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Kristina Henz, Aoula Al-Zebeeby, Marion Basoglu, Simone Fulda, Gerald M Cohen, Shankar Varadarajan, Meike Vogler
Induction of apoptosis by selective BH3-mimetics is currently investigated as a novel strategy for cancer treatment. Here, we report that selective BH3-mimetics induce apoptosis in a variety of hematological malignancies. Apoptosis is accompanied by severe mitochondrial toxicities upstream of caspase activation. Specifically, the selective BH3-mimetics ABT-199, A-1331852 and S63845, which target BCL-2, BCL-XL and MCL-1, respectively, induce comparable ultrastructural changes including mitochondrial swelling, a decrease of mitochondrial matrix density and severe loss of cristae structure...
June 1, 2018: Biological Chemistry
Laurence Booth, Jane L Roberts, Rumeesa Rais, Andrew Poklepovic, Paul Dent
PARP1 inhibitors are approved therapeutic agents in ovarian carcinomas, and have clinical activity in some breast cancers. As a single agent, niraparib killed ovarian and mammary tumor cells via an ATM-AMPK-ULK1 pathway which resulted in mTOR inactivation and the formation of autophagosomes, temporally followed by autolysosome formation. In parallel, niraparib activated a CD95-FADD-caspase 8 pathway, and collectively these signals caused tumor cell death that was suppressed by knock down of Beclin1, ATG5, CD95, FADD or AIF; or by expression of c-FLIP-s, BCL-XL or dominant negative caspase 9...
June 20, 2018: Cancer Biology & Therapy
Jie Yu, Hongwei Gao, Chuanhong Wu, Qiong-Ming Xu, Jin-Jian Lu, Xiuping Chen
Doxorubicin (DOX) is a widely used antineoplastic agent in clinics. However, its clinical application is largely limited by its cardiotoxicity. Diethyl blechnic (DB) is a novel compound isolated from Salvia miltiorrhiza Bunge. Here, we study the effect of DB on DOX-induced cardiotoxicity and its underlying mechanisms. Cellular viability was tested by 3-[-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and protein level was evaluated by Western blotting. 5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining was performed to determine the mitochondrial membrane potential (MMP)...
June 19, 2018: International Journal of Molecular Sciences
Hye-Rim Won, Hyun-Wook Ryu, Dong-Hee Shin, Soo-Keun Yeon, Dong Hoon Lee, So Hee Kwon
Although histone deacetylase inhibitors (HDACi) alone could be clinically useful, these are most recently used in combination with other anticancer agents in clinical trials for cancer treatment. Recently, we reported the anticancer activity of an HDAC6-selective inhibitor A452 towards various cancer cell types. This study aims to present a potent synergistic antiproliferative effect of A452/anticancer agent treatment in colorectal cancer cells (CRC) cells, independently of the p53 status. A452 in combination with irinotecan, or SAHA is more potent than either drug alone in the apoptotic pathway as evidenced by activated caspase-3 and PARP, increased Bak and pp38, decreased Bcl-xL, pERK and pAKT, and induced apoptotic cells...
June 19, 2018: Molecular Carcinogenesis
Christian Lis, Stefan Rubner, Corinna Gröst, Ralf Hoffmann, Daniel Knappe, Thorsten Berg
Strain-promoted azide-alkyne cycloadditions (SPAAC) have proven extremely useful for labeling of biomolecules, but typically produce isomeric mixtures. This is not appropriate for the formation of bioactive molecules in living cells. Here, we report the first use of SPAAC for the isomer-free synthesis of a bioactive molecule, both in vitro and inside cultured cells. We developed the symmetrical cyclooctyne SYPCO and used it for the generation of a chemically uniform triazole inhibitor of protein-protein interactions mediated by Bcl-xL via isomer-free SPAAC (iSPAAC)...
June 19, 2018: Chemistry: a European Journal
Deng-Xuan Fan, Wen-Jie Zhou, Li-Ping Jin, Ming-Qing Li, Xiang-Hong Xu, Cong-Jian Xu
BACKGROUND: Decidual γδ T cells are known to regulate the function of trophoblasts at the maternal-fetal interface; however, little is known about the molecular mechanisms of cross talk between trophoblast cells and decidual γδ T cells. METHODS: Expression of chemokine C-X-C motif ligand 6 (CXCL16) and its receptor CXCR6 was evaluated in first-trimester human villus and decidual tissues by immunohistochemistry. γδ T cells were isolated from first-trimester human deciduae and cocultured with JEG3 trophoblast cells...
January 1, 2018: Reproductive Sciences
Kyung-Tae Shin, Jing Guo, Ying-Jie Niu, Xiang-Shun Cui
Aflatoxin B1 (AFB1) is a type of mycotoxin produced by the fungi Aspergillus flavus and Aspergillus parasiticus. AFB1 is considered as the most toxic mycotoxin owing to its toxic effect on health. In the present study, the toxic effect of AFB1 on early porcine embryonic development and its possible mechanism were investigated. Blastocyst formation was impaired with treatment of 1 nM AFB1 compared with control, 0.01, 0.1 group (40.13 ± 2.10%, 28.21 ± 1.62%, 32.34 ± 2.07% vs 19.01 ± 1.06%)...
June 8, 2018: Theriogenology
Tingwang Guo, Peng Ren, Xiaofei Li, Tiantian Luo, Yuhua Gong, Shilei Hao, Bochu Wang
Mass effect induced by growing hematoma is one of the mechanisms by which intracerebral hemorrhage (ICH) may result in brain injuries. Our goal was to investigate the damage mechanism of hydrostatic pressure associated with mass effect and the cooperative effect of hydrostatic pressure plus hemoglobin on neural injuries. Loading hydrostatic pressure on neurons and injecting agarose gel in the right striatum of rats was performed to establish the in vitro and vivo ICH models, respectively. The elevated hydrostatic pressure associated with ICH suppressed neurons and neural tissues viability, and disturbed the axons and dendrites in vitro and vivo...
June 15, 2018: Scientific Reports
Kunal Kumar, Akash Sabarwal, Rana P Singh
Mancozeb (Manganese ethylene bis-dithiocarbamate with zinc salt) is a dithiocarbamate fungicide used to control fungal disease in many fruit plants, flowers and the maintenance of field crops. The effect of mancozeb on cell viability of human gastric adenocarcinoma AGS, SNU-1 cells and human normal FHs 74 Int cells were investigated. This study demonstrated that mancozeb was able to inhibit cell proliferation by 56-82% at 5-10 μM concentrations after 48 h. Mancozeb treatment for 48 h resulted in 33% (P < 0...
June 11, 2018: Mitochondrion
Tao Shen, Hai-Zhen Li, Ai-Ling Li, Yan-Ru Li, Xiao-Ning Wang, Dong-Mei Ren
Excess intracellular reactive oxygen species (ROS) production is a significant causative factor of many diseases, exemplified by vascular diseases. Mitochondria are a major source of endogenous ROS, which simultaneously induce mitochondrial dysfunction. Nuclear factor-erythroid 2-related factor 2 (Nrf2) represents an important intracellular defense system that protects cells against oxidative insults caused by ROS. Therefore, molecules with the capacities of inducing Nrf2, and preventing mitochondrial dysfunction can inhibit cell apoptosis, and thus are potential drug candidates for the therapy of ROS-mediated vascular diseases...
June 11, 2018: Vascular Pharmacology
Fuqin Guan, Yu Shan, Qizhi Wang, Ming Wang, Yu Chen, Min Yin, Fei Liu, Youyi Zhao, Jianhua Zhang, Xu Feng
Bigelovii A is a 30‑nortriterpenoid glycoside, isolated from Salicornia bigelovii Torr. Until now, the effect of Bigelovii A on breast cancer treatment was unknown. The present research indicated that Bigelovii A significantly inhibited the proliferation of human breast cancer cells (MCF‑7, MDA‑MB‑231 and MDA‑MB‑468) in a concentration‑dependent manner. It was particularly effective in MCF7 cells, with an IC50 value of 4.10±1.19 µM. The anti‑proliferative effect of Bigelovii A was ascribed to the induction of apoptosis, which was characterized by chromatin condensation, externalization of phosphatidylserine on the plasma membrane, hypodiploid DNA, activation of caspases and poly (ADP‑ribose) polymerase cleavage...
May 30, 2018: Molecular Medicine Reports
Young Yun Jung, Jong Hyun Lee, Dongwoo Nam, Acharan S Narula, Ojas A Namjoshi, Bruce E Blough, Jae-Young Um, Gautam Sethi, Kwang Seok Ahn
Because of the essential role of signal transducer and activator of transcription 3 (STAT3) in proliferation, anti-apoptosis, and chemoresistance of multiple myeloma (MM), we investigated whether icariin, a prenylated flavonol glycoside, inhibits both constitutive and inducible STAT3 activation in human myeloma cell lines. We noted that icariin could block constitutive STAT3 phosphorylation as well as its nuclear translocation and DNA binding ability in U266 cells. Icariin also suppressed IL-6-induced STAT3 activation through the inhibition of upstream kinases (Janus activated kinase-1 and -2, and c-Src)...
2018: Frontiers in Pharmacology
Manar A Elhinnawi, Rafat M Mohareb, Hanaa M Rady, Wagdy K B Khalil, Mervat M Abd Elhalim, Gamal A Elmegeed
A series of pregnenolone derivatives were synthesized and assessed for anti-cancer activity against hepatocellular carcinoma cell line (HepG2). The synthesized hetero-steroids (compounds 3, 4, 5, 6, 7, 8a and 8b) were evaluated for their cytotoxic activities using MTT (3-(4,5-Dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide) assay. Apoptotic activity was assessed using dual acridine orange/ethidium bromide staining method and DNA fragmentation assay. Pro-apoptotic genes (Bax and Bak) and anti-apoptotic genes (Bcl-2 and Bcl-xL) were analyzed using quantitative real time PCR...
June 10, 2018: Journal of Steroid Biochemistry and Molecular Biology
Chan-Hun Jung, Ah-Reum Han, Hwa-Jin Chung, In-Hyuk Ha, Hong-Duck Um
Radiotherapy is routinely used in the treatment of lung cancer patients. However, it often causes malignant effects, such as promoting cancer cell migration and invasion. Previous studies demonstrated that ionizing radiation (IR) promotes cancer cell invasion by stimulating the β-catenin, IL-6, STAT3, and Bcl-XL signaling pathway or the PI3K, Akt, and NF-κB signaling pathway. Both Bcl-XL and NF-κB stimulate the secretion of matrix metalloproteases (MMPs), including MMP-2 and MMP-9. In the present study, linarin isolated from Chrysanthemum morifolium flowers significantly decreased the IR-induced cell migration and invasion at a concentration of 5 μM in A549 cells...
June 13, 2018: Natural Product Research
Xiao-Lan Ai, Fang Yao, Xiao-Jing Wang, Dong-Bei Duan, Ke Li, Zi-You Hu, Guo Yin, Mei Wang, Bing-Yi Wu
OBJECTIVE: To investigate the role of allograft inflammatory factor-1 (AIF-1) in colorectal cancer (CRC) progression and explore the possible mechanism. METHODS: The expression levels of AIF-1 in 70 CRC tissues and paired adjacent tissues were detected using immunohistochemistry and Western blotting, and the correlation of AIF-1 expression with the clinicopathological features of the patients was analyzed. In the CRC cell line SW480, the functional role of AIF-1 in regulating tumor progression was investigated by transfecting the cells with an AIF-1-overexpressing plasmid (AIF-1) and a negative control plasmid (NC)...
May 20, 2018: Nan Fang Yi Ke da Xue Xue Bao, Journal of Southern Medical University
Xiongxin Zhang, Shifang Yu, Gang Deng, Yunlei He, Qiang Li, Lu Yu, Yong Yu
OBJECTIVES: The aim of this study is to investigate the effects of a Nitric oxide (NO) donor, S-nitrosoglutathione (GSNO), on apoptosis and the improvement of preservation quality in apheresis platelets. METHODS: A GSNO solution - to make the final GSNO concentration of 100 uM was added into fresh apheresis platelets, and the parameters associated with platelet morphology, metabolism, and apoptosis were dynamically monitored for seven days. RESULTS: The results showed that the NO level was remarkably higher during the whole storage stageafter GSNO injection...
June 11, 2018: Hematology (Amsterdam, Netherlands)
Haiyan Jin, Minyan Wang, Jiangmei Wang, Hongmin Cao, Wanting Niu, Lizhong Du
OBJECTIVE: Volatile anaesthetic such as isoflurane causes widespread neurodegeneration in the developing animal brains and also induces cognitive impairments. Paeonol, is a plant-derived phenolic compound possessing numerous bioactive properties. The study investigates the neuroprotective effects of paeonol against isoflurane-induced neurodegeneration and cognitive disturbances in neonatal rats. METHODS: Paeonol (50, 100 and 150 mg/kg body weight/ day) was given orally to separate groups of neonatal rats from postnatal day 3 (P3) to P21 and were exposed to isoflurane (0...
June 10, 2018: Journal of Maternal-fetal & Neonatal Medicine
Xiaoqin Ran, Changxin Liu, Panwei Weng, Xiaowen Xu, Gang Lin, Guoqin Qi, Ningli Yu, Kang Xu, Zhen Wu, Chengyu Hu
In mammals, signal transducer and activator of transcription 6 (STAT6) is a broad-spectrum transcriptional regulator involved in cellular immune responses and apoptosis by regulating the immune-related genes and various functional genes. The structure, expression and tyrosine-based phosphorylation of STAT6 are conserved from fish to mammal. However, except the sporadic reports from zebra fish, the function of fish STAT6 has not been well reported. Here, we cloned and characterized the full length cDNA sequence of grass carp (Ctenopharyngodon idella) STAT6 (CiSTAT6)...
June 7, 2018: Fish & Shellfish Immunology
Yuting Wang, Ardhendu Kumar Mandal, Young-Ok Son, Poyil Pratheeshkumar, James T F Wise, Lei Wang, Zhuo Zhang, Xianglin Shi, Zhimin Chen
Environmental and occupational exposures to cadmium increase the risk of various cancers, including lung cancer. The carcinogenic mechanism of cadmium, including its prevention remains to be investigated. Using fluorescence and electron spin resonance spin trapping, the present study shows that in immortalized lung cells (BEAS-2BR cells), exposure cadmium generated reactive oxygen species (ROS). Through ROS generation, cadmium increased the protein level of TNF-α, which activated NF-κB and its target protein COX-2, creating an inflammatory microenvironment...
June 6, 2018: Toxicology and Applied Pharmacology
Qing Li, Li Zhang, Li Ma, Xue Bai, Xin Li, Mingfeng Zhao, Tao Sui
STAT5 is an important transcription factor that is constitutively activated in various types of malignancies, including chronic myelogenous leukemia (CML). Whether the antitumor effects of resveratrol (RES) are linked to its capability to inhibit STAT5 activation in CML cells was investigated. We found that RES inhibited STAT5 activation in K562 and KU812 cell lines; RES also reduced the STAT5 concentration in the nucleus of K562 and KU812 cells. Protein tyrosine phosphatase (PTP) inhibitor, sodium pervanadate, reversed the RES-induced downregulation of STAT5, suggesting the involvement of a PTP...
June 6, 2018: Anti-cancer Drugs
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