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https://www.readbyqxmd.com/read/28822281/an-integrative-study-to-identify-novel-scaffolds-for-sphingosine-kinase-1-inhibitors
#1
Marcela Vettorazzi, Emilio Angelina, Santiago Lima, Tomas Gonec, Jan Otevrel, Pavlina Marvanova, Tereza Padrtova, Petr Mokry, Pavel Bobal, Lina M Acosta, Alirio Palma, Justo Cobo, Janette Bobalova, Jozef Csollei, Ivan Malik, Sergio Alvarez, Sarah Spiegel, Josef Jampilek, Ricardo D Enriz
Sphingosine kinase 1 (SphK1), the enzyme that produces the bioactive sphingolipid metabolite, sphingosine-1-phosphate, is a promising new molecular target for therapeutic intervention in cancer and inflammatory diseases. In view of its importance, the main objective of this work was to find new and more potent inhibitors for this enzyme possessing different structural scaffolds than those of the known inhibitors. Our theoretical and experimental study has allowed us to identify two new structural scaffolds (three new compounds), which could be used as starting structures for the design and then the development of new inhibitors of SphK1...
August 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28822219/regulation-of-protein-function-by-s-nitrosation-and-s-glutathionylation-processes-and-targets-in-cardiovascular-pathophysiology
#2
Eugenia Belcastro, Caroline Gaucher, Alessandro Corti, Pierre Leroy, Isabelle Lartaud, Alfonso Pompella
Decades of chemical, biochemical and pathophysiological research have established the relevance of post-translational protein modifications induced by processes related to oxidative stress, with critical reflections on cellular signal transduction pathways. A great deal of the socalled 'redox regulation' of cell function is in fact mediated through reactions promoted by reactive oxygen and nitrogen species on more or less specific aminoacid residues in proteins, at various levels within the cell machinery. Modifications involving cysteine residues have received most attention, due to the critical roles they play in determining the structure/function correlates in proteins...
August 28, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28822069/characterization-of-ofloxacin-interaction-with-mutated-a91v-quinolone-resistance-determining-region-of-dna-gyrase-in-mycobacterium-leprae-through-computational-simulation
#3
J Nisha, V Shanthi
Mycobacterium leprae, the causal agent of leprosy is non-cultivable in vitro. Thus, the assessment of antibiotic activity against Mycobacterium leprae depends primarily upon the time-consuming mouse footpad system. The GyrA protein of Mycobacterium leprae is the target of the antimycobacterial drug, Ofloxacin. In recent times, the GyrA mutation (A91V) has been found to be resistant to Ofloxacin. This phenomenon has necessitated the development of new, long-acting antimycobacterial compounds. The underlying mechanism of drug resistance is not completely known...
August 18, 2017: Cell Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28822039/stimulation-of-nachr%C3%AE-7-receptor-inhibits-tnf-synthesis-and-secretion-in-response-to-lps-treatment-of-mast-cells-by-targeting-erk1-2-and-tace-activation
#4
F Guzmán-Mejía, C López-Rubalcava, C González-Espinosa
The cholinergic anti-inflammatory pathway is recognized as one of the main mechanisms of neuromodulation of the immune system. Activation of the α7 nicotinic acetylcholine receptor (nAchRα7) suppresses cytokine synthesis in distinct immune cells but the molecular mechanisms behind this effect remain to be fully described. Mast cells (MCs) are essential players of allergic reactions and innate immunity responses related to chronic inflammation. Activation of TLR4 receptor in MCs leads to the rapid secretion of pre-synthesized TNF from intracellular pools and to the activation of NFκB, necessary for de novo synthesis of TNF and other cytokines...
August 18, 2017: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://www.readbyqxmd.com/read/28822012/mtor-co-targeting-strategies-for-head-and-neck-cancer-therapy
#5
Zhiyong Wang, Juan Callejas Valera, Xuefeng Zhao, Qianming Chen, J Silvio Gutkind
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. There is an urgent need to develop effective therapeutic approaches to prevent and treat HNSCC. Recent deep sequencing of the HNSCC genomic landscape revealed a multiplicity and diversity of genetic alterations in this malignancy. Although a large variety of specific molecules were found altered in each individual tumor, they all participate in only a handful of driver signaling pathways. Among them, the PI3K/mTOR pathway is the most frequently activated, which plays a central role in cancer initiation and progression...
August 18, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/28822004/in-vitro-validation-of-the-hippo-pathway-as-a-pharmacological-target-for-canine-mammary-gland-tumors
#6
Samantha Guillemette, Charlène Rico, Philippe Godin, Derek Boerboom, Marilène Paquet
Canine mammary tumors (CMTs) are the most common neoplasms in intact female dogs. Some clinical and molecular similarities between certain CMT subtypes and breast cancer make them a potential model for the study of the human disease. As misregulated Hippo signaling is thought to play an important role in breast cancer development and also occurs in CMTs, we sought to determine if Hippo represents a valid pharmacological target for the treatment of CMTs. Six CMT cell lines were assessed for their expression of the Hippo pathway effectors YAP and TAZ and for their sensitivity to verteporfin, an inhibitor of YAP-mediated transcriptional coactivation...
August 18, 2017: Journal of Mammary Gland Biology and Neoplasia
https://www.readbyqxmd.com/read/28821955/targeted-next-generation-sequencing-for-analyzing-the-genetic-alterations-in-atypical-adenomatous-hyperplasia-and-adenocarcinoma-in-situ
#7
Xuan Xu, Na Li, Ruiying Zhao, Lei Zhu, Jinchen Shao, Jie Zhang
PURPOSE: Atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS) have been defined as preinvasive pulmonary adenocarcinoma lesions according to the 2015 World Health Organization lung adenocarcinoma classification. We aimed to search for the most common gene mutations in patients with AAH and AIS and investigate the distinctions between the two groups at the molecular level. METHODS: We performed targeted next-generation sequencing on 18 cases with AAH and 28 cases with AIS to screen for mutations with the Ion Torrent Oncomine Solid Tumor DNA panel...
August 18, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28821867/identification-of-the-n-terminal-transmembrane-domain-of-stard7-and-its-importance-for-mitochondrial-outer-membrane-localization-and-phosphatidylcholine-transfer
#8
Yasuhiro Horibata, Hiromi Ando, Motoyasu Satou, Hiroaki Shimizu, Satomi Mitsuhashi, Yasuo Shimizu, Masahiko Itoh, Hiroyuki Sugimoto
StarD7 facilitates phosphatidylcholine (PC) transfer to mitochondria, and is essential for mitochondrial homeostasis. However, the molecular mechanism for PC transfer by protein remains poorly understood. Herein, we describe a putative novel transmembrane (TM) domain C-terminal to the mitochondria-targeting signal (MTS) sequence at the N-terminus of StarD7. The mature form of StarD7 is integrated and/or associated onto the outer leaflet of the outer mitochondrial membrane (OMM) in HEPA-1 and HepG2 cells. A truncated form of StarD7 lacking the TM domain is distributed in the inner space of the mitochondria, and cannot reverse mitochondrial abnormalities, such as complex formation and PC content, when re-expressed in StarD7-KO HEPA-1 cells...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28821740/irs4-a-novel-modulator-of-bmp-smad-and-akt-signalling-during-early-muscle-differentiation
#9
Gina Dörpholz, Arunima Murgai, Jerome Jatzlau, Daniel Horbelt, Mohammad Poorgholi Belverdi, Christina Heroven, Isabelle Schreiber, Gisela Wendel, Karen Ruschke, Sigmar Stricker, Petra Knaus
Elaborate regulatory networks of the Bone Morphogenetic Protein (BMP) pathways ensure precise signalling outcome during cell differentiation and tissue homeostasis. Here, we identified IRS4 as a novel regulator of BMP signal transduction and provide molecular insights how it integrates into the signalling pathway. We found that IRS4 interacts with the BMP receptor BMPRII and specifically targets Smad1 for proteasomal degradation consequently leading to repressed BMP/Smad signalling in C2C12 myoblasts while concomitantly activating the PI3K/Akt axis...
August 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28821643/changes-in-the-excitability-of-neocortical-neurons-in-a-mouse-model-of-amyotrophic-lateral-sclerosis-are-not-specific-to-corticospinal-neurons-and-are-modulated-by-advancing-disease
#10
Juhyun Kim, Ethan G Hughes, Ashwin S Shetty, Paola Arlotta, Loyal A Goff, Dwight E Bergles, Solange P Brown
Cell-type specific changes in neuronal excitability have been proposed to contribute to the selective degeneration of corticospinal neurons in amyotrophic lateral sclerosis (ALS) and to neocortical hyperexcitability, a prominent feature of both inherited and sporadic variants of the disease, but the mechanisms underlying selective loss of specific cell types in ALS are not known. We analyzed the physiological properties of distinct classes of cortical neurons in the motor cortex of hSOD1(G93A) mice of both sexes and found that they all exhibit increases in intrinsic excitability that depend on disease stage...
August 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28821618/region-specific-protein-misfolding-cyclic-amplification-reproduces-brain-tropism-of-prion-strains
#11
Nicolas Privat, Etienne Levavasseur, Serfildan Yildirim, Samia Hannaoui, Jean-Philippe Brandel, Jean-Louis Laplanche, Vincent Béringue, Danielle Seilhean, Stéphane Haïk
Human prion diseases such as Creutzfeldt-Jakob disease are transmissible brain proteinopathies, characterized by the accumulation of a misfolded isoform of the host cellular prion protein (PrP) in the brain. According to the prion model, prions are defined as proteinaceous infectious particles composed solely of this abnormal isoform of PrP (PrPSc). Even in the absence of genetic material, various prion strains can be propagated in experimental models. They can be distinguished by the pattern of disease they produce and especially by the localization of PrPSc deposits within the brain and the spongiform lesions they induce...
August 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28821607/two-plant-derived-aporphinoid-alkaloids-exert-their-antifungal-activity-by-disrupting-mitochondrial-iron-sulfur-cluster-biosynthesis
#12
Siddharth K Tripathi, Tao Xu, Qin Feng, Bharathi Avula, Xiaomin Shi, Xuewen Pan, Melanie M Mask, Scott R Baerson, Melissa R Jacob, Ranga Rao Ravu, Shabana I Khan, Xing-Cong Li, Ikhlas A Khan, Alice M Clark, Ameeta K Agarwal
Eupolauridine and liriodenine are plant-derived aporphinoid alkaloids that exhibit potent inhibitory activity against the opportunistic fungal pathogens Candida albicans and Cryptococcus neoformans However, the molecular mechanism of this antifungal activity is unknown. In this study, we show that eupolauridine 9591 (E9591), a synthetic analog of eupolauridine, and liriodenine methiodide (LMT), a methiodide salt of liriodenine, mediate their antifungal activities by disrupting mitochondrial iron-sulfur (Fe-S) cluster synthesis...
August 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28821459/clinical-multi-omics-strategies-for-the-effective-cancer-management
#13
REVIEW
Byong Chul Yoo, Kyung-Hee Kim, Sang Myung Woo, Jae Kyung Myung
Cancer is a global health issue as a multi-factorial complex disease, and early detection and novel therapeutic strategies are required for more effective cancer management. With the development of systemic analytical -omics strategies, the therapeutic approach and study of the molecular mechanisms of carcinogenesis and cancer progression have moved from hypothesis-driven targeted investigations to data-driven untargeted investigations focusing on the integrated diagnosis, treatment, and prevention of cancer in individual patients...
August 15, 2017: Journal of Proteomics
https://www.readbyqxmd.com/read/28821161/britannin-induces-apoptosis-through-akt-foxo1-pathway-in-human-pancreatic-cancer-cells
#14
Marzieh Moeinifard, Zuhair Mohammad Hassan, Faranak Fallahian, Maryam Hamzeloo-Moghadam, Mohammad Taghikhani
Induction of apoptosis in cancerous cells is considered as a promising treatment option for cancer therapy. The present study was designed to evaluate the anticancer properties of Britannin and its possible mechanisms of action in human pancreatic cancer cells. Apoptosis induction by Britannin was confirmed by annexin V-FITC/PI staining, Hoechst 33258 staining and caspase-3 activity assay in both AsPC-1 and Panc-1 cells. Additionally, by using western blot and Real-time PCR, we observed that Britannin induced apoptosis by decreasing the expression of BCL-2 and increasing the expression of BAX...
August 14, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28821160/leuconostoc-mesenteroides-derived-anticancer-pharmaceuticals-hinder-inflammation-and-cell-survival-in-colon-cancer-cells-by-modulating-nf-%C3%AE%C2%BAb-akt-pten-mapk-pathways
#15
Sepideh Zununi Vahed, Abolfazl Barzegari, Yalda Rahbar Saadat, Ali Goreyshi, Yadollah Omidi
Promising results from different studies on the effect of probiotics in cancer prevention and therapy have so far been reported. However, the molecular mechanism of the interaction of probiotics with cancer cells is yet to be fully understood. In the present study, Leuconostoc mesenteroides was isolated from traditional dairy products, and its probiotic characteristics were determined. HT-29 cells were treated with conditioned-medium of designated bacteria and the cell apoptosis was studied at cellular and molecular level using DAPI staining, flow cytometry, DNA ladder assays, and real-time quantitative-PCR (q-PCR)...
August 14, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28821136/discovery-of-enzymatically-depolymerized-heparins-capable-of-treating-bleomycin-induced-pulmonary-injury-and-fibrosis-in-mice
#16
Yishu Yan, Shanshan Du, Yang Ji, Nan Su, Yi Wang, Xiang Mei, Wenming Zhu, Dong He, Yuan Lu, Chong Zhang, Xin-Hui Xing
Heparin has recently been shown to slow down idiopathic pulmonary fibrosis (IPF) process and improve survival of patients in some cases. To improve the anti-IPF function while minimizing their side effects, we developed heparin libraries with different structures depolymerized by single or combined heparinases, and systematically screened the efficacy of the different heparins for treatment of Bleomycin-induced pulmonary injury and fibrosis using mice model. Then we characterized the structural properties of the components capable of treating pulmonary injury and fibrosis by use of chip-based amide hydrophilic interaction chromatography (HILIC)-fourier transform (FT)-ESI-MS, polyacrylamide gel electrophoresis (PAGE), and high performance liquid chromatography (HPLC)...
October 15, 2017: Carbohydrate Polymers
https://www.readbyqxmd.com/read/28821013/rictor-positively-regulates-b-cell-receptor-signaling-by-modulating-actin-reorganization-via-ezrin
#17
Lu Huang, Yongjie Zhang, Chenguang Xu, Xiaomei Gu, Linlin Niu, Jinzhi Wang, Xiaoyu Sun, Xiaoming Bai, Xingtian Xuan, Qubei Li, Chunwei Shi, Bing Yu, Heather Miller, Gangyi Yang, Lisa S Westerberg, Wanli Liu, Wenxia Song, Xiaodong Zhao, Chaohong Liu
As the central hub of the metabolism machinery, the mammalian target of rapamycin complex 2 (mTORC2) has been well studied in lymphocytes. As an obligatory component of mTORC2, the role of Rictor in T cells is well established. However, the role of Rictor in B cells still remains elusive. Rictor is involved in B cell development, especially the peripheral development. However, the role of Rictor on B cell receptor (BCR) signaling as well as the underlying cellular and molecular mechanism is still unknown. This study used B cell-specfic Rictor knockout (KO) mice to investigate how Rictor regulates BCR signaling...
August 2017: PLoS Biology
https://www.readbyqxmd.com/read/28820943/the-active-site-flexibility-of-mycobacterium-tuberculosis-isocitrate-lyase-in-dimer-form
#18
Yie-Vern Lee, Sybing Choi, Habibah Wahab, Yee Siew Choong
Tuberculosis (TB) still remains as global threat due to the emerging of drug resistant strain. Instead of focus on drug target of active stage TB, we are highlighting the isocitrate lyase (ICL) at the dormant stage TB. ICL is one of the persistent factors for Mycobacterium tuberculosis (MTB) to survive during dormant phase. In addition, the absent of ICL in human has made ICL a potential drug target for TB therapy. However, the dynamics details of ICL which could give insights to the ICL-ligand interaction is yet to be solved...
August 18, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28820900/secy-seca-fusion-protein-retains-the-ability-to-mediate-protein-transport
#19
Yasunori Sugano, Arata Furukawa, Osamu Nureki, Yoshiki Tanaka, Tomoya Tsukazaki
In bacteria, the membrane protein complex SecY/E/G and SecA ATPase are essential for protein translocation. About 30% of newly synthesized proteins in the cytosol are targeted to and translocated across the cytoplasmic membrane by the Sec factors. Although a number of single-molecule analyses and structural studies, including the crystal structure of SecYEG complexed with SecA, have been published, the underlying molecular mechanisms and the functional oligomer states remain elusive. In this study, we constructed a fusion protein SecY-SecA, which induces the formation of the SecY-A/SecE/SecG complex (SecYAEG), to enable investigation of the molecular mechanisms by advanced single-molecule analyses...
2017: PloS One
https://www.readbyqxmd.com/read/28820886/circulating-mirnas-in-sepsis-a-network-under-attack-an-in-silico-prediction-of-the-potential-existence-of-mirna-sponges-in-sepsis
#20
Catalin Vasilescu, Mihnea Dragomir, Mihai Tanase, Dana Giza, Raluca Purnichescu-Purtan, Meng Chen, Sai-Ching Jim Yeung, George A Calin
Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and treatment. A large panel of small non-coding microRNAs was reported to modulate the immune response in sepsis but have not been tested in clinical practice. Large-scale identification of microRNA networks in sepsis might reveal a new biological mechanism that can be also targeted by gene therapy. Therefore, the main objective of this study is to perform a comparison of the miRNA network between septic patients and healthy controls...
2017: PloS One
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