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Enxiang Zhang, Shutao Yin, Xiaotong Lu, Linhu Ye, Lihong Fan, Hongbo Hu
Glycycoumarin (GCM) is a representative of bioactive coumarin compounds isolated from licorice, an edible and medicinal plant widely used for treating various diseases including liver diseases. The purpose of the present study is to examine the possibility of GCM as a sensitizer to improve the efficacy of BH3 mimetic ABT-737 against liver cancer. Three liver cancer cell lines (HepG2, Huh-7 and SMMC-7721) were used to evaluate the in vitro combinatory effect of ABT-737/GCM. HepG2 xenograft model was employed to assess the in vivo efficacy of ABT-737/GCM combination...
March 15, 2018: Nutrients
Anne Harrison-Marchand, Jie Guang, Romain Duwald, Jacques Maddaluno, Hassan Oulyadi, Sami Lakhdar, Annie-Claude Gaumont
The synthesis and identification of unprecedented gem-dianionic phosphorus compounds, i.e. gem-dilithium phosphido-boranes Li2[RP*BH3], with R = Ph or Cy, are reported in THF solution. Those are obtained by double deprotonation of the corresponding primary phosphine-borane precursors RPH2*BH3. Their in-depth structural study, based on multinuclear (1H, 6Li, 7Li, 11B, 13C, 31P) mono- and bi-dimensional NMR analyses, indicates a strong influence of the phosphorus substituent on the structure of the gem-dianionic phosphorus structure: while a monomeric arrangement is obtained when R = phenyl, a cyclic oligomer is observed for R = cyclohexyl...
March 13, 2018: Chemistry: a European Journal
Srinivasulu Cheemanapalli, Anuradha C M, Suresh Babu Pakala, Suresh Kumar Chitta
Although BAX, which is a molecular hit squad that incentive apoptosis was found to be an attractive emerging target for anticancer agents. The molecular mechanism of small molecules/peptides involved in the BAX activation was remain unknown. The present focus of the study is to identification and development of novel molecules which are precisely activates BAX mediated apoptosis. In this process we identified some syringic acid analogues associated with the BAX hydrophobic groove by a virtual-screen approach...
March 9, 2018: Computational Biology and Chemistry
Noel Lugan, Dmitry A Valyaev, Alina A Grineva, Vincent César, Oleg A Filippov, Victor N Khrustalev, Sergei N Nefedov
The oxidative coupling of anionic imidazol-4-ylidenes protected at the C2 position with [MnCp(CO)2] or BH3 leads to the corresponding 4,4'-bis(2H-imidazol-2-ylidenes) complexes or adducts, in which the two carbenic moieties are connected through a single C-C bond. Subsequent acidic treatment of the later species leads to the corresponding 4,4'-bis(imidazolium) salts in good yields, the overall procedure offering a practical access to a novel class of Janus-type bis(NHC)s. Strikingly, the coplanarity of the two NHC rings within the mesityl derivative 4,4'-bis(IMes), favored by steric hindrance along with stabilizing intramolecular C-H...
March 12, 2018: Angewandte Chemie
Rami Z Morsi, Rouba Hage-Sleiman, Hadile Kobeissy, Ghassan Dbaibo
The B-cell lymphoma 2 (Bcl-2) family proteins play an important role in regulating apoptosis, or programmed cell death, in response to several extracellular and intracellular signals. These proteins are either pro-apoptotic or anti-apoptotic. The pro-apoptotic Noxa is a Bcl-2 family protein that belongs to a subclass of BH3-only proteins. Noxa induces apoptosis via p53-dependent and/or p53-independent mechanisms. While Noxa may play a limited role in apoptosis, it is a crucial player that interacts with several proteins in the apoptosis pathway, highlighting its importance in the pathogenesis and treatment of certain cancers...
March 7, 2018: Current Cancer Drug Targets
Nadia Khan, Brad Kahl
Resistance to apoptosis is one of the hallmarks of cancer and members of the B-cell lymphoma 2 (BCL-2) family of proteins are central regulators of apoptosis. Many cancers become resistant to chemotherapy and apoptosis by up-regulating BCL-2 and other family members, making these proteins attractive targets for cancer therapy. Venetoclax is an orally administered, small-molecule apoptosis stimulant that targets BCL-2 proteins by acting as a BCL-2 homology domain 3 (BH3) mimetic. The drug is approved in the USA and EU as a monotherapy for the for the treatment of certain patients with chronic lymphocytic leukemia (CLL) and is in phase III clinical development for multiple myeloma (MM), and in phase II or I/II clinical trials for acute myeloid leukemia, and several B-cell malignancies, including diffuse large B-cell lymphoma, Waldenstrom's macroglobulinaemia, follicular lymphoma, and mantle-cell lymphoma...
March 8, 2018: Targeted Oncology
Hong-Qiang Chen, Ji Zhao, Yan Li, Li-Xiong He, Yu-Jing Huang, Wei-Qun Shu, Jia Cao, Wen-Bin Liu, Jin-Yi Liu
Microcystin (MC) is a cyclic heptapeptide compound which could lead to the development of hepatocellular carcinoma. However, the underlying epigenetic regulation mechanism is largely unknown. In this study, microcystin-LR (L: lysine, R: arginine, MC-LR) was used to induce the malignant transformation of human hepatocyte L02 cell line. The profile of gene expression, microRNA (miRNA) and DNA methylation were detected through high-throughput sequencing. Compared with control group, the expression of 826 genes and 187 miRNAs changed significantly in MC-LR treated group...
March 5, 2018: Toxicology Letters
Nomeda Girnius, Yvonne J K Edwards, Roger J Davis
Involution returns the lactating mammary gland to a quiescent state after weaning. The mechanism of involution involves collapse of the mammary epithelial cell compartment. To test whether the cJUN NH2 -terminal kinase (JNK) signal transduction pathway contributes to involution, we established mice with JNK deficiency in the mammary epithelium. We found that JNK is required for efficient involution. JNK deficiency did not alter the STAT3/5 or SMAD2/3 signaling pathways that have been previously implicated in this process...
March 6, 2018: Cell Death and Differentiation
Keigo Okada, Ayako Nogami, Shinya Ishida, Hiroki Akiyama, Cheng Chen, Yoshihiro Umezawa, Osamu Miura
FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. The specific pan-Pim kinase inhibitor AZD1208 as well as PIM447 in combination with the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 cooperatively downregulated the mTORC1/4EBP1 pathway, formation of the eIF4E/eIF4G complex, and Mcl-1 expression leading to activation of Bak and Bax to induce caspase-dependent apoptosis synergistically in these cells...
February 6, 2018: Oncotarget
Ariele Viacava Follis, Fabien Llambi, Halime Kalkavan, Yong Yao, Aaron H Phillips, Cheon-Gil Park, Francesca M Marassi, Douglas R Green, Richard W Kriwacki
Intrinsically disordered regions (IDRs) of proteins often regulate function upon post-translational modification (PTM) through interactions with folded domains. An IDR linking two α-helices (α1-α2) of the antiapoptotic protein Bcl-xL experiences several PTMs that reduce antiapoptotic activity. Here, we report that PTMs within the α1-α2 IDR promote its interaction with the folded core of Bcl-xL that inhibits the proapoptotic activity of two types of regulatory targets, BH3-only proteins and p53. This autoregulation utilizes an allosteric pathway whereby, in one direction, the IDR induces a direct displacement of p53 from Bcl-xL coupled to allosteric displacement of simultaneously bound BH3-only partners...
March 5, 2018: Nature Chemical Biology
Rumana Akhter, Suraiya Saleem, Akash Saha, Subhas Chandra Biswas
The pro-apoptotic Bcl-2 homology 3 domain only (BH3-only) proteins are central regulators of cell death in various physiological and pathological conditions, including Alzheimer's disease (AD). Bcl-2 modifying factor (Bmf) is one such BH3-only protein that is implicated in various death paradigms such as anoikis, seizures, cancer and autoimmunity. It also co-operates with other BH3-only proteins such as Bim in various death paradigms. However, its role in neurodegeneration is under-investigated. Here, we report for the first time the essential role of Bmf and its co-operativity with direct activator BH3-only proteins Bim and Puma in neuron death induced by beta-amyloid (Aβ) toxicity or NGF deprivation...
February 27, 2018: Molecular and Cellular Neurosciences
Silvia Escudero, Elma Zaganjor, Susan Lee, Christopher P Mill, Ann M Morgan, Emily B Crawford, Jiahao Chen, Thomas E Wales, Rida Mourtada, James Luccarelli, Gregory H Bird, Ulrich Steidl, John R Engen, Marcia C Haigis, Joseph T Opferman, Loren D Walensky
MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) α helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid β-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1Matrix ) interacts with VLCAD...
March 1, 2018: Molecular Cell
Simone Wicki, Ursina Gurzeler, Nadia Corazza, Vera Genitsch, Wendy Wei-Lynn Wong, Thomas Kaufmann
Neutrophils are key players in the early defense against invading pathogens. Due to their potent effector functions, programmed cell death of activated neutrophils has to be tightly controlled; however, its underlying mechanisms remain unclear. Fas ligand (FASL/CD95L) has been shown to induce neutrophil apoptosis, which is accelerated by the processing of the BH3-only protein BH3 interacting domain death agonist (BID) to trigger mitochondrial apoptotic events, and been attributed a regulatory role during viral and bacterial infections...
February 28, 2018: International Journal of Molecular Sciences
M'hamed Esseffar, Carol A Parish, Rachid Jalal, Al Mokhtar Lamsabhi
The G4-level of theory has been used to evaluate the acidity of a series of triazepines, i.e. 3-thioxo-5-oxo-, 5-thioxo-3-oxo-, 3,5-dioxo-, and 3,5-dithioxo- derivatives of 2,7-dimethyl-[1,2,4]-triazepine. The ability of their available nitrogen lone pair to form a dative bond with BH3 has also been studied to highlight the resulting changes in acidity and to understand the behavior of the complexes formed. The effect of the substitution of sulfur by oxygen on the stability of the complex and the activation barrier of dehydrogenation has also been evaluated...
February 27, 2018: Journal of Physical Chemistry. A
Feliu Roset, Jesus M Ureña, Tiziana Cotrufo, José Carreras, Pablo Pérez de la Ossa, Fernando Climent
BACKGROUND Heart transplantation is a therapeutic option for patients with severe coronary artery disease or heart failure. One of the difficulties to overcome is the apoptosis of cardiomyocytes in the donor organ. To prevent apoptosis in the donor organ, we developed a fusion protein containing FLIP (FADD-like interleukin beta-converting enzyme (FLICE)-like inhibitory protein) to inhibit caspase-8. MATERIAL AND METHODS We linked the cDNA coding for the FLIP protein to the transduction domain of HIV (human immunodeficiency virus) to allow the protein to enter cells...
February 27, 2018: Annals of Transplantation: Quarterly of the Polish Transplantation Society
Suresh Banjara, Jiahao Mao, Timothy M Ryan, Sofia Caria, Marc Kvansakul
Programmed cell death or apoptosis is a critical mechanism for the controlled removal of damaged or infected cells, and proteins of the BCL-2 family are important arbiters of this process. Viruses have been shown to encode functional and structural homologs of BCL-2 to counter premature host-cell apoptosis and ensure viral proliferation or survival. Grouper iridovirus (GIV) is a large DNA virus belonging to the Iridoviridae family and harbors GIV66, a putative BCL-2 like protein and mitochondrially localized apoptosis inhibitor...
February 26, 2018: Journal of Biological Chemistry
M Edward Quach, Wenchun Chen, Renhao Li
Hundreds of billions of platelets are cleared daily from circulation via efficient and highly regulated mechanisms. These mechanisms may be stimulated by exogenous reagents or environmental changes to accelerate platelet clearance, leading to thrombocytopenia. The interplay between anti-apoptotic Bcl-xL and pro-apoptotic molecules Bax and Bak sets an internal clock for the platelet lifespan, and BH3-only proteins, mitochondrial permeabilization, and phosphatidylserine (PS) exposure may also contribute to apoptosis-induced platelet clearance...
February 23, 2018: Blood
Marta Di Martile, Marianna Desideri, Maria Grazia Tupone, Simonetta Buglioni, Barbara Antoniani, Carlotta Mastroiorio, Rita Falcioni, Virginia Ferraresi, Nicola Baldini, Roberto Biagini, Michele Milella, Daniela Trisciuoglio, Donatella Del Bufalo
Sarcomas are rare tumors with generally poor prognosis, for which current therapies have shown limited efficacy. Histone deacetylase inhibitors (HDACi) are emerging anti-tumor agents; however, little is known about their effect in sarcomas. By using established and patient-derived sarcoma cells with different subtypes, we showed that the pan-HDACi, ITF2357, potently inhibited in vitro survival in a p53-independent manner. ITF2357-mediated cell death implied the activation of mitochondrial apoptosis, as attested by induction of pro-apoptotic BH3-only proteins and a caspases-dependent mechanism...
February 23, 2018: Oncogenesis
Meng-Yeh Lin, Tzu-Ping Huang, Chih-Hao Chin, Yu-Jong Wu
The infrared (IR) spectrum of borane(3) anions (BH3 - ) isolated in solid Ar was recorded; two vibrational modes were observed at 2259.4 and 606.6 cm-1 , which were assigned to the BH2 stretching (ν3 ) and out-of-plane large-amplitude (ν2 ) modes, respectively. These anions were produced by the electron bombardment of an Ar matrix sample containing a small proportion of B2 H6 and H2 during matrix deposition or by the photolysis of single-bridged-B2 H5 - in an Ar matrix with the selected ultraviolet light...
February 21, 2018: Journal of Chemical Physics
Jonathan Ausman, Joelcio Abbade, Leonardo Ermini, Abby Farrell, Andrea Tagliaferro, Martin Post, Isabella Caniggia
Mitochondria are in a constant balance of fusing and dividing in response to cellular cues. Fusion creates healthy mitochondria, whereas fission results in removal of non-functional organelles. Changes in mitochondrial dynamics typify several human diseases. However, the contribution of mitochondrial dynamics to preeclampsia, a hypertensive disorder of pregnancy characterized by placental cell autophagy and death, remains unknown. Herein, we show that the mitochondrial dynamic balance in preeclamptic placentae is tilted toward fission (increased DRP1 expression/activation and decreased OPA1 expression)...
February 20, 2018: Cell Death & Disease
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