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Haresh Ajani, Josef Jansa, Cemal Köprülüoğlu, Pavel Hobza, Vladimír Kryštof, Antonín Lyčka, Martin Lepsik
We report on the synthesis, activity testing, docking, and quantum mechanical scoring of novel imidazo[1,2-c]pyrimidin-5(6H)-one scaffold for cyclin-dependent kinase 2 (CDK2) inhibition. A series of 26 compounds substituted with aromatic moieties at position 8 has been tested in in vitro enzyme assays and shown to inhibit CDK2. 2D structure-activity relationships have ascertained that small substituents at position 8 (up to the size of naphtyl or methoxyphenyl) generally lead to single-digit micromolar IC50 values, whereas bigger substituents (substituted biphenyls) decreased the compounds' activities...
April 23, 2018: Journal of Molecular Recognition: JMR
Liandong Jing, Yanbo Tang, Masuo Goto, Kuo-Hsiung Lee, Zhiyan Xiao
Cyclin-dependent kinases (CDKs) are pivotal kinases in cell cycle transition and gene transcription. A series of N 2 , N 4 -diphenylpyrimidine-2,4-diamines were previously identified as potent CDK2/CDK9 inhibitors. To explore the SAR of this structural prototype, twenty-four novel N 2 , N 4 -disubstituted pyrimidine-2,4-diamines were designed and synthesized. Among them, twenty-one compounds exhibited potent inhibitory activities against both CDK2/cyclin A and CDK9/cyclin T1 systems, and the most potent CDK2 and CDK9 inhibitors, 3g and 3c , showed IC50 values of 83 nM and 65 nM respectively...
April 2, 2018: RSC Advances
Jing Hu, Na Dai, Bing-Yan Xu, Fang-Liang Zhou, Ting Lin, Jing-Jing Luo, Jing-Ying Fan, Ying-Chun He
To study the effect of aqueous extracts of Yiqi Jiedu formula (YQ) on the proliferation of CNE2 cells in human nasopharyngeal carcinoma, and investigate its mechanism to provide a new theoretical basis for the clinical application of YQ. CNE2 cells were treated with different concentrations (0.125, 0.25, 0.5, 0.25 g·L⁻¹) of YQ, positive control medicine (cisplatin 4.0 mg·L⁻¹), inhibitor PD98059 (50 μmol·L⁻¹), activator isoproterenol hydrochloride (20 μmol·L⁻¹), activator isoproterenol hydrochloride (ISO)+YQ 0...
March 2018: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Meng-Die Yang, Qiu-Xiang Xu, Lian-Bao Ye, Ming Li, Yu Feng, Wei-Qiang Chen
Based on the anticancer mechanism of biological alkylating agent, we designed and synthesized two alpha pinene derivatives:(1R,5S)-(6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl)methyl benzenesulfonate and (1R,5S)-(6,6-dimethylbicyclo[3,1,1]hept-2-en-2-yl)methyl 4-methylbenzenesulfonate, of which structures were confirmed by ¹H-NMR, HPLC and MS date. These two compounds showed a good inhibition of tumor cells' proliferation. Further, the computer siuulation of molecular docking and metabolic kinetics indicated that these two copounds may have stable molecular complexation with protein CDK2, which closely related to the cell cycle...
March 2018: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Kuang-Chen Hung, Meng-Liang Lin, Shih-Wei Hsu, Chuan-Chun Lee, Ren-Yu Huang, Tian-Shung Wu, Shih-Shun Chen
Targeting cell cycle regulators has been a suggested mechanism for therapeutic cancer strategies. We report here that the bichalcone analog TSWU-CD4 induces S phase arrest of human cancer cells by inhibiting the formation of cyclin A-phospho (p)-cyclin-dependent kinase 2 (CDK2, threonine [Thr] 39) complexes, independent of mutant p53 expression. Ectopic expression of CDK2 (T39E), which mimics phosphorylation of the Thr 39 residue of CDK2, partially rescues the cells from TSWU-CD4-induced S phase arrest, whereas phosphorylation-deficient CDK2 (T39A) expression regulates cell growth with significant S phase arrest and enhances TSWU-CD4-triggered S phase arrest...
April 14, 2018: European Journal of Pharmacology
S Abood, M L Veisaga, L A López, M A Barbieri
Aberrant levels of preadipocyte differentiation, triggered by adipocyte hyperplasia and hypertrophy, results in the obesogenic phenotype. Obesity is a risk factor for several metabolic disorders. In this paper, dehydroleucodine inhibited the accumulation of lipid droplets and decreased the elevations of triglycerides, and this inhibitory effect occurred during the early stage of adipogenesis. Thus, not only did dehydroleucodine downregulate the expression of C/EBPα and PPARγ, it also strongly blocked the expression of C/EBPβ, an early stage biomarker of early adipogenesis, in a concentration-dependent manner...
April 16, 2018: Phytotherapy Research: PTR
Yi Qian, Qing-Hua Han, Li-Chao Wang, Qiang Guo, Xu-Da Wang, Peng-Fei Tu, Ke-Wu Zeng, Hong Liang
ETHNOPHARMACOLOGICAL RELEVANCE: Albiziae Cortex (AC) is a widely used traditional medicine in China. It is possess various properties to treat insomnia, traumatic injuries, diuresis, sthenia, and confusion. Total saponins of Albiziae Cortex (TSAC) are the most abundant bioactive components of AC, which were reported to show significant anti-tumor effects in vivo and in vitro. But the underlying mechanism of TSAC remained to be revealed. AIM OF STUDY: In this study, we investigated the anti- hepatoma carcinoma effects and the potential mechanism of TSAC in vivo and in vitro...
April 12, 2018: Journal of Ethnopharmacology
Sadia Afrin, Francesca Giampieri, Massimiliano Gasparrini, Tamara Y Forbes-Hernández, Danila Cianciosi, Patricia Reboredo-Rodriguez, Adolfo Amici, Josè L Quiles, Maurizio Battino
Numerous investigations have been made on plant phenolic compounds and cancer prevention in recent decades. Manuka honey (MH) represents a good source of phenolic compounds such as luteolin, kaempferol, quercetin, gallic acid and syringic acid. The aim of this work was to evaluate the chemopreventive effects of MH on human colon cancer HCT-116 and LoVo cells. Both cells were exposed to different concentrations of MH (0-20 mg mL-1 for HCT-116 cells and 0-50 mg mL-1 for LoVo cells) for 48 h to measure apoptosis and cell cycle arrest as well as apoptosis and cell cycle regulatory gene and protein expression...
April 12, 2018: Food & Function
Tsai-Der Chuang, Omid Khorram
The objective of this study was to determine whether miR-93, miR-29c, and miR-200c, which we previously reported to be downregulated in leiomyomas, target cell cycle regulatory proteins that influence cell proliferation. Based on TargetScan algorithm 3 cell cycle regulatory proteins namely, E2F transcription factor 1 (E2F1), Cyclin D1 (CCND1) and CDK2 which were predicted to be targets of these miRNAs were  further analyzed. In 30 hysterectomy specimens, we found the expression of E2F1 and CCND1 messenger RNA (mRNA) was increased in leiomyoma as compared to matched myometrium, with no significant changes in CDK2 mRNA levels...
January 1, 2018: Reproductive Sciences
Jun Hee Lee, Chul Won Yun, Jin Hur, Sang Hun Lee
Mesenchymal stem cells (MSCs) are a source for cell-based therapy. Although MSCs have the potential for tissue regeneration, their therapeutic efficacy is restricted by the uremic toxin, p -cresol, in chronic kidney disease (CKD). To address this issue, we investigated the effect of fucoidan, a marine sulfated polysaccharide, on cellular senescence in MSCs. After p -cresol exposure, MSC senescence was induced, as indicated by an increase in cell size and a decrease in proliferation capacity. Treatment of senescent MSCs with fucoidan significantly reversed this cellular senescence via regulation of SMP30 and p21, and increased proliferation through the regulation of cell cycle-associated proteins (CDK2, CDK4, cyclin D1, and cyclin E)...
April 6, 2018: Marine Drugs
Clement Opoku-Temeng, Neetu Dayal, Delmis E Hernandez, N Naganna, Herman O Sintim
Cyclin-dependent kinases have emerged as important targets for cancer therapy. HSD992, containing a novel scaffold based on the tetrahydro-3H-pyrazolo[4,3-a]phenanthridine core, inhibits CDK2/3 but not other CDKs and also potently inhibits several cancer cell lines.
April 9, 2018: Chemical Communications: Chem Comm
Kader Turkekul, R Dilsu Colpan, Talha Baykul, Mehmet D Ozdemir, Suat Erdogan
Background: Prostate cancer (PCa) is one of the most important causes of death in men and thus new therapeutic approaches are needed. In this study, antiproliferative and anti-migration properties of a coumarin derivative esculetin were evaluated. Methods: Human PCa cell lines PC3, DU145, and LNCaP were treated with various concentrations of esculetin for 24 to 72 hours, and cell viability was determined by the MTT test. Cell cycle and apoptosis were analyzed by using cell-based cytometer...
March 2018: Journal of Cancer Prevention
Xinkui Liu, Jiarui Wu, Dan Zhang, Kaihuan Wang, Xiaojiao Duan, Xiaomeng Zhang
Background: As one of the most frequently diagnosed cancer diseases globally, colorectal cancer (CRC) remains an important cause of cancer-related death. Although the traditional Chinese herb Hedyotis diffusa Willd. (HDW) has been proven to be effective for treating CRC in clinical practice, its definite mechanisms have not been completely deciphered. Objective: The aim of our research is to systematically explore the multiple mechanisms of HDW on CRC. Methods: This study adopted the network pharmacology approach, which was mainly composed of active component gathering, target prediction, CRC gene collection, network analysis, and gene enrichment analysis...
2018: Evidence-based Complementary and Alternative Medicine: ECAM
Jeff C Liu, Letizia Granieri, Mariusz Shrestha, Dong-Yu Wang, Ioulia Vorobieva, Elizabeth A Rubie, Rob Jones, YoungJun Ju, Giovanna Pellecchia, Zhe Jiang, Carlo A Palmerini, Yaacov Ben-David, Sean E Egan, James R Woodgett, Gary D Bader, Alessandro Datti, Eldad Zacksenhaus
CDK4/6 inhibitors are effective against cancer cells expressing the tumor suppressor RB1, but not RB1-deficient cells, posing the challenge of how to target RB1 loss. In triple-negative breast cancer (TNBC), RB1 and PTEN are frequently inactivated together with TP53. We performed kinome/phosphatase inhibitor screens on primary mouse Rb/p53-, Pten/p53-, and human RB1/PTEN/TP53-deficient TNBC cell lines and identified CDC25 phosphatase as a common target. Pharmacological or genetic inhibition of CDC25 suppressed growth of RB1-deficient TNBC cells that are resistant to combined CDK4/6 plus CDK2 inhibition...
April 3, 2018: Cell Reports
Hee-Weon Lee, Dong-Kwon Rhee, Byung-Oh Kim, Suhkneung Pyo
Adipocyte differentiation is a critical adaptive response to nutritional overload and affects the metabolic outcome of obesity. Sinigrin (2-propenyl glucosinolate) is a glucosinolate belong to the glucoside contained in broccoli, brussels sprouts, and black mustard seeds. We investigated the effects of sinigrin on adipogenesis in 3T3-L1 preadipocytes and its underlying mechanisms. Sinigrin remarkably inhibited the accumulation of lipid droplets and adipogenesis by downregulating the expression of CCAAT-enhancer-binding protein α (C/EBPα), peroxisome proliferator-activated receptor gamma (PPARγ), leptin and aP2...
March 28, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Xiong Weng, Shun-Qin Zhu, Hong-Juan Cui
Glioblastoma is a common brain tumor and the overall survival rate of the patients is very low, so it is an effective way to develop the potential chemotherapy or adjuvant chemotherapy drugs in glioblastoma treatment. As a well-known antimalarial drug, artesunate(ARTs) has clear side effects, and recently it has been reported to have antitumor effects, but rarely reported in glioblastoma. Different concentrations of ARTs were used to treat the glioblastoma cells, and then the inhibitory effect of ARTs on glioblastoma proliferation was detected by MTT assay; Ki67 immunofluorescence assay was used to detect the proliferation of cells; Soft agar experiment was used to explain the clonal formation abilities in vitro ; Flow Cytometry was used to detect the cell cycle; and Western blot assay was used to determine the expression of key cell cycle protein...
February 2018: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
Xiaotong Li, Hongqing Xie, Yajie Chen, Mingzi Lang, Yuyin Chen, Liangen Shi
Silkworm pupae ( Bombyx mori ) are a high-protein nutrition source consumed in China since more than 2 thousand years ago. Recent studies revealed that silkworm pupae have therapeutic benefits to treat many diseases. However, the ability of the compounds of silkworm pupae to inhibit tumourigenesis remains to be elucidated. Here, we separated the protein of silkworm pupae and performed alcalase hydrolysis. Silkworm pupa protein hydrolysate (SPPH) can specifically inhibit the proliferation and provoke abnormal morphologic features of human gastric cancer cells SGC-7901 in a dose- and time-dependent manner...
March 28, 2018: International Journal of Molecular Sciences
Celio J da Costa Fernandes, Marcel Rodrigues Ferreira, Fábio J B Bezerra, Willian F Zambuzzi
The biological response to zirconia (ZrO2 ) is not completely understood, which prompted us to address its effect on pre-osteoblastic cells in both direct and indirect manner. Our results showed that zirconia triggers important intracellular signaling mainly by governing survival signals which leads to cell adhesion and proliferation by modulating signaling cascade responsible for dynamic cytoskeleton rearrangement, as observed by fluorescence microscopy. The phosphorylations of Focal Adhesion Kinase (FAK) and Rac1 decreased in response to ZrO2 enriched medium...
March 26, 2018: Journal of Materials Science. Materials in Medicine
Raghava Potula, Bijayesh Haldar, Jonathan M Cenna, Uma Sriram, Shongshan Fan
We and others have demonstrated that stimulants such as methamphetamine (METH) exerts immunosuppressive effects on the host's innate and adaptive immune systems and has profound immunological implications. Evaluation of the mechanisms responsible for T-cell immune dysregulation may lead to ways of regulating immune homeostasis during stimulant use. Here we evaluated the effects of METH on T cell cycle entry and progression following activation. Kinetic analyses of cell cycle progression of T-cell subsets exposed to METH demonstrated protracted G1/S phase transition and differentially regulated genes responsible for cell cycle regulation...
2018: Cell Death Discovery
Alice Grison, Carine Gaiser, Andrea Bieder, Constanze Baranek, Suzana Atanasoski
Little is known about the molecular players driving proliferation of neural progenitor cells (NPCs) during embryonic mouse development. Here, we demonstrate that proliferation of NPCs in the developing forebrain depends on a particular combination of cell cycle regulators. We have analyzed the requirements for members of the cyclin-dependent kinase (cdk) family using cdk-deficient mice. In the absence of either cdk4 or cdk6, which are both regulators of the G1 phase of the cell cycle, we found no significant effects on the proliferation rate of cortical progenitor cells...
March 23, 2018: Developmental Neurobiology
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