Drug Development Research最新文献

{"title":"Explore new quinoxaline pharmacophore tethered sulfonamide fragments as in vitro α-glucosidase, α-amylase, and acetylcholinesterase inhibitors with ADMET and molecular modeling simulation","authors":"Ahmed Ragab,&nbsp;Mohamed A. Salem,&nbsp;Yousry A. Ammar,&nbsp;Wael M. Aboulthana,&nbsp;Mohamed H. Helal,&nbsp;Moustafa S. Abusaif","doi":"10.1002/ddr.22216","DOIUrl":"10.1002/ddr.22216","url":null,"abstract":"<p>A new series of quinoxaline-sulfonamide derivatives <b>3</b>–<b>12</b> were synthesized using fragment-based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline-sulfonamide derivatives were evaluated for antidiabetic and anti-Alzheimer's potential against α-glucosidase, α-amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α-amylase and α-glucosidase with inhibitory percentages between 24.34 ± 0.01%–63.09 ± 0.02% and 28.95 ± 0.04%–75.36 ± 0.01%, respectively. Surprisingly, <i>bis</i>-sulfonamide quinoxaline derivative <b>4</b> revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against <i>α</i>-glucosidase and α-amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative <b>3</b> exhibited potency as α-glucosidase and α-amylase inhibitory with a minute decline from compound <b>4</b> and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide-quinoxaline derivative <b>3</b> emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141237564","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":"New benzimidazole-oxadiazole derivatives as potent VEGFR-2 inhibitors: Synthesis, anticancer evaluation, and docking study","authors":"Ulviye Acar Çevik,&nbsp;Ismail Celik,&nbsp;Şennur Görgülü,&nbsp;Zeynep Deniz Şahin Inan,&nbsp;Hayrani Eren Bostancı,&nbsp;Yusuf Özkay,&nbsp;Zafer Asım Kaplacıklı","doi":"10.1002/ddr.22218","DOIUrl":"10.1002/ddr.22218","url":null,"abstract":"<p>We report herein, the design and synthesis of benzimidazole-oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor-2 (VEGFR-2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF-7, PANC-1, hTERT-HPNE and CCD-19Lu. Compounds <b>4c</b> and <b>4d</b> were found to be the most effective compounds against three cancer cell lines. Compounds <b>4c</b> and <b>4d</b> were then tested for their in vitro VEGFR-2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT-HPNE and CCD-19Lu cell lines. It was determined that compound <b>4c</b> was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A (VEGFA) immunolocalizations of compounds <b>4c</b> and <b>4d</b> were evaluated relative to control by VEGFA immunofluorescence staining. Compounds <b>4c</b> and <b>4d</b> inhibited VEGFR-2 enzyme with half-maximal inhibitory concentration values of 0.475 ± 0.021 and 0.618 ± 0.028 µM, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR-2 (Protein Data Bank: 4ASD).</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199486","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":"Hesperidin, vanillic acid, and sinapic acid attenuate atorvastatin-induced mitochondrial dysfunction via inhibition of mitochondrial swelling and maintenance of mitochondrial function in pancreas isolated mitochondria","authors":"Ahmad Salimi,&nbsp;Saleh Khezri,&nbsp;Zoleikhah Vahabzadeh,&nbsp;Paria Rajabi,&nbsp;Rojin Samimi,&nbsp;Vahed Adhami","doi":"10.1002/ddr.22199","DOIUrl":"10.1002/ddr.22199","url":null,"abstract":"<p>It has been reported that lipophilic statins such as atorvastatin can more readily penetrate into β-cells and reach the mitochondria, resulting in mitochondrial dysfunction, oxidative stress, decrease in insulin release. Many studies have shown that natural products can protect mitochondrial dysfunction induced by drug in different tissue. We aimed to explore mitochondrial protection potency of hesperidin, vanillic acid, and sinapic acid as natural compounds against mitochondrial dysfunction induced by atorvastatin in pancreas isolated mitochondria. Mitochondria were isolated form rat pancreas and directly treated with toxic concentration of atorvastatin (500 µM) in presence of various concentrations hesperidin, vanillic acid, and sinapic acid (1, 10, and 100 µM) separately. Mitochondrial toxicity parameters such as the reactive oxygen species (ROS) formation, succinate dehydrogenases (SDH) activity, mitochondrial swelling, depletion of glutathione (GSH), mitochondrial membrane potential (MMP) collapse, and malondialdehyde (MDA) production were measured. Our findings demonstrated that atorvastatin directly induced mitochondrial toxicity at concentration of 500 μM and higher in pancreatic mitochondria. Except MDA, atorvastatin caused significantly reduction in SDH activity, mitochondrial swelling, ROS formation, depletion of GSH, and collapse of MMP. While, our data showed that all three protective compounds at low concentrations ameliorated atorvastatin-induced mitochondrial dysfunction with the increase of SDH activity, improvement of mitochondrial swelling, MMP collapse and mitochondrial GSH, and reduction of ROS formation. We can conclude that hesperidin, vanillic acid, and sinapic acid can directly reverse the toxic of atorvastatin in rat pancreas isolated mitochondria, which may be beneficial for protection against diabetogenic-induced mitochondrial dysfunction in pancreatic β-cells.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174897","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":"Synthesis of new N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives and evaluation of their AChE, BChE, and BACE-1 inhibitory activities","authors":"Beyzanur Tutuş,&nbsp;Aybüke Züleyha Kaya,&nbsp;Yonca Baz,&nbsp;Asaf Evrim Evren,&nbsp;Begüm Nurpelin Sağlik Özkan,&nbsp;Leyla Yurttaş","doi":"10.1002/ddr.22214","DOIUrl":"10.1002/ddr.22214","url":null,"abstract":"<p>In this study, the synthesis of <i>N</i>-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives (<b>3a</b>-<b>3k</b>) and to investigate their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-secretase 1 (BACE-1) inhibition activity were aimed. Mass, ¹H NMR, and ¹³C NMR spectra were utilized to determine the structure of the synthesized compounds. Compounds <b>3b</b>, <b>3c</b>, <b>3f</b>, and <b>3j</b> showed AChE inhibitory activity which compound <b>3c</b> (IC₅₀ = 0.030 ± 0.001 µM) showed AChE inhibitory activity as high as the reference drug donepezil (IC₅₀ = 0.0201 ± 0.0010 µM). Conversely, none of the compounds showed BChE activity. Compounds <b>3c</b> and <b>3j</b> showed the highest BACE-1 inhibitory activity and IC₅₀ value was found as 0.119 ± 0.004 µM for compound <b>3j</b> whereas IC₅₀ value was 0.110 ± 0.005 µM for donepezil, which is one of the reference substance. Molecular docking studies have been carried out using the data retrieved from the server of the Protein Data Bank (PDBID: 4EY7 and 2ZJM). Using in silico approach behavior active compounds (<b>3c</b> and <b>3j</b>) and their binding modes clarified.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22214","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179234","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":"Modafinil lightens apoptosis and inflammatory response in hepatic ischemia-reperfusion injury through inactivation of TLR9/Myd88/p38 signaling","authors":"Tairan Zhang,&nbsp;Xidong Wang","doi":"10.1002/ddr.22210","DOIUrl":"10.1002/ddr.22210","url":null,"abstract":"<p>Hepatic ischemia/reperfusion injury (IRI) remains a severe threat during liver surgery and transplantation, accounting for unfavorable clinical outcomes. Modafinil (MOD), a wakefulness-inducing compound, is increasingly disclosed to protect against IRI. However, the specific literatures covering the association between MOD and hepatic IRI are few. Here, this paper is committed to unraveling the role and response mechanism of MOD in hepatic IRI. After the establishment of hepatic IRI mice model and cell model, relevant assay kits measured the concentrations of biochemical indicators of hepatotoxicity and hematoxylin and eosin staining estimated liver morphology. Enzyme-linked immunosorbent assay, reverse-transcription quantitative polymerase chain reaction, and western blot evaluated inflammatory levels. Terminal-deoxynucleoitidyl transferase-mediated nick end labeling assay and western blot appraised apoptosis. Western blot also analyzed the expression of Toll-like receptor 9 (TLR9)/myeloid differentiation primary response gene 88 (MyD88)/p38 signaling-associated proteins. Cell counting kit-8 method judged cell viability. MOD was discovered to mitigate liver dysfunction and morphological damage, inflammatory response, apoptosis in vivo and improve cell viability, suppress inflammatory response and apoptosis in vitro. In addition, MOD inactivated TLR9/Myd88/p38 signaling both in vitro and in vivo. Further, TLR9 elevation reversed the inhibitory role of MOD in inflammatory response and cell apoptosis in vitro. Anyway, MOD blocked TLR9/Myd88/p38 signaling to exhibit anti-inflammatory and anti-apoptotic properties in hepatic IRI.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174900","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":"Apigenin alleviates doxorubicin-induced myocardial pyroptosis by inhibiting glycogen synthase kinase-3β in vitro and in vivo","authors":"Feng Wang,&nbsp;Xinxin Yan,&nbsp;Anna Yue,&nbsp;Kaiyu Zhang,&nbsp;Ping Li,&nbsp;Jingyi Xu,&nbsp;Kangyun Sun,&nbsp;Qian Zhang,&nbsp;Yuan Li","doi":"10.1002/ddr.22196","DOIUrl":"10.1002/ddr.22196","url":null,"abstract":"<p>Apigenin, a natural flavonoid compound found in chamomile (<i>Matricaia chamomilla</i> L.) from the Asteraceae family, has been shown in our previous study to possess antimyocardial hypertrophy and anti-cardiac fibrosis effects. However, its effects and mechanisms on the pyroptosis of cardiomyocytes induced by doxorubicin (DOX) are poorly understood. The objective of this study was to investigate the role of GSK-3β and the effects of apigenin in DOX-induced cardiotoxicity. H9c2 cells stimulated with DOX were treated with SB216763 and apigenin. Additionally, a mouse model of DOX-induced cardiotoxicity was prepared and further treated with apigenin and SB216763 for 30 days. The findings revealed that treatment with SB216763 or apigenin resulted in a significant reduction in the levels of pyroptosis-related factors. Furthermore, the phosphorylation of GSK-3β was enhanced while the phosphorylation of nuclear factor-kB (NF-κB) p65 was reduced following treatment with either SB216763 or apigenin. Conversely, the effects of apigenin treatment were nullified in siRNA-GSK-3β-transfected cells. Results from computer simulation and molecular docking analysis supported that apigenin could directly target the regulation of GSK-3β. Therefore, our study confirmed that the inhibition of GSK-3β and treatment with apigenin effectively suppressed the pyroptosis of cardiomyocytes in both DOX-stimulated H9c2 cells and mice. These benefits may be attributed in part to the decrease in GSK-3β expression and subsequent reduction in NF-κB p65 activation. Overall, our findings revealed that the pharmacological targeting of GSK-3β may offer a promising therapeutic approach for alleviating DOX-induced cardiotoxicity.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141174895","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":"Repurposing of drugs against bacterial infections: A pharmacovigilance-based data mining approach","authors":"Simran Ohra,&nbsp;Ruchika Sharma,&nbsp;Anoop Kumar","doi":"10.1002/ddr.22211","DOIUrl":"10.1002/ddr.22211","url":null,"abstract":"<p>The World Health Organization (WHO) has published a list of priority pathogens that urgently require research to develop new antibiotics. The main aim of the current study is to identify potential marketed drugs that can be repurposed against bacterial infections. A pharmacovigilance-based drug repurposing approach was used to identify potential drugs. OpenVigil 2.1 tool was used to query the FDA Adverse Event Reporting System database. The reporting odds ratio (ROR) &lt; 1, ROR95CI upper bound &lt;1, and no. of cases ≥30 were used for filtering and sorting of drugs. Sunburst plot was used to represent drugs in a hierarchical order using the Anatomical Therapeutic Chemical classification. Molecular docking and dynamics were performed using the Maestro and Desmond modules of Schrodinger 2023 software respectively. A total of 40 drugs with different classes were identified based on the pharmacovigilance approach which has antibacterial potential. The molecular docking results have shown energetically favored binding conformation of lisinopril against 3-deoxy-manno-octulosonate cytidylyltransferase, UDP-2,3-diacylglucosamine hydrolase, and penicillin-binding protein 3 (PBP3) of <i>Pseudomonas aeruginosa</i>; olmesartan, atorvastatin against lipoteichoic acids flippase LtaA and rosiglitazone and varenicline against \u0000<span>d</span>-alanine ligase of <i>Staphylococcus aureus</i>; valsartan against peptidoglycan deacetylase (SpPgdA) and atorvastatin against CDP-activated ribitol for teichoic acid precursors of <i>Streptococcus pneumoniae</i>. Further, molecular dynamic results have shown the stability of identified drugs in the active site of bacterial targets except lisinopril with PBP3. Lisinopril, olmesartan, atorvastatin, rosiglitazone, varenicline, and valsartan have been identified as potential drugs for repurposing against bacterial infection.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141161232","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":"Newly synthesized acridone derivatives targeting lung cancer: A toxicity and xenograft model study","authors":"Nilam Bhusare,&nbsp;Tanuja Yadav,&nbsp;Mukesh Nandave,&nbsp;Amruta Gadade,&nbsp;Vikas Dighe,&nbsp;Godefridus J. Peters,&nbsp;Maushmi S. Kumar,&nbsp;Mayur C. Yergeri","doi":"10.1002/ddr.22212","DOIUrl":"10.1002/ddr.22212","url":null,"abstract":"<p>AKT is one of the overexpressed targets in nonsmall cell lung cancer (NSCLC) and plays an important role in its progression and offers an attractive target for the therapy. The PI3K/AKT/mTOR pathway is upregulated in NSCLC. Acridone is an important heterocycle compound which treats cancer through various mechanisms including AKT as a target. In the present work, the study was designed to evaluate the safety profile of three acridone derivatives (<b>AC-2</b>, <b>AC-7</b>, and <b>AC-26</b>) by acute and repeated dose oral toxicity. In addition to this, we also checked the pAKT overexpression and its control by these derivatives in tumor xenograft model. The results from acute and repeated dose toxicity showed these compounds to be highly safe and free from any toxicity, mortality, or significant alteration in body weight, food, and water intake in the rats. In the repeated dose toxicity, compounds showed negligible variations in a few hematological parameters at 400 mg/kg. The histopathology, biochemical, and urine parameters remained unchanged. The xenograft model study demonstrated <b>AC-2</b> to be inhibiting HOP-62 induced tumor via reduction in p-AKT1 (Ser⁴⁷³) expression significantly. In immunofluorescence staining <b>AC-2</b> treated tissue section showed 2.5 fold reduction in the expression of p-AKT1 (Ser⁴⁷³). Histopathology studies showed the destruction of tumor cells with increased necrosis after treatment. The study concluded that <b>AC-2</b> causes cell necrosis in tumor cells via blocking the p-AKT1 expression. The findings may provide a strong basis for further clinical applications of acridone derivatives in NSCLC.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141155189","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":"Asprosin aggravates nonalcoholic fatty liver disease via inflammation and lipid metabolic disturbance mediated by reactive oxygen species","authors":"Chaowen Wang,&nbsp;Wenjing Zeng,&nbsp;Li Wang,&nbsp;Xiaowei Xiong,&nbsp;Sheng Chen,&nbsp;Qianqian Huang,&nbsp;Guohua Zeng,&nbsp;Qiren Huang","doi":"10.1002/ddr.22213","DOIUrl":"10.1002/ddr.22213","url":null,"abstract":"<p>Asprosin (ASP) is a newly-identified adipokine and plays important roles in energy metabolism homeostasis. However, there is no report on whether and how ASP is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Therefore, in the study, we investigated the protective effects of ASP-deficiency on the liver in the NAFLD model mice and the detrimental effects of ASP treatment on the human normal hepatocytes (LO2 cell line). More important, we explored the underlying mechanism from the perspective of lipid metabolism and inflammation. In the in vivo experiments, our data showed that the ASP-deficiency significantly alleviated the high-fat diet-induced inflammation and NAFLD, inhibited the hepatic fat deposition and downregulated the expressions of fat acid synthase (FASN), peroxisome proliferator-activated receptor γ (PPARγ) and forkhead box protein O1 (FOXO1); moreover, the ASP-deficiency attenuated the inflammatory state and inhibited the activation of the IKK/NF-κBp65 inflammation pathway. In the in vitro experiments, our results revealed that ASP treatment caused and even exacerbated the injury of LO2 cells induced by FFA; In contrast, the ASP treatment upregulated the expressions of PPARγ, FOXO1, FASN, ACC and acyl-CoA oxidase 1 (ACOX1) and elevated the reactive oxygen species (ROS) levels. Accordingly, these results demonstrate that ASP causes NAFLD through disrupting lipid metabolism and promoting the inflammation mediated by ROS.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141155167","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":"Pantoprazole suppresses carcinogenesis and growth of hepatocellular carcinoma by inhibiting glycolysis and Na+/H+ exchange","authors":"Hai Jin,&nbsp;Guorong Wen,&nbsp;Jiaxing Zhu,&nbsp;Jielong Liu,&nbsp;Jingguo Li,&nbsp;Shun Yao,&nbsp;Zhenglan Zhao,&nbsp;Zhiqi Dong,&nbsp;Xue Zhang,&nbsp;Jiaxing An,&nbsp;Xuemei Liu,&nbsp;Biguang Tuo","doi":"10.1002/ddr.22198","DOIUrl":"10.1002/ddr.22198","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The prevention and therapy for this deadly disease remain a global medical challenge. In this study, we investigated the effect of pantoprazole (PPZ) on the carcinogenesis and growth of HCC. Both diethylnitrosamine (DEN) plus CCl4-induced and DEN plus high fat diet (HFD)-induced HCC models in mice were established. Cytokines and cell proliferation-associated gene in the liver tissues of mice and HCC cells were analyzed. Cellular glycolysis and Na⁺/H⁺ exchange activity were measured. The preventive administration of pantoprazole (PPZ) at a clinically relevant low dose markedly suppressed HCC carcinogenesis in both DEN plus CCl4-induced and HFD-induced murine HCC models, whereas the therapeutic administration of PPZ at the dose suppressed the growth of HCC. In the liver tissues of PPZ-treated mice, inflammatory cytokines, IL1, CXCL1, CXCL5, CXCL9, CXCL10, CCL2, CCL5, CCL6, CCL7, CCL20, and CCL22, were reduced. The administration of CXCL1, CXCL5, CCL2, or CCL20 all reversed PPZ-suppressed DEN plus CCL4-induced HCC carcinogenesis in mice. PPZ inhibited the expressions of CCNA2, CCNB2, CCNE2, CDC25C, CDCA5, CDK1, CDK2, TOP2A, TTK, AURKA, and BIRC5 in HCC cells. Further results showed that PPZ reduced the production of these inflammatory cytokines and the expression of these cell proliferation-associated genes through the inhibition of glycolysis and Na⁺/H⁺ exchange. In conclusion, PPZ suppresses the carcinogenesis and growth of HCC, which is related to inhibiting the production of inflammatory cytokines and the expression of cell proliferation-associated genes in the liver through the inhibition of glycolysis and Na⁺/H⁺ exchange.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141064925","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}