Drug Development Research最新文献

{"title":"Cover Image, Volume 85, Issue 1","authors":"Judith Eschbach,&nbsp;Alain Wagner,&nbsp;Corinne Beahr,&nbsp;Akkiz Bekel,&nbsp;Anne-Sophie Korganow,&nbsp;Angelique Quartier,&nbsp;Jean-Christophe Peter,&nbsp;Pierre Eftekhari","doi":"10.1002/ddr.22176","DOIUrl":"https://doi.org/10.1002/ddr.22176","url":null,"abstract":"<p><b>Cover Caption:</b> The cover image is based on the Research Article <i>Drug upgrade: A complete methodology from old drug to new chemical entities using Nematic Protein Organization Technique</i> by Judith Eschbach et al., https://doi.org/10.1002/ddr.22151.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22176","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140321785","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":"The contribution of the WNT pathway to the therapeutic effects of montelukast in experimental murine airway inflammation induced by ovalbumin and lipopolysaccharide","authors":"Yesim Kaya-Yasar,&nbsp;Seckin Engin,&nbsp;Elif Nur Barut,&nbsp;Cihan Inan,&nbsp;Ismail Saygin,&nbsp;Ilknur Erkoseoglu,&nbsp;Sena F. Sezen","doi":"10.1002/ddr.22178","DOIUrl":"10.1002/ddr.22178","url":null,"abstract":"<p>The wingless/integrase-1 (WNT) pathway involved in the pathogenesis of inflammatory airway diseases has recently generated considerable research interest. Montelukast, a leukotriene receptor antagonist, provides therapeutic benefits in allergic asthma involving eosinophils. We aimed to investigate the role of the WNT pathway in the therapeutic actions of montelukast (MT) in a mixed type of allergic-acute airway inflammation model induced by ovalbumin (OVA) and lipopolysaccharide (LPS) in mice. Female mice were sensitized with intraperitoneal OVA-Al(OH)₃ administration in the initiation phase and intranasal OVA followed by LPS administration in the challenge phase. The mice were divided into eight groups: control, asthmatic, and control/asthmatic treated with XAV939 (inhibitor of the canonical WNT pathway), LGK-974 (inhibitor of the secretion of WNT ligands), or MT at different doses. The inhibition of the WNT pathway prevented tracheal 5-HT and bradykinin hyperreactivity, while only the inhibition of the canonical WNT pathway partially reduced 5-HT and bradykinin contractions compared to the inflammation group. Therefore, MT treatment hindered 5-HT and bradykinin hyperreactivity associated with airway inflammation. Furthermore, MT prevented the increases in the phosphorylated GSK-3β and WNT5A levels, which had been induced by airway inflammation, in a dose-dependent manner. Conversely, the MT application caused a further increase in the fibronectin levels, while there was no significant alteration in the phosphorylation of the Smad-2 levels in the isolated lungs of the mice. The MT treatment reversed the increase in the mRNA expression levels of interleukin-17A. An increase in eosinophil and neutrophil counts was observed in bronchoalveolar lavage fluid samples obtained from the mice in the inflammation group, which was hampered by the MT treatment. The inhibition of the WNT pathway did not alter inflammatory cytokine expression or cell infiltration. The WNT pathway mediated the therapeutic effects of MT due to the inhibition of GSK-3β phosphorylation as well as the reduction of WNT5A levels in a murine airway inflammation model.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140287110","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":"Cellular and molecular mechanisms involved in the analgesic effects of botulinum neurotoxin: A literature review","authors":"Saereh Hosseindoost,&nbsp;Seyed Hassan Inanloo,&nbsp;Seyed Khalil Pestehei,&nbsp;Mojgan Rahimi,&nbsp;Reza Atef Yekta,&nbsp;Alireza Khajehnasiri,&nbsp;Maziyar Askari Rad,&nbsp;Hossein Majedi,&nbsp;Ahmad Reza Dehpour","doi":"10.1002/ddr.22177","DOIUrl":"10.1002/ddr.22177","url":null,"abstract":"<p>Botulinum neurotoxins (BoNTs), derived from <i>Clostridium botulinum</i>, have been employed to treat a range of central and peripheral neurological disease. Some studies indicate that BoNT may be beneficial for pain conditions as well. It has been hypothesized that BoNTs may exert their analgesic effects by preventing the release of pain-related neurotransmitters and neuroinflammatory agents from sensory nerve endings, suppressing glial activation, and inhibiting the transmission of pain-related receptors to the neuronal cell membrane. In addition, there is evidence to suggest that the central analgesic effects of BoNTs are mediated through their retrograde axonal transport. The purpose of this review is to summarize the experimental evidence of the analgesic functions of BoNTs and discuss the cellular and molecular mechanisms by which they can act on pain conditions. Most of the studies reviewed in this article were conducted using BoNT/A. The PubMed database was searched from 1995 to December 2022 to identify relevant literature.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140287109","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":"Pyridazine and pyridazinone derivatives: Synthesis and in vitro investigation of their anti-inflammatory potential in LPS-induced RAW264.7 macrophages","authors":"Eman O. Osman,&nbsp;Nadia A. Khalil,&nbsp;Alaa Magdy,&nbsp;Yara El-Dash","doi":"10.1002/ddr.22173","DOIUrl":"10.1002/ddr.22173","url":null,"abstract":"<p>New pyridazine and pyridazinone derivatives <b>3a</b>–<b>g</b>, <b>4a</b>–<b>f</b>, <b>6a</b>, and <b>6b</b> were designed and synthesized. Cell viability of all compounds was established based on the viability of lipopolysaccharide-induced RAW264.7 macrophage cells determined via the MTT assay. In vitro inhibition assays on human COX-1 and COX-2 enzymes were conducted to probe the newly synthesized compounds' anti-inflammatory activity. The half maximal inhibitory concentration values for the most active compounds, <b>3d</b>, <b>3e</b>, and <b>4e</b> towards COX-2 were 0.425, 0.519, and 0.356 µM, respectively, in comparison with celecoxib. The newly synthesized compounds' ability to inhibit the production of certain proinflammatory cytokines, such as inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-6, and prostaglandin-E2, was also estimated in lipopolysaccharide-induced macrophages (RAW264.7 cells). Compounds <b>3d</b> and <b>3e</b> were identified as the most potent cytokine production inhibitors. The results of molecular modeling studies suggested that these compounds were characterized by a reasonable binding affinity toward the active site of COX-2, when compared to a reference ligand. These results might be taken into consideration in further investigations into new anti-inflammatory agents.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140184028","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 apoptotic effects of Cucurbitacin D, I, and E mediated by Bax/Bcl-xL, caspase-3/9, and oxidative stress modulators in HepG2 cell line","authors":"Muhammed Mehdi Üremiş,&nbsp;Yusuf Türköz,&nbsp;Nuray Üremiş","doi":"10.1002/ddr.22174","DOIUrl":"10.1002/ddr.22174","url":null,"abstract":"<p>Cucurbitacins, natural compounds highly abundant in the <i>Cucurbitaceae</i> plant family, are characterized by their anticancer, anti-inflammatory, and hepatoprotective properties. These compounds have potential as therapeutic agents in the treatment of liver cancer. This study investigated the association of cucurbitacin D, I, and E (CuD, CuI, and CuE) with the caspase cascade, Bcl-2 family, and oxidative stress modulators in the HepG2 cell line. We evaluated the antiproliferative effects of CuD, CuI, and CuE using the MTT assay. We analyzed Annexin V/PI double staining, cell cycle, mitochondrial membrane potential, and wound healing assays at different doses of the three compounds. To examine the modulation of the caspase cascade, we determined the protein and gene expression levels of Bax, Bcl-xL, caspase-3, and caspase-9. We evaluated the total antioxidant status (TAS), total oxidant status (TOS), superoxide dismutase (SOD), glutathione (GSH), Total, and Native Thiol levels to measure cellular redox status. CuD, CuI, and CuE suppressed the proliferation of HepG2 cells in a dose-dependent manner. The cucurbitacins induced apoptosis by increasing caspase-3, caspase-9, and Bax activity, inhibiting Bcl-xL activation, causing loss of ΔΨm, and suppressing cell migration. Furthermore, cucurbitacins modulated oxidative stress by increasing TOS levels and decreasing SOD, GSH, TAS, and total and native Thiol levels. Our findings suggest that CuD, CuI, and CuE exert apoptotic effects on the hepatocellular carcinoma cell line by regulating Bax/Bcl-xL, caspase-3/9 signaling, and causing intracellular ROS increase in HepG2 cells.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22174","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140142997","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":"Improving therapeutic potential in breast cancer via histone deacetylase inhibitor loaded nanofibrils","authors":"Praveetha Senthilkumar,&nbsp;Bhaskar Gogoi,&nbsp;Swati Smita Dhan,&nbsp;Ramesh Subramani,&nbsp;Charumathi Pushparaj,&nbsp;Ayyavu Mahesh","doi":"10.1002/ddr.22172","DOIUrl":"10.1002/ddr.22172","url":null,"abstract":"<p>Epigenetic modifications play a significant role in cancer progression, making them potential targets for therapy. Histone deacetylase inhibitors have shown promise in inhibiting cancer cell growth, including in breast cancer (BC). In this research, we examined the potential of using suberoyl anilide hydroxamic acid (SAHA)-loaded β-lg nanofibrils as a drug delivery system for triple-negative BC cell lines. We assessed their impact on cell cycle progression, apoptosis, levels of reactive oxygen species, and mitochondrial membrane potential in cancer cells. The combination of SAHA and β-lg nanofibrils demonstrated enhanced efficacy in inhibiting cell growth, inducing cell cycle arrest, and promoting apoptosis (43.78%) compared to SAHA alone (40.09%). Moreover, it effectively targeted cancer cells without promoting drug resistance while using a low concentration of the nanofibrils. These findings underscore the promising potential of nanofibril-based drug delivery systems for BC treatment.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130978","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":"Neutrophil hitchhiking: Riding the drug delivery wave to treat diseases","authors":"Menghui Wang,&nbsp;Zhenhua Jin,&nbsp;Haoyu Huang,&nbsp;Xifu Cheng,&nbsp;Qin Zhang,&nbsp;Ying Tang,&nbsp;Xiaoping Zhu,&nbsp;Zhen Zong,&nbsp;Hui Li,&nbsp;Zhikun Ning","doi":"10.1002/ddr.22169","DOIUrl":"10.1002/ddr.22169","url":null,"abstract":"<p>Neutrophils are a crucial component of the innate immune system and play a pivotal role in various physiological processes. From a physical perspective, hitchhiking is considered a phenomenon of efficient transportation. The combination of neutrophils and hitchhikers has given rise to effective delivery systems both in vivo and in vitro, thus neutrophils hitchhiking become a novel approach to disease treatment. This article provides an overview of the innovative and feasible application of neutrophils as drug carriers. It explores the mechanisms underlying neutrophil function, elucidates the mechanism of drug delivery mediated by neutrophil-hitchhiking, and discusses the potential applications of this strategy in the treatment of cancer, immune diseases, inflammatory diseases, and other medical conditions.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109616","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":"Xanthones with multiple roles against diabetes: their synthesis, structure-activity relationship, and mechanism studies","authors":"Youhong Ke,&nbsp;Qinfang Xu,&nbsp;Jianling Hu,&nbsp;Jianrun Zhang,&nbsp;Shijian Chen,&nbsp;Zhijun Liu,&nbsp;Shuling Peng,&nbsp;Chao Zhang,&nbsp;Zhenqiang Chen,&nbsp;Heru Chen","doi":"10.1002/ddr.22170","DOIUrl":"10.1002/ddr.22170","url":null,"abstract":"<p>A four-step synthetic process has been developed to prepare 1,3,5,8-tetrahydroxyxanthone (<b>2a</b>) and its isomer 1,3,7,8-tetrahydroxyxanthone (<b>2b</b>). 25 more xanthones were also synthesized by a modified scheme. Xanthone <b>2a</b> was identified as the most active inhibitor against both α-glucosidase and aldose reductase (ALR2), with IC₅₀ values of 7.8 ± 0.5 μM and 63.2 ± 0.6 nM, respectively, which was far active than acarbose (35.0 ± 0.1 μM), and a little more active than epalrestat (67.0 ± 3.0 nM). <b>2a</b> was also confirmed as the most active antioxidant in vitro with EC₅₀ value of 8.9 ± 0.1 μM. Any structural modification including methylation, deletion, and position change of hydroxyl group in <b>2a</b> will cause an activity loss in inhibitory and antioxidation. By applying a H₂O₂-induced oxidative stress nematode model, it was confirmed that xanthone <b>2a</b> can be absorbed by <i>Caenorhabditis elegans</i> and is bioavailable to attenuate in vivo oxidative stress, including the effects on lifespan, superoxide dismutase, Catalase, and malondialdehyde. <b>2a</b> was verified with in vivo hypoglycemic effect and mitigation of embryo malformations in high glucose. All our data support that xanthone <b>2a</b> behaves triple roles and is a potential agent to treat diabetic mellitus, gestational diabetes mellitus, and diabetic complications.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119096","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":"Protective effect of thymoquinone nanoemulsion in reducing the cardiotoxic effect of 5-fluorouracil in rats","authors":"Bardia Karim,&nbsp;Motahare Arabameri,&nbsp;Fatemeh Alimoradi,&nbsp;Razieh Mansoori,&nbsp;Ali A. Moghadamnia,&nbsp;Sohrab Kazemi,&nbsp;Seyed M. Hosseini","doi":"10.1002/ddr.22171","DOIUrl":"10.1002/ddr.22171","url":null,"abstract":"<p>5-Fluorouracil (5-FU), which is one of the most widely used chemotherapy drugs, has various side effects on the heart. Thymoquinone (TMQ), the main bioactive component of <i>Nigella sativa</i>, has antioxidant and protective effects against toxicity. In this study, we investigated the protective effect of thymoquinone against cardiotoxicity caused by 5-FU in vitro and in vivo models. H9C2 cells were exposed to 5-FU and TMQ, and cell viability was evaluated in their presence. Also, 25 male Wistar rats were divided into five control groups, 5-FU, 2.5, and 5 mg TMQ in nanoemulsion form (NTMQ) + 5-FU and 5 mg NTMQ. Cardiotoxicity was assessed through electrocardiography, cardiac enzymes, oxidative stress markers, and histopathology. 5-FU induced cytotoxicity in H9c2 cells, which improved dose-dependently with NTMQ cotreatment. 5-FU caused body weight loss, ECG changes (increased ST segment, prolonged QRS, and QTc), increased cardiac enzymes (aspartate aminotransferase [AST], creatine kinase-myocardial band [CK-MB], and lactate dehydrogenase [LDH]), oxidative stress (increased malondialdehyde, myeloperoxidase, nitric acid; decreased glutathione peroxidase enzyme activity), and histological damage such as necrosis, hyperemia, and tissue hyalinization in rats. NTMQ ameliorated these 5-FU-induced effects. Higher NTMQ dose showed greater protective effects. Thus, the results of our study indicate that NTMQ protects against 5-FU cardiotoxicity likely through antioxidant mechanisms. TMQ warrants further research as an adjuvant to alleviate 5-FU chemotherapy side effects.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140065053","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":"Hypoxia expedites the progression of papillary thyroid carcinoma by promoting the CPT1A-mediated fatty acid oxidative pathway","authors":"Zhou Liang,&nbsp;Hongsheng He,&nbsp;Bing Zhang,&nbsp;Zhentian Kai,&nbsp;Liang Zong","doi":"10.1002/ddr.22168","DOIUrl":"10.1002/ddr.22168","url":null,"abstract":"<p>Hypoxia has been reported to promote the proliferation and migration of thyroid cancer, while the special mechanism was still unclear. HIF-1α/carnitine palmitoyl-transferase 1A (CPT1A) was found to be associated with papillary thyroid carcinoma (PTC) but the biological role of CPT1A in PTC was not explored. The effects of hypoxia and carnitine palmitoyl-transferase 1A (CPT1A) expression on PTC cells were determined by cell counting kit-8 assay, detection of oxidative stress, inflammation response and mitochondrial membrane motential (MMP). Oil Red O staining and the detection of free fatty acids were performed to assess the status of lipid metabolism. Flow cytometric analysis was performed to assess cell apoptosis. Quantitative polymerase chain reaction (qPCR) and western blot analysis were applied to investigate the expressions of CPT1A and HIF-1α and the molecules involved cell function. The expressions of CPT1A and HIF-1α were significantly increased in PTC cells with or without hypoxia treatment. CPT1A overexpression or silencing promoted or inhibited cell viability, and hypoxia further repressed cell viability. In addition, CPT1A overexpression alleviates hypoxia-induced increased oxidative stress, inflammation response and elevated MMP. CPT1A overexpression enhanced palmitic acid-induced decreased cell growth, enhanced the metabolic capacity of free fatty acid and suppressed cell apoptosis. Animal experiments showed that CPT1A overexpression promoted PTC tumor growth, reduced lipid deposition, oxidative stress and inflammation, as well as enhancing cell function indicators. However, CPT1A silencing showed the opposite effects both in vitro and in vivo. Hypoxia induces the high expression of HIF-1α/CPT1A, thereby reprogramming the lipid metabolism of PTC cells for adapting the hypoxia environment, meanwhile inhibiting the cell damage and apoptosis caused by oxidative stress.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":null,"pages":null},"PeriodicalIF":3.8,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049002","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}