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Ceramide autophagy

Kengo Koike, Evgeny V Berdyshev, Russell P Bowler, April K Scruggs, Danting Cao, Kelly S Schweitzer, Karina A Serban, Irina Petrache
A better understanding of the pathogenesis of distinct chronic obstructive pulmonary disease (COPD) phenotypes will improve diagnostic and therapeutic options for this common disease. We present evidence that sphingolipids such as ceramides are involved in the emphysema pathogenesis. Whereas distinct ceramide species cause cell death by apoptosis and necroptosis, cell adaptation leads to accumulation of other sphingolipid metabolites that extend cell survival by triggering autophagy. Cigarette smoke-released sphingolipids have been involved in both the initiation and persistence of lung injury via intracellular signaling and paracrine effects mediated via exosomes and plasma membrane-bound microparticles...
December 2018: Annals of the American Thoracic Society
Stacey N Keenan, Ruth C Meex, Jennifer C Y Lo, Andrew Ryan, Shuai Nie, Magdalene K Montgomery, Matthew J Watt
Defects in hepatic lipid metabolism cause non-alcoholic fatty liver disease and insulin resistance, and these pathologies are closely linked. Regulation of lipid droplet metabolism is central to the control of intracellular fatty acid fluxes and perilipin (PLIN) 5 is important in this process. We examined the role of PLIN5 on hepatic lipid metabolism and systemic glycemic control using liver-specific Plin5 deficient mice ( Plin5 LKO ). Hepatocytes isolated from Plin5 LKO mice exhibited marked changes in lipid metabolism characterized by decreased fatty acid uptake and storage, decreased fatty acid oxidation that was associated with reduced contact between lipid droplets and mitochondria, and reduced triglyceride secretion...
January 7, 2019: Diabetes
Farkas Sarnyai, Mária Berinkeiné Donkó, Judit Mátyási, Zsófia Gór-Nagy, Ildikó Marczi, Laura Simon-Szabó, Veronika Zámbó, Anna Somogyi, Tamás Csizmadia, Péter Lőw, Péter Szelényi, Éva Kereszturi, Blanka Tóth, Miklós Csala
High fatty acid (FA) levels are deleterious to pancreatic β-cells, largely due to the accumulation of biosynthetic lipid intermediates, such as ceramides and diglycerides, which induce ER stress and apoptosis. Toxicity of palmitate (16:0) and oleate (18:1 cis-Δ9 ) has been widely investigated, while very little data is available on the cell damages caused by elaidate (18:1 trans-Δ9 ) and vaccenate (18:1 trans-Δ11 ), although the potential health effects of these dietary trans fatty acids (TFAs) received great publicity...
December 17, 2018: Food and Chemical Toxicology
Hung Nguyen, Sandeepkumar Kuril, David Bastian, Jisun Kim, Mengmeng Zhang, Silvia G Vaena, Mohammed Dany, Min Dai, Jessica Lauren Heinrichs, Anusara Daenthanasanmak, Supinya Iamsawat, Steven Schutt, Jianing Fu, Yongxia Wu, David P Fairlie, Carl Atkinson, Besim Ogretmen, Stephen Tomlinson, Xue-Zhong Yu
Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT). DCs play critical roles in GVHD induction. Modulating autophagy represents a promising therapeutic strategy for the treatment of immunological diseases. Complement receptors C3aR/C5aR expressed on DCs regulate immune responses by translating extracellular signals into intracellular activity. In the current study, we found that C3aR/C5aR deficiency enhanced ceramide-dependent lethal mitophagy (CDLM) in DCs...
December 20, 2018: JCI Insight
N G Chavez Soria, D S Aga, G E Atilla-Gokcumen
Engineered nanomaterials have unique properties compared to their bulk counterparts. Copper oxide nanoparticles (CuO NPs) are one example of nanomaterials used in a wide range of consumer products due to their conductivity and biocidal properties. While CuO NPs can induce toxicity in various organisms, their interactions with different organisms and how they affect cellular homeostasis is yet to be fully understood. In this work, the toxicity of CuO NPs was evaluated in different human cell lines (colorectal carcinoma, cervical cancer, embryonic kidney, and lung fibroblast), showing a dose-dependent toxicity...
December 18, 2018: Molecular omics
Marion Orsini, Sébastien Chateauvieux, Jiyun Rhim, Anthoula Gaigneaux, David Cheillan, Christo Christov, Mario Dicato, Franck Morceau, Marc Diederich
Elevated levels of the pro-inflammatory cytokine tumor necrosis factor-α (TNFα) inhibit erythropoiesis and cause anemia in patients with cancer and chronic inflammatory diseases. TNFα is also a potent activator of the sphingomyelinase (SMase)/ceramide pathway leading to ceramide synthesis and regulating cell differentiation, proliferation, apoptosis, senescence, and autophagy. Here we evaluated the implication of the TNFα/SMase/ceramide pathway on inhibition of erythropoiesis in human CD34+ hematopoietic stem/progenitor cells (CD34/HSPCs) from healthy donors...
December 13, 2018: Cell Death and Differentiation
Manish Bodas, Garrett Pehote, David Siverberg, Erich Gulbins, Neeraj Vij
In this study, we aimed to investigate precise mechanism(s) of sphingolipid-imbalance and resulting ceramide-accumulation in COPD-emphysema. Where, human and murine emphysema lung tissues or human bronchial epithelial cells (Beas2b) were used for experimental analysis. We found that lungs of smokers and COPD-subjects with increasing emphysema severity demonstrate sphingolipid-imbalance, resulting in significant ceramide-accumulation and increased ceramide/sphingosine ratio, as compared to non-emphysema/non-smoker controls...
November 27, 2018: Free Radical Biology & Medicine
Janine Schulte-Zweckel, Tabea Schneidewind, Jose Luis Abad, Andreas Brockmeyer, Petra Janning, Gemma Triola
Ceramide plays key roles in autophagy, inflammation and apoptosis. However, little is known about the molecular mechanisms regulating its function and only a handful of cellular effectors are known for this lipid. Here we show that azide-tagged sphingolipids are powerful tools to identify ceramide targets. The combination of a protein array analysis and a mass spectrometry-based proteomic profiling successfully detects known ceramide-binding proteins and identifies others not yet reported, several of which we validated using a variety of techniques...
November 20, 2018: Chemical Communications: Chem Comm
Facundo H Prado Spalm, Marcela S Vera, Marcos J Dibo, M Victoria Simón, Luis E Politi, Nora P Rotstein
Ceramide (Cer) has a key role inducing cell death and has been proposed as a messenger in photoreceptor cell death in the retina. Here, we explored the pathways induced by C2 -acetylsphingosine (C2 -Cer), a cell-permeable Cer, to elicit photoreceptor death. Treating pure retina neuronal cultures with 10 μM C2 -Cer for 6 h selectively induced photoreceptor death, decreasing mitochondrial membrane potential and increasing the formation of reactive oxygen species (ROS). In contrast, amacrine neurons preserved their viability...
November 1, 2018: Molecular Neurobiology
Erica W Mandell, Rashmin C Savani
No abstract text is available yet for this article.
October 29, 2018: American Journal of Respiratory and Critical Care Medicine
Behzad Yeganeh, Joyce Lee, Claudia Bilodeau, Irene Lok, Leonardo Ermini, Cameron Ackerley, Isabella Caniggia, Jeroen Tibboel, Andre Kroon, Martin Post
RATIONALE: Premature infants subjected to mechanical ventilation (MV) are prone to lung injury that may result in bronchopulmonary dysplasia. Mechanical ventilation causes epithelial cell death and halts alveolar development. The exact mechanism of MV-induced epithelial cell death is unknown. OBJECTIVE: To determine the contribution of autophagy to MV-induced epithelial cell death in newborn rat lungs. METHODS: Newborn rat lungs and fetal rat lung epithelial (FLRE) cells were exposed to MV and cyclic stretch, respectively, and were then analyzed by immunoblotting and mass spectrometry for autophagy, apoptosis and bioactive sphingolipids...
October 16, 2018: American Journal of Respiratory and Critical Care Medicine
Guanghu Wang, Erhard Bieberich
For many decades, research on sphingolipids associated with neurodegenerative disease focused on alterations in glycosphingolipids, particularly glycosylceramides (cerebrosides), sulfatides, and gangliosides. This seemed quite natural since many of these glycolipids are constituents of myelin and accumulated in lipid storage diseases (sphingolipidoses) resulting from enzyme deficiencies in glycolipid metabolism. With the advent of recognizing ceramide and its derivative, sphingosine-1-phosphate (S1P), as key players in lipid cell signaling and regulation of cell death and survival, research focus shifted toward these two sphingolipids...
December 2018: Advances in Biological Regulation
Younju Lee, Jinuk Na, Myung Sun Lee, Eun Young Cha, Ji Young Sul, Jun Beom Park, Jin Sun Lee
Pristimerin, a quinonemethide triterpenoid, has demonstrated anticancer activity against a number of types of cancer, including breast cancer. However, its mechanism of action remains unclear. The present study investigated the autophagy‑induced anticancer efficacy of pristimerin on MDA‑MB‑231 human breast cancer cells. Pristimerin inhibited the growth of these cells in a concentration‑dependent manner. Treatment with pristimerin dose‑dependently induced an increase of light chain 3B (LC3‑II), whereas autophagy inhibitor 3‑methyladenine (3‑MA) inhibited pristimerin‑induced LC3‑II accumulation and cytotoxic effects...
September 14, 2018: Molecular Medicine Reports
Gulpreet Kaur, Li Xuan Tan, Gurugirijha Rathnasamy, Nilsa La Cunza, Colin J Germer, Kimberly A Toops, Marie Fernandes, Timothy A Blenkinsop, Aparna Lakkaraju
Abnormally enlarged early endosomes (EEs) are pathological features of neurodegenerative diseases, yet insight into the mechanisms and consequences of EE expansion remains elusive. Here, we report swollen apical EEs in the retinal pigment epithelium (RPE) of aged human donors and in the pigmented Abca4 -/- mouse model of Stargardt early-onset macular degeneration. Using high-resolution live-cell imaging, we show that age-related and pathological accumulation of lipofuscin bisretinoids increases ceramide at the apical surface of the RPE, which promotes inward budding and homotypic fusion of EEs...
September 4, 2018: Proceedings of the National Academy of Sciences of the United States of America
Toni Petan, Eva Jarc, Maida Jusović
Cancer cells possess remarkable abilities to adapt to adverse environmental conditions. Their survival during severe nutrient and oxidative stress depends on their capacity to acquire extracellular lipids and the plasticity of their mechanisms for intracellular lipid synthesis, mobilisation, and recycling. Lipid droplets, cytosolic fat storage organelles present in most cells from yeast to men, are emerging as major regulators of lipid metabolism, trafficking, and signalling in various cells and tissues exposed to stress...
August 3, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Megan M Young, Hong-Gang Wang
Macroautophagy (herein referred to as autophagy) is a highly conserved stress response that engulfs damaged proteins, lipids, and/or organelles within double-membrane vesicles called autophagosomes for lysosomal degradation. Dysregulated autophagy is a hallmark of cancer; and thus, there is great interest in modulating autophagy for cancer therapy. Sphingolipids regulate each step of autophagosome biogenesis with roles for sphingolipid metabolites and enzymes spanning from the initial step of de novo ceramide synthesis to the sphingosine-1-phosphate lyase 1-mediated exit from the sphingolipid pathway...
2018: Advances in Cancer Research
Kristen A Jeffries, Natalia I Krupenko
Ceramides, important players in signal transduction, interact with multiple cellular pathways, including p53 pathways. However, the relationship between ceramide and p53 is very complex, and mechanisms underlying their coregulation are diverse and not fully characterized. The role of p53, an important cellular regulator and a transcription factor, is linked to its tumor suppressor function. Ceramides are involved in the regulation of fundamental processes in cancer cells including cell death, proliferation, autophagy, and drug resistance...
2018: Advances in Cancer Research
Sebastian Brachtendorf, Ruth Anna Wanger, Kerstin Birod, Dominique Thomas, Sandra Trautmann, Marthe-Susanna Wegner, Dominik C Fuhrmann, Bernhard Brüne, Gerd Geisslinger, Sabine Grösch
Resistance against chemotherapy is a life-threatening complication in colon cancer therapy. To increase response rate, new additional targets that contribute to chemoresistance are still needed to be explored. Ceramides, which belong to the group of sphingolipids, are well-known regulators of cell death and survival, respectively. Here, we show that in human wild-type (wt ) p53 HCT-116 colon cancer cells treatment with oxaliplatin or 5-fluorouracil (5-FU) leads to a strong increase in ceramide synthase 5 (CerS5) expression and C16:0 -ceramide levels, which was not shown in HCT-116 lacking p53 expression (HCT-116 p53-/- )...
July 27, 2018: Biochimica et biophysica acta. Molecular and cell biology of lipids
Shengjiao Li, Yangou Wu, Yunpeng Ding, Miao Yu, Zexin Ai
Chemoresistance remains a challenge in the effective treatment of solid tumors, including oral squamous cell carcinoma (OSCC). Mitochondrial dynamics and autophagy have recently been implicated in the chemoresistance of cancer cells. The neutralization of ceramide is also associated with multidrug resistance, and ceramide synthase 6 (CerS6) is known to induce apoptosis. However, whether CerS6 regulates chemoresistance in OSCC is not clearly understood. Therefore, we investigated the role of CerS6 in the susceptibility of OSCC cells to cisplatin...
December 2018: Journal of Cellular Physiology
Aneta Rogalska, Arkadiusz Gajek, Małgorzata Łukawska, Irena Oszczapowicz, Agnieszka Marczak
Chemical modification of known, effective drugs are one method to improve the chemotherapy of tumors. We reported ability of oxazoline analogs of doxorubicin (O-DOX) and daunorubicin (O-DAU) to induce apoptosis and autophagy in ovarian and liver cancer cells. Reactive oxygen and nitrogen species (ROS and RNS, respectively), together with intracellular calcium-mediated downstream signaling, are essential for the anticancer effect of these new anthracycline analogs. The changes of mitochondrial membrane potential and induction of the ceramide pathway suggests that these compounds induce cell death by apoptosis...
2018: PloS One
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