Pub Date : 2023-10-06DOI: 10.2174/0115701808258777230926092527
Xianqiang Zhou, Tiansong Zhang
Introduction:: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Banzhilian (BZL) and Baihuasheshecao (BHSSC) are classical Chinese herbs used in tumor therapy. However, the underlying mechanisms of BZL-BHSSC in treating PDAC have not been identified. Combining network pharmacology with single-cell RNA sequencing (scRNAseq), this study systematically explored the potential mechanisms of BZL-BHSSC in the treatment of PDAC. Methods:: The bioactive ingredients of BZL-BHSSC were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, while the PDAC-related datasets were obtained from the Gene Expression Omnibus (GEO) database. Based on the dataset GSE62452, we adopted differential expression analysis and weighted gene co-expression network analysis (WGCNA) to screen the signature genes of PDAC. To reveal the cell types of the pharmacological targets of BZL-BHSSC against PDAC, we performed scRNA-seq analysis and principal component analysis (PCA) on the dataset GSE111672. Molecular docking and immunohistochemical staining were used to validate our initial results. Results:: We obtained 29 bioactive ingredients from BZL-BHSSC and screened 210 signature genes of PDAC. Using network pharmacology, we identified 7 key therapeutic targets CDK1, MYC, CCNB1, TOP2A, CLDN4, NUF2, and MET, revealing that baicalein, quercetin, and luteolin are core components for the efficacy of BZL-BHSSC. The main signaling pathways involved in therapy were the PI3K-AKT signaling pathway and the p53 signaling pathway. The molecular docking results verified the strong binding activity (binding energy > -7 kJ/mol) between active ingredients and targets. The scRNA-seq results informed that cells from 3 PDAC samples could aggregate into 19 clusters and 3 cell types. The target genes were almost concentrated on the immune cells. Immunoinfiltration analysis suggested that the expression of Macrophages M0 and Dendritic cells activated was significantly upregulated in the PDAC group (p<0.001), while the opposite was true for B cells naïve and T cells CD8 expression (p<0.05). Conclusion:: We concluded that BZL-BHSSC can improve the overall survival prognosis of PDAC patients by interfering with the signature genes of PDAC through direct and indirect pathways and improving immunity. Our study provides a basis for subsequent studies. other: No
胰腺导管腺癌(PDAC)是癌症相关死亡的主要原因之一。板芝连和白花舍草是治疗肿瘤的中草药。然而，BZL-BHSSC治疗PDAC的潜在机制尚未确定。本研究将网络药理学与单细胞RNA测序(scRNAseq)相结合，系统探索BZL-BHSSC治疗PDAC的潜在机制。方法:从中药系统药理学数据库和分析平台(TCMSP)数据库中筛选BZL-BHSSC的生物活性成分，从Gene Expression Omnibus (GEO)数据库中筛选pdac相关数据集。基于数据集GSE62452，我们采用差异表达分析和加权基因共表达网络分析(WGCNA)筛选PDAC的特征基因。为了揭示BZL-BHSSC抗PDAC药理学靶点的细胞类型，我们对数据集GSE111672进行了scRNA-seq分析和主成分分析(PCA)。分子对接和免疫组织化学染色用于验证我们的初步结果。结果:从BZL-BHSSC中获得29种活性成分，筛选出210个PDAC特征基因。利用网络药理学，我们确定了7个关键治疗靶点CDK1、MYC、CCNB1、TOP2A、CLDN4、NUF2和MET，揭示了黄芩素、槲皮素和木草素是BZL-BHSSC有效的核心成分。参与治疗的主要信号通路为PI3K-AKT信号通路和p53信号通路。分子对接结果验证了其较强的结合活性(结合能>- 7kj /mol)。scRNA-seq结果表明，来自3个PDAC样本的细胞可以聚集成19个簇和3种细胞类型。靶基因几乎集中在免疫细胞上。免疫浸润分析显示，PDAC组活化的巨噬细胞M0和树突状细胞表达显著上调(p<0.001)，而B细胞naïve和T细胞CD8表达则相反(p<0.05)。结论:BZL-BHSSC可通过直接和间接途径干扰PDAC的特征基因，提高机体免疫力，改善PDAC患者的总体生存预后。本研究为后续研究提供了基础。其他:不
{"title":"Mechanisms Underlying the Therapeutic Effects of Banzhilian- Baihuasheshecao for Treating Pancreatic Ductal Adenocarcinoma Based on Bioinformatics Strategy","authors":"Xianqiang Zhou, Tiansong Zhang","doi":"10.2174/0115701808258777230926092527","DOIUrl":"https://doi.org/10.2174/0115701808258777230926092527","url":null,"abstract":"Introduction:: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths. Banzhilian (BZL) and Baihuasheshecao (BHSSC) are classical Chinese herbs used in tumor therapy. However, the underlying mechanisms of BZL-BHSSC in treating PDAC have not been identified. Combining network pharmacology with single-cell RNA sequencing (scRNAseq), this study systematically explored the potential mechanisms of BZL-BHSSC in the treatment of PDAC. Methods:: The bioactive ingredients of BZL-BHSSC were screened from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, while the PDAC-related datasets were obtained from the Gene Expression Omnibus (GEO) database. Based on the dataset GSE62452, we adopted differential expression analysis and weighted gene co-expression network analysis (WGCNA) to screen the signature genes of PDAC. To reveal the cell types of the pharmacological targets of BZL-BHSSC against PDAC, we performed scRNA-seq analysis and principal component analysis (PCA) on the dataset GSE111672. Molecular docking and immunohistochemical staining were used to validate our initial results. Results:: We obtained 29 bioactive ingredients from BZL-BHSSC and screened 210 signature genes of PDAC. Using network pharmacology, we identified 7 key therapeutic targets CDK1, MYC, CCNB1, TOP2A, CLDN4, NUF2, and MET, revealing that baicalein, quercetin, and luteolin are core components for the efficacy of BZL-BHSSC. The main signaling pathways involved in therapy were the PI3K-AKT signaling pathway and the p53 signaling pathway. The molecular docking results verified the strong binding activity (binding energy > -7 kJ/mol) between active ingredients and targets. The scRNA-seq results informed that cells from 3 PDAC samples could aggregate into 19 clusters and 3 cell types. The target genes were almost concentrated on the immune cells. Immunoinfiltration analysis suggested that the expression of Macrophages M0 and Dendritic cells activated was significantly upregulated in the PDAC group (p<0.001), while the opposite was true for B cells naïve and T cells CD8 expression (p<0.05). Conclusion:: We concluded that BZL-BHSSC can improve the overall survival prognosis of PDAC patients by interfering with the signature genes of PDAC through direct and indirect pathways and improving immunity. Our study provides a basis for subsequent studies. other: No","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134944946","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}
Background:: Prostate cancer is one of the most complex cancer and most common in elderly males. The prostate gland's malignant growth known as benign prostatic hyperplasia (BPH) is associated with lower urinary tract symptoms (LUTS) such as frequency hesitancy, and urgency. Various treatment strategies have been employed for management of prostate cancer. Due to its prolonged treatment, varying clinical treatment and high association with treatment related morbidity raise serious questions about the ideal treatment strategy for the patients. Except for skin cancer, prostate cancer is the most frequent cancer among men. Introduction:: Prostate cancer cases were estimated at 14, 14,259 and 3, 75,304 persons were died globally in 2020. It is the fourth most frequent type of cancer to be discovered worldwide. It impacts over 75% of people by the time they turn 65 and its prevalence increases with age. It seems sensible that 5-alpha reductase inhibitors prevent the conversion of testosterone to dihydrotestosterone and would be used to treat benign prostatic hyperplasia because high levels of the 5-alpha reductase enzymes in humans lead to excessive levels of dihydrotestosterone in peripheral tissues. Method:: Finasteride (Proscar) and dutasteride (Avodart) are 5-alpha reductase inhibitors (5-ARIs) used in the treatment of lower urinary tract symptoms (LUTS) with prostatic enlargement as these suppress the androgens. Finasteride in clinical trials shows a 25% reduction in prostate cancer in randomized trials. Dutasteride (Avodart) shows the reduction in risk of prostate cancer by 23 % (approx.) but it also affects the detection of prostate cancer by affecting the levels of prostate-specific antigen. Result:: The structural requirements for potential 5-alpha reductase inhibitors might be revealed via ligand-based comparative pharmacophore research employing the known strong inhibitors. These approaches can generate data can be utilized to create more effective and selective inhibitors that pharmaceutical industries can produce at a lesser price. Conclusion:: 5-alpha reductase inhibitors are useful in the management of prostate cancer. However, further studies are needed to elucidate the optimal utilization, long-term effects and potential risks in prostate cancer treatment. All 5-alpha reductase inhibitor subcategories have been addressed in this review.
{"title":"A Review of the Azasteroid-type 5-alpha Reductase Inhibitors for the Management of Benign Prostatic Hyperplasia","authors":"Girish Chandra Arya, Ankit Rathee, Rajiv Sharma, Shefali Mehla, Preeti Bisht","doi":"10.2174/0115701808241219230923154750","DOIUrl":"https://doi.org/10.2174/0115701808241219230923154750","url":null,"abstract":"Background:: Prostate cancer is one of the most complex cancer and most common in elderly males. The prostate gland's malignant growth known as benign prostatic hyperplasia (BPH) is associated with lower urinary tract symptoms (LUTS) such as frequency hesitancy, and urgency. Various treatment strategies have been employed for management of prostate cancer. Due to its prolonged treatment, varying clinical treatment and high association with treatment related morbidity raise serious questions about the ideal treatment strategy for the patients. Except for skin cancer, prostate cancer is the most frequent cancer among men. Introduction:: Prostate cancer cases were estimated at 14, 14,259 and 3, 75,304 persons were died globally in 2020. It is the fourth most frequent type of cancer to be discovered worldwide. It impacts over 75% of people by the time they turn 65 and its prevalence increases with age. It seems sensible that 5-alpha reductase inhibitors prevent the conversion of testosterone to dihydrotestosterone and would be used to treat benign prostatic hyperplasia because high levels of the 5-alpha reductase enzymes in humans lead to excessive levels of dihydrotestosterone in peripheral tissues. Method:: Finasteride (Proscar) and dutasteride (Avodart) are 5-alpha reductase inhibitors (5-ARIs) used in the treatment of lower urinary tract symptoms (LUTS) with prostatic enlargement as these suppress the androgens. Finasteride in clinical trials shows a 25% reduction in prostate cancer in randomized trials. Dutasteride (Avodart) shows the reduction in risk of prostate cancer by 23 % (approx.) but it also affects the detection of prostate cancer by affecting the levels of prostate-specific antigen. Result:: The structural requirements for potential 5-alpha reductase inhibitors might be revealed via ligand-based comparative pharmacophore research employing the known strong inhibitors. These approaches can generate data can be utilized to create more effective and selective inhibitors that pharmaceutical industries can produce at a lesser price. Conclusion:: 5-alpha reductase inhibitors are useful in the management of prostate cancer. However, further studies are needed to elucidate the optimal utilization, long-term effects and potential risks in prostate cancer treatment. All 5-alpha reductase inhibitor subcategories have been addressed in this review.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134944947","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}
Background:: Breast cancer accounts for 30% of all new female cancers yearly. Bioinformatics serves us to find new biomarkers and facilitate future experimental research. Exploring a distinct network of competing endogenous RNA (ceRNA) that includes potential prognostic, diagnostic, and therapeutic biomarkers is captivating. Methods:: Differentially expressed lncRNAs, mRNAs, and miRNAs were collected using Gene Expression Omnibus datasets. DEGs were validated based on TCGA. Functional analysis and pathway activity were also done. Drug sensitivity analyses were done, and IC50 vs. gene expression plots were depicted. Results:: A total of 696 mRNAs, 48 lncRNAs, and, 43 miRNAs were identified to have significant differential expression in cancerous breast tissue than normal breast tissue samples. Functional analysis showed significant pathway enrichments in cancer. We found that 13 individual genes, lncRNAs, and miRNAs, CDC6, ERBB2, EZR, HELLS, MAPK13, MCM2, MMP1, SLC7A5, TINCR, TRIP13, hsa-miR-376a, hsa-miR-21, hsa-miR-454 were significantly predictive of poor overall survival and AKAP12, CXCL12, FGF2, IRS2, LINC00342, LINC01140, MEG3, MIR250HG, NAV3, NDRG2, NEAT1, TGFBR3 and, hsa-miR-29c were associated with favorable overall survival. We reached a set of five genes (EGR1, NFIB, TGFBR3, SMARCA4, and MCM2) that exhibit altered expression patterns in breast cancer, resulting in increased susceptibility of cancer cells to certain drug treatments. Conclusion:: We successfully made a unique ce-network, providing new clues to understand the regulatory functions of non-coding RNAs (miRNAs and lncRNAs) in the pathogenesis and prognosis of breast cancer and will facilitate further experimental studies to develop new biomarkers in the diagnosis, prognosis and, therapy of breast cancer. result: Functional analysis showed significant pathway enrichments in cancer, and we found that 13 individual genes, lncRNAs, and miRNAs, CDC6, ERBB2, EZR, HELLS, MAPK13, MCM2, MMP1, SLC7A5, TINCR, TRIP13, hsa-miR-376a, hsa-miR-21, hsa-miR-454 were significantly predictive of poor overall survival and AKAP12, CXCL12, FGF2, IRS2, LINC00342, LINC01140, MEG3, MIR250HG, NAV3, NDRG2, NEAT1, TGFBR3 and, hsa-miR-29c were associated with favorable overall survival. other: None
{"title":"Construction of Prognostic ceRNA Network Landscape in Breast Cancer to Explore Impacting Genes on Drug Response by Integrative Bioinformatics Analysis","authors":"Mahboubeh Sadeghi, Claudia Cava, Pegah Mousavi, Soudabeh Sabetian, Mohammad Hossein Morowvat","doi":"10.2174/0115701808255183230922110002","DOIUrl":"https://doi.org/10.2174/0115701808255183230922110002","url":null,"abstract":"Background:: Breast cancer accounts for 30% of all new female cancers yearly. Bioinformatics serves us to find new biomarkers and facilitate future experimental research. Exploring a distinct network of competing endogenous RNA (ceRNA) that includes potential prognostic, diagnostic, and therapeutic biomarkers is captivating. Methods:: Differentially expressed lncRNAs, mRNAs, and miRNAs were collected using Gene Expression Omnibus datasets. DEGs were validated based on TCGA. Functional analysis and pathway activity were also done. Drug sensitivity analyses were done, and IC50 vs. gene expression plots were depicted. Results:: A total of 696 mRNAs, 48 lncRNAs, and, 43 miRNAs were identified to have significant differential expression in cancerous breast tissue than normal breast tissue samples. Functional analysis showed significant pathway enrichments in cancer. We found that 13 individual genes, lncRNAs, and miRNAs, CDC6, ERBB2, EZR, HELLS, MAPK13, MCM2, MMP1, SLC7A5, TINCR, TRIP13, hsa-miR-376a, hsa-miR-21, hsa-miR-454 were significantly predictive of poor overall survival and AKAP12, CXCL12, FGF2, IRS2, LINC00342, LINC01140, MEG3, MIR250HG, NAV3, NDRG2, NEAT1, TGFBR3 and, hsa-miR-29c were associated with favorable overall survival. We reached a set of five genes (EGR1, NFIB, TGFBR3, SMARCA4, and MCM2) that exhibit altered expression patterns in breast cancer, resulting in increased susceptibility of cancer cells to certain drug treatments. Conclusion:: We successfully made a unique ce-network, providing new clues to understand the regulatory functions of non-coding RNAs (miRNAs and lncRNAs) in the pathogenesis and prognosis of breast cancer and will facilitate further experimental studies to develop new biomarkers in the diagnosis, prognosis and, therapy of breast cancer. result: Functional analysis showed significant pathway enrichments in cancer, and we found that 13 individual genes, lncRNAs, and miRNAs, CDC6, ERBB2, EZR, HELLS, MAPK13, MCM2, MMP1, SLC7A5, TINCR, TRIP13, hsa-miR-376a, hsa-miR-21, hsa-miR-454 were significantly predictive of poor overall survival and AKAP12, CXCL12, FGF2, IRS2, LINC00342, LINC01140, MEG3, MIR250HG, NAV3, NDRG2, NEAT1, TGFBR3 and, hsa-miR-29c were associated with favorable overall survival. other: None","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135546199","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}
Pub Date : 2023-10-05DOI: 10.2174/0115701808265088230922110240
Saad Salman, Fahad Hassan Shah, Song Ja Kim
Abstract: Statistical physics (SP) formalism in medicine involves applying concepts and methods to study biological systems and medical problems. It is an interdisciplinary field that combines physics, mathematics, and biology to analyze complex biological processes at molecular, cellular, and tissue levels. The goal of SP in medicine is to gain insights into biological systems' mechanisms and develop new strategies for diagnosing and treating diseases. SP is used in drug discovery, disease modeling, medical imaging, and the study of pharmaceutical systems in pharmacy. SP is applied to understand the anticoagulant properties of substances by modeling interactions between blood components and studying blood properties affecting coagulation. For antiviral drugs, SP models simulate interactions between antiviral molecules, virus particles, and other biological components to optimize drug efficacy. SP models are also used in studying antifungals, antibiotics, and anticancer drugs to understand drug behavior in complex systems and improve treatments. In PS, mathematical models are used for drug absorption, dosage regimens, target-mediated drug disposition, population pharmacokinetics, and physiological-based pharmacokinetic modeling and simulation (PBPK). In rheology, SP is applied to study the flow and deformation of materials like liquids and semi-solids. In understanding physicochemical principles/processes, SP helps predict and explain the behavior of systems with many particles, such as solutions, solubilization, and adsorption. For drug delivery systems, SP is used to study drug transport and distribution in the body, improving drug efficacy and safety. Metal nanocomposites are studied using SP to understand their behavior as antibacterial agents and anticoagulants. SP models predict the mechanical, electrical, and thermal properties of metal nanocomposites for various applications.
{"title":"Role of Statistical Physics Formalism in Pharmaceutical Science","authors":"Saad Salman, Fahad Hassan Shah, Song Ja Kim","doi":"10.2174/0115701808265088230922110240","DOIUrl":"https://doi.org/10.2174/0115701808265088230922110240","url":null,"abstract":"Abstract: Statistical physics (SP) formalism in medicine involves applying concepts and methods to study biological systems and medical problems. It is an interdisciplinary field that combines physics, mathematics, and biology to analyze complex biological processes at molecular, cellular, and tissue levels. The goal of SP in medicine is to gain insights into biological systems' mechanisms and develop new strategies for diagnosing and treating diseases. SP is used in drug discovery, disease modeling, medical imaging, and the study of pharmaceutical systems in pharmacy. SP is applied to understand the anticoagulant properties of substances by modeling interactions between blood components and studying blood properties affecting coagulation. For antiviral drugs, SP models simulate interactions between antiviral molecules, virus particles, and other biological components to optimize drug efficacy. SP models are also used in studying antifungals, antibiotics, and anticancer drugs to understand drug behavior in complex systems and improve treatments. In PS, mathematical models are used for drug absorption, dosage regimens, target-mediated drug disposition, population pharmacokinetics, and physiological-based pharmacokinetic modeling and simulation (PBPK). In rheology, SP is applied to study the flow and deformation of materials like liquids and semi-solids. In understanding physicochemical principles/processes, SP helps predict and explain the behavior of systems with many particles, such as solutions, solubilization, and adsorption. For drug delivery systems, SP is used to study drug transport and distribution in the body, improving drug efficacy and safety. Metal nanocomposites are studied using SP to understand their behavior as antibacterial agents and anticoagulants. SP models predict the mechanical, electrical, and thermal properties of metal nanocomposites for various applications.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135546209","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}
Pub Date : 2023-10-03DOI: 10.2174/0115701808235958230923042422
Jianmao Hong, Yanqiong Ye, Dingwen Zheng, Ximing Qian
Background:: Myocardial ischemia-reperfusion injury (MI/RI) is a serious complication after revascularization of myocardial infarction, which causes myocardium damage. Kukoamine A (KuA) can repress oxidative stress and neuronal apoptosis in cerebral ischemia animal models. background: Myocardial ischemia-reperfusion injury (MI/RI) is a serious complication after revascularization of myocardial infarction which causes myocardium damage. Kukoamine A (KuA) can repress oxidative stress and neuronal apoptosis in cerebral ischemia animal model. However, the role of KuA in MI/RI is not clear. Objective:: In the present study, our objective was to explore the role of KuA in MI/RI and the underlying mechanism of KuA in oxidative stress and inflammation of MI/RI. Methods:: H9c2 cells’ cytotoxicity was detected using the lactate dehydrogenase (LDH) assay kit. ROS level was measured by immunofluorescence. Male C57BL/6 mice were used to establish MI/RI mice by ligating the left anterior descending coronary artery (LAD). Results:: KuA treatment decreased the apoptosis and the cytotoxicity, increased the viability, and reduced the activities of myocardial infarction markers (CKMB, MYO, and cTnI) in hypoxia/ reoxygenation (H/R)-induced H9c2 cells. KuA reduced the levels of ROS, MDA, and inflammatory factors (IL-6, IL-1β, and TNF-α), and facilitated MMP and SOD levels in H/R-induced H9c2 cells. Besides, KuA activated Akt/GSK-3β axis, which was repressed by PI3K inhibitor LY294002. Moreover, KuA improved survival times, decreased the infarct size of mice, and recovered cardiac function in MI/RI mice. Finally, KuA alleviated MI/RI through Akt/GSK-3β pathway in vivo. Conclusion:: Thus, KuA exerts a protective function in MI/RI through the Akt/GSK-3β axis to repress oxidative stress and inflammation. other: none
背景:心肌缺血再灌注损伤(MI/RI)是心肌梗死血运重建术后的严重并发症，可引起心肌损伤。Kukoamine A (KuA)可以抑制脑缺血动物模型的氧化应激和神经元凋亡。背景:心肌缺血再灌注损伤(MI/RI)是心肌梗死血运重建术后引起的严重并发症。Kukoamine A (KuA)可以抑制脑缺血动物模型的氧化应激和神经元凋亡。然而，KuA在MI/RI中的作用尚不清楚。目的:在本研究中，我们的目的是探讨KuA在MI/RI中的作用以及KuA在MI/RI氧化应激和炎症中的潜在机制。方法:采用乳酸脱氢酶(LDH)测定试剂盒检测H9c2细胞的细胞毒性。免疫荧光法检测ROS水平。用雄性C57BL/6小鼠结扎左冠状动脉前降支(LAD)建立心肌梗死/心肌梗死小鼠。结果:KuA可降低缺氧/再氧化(H/R)诱导的H9c2细胞的凋亡和细胞毒性，提高细胞活力，降低心肌梗死标志物(CKMB、MYO和cTnI)的活性。KuA降低了H/ r诱导的H9c2细胞中ROS、MDA和炎症因子(IL-6、IL-1β和TNF-α)的水平，并促进了MMP和SOD的水平。此外，KuA激活Akt/GSK-3β轴，该轴被PI3K抑制剂LY294002抑制。此外，KuA改善了MI/RI小鼠的生存时间，减少了小鼠的梗死面积，并恢复了心功能。最后，KuA在体内通过Akt/GSK-3β通路缓解MI/RI。结论:由此可见，KuA通过Akt/GSK-3β轴对MI/RI具有抑制氧化应激和炎症的保护作用。其他:无
{"title":"Kukoamine a Activates Akt/GSK-3β Pathway to Repress Oxidative Stress and Inflammation to Alleviate Myocardial Ischemia-reperfusion Injury","authors":"Jianmao Hong, Yanqiong Ye, Dingwen Zheng, Ximing Qian","doi":"10.2174/0115701808235958230923042422","DOIUrl":"https://doi.org/10.2174/0115701808235958230923042422","url":null,"abstract":"Background:: Myocardial ischemia-reperfusion injury (MI/RI) is a serious complication after revascularization of myocardial infarction, which causes myocardium damage. Kukoamine A (KuA) can repress oxidative stress and neuronal apoptosis in cerebral ischemia animal models. background: Myocardial ischemia-reperfusion injury (MI/RI) is a serious complication after revascularization of myocardial infarction which causes myocardium damage. Kukoamine A (KuA) can repress oxidative stress and neuronal apoptosis in cerebral ischemia animal model. However, the role of KuA in MI/RI is not clear. Objective:: In the present study, our objective was to explore the role of KuA in MI/RI and the underlying mechanism of KuA in oxidative stress and inflammation of MI/RI. Methods:: H9c2 cells’ cytotoxicity was detected using the lactate dehydrogenase (LDH) assay kit. ROS level was measured by immunofluorescence. Male C57BL/6 mice were used to establish MI/RI mice by ligating the left anterior descending coronary artery (LAD). Results:: KuA treatment decreased the apoptosis and the cytotoxicity, increased the viability, and reduced the activities of myocardial infarction markers (CKMB, MYO, and cTnI) in hypoxia/ reoxygenation (H/R)-induced H9c2 cells. KuA reduced the levels of ROS, MDA, and inflammatory factors (IL-6, IL-1β, and TNF-α), and facilitated MMP and SOD levels in H/R-induced H9c2 cells. Besides, KuA activated Akt/GSK-3β axis, which was repressed by PI3K inhibitor LY294002. Moreover, KuA improved survival times, decreased the infarct size of mice, and recovered cardiac function in MI/RI mice. Finally, KuA alleviated MI/RI through Akt/GSK-3β pathway in vivo. Conclusion:: Thus, KuA exerts a protective function in MI/RI through the Akt/GSK-3β axis to repress oxidative stress and inflammation. other: none","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135789233","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}
Pub Date : 2023-10-01DOI: 10.2174/1570180819666220816114613
Lifang Guo, Benshan Xu, Bin Hu, He Liu, Nan Song
Background: A series of aryl-piperazine derivatives of 1,7,8,9-tetrachloro-10,10-dimethoxy-4- azatricyclo [5.2.1.02,6] dec-8-ene-3,5-dione were designed, synthesized, and their biological activities were evaluated. Methods: The chemical structures of the desired compounds were identified by 1H NMR, ESI-MS and elementary analysis. The anti-cancer and anti-angiogenesis activities of the newly synthesized compounds were evaluated by proliferation and migration assays, respectively. Results: The screening results demonstrated that compounds 2 and 5 showed potent anti-tumor activity (IC50 values ranging from 7.1 to 15.9μM) with low cytotoxic activities (IC50＞79.3μM). Although compound 5 had no effects on endothelial proliferation (IC50=65.3μM), it significantly abrogated endothelial cell migration (IC50=6.7μM). Conclusion: This work may impart new direction for the investigations of aryl-piperazine derivatives and lead to the development of potent novel anti-tumor and anti-angiogenesis agents.
{"title":"Synthesis and Biological Evaluation of 4-substituted Aryl-piperazine Derivatives of 1,7,8,9-tetrachloro-10,10-dimethoxy-4-azatricyclo [5.2.1.02,6] dec-8-ene-3,5-dione as Anti-cancer and Anti-angiogenesis Agents","authors":"Lifang Guo, Benshan Xu, Bin Hu, He Liu, Nan Song","doi":"10.2174/1570180819666220816114613","DOIUrl":"https://doi.org/10.2174/1570180819666220816114613","url":null,"abstract":"Background: A series of aryl-piperazine derivatives of 1,7,8,9-tetrachloro-10,10-dimethoxy-4- azatricyclo [5.2.1.02,6] dec-8-ene-3,5-dione were designed, synthesized, and their biological activities were evaluated. Methods: The chemical structures of the desired compounds were identified by 1H NMR, ESI-MS and elementary analysis. The anti-cancer and anti-angiogenesis activities of the newly synthesized compounds were evaluated by proliferation and migration assays, respectively. Results: The screening results demonstrated that compounds 2 and 5 showed potent anti-tumor activity (IC50 values ranging from 7.1 to 15.9μM) with low cytotoxic activities (IC50＞79.3μM). Although compound 5 had no effects on endothelial proliferation (IC50=65.3μM), it significantly abrogated endothelial cell migration (IC50=6.7μM). Conclusion: This work may impart new direction for the investigations of aryl-piperazine derivatives and lead to the development of potent novel anti-tumor and anti-angiogenesis agents.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136119317","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}
Pub Date : 2023-10-01DOI: 10.2174/1570180819666220530151210
Ayse ER
Abstract: Enzymes are highly specific catalysts that accelerate reactions in biological systems. Carbonic anhydrase (CA) is an enzyme found in plants, microorganisms, and vertebrates. CA catalyses CO2 hydration/ dehydration. There are different families and isoenzymes of CAs. Fifteen α-CA isoenzymes have been reported in humans. The status of CO2 hydration and dehydration is important for a variety of biological processes. CAs play an important role in many physiological and pathological events in several tissue types. Their levels are increased in some diseases; therefore, CA inhibition has been applied as a therapeutic option. However, the high diversity of these isoenzymes is an important consideration. Isoenzyme- specific CA inhibitors can reduce the side effects of treatment. Some agents containing additional sulfonamides approved for other therapeutic applications, such as topiramate, celecoxib/valdecoxib, sulpiride, and famotidine, have inhibitory effects on CA isoenzymes. These bind to the zinc ion in the CA active site. Recently, research has been conducted on the use of a hybrid form of active ingredient and a CA inhibitor. CA inhibitor-NSAID hybrid compounds demonstrated more efficacy than NSAIDs in arthritis, which has attracted further attention of researchers in conducting research on CA-hybrid drugs.
{"title":"Various Carbonic Anhydrases in Physiopathological Events, Carbonic Anhydrase Inhibitors, and Hybrid Compounds","authors":"Ayse ER","doi":"10.2174/1570180819666220530151210","DOIUrl":"https://doi.org/10.2174/1570180819666220530151210","url":null,"abstract":"Abstract: Enzymes are highly specific catalysts that accelerate reactions in biological systems. Carbonic anhydrase (CA) is an enzyme found in plants, microorganisms, and vertebrates. CA catalyses CO2 hydration/ dehydration. There are different families and isoenzymes of CAs. Fifteen α-CA isoenzymes have been reported in humans. The status of CO2 hydration and dehydration is important for a variety of biological processes. CAs play an important role in many physiological and pathological events in several tissue types. Their levels are increased in some diseases; therefore, CA inhibition has been applied as a therapeutic option. However, the high diversity of these isoenzymes is an important consideration. Isoenzyme- specific CA inhibitors can reduce the side effects of treatment. Some agents containing additional sulfonamides approved for other therapeutic applications, such as topiramate, celecoxib/valdecoxib, sulpiride, and famotidine, have inhibitory effects on CA isoenzymes. These bind to the zinc ion in the CA active site. Recently, research has been conducted on the use of a hybrid form of active ingredient and a CA inhibitor. CA inhibitor-NSAID hybrid compounds demonstrated more efficacy than NSAIDs in arthritis, which has attracted further attention of researchers in conducting research on CA-hybrid drugs.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136119318","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}
Pub Date : 2023-09-28DOI: 10.2174/1570180820666230627124449
Daiana Teixeira Mancini, Isabela Aparecida Militani, Alexandre Alves de Castro, Letícia Cristina Assis, Teodorico de Castro Ramalho
Background: The Amyotrophic lateral sclerosis (ALS) is a degenerative and most frequent motor neuron disease characterized by the progressive impairment of upper and lower motor neurons. The treatment of the disease is still palliative and limited to the use of only two drugs, riluzole and edaravone, which only prolong survival by a few months. Taking into account the low number of therapy available for this disease, identification of novel therapeutic strategies for ALS is urgently needed. The superoxide dismutase 1 (SOD1) was the first gene in which mutations were found to be causative for the neurodegenerative disease and has been used as a promising target for the ALS treatment. Methods: In this work we used powerful computational tools (in silico method) such as Ligand-based Virtual Screening (SBVS), docking and molecular dynamics techniques to collaborate with the discovery of new candidates for more potent drugs to be used in the ALS disease treatment. Results: Compound 1 shows good stability in the active site of the SOD1 enzyme, with an intermolecular interaction energy of -154.80 kcal/mol. In addition, the presence of some amino acids such as Glu24, Glu21, Pro28, Lys23 and Lys30 is important for to maintain stability of this compound inside SOD1. Conclusion: This study was essential due to a low number of therapy available for this disease until the moment. With this study, it was possible to observe that Compound 1 is the most promising for the design of SOD1 mutant enzyme potential inhibitors. However, experimental tests in the SOD1 mutant to validate the inhibitory effect of Compound 1 will be required.
{"title":"Modeling Molecular Study between SDO1/Inhibitors: Search of New Treatments for Amyotrophic Lateral Sclerosis","authors":"Daiana Teixeira Mancini, Isabela Aparecida Militani, Alexandre Alves de Castro, Letícia Cristina Assis, Teodorico de Castro Ramalho","doi":"10.2174/1570180820666230627124449","DOIUrl":"https://doi.org/10.2174/1570180820666230627124449","url":null,"abstract":"Background: The Amyotrophic lateral sclerosis (ALS) is a degenerative and most frequent motor neuron disease characterized by the progressive impairment of upper and lower motor neurons. The treatment of the disease is still palliative and limited to the use of only two drugs, riluzole and edaravone, which only prolong survival by a few months. Taking into account the low number of therapy available for this disease, identification of novel therapeutic strategies for ALS is urgently needed. The superoxide dismutase 1 (SOD1) was the first gene in which mutations were found to be causative for the neurodegenerative disease and has been used as a promising target for the ALS treatment. Methods: In this work we used powerful computational tools (in silico method) such as Ligand-based Virtual Screening (SBVS), docking and molecular dynamics techniques to collaborate with the discovery of new candidates for more potent drugs to be used in the ALS disease treatment. Results: Compound 1 shows good stability in the active site of the SOD1 enzyme, with an intermolecular interaction energy of -154.80 kcal/mol. In addition, the presence of some amino acids such as Glu24, Glu21, Pro28, Lys23 and Lys30 is important for to maintain stability of this compound inside SOD1. Conclusion: This study was essential due to a low number of therapy available for this disease until the moment. With this study, it was possible to observe that Compound 1 is the most promising for the design of SOD1 mutant enzyme potential inhibitors. However, experimental tests in the SOD1 mutant to validate the inhibitory effect of Compound 1 will be required.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135469966","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}
aims: To discover novel and potent RORγt inverse agonists for the treatment of Th17 cell-related autoimmune diseases such as psoriasis, and rheumatoid arthritis. background: The nuclear receptor retinoic acid receptor-related orphan receptor γt (RORγt) is an important transcription factor in immune cells. Functionally, RORγt plays an important role in promoting the differentiation of T helper 17 cells and regulating the expression of pro-inflammatory factors such as interleukin 17. Therefore, RORγt is considered a promising target for the treatment of the autoimmune disorder. Currently, 21 RORγt inverse agonists with various scaffolds have entered clinical trials. objective: To discover novel and potent RORγt inverse agonists, a series of novel 6-(trifluoromethyl) pyridine derivatives were designed and synthesized. method: We designed and synthesized a series of potent RORγt inverse agonists W1~W16 based on VTP-43742. Molecular docking, molecular dynamics (MD) simulation, and MM/GBSA were used to study the structure-activity relationship (SAR) of the derivatives. result: The biological activity evaluation indicated that the target compounds showed potent RORγt inhibitory activities. The most active compound W14 exhibited low nanomolar inhibitory activity (IC50 = 7.5 nM) in the luciferase reporter assay, which was superior to the clinical compound VTP-43742. Analysis of the binding mode of W14 demonstrated that the interaction of -CF3 with Leu324, Leu396, and His479 has an important contribution to the binding. Furthermore, W14 broke the H-bond formed by His479 and Tyr502 via a “push-pull” mechanism. conclusion: Compound W14 could be used as a potential RORγt inverse agonist for further modification. other: No
{"title":"An SAR Study on a Class of 6-(Trifluoromethyl)-pyridine Derivatives as RORγt Inverse Agonists","authors":"Yi-Yuan Ma, Yu-Hao Cao, Li-Jin Yang, Shi-Han Wu, Zhen-Jiang Tong, Jia-Zhen Wu, Yi-Bo Wang, Jiu-Kai Sha, Chen-Qian Zhang, Xin-Rui Zheng, Jiao Cai, Zi-Jun Chen, Qing-Xin Wang, Jing-Jing Wang, Jing-Han Zhao, Liang Chang, Ning Ding, Xue-Jiao Leng, Jin-Guo Xu, Wei-Chen Dai, Shan-Liang Sun, Yan-Cheng Yu, Xiao-Long Wang, Xin Xue, Nian-Guang Li","doi":"10.2174/0115701808234886230921063622","DOIUrl":"https://doi.org/10.2174/0115701808234886230921063622","url":null,"abstract":"aims: To discover novel and potent RORγt inverse agonists for the treatment of Th17 cell-related autoimmune diseases such as psoriasis, and rheumatoid arthritis. background: The nuclear receptor retinoic acid receptor-related orphan receptor γt (RORγt) is an important transcription factor in immune cells. Functionally, RORγt plays an important role in promoting the differentiation of T helper 17 cells and regulating the expression of pro-inflammatory factors such as interleukin 17. Therefore, RORγt is considered a promising target for the treatment of the autoimmune disorder. Currently, 21 RORγt inverse agonists with various scaffolds have entered clinical trials. objective: To discover novel and potent RORγt inverse agonists, a series of novel 6-(trifluoromethyl) pyridine derivatives were designed and synthesized. method: We designed and synthesized a series of potent RORγt inverse agonists W1~W16 based on VTP-43742. Molecular docking, molecular dynamics (MD) simulation, and MM/GBSA were used to study the structure-activity relationship (SAR) of the derivatives. result: The biological activity evaluation indicated that the target compounds showed potent RORγt inhibitory activities. The most active compound W14 exhibited low nanomolar inhibitory activity (IC50 = 7.5 nM) in the luciferase reporter assay, which was superior to the clinical compound VTP-43742. Analysis of the binding mode of W14 demonstrated that the interaction of -CF3 with Leu324, Leu396, and His479 has an important contribution to the binding. Furthermore, W14 broke the H-bond formed by His479 and Tyr502 via a “push-pull” mechanism. conclusion: Compound W14 could be used as a potential RORγt inverse agonist for further modification. other: No","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134960039","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}
Pub Date : 2023-09-15DOI: 10.2174/1570180820666230915103737
Alireza Moslem, Mohsen Aliakbarian, Rozita Khodashahi, Mahmoud Tavakkoli, Gordon A Ferns, Hoda Rahimi, Kiarash Ashrafzadeh, Mohammad-Hassan Arjmand
Abstract: Allograft rejection is one of the main problems that must be overcome. Evidence suggests a role of the local renin-angiotensin system (RAS) in the progress of chronic allograft injury. Angiotensin II, generated by the renin-angiotensin system, is well-known as a major regulator molecule to control the blood pressure and fluid system. Evidence suggests that this bioactive molecule and its receptor increase the risk of tissue injuries and organ transplant rejection through different molecular mechanisms such as activation of innate and cellular immunity, upregulation of inflammatory pathways, and accumulation of extracellular matrix by expression pro-fibrotic molecules like transforming growth factor β (TGF-β) to increase the risk of fibrosis. Based on these findings, AT1R antagonists might have therapeutic potential to prevent the risk of tissue injuries and allograft rejection by regulating immune response, inflammation pathway, and fibrogenesis to improve organ functions.
{"title":"The Angiotensin type 1 receptor: a drug target to reduce the risk of organ transplant rejection","authors":"Alireza Moslem, Mohsen Aliakbarian, Rozita Khodashahi, Mahmoud Tavakkoli, Gordon A Ferns, Hoda Rahimi, Kiarash Ashrafzadeh, Mohammad-Hassan Arjmand","doi":"10.2174/1570180820666230915103737","DOIUrl":"https://doi.org/10.2174/1570180820666230915103737","url":null,"abstract":"Abstract: Allograft rejection is one of the main problems that must be overcome. Evidence suggests a role of the local renin-angiotensin system (RAS) in the progress of chronic allograft injury. Angiotensin II, generated by the renin-angiotensin system, is well-known as a major regulator molecule to control the blood pressure and fluid system. Evidence suggests that this bioactive molecule and its receptor increase the risk of tissue injuries and organ transplant rejection through different molecular mechanisms such as activation of innate and cellular immunity, upregulation of inflammatory pathways, and accumulation of extracellular matrix by expression pro-fibrotic molecules like transforming growth factor β (TGF-β) to increase the risk of fibrosis. Based on these findings, AT1R antagonists might have therapeutic potential to prevent the risk of tissue injuries and allograft rejection by regulating immune response, inflammation pathway, and fibrogenesis to improve organ functions.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135485369","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}
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