Sandhoff disease/GM2 gangliosidosis/deficiency of Hex A and Hex B subunit deficiency
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
Patients with Sandhoff disease accumulate GM2 ganglioside in the brain [1]. The amounts found are 100–300 times the normal concentrations and quite similar to those of Tay-Sachs disease. In contrast to patients with Tay-Sachs disease, these patients also accumulate globoside, the common neutral glycolipid of erythrocyte and renal membranes, which has the same amino terminal sugar as GM2 ganglioside, N-acetyl galactosamine, in extraneural tissues, especially the liver, kidney, and spleen [17–20]. In the brain, there is storage of GM2; in addition, the asialo derivative of GM2 (GA2) accumulates, and this too is a difference from Tay-Sachs disease. Globoside may be demonstrated in urinary sediments and plasma [18]. The stored compounds are all structurally related. The asialo derivative differs from GM2 in the absence of the N-acetylneuraminic side chain, whereas globoside contains an extra galactose moiety. GA2 is found in the brain in Sandhoff disease in amounts 100 times normal [17]. Oligosaccharides and glycopeptides, which have a glycosidically bound N-acetylhexosamine, accumulate in various tissues, and they are excreted in the urine [21, 22], providing a readily accessible approach to diagnosis.
Peripheral Autonomic Neuropathies
David Robertson, Italo Biaggioni in Disorders of the Autonomic Nervous System, 2019
Fabry disease is characterized by cell storage of glycolipid ceramide trihexoside within the nervous system, including neurons of the autonomic nervous system, and a dying-back neuropathy, most prominent in small myelinated and unmyelinated fibres. Autonomic dysfunction has been demonstrated in this disease (Cable, Kolodny and Adams, 1980). Nine males with the disorder were examined and showed impaired sweating, absent corrugation of the skin induced by warm water immersion (a sign of autonomic denervation), and an abnormal flare component of the triple response of Lewis. Abnormal pupillary responses to pilocarpine, reduced saliva production, tear formation and abnormal cardiovascular responses, including decreased reflex rises in plasma noradrenaline, were also present. Sympathetic and parasympathetic function was impaired and was thought to represent small nerve fibre dysfunction in peripheral nerves. Autonomic nervous system involvement is rarely as incapacitating in this disease as in acute pandysautonomia.
Cell Structure and Functions
Malgorzata Lekka in Cellular Analysis by Atomic Force Microscopy, 2017
Glycolipids form the second group of lipids. They have covalently bound mono- or polysaccharides in the hydrophilic region (through glycosidic bonds). The most common saccharides molecules are galactose, glucose or lactose [1, 2]. Glycolipids can be found in lipid membranes of various organs like brain, nerve system, spleen, kidney, lung, liver, and erythrocytes. Analogously as phospholipids, glycolipids have amphipathic character (Fig. 2.7a). There are several sub-families of glycolipids such as glycosphingolipids, commonly found in nerve tissue, made up of ceramides connected to a carbohydrate moiety. Galactocerebroside (Fig. 2.7b) is a type of glycolipid that is commonly found in the myelin sheath around the nerves of vertebrates.
Surface-modified polymeric nanoparticles for drug delivery to cancer cells
Published in Expert Opinion on Drug Delivery, 2021
Arsalan Ahmed, Shumaila Sarwar, Yong Hu, Muhammad Usman Munir, Muhammad Farrukh Nisar, Fakhera Ikram, Anila Asif, Saeed Ur Rahman, Aqif Anwar Chaudhry, Ihtasham Ur Rehman
Cell membrane functions as the main barrier for inward and outward movement of bio-entities [33]. Similarly, drug-loaded polymeric nanoparticles are also needed to cross the cell membrane to exhibit their efficiency. The composition, morphology, and functions of cell membrane have attracted scientists to fabricate nanoparticles, whose surfaces mimic cell membrane (Figure 3a). The cell membrane is composed of a phospholipid bilayer with embedded proteins and carbohydrates. Phospholipids consist of hydrophobic phosphate group-containing head linked to the hydrophobic tail of fatty acids. These phospholipids self-assemble into bilayers with hydrophilic regions facing toward outside and inside of the cell, while hydrophobic tails of phospholipids face each other. The incorporation of cholesterol and proteins enhances the stability of the cell membrane. Membrane proteins are inserted throughout the cell membrane asymmetrically. They are arranged in a way that their exterior surfaces can act as receptors for signaling molecules, whereas interior sides change their conformation in response to the binding signal. In some cases, membrane carbohydrates, in the form of glycolipids, work as recognition sites for proteins [34]. Research on biologically inspired nanoparticles has revealed that surface modification of nanoparticles with lipid bilayer or protein/carbohydrate embedding enhances the efficacy of drug-loaded nanoparticles [35], for instance increase in circulation time, improved biocompatibility, low toxicity and immunogenicity [36] and enhanced stability [37].
Kazak faecal microbiota transplantation induces short-chain fatty acids that promote glucagon-like peptide-1 secretion by regulating gut microbiota in db/db mice
Published in Pharmaceutical Biology, 2021
Xue Han, Ye Wang, Peipei Zhang, Manli Zhu, Ling Li, Xinmin Mao, Xiaoting Sha, Linlin Li
Our study showed significant gut differences between individuals with normal glucose tolerance (NGT) and T2DM (Wang et al. 2017). Disturbances in gut microbiota can lead to changes in the type and proportion of short-chain fatty acids (SCFAs) generated in the gut, which are closely related to obesity and T2DM (Qin et al. 2012). SCFAs, especially acetate, propionate, and butyrate, are the main products of intestinal microbial fermentation (Cummings et al. 1987). Interestingly, a previous study revealed that SCFAs improved glycolipid disorders in rodents (Koh et al. 2016). SCFAs act as signal transduction molecules that bind to and activate G protein-coupled receptors (GPRs), such as GPR43 and GPR41 (also called free fatty acid receptors 2 and 3, respectively [FFAR2 and FFAR3]) (Lu et al. 2016). A study focussing on SCFA target molecules in ffar2–/– and ffar3–/– mice showed that GPR43 and GPR41 were mainly activated by SCFAs, which promoted GLP-1 and peptide-yy (PYY) secretion from L cells and improved glucose tolerance (Samuel et al. 2008; Tolhurst et al. 2012).
Design and optimization strategies for the development of new drugs that treat chronic kidney disease
Published in Expert Opinion on Drug Discovery, 2020
Adrián M. Ramos, Beatriz Fernández-Fernández, María Vanessa Pérez-Gómez, Sol María Carriazo Julio, María Dolores Sanchez-Niño, Ana Sanz, Marta Ruiz-Ortega, Alberto Ortiz
Fabry disease is an X-linked hereditary disease characterized by intra- (mainly in lysosomes) and extracellular accumulation of glycolipids as a consequence of mutations in the GLA gene encoding the alfa-galactosidase A [33]. Key disease manifestations are childhood neuropathic pain and angiokeratoma followed by the development of proteinuric CKD and an arrhythmogenic left ventricular hypertrophy. Fabry nephropathy may be treated by the intravenous replacement of the missing enzyme (agalsidase) or, for certain mutations, the oral chaperone migalastat. Long-term therapy with agalsidase is associated with a lower incidence of severe clinical events [34,35], including need for dialysis. However, outcomes may be improved by providing concomitant nephroprotective medication once CKD has already developed. Up to now, RAS blockade has been used based on its efficacy in DKD. However, ongoing research into pathogenic pathways recruited by accumulated glycolipids, such as lyso-Gb3, has identified podocyte stress and Notch1, TGFβ-1, CD80, CD74 and inflammatory chemokines as key mediators of kidney injury leading to kidney fibrosis and as potential therapeutic targets [36–39]. The involvement of podocytes is thought to be responsible for the dose-dependency of the kidney response to ERT [40]. Interestingly, drugs originally developed for Fabry disease, such as the oral glucosylceramide synthase inhibitor venglustat were shown to successfully treat PKD in mice and clinical trials are ongoing in ADPKD [41]. This opens the door to the involvement of pathogenic mechanisms uncovered in Fabry disease in other nephropathies.
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