Hassan M. Eisa,&nbsp;Sahar M. I. Badr","doi":"10.1002/ddr.70035","DOIUrl":"10.1002/ddr.70035","url":null,"abstract":"<div>\u0000 \u0000 <p>Five series of new 1,3,4-thiadiazole hybrids were designed and synthesized as promising EGFR inhibitors. Three human cancer cell lines were employed for testing each hybrid's in vitro antiproliferative efficacy; colon HCT-116, liver HepG-2 and breast MCF-7 using MTT assay. Comparing compound <b>9a</b> to the reference doxorubicin, <b>9a</b> shown superior activity to that of Dox with respect to MCF-7 (IC₅₀ 3.31 µM) while being secure for normal cells WI-38 (IC₅₀ = 43.99 µM). Further evaluation of the EGFR inhibitory activity of the most active candidates—<b>4a, 6b</b>, <b>8b, 9a</b>, and <b>9 d</b>—was performed. Of them, compounds <b>9a</b> and <b>8b</b> demonstrated the highest IC₅₀ values, 0.08 and 0.15 µM, respectively, relative to the reference gefitinib (IC₅₀ = 0.04 µM). Subsequent mechanistic analysis of compound <b>9a</b> revealed a notable 14.24-fold increase in overall apoptosis and a 28.92% cell cycle arrest at G2/M. Additionally, research on apoptosis demonstrated that it triggered the mitochondrial apoptotic pathway. In MCF-7 cells, it also led to an increase in ROS buildup. For the most powerful EGFR inhibitors, <b>9a</b> and <b>8b</b>, a molecular docking research was conducted, and all of the findings agreed with the biological findings.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881619","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":"Phthalazine Derivatives as VEGFR-2 Inhibitors: Docking, ADMET, Synthesis, Design, Anticancer Evaluations, and Apoptosis Inducers","authors":"Hatem Hussein Bayoumi,&nbsp;Mohamed-Kamal Ibrahim,&nbsp;Mohammed A. Dahab,&nbsp;Fathalla Khedr,&nbsp;Khaled El-Adl","doi":"10.1002/ddr.70037","DOIUrl":"10.1002/ddr.70037","url":null,"abstract":"<div>\u0000 \u0000 <p>New phthalazine-derived inhibitors for VEGFR-2 were synthesized for anticancer evaluations. Also, docking studies were performed to explore the suggested binding orientations of the novel derivatives inside the binding site of VEGFR-2. The achieved biological data were extremely interrelated to that of docking study. In specific, derivative <b>3f</b> was the greatest effective compound against HepG2 and MCF-7 cancer cell lines with IC₅₀ = 0.17 ± 0.01 and 0.08 ± 0.01 µM individually. The six highly active derivatives <b>3b, 3e, 3f, 3g, 6a,</b> and <b>6b</b> were estimated for their VEGFR-2 inhibitory effects. Derivative <b>3f</b> was the greatest effective compound which inhibited VEGFR-2 at IC₅₀ = 0.0557 ± 0.002 µM. The activities of <b>3f</b> were assessed against MCF-7 cancer cells for apoptosis induction, cell cycle distribution, and growth inhibition. Compound <b>3f</b> induced early apoptosis (21.44%) by more than 36 folds over the control (0.59%). The obtained results showed that compound <b>3f</b> induced necrotic effect (6.03%) by more than threefolds over the control (1.75%). On the other hand, compound <b>3f</b> improved the level of the pro-apoptotic protein; Bax by approximately fivefolds. Moreover, compound <b>3f</b> noticeably decreased the levels of the anti-apoptotic proteins Bcl-2 by nearly fourfolds in comparison to the control. In addition, derivative <b>3f</b> remarkably enhanced the Bax/Bcl2 ratio by nearly 18 folds, as compared to the control. Finally, our derivatives <b>3f, 3g,</b> and <b>6b</b> revealed good in silico considered ADMET profile in comparing to sorafenib.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881629","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":"Exosome-Shuttled METTL14 From AML-Derived Mesenchymal Stem Cells Promotes the Proliferation and Radioresistance in AML Cells by Stabilizing ROCK1 Expression via an m6A-IGF2BP3-Dependent Mechanism","authors":"Cheng Wang,&nbsp;Rui Song,&nbsp;Jinjin Yuan,&nbsp;Ge Hou,&nbsp;A lan Chu,&nbsp;Yangyang Huang,&nbsp;Chenhu Xiao,&nbsp;Ting Chai,&nbsp;Chen Sun,&nbsp;Zongwen Liu","doi":"10.1002/ddr.70025","DOIUrl":"10.1002/ddr.70025","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <p>Acute myelogenous leukemia (AML)-derived mesenchymal stem cells (MSCs) (AML-MSCs) have been identified to play a significant role in AML progression. The functions of MSCs mainly depend on their paracrine action. Here, we investigated whether AML-MSCs functioned in AML cells by transferring METTL14 (Methyltransferase 14) into AML cells via exosomes. Functional analyses were conducted using MTT assay, 5-ethynyl-2-deoxyuridine assay and flow cytometry. qRT-PCR and western blot analyses detected levels of mRNAs and proteins. Exosomes (exo) were isolated from AML-MSCs by ultracentrifugation. The m6A modification profile was determined by methylated RNA immunoprecipitation (MeRIP) assay. The interaction between Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and Rho Kinase 1 (ROCK1) was validated using RIP assay. AML-MSCs incubation promoted the proliferation and radioresistance in AML cells. Moreover, AML-MSCs incubation led to increases in m6A levels and METTL14 levels in AML cells. METTL14 was transferred into AML cells by packaging into exosomes of AML-MSCs. The knockdown of METTL14 in AML-MSCs exosomes could reduce the proliferation and radioresistance in AML cells. Mechanistically, METTL14 induced ROCK1 m6A modification and stabilized its expression by an m6A-IGF2BP3-dependent mechanism. Rescue assay showed that ROCK1 overexpression reversed the inhibitory effects of METTL14 silencing in AML-MSCs exosomes on AML cell proliferation and radioresistance. Exosome-shuttled METTL14 from AML-MSCs promoted proliferation and conferred radioresistance in AML cells by stabilizing ROCK1 expression via an m6A-IGF2BP3-dependent mechanism.</p>\u0000 </section>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846131","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":"Structural Diversity and Mutational Challenges of Toll-Like Receptor 4 Antagonists as Inflammatory Pathway Blocker","authors":"S. K. Batin Rahaman,&nbsp;Sandip K. Nandi,&nbsp;Sudip Kumar Mandal,&nbsp;Utsab Debnath","doi":"10.1002/ddr.70031","DOIUrl":"10.1002/ddr.70031","url":null,"abstract":"<div>\u0000 \u0000 <p>Toll-like receptor 4 (TLR4) is an important mediator that activates bacterial inflammation through its signaling pathway. It binds lipopolysaccharide (LPS) in the presence of myeloid differentiation protein 2 (MD2) to dimerise the TLR4-MD2-LPS complex. The TLR4 mediated signaling pathway stimulates cytokine production in humans, initiating inflammatory responses. Overactivation of the TLR4 pathway can trigger binding of LPS to the TLR4-MD2 complex, which may lead to the development of several inflammatory disorders. Therefore, the TLR4-MD2 complex is a potential therapeutic target for the identification of new and effective anti-inflammatory agents. Various biologically active TLR4 and MD2 targeting natural and synthetic molecules are explored with anti-inflammatory activity in micromolar ranges. But no FDA-approved drugs are available in the market as of now, and some are discontinued in clinical trials due to drug resistance and severe side effects. In this review, we have assessed recent molecular advancements in TLR4-MD2 antagonists which are showing direct inhibition in lower micro and nanomolar levels. Along with it, protein informatics analysis of the binding pockets of wild type and mutated TLR4-MD2 proteins are also discussed here to give a new insight about the changes in physicochemical properties of the ligand binding area. We have also pointed out several important residues in three different sites of the large LPS binding pocket of TLR4-MD2 complex to understand probable binding affinity of small molecule inhibitors (SMIs). In addition, the present status of clinical trials for TLR4 antagonists is also reviewed. The current assessment will pave a future perspective to design different small molecules as a direct inhibitor of TLR4-MD2 complex for anti-inflammatory activities.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 1","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846144","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":"Research Progress of Endoplasmic Reticulum Targeting Metal Complexes in Cancer Therapy","authors":"Shihang Xu,&nbsp;Xiaoling Wu,&nbsp;Jia Zhu,&nbsp;Qiuming Wu,&nbsp;Lijuan Gao,&nbsp;Feng Yang,&nbsp;Zhenlei Zhang","doi":"10.1002/ddr.70027","DOIUrl":"10.1002/ddr.70027","url":null,"abstract":"<div>\u0000 \u0000 <p>The development of anticancer drugs that target different organelles has received extensive attention due to the characteristics of cancer recurrence, metastasis, and drug resistance. The endoplasmic reticulum (ER) is an important structure within the cell that is primarily responsible for protein synthesis, folding, modification, and transport and plays a crucial role in cell function and health. ER stress activation induces cancer cell apoptosis. New anticancer drugs with different anticancer mechanisms and selectivity can be designed because of redox activity, composition diversity, and metal complexes structure regulation. Over the past few decades, dozens of metal complexes have killed cancer cells through ER stress, showing powerful tumor-suppressive effects. This review summarizes the progress of research on anticancer metallic drugs that induce ER stress over the past few years, which is expected to bring more breakthroughs in the field of medicine and life science.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827746","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":"Lifitegrast, a Lymphocyte Function-Associated Antigen-1 Antagonist Demonstrates Beneficial Effect in Psoriasis","authors":"Rahul Sudhakar Gawande,&nbsp;Lakshmi Rao Thakkalapally,&nbsp;Anil M. Pethe","doi":"10.1002/ddr.70034","DOIUrl":"10.1002/ddr.70034","url":null,"abstract":"<div>\u0000 \u0000 <p>Lifitegrast is a lymphocyte function-associated antigen-1 (LFA-1) antagonist, which is approved for treatment of dry eye disease. In this work we explored the effect of lifitegrast in imiquimod induced psoriasis model in mice. Lifitegrast (5% solution) was tested in imiquimod-induced psoriasis model in C57 mice. Lifitegrast was topically administered twice a day to the psoriatic skin for 6 days and epidermal skin thickness, psoriasis area and severity index (PASI) score and inflammation markers were assessed. Lifitegrast inhibited the imiquimod-induced increase in the epidermal thickness, histopathological changes and PASI score. This decrease in psoriasis inflammation was accompanied by decrease in TNF-α, IL-6, IL-22 and IL-17/IL-23 axis gene expression in the skin, and the effect is comparable to the oral cyclosporine A(5 mg/kg, twice a day) treatment. Lifitegrast demonstrated significant anti-inflammatory activity, mainly through reduction in cytokine gene expression related to psoriasis and decreased the severity of psoriasis in vivo. The significant effect shown by this LFA-1 and ICAM-1 antagonist indicates a novel topical treatment for psoriasis.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827742","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":"Fluorinated Sulfonamides: Synthesis, Characterization, In Silico, Molecular Docking, ADME, DFT Predictions, and Structure-Activity Relationships, as Well as Assessments of Antimicrobial and Antioxidant Activities","authors":"Mohamed A. M. Abdel Reheim,&nbsp;Basma Ghazal,&nbsp;Sayeda Abdelrazek Abdelhamid,&nbsp;Gameel A. M. Elhagali,&nbsp;Mohamed S. A. El-Gaby","doi":"10.1002/ddr.70029","DOIUrl":"10.1002/ddr.70029","url":null,"abstract":"<div>\u0000 \u0000 <p>The design and synthesis of unique two series of fluorinated sulfonamides 3a-f and 5a-g utilizing nucleophilic aromatic substitution reactions of tetrafluorophthalonitrile <b>1</b> with various sulfonamides 2 under a variety of different reactions conditions were the key goals of the current research. The chemical composition of the generated products has been investigated via mass spectroscopy, ¹HNMR, ¹³CNMR, infrared, and elemental analyzes. Antimicrobial studies were conducted in vitro to evaluate the activity of all new synthesized compounds against resistant strains. The first series showed high potency in very low concentrations. All compounds were studied against DPPH Radical Scavenging Activity and the other series showed high activity even in low molar ratio. In silico molecular docking was used to investigate the potential binding pathways for different receptors: dihydroprotien synthase protein (ID Code: 1AJ0) as an antibacterial and EGFR^WT co-crystallized with erlotinib [PDB ID code 1m17]. Furthermore, synthesized compounds with good ADME predictions to the Lipinski rule of five demonstrated that the recently synthesized compounds had high drug-likeness qualities when the physicochemical parameter for the most powerful novel candidates was determined. Moreover, the DFT/B3LYP method functionalized with a 6-31G (d, p) basis set was employed to calculate quantum parameters, MEP analysis, HUMO, and LUMO.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827737","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":"AEBP1 Silencing Protects Against Cerebral Ischemia/Reperfusion Injury by Regulating Neuron Ferroptosis and Microglia M2 Polarization Through PRKCA-PI3K-Akt Axis","authors":"Yafen Zhang,&nbsp;Yan Li,&nbsp;Fengli Liu","doi":"10.1002/ddr.70032","DOIUrl":"10.1002/ddr.70032","url":null,"abstract":"<div>\u0000 \u0000 <p>Cerebral ischemia/reperfusion injury is one of the main causes of neuronal damage. Neuron ferroptosis and microglia polarization are considered as critical processes during cerebral ischemia/reperfusion. Adipocyte enhancer-binding protein 1 (AEBP1) usually acts as a transcriptional repressor which is involved in various diseases. However, it is still remains unknown whether AEBP1 could have important roles in regulating the neuron ferroptosis and microglia polarization in cerebral ischemia/reperfusion injury. The oxygen-glucose deprivation and reperfusion (OGD/R)-treated cells and middle cerebral artery occlusion (MCAO)-treated mice were used as in vitro and in vivo models. The differentially expressed factors were analyzed according to GEO datasets. Relative mRNA and protein expression levels were detected by qRT-PCR and western blot analysis. Cell viability was measured by CCK-8 assay. ROS, GSH and iron contents were detected using specifical assay kits. CD26 and CD206 levels were measured by immunofluorescence assay. Inflammatory cytokines were detected by ELISA. The association between AEBP1 and PRKCA was assessed by luciferase reporter and ChIP analyses. The neuron damage in mice was analyzed by TTC staining and neurological deficit score. Transcription factor AEBP1 was increased in OGD/R-treated HT22 and BV2 cells. AEBP1 silencing attenuated OGD/R-induced HT22 cell ferroptosis through increasing cell viability, GSH and GPX4 levels, and decreasing ROS, iron and ACSL4 levels. AEBP1 knockdown promoted microglia M2 polarization by increasing CD206-positive cells and Arg-1 level, and reducing iNOS, TNF-α, IL-1β and IL-6 levels in BV2 cells. AEBP1 transcriptionally repressed PRKCA expression, and further regulated PI3K/Akt signaling activation. Inhibition of PRKCA or PI3K/Akt reversed the effects of AEBP1 silencing on neuron ferroptosis and microglia M2 polarization. AEBP1 downregulation attenuated neuronal damage by decreasing infarct size and deficit scores in MCAO-treated mice. AEBP1 silencing mitigated neuron ferroptosis and promoted microglia M2 polarization through increasing PRKCA and activating PI3K/Akt signaling, indicating the potentially protective action of AEBP1 knockdown in cerebral ischemia/reperfusion injury.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817198","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":"Design and Discovery of New Dual Carbonic Anhydrase IX and VEGFR-2 Inhibitors Based on the Benzenesulfonamide-Bearing 4-Thiazolidinones/2,4-Thiazolidinediones Scaffold","authors":"Merve Zengin,&nbsp;Oya Unsal Tan,&nbsp;Suna Sabuncuoglu,&nbsp;Reem K. Arafa,&nbsp;Ayla Balkan","doi":"10.1002/ddr.70030","DOIUrl":"10.1002/ddr.70030","url":null,"abstract":"<div>\u0000 \u0000 <p>Dual-targeting drug design has become a popular approach in investigating and developing potent anticancer agents. In this regard, carbonic anhydrase (CAIX) and vascular endothelial growth factor receptor (VEGFR-2) are emerging as highly effective targets in the battle against cancer. In the present study, two series of 4-thiazolidinones/2,4-thiazolidinediones carrying 2-methylbenzenesulfonamide derivatives were designed and synthesized as potential dual CAIX/VEGFR-2 inhibitors. All the target compounds were evaluated against CAIX enzyme compared to dorzolamide and acetazolamide, subsequently the most potent CAIX inhibitors (<b>3a</b>, <b>3b</b>, <b>3o</b>, <b>6d</b>, <b>6g</b>, and <b>6i</b>) were selected to evaluate their inhibitory activity against VEGFR-2 using sorafenib as a reference drug. These compounds were also evaluated against MCF-7 breast cancer cells and the murine fibroblast 3T3 cell line. According to the results, <b>3b</b> (CAIX IC₅₀ = 0.035 µM, VEGFR-2 IC₅₀ = 0.093 µM) and <b>6i</b> (CAIX IC₅₀ = 0.041 µM, VEGFR-2 IC₅₀ = 0.048 µM) emerged the most potent compounds against CAIX and VEGFR-2. Furthermore, docking studies of selected compounds were performed with the CAIX and the tyrosine kinase domain of VEGFR-2 to comprehend the ligand-binding interactions. Physicochemical predictions were examined using in silico techniques. In conclusion, these scaffolds present promising leads and furnish promising chemical backbones for the design of potent dual CAIX and VEGFR-2 inhibitors.b</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806118","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":"Heme Oxygenase-1 Overexpression Activates the IRF1/DRP1 Signaling Pathway to Promote M2-Type Polarization of Spinal Cord Microglia","authors":"Wenping Lin,&nbsp;Ziming Cai,&nbsp;Jinzhu Liang,&nbsp;Ping Miao,&nbsp;Ye Ruan,&nbsp;Pian Li,&nbsp;Shuhui Lin,&nbsp;He Tian,&nbsp;Qinghe Yu,&nbsp;Xu He","doi":"10.1002/ddr.70033","DOIUrl":"10.1002/ddr.70033","url":null,"abstract":"<div>\u0000 \u0000 <p>Microglia-mediated neuroinflammatory responses have a critical function in the spinal cord injury (SCI) mechanism, and targeted modulation of microglia activity has emerged as a new therapeutic strategy for SCI. Heme oxygenase 1(HO-1) regulates the close dynamic crosstalk between oxidative stress and inflammatory responses. This investigation aimed to study the molecular pathways by which HO-1 regulates the inflammatory response of microglia. We cultivated primary rat spinal cord microglia and BV2 cell lines and used lipopolysaccharide (LPS) to stimulate microglia to establish an in vitro model. The adeno-associated virus (AAV) was used to induce HO-1 overexpression to observe the effects of HO-1 overexpression on microglia survival, morphological changes, microglia activation, inflammatory cytokines secretion, mitochondrial dynamics, and nucleotide-binding oligomerization domain-like receptor protein (NLRP3) inflammatory complex and nuclear factor-κB (NF-κB) signaling pathways. It was found that HO-1 overexpression was successfully induced using an AAV on microglia in vitro. HO-1 overexpression increased microglia survival and reduced microglia apoptosis in the inflammatory microenvironment. Overexpressed HO-1 inhibited microglia M1-type polarization, downregulated the NF-κB signaling pathway, inhibited NLRP3 inflammatory complex activation, and reduced the secretion of inflammatory factors. Overexpressed HO-1 maintained the stability of mitochondrial dynamics and inhibited excessive mitochondrial cleavage. Further experiments showed that overexpression of HO-1 activated the interferon regulatory factor 1 (IRF1)/dynamin-related protein 1 (DRP1) signaling pathway, thereby promoting microglia M2-type polarization and improving neuronal survival. This study demonstrates that HO-1 activates the IRF1/DRP1 axis, promoting M2 polarization in microglia and attenuating neuroinflammation by suppressing the NF-κB signaling pathway. These outcomes offer new visions and important clues for effectively managing SCI in the clinic.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 8","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806035","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}