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Paul Simon, Aelna Krajčoviechová, Francois Harvey, Mousnif Haloui, Francois-Christophe Marois-Blanchet, John Chalmers, Mark Woodward, Michel Marre, Johanne Tremblay, Pavel Hamet
OBJECTIVE: We have previously reported the genetic determinants of unmet renal needs in Type 2 Diabetic (T2D) patients of the ADVANCE study (Abstract 0105-PD, IDF - World Diabetes Congress, Vancouver, 2015). We report here the external validation of several of these loci. An improved knowledge of the genetics linked to worsening diabetic nephropathy will offer insights on how to better manage this complication of diabetes and hypertension in T2D patients. DESIGN AND METHOD: We investigated 3,500 T2D patients of Caucasian origin included in the ADVANCE trial who were all treated with current standard therapies...
September 2016: Journal of Hypertension
Paul Simon, Aelna Krajčoviechová, Francois Harvey, Mousnif Haloui, Francois-Christophe Marois-Blanchet, John Chalmers, Mark Woodward, Michel Marre, Johanne Tremblay, Pavel Hamet
OBJECTIVE: We have previously reported the genetic determinants of unmet renal needs in Type 2 Diabetic (T2D) patients of the ADVANCE study (Abstract 0105-PD, IDF - World Diabetes Congress, Vancouver, 2015). We report here the external validation of several of these loci. An improved knowledge of the genetics linked to worsening diabetic nephropathy will offer insights on how to better manage this complication of diabetes and hypertension in T2D patients. DESIGN AND METHOD: We investigated 3,500 T2D patients of Caucasian origin included in the ADVANCE trial who were all treated with current standard therapies...
September 2016: Journal of Hypertension
Baharan Fekry, Kristen A Jeffries, Amin Esmaeilniakooshkghazi, Besim Ogretmen, Sergey A Krupenko, Natalia I Krupenko
Our previous study suggested that ceramide synthase 6 (CerS6), an enzyme in sphingolipid biosynthesis, is regulated by p53: CerS6 was elevated in several cell lines in response to transient expression of p53 or in response to folate stress, which is known to activate p53. It was not clear, however, whether CerS6 gene is a direct transcriptional target of p53 or whether this was an indirect effect through additional regulatory factors. In the present study, we have shown that the CerS6 promoter is activated by p53 in luciferase assays, whereas transcriptionally inactive R175H p53 mutant failed to induce the luciferase expression from this promoter...
August 5, 2016: Journal of Biological Chemistry
B V S K Chakravarthi, M T Goswami, S S Pathi, A D Robinson, M Cieślik, D S Chandrashekar, S Agarwal, J Siddiqui, S Daignault, S L Carskadon, X Jing, A M Chinnaiyan, L P Kunju, N Palanisamy, S Varambally
MicroRNA-101, a tumor suppressor microRNA (miR), is often downregulated in cancer and is known to target multiple oncogenes. Some of the genes that are negatively regulated by miR-101 expression include histone methyltransferase EZH2 (enhancer of zeste homolog 2), COX2 (cyclooxygenase-2), POMP (proteasome maturation protein), CERS6, STMN1, MCL-1 and ROCK2, among others. In the present study, we show that miR-101 targets transcriptional coactivator SUB1 homolog (Saccharomyces cerevisiae)/PC4 (positive cofactor 4) and regulates its expression...
December 8, 2016: Oncogene
Yuanyuan Tang, Ke Cao, Qi Wang, Jia Chen, Rui Liu, Shaohua Wang, Jianda Zhou, Huiqing Xie
Ceramide synthases (CerSs) have been shown to regulate numerous aspects of cancer development. CerS6 has been suggested to be involved in cancer etiology. However, little is known concerning the exact effect of CerS6 on the malignant behavior of melanoma, including glycolysis, proliferation and invasion. In the present study, we found that the expression of CerS6 was low in the melanoma cell lines, including WM35, WM451 and SK-28, and the expression level was related to the malignanct behavior of the melanoma cell lines...
May 2016: Oncology Reports
Baharan Fekry, Amin Esmaeilniakooshkghazi, Sergey A Krupenko, Natalia I Krupenko
We previously reported that ceramide synthase 6 (CerS6) is elevated in response to folate stress in cancer cells, leading to enhanced production of C16-ceramide and apoptosis. Antifolate methotrexate (MTX), a drug commonly used in chemotherapy of several types of cancer, is a strong inhibitor of folate metabolism. Here we investigated whether this drug targets CerS6. We observed that CerS6 protein was markedly elevated in several cancer cell lines treated with MTX. In agreement with the enzyme elevation, its product C16-ceramide was also strongly elevated, so as several other ceramide species...
2016: PloS One
Motoshi Suzuki, Ke Cao, Seiichi Kato, Yuji Komizu, Naoki Mizutani, Kouji Tanaka, Chinatsu Arima, Mei Chee Tai, Kiyoshi Yanagisawa, Norie Togawa, Takahiro Shiraishi, Noriyasu Usami, Tetsuo Taniguchi, Takayuki Fukui, Kohei Yokoi, Keiko Wakahara, Yoshinori Hasegawa, Yukiko Mizutani, Yasuyuki Igarashi, Jin-ichi Inokuchi, Soichiro Iwaki, Satoshi Fujii, Akira Satou, Yoko Matsumoto, Ryuichi Ueoka, Keiko Tamiya-Koizumi, Takashi Murate, Mitsuhiro Nakamura, Mamoru Kyogashima, Takashi Takahashi
Sphingolipids make up a family of molecules associated with an array of biological functions, including cell death and migration. Sphingolipids are often altered in cancer, though how these alterations lead to tumor formation and progression is largely unknown. Here, we analyzed non-small-cell lung cancer (NSCLC) specimens and cell lines and determined that ceramide synthase 6 (CERS6) is markedly overexpressed compared with controls. Elevated CERS6 expression was due in part to reduction of microRNA-101 (miR-101) and was associated with increased invasion and poor prognosis...
January 2016: Journal of Clinical Investigation
Sergei A Novgorodov, Christopher L Riley, Jarryd A Keffler, Jin Yu, Mark S Kindy, Wendy B Macklin, David B Lombard, Tatyana I Gudz
Experimental evidence supports the role of mitochondrial ceramide accumulation as a cause of mitochondrial dysfunction and brain injury after stroke. Herein, we report that SIRT3 regulates mitochondrial ceramide biosynthesis via deacetylation of ceramide synthase (CerS) 1, 2, and 6. Reciprocal immunoprecipitation experiments revealed that CerS1, CerS2, and CerS6, but not CerS4, are associated with SIRT3 in cerebral mitochondria. Furthermore, CerS1, -2, and -6 are hyperacetylated in the mitochondria of SIRT3-null mice, and SIRT3 directly deacetylates the ceramide synthases in a NAD(+)-dependent manner that increases enzyme activity...
January 22, 2016: Journal of Biological Chemistry
Joelle Makoukji, Mohamad Raad, Katia Genadry, Sally El-Sitt, Nadine J Makhoul, Ehab Saad Aldin, Eden Nohra, Mark Jabbour, Ajanthah Sangaralingam, Claude Chelala, Robert H Habib, Fouad Boulos, Arafat Tfayli, Rose-Mary Boustany
Breast cancer is the most common cancer in women worldwide. Elucidation of underlying biology and molecular pathways is necessary for improving therapeutic options and clinical outcomes. CLN3 protein (CLN3p), deficient in neurodegenerative CLN3 disease is anti-apoptotic, and defects in the CLN3 gene cause accelerated apoptosis of neurons in CLN3 disease and up-regulation of ceramide. Dysregulated apoptotic pathways are often implicated in the development of the oncogenic phenotype. Predictably, CLN3 mRNA expression and CLN3 protein were up-regulated in a number of human and murine breast cancer-cell lines...
2015: Frontiers in Oncology
María José Hernández-Corbacho, Daniel Canals, Mohamad M Adada, Mengling Liu, Can E Senkal, Jae Kyo Yi, Cungui Mao, Chiara Luberto, Yusuf A Hannun, Lina M Obeid
Ceramide synthases (CerS1-CerS6), which catalyze the N-acylation of the (dihydro)sphingosine backbone to produce (dihydro)ceramide in both the de novo and the salvage or recycling pathway of ceramide generation, have been implicated in the control of programmed cell death. However, the regulation of the de novo pathway compared with the salvage pathway is not fully understood. In the current study, we have found that late accumulation of multiple ceramide and dihydroceramide species in MCF-7 cells treated with TNFα occurred by up-regulation of both pathways of ceramide synthesis...
October 16, 2015: Journal of Biological Chemistry
Seong-Hoon Yun, Eun-Seon Park, Sung-Won Shin, Mi-Ha Ju, Jin-Yeong Han, Jin-Sook Jeong, Sung-Hyun Kim, Valentin A Stonik, Jong-Young Kwak, Joo-In Park
Stichoposide D (STD) is a marine triterpene glycoside isolated from sea cucumbers. We examined the molecular mechanisms underlying the antitumor activity of STD in human leukemia cells. The role of Fas (CD95), ceramide synthase 6 (CerS6) and p38 kinase during STD-induced apoptosis was examined in human leukemia cells. In addition, the antitumor effects of STD in K562 and HL-60 leukemia xenograft models were investigated. We found that STD induces Fas translocation to lipid rafts, and thus mediates cell apoptosis...
September 29, 2015: Oncotarget
Catherine Labbé, Kotaro Ogaki, Oswaldo Lorenzo-Betancor, Minerva M Carrasquillo, Michael G Heckman, Allan McCarthy, Alexandra I Soto-Ortolaza, Ronald L Walton, Timothy Lynch, Joanna Siuda, Grzegorz Opala, Anna Krygowska-Wajs, Maria Barcikowska, Krzysztof Czyzewski, Dennis W Dickson, Ryan J Uitti, Zbigniew K Wszolek, Owen A Ross
Genome-wide association studies (GWAS) in Parkinson's disease (PD) have identified over 20 genomic regions associated with disease risk. Many of these loci include several candidate genes making it difficult to pinpoint the causal gene. The locus on chromosome 2q24.3 encompasses three genes: B3GALT1, STK39, and CERS6. In order to identify if the causal variants are simple missense changes, we sequenced all 31 exons of these three genes in 187 patients with PD. We identified 13 exonic variants including four non-synonymous and three insertion/deletion variants (indels)...
2015: PloS One
Liang Qu, Feng Qu, Zhixin Jia, Caihong Wang, Caisheng Wu, Jinlan Zhang
ETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii Hook F (TWHF) is a traditional herbal medicine in China. Triptolide (TP), the primary bioactive compound of TWHF, is an anti-inflammatory and immunosuppressive compound that can also injure the liver and kidney. Unfortunately, the toxicity mechanism remains unknown. AIM OF THE STUDY: The aim of this study is to understand the regulatory role of sphingolipid (SPL) pathways in the TP-induced toxic mechanism in the liver and kidney in delayed-type hypersensitivity (DTH) Balb\c mouse...
July 21, 2015: Journal of Ethnopharmacology
Ling Chen, Huixia Chen, Yanting Li, Lei Li, Yan Qiu, Jie Ren
Endocannabinoids and ceramides have demonstrated growth inhibition, cell death induction and pro-apoptotic activity in cancer research. In the present study, we describe the profiles of two major endocannabinoids, ceramides, free fatty acids and relevant metabolic enzymes in 47 pairs of human colorectal cancer tissues and adjacent non-tumor tissues. Among them, anandamide (AEA) and its metabolite, arachidonic acid (AA), were markedly upregulated in cancer tissues particularly in those with lymphatic metastasis...
July 2015: Oncology Reports
Tejas S Tirodkar, Ping Lu, Aiping Bai, Matthew J Scheffel, Salih Gencer, Elizabeth Garrett-Mayer, Alicja Bielawska, Besim Ogretmen, Christina Voelkel-Johnson
A family of six ceramide synthases with distinct but overlapping substrate specificities is responsible for generation of ceramides with acyl chains ranging from ∼14-26 carbons. Ceramide synthase 6 (CerS6) preferentially generates C14- and C16-ceramides, and we have previously shown that down-regulation of this enzyme decreases apoptotic susceptibility. In this study, we further evaluated how increased CerS6 expression impacts sphingolipid composition and metabolism. Overexpression of CerS6 in HT29 colon cancer cells resulted in increased apoptotic susceptibility and preferential generation of C16-ceramide, which occurred at the expense of very long chain, saturated ceramides...
May 22, 2015: Journal of Biological Chemistry
Max Eberle, Philipp Ebel, Christoph A Mayer, Julia Barthelmes, Nadja Tafferner, Nerea Ferreiros, Thomas Ulshöfer, Marina Henke, Christian Foerch, Anika Männer de Bazo, Sabine Grösch, Gerd Geisslinger, Klaus Willecke, Susanne Schiffmann
Ceramides are mediators of inflammatory processes. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we observed that CerS6 mRNA expression was upregulated 15-fold in peripheral blood leukocytes before the onset of EAE symptoms. In peripheral blood leukocytes from MS patients, a 3.9-fold upregulation was found. Total genetic deletion of CerS6 and the selective deletion of CerS6 in peripheral blood leucocytes exacerbated the progression of clinical symptoms in EAE mice...
October 2015: Immunology and Cell Biology
S Schüll, S D Günther, S Brodesser, J M Seeger, B Tosetti, K Wiegmann, C Pongratz, F Diaz, A Witt, M Andree, K Brinkmann, M Krönke, R J Wiesner, H Kashkar
Although numerous pathogenic changes within the mitochondrial respiratory chain (RC) have been associated with an elevated occurrence of apoptosis within the affected tissues, the mechanistic insight into how mitochondrial dysfunction initiates apoptotic cell death is still unknown. In this study, we show that the specific alteration of the cytochrome c oxidase (COX), representing a common defect found in mitochondrial diseases, facilitates mitochondrial apoptosis in response to oxidative stress. Our data identified an increased ceramide synthase 6 (CerS6) activity as an important pro-apoptotic response to COX dysfunction induced either by chemical or genetic approaches...
2015: Cell Death & Disease
Marthe-Susanna Wegner, Ruth Anna Wanger, Stephanie Oertel, Sebastian Brachtendorf, Daniela Hartmann, Susanne Schiffmann, Rolf Marschalek, Yannick Schreiber, Nerea Ferreirós, Gerd Geisslinger, Sabine Grösch
Ceramide synthases (CerS) are important enzymes of the sphingolipid pathway, responsible for the production of ceramides with distinct chain lengths. In human breast cancer tissue, we detected a significant increase in CerS4 and CerS6 mRNA in estrogen receptor positive (ER+) cancer tissue. To clarify the molecular mechanism of this upregulation, we cloned CerS2, -4, -5 and CerS6 promoter and 3'-UTR fragments into luciferase reporter gene plasmids and determined luciferase activity in MCF-7 (ERα/β) and MDA-MB-231 (ERβ) cells after 17β-estradiol treatment...
December 15, 2014: Biochemical Pharmacology
Suryaprakash Raichur, Siew Tein Wang, Puck Wee Chan, Ying Li, Jianhong Ching, Bhagirath Chaurasia, Bghagirath Chaurasia, Shaillay Dogra, Miina K Öhman, Kosuke Takeda, Shigeki Sugii, Yael Pewzner-Jung, Anthony H Futerman, Scott A Summers
Inhibition of ceramide synthesis prevents diabetes, steatosis, and cardiovascular disease in rodents. Six different ceramide synthases (CerS) that differ in tissue distribution and substrate specificity account for the diversity in acyl-chain composition of distinct ceramide species. Haploinsufficiency for ceramide synthase 2 (CerS2), the dominant isoform in the liver that preferentially makes very-long-chain (C22/C24/C24:1) ceramides, led to compensatory increases in long-chain C16-ceramides and conferred susceptibility to diet-induced steatohepatitis and insulin resistance...
October 7, 2014: Cell Metabolism
Sarah M Turpin, Hayley T Nicholls, Diana M Willmes, Arnaud Mourier, Susanne Brodesser, Claudia M Wunderlich, Jan Mauer, Elaine Xu, Philipp Hammerschmidt, Hella S Brönneke, Aleksandra Trifunovic, Giuseppe LoSasso, F Thomas Wunderlich, Jan-Wilhelm Kornfeld, Matthias Blüher, Martin Krönke, Jens C Brüning
Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C14:0 to C30:0 and are synthesized by six ceramide synthase enzymes (CerS1-6). It remains unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Here we reveal that CERS6 mRNA expression and C16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance...
October 7, 2014: Cell Metabolism
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