Drug Development Research最新文献

{"title":"Development of Efficient Covalent Inactivators of a Fungal Aspartate Semialdehyde Dehydrogenase","authors":"Samantha N. Friday,&nbsp;Liezel A. Koellner,&nbsp;Spencer W. Brown,&nbsp;Christopher N. Calbat,&nbsp;Catherine F. Curran,&nbsp;Jordan D. Dietz,&nbsp;Andreas Koenig-Dummer,&nbsp;Paul D. Friday,&nbsp;James A. Parker,&nbsp;Noah A. Simmons,&nbsp;Finnean A. Urmey,&nbsp;Alexis N. West,&nbsp;Sebastian G. Zagler,&nbsp;Ronald E. Viola,&nbsp;Christopher J. Halkides","doi":"10.1002/ddr.70095","DOIUrl":"https://doi.org/10.1002/ddr.70095","url":null,"abstract":"<p>Aspartate semialdehyde dehydrogenase (ASADH) catalyzes the second step in the fungal pathway towards the synthesis of threonine, isoleucine, and methionine, and it has been identified as a viable target for antifungal drug development. Our previous work produced a group of vinyl sulfones that function as irreversible covalent inactivators of this enzyme. We have now expanded this initial set to produce vinyl sulfones with higher kinetic efficiency as covalent inactivators of ASADH purified from the pathogenic fungal species <i>Candida albicans</i>. The catalytic efficiency of these inactivators has also been compared to related classes of irreversible inactivators, vinyl sulfonamides, acrylamides, and sulfonyl ketones.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70095","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919344","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":"Multilayer Antibacterial Hydrogel Wound Dressings Incorporated With Green Synthesized Silver Nanoparticles","authors":"Ali Alipour,&nbsp;Omid Nejati,&nbsp;Gökçen Yaşayan,&nbsp;Ayça Girgin,&nbsp;Buse Tuğba Zaman,&nbsp;Betül Giray,&nbsp;Okşan Karal-Yılmaz,&nbsp;Sezgin Bakırdere,&nbsp;Ayça Bal-Öztürk","doi":"10.1002/ddr.70102","DOIUrl":"https://doi.org/10.1002/ddr.70102","url":null,"abstract":"<p>Multilayer antibacterial hydrogel wound dressings were fabricated and characterized for wound healing applications. Dressings are designed to achieve infection control, moisture management in the wound area and to support wound healing. Multilayer wound dressings were prepared as three layers by solvent casting method. The upper layer is composed of kappa carrageenan and green synthesized silver nanoparticles (AgNPs, ~122 nm in size, zeta potential of –35 mV) to provide the moist control, and to form a barrier against microorganism attack. Lidocaine HCl loaded polyvinyl alcohol and chitosan-based middle layer was designed to achieve controlled drug release and to add strength to the hydrogel structure. The lower layer is composed of hyaluronic acid and ovalbumin to serve a controlling membrane for controlled drug release, and to further support wound healing. Different amounts of AgNPs were used in formulations to evaluate their impact on multilayer wound dressings. The incorporation of AgNPs resulted in reduced swelling values and degradation rates of the multilayer wound dressings, enhanced mechanical capabilities, and no significant change in water vapor permeability values. They have demonstrated enhanced antibacterial efficacy against <i>Klebsiella pneumoniae</i>, <i>Bacillus subtilis</i> and <i>Candida albicans</i>. The optimal multilayered hydrogel, incorporating AgNPs and loaded with lidocaine HCl, has shown biocompatibility and hemocompatibility, exhibiting 60% degradation by day 14, water vapor permeability of 2022 ± 460 g/m² over 24 h, a tensile strength of 6.71 ± 0.62 MPa, 36.38% ± 3.62% elongation at break, and 65.72% ± 14.80% drug release within 10 h, making it a promising candidate for facilitating the wound healing process.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70102","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919571","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":"Cytotoxicity, Cell Line Selectivity and Proapoptotic Activity of New Anticancer Agents Derived From N,N’-Functionalised Benzimidazolium Salts and Their Silver(I)-N-Heterocyclic Carbene Complexes","authors":"Choon Hoe Wong,&nbsp;Boon-Keat Khor,&nbsp;Vikneswaran Murugaiyah,&nbsp;Nelson Jeng-Yeou Chear,&nbsp;WanSinn Yam","doi":"10.1002/ddr.70100","DOIUrl":"https://doi.org/10.1002/ddr.70100","url":null,"abstract":"<div>\u0000 \u0000 <p>A new series of <i>N</i>-decyl-<i>N</i>’-benzylbenzimidazolium <i>N</i>-heterocyclic carbene (NHC) precursors and their mononuclear silver(I)-NHC complexes were synthesised and characterised. The benzyl group was functionalised with various <i>para</i> substituents (H, CH₃, F, Cl, Br, CN, NO₂). The effect of these substituents on cytotoxicity and cell line selectivity against human cervical cancer (HeLa), oestrogen-positive human breast cancer (MCF-7), and normal skin fibroblasts (Hs-27) was investigated. All compounds exhibited significant growth inhibition against the tested cell lines. The activity and selectivity of the compounds were influenced by the <i>para</i> substituents and the type of cell line. The electron-donating methylated NHC precursor and its silver complex generally demonstrated higher growth inhibition potentials than the analogues with electron-withdrawing groups, except in two cases where the fluorinated compounds were more potent against Hs-27 and HeLa, while the chlorinated NHC precursor was more active against MCF-7. Notably, all compounds, particularly the silver(I)-NHC complexes, were more active towards MCF-7 but less toxic towards Hs-27. The methyl-, bromo-, and cyano-containing silver(I)-NHC complexes broadened the safety windows against MCF-7 (selectivity indices ≥ 3). The most selective (against MCF-7) chlorinated NHC precursor and its silver(I)-NHC exhibited ROS-mediated proapoptotic activity, which indicated that these compounds promoted cell death by inducing intracellular ROS formation and accumulation. Our findings highlight the potential use of silver(I)-NHC complexes in the design and development of safe and selective anticancer agents.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919576","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":"Tannic Acid as an Ion Channel Modulator: An Understanding of Its Pharmacological Spectrum","authors":"King-Chuen Wu,&nbsp;Chiu-Yin Lee,&nbsp;Paul Chan,&nbsp;Iat-Lon Leong,&nbsp;Yuk-Man Leung","doi":"10.1002/ddr.70098","DOIUrl":"https://doi.org/10.1002/ddr.70098","url":null,"abstract":"<div>\u0000 \u0000 <p>Tannic acid (TA) is a polyphenol present in many plant foods and beverages such as green tea and wines. As a food additive, it has been recognized by Food and Drug Administration as generally safe. As a candidate drug, its pharmacological effects cover a wide spectrum, ranging from antibacterial, anticancer, cardioprotection to neuroprotection. TA has been shown to modulate a number of ion channels such as Ca²⁺-activated Cl⁻ channels (CaCC), voltage-gated K⁺ (Kv) channels and transient receptor potential (TRP) channels, producing effects such as analgesia, antihypertensive effects and reduction of airway hypersensitivity. In this review we focus on how ion channel modulation by TA may account for the pharmacological effects of TA in various cells and organ systems. Further emphasis should be paid to factors, such as dosage and routes of administration, before the pharmacological actions of TA could be translated into therapeutic applications.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143919577","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":"Investigation of New Biologically Active Benzo[4,5]imidazo[1,2-a]pyrimidine Derivatives as Broad-Spectrum Antimicrobial Agents: Synthesis, Anti-Biofilm, ROS and in Silico Studies","authors":"Farid M. Sroor,&nbsp;Ahmed F. El-Sayed,&nbsp;Mohamed Abdelraof","doi":"10.1002/ddr.70096","DOIUrl":"https://doi.org/10.1002/ddr.70096","url":null,"abstract":"<div>\u0000 \u0000 <p>A new series of biologically active benzo[4,5]imidazo[1,2-<i>a</i>]pyrimidine derivatives containing different substitutions such as thiophene, pyridine, pyrrole, and 3,4-dimethoxyphenyl at carbon 2 and, phenyl-pyrrolidinyl, -morpholinyl, -piperidinyl at carbon 4 were synthesized. The treatment of chalcone derivatives <b>5-16</b> with 2-aminobenzimidazole in DMF and drops of TEA afforded the targeted benzo[4,5]imidazo[1,2-<i>a</i>]pyrimidine derivatives (<b>18-29</b>) in good to excellent yields. These compounds were tested to evaluate their antimicrobial activity against different microbial pathogens such as <i>Aspergillus niger, Candida albicans, Staphylococcus aureus</i> and <i>Salmonella typhimurium</i>. Potently compounds <b>19</b> and <b>23</b> were contributed in a broad-spectrum inhibition process against all tested pathogens with lower MIC values ranging between 10 and 60 µg/mL. Furthermore, the efficiency of the potent compounds to inhibit the biofilm formation was moderately detected by compounds <b>18</b>, <b>19</b> and <b>23</b>. This study investigated the antimicrobial potential of synthesized compounds through experimental and computational approaches. Compounds <b>18</b>, <b>19</b>, <b>23</b>, <b>25</b>, and <b>28</b> demonstrated strong binding affinities to antimicrobial target proteins (1AD4, 2SIL, 4ZA5, and 5TZ1), suggesting their ability to inhibit key enzymes via diverse molecular interactions. Computational ADMET profiling confirmed their compliance with Lipinski's rules, indicating favorable drug-like properties. Molecular dynamics simulations further validated the stability of complexes formed by compounds <b>19</b> and <b>28</b>, with stable RMSD values (0.17–0.45 nm), low RMSF fluctuations (0.10–0.7 nm), and consistent structural compactness (Rg: 1.45–1.75 nm). Solvent exposure (SASA: 120–220 nm²) varied across complexes. These results highlight the compounds’ potential as promising candidates for antimicrobial drug development, warranting further preclinical exploration.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905253","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":"Novel Oxadiazole-Based Bioisostere of Caffeic Acid Phenethyl Ester: Synthesis, Anticancer Activity, and Inhibition of Lipoxygenase Product Biosynthesis","authors":"Mika A. Robichaud,&nbsp;Audrey Isabel Chiasson,&nbsp;Jérémie A. Doiron,&nbsp;Mathieu P. A. Hébert,&nbsp;Marc E. Surette,&nbsp;Mohamed Touaibia","doi":"10.1002/ddr.70099","DOIUrl":"https://doi.org/10.1002/ddr.70099","url":null,"abstract":"<p>Caffeic acid phenethyl ester (<b>1</b>), a honeybee propolis component, possesses many bioactive properties, making it a useful scaffold for drug research. Further, CAPE (<b>1</b>) is a more effective inhibitor of the biosynthesis of 5-lipoxygenase (5-LO) products compared to Zileuton, the only clinically-approved direct 5-LO inhibitor. However, CAPE (<b>1</b>) suffers from a poor metabolic profile, being rapidly metabolized to caffeic acid (CA). In this study, we synthesized and performed several biological assays on a new bioisostere of CAPE (<b>1</b>) possessing a 1,2,4-oxadiazole ring. The new bioisostere (OB-CAPE (<b>5</b>)) has a similar antiproliferative effect to CAPE (<b>1</b>) on NCI-60 cancer cell lines and maintains the activity of CAPE (<b>1</b>) as an inhibitor of the biosynthesis of 5-, 12- and 15-LO products and as an iron chelator. In human polymorphonuclear leukocytes, OB-CAPE (<b>5</b>) inhibits the biosynthesis of 5-LO products with an IC₅₀ of 0.93 µM compared to 1.0 µM for CAPE (<b>1</b>). Both compounds have similar antioxidant activity, with IC₅₀ values of 1.2 µM for OB-CAPE (<b>5</b>) and 1.1 µM for CAPE (<b>1</b>). The new hydrogen bond predicted for the oxadiazole ring and the GLN363 amino acid in the 5-LO active site may explain the small improvement in the affinity of OB-CAPE (<b>5</b>) for the protein compared to CAPE (<b>1</b>). Finally, stability studies in human plasma reveal that OB-CAPE (<b>5</b>) is 25% more stable than CAPE (<b>1</b>). Therefore, the increase in stability associated with the replacement of the ester function with its bioisostere, while maintaining the anti-inflammatory and anticancer properties of CAPE (<b>1</b>), suggests that OB-CAPE (<b>5</b>) may be a comparable yet more stable candidate for in vivo studies in disease models.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70099","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905318","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":"Inhibition of Glutathione Pathway by Oleanolic Acid via PSAT1 Leads to Ferroptosis in Colorectal Cancer","authors":"Qing Sun,&nbsp;Ruolin Sun,&nbsp;Bokun He,&nbsp;Hongjie Meng,&nbsp;Jie Jin,&nbsp;Juhui He","doi":"10.1002/ddr.70097","DOIUrl":"https://doi.org/10.1002/ddr.70097","url":null,"abstract":"<div>\u0000 \u0000 <p>Phosphoserine aminotransferase 1 (PSAT1), a pivotal regulator of serine metabolism, is overexpressed in a variety of cancers, yet its role in colorectal cancer (CRC) remains to be elucidated. Oleanolic acid (OA), a naturally occurring pentacyclic triterpenoid, is suspected to have the potential to regulate ferroptosis, though this capability has not been confirmed. Utilizing bioinformatics tools, we conducted an analysis of PSAT1 expression in CRC, pathway enrichment, and its correlation with proteins pivotal to glutathione metabolism and the induction of ferroptosis. Expression levels of PSAT1 were validated by Quantitative Polymerase Chain Reaction (qPCR) and western blot analysis (WB). Cell Counting Kit-8 (CCK-8) was employed to measure the viability of CRC cells. Ferroptosis was assessed via flow cytometry, Fe²⁺ detection, malondialdehyde (MDA) levels, and WB. The metabolic pathway of glutathione was examined by analyzing the levels of reduced glutathione (GSH) and glutathione disulfide (GSSG), glutamate, glutamine, and α-ketoglutarate, and by assessing the expression of rate-limiting enzymes in glutamine metabolism. The interaction between OA and PSAT1 was predicted by molecular docking and validated with the cellular thermal shift assay (CETSA) -WB assay. The results showed that PSAT1 was found to be highly expressed in CRC and enriched in pathways associated with ferroptosis and glutathione metabolism, instrumental in preserving the vitality of CRC cells. PSAT1 knockdown increased cellular lipid reactive oxygen species (ROS) and MDA, and ferrous ion accumulation, while also inhibiting the expression of ferroptosis markers Solute carrier family 7, membrane 11 (SLC7A11) and Glutathione peroxidase 4 (GPX4). Overexpression of PSAT1 raised the levels of glutathione metabolic intermediates and the GSH ratio, inhibiting ferroptosis, and these effects were reversed by methionine sulfoximine. OA was identified through molecular docking and CETSA-WB to effectively dock with PSAT1 and target it to inhibit glutathione metabolism, enhancing lipid peroxidation and Fe²⁺ accumulation in CRC cells. In conclusion, OA, upon binding to PSAT1, curbs its expression, which in turn downregulates glutathione metabolism and enhances ferroptosis in CRC cells.</p></div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905317","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":"Anticancer and Anti-Inflammatory Potential of Coptisine as a Planar Quaternary Benzo[C]Phenanthridine Alkaloid With G-Quadruplex DNA Telomeric Induction Activity","authors":"Mehdi Valipour,&nbsp;Mohammad Sheibani,&nbsp;Maryam Dibaei,&nbsp;Zahra Zakeri Khatir,&nbsp;Adileh Ayati,&nbsp;Farzaneh Motafeghi,&nbsp;Hamid Irannejad","doi":"10.1002/ddr.70071","DOIUrl":"https://doi.org/10.1002/ddr.70071","url":null,"abstract":"<div>\u0000 \u0000 <p>Coptisine, an isoquinoline-based phytochemical, exhibits a broad spectrum of biological activities, including anticancer and anti-inflammatory properties. Its planar chemical structure allows for the induction of anticancer effects by forming telomeric G-quadruplex structures. Despite its promising medicinal benefits, the clinical utilization of this compound is limited by critical shortcomings such as low efficacy and poor pharmacokinetics. While in vitro studies demonstrate high cytotoxicity, in vivo research highlights its favorable toxicity profile, attributed to the conversion of its iminium form to a less toxic alkanolamine form within the physiological setting. Past endeavors have focused on rectifying these limitations through structural modifications to yield more efficacious molecules. In the current review, we provide an overview of the anti-inflammatory and anticancer properties of coptisine and its semisynthetic derivatives, in conjunction with its pharmacokinetic profile, synthesis, and safety/toxicity considerations. This review draws upon information sourced from publications indexed in esteemed scientific databases like Web of Science, PubMed, and Scopus, among others. To prepare each section, we utilized Coptisine and section-specific keywords, emphasizing recent literature findings (2014–2024) while maintaining a broad scope due to the study's nature. In conclusion, this review underscores coptisine's remarkable anticancer and anti-inflammatory properties, suggesting that further exploration of structural modifications may yield semisynthetic derivatives with enhanced safety/toxicity profiles, pharmacokinetics, and therapeutic potential.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897154","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":"Molecular Pathways in Idiopathic Pulmonary Fibrosis: A Review of Novel Insights for Drug Design","authors":"Dilay Kahvecioglu","doi":"10.1002/ddr.70094","DOIUrl":"https://doi.org/10.1002/ddr.70094","url":null,"abstract":"<div>\u0000 \u0000 <p>Idiopathic pulmonary fibrosis is a progressive, irreversible lung disease of unknown cause, characterized by gradual thickening and scarring of lung tissue, impairing oxygen transfer into the bloodstream. As a result, symptoms such as shortness of breath, fatigue, and a persistent dry cough occur. Currently, the FDA-approved antifibrotic agents Pirfenidone and Nintedanib can slow the progression of the disease. However, these treatments cannot completely stop the loss of lung function and do not provide a significant improvement in the quality of life of patients. As fibrosis progresses, lung capacity decreases, shortness of breath increases, and general health deteriorates significantly. Therefore, new more effective, and targeted therapies that can halt the progression of IPF are urgently needed. This review addresses novel strategies to slow or halt the disease-related loss of lung function by targeting key mechanisms involved in the pathogenesis of IPF. The molecular structure–activity relationships (SARs) of synthesized compounds targeting JAK/STAT, TGF-β/Smad, Wnt/β-catenin, PI3K, JNK1, and other critical signaling pathways were examined. These targeted approaches have great potential for the development of more potent and selective therapeutic agents for the treatment of IPF. The insights provided in this review may contribute to the future development of more efficient and selective antifibrotic drugs.</p>\u0000 </div>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883966","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":"Dihydroartemisinin Attenuates Radiation-Induced Lung Injury by Inhibiting the cGAS/STING/NF-κB Signaling Pathway","authors":"Cailan Wang,&nbsp;Xinyi Lin,&nbsp;Shichun Guan,&nbsp;Qiaoyuan Wu,&nbsp;Shixiong Liang","doi":"10.1002/ddr.70090","DOIUrl":"https://doi.org/10.1002/ddr.70090","url":null,"abstract":"<p>Dihydroartemisinin (DHA) is a derivative of artemisinin, which affects inflammation, oxidative stress, and immune regulation. However, the mechanism underlying its effects remains largely unknown. This study aims to explore the mechanism by which DHA affects radiation-induced lung injury (RILI), providing new insights for lung radiotherapy. To elucidate its mechanism of action, C57BL/6 J mice were irradiated with 15 Gy whole chest. RILI was evaluated by qRT-PCR, ELISA, histology, Western blot analysis, immunohistochemistry, and RILI signaling cascade studies. In addition, small interfering RNAs were employed to knockdown cGAS proteins in the cGAS-STING signaling pathway in the human bronchial epithelium cell line (BEAS-2B). Both In Vivo and Vitro experiments were conducted to investigate the specific mechanism by which DHA alleviated RILI. We observed the activation of the cGAS-STING pathway, along with the phosphorylation of the downstream target NF-κB and an increase in inflammatory factor levels in the mouse model following radiation exposure. In the cell model, irradiation also triggered the activation of the cGAS-STING signaling pathway and its downstream targets, leading to elevated levels of inflammatory factors. Notably, knocking down the cGAS using small interfering RNA in the BEAS-2B cells significantly alleviated RILI in the cell model. Our study elucidated the mechanism of DHA reducing RILI through the cGAS/STING/NF-κB signaling pathway, and revealed that the GAS/STING/NF-κB axis may be a potential therapeutic target for RILI.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"86 3","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.70090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875647","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}