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Lysosomal Storage Disorders and Enzyme Replacement Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
A comparison between CS and DS (skin, blood vessels, heart valves) exhibits that they differ from each other only in the position of the C5 of β-D-glucuronate; DS is generated in the organism from CS by enzymatic epimerisation (chondroitinglucoronate 5-epimerase). Hence, DS may be looked at as derived from chondroitin 4-sulfate in that it consists of GalNAc residues alternating with varying portions of glucuronyl and iduronyl moieties. Proteoglycans with dermatan chains often require repeating 2-sulfated iduronyl-containing disaccharide motifs for exerting biological activity. Chondroitin 4-sulfate is one of the structural GAG motifs of the above-mentioned serglycin, required for mast cell maturation. ADAMs is the abbreviation for a disintegrin and metalloproteinases (adamalysin family) belonging to the sheddases as they cleave extracellular parts of transmembrane proteins (see above). ADAMTS are ADAMs thrombosponding motifs; for a review of the ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs] protein family, see Kelwick et al. (2015). Their activation depends on the presence of CS-decorated syndecans. ADAMTS13 is a Zn-containing protease that cleaves the vWf (Von Willebrand factor), a multimeric glycoprotein involved in blood clotting/hemostasis. Multimers of plasma vWf are formed in the absence of ADAMTS13 and cause life-threatening thrombotic thrombocytopenic purpura characterized by the formation of thromboses in small blood vessels. For management approaches of this thrombotic microangiopathy, see Blombery and Scully (2014). Several ADAMTS exhibit aggrecanase activity, i.e., they cleave peptide bonds within the ECM proteoglycan aggrecan, e.g., between Glu372 and Ala374 in case of ADAMTS8, expressed in human articular cartilage. Some ADAMTSs are assumed to be involved in the depletion of articular cartilage in osteoathritic diseases (Collins-Racie et al., 2004; Yang et al., 2017). CS and DS proteoglycans further occur abundantly in the CNS. The receptor-like protein tyrosine phosphatase PTPζ/RPTPβ is developmentally regulated and localized in the Purkinje cell layer of the cerebrellum. It is involved in the morphogenesis of Purkinje cell dentrites which are essential for information processing by making contacts with the axons of granule cells. The extracellular domain of PTPζ/RPTPβ is the CS proteoglycan phosphacan to which the two heparin-binding growth factors pleiotrophin and midkine bind with high affinity to trigger PTPζ/RPTPβ-signaling in the developing cerebellum. Among others, the addition of polyclonal antibodies against the extracellular domain of PTPζ/RPTPβ or enzymatic removal of the CS chain induces a perturbation of PTPζ/RPTPβ-signaling and leads to the formation of Purkinje cells with abnormal dendrites (Tanaka et al., 2003). Novel splicing variants of protein tyrosine phosphatase receptor suggesting that sub-isoforms of PTPRZ have different functions have been identified by Fujikawa et al. (2017).
Posthumanism: Creation of ‘New Men’ Through Technological Innovation
Published in The New Bioethics, 2021
The environment influences intelligence and disentangling the contributions of genes from that of the environment is difficult; it might also influence how heritable IQ is. It is not just that both nature and nurture matter, but that they influence each other in different ways in different people. Reviews of the field of intelligence found that heritability of IQ varies significantly by social class. The importance of the environment for IQ is established by a 12-point to 18-point increase in IQ when children are adopted from working-class to middle-class homes (Nisbett et al. 2012a). Moreover, group differences in IQ are best understood as environmental in origin (Nisbett et al. 2012b). A case–control GWAS consisting of 1238 individuals of extremely high IQ and 8172 unselected population-based controls identified an SNP with the highest heritability known for a cognitive phenotype. Three variants in the ADAM12 locus encoding disintegrin and metalloproteinase domain-containing protein 12 were associated with extremely high IQ, as well as with the Plexin protein-expressing gene family plexins of the plexin-semaphorin pathway. This pathway has been linked to axon guidance, mental disability and neural connectivity, axon regeneration in the central nervous system, bone disorders, cancer and inflammatory diseases (Zabaneh et al. 2018).
Potential protective roles of curcumin against cadmium-induced toxicity and oxidative stress
Published in Journal of Toxicology and Environmental Health, Part B, 2021
Jae Hyeon Park, Byung Mu Lee, Hyung Sik Kim
The neuroprotective effects of turmeric and its main active constituents are well established. Although the underlying mechanisms of their action are not fully understood, the presence of a phenolic group was postulated to be responsible for the neuroprotective effect. Curcumin was noted to improve cellular injury induced by oxygen-glucose deprivation, as well as increase survival of cortical neurons (Wu et al. 2013). In rats with middle cerebral artery occlusion, curcumin diminished oxidative stress after focal cerebral ischemia/reperfusion injury and decreased infarct volume (Wu et al. 2013). Mary, Vijayakumar, and Shankar (2018) reported that curcumin exerted protective effects in neurodegenerative disorders of the brain by binding to redox-active metal ions such as Pb2+, Cu2+, Hg2+, Cd2+, and Mn2+. Curcumin was shown to improve brain function in mice with subarachnoid hemorrhage-induced neurological damage by inhibiting microglial activation and downregulating MMP-9 (Yuan et al. 2017). Curcumin might also improve the integrity of the blood-brain barrier, reverse apoptosis, and restore key proteins associated with Alzheimer’s disease, such as the receptors for advanced glycation end products, β-amyloid enzyme 1, and amyloid precursor protein. In addition, curcumin was found to downregulate expression of A disintegrin and metalloprotease domain-containing protein 10 (Shi et al. 2018) and upregulate expression of BDNF/TrkB and cyclic AMP response element-binding protein (CREB). Curcumin also exerted protective effects against frontal and hippocampal neuronal damage induced by stress (Srivastava et al. 2018; Wang et al. 2010). Further, Motaghinejad et al. 2017) noted that curcumin alleviated nicotine-induced neurotoxicity through p-CREB/BDNF signaling.