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Baicalein, a component of banxia xiexin decoction, alleviates CPT-11-induced gastrointestinal dysfunction by inhibiting ALOX15-mediated ferroptosis. 黄芩苷是板下泻心汤的一种成分,通过抑制ALOX15介导的脱铁性贫血来减轻CPT-11诱导的胃肠道功能障碍。
Pub Date : 2023-12-01 Epub Date: 2023-09-21 DOI: 10.1111/cbdd.14349
Jingbo Pei, Yuanyuan Zou, Wenying Zhou, Yakun Wang

Baicalein, one of the active ingredients of banxia xiexin decoction, has good therapeutic efficacy in treating diarrhea and improving gastrointestinal dysfunction. The role and mechanism of Baicalein on irinotecan (CPT-11)-induced gastrointestinal dysfunction are the focus of this study. Concretely, CPT-11 induced delayed diarrhea rat model and intestinal epithelial cell (IEC)-6 cell injury model with Baicalein treatment as needed. Colonic pathological changes were analyzed by hematoxylin-eosin staining, and inflammatory factor expressions in serum were determined by enzyme-linked immunosorbent assay. Immunohistochemistry and western blot were performed to quantify ferroptosis-related protein expressions. Thiobarbituric acid reactive substances (TBARS) kits and colorimetric assay kit were applied to detect lipid peroxidation levels and Fe2+ content, respectively. In vitro experiments also included quantitative real-time polymerase chain reaction, cell counting kit-8, and C11 BODIPY staining. CPT-11 induced aggravation of intestinal tissue damage, inflammatory factor release, Fe2+ accumulation, upregulation of lipid peroxidation and 15-Lipoxygenase (ALOX15) expression, and downregulation of glutathione peroxidase 4 (Gpx4) and SLC7A11 in vivo in rats; however, Baicalein dose-dependently reversed the effects of CPT-11. Baicalein elevated cell viability, reduced lipid peroxidation and Fe2+ accumulation, and elevated Gpx4 and SLC7A11 levels, whereas ALOX15 overexpression reversed the effects of Baicalein on a CPT-11-induced IEC-6 cell injury model. In conclusion, Baicalein plays a mitigating role in CPT-11-induced delayed diarrhea via ALOX15-mediated ferroptosis.

黄芩苷是板下泻心汤的有效成分之一,对治疗腹泻、改善胃肠功能障碍有良好疗效。黄芩苷对伊立替康(CPT-11)诱导的胃肠道功能障碍的作用及其机制是本研究的重点。具体地,CPT-11诱导延迟性腹泻大鼠模型和肠上皮细胞(IEC)-6细胞损伤模型,并根据需要给予黄芩苷治疗。苏木精-伊红染色分析结肠病理变化,酶联免疫吸附测定血清中炎症因子的表达。免疫组织化学和蛋白质印迹法测定脱铁相关蛋白的表达。应用硫代巴比妥酸反应物质(TBARS)试剂盒和比色法试剂盒分别检测脂质过氧化水平和Fe2+含量。体外实验还包括定量实时聚合酶链反应、细胞计数试剂盒-8和C11 BODIPY染色。CPT-11在体内诱导大鼠肠道组织损伤加重、炎症因子释放、Fe2+积累、脂质过氧化和15脂氧合酶(ALOX15)表达上调,谷胱甘肽过氧化物酶4(Gpx4)和SLC7A11下调;黄芩苷可剂量依赖性逆转CPT-11的作用。黄芩素提高细胞活力,减少脂质过氧化和Fe2+积累,并提高Gpx4和SLC7A11水平,而ALOX15过表达逆转了黄芩素对CPT-11诱导的IEC-6细胞损伤模型的影响。总之,黄芩素通过ALOX15介导的脱铁性贫血在CPT-11诱导的延迟性腹泻中起到减轻作用。
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引用次数: 0
Assessment of the anti-inflammatory mechanism of quercetin 3,7-dirhamnoside using an integrated pharmacology strategy. 采用综合药理学策略评估槲皮素3,7-dirhamnoside的抗炎机制。
Pub Date : 2023-12-01 Epub Date: 2023-10-08 DOI: 10.1111/cbdd.14346
Xinqian He, Yongzhi Sun, Xiaomeng Lu, Fan Yang, Ting Li, Changsheng Deng, Jianping Song, Xin'an Huang

Pouzolzia zeylanica (L.) Benn. is a Chinese herbal medicine widely used for its anti-inflammatory and pus-removal properties. To explore its potential anti-inflammatory mechanism, quercetin 3,7-dirhamnoside (QDR), the main flavonoid component of P. zeylanica (L.) Benn., was extracted and purified. The potential anti-inflammatory targets of QDR were predicted using network analysis. These potential targets were verified using molecular docking, molecular dynamics simulations, and in vitro experiments. Consequently, 342 potential anti-inflammatory QDR targets were identified. By analyzing the intersection between the protein-protein interaction and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we identified several potential protein targets of QDR, including RAC-alpha serine/threonine-protein kinase (AKT1), Ras-related C3 botulinum toxin substrate 1 (RAC1), nitric oxide synthase 3 (NOS3), serine/threonine-protein kinase mTOR (mTOR), epidermal growth factor receptor (EGFR), growth factor receptor-bound protein 2 (GRB2), and endothelin-1 receptor (EDNRA). QDR has anti-inflammatory activity and regulates immune responses and apoptosis through chemokines, Phosphatidylinositol 3-kinase 3(PI3K)/AKT, cAMP, T-cell receptor, and Ras signaling pathways. Molecular docking analysis showed that QDR has good binding abilities with AKT1, mTOR, and NOS3. In addition, molecular dynamics simulations demonstrated that the protein-ligand complex systems formed between QDR and AKT1, mTOR, and NOS3 have high dynamic stability, and their protein-ligand complex systems possess strong binding ability. In RAW264.7 macrophages, QDR significantly inhibited lipopolysaccharides (LPS)-induced inducible nitric oxide synthase expression, nitric oxide (NO) release and the generation of proinflammatory cytokines IL-6, IL-1β, and TNF-α. QDR downregulated the expression of p-AKT1(Ser473)/AKT1 and p-mTOR (Ser2448)/mTOR, and upregulated the expression of NOS3, Rictor, and Raptor. This indicates that the anti-inflammatory mechanisms of QDR involve regulation of AKT1 and mTOR to prevent apoptosis and of NOS3 which leads to the release of endothelial NO. Thus, our study elucidated the potential anti-inflammatory mechanism of QDR, the main flavonoid found in P. zeylanica (L.) Benn.

zeylanica Pouzolzia。是一种中草药,因其抗炎和排脓特性而被广泛使用。为了探讨其潜在的抗炎机制,研究了泽兰的主要黄酮类成分槲皮素3,7-二氢吡喃糖苷(QDR)。,提取并纯化。使用网络分析预测了QDR的潜在抗炎靶点。通过分子对接、分子动力学模拟和体外实验验证了这些潜在的靶点。因此,确定了342个潜在的抗炎QDR靶点。通过分析蛋白质-蛋白质相互作用与京都基因和基因组百科全书(KEGG)途径之间的交叉点,我们确定了QDR的几个潜在蛋白质靶标,包括RACα丝氨酸/苏氨酸蛋白激酶(AKT1)、Ras相关的C3肉毒杆菌毒素底物1(RAC1)、一氧化氮合酶3,表皮生长因子受体(EGFR)、生长因子受体结合蛋白2(GRB2)和内皮素-1受体(EDNRA)。QDR具有抗炎活性,并通过趋化因子、磷脂酰肌醇3-激酶3(PI3K)/AKT、cAMP、T细胞受体和Ras信号通路调节免疫反应和细胞凋亡。分子对接分析表明,QDR与AKT1、mTOR和NOS3具有良好的结合能力。此外,分子动力学模拟表明,QDR与AKT1、mTOR和NOS3形成的蛋白质-配体复合物系统具有较高的动力学稳定性,其蛋白质-配体配合物系统具有较强的结合能力。在RAW264.7巨噬细胞中,QDR显著抑制脂多糖(LPS)诱导的诱导型一氧化氮合酶表达、一氧化氮(NO)释放以及促炎细胞因子IL-6、IL-1β和TNF-α的产生。QDR下调p-AKT1(Ser473)/AKT1和p-mTOR(Ser2448)/mTOR的表达,并上调NOS3、Rictor和Raptor的表达。这表明QDR的抗炎机制涉及调节AKT1和mTOR以防止细胞凋亡,以及调节NOS3以导致内皮NO的释放。因此,我们的研究阐明了QDR的潜在抗炎机制,QDR是在泽兰中发现的主要类黄酮。
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引用次数: 0
Design and synthesis of novel 1,2,3,4-tetrazines as new anti-leukemia cancer agents 新型抗白血病癌症药物1,2,3,4-四嗪的设计与合成。
Pub Date : 2023-09-20 DOI: 10.1111/cbdd.14328
Oznur Eyilcim, Fulya Gunay, Omer Tahir Gunkara, Yuk Yin Ng, Ozlem Ulucan, Ihsan Erden

A series of novel 1,2,3,4-tetrazines were designed and synthesized. 1H-NMR spectroscopy, 13C NMR spectroscopy, and HRMS were used to determine the structures of this novel compounds. Computational approaches suggested that DHFR is a putative target for the newly synthesized 11 compounds. Extensive molecular dynamics simulations followed by molecular docking simulations were employed to evaluate DHFR as a potential target protein. The anticancer activities of the compounds were evaluated against five different types of leukemia cell lines (Jurkat, Nalm-6, Reh, K562, and Molt-4) and one non-leukemic cell line (Hek293T) by MTT test in vitro and imatinib was used as a control drug. Among these compounds, 3a exhibited the best activity against all the leukemic cell lines, except Reh cell line. For Nalm-6, K562, Jurkat, and Molt-4 cell lines, IC50 values were found to be 15.98, 19.12, 23.15, and 25.80 μM, respectively. Our work focuses on the synthesis of original and novel 1,2,3,4-tetrazine derivatives while contributing to the ongoing effort to discover more potent new antileukemia agents.

设计合成了一系列新的1,2,3,4-四嗪类化合物。用1H-NMR谱、13CNMR谱和HRMS测定了这些新化合物的结构。计算方法表明,DHFR是新合成的11个化合物的假定靶标。广泛的分子动力学模拟和分子对接模拟被用来评估DHFR作为一种潜在的靶蛋白。通过体外MTT试验评估了化合物对五种不同类型的白血病细胞系(Jurkat、Nalm-6、Reh、K562和Molt-4)和一种非白血病细胞株(Hek293T)的抗癌活性,并使用伊马替尼作为对照药物。在这些化合物中,3a对除Reh细胞系外的所有白血病细胞系表现出最好的活性。对于Nalm-6、K562、Jurkat和Molt-4细胞系,发现IC50值分别为15.98、19.12、23.15和25.80 μM。我们的工作重点是合成原始和新的1,2,3,4-四嗪衍生物,同时为发现更有效的新抗白血病药物做出贡献。
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引用次数: 0
A review of recent advancements in Actinium-225 labeled compounds and biomolecules for therapeutic purposes 用于治疗目的的锕-225标记化合物和生物分子的最新进展综述。
Pub Date : 2023-09-15 DOI: 10.1111/cbdd.14311
Maria Hassan, Tanveer Hussain Bokhari, Nadeem Ahmed Lodhi, Muhammad Kaleem Khosa, Muhammad Usman

In nuclear medicine, cancers that cannot be cured or can only be treated partially by traditional techniques like surgery or chemotherapy are killed by ionizing radiation as a form of therapeutic treatment. Actinium-225 is an alpha-emitting radionuclide that is highly encouraging as a therapeutic approach and more promising for targeted alpha therapy (TAT). Actinium-225 is the best candidate for tumor cells treatment and has physical characteristics such as high (LET) linear energy transfer (150 keV per μm), half-life (t1/2 = 9.92d), and short ranges (400–100 μm) which prevent the damage of normal healthy tissues. The introduction of various new radiopharmaceuticals and radioisotopes has significantly assisted the advancement of nuclear medicine. Ac-225 radiopharmaceuticals continuously demonstrate their potential as targeted alpha therapeutics. 225Ac-labeled radiopharmaceuticals have confirmed their importance in medical and clinical areas by introducing [225Ac]Ac-PSMA-617, [225Ac]Ac-DOTATOC, [225Ac]Ac-DOTA-substance-P, reported significantly improved response in patients with prostate cancer, neuroendocrine, and glioma, respectively. The development of these radiopharmaceuticals required a suitable buffer, incubation time, optimal pH, and reaction temperature. There is a growing need to standardize quality control (QC) testing techniques such as radiochemical purity (RCP). This review aims to summarize the development of the Ac-225 labeled compounds and biomolecules. The current state of their reported resulting clinical applications is also summarized as well.

在核医学中,不能治愈或只能通过手术或化疗等传统技术部分治疗的癌症,会被电离辐射作为一种治疗方法杀死。锕-225是一种发射α的放射性核素,作为一种治疗方法非常令人鼓舞,在靶向α治疗(TAT)方面更有前景。肌动蛋白-225是治疗肿瘤细胞的最佳候选者,具有高(LET)线性能量转移(150 keV/μm),半衰期(t1/2 = 9.92d)和短距离(400-100 μm),防止对正常健康组织的损伤。各种新的放射性药物和放射性同位素的引入极大地促进了核医学的发展。Ac-225放射性药物不断展示其作为靶向α疗法的潜力。225 Ac标记的放射性药物通过引入[225 Ac]Ac-PSMA-617、[225 Ac]Ac-DOTATOC、[225 Ac]Ac-DOTA-底物-P,证实了其在医学和临床领域的重要性,报告分别显著改善了前列腺癌症、神经内分泌和神经胶质瘤患者的反应。这些放射性药物的开发需要合适的缓冲液、孵育时间、最佳pH和反应温度。越来越需要标准化质量控制(QC)测试技术,如放射化学纯度(RCP)。本文综述了Ac-225标记化合物和生物分子的研究进展。还总结了其所报道的临床应用的现状。
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引用次数: 1
Resveratrol alleviates amyloid β-induced neuronal apoptosis, inflammation, and oxidative and endoplasmic reticulum stress by circ_0050263/miR-361-3p/PDE4A axis during Alzheimer's disease 在阿尔茨海默病期间,白藜芦醇通过circ_0050263/miR-361-3p/PDE4A轴减轻淀粉样蛋白β诱导的神经元凋亡、炎症以及氧化和内质网应激。
Pub Date : 2023-08-24 DOI: 10.1111/cbdd.14313
Yanchun Zhang, Deqiang Chen, Rui Tian, Xinyue Yan, Yingwen Zhou

Resveratrol (Res) has been identified to reduce neurodegeneration. Circular RNAs (circRNAs) are stable noncoding RNAs that are considered to be ideal biomarkers for molecular targeting treatment. Here, this study focused on investigating the function and relationship of circ_0050263 and Res in Alzheimer's Disease (AD). Human neuroblastoma cell line SK-N-SH was exposed to amyloid-β (Aβ) to induce AD cell model in vitro. Cell viability, apoptosis, and inflammatory reaction were evaluated by CCK-8 assay, flow cytometery, and ELISA analysis. The oxidative stress and endoplasmic reticulum stress (ERS) were determined by detecting related markers. Levels of genes and proteins were detected by qRT-PCR and Western blot. Dual-luciferase reporter assay was adopted to verify the binding between miR-361-3p and circ_0050263 or PDE4A (Phosphodiesterase 4A). Subsequently, we found that Res treatment alleviated Aβ-induced apoptosis, inflammatory response, oxidative stress, and ERS in SK-N-SH cells. Circ_0050263 is a stable circRNA, which was increased by Aβ, but decreased by Res in SK-N-SH cells. Circ_0050263 overexpression reversed Res-induced neuroprotective effects. Mechanistically, circ_0050263 acted as a sponge for miR-361-3p, which targeted PDE4A. Circ_0050263 silencing abated Aβ-induced neuronal injury, which were counteracted by following PDE4A overexpression. Moreover, PDE4A upregulation could attenuate Res-mediated neuroprotective effects. In all, Res alleviated Aβ-induced neuronal apoptosis, inflammation, oxidative stress, and ERS via circ_0050263/miR-361-3p/PDE4A axis, providing new insights for AD therapy.

白藜芦醇(Res)已被证实可以减少神经退行性变。环状RNA(circRNAs)是一种稳定的非编码RNA,被认为是分子靶向治疗的理想生物标志物。在此,本研究重点研究了circ_0050263和Res在阿尔茨海默病(AD)中的作用及其关系。将人神经母细胞瘤细胞系SK-N-SH暴露于淀粉样蛋白-β(Aβ),体外诱导AD细胞模型。通过CCK-8测定、流式细胞仪和ELISA分析评估细胞活力、细胞凋亡和炎症反应。通过检测相关标志物测定氧化应激和内质网应激(ERS)。通过qRT-PCR和蛋白质印迹检测基因和蛋白质水平。采用双荧光素酶报告基因测定来验证miR-361-3p与circ_0050263或PDE4A(磷酸二酯酶4A)之间的结合。随后,我们发现Res治疗减轻了Aβ诱导的SK-N-SH细胞凋亡、炎症反应、氧化应激和ERS。Circ_0050263是一种稳定的circRNA,在SK-N-SH细胞中,aβ使其增加,但Res使其减少。Circ_0050263过表达逆转了Res诱导的神经保护作用。从机制上讲,circ_0050263充当靶向PDE4A的miR-361-3p的海绵。Circ_0050263沉默减轻了Aβ诱导的神经元损伤,随后PDE4A过表达抵消了这种损伤。此外,PDE4A的上调可能减弱Res介导的神经保护作用。总之,Res通过circ_0050263/miR-361-3p/PDE4A轴减轻了Aβ诱导的神经元凋亡、炎症、氧化应激和ERS,为AD治疗提供了新的见解。
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引用次数: 1
N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfunctional agents against Alzheimer's disease: Design, synthesis and biological evaluation N-甲基哌嗪基和哌啶烷基-O-查尔酮衍生物作为潜在的抗阿尔茨海默病多功能药物:设计、合成和生物学评价。
Pub Date : 2023-08-20 DOI: 10.1111/cbdd.14318
Pratibha Sharma, Varinder Singh, Manjinder Singh

The series of N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfuctional agents against Alzheimer's disease that have been designed, synthesized and then evaluated biologically using in vitro assays for the inhibition of acetylcholinesterase (AChE) activity, AGEs, and free radical formation. The majority of synthesized compounds inhibited AChE & AGEs with additional free radical scavenging activities at nanomolar concentrations. Among these, compound 5k was found to have potent AChE inhibitory activity (IC50 = 11.6 nM), superior than the reference compound donepezil (15.68 nM) along with the good anti-AGEs and free radical formation effect. Its potency was justified by docking studies that revealed its dual binding characteristic with both catalytic active site and peripheral anionic site of AChE, simultaneously. Furthermore, the in vivo evaluation of 5k against streptozotocin (STZ)-induced dementia in rats also showed improvement of memory functions (Morris water maze test) in animals. Also, 5k inhibited STZ-inudced brain AChE activity and oxidative stress which further strengthen the observed in vitro effects. The stability of the ligand-protein complex was then analyzed using a simulation-based interaction protocol. The results revealed that these N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives could be considered for potential polyfunctional anti-Alzheimer's molecules.

一系列N-甲基哌嗪基和哌啶烷基-O-查尔酮衍生物作为潜在的抗阿尔茨海默病多功能药物,已被设计、合成,然后使用体外试验对乙酰胆碱酯酶(AChE)活性、AGEs和自由基形成的抑制作用进行了生物学评估。大多数合成的化合物在纳摩尔浓度下以额外的自由基清除活性抑制AChE和AGEs。其中,发现化合物5k具有有效的AChE抑制活性(IC50 = 11.6 nM),优于参考化合物多奈哌齐(15.68 nM)以及良好的抗AGEs和自由基形成作用。对接研究证明了其效力,同时揭示了其与乙酰胆碱酯酶催化活性位点和外周阴离子位点的双重结合特性。此外,5k对链脲佐菌素(STZ)诱导的大鼠痴呆的体内评估也显示出动物记忆功能的改善(Morris水迷宫试验)。此外,5k抑制STZ诱导的脑AChE活性和氧化应激,这进一步加强了观察到的体外效应。然后使用基于模拟的相互作用方案分析配体-蛋白质复合物的稳定性。结果表明,这些N-甲基哌嗪基和哌啶烷基-O-查尔酮衍生物可被认为是潜在的多功能抗阿尔茨海默病分子。
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引用次数: 2
Curcumin inhibits malignant behavior of colorectal cancer cells by regulating M2 polarization of tumor-associated macrophages and metastasis associated in colon cancer 1 (MACC1) expression 姜黄素通过调节肿瘤相关巨噬细胞M2极化和结肠癌转移相关的癌症1(MACC1)表达来抑制结直肠癌癌症细胞的恶性行为。
Pub Date : 2023-08-20 DOI: 10.1111/cbdd.14330
Shuke Ge, Xu Sun, Limin Sang, Min Zhang, Xubo Yan, Qi Ju, Xuefeng Ma, Meng Xu

The present study was to investigate the underlying mechanism of the antitumor effect of curcumin in colorectal cancer cells, focusing on the M2 polarization of tumor-associated macrophages (TAMs). The effect of curcumin on the malignant behavior of colorectal cancer cells was investigated by WST assay for cell growth, and Transwell assay for cell migration/invasion. THP-1 cells were differentiated into macrophages and coculture with colorectal cancer cells to study the influence of curcumin on M2 polarization, presenting as the levels of ARG1 mRNA, IL-10, and CD163-positive cells. GEO database was searched for the shared altered gene of curcumin in colorectal cells and human monocytes. Molecular docking was used to visualize the binding between curcumin and MACC1. Curcumin restricted the proliferation, apoptosis, and migration/invasion of HCT 116 and SW620 cells. Curcumin attenuated levels of the M2 macrophage markers, CD163 + cells, IL-10 secretion, and ARG1 mRNA. MACC1 was a target of curcumin in colorectal cancer cells, relating to macrophage. Rescue experiments showed that MACC1 overexpression can reverse the antitumor effect of curcumin in colorectal cancer cells and M2 polarization of TAMs. Curcumin's antiproliferative and anti-migratory effects in colorectal cancer cells may be mediated by MACC1 and inhibition of M2 polarization of TAMs.

本研究旨在研究姜黄素对结直肠癌癌症细胞抗肿瘤作用的潜在机制,重点研究肿瘤相关巨噬细胞(TAMs)的M2极化。通过细胞生长的WST测定和细胞迁移/侵袭的Transwell测定,研究了姜黄素对结直肠癌癌症细胞恶性行为的影响。将THP-1细胞分化为巨噬细胞,并与结直肠癌癌症细胞共培养,以研究姜黄素对M2极化的影响,表现为ARG1 mRNA、IL-10和CD163阳性细胞的水平。在GEO数据库中搜索结肠直肠癌细胞和人单核细胞中姜黄素的共享改变基因。使用分子对接来观察姜黄素和MACC1之间的结合。姜黄素抑制HCT 116和SW620细胞的增殖、凋亡和迁移/侵袭。姜黄素降低M2巨噬细胞标志物CD163的水平 + 细胞、IL-10分泌和ARG1 mRNA。MACC1是结直肠癌癌症细胞中姜黄素的靶点,与巨噬细胞有关。拯救实验表明,MACC1过表达可以逆转姜黄素对结直肠癌癌症细胞的抗肿瘤作用和TAM的M2极化。姜黄素在结直肠癌癌症细胞中的抗增殖和抗迁移作用可能是由MACC1和抑制TAM的M2极化介导的。
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引用次数: 0
Elucidation of the mechanisms and molecular targets of KeChuanLiuWei-Mixture for treatment of severe asthma based on network pharmacology 基于网络药理学阐明咳喘六味合剂治疗重症哮喘的作用机制和分子靶点。
Pub Date : 2023-08-13 DOI: 10.1111/cbdd.14302
Yanqi Cheng, Ding Sun, Lu Zou, Shaobin Li, Ling Tang, Xiao Yu, Binqing Tang, Yingen Wu, Hong Fang

KeChuanLiuWei-Mixture (KCLW) is widely used as a Chinese medicine prescription to treat severe asthma. However, the underlying therapeutic mechanism of KCLW remains unclear. In this study, a network pharmacology method was used to identify the chemical constituents of KCLW by the TCMSP database and ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry. Differential expression identification, protein–protein interaction (PPI) network and functional enrichment analysis were used to screen key targets of KCLW for severe asthma. Our results confirmed that quercetin, luteolin, kaempferol, and wogonin are the most critical active ingredients in KCLW. Moreover, the 16 relevant severe asthma-related targets of KCLW were obtained by overlapping the PPI networks of the KCLW putative targets and severe asthma-related genes, among which the most important targets were IL-6, NOS2, VEGFA, CXCL2, and PLAT. Functionally, the 16-targets and their interacting differentially expressed genes were primarily related to biological functions and pathways related to immunity and inflammation, such as inflammatory response, T cell differentiation, Nrf2/HO-1 signaling pathway, TGF-β/Smad signaling pathway, and NF-κB signaling pathway. KCLW inhibited inflammation in PDGF-BB-induced airway smooth muscle cells. In summary, this study demonstrates the active substance and potential therapeutic mechanism of KCLW in severe asthma, and offers a clinical direction for KCLW against severe asthma.

咳喘六味合剂是治疗严重哮喘的常用中药方剂。然而,KCLW的潜在治疗机制尚不清楚。本研究采用网络药理学方法,通过TCMSP数据库和超高效液相色谱-飞行时间质谱联用,对KCLW的化学成分进行了鉴定。采用差异表达鉴定、蛋白质-蛋白质相互作用(PPI)网络和功能富集分析筛选KCLW治疗严重哮喘的关键靶点。我们的研究结果证实,槲皮素、木犀草素、山奈酚和汉黄芩素是KCLW中最关键的活性成分。此外,通过重叠KCLW推定靶标和严重哮喘相关基因的PPI网络,获得了KCLW的16个相关严重哮喘相关靶标,其中最重要的靶标是IL-6、NOS2、VEGFA、CXCL2和PLAT。在功能上,16个靶点及其相互作用的差异表达基因主要与免疫和炎症相关的生物学功能和途径有关,如炎症反应、T细胞分化、Nrf2/HO-1信号通路、TGF-β/Smad信号通路和NF-κB信号通路。KCLW抑制PDGF BB诱导的气道平滑肌细胞的炎症。总之,本研究揭示了KCLW治疗严重哮喘的活性物质及其潜在的治疗机制,为KCLW对抗严重哮喘提供了临床指导。
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引用次数: 1
A novel alpha-amylase inhibitor-based spirooxindole-pyrrolidine-clubbed thiochromene-pyrzaole pharmacophores: Unveiling the [3+2] cycloaddition reaction by molecular electron density theory 一种新的基于α-淀粉酶抑制剂的螺环吲哚-吡咯烷棒状硫铬酮-吡喃酮药效团:用分子电子密度理论揭示[3+2]环加成反应。
Pub Date : 2023-08-10 DOI: 10.1111/cbdd.14299
Mohammad Shahidul Islam, Abdullah Mohammed Al-Majid, Matti Haukka, Zahida Parveen, Nabeela Ravaiz, Abdul Wadood, Ashfaq Ur Rehman, Mar Ríos-Gutiérrez, Luis R. Domingo, Assem Barakat

A novel spirooxindole-pyrrolidine clubbed thiochromene and pyrazole motifs were synthesized by [3+2] cycloaddition (32CA) reactions in one step process starting from the ethylene-based thiochromene and pyrazole scaffolds with the secondary amino-acids and substituted isatins in high yield. The 32CA reaction of AY 10 with ethylene derivative 6 has also been studied with Molecular Electron Density Theory. The high nucleophilic character of AY 10, N = 4.39 eV, allows explaining that the most favorable TS-on is 13.9 kcal mol−1 below the separated reagent. This 32CA, which takes place through a non-concerted one-step mechanism, presents a total ortho regio- and endo stereoselectivity, which is controlled by the formation of two intramolecular HO hydrogen bonds. The design of spirooxindole-pyrrolidines engrafted thiochromene and pyrazole was tested for alpha-amylase inhibition and show a high efficacy in nanoscale range of reactivity. The key interaction between the most active hybrids and the receptor was studied by molecular docking. The physiochemical properties of the designed spirooxindole-pyrrolidines were carried out by in silico ADMET prediction. The newly synthesized most potent hybrid could be considered as a lead compound for drug discovery development for type 2 diabetes mellitus (T2DM).

以乙烯基硫铬烯和吡唑支架为原料,通过[3+2]环加成(32CA)反应,以仲氨基酸和取代的靛蓝为原料,一步合成了一种新的螺氧吲哚-吡咯烷棒状硫铬烯基序和吡唑基序。用分子电子密度理论研究了AY10与乙烯衍生物6的32CA反应。AY10,N的高亲核性 = 4.39 eV,可以解释最有利的TS on是13.9 kcal mol-1。这种32CA通过非协同一步机制发生,呈现出完全的邻位和内立体选择性,这是由两个分子内H…O氢键的形成控制的。螺环吲哚吡咯烷接枝硫铬酮和吡唑的设计测试了α-淀粉酶的抑制作用,并在纳米级反应范围内显示出高效性。通过分子对接研究了最活跃的杂交种和受体之间的关键相互作用。通过计算机ADMET预测,对所设计的螺环吲哚吡咯烷的理化性质进行了研究。新合成的最有效的杂交体可以被认为是2型糖尿病(T2DM)药物发现开发的先导化合物。
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引用次数: 2
Evaluation of linagliptin and insulin combined therapy on unfolded protein response in type 1 diabetic mouse heart 利格列汀和胰岛素联合治疗对1型糖尿病小鼠心脏未折叠蛋白反应的评价。
Pub Date : 2023-08-02 DOI: 10.1111/cbdd.14308
Züleyha Doğanyiğit, Aslı Okan, Serpil Taheri, Zeynep Yılmaz, Enes Akyüz, Necdet Demir

The aim of this study is to reveal the effects of the use of linagliptin, a DPP-4 inhibitor due to its beneficial cardiovascular effects, on endoplasmic reticulum stress (ERS) signaling, which is involved in the pathogenesis of cardiovascular complications related to type 1 diabetes. BALB/c female mice (n = 72) were divided into six groups: control, diabetes+insulin, diabetes+linagliptin, diabetes+linagliptin+insulin, diabetes+TUDCA, and diabetes+TUDCA+insulin. Immunohistochemistry and western blot method, qRT-PCR, ELISA method, and malondialdehyde (MDA) measurements were performed. Linagliptin administered to the type 1 diabetic mouse heart significantly reduced the expression levels of the total and cleaved forms of ATF6, ATF4, and p-JNK, caspase 3. Immunohistochemical and western blot analyses revealed that cleaved caspase 3 protein expression was significantly increased in the diabetes+insulin group compared to the other groups. According to ELISA findings, TUDCA was more effective in reducing NOX 1 and MDA levels than linagliptin. While linagliptin decreased the Chop mRNA level, no change was observed in the Grp78 mRNA level. Our findings showed that there was not much difference between the administration of linagliptin alone or in combination with insulin. Our study reveals that linagliptin is an effective therapeutic agent on ERS and apoptotic UPR in type 1 diabetic hearts.

本研究的目的是揭示利格列汀(一种DPP-4抑制剂,由于其有益的心血管作用)对内质网应激(ERS)信号传导的影响,该信号传导参与了与1型糖尿病相关的心血管并发症的发病机制。BALB/c雌性小鼠(n = 72)分为6组:对照组、糖尿病+胰岛素组、糖尿病+利格列汀组、糖尿病+TUDCA组和糖尿病+TUDCA+胰岛素组。免疫组织化学和蛋白质印迹法、qRT-PCR、ELISA法和丙二醛(MDA)测定。给予1型糖尿病小鼠心脏的利那列汀显著降低了ATF6、ATF4和p-JNK、胱天蛋白酶3的总形式和裂解形式的表达水平。免疫组织化学和蛋白质印迹分析显示,与其他组相比,糖尿病+胰岛素组中裂解的胱天蛋白酶3蛋白表达显著增加。根据ELISA结果,TUDCA在降低NOX1和MDA水平方面比利格列汀更有效。虽然利格列汀降低了Chop mRNA水平,但Grp78 mRNA水平没有变化。我们的研究结果表明,利格列汀单独给药或与胰岛素联合给药之间没有太大差异。我们的研究表明,利格列汀是治疗1型糖尿病心脏ERS和凋亡UPR的有效药物。
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引用次数: 0
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