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https://www.readbyqxmd.com/read/29138469/adoptive-transfer-of-ceramide-synthase-6-deficient-splenocytes-reduces-the-development-of-colitis
#1
Matthew J Scheffel, Kristi Helke, Ping Lu, Jacob S Bowers, Besim Ogretmen, Elizabeth Garrett-Mayer, Chrystal M Paulos, Christina Voelkel-Johnson
Sphingolipids regulate critical cellular processes including inflammation. Ceramide, which serves a central role in sphingolipid metabolism, is generated by six ceramide synthases (CerS) that differ in substrate specificity. CerS6 preferentially generates C16-ceramide and its mRNA is highly expressed in immune tissues. In this study we analyzed how deficiency of CerS6 impacts on the development of colitis using an adoptive transfer model. Adoptive transfer of CerS6-deficient splenocytes, which have significantly decreased levels of C16-ceramide, showed that CerS6-deficiency protected against the development of colitis...
November 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29127192/lipotoxic-very-long-chain-ceramides-cause-mitochondrial-dysfunction-oxidative-stress-and-cell-death-in-cardiomyocytes
#2
Brittany A Law, Xianghai Liao, Kelsey S Moore, Abigail Southard, Patrick Roddy, Ruiping Ji, Zdzislaw Sculz, Ala Bielawska, P Christian Schulze, L Ashley Cowart
Accumulating data support a role for bioactive lipids as mediators of lipotixicity in cardiomyocytes. One class of these, the ceramides, constitutes a family of molecules that differ in structure and are synthesized by distinct enzymes, ceramide synthase (CerS)1-CerS6. Data support that specific ceramides and the enzymes that catalyze their formation play distinct roles in cell function. In a mouse model of diabetic cardiomyopathy, sphingolipid profiling revealed increases in not only the CerS5-derived ceramides but also in very long chain (VLC) ceramides derived from CerS2...
November 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28864659/a-novel-role-for-ceramide-synthase-6-in-mouse-and-human-alcoholic-steatosis
#3
Bianca Williams, Jason Correnti, Amanke Oranu, Annie Lin, Victoria Scott, Maxine Annoh, James Beck, Emma Furth, Victoria Mitchell, Can E Senkal, Lina Obeid, Rotonya M Carr
Perilipin 2 (PLIN2) is a lipid-droplet protein that is up-regulated in alcoholic steatosis and associated with hepatic accumulation of ceramides, bioactive lipids implicated in alcoholic liver disease pathogenesis. The specific role of ceramide synthetic enzymes in the regulation of PLIN2 and promotion of hepatocellular lipid accumulation is not well understood. We examined the effects of pharmacologic ceramide synthesis inhibition on hepatic PLIN2 expression, steatosis, and glucose and lipid homeostasis in mice with alcoholic steatosis and in ethanol-incubated human hepatoma VL17A cells...
September 1, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28812434/-pemetrexed-sildenafil-via-autophagy-dependent-hdac-downregulation-enhances-the-immunotherapy-response-of-nsclc-cells
#4
Laurence Booth, Jane L Roberts, Andrew Poklepovic, Paul Dent
Pemetrexed is an approved therapeutic in NSCLC and ovarian cancer. Our studies focused on the ability of [pemetrexed + sildenafil] exposure to alter the immunogenicity of lung and ovarian cancer cells. Treatment of lung and ovarian cancer cells with [pemetrexed + sildenafil] in vitro rapidly reduced the expression of PD-L1, PD-L2 and ornithine decarboxylase (ODC), and increased the expression of class I MHCA. In a cell-specific fashion, some cells also released the immunogenic nuclear protein HMGB1 into the extracellular environment...
September 2, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28709640/genome-wide-identification-of-genes-essential-for%C3%A2-podocyte-cytoskeletons-based%C3%A2-on%C3%A2-single-cell-rna%C3%A2-sequencing
#5
Yuqiu Lu, Yuting Ye, Wenduona Bao, Qianqian Yang, Jinquan Wang, Zhihong Liu, Shaolin Shi
Gene expression differs substantially among individual cells of the same type. We speculate that genes that are expressed in all but a portion of cells of a given cell type would be likely essential and required for either the cell survival (housekeeping) or for the cell type's unique structure and function, enabling the organism to survive. Here, we performed RNA-seq of 20 mouse podocytes using the Fluidigm C1 system and identified 335 genes that were expressed in all of them. Among them, 239 genes were also expressed in mesangial and endothelial cells and were involved in energy metabolism, protein synthesis, etc...
November 2017: Kidney International
https://www.readbyqxmd.com/read/28515365/ceramide-synthesis-regulates-t-cell-activity-and-gvhd-development
#6
M Hanief Sofi, Jessica Heinrichs, Mohammed Dany, Hung Nguyen, Min Dai, David Bastian, Steven Schutt, Yongxia Wu, Anusara Daenthanasanmak, Salih Gencer, Aleksandra Zivkovic, Zdzislaw Szulc, Holger Stark, Chen Liu, Ying-Jun Chang, Besim Ogretmen, Xue-Zhong Yu
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy for a variety of hematologic malignances, yet its efficacy is impeded by the development of graft-versus-host disease (GVHD). GVHD is characterized by activation, expansion, cytokine production, and migration of alloreactive donor T cells. Hence, strategies to limit GVHD are highly desirable. Ceramides are known to contribute to inflammation and autoimmunity. However, their involvement in T-cell responses to alloantigens is undefined...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28515139/changes-in-ceramide-metabolism-are-essential-in-madin-darby-canine-kidney-cell-differentiation
#7
Lucila Gisele Pescio, Bruno Jaime Santacreu, Vanina Gisela Lopez, Carlos Humberto Paván, Daniela Judith Romero, Nicolás Octavio Favale, Norma Beatriz Sterin-Speziale
Ceramides (Cers) and complex sphingolipids with defined acyl chain lengths play important roles in numerous cell processes. Six Cer synthase (CerS) isoenzymes (CerS1-6) are the key enzymes responsible for the production of the diversity of molecular species. In this study, we investigated the changes in sphingolipid metabolism during the differentiation of Madin-Darby canine kidney (MDCK) cells. By MALDI TOF TOF MS, we analyzed the molecular species of Cer, glucosylceramide (GlcCer), lactosylceramide (LacCer), and SM in nondifferentiated and differentiated cells (cultured under hypertonicity)...
July 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28035360/hepatic-inflammatory-cytokine-production-can-be-regulated-by-modulating-sphingomyelinase-and-ceramide-synthase-6
#8
Min Hee Kim, Hee Kyung Ahn, Eun-Ji Lee, Su-Jeong Kim, Ye-Ryung Kim, Joo-Won Park, Woo-Jae Park
Chronic inflammation is associated with the pathogenesis of type 2 diabetes and diabetic complications, and palmitate has been nominated as a candidate for the molecular link between these disorders. Recently, a crucial role of ceramide in inflammation and metabolic diseases has been reported. Therefore, in this study, we investigated whether ceramide formation is involved in palmitate‑induced hepatic inflammation in vitro and in vivo. Ceramide can be generated either by the de novo pathway or by sphingomyelin degradation, and six different ceramide synthases (CerS) determine the specific acyl chain length of ceramide in mammals...
February 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/27754025/yia-03-01-validation-of-genetic-determinants-of-unmet-needs-in-the-treatment-of-kidney-disease-in-type-2-diabetes
#9
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
https://www.readbyqxmd.com/read/27642943/yia-03-01-validation-of-genetic-determinants-of-unmet-needs-in-the-treatment-of-kidney-disease-in-type-2-diabetes
#10
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
https://www.readbyqxmd.com/read/27302066/cers6-is-a-novel-transcriptional-target-of-p53-protein-activated-by-non-genotoxic-stress
#11
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
https://www.readbyqxmd.com/read/27270442/microrna-101-regulated-transcriptional-modulator-sub1-plays-a-role-in-prostate-cancer
#12
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
https://www.readbyqxmd.com/read/26934938/silencing-of-cers6-increases-the-invasion-and-glycolysis-of-melanoma-wm35-wm451-and-sk28-cell-lines-via-increased-glut1-induced-downregulation-of-wnt5a
#13
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
https://www.readbyqxmd.com/read/26783755/ceramide-synthase-6-is-a-novel-target-of-methotrexate-mediating-its-antiproliferative-effect-in-a-p53-dependent-manner
#14
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
https://www.readbyqxmd.com/read/26650179/targeting-ceramide-synthase-6-dependent-metastasis-prone-phenotype-in-lung-cancer-cells
#15
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
https://www.readbyqxmd.com/read/26620563/sirt3-deacetylates-ceramide-synthases-implications-for-mitochondrial-dysfunction-and-brain-injury
#16
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
https://www.readbyqxmd.com/read/26528430/association-between-cln3-neuronal-ceroid-lipofuscinosis-cln3-type-gene-expression-and-clinical-characteristics-of-breast-cancer-patients
#17
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
https://www.readbyqxmd.com/read/26318452/tumor-necrosis-factor-%C3%AE-tnf%C3%AE-induced-ceramide-generation-via-ceramide-synthases-regulates-loss-of-focal-adhesion-kinase-fak-and-programmed-cell-death
#18
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
https://www.readbyqxmd.com/read/26318294/by-activating-fas-ceramide-synthase-6-p38-kinase-in-lipid-rafts-stichoposide-d-inhibits-growth-of-leukemia-xenografts
#19
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
https://www.readbyqxmd.com/read/26090850/exonic-re-sequencing-of-the-chromosome-2q24-3-parkinson-s-disease-locus
#20
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
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