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Detection of Lysosomal Membrane Permeabilization
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Anne-Marie Ellegaard, Line Groth-Pedersen, Marja Jäättelä
The interest in lysosomotropic agents as potential anti-cancer drugs has revived recently due to the realization that many commonly used cationic amphiphilic drugs show cancer-specific toxicity (Ellegaard et al., 2013; Jahchan et al., 2013; Petersen et al., 2013; Shchors et al., 2015; Sukhai et al., 2013). Most cationic amphiphilic drugs accumulate in the lysosome, where they inhibit the conversion of sphingomyelin to ceramide by inhibiting acid sphingomyelinase (Kornhuber et al., 2010). The subsequent accumulation of sphingomyelin decreases the stability of the lysosomal limiting membrane and, hence, LMP is more likely to occur (Kirkegaard et al., 2010; Petersen et al., 2013).
Lysosomal, sterol and lipid disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
This condition belongs to the Niemann-Pick group of disorders, in which the breakdown of a particular type of fatty acid, called sphingomyelin, is impaired. There are thought to be up to six forms in this group of disorders – types A to F – each with distinctive characteristics. Type A is the commonest form, and it presents in infants and young children. It is characterised by enlargement of the liver (hepatomegaly) and/or spleen (splenomegaly), often with jaundice and anaemia, and other symptoms include poor feeding, failure to thrive and severe developmental delay, with loss of learned skills. There is a deiciency of the enzyme known as acid sphingomyelinase (ASM), which is required to break down sphingomyelin, a fatty substance that occurs in all types of cells. As a result, sphingomyelin accumulates in certain organs of the body. Niemann-Pick disease is more common in people of Ashkenazi Jewish descent.
Metabolic Disorders III
Published in John F. Pohl, Christopher Jolley, Daniel Gelfond, Pediatric Gastroenterology, 2014
Laurie A. Tsilianidis, David A. Weinstein, Roberto Zori
Niemann–Pick types A and B are autosomal recessive conditions caused by mutations in the acid sphingomyelinase (ASM) gene SMPD1. Type A refers to the severe phenotype while Type B describes the milder form thought to have residual enzyme activity. Both types are panethnic but Type A has a higher incidence amongst Ashkenazi Jews. Worldwide population frequency is estimated to be 0.5–1 in 100,000.
Analysis of the urinary metabolic profiles in irradiated rats treated with Activated Protein C (APC), a potential mitigator of radiation toxicity
Published in International Journal of Radiation Biology, 2023
Shivani Bansal, Sunil Bansal, Brian L. Fish, Yaoxiang Li, Xiao Xu, Jose A. Fernandez, John H. Griffin, Heather A. Himburg, Marjan Boerma, Meetha Medhora, Amrita K. Cheema
The observed inflammatory phenotype in the urinary profiles of irradiated rats is suggestive of severe dyslipidemia. Lipids could be appropriate biomarkers to study long term effects of IR that are proportional to lipoxidative stress intensity (Pannkuk et al. 2017). Glycerophospholipid metabolism is considered as the most significant pathway among the IR-responsive lipids (Maceyka and Spiegel 2014). SMs, as important components of lipid raft domain within the plasma membrane are essential for cell signaling and the endothelial cell stress response (Mathias et al. 1998; Hammad 2011; Peter Slotte 2013). However, IR-induced oxidative stress could result into enzymatic hydrolysis of sphingomyelins by activation of acid sphingomyelinase and generate ceramides (Kolesnick 1991). Elevated levels of ceramides could disrupt lipid rafts and impair cellular signaling. Ceramides are significant radiation injury biomarkers and IR-induced elevation in ceramide levels have been detected in many pathological conditions (Yun et al. 2020; Choi et al. 2021).
Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design
Published in Expert Opinion on Drug Discovery, 2022
Kashif Haider, Anku Sharma, M Shahar Yar, Prasanna Anjaneyulu Yakkala, Syed Shafi, Ahmed Kamal
The cellular activity of KRAS depends on the level of GTP-RAS in plasma membrane. Agents that facilitate dissociation of KRAS from plasma membrane could be effective for targeting mutant KRAS related cancer cells. The post translational modifications (PTM) at the hyper variable regions of the RAS are important for their membrane localization. The CAAX motif in RAS governs PTM steps which include prenylation, cleavage of AAX motifs, and methylation of carboxy terminal group, respectively. Small molecules that targets prenylation step have been extensively investigated for the development of RAS-dependent therapies [71]. Although KRAS mutant cancer cells show high resistance to FTIs and can undergo alternative geranylation, Tipifarnib a small molecule FTI is presently being studied under phase II clinical trials for the treatment of HRAS mutant bearing head and neck cancers (NCT03719690) [72]. Deltarasin is a PDE6δ inhibitor that blocks the redistribution of KRAS from perinuclear region into plasma membrane [73]. Similarly, it inhibits the acid sphingomyelinase (ASM) and sphingolipid biosynthesis, which are important components for KRAS plasma membrane localization. During phosphorylation by protein kinase C, KRAS dissociates from plasma membrane that leads to the apoptosis of KRAS proteins [74].
Biological membranes in EV biogenesis, stability, uptake, and cargo transfer: an ISEV position paper arising from the ISEV membranes and EVs workshop
Published in Journal of Extracellular Vesicles, 2019
Ashley E. Russell, Alexandra Sneider, Kenneth W. Witwer, Paolo Bergese, Suvendra N. Bhattacharyya, Alexander Cocks, Emanuele Cocucci, Uta Erdbrügger, Juan M. Falcon-Perez, David W. Freeman, Thomas M. Gallagher, Shuaishuai Hu, Yiyao Huang, Steven M. Jay, Shin-ichi Kano, Gregory Lavieu, Aleksandra Leszczynska, Alicia M. Llorente, Quan Lu, Vasiliki Mahairaki, Dillon C. Muth, Nicole Noren Hooten, Matias Ostrowski, Ilaria Prada, Susmita Sahoo, Tine Hiorth Schøyen, Lifu Sheng, Deanna Tesch, Guillaume Van Niel, Roosmarijn E. Vandenbroucke, Frederik J. Verweij, Ana V. Villar, Marca Wauben, Ann M. Wehman, Hang Yin, David Raul Francisco Carter, Pieter Vader
Sphingomyelin is a sphingolipid normally found in the outer leaflet of membranes (extracellular or luminal side). Enzymes such as neutral sphingomyelinase (nSMase) and acid sphingomyelinase (aSMase) convert sphingomyelin into phosphocholine and ceramide, which alters membrane fluidity and promotes microdomain formation. Interestingly, 62% of survey respondents believe that lipid rafts/microdomains contribute to the formation of vesicles [69,70] (Figure 6). nSMase inhibitors, such as GW4869, have been shown to significantly reduce small EV release from some [71], but not all systems [72], and even results in a compensatory increase in large EVs in some systems [73]. Conversely, overexpressing nSMase2 increases ILV formation, which is thought to occur via an ESCRT-independent biogenesis pathway [71]. More than half (59%) of ISEV workshop participants doubted nSMase2 involvement in the biogenesis of all EV subtypes (Figure 6), but there is also evidence that aSMases are involved in EV release [74]. Thus, the roles of various sphingomyelinases, ceramide, and lipid rafts in EV biogenesis require further investigation.