Chemical Biology & Drug Design

doi: 10.1111/cbdd.14080pmid: N/A

Cao, Shuying; Ma, Hui; Xu, Zhaomin; Fang, Wenqing; Huang, Jin; Huang, Ying

doi: 10.1111/cbdd.14256pmid: 37088711

Human dihydroorotate dehydrogenase (hDHODH) is a promising drug target for many diseases including autoimmune diseases, cancer, and viral infection. To develop more novel and potent hDHODH inhibitors, we screened our in‐house library of old drugs. We found that tiratricol (3,3′,5‐triiodothyroacetic acid), a thyroid hormone metabolite, has potent hDHODH inhibitory activity (IC50: 0.754 ± 0.126 μM), and its precursor tetrac (3,3′,5,5′‐tetraiodothyroacetic acid) also shows a certain inhibitory activity against hDHODH (IC50: 11.960 ± 1.453 μM). Enzyme kinetic analysis shows that tiratricol and tetrac are noncompetitive inhibitors versus CoQ0, which is different from the positive control A771726. ThermoFMN assay, molecular docking and site‐directed mutagenesis all indicate that tiratricol and tetrac interact with more key residues of hDHODH than A771726, especially some hydrophobic residues in Subsite 1. In conclusion, our experiment results indicate a potential new use for the old drug, tiratricol, and provide a novel chemical scaffold for the design of hDHODH inhibitors.

Wan, Peng; He, Xiaolan; Han, Ying; Wang, Liangliang; Yuan, Zuguo

doi: 10.1111/cbdd.14229pmid: 36905318

The treatment of breast cancer (BC) calls for targeted methods to overcome chemoresistance (CR). This study is expected to figure out the mechanism of signal transducer and activator of transcription 5 (STAT5) in NOD‐like receptor family pyrin domain containing 3 (NLRP3)‐mediated pyroptosis and CR in BC cells. BC cell lines resistant to paclitaxel (PTX) and cis‐diamminedichloro‐platinum (DDP) were prepared. Expressions of Stat5, miR‐182, and NLRP3 were detected. The 50% inhibition concentration (IC50), proliferation, colony formation, apoptosis rate, and levels of pyroptosis‐related factors were appraised and determined. The binding relationships of Stat5 and miR‐182, and miR‐182 and NLRP3 were testified. Stat5 and miR‐182 were highly expressed in drug‐resistant BC cells. Silencing Stat5 reduced proliferation and colony formation of drug‐resistant BC cells, coincided with elevated levels of pyroptosis‐related factors. Stat5 bound to the promoter region of miR‐182 to promote miR‐182 expression. miR‐182 inhibition reversed the role of silencing Stat5 in BC cells. miR‐182 inhibited NLRP3. Overall, Stat5 bound to the promoter region of miR‐182 to promote miR‐182 expression and inhibit NLRP3 transcription, thereby suppressing pyroptosis and enhancing CR of BC cells.

Song, Miaomiao; Chen, Yaping

doi: 10.1111/cbdd.14252pmid: 37076428

Diabetic nephropathy (DN) is a serious devastating disease. However, the current clinical options to treat DN are not adequate. Thus, in the present study, we intend to develop novel series of procaine‐embedded thiazole‐pyrazoles as protective agent against DN. The compounds were tested for inhibition of dipeptidyl peptidase (DPP)‐4, −8, and − 9 enzyme subtypes, where they selectively and potently inhibit DPP‐4 as compared to other subtypes. The top three ranked DPP‐4 inhibitors (8i, 8e and 8k) were further screened for inhibitory activity against NF‐ĸB transcription. Among these three, compound 8i was identified as the most potent NF‐ĸB inhibitor. The pharmacological benefit of compound 8i was further established in streptozotocin‐induced diabetic nephropathy in rats. Compound 8i showed marked improvements in blood glucose, ALP, ALT, total protein, serum lipid profile such as total cholesterol, triglyceride, HDL levels and renal functions such as urine volume, urinary protein excretion, serum creatinine, blood urea nitrogen and creatinine clearance as compared to nontreated diabetic control group. It also reduces oxidative stress (MDA, SOD and GPx) and inflammation (TNF‐α, IL‐1β and IL‐6) in the rats as compared to disease control group rats. This study demonstrated the discovery of procaine‐embedded thiazole‐pyrazole compounds as a novel class of agent against diabetic nephropathy.

Tripathi, Nancy; Bhardwaj, Nivedita; Kumar, Sanjay; Jain, Shreyans K.

doi: 10.1111/cbdd.14250pmid: 37060274

Vascular endothelial growth factors (VEGFs) are specific cytokines involved in angiogenesis and do so via binding to vascular endothelial growth factor receptors (VEGFRs), a type of receptor tyrosine kinase. VEGFs are reported to facilitate angiogenesis in physiological (embryogenesis) and pathological (tumor) conditions. The overexpression of VEGFs and consequently VEGFRs is reported in tumorigenic conditions. Several VEGFR inhibitors currently used as anticancer drugs to prevent angiogenesis are sunitinib, sorafenib, etc. To identify new potential candidates as VEGFR inhibitors, a classification study using a large and diverse dataset of VEGFR inhibitors from the BindingDB database has been conducted. The KNIME platform was used to calculate molecular and fingerprint‐based descriptors and several classification algorithms viz. linear regression (LR), k‐nearest neighbor (kNN), decision tree (DT), random forest (RF), and gradient boosted tree (GBT) were employed to build the classification model. The model performance was evaluated by accuracy, precision, recall, and F1 score of the test set. The best LR, kNN, DT, RF, and GBT classifiers had the F1 score of 0.81, 0.87, 0.82, 0.87, and 0.87, respectively. The assorted 5120 VEGFR inhibitors were clustered into 10 subsets, and the structural features of each subset were assessed along with the identification of significant fragments in active and inactive compounds. The automated classifier model developed using the KNIME platform could serve as an important platform for screening and designing molecules as VEGFR inhibitors.

Qu, Ru; Zhang, Wang; Ma, Zhuang; Ma, Qianwen; Chen, Mingju; Lan, Tian; Zhou, Lin; Hu, Xuguang

doi: 10.1111/cbdd.14241pmid: 37060267

Liver fibrosis refers to the pathophysiological process of dysplasia on the connective tissue of the liver, caused by a variety of pathogenic factors. Glaucocalyxin A (GLA) has anticoagulation, antibacterial, anti‐inflammation, antioxidant and antitumour properties. However, whether GLA ameliorates liver fibrosis or not is still unclear. In this study, a liver fibrosis model was established using male C57BL/6 mice. The mice were treated with 5 and 10 mg/kg GLA via intraperitoneal injection, respectively. The ones that were treated with 5 mg/kg OCA were used as the positive control group. The levels of liver function, liver fibrosis biomarkers and liver pathological changes were then evaluated. We also explored the effects of GLA on inflammatory response and liver cell apoptosis. In addition, we investigated the gut microbiota mechanisms of GLA on liver fibrosis. The results from this study that GLA could significantly decrease the level of liver function (AST, ALT, TBA) and liver fibrosis (HA, LN, PC‐III, IV‐C). On the other hand, a significant decrease in inflammation levels (IL‐1β, TNF‐α) were also noted. GLA also improves CCl4‐induced pathological liver injuries and collagen deposition, in addition to decreasing apoptosis levels. In addition, an increase in the ratio of Bacteroidetes and Firmicutes in liver disease was also observed. GLA also improves the gut microbiota. In conclusion, GLA attenuates CCl4‐induced liver fibrosis and improves the associated gut microbiota imbalance.

Celikkaya, Busra; Durak, Taner; Farooqi, Ammad Ahmad; Inci, Kubilay; Tokgun, Pervin Elvan; Tokgun, Onur

doi: 10.1111/cbdd.14245pmid: 37118982

MYC amplification and overexpression in breast cancer occur 16% and 22%, respectively, and MYC has a linchpin role in breast carcinogenesis. Emerging evidence has started to shed light on central role of MYC in breast cancer progression. On the contrary, tumor‐derived exosomes and their cargo molecules are required for the modulation of the tumor environment and to promote carcinogenesis. Still, how MYC regulates tumor‐derived exosomes is still a matter of investigation in the context of breast cancer. Here, we investigated for the first time how MYC affects the biological functions of normal breast cells cocultured with exosomes derived from MYC‐expression manipulated breast cancer cells. Accordingly, exosomes were isolated from MCF‐7 and MDA‐MB‐231 cells that MYC expression was manipulated through siRNAs or lentiviral vectors by using exosome isolation reagent. Then, normal breast epithelial MCF‐10A cells were treated with breast cancer cell‐derived exosomes. The cellular activity of MCF‐10A was investigated by cell growth assay, wound healing assay, and transwell assay. Our results suggested that MCF‐10A cells treated with exosomes derived from MYC‐overexpressing breast cancer cells demonstrated higher proliferation and migration capability compared with nontreated cells. Likewise, MCF‐10A cells treated with exosomes derived from MYC‐silenced cancer cells did not show high proliferation and invasive capacity. Overall, MYC can drive the functions of exosomes secreted from breast cancer cells. This may allow exploring a new mechanism how tumor cells regulate cancer progression and modulate tumor environment. The present study clears the way for further researches as in vivo studies and multi‐omics that clarify exosomal content in an MYC‐dependent manner.

Liu, Shunyao; Li, Bo; Ma, Danna; Tao, Yuejia; Song, Jiang; Bao, Li; Zhang, Guoqing; Luo, Hongyan; Cao, Shilu; E, Jing; Zheng, Yali

doi: 10.1111/cbdd.14235pmid: 37005089

Islet β‐cell damage and dysfunction represent the pathophysiological basis of diabetes. Excessive activation of cyclin‐dependent kinase 5 (CDK5) is involved in the pathogenesis of type 2 diabetes mellitus (T2DM), although the exact mechanism remains unclear. Therefore, this study investigated the role of a CDK5 inhibitor (TFP5) in islet β‐cell damage under diabetic conditions by regulating the expression of CDK5 in vitro and in vivo. CDK5 was upregulated under high glucose conditions in vivo and in vitro, which resulted in inflammation, oxidative stress, and apoptosis of islet β‐cells, thereby decreasing insulin secretion. However, TFP5 treatment inhibited the overexpression of CDK5; reduced the inflammatory response, oxidative stress, and apoptosis of islet β cells; and restored insulin secretion. In conclusion, CDK5 is involved in islet β‐cell damage under high glucose conditions, and TFP5 may represent a promising candidate for the development of treatments for T2DM.

Guo, Jia‐yi; Wang, Yong‐jun; Li, Si‐qi; Wu, Yu‐ping

doi: 10.1111/cbdd.14234pmid: 36977503

The objective of this study was to analyze potential targets of metformin against ovarian cancer (OC) through network pharmacology. Pharmacodynamic targets of metformin were predicted using the Bioinformatics Analysis Tool for the molecular mechanism of traditional Chinese medicine (BATMAN), Drugbank, PharmMapper, SwissTargetPrediction, and TargetNet databases. R was utilized to analyze the gene expression of OC tissues, normal/adjacent noncancerous tissues, and screen differentially expressed genes (DEGs) in the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) + Genotype‐Tissue Expression (GTEx) datasets. STRING 11.0 was utilized to explore the protein–protein interaction (PPI) of metformin target genes differentially expressed in OC. Cytoscape 3.8.0 was used to construct the network and screen the core targets. Additionally, gene ontology (GO) annotation and enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for the common targets of metformin and OC through the DAVID 6.8 database. A total of 95 potential common targets of metformin and OC were identified from the intersection of 255 potential pharmacodynamic targets of metformin and 10,463 genes associated with OC. Furthermore, 10 core targets were screened from the PPI network [e.g., interleukin (IL) 1B, KCNC1, ESR1, HTR2C, MAOB, GRIN2A, F2, GRIA2, APOE, PTPRC]. In addition, it was shown in GO enrichment analysis that the common targets were mainly associated with biological processes (i.e., response to stimuli or chemical, cellular processes, and transmembrane transport), cellular components (i.e., plasma membrane, cell junction, and cell projection), and molecular functions (i.e., binding, channel activities, transmembrane transporter activity, and signaling receptor activities). Furthermore, it was indicated by KEGG pathway analysis that the common targets were enriched in metabolic pathways. The critical molecular targets and molecular pathways of metformin against OC were preliminarily determined by bioinformatics‐based network pharmacology analysis, providing a basis, and reference for further experimental studies.

Mao, Meiya; Zheng, Xiaojiao; Sheng, Yuehua; Chai, Jinghan; Ding, Huiqing

doi: 10.1111/cbdd.14228pmid: 36892495

Evodiamine (EVO) has been demonstrated to promote apoptosis of ovarian cancer cells, and upregulate miR‐152‐3p level in colorectal cancer. Here, we explore part of the network mechanism of EVO and miR‐152‐3p in ovarian cancer. The bioinformatics website, dual luciferase reporter assay, and quantitative real‐time polymerase chain reaction were applied to analyze the network among EVO, lncRNA, miR‐152‐3p, and mRNA. The effect and mechanism of EVO on ovarian cancer cells were determined using cell counting kit‐8, flow cytometry, TUNEL, Western blot, and rescue experiments. As a result, EVO dose‐dependently attenuated cell viability, induced G2/M phase arrest and apoptosis, promoted miR‐152‐3p level (4.5‐ or 2‐fold changes), and inhibited expressions of NEAT1 (0.225‐ or 0.367‐fold changes), CDK8 (0.625‐ or 0.571‐fold changes), and CDK19 (0.25‐ or 0.147‐fold changes) in OVCAR‐3 and SKOV‐3 cells. In addition, EVO decreased Bcl‐2 expression, but increased the expressions of Bax and c‐caspase‐3. NEAT1 targeted miR‐152‐3p which bound to CDK19. The impacts of EVO on cell viability, cycle, apoptosis, and apoptosis‐related proteins were partially reversed by miR‐152‐3p inhibitor, NEAT1 overexpression, or CDK19 overexpression. Furthermore, miR‐152‐3p mimic offset the effects of NEAT1 or CDK19 overexpression. The role of NEAT1 overexpression in the biological phenotype of ovarian cancer cells was counteracted by shCDK19. In conclusion, EVO attenuates ovarian cancer cell progression via the NEAT1‐miR‐152‐3p‐CDK19 axis.