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Ceramide autophagy

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
Anne Gulbins, Fabian Schumacher, Katrin Anne Becker, Barbara Wilker, Matthias Soddemann, Francesco Boldrin, Christian P Müller, Michael J Edwards, Michael Goodman, Charles C Caldwell, Burkhard Kleuser, Johannes Kornhuber, Ildiko Szabo, Erich Gulbins
Major depressive disorder (MDD) is a common and severe disease characterized by mood changes, somatic alterations, and often suicide. MDD is treated with antidepressants, but the molecular mechanism of their action is unknown. We found that widely used antidepressants such as amitriptyline and fluoxetine induce autophagy in hippocampal neurons via the slow accumulation of sphingomyelin in lysosomes and Golgi membranes and of ceramide in the endoplasmic reticulum (ER). ER ceramide stimulates phosphatase 2A and thereby the autophagy proteins Ulk, Beclin, Vps34/Phosphatidylinositol 3-kinase, p62, and Lc3B...
July 23, 2018: Molecular Psychiatry
Asaf A Qureshi, Dilshad A Khan, Shahida Mushtaq, Shui Qing Ye, Min Xiong, Nilofer Qureshi
BACKGROUND: δ-Tocotrienol is a naturally occurring proteasome inhibitor, which has the capacity to inhibit proliferation and induce apoptosis in several cancer cells obtained from several organs of humans, and other cancer cell lines. Moreover, results of plasma total mRNAs after δ-tocotrienol feeding to hepatitis C patients revealed significant inhibition in the expression of pro-inflammatory cytokines (TNF-α, VCAM1, proteasome subunits) and induction in the expression of ICAM1 and IFN-γ after post-treatment...
July 21, 2018: Lipids in Health and Disease
Núria Dalmau, Nathalie Andrieu-Abadie, Romà Tauler, Carmen Bedia
BACKGROUND: Ultraviolet (UV) radiation is known to be one of the most important environmental hazards acting on the skin. The most part of UV radiation is absorbed in the epidermis, where keratinocytes are the most abundant and exposed cell type. Lipids have an important role in skin biology, not only for their important contribution to the maintenance of the permeability barrier but also for the production and storage of energy, membrane organization and cell signalling functions. However, the effects on the lipid composition of keratinocytes under UV radiation are little explored...
October 2018: Journal of Dermatological Science
Geoffrey C Farrell, Fahrettin Haczeyni, Shivakumar Chitturi
Overnutrition, usually with obesity and genetic predisposition, lead to insulin resistance, which is an invariable accompaniment of nonalcoholic fatty liver disease (NAFLD). The associated metabolic abnormalities, pre- or established diabetes, hypertension and atherogenic dyslipidemia (clustered as metabolic syndrome) tend to be worse for nonalcoholic steatohepatitis (NASH), revealing it as part of a continuum of metabolic pathogenesis. The origins of hepatocellular injury and lobular inflammation which distinguish NASH from simple steatosis have intrigued investigators, but it is now widely accepted that NASH results from liver lipotoxicity...
2018: Advances in Experimental Medicine and Biology
Moon Jung Back, Hae Chan Ha, Zhicheng Fu, Jong Min Choi, Yongwei Piao, Jong Hoon Won, Ji Min Jang, In Chul Shin, Dae Kyong Kim
Autophagy is essential for optimal cell function and survival, and the entire process accompanies membrane dynamics. Ceramides are produced by different enzymes at different cellular membrane sites and mediate differential signaling. However, it remains unclear which ceramide-producing pathways/enzymes participate in autophagy regulation under physiological conditions such as nutrient starvation, and what the underlying mechanisms are. In this study, we demonstrate that among ceramide-producing enzymes, neutral sphingomyelinase 2 (nSMase2) plays a key role in autophagy during nutrient starvation...
June 4, 2018: Cell Death & Disease
Kecheng Zhou, Andrea Dichlberger, Hector Martinez-Seara, Thomas K M Nyholm, Shiqian Li, Young Ah Kim, Ilpo Vattulainen, Elina Ikonen, Tomas Blom
Membrane proteins are functionally regulated by the composition of the surrounding lipid bilayer. The late endosomal compartment is a central site for the generation of ceramide, a bioactive sphingolipid, which regulates responses to cell stress. The molecular interactions between ceramide and late endosomal transmembrane proteins are unknown. Here, we uncover in atomistic detail the ceramide interaction of Lysosome Associated Protein Transmembrane 4B (LAPTM4B), implicated in ceramide-dependent cell death and autophagy, and its functional relevance in lysosomal nutrient signaling...
May 23, 2018: ACS Central Science
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