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https://www.readbyqxmd.com/read/29667105/the-role-of-autophagy-in-the-resistance-to-braf-inhibition-in-braf-mutated-melanoma
#1
Xiao Liu, Jinfeng Wu, Haihong Qin, Jinhua Xu
Malignant melanoma is the most aggressive and notorious skin cancer, and metastatic disease is associated with very poor long-term survival outcomes. Although metastatic melanoma patients with oncogenic mutations in the BRAF gene initially respond well to the treatment with specific BRAF inhibitors, most of them will eventually develop resistance to this targeted therapy. As a highly conserved catabolic process, autophagy is responsible for the maintenance of cellular homeostasis and cell survival, and is involved in multiple diseases, including cancer...
April 17, 2018: Targeted Oncology
https://www.readbyqxmd.com/read/29667084/investigation-of-the-aryl-hydrocarbon-receptor-and-the-intrinsic-tumoral-component-of-the-kynurenine-pathway-of-tryptophan-metabolism-in-primary-brain-tumors
#2
Anthony R Guastella, Sharon K Michelhaugh, Neil V Klinger, Hassan A Fadel, Sam Kiousis, Rouba Ali-Fehmi, William J Kupsky, Csaba Juhász, Sandeep Mittal
INTRODUCTION: There is mounting evidence supporting the role of tryptophan metabolism via the kynurenine pathway (KP) in the pathogenesis of primary brain tumors. Under normal physiological conditions, the KP is the major catabolic pathway for the essential amino acid tryptophan. However, in cancer cells, the KP becomes dysregulated, depletes local tryptophan, and contributes to an immunosuppressive tumor microenvironment. METHODS: We examined the protein expression levels (in 73 gliomas and 48 meningiomas) of the KP rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase (TDO2), as well as, the aryl hydrocarbon receptor (AhR), a carcinogenic transcription factor activated by KP metabolites...
April 17, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29666162/two-abscisic-acid-responsive-plastid-lipase-genes-involved-in-jasmonic-acid-biosynthesis-in-arabidopsis-thaliana
#3
Kun Wang, Qiang Guo, John E Froehlich, Hope Lynn Hersh, Agnieszka Zienkiewicz, Gregg A Howe, Christoph Benning
Chloroplast membranes with their unique lipid composition are crucial for photosynthesis. Maintenance of the chloroplast membranes requires finely tuned lipid anabolic and catabolic reactions. Despite the presence of a large number of predicted lipid-degrading enzymes in the chloroplasts, their biological functions remain largely unknown. Recently, we described PLASTID LIPASE1 (PLIP1), a plastid phospholipase A1 that contributes to seed oil biosynthesis. The Arabidopsis thaliana genome encodes two putative PLIP1 paralogs, which we designated PLIP2 and PLIP3...
April 17, 2018: Plant Cell
https://www.readbyqxmd.com/read/29665429/autophagy-in-mammalian-neurodevelopment-and-implications-for-childhood-neurological-disorders
#4
REVIEW
Derek Marsh, Joanna M Dragich
Here we explore the neurodevelopmental aspects of macroautophagy (henceforth known as autophagy), the process by which cells remove and remodel their structure in a regulated and spatially restricted manner. Autophagy is a catabolic pathway in which cytosolic substances, such as protein complexes, lipids, and organelles, are engulfed by an autophagic vesicle. Degradation occurs once an autophagosome fuses with a lysosome, allowing the macromolecular cargo sequestered within the autophagic vesicle to be recycled...
April 14, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29664912/metatranscriptome-analysis-of-the-microbial-fermentation-of-dietary-milk-proteins-in-the-murine-gut
#5
Floor Hugenholtz, Mark Davids, Jessica Schwarz, Michael Müller, Daniel Tomé, Peter Schaap, Guido J E J Hooiveld, Hauke Smidt, Michiel Kleerebezem
Undigestible food ingredients are converted by the microbiota into a large range of metabolites, predominated by short chain fatty acids (SCFA). These microbial metabolites are subsequently available for absorption by the host mucosa and can serve as an energy source. Amino acids fermentation by the microbiota expands the spectrum of fermentation end-products beyond acetate, propionate and butyrate, to include in particular branched-SCFA. Here the long-term effects of high protein-diets on microbial community composition and functionality in mice were analyzed...
2018: PloS One
https://www.readbyqxmd.com/read/29662780/distinct-metabolic-programs-induced-by-tgf-%C3%AE-1-and-bmp2-in-human-articular-chondrocytes-with-osteoarthritis
#6
Cuicui Wang, Richard M Silverman, Jie Shen, Regis J O'Keefe
Objectives: Cellular energy metabolism is important for the function of all tissues, including cartilage. Recent studies indicate that superficial and deep subpopulations of articular chondrocytes (ACs) have distinct metabolic profiles. At the cellular and molecular level, osteoarthritis (OA) is characterised by alteration from a healthy homoeostatic state towards a catabolic state. Several molecular pathways, including transforming growth factor beta (TGF-β) and bone morphogenetic protein (BMP) signalling, have been identified as critical players in the pathogenesis and progression of OA...
January 2018: Journal of Orthopaedic Translation
https://www.readbyqxmd.com/read/29662657/5-nucleotidase-cn-ii-emerges-as-a-new-predictive-biomarker-of-response-to-gemcitabine-platinum-combination-chemotherapy-in-non-small-cell-lung-cancer
#7
Francesca Toffalorio, Mariacarmela Santarpia, Davide Radice, Christopher Adrian Jaramillo, Gianluca Spitaleri, Michela Manzotti, Chiara Catania, Lars Petter Jordheim, Giuseppe Pelosi, Godefridus J Peters, Carmelo Tibaldi, Niccola Funel, Lorenzo Spaggiari, Filippo de Braud, Tommaso De Pas, Elisa Giovannetti
A number of pharmacogenetic studies have been carried out in non-small-cell lung cancer (NSCLC) to identify and characterize genes involved in chemotherapy activity. However, the results obtained so far are controversial and no reliable biomarker is currently used to predict clinical benefit from platinum-based chemotherapy, which represents the cornerstone of treatment of advanced NSCLC. This study investigated the expression levels of ERCC1 and of six genes (RRM1, RRM2, hENT1, dCK, cN-II and CDA) involved in gemcitabine metabolism in locally/advanced NSCLC patients treated with gemcitabine/platinum combination...
March 27, 2018: Oncotarget
https://www.readbyqxmd.com/read/29662003/ppar-agonists-and-metabolic-syndrome-an-established-role
#8
REVIEW
Margherita Botta, Matteo Audano, Amirhossein Sahebkar, Cesare R Sirtori, Nico Mitro, Massimiliano Ruscica
Therapeutic approaches to metabolic syndrome (MetS) are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (PPARs) are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (TGs), blood glucose, and abdominal adiposity. PPARs may be classified into the α, β/δ and γ subtypes. The PPAR-α agonists, mainly fibrates (including newer molecules such as pemafibrate) and omega-3 fatty acids, are powerful TG-lowering agents...
April 14, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29661920/dhtkd1-deficiency-causes-charcot-marie-tooth-disease-in-mice
#9
Wang-Yang Xu, Houbao Zhu, Yan Shen, Ying-Han Wan, Xiao-Die Tu, Wen-Ting Wu, Lingyun Tang, Hong-Xin Zhang, Shun-Yuan Lu, Xiao-Long Jin, Jian Fei, Zhu-Gang Wang
DHTKD1, a part of 2-ketoadipic acid dehydrogenase complex, is involved in lysine and tryptophan catabolism. Mutations in DHTKD1 block the metabolic pathway and cause 2-aminoadipic and 2-oxoadipic aciduria (AMOXAD), an autosomal recessive inborn metabolic disorder. In addition, a nonsense mutation in DHTKD1 we identified previously causes Charcot-Marie-Tooth disease (CMT) type 2Q, one of the most common inherited neurological disorders affecting the peripheral nerves in the musculature. However, the comprehensive molecular mechanism underlying CMT2Q remains elusive...
April 16, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29659898/cholesterol-metabolism-is-enhanced-in-the-liver-and-brain-of-children-with-citrin-deficiency
#10
Satoshi Hirayama, Hironori Nagasaka, Akira Honda, Haruki Komatsu, Takahiro Kodama, Ayano Inui, Ichiro Morioka, Shunsaku Kaji, Tsuyoshi Ueno, Kenji Ihara, Mariko Yagi, Zenro Kizaki, Kazuhiko Bessho, Hiroki Kondou, Tohru Yorifuji, Hirokazu Tsukahara, Kazumoto Iijima, Takashi Miida
Context: Citrin-deficient infants present neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), which resolves at 12 months. Thereafter, they have normal liver function associated with hypercholesterolemia, and a preference for lipid-rich carbohydrate-restricted diets. However, some develop adult-onset type II citrullinemia (CTLN2), which is associated with metabolic abnormalities. Objectives: To identify the causes of hypercholesterolemia in citrin-deficient children post-NICCD...
April 5, 2018: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/29659022/transcription-factor-rd26-is-a-key-regulator-of-metabolic-reprogramming-during-dark-induced-senescence
#11
Iman Kamranfar, Gang-Ping Xue, Takayuki Tohge, Mastoureh Sedaghatmehr, Alisdair R Fernie, Salma Balazadeh, Bernd Mueller-Roeber
Leaf senescence is a key process in plants that culminates in the degradation of cellular constituents and massive reprogramming of metabolism for the recovery of nutrients from aged leaves for their reuse in newly developing sinks. We used molecular-biological and metabolomics approaches to identify NAC transcription factor (TF) RD26 as an important regulator of metabolic reprogramming in Arabidopsis thaliana. RD26 directly activates CHLOROPLAST VESICULATION (CV), encoding a protein crucial for chloroplast protein degradation, concomitant with an enhanced protein loss in RD26 overexpressors during senescence, but a reduced decline of protein in rd26 knockout mutants...
April 16, 2018: New Phytologist
https://www.readbyqxmd.com/read/29659013/dietary-fat-and-fiber-interact-to-uniquely-modify-global-histone-post-translational-epigenetic-programming-in-a-rat-colon-cancer-progression-model
#12
Karen Triff, Mathew W McLean, Evelyn Callaway, Jennifer Goldsby, Ivan Ivanov, Robert S Chapkin
Dietary fermentable fiber generates short-chain fatty acids (SCFA), e.g., butyrate, in the colonic lumen which serves as a chemoprotective histone deacetylase inhibitor and/or as an acetylation substrate for histone acetylases. In addition, n-3 polyunsaturated fatty acids (n-3 PUFA) in fish oil can affect the chromatin landscape by acting as ligands for tumor suppressive nuclear receptors. In an effort to gain insight into the global dimension of post-translational modification of histones (including H3K4me3 and H3K9ac) and clarify the chemoprotective impact of dietary bioactive compounds on transcriptional control in a preclinical model of colon cancer, we generated high-resolution genome-wide RNA (RNA-Seq) and "chromatin-state" (H3K4me3-seq and H3K9ac-seq) maps for intestinal (epithelial colonocytes) crypts in rats treated with a colon carcinogen and fed diets containing bioactive (i) fish oil, (ii) fermentable fiber (a rich source of SCFA), (iii) a combination of fish oil plus pectin or (iv) control, devoid of fish oil or pectin...
April 16, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29658431/in-silico-identification-and-screening-of-cyp24a1-inhibitors-3d-qsar-pharmacophore-mapping-and-molecular-dynamics-analysis
#13
Jayaraj John Marshal, Gopinath Krishnasamy, Jung-Kul Lee, Karthikeyan Muthusamy
Vitamin D is a key signalling molecule that plays a vital role in the regulation of calcium-phosphate homeostasis and bone remodelling. The circulating biologically active form of vitamin D is regulated by the catabolic mechanism of cytochrome P450 24-hydroxylase (CYP24A1) enzyme. The over-expression of CYP24A1 negatively regulates the vitamin D level, which is the causative agent of chronic kidney disease, osteoporosis, and several types of cancers. In this study, we found three potential lead molecules adverse to CYP24A1 through structure-based, atom-based pharmacophore and e-pharmacophore-based screening methods...
April 16, 2018: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29658076/expression-of-bcl-2-family-proteins-in-the-ovarian-follicular-apparatus-in-the-acute-period-after-experimental-hyperthermia
#14
S V Michurina, S I Kolesnikov, A L Bochkareva, S A Arkhipov, I Yu Ishchenko
The expression of apoptosis regulators (proapoptotic protein Bad and anti-apoptotic protein Bcl-2) was analyzed and Bcl-2/Bad ratio in the follicular apparatus of the rat ovary was determined on day 3 after hyperthermia (rectal temperature 43.5°C). Hyperthermia in the catabolic phase leads to different degrees of activation of the molecular "switches" of apoptosis in cells of ovarian follicular epithelium. This was seen from increased intensity of immunohistochemical staining for Bad protein against the background of more pronounced expression of Bcl-2 protein...
April 16, 2018: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/29657865/stress-adaptive-responses-associated-with-high-level-carbapenem-resistance-in-kpc-producing-klebsiella-pneumoniae
#15
Sheila Adams-Sapper, Adam Gayoso, Lee W Riley
Carbapenem-resistant Enterobacteriaceae (CRE) organisms have emerged to become a major global public health threat among antimicrobial resistant bacterial human pathogens. Little is known about how CREs emerge. One characteristic phenotype of CREs is heteroresistance, which is clinically associated with treatment failure in patients given a carbapenem. Through in vitro whole-transcriptome analysis we tracked gene expression over time in two different strains (BR7, BR21) of heteroresistant KPC-producing Klebsiella pneumoniae, first exposed to a bactericidal concentration of imipenem followed by growth in drug-free medium...
2018: Journal of Pathogens
https://www.readbyqxmd.com/read/29657030/rewiring-of-glutamine-metabolism-is-a-bioenergetic-adaptation-of-human-cells-with-mitochondrial-dna-mutations
#16
Qiuying Chen, Kathryne Kirk, Yevgeniya I Shurubor, Dazhi Zhao, Andrea J Arreguin, Ifrah Shahi, Federica Valsecchi, Guido Primiano, Elizabeth L Calder, Valerio Carelli, Travis T Denton, M Flint Beal, Steven S Gross, Giovanni Manfredi, Marilena D'Aurelio
Using molecular, biochemical, and untargeted stable isotope tracing approaches, we identify a previously unappreciated glutamine-derived α-ketoglutarate (αKG) energy-generating anaplerotic flux to be critical in mitochondrial DNA (mtDNA) mutant cells that harbor human disease-associated oxidative phosphorylation defects. Stimulating this flux with αKG supplementation enables the survival of diverse mtDNA mutant cells under otherwise lethal obligatory oxidative conditions. Strikingly, we demonstrate that when residual mitochondrial respiration in mtDNA mutant cells exceeds 45% of control levels, αKG oxidative flux prevails over reductive carboxylation...
April 9, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29653253/cholesterol-and-bile-acid-mediated-regulation-of-autophagy-in-fatty-liver-diseases-and-atherosclerosis
#17
REVIEW
Yifeng Wang, Wen-Xing Ding, Tiangang Li
Liver is the major organ that regulates whole body cholesterol metabolism. Disrupted hepatic cholesterol homeostasis contributes to the pathogenesis of nonalcoholic steatohepatitis, dyslipidemia, atherosclerosis, and cardiovascular diseases. Hepatic bile acid synthesis is the major catabolic mechanism for cholesterol elimination from the body. Furthermore, bile acids are signaling molecules that regulate liver metabolism and inflammation. Autophagy is a highly-conserved lysosomal degradation mechanism, which plays an essential role in maintaining cellular integrity and energy homeostasis...
April 10, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29652915/protein-kinase-d3-modulates-mmp1-and-mmp13-expression-in-human-chondrocytes
#18
Jonathan Baker, Adrian M D Falconer, David J Wilkinson, G Nicholas Europe-Finner, Gary J Litherland, Andrew D Rowan
Many catabolic stimuli, including interleukin-1 (IL-1) in combination with oncostatin M (OSM), promote cartilage breakdown via the induction of collagen-degrading collagenases such as matrix metalloproteinase 1 (MMP1) and MMP13 in human articular chondrocytes. Indeed, joint diseases with an inflammatory component are characterised by excessive extracellular matrix (ECM) catabolism. Importantly, protein kinase C (PKC) signalling has a primary role in cytokine-induced MMP1/13 expression, and is known to regulate cellular functions associated with pathologies involving ECM remodelling...
2018: PloS One
https://www.readbyqxmd.com/read/29651242/discovery-of-novel-inhibitors-of-indoleamine-2-3-dioxygenase-1-through-structure-based-virtual-screening
#19
Guoqing Zhang, Jing Xing, Yulan Wang, Lihao Wang, Yan Ye, Dong Lu, Jihui Zhao, Xiaomin Luo, Mingyue Zheng, Shiying Yan
Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular monomeric heme-containing enzyme that catalyzes the first and the rate limiting step in catabolism of tryptophan via the kynurenine (KYN) pathway, which plays a significant role in the proliferation and differentiation of T cells. IDO1 has been proven to be an attractive target for anticancer therapy and chronic viral infections. In the present study, a class of IDO1 inhibitors with novel scaffolds were identified by virtual screening and biochemical validation, in which the compound DC-I028 shows moderate IDO1 inhibitory activity with an IC50 of 21...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29649791/the-long-term-impact-of-high-levels-of-alpha-melanocyte-stimulating-hormone-in-energy-balance-among-obese-adolescents
#20
Ana Claudia Pelissari Kravchychyn, Raquel Munhoz da Silveira Campos, Flávia Campos Corgosinho, Deborah Cristina Landi Masquio, Sofia Emanuelle de Castro Ferreira Vicente, Yasmin Alaby Martins Ferreira, Patrícia Leão Silva, Aline de Piano Ganen, Lila Missae Oyama, Lian Tock, Marco Túlio de Mello, Sérgio Tufik, Ana Raimunda Dâmaso
BACKGROUND: Deregulation of orexigenic and anorexigenic pathways occurs among adolescents with obesity. Alpha-melanocyte-stimulating hormone (α-MSH) is a key catabolic mediator of energy homeostasis and an important anorexigenic neuropeptide in the control of energy balance and thermogenesis. However, it was not well explored if α-MSH can modulate long-term weight loss therapy responses in a dependent manner according to its concentration. Our hypothesis is that a high α-MSH concentration at baseline promotes better modulation of anorexigenic/orexigenic pathways in obese adolescents...
April 12, 2018: Annals of Nutrition & Metabolism
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