Native And Acquired Resistance To Infection With Cryptococcus Neoformans
Hans H. Gadebusch in Phagocytes and Cellular Immunity, 2020
The mechanism for the release of lysosomal enzymes from leukocytes is apparently more complex than had hitherto been thought (reviewed by Silverstein et al.,76 Schorlemmer et al.,43 and Zurier et al.77). Acid hydrolase release into the surrounding medium usually is associated with particle ingestion, can be enhanced by compounds that elevate cyclic GMP (cGMP) levels, and is inhibited by removal of Ca2+ from the extracellular medium,72 but may also occur in the absence of ingestion. It has been postulated that free calcium locally available in the cytoplasm leads to fusion of the lysosome with a specific region of the plasma membrane78 resulting in release of enzymes. Cytochalasin B, an inhibitor of phagocytosis, is thought to potentiate this effect.78,79
Hepatorenal tyrosinemia/fumarylacetoacetate hydrolase deficiency
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop in Atlas of Inherited Metabolic Diseases, 2020
The molecular defect in hepatorenal tyrosinemia is in the hepatic fumarylacetoacetic acid hydrolase (fumarylacetoacetase, EC 3.7.1.2) (see Figure 22.1). This was originally proposed on the basis of the accumulation of succinylacetone [10]. Deficiency of this enzyme was then documented by assay of activity in liver [12]. The level was 6 percent of normal in six patients with the acute disease and 20 percent in two patients with the chronic form. The activity of maleylacetoacetic acid hydrolase was also deficient in some samples of liver. A problem with enzyme assay is that in the presence of liver disease, the activities of many enzymes are reduced, but the fundamental enzyme deficiency may also be demonstrated in lymphocytes and fibroblasts [54]. The gold standard in the diagnosis of this disease is the demonstration of succinylacetone in the urine.
Structural Organization of the Liver
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
Lysosomes are defined as organelles specialized for intracellular digestion. They contain a wide variety of hydrolytic enzymes called acid hydrolases because they operate best at an acidic pH (about 5). Although it is simple to define lysosomes conceptually, it is difficult to identify them morphologically because they are highly pleomorphic. Lysosomal content may be homogeneous or heterogeneous and may include dense pigments, myelin figures, or partially digested organelles (Figure 20). Their positive identification in electron micrographs requires that the organelle be bound by a single membrane and show a positive histochemical reaction for acid phosphatase, a representative acid hydrolase (Bainton, 1981; deDuve, 1969, 1975; Novikoff et al., 1956; Novikoff, 1973). In addition, histochemistry has identified a region of SER and Golgi complex rich in acid phosphatase (Novikoff and Yam, 1978). It is thought that lysosomal enzymes synthesized in the RER and transported to the SER are subsequently transferred to the Golgi complex, where the enzymes are modified and packaged as lysosomes (Hasilik, 1980). The aforementioned group of acid-phosphatase-rich organelles (the Golgi complex, ER and lysosomes) has been called GERL (Novikoff and Yam, 1978).
At the heart of microbial conversations: endocannabinoids and the microbiome in cardiometabolic risk
Published in Gut Microbes, 2021
Ramsha Nabihah Khan, Kristal Maner-Smith, Joshua A. Owens, Maria Estefania Barbian, Rheinallt M. Jones, Crystal R. Naudin
Through interactions with CB1 and CB2, AEA and 2-AG induce a myriad of bioactivities, known as the cannabinoid tetrad which includes hypothermia, catalepsy, hypo-locomotion and analgesia. Furthermore, activation of the cannabinoid receptors by AEA and 2-AG has been linked to a reduction in intraocular pressure and blood pressure, as well as bradycardia.32,33 Throughout various tissue types, 2-AG is detected at hundreds of times more abundant than AEA.31 Studies have shown that when fatty acid hydrolase (FAAH), an AEA-degrading enzyme, is inhibited or genetically deficient, the concentration of local AEA increases. This AEA abundance has a more potent influence in driving CB1-mediated activities than when AEA levels are low,34 suggesting divergent signaling effects based on the level of AEA present.
Putative adjunct therapies to target mitochondrial dysfunction and oxidative stress in phenylketonuria, lysosomal storage disorders and peroxisomal disorders
Published in Expert Opinion on Orphan Drugs, 2020
Nadia Turton, Tricia Rutherford, Dick Thijssen, Iain P Hargreaves
The lysosome is a vitally important organelle involved in macromolecule catabolism, recycling, and signaling, and defects in these functions, due to defects in the lysosomal acid hydrolase enzymes or cofactors, can result in the accumulation of metabolites which cause cellular toxicity [45]. There are over 70 diseases which are identified as LSDs, most of which are inherited autosomal recessively [45]. Generally, LSDs are categorized according to the type of accumulated macromolecule, with the major categories including glycogenoses, mucopolysaccharidoses, and sphingolipidoses [46]. The pathophysiology of LSDs is directly associated with the accumulated toxic metabolite with affected individuals presenting with a wide spectrum of clinical symptoms [47–49]. An accumulation of toxic metabolites may be linked with an increase in lysosomal size/number, which has been associated with an increase in cellular OS, although the mechanisms responsible have yet to be fully elucidated [50]. Alternatively, since lysosomes are essential for autophagy, lysosomal dysfunction in LSDs may result in impaired autophagic clearance of dysfunctional mitochondria [51,52]. The observed accumulation of damaged mitochondria in LSDs has been associated with ROS generation, which may cause further mitochondrial impairment.
Glycan modification of glioblastoma-derived extracellular vesicles enhances receptor-mediated targeting of dendritic cells
Published in Journal of Extracellular Vesicles, 2019
Sophie A. Dusoswa, Sophie K. Horrevorts, Martino Ambrosini, Hakan Kalay, Nanne J. Paauw, Rienk Nieuwland, Michiel D. Pegtel, Tom Würdinger, Yvette Van Kooyk, Juan J. Garcia-Vallejo
Surface glycans may be important for the uptake of EVs by recipient cells [9,68,69]. B cell-derived EVs, for example, are enriched with α-2,3-linked sialic acid allowing their capture by Siglec-1 (CD169) on macrophages in both spleen and lymph nodes [6]. The inhibitory effect of heparin on EV uptake indicates an important role for heparin sulphate proteoglycans in EV uptake [70,71], and interference of D-mannose with EV uptake by DCs suggests an EV uptake mechanism via C-type lectin receptors [72]. Glycoengineering has been used previously to alter the stability and pharmacokinetics of protein biopharmaceuticals [73]. In this study, we enzymatically removed immune inhibitory sialic acids using a pan-sialic acid hydrolase. These sialidases have also been used to effectively remove sialic acids from EVs as a control for lectin binding to EV-associated sialic acids [74]. We have previously demonstrated efficient DC targeting via DC-SIGN with glycopeptides and glyco-liposomes for antigen presentation and CD4+ and CD8+ T cell induction [41,65,75]. Here we incorporated the high-affinity DC-SIGN ligand LeY into glioblastoma EVs for targeting of DCs.