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Lysosomal Storage Disorders and Enzyme Replacement Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
The development of ERTs for treating Faber’s disease is still in its infancies. He et al. (2017) used Chinese hamster ovary (CHO) cells overexpressing human recombinant acid ceramidase (rhAC) for treating fibroblasts from a Farber disease patient, resulting in significantly reduced ceramide levels. The enzyme’s bioactivity in vivo was confirmed in Farber disease mice; safely administering at doses up to 50 mg/kg was possible. Gebai et al. (2018) recently published the crystal structures of mammalian AC. Structural mapping of disease mutations revealed that most of them contribute to a destabilization of the protein fold. These results provide information for the rational design of AC inhibitors and recombinant AC as disease therapeutics. By means of liquid chromatography multiple reaction mass spectrometry (LC/MRMMS) studies Cozma et al. (2017) could show that the ceramide C26:0 and especially its isoform 1 is a highly sensitive and specific biomarker for FD.
The Emerging Role of Exosome Nanoparticles in Regenerative Medicine
Published in Harishkumar Madhyastha, Durgesh Nandini Chauhan, Nanopharmaceuticals in Regenerative Medicine, 2022
Zahra Sadat Hashemi, Mahlegha Ghavami, Saeed Khalili, Seyed Morteza Naghib
The liver is one of the most essential organs having the highest intrinsic regenerative capacity. It has several indispensable functions in metabolic homeostasis and detoxification. However, the prolonged exposure of hepatic tissue to various damaging conditions could lead to cell death and hepatic dysfunction (Sookoian and Pirola 2015). Liver regeneration is a preparatory process to restore the function of liver mass loss following damage, or diseases (Michalopoulos 2013). Regenerative medicine has opened new horizons for the acute and chronic liver disease therapy and restoring homeostasis after liver injury, dysfunction, or disease. Hepatocyte-derived exosomes can be used as a diagnostic tool to indicate an injury. They may also serve as a novel mechanism to enhance repair and regeneration (Cho et al. 2017; Momen-Heravi et al. 2015; Thulin et al. 2017; Povero et al. 2014). The modulatory effect of exogenously-applied exosomes has already been delineated. These exosomes could trigger liver repair and regeneration via intercellular communication. The exosome level of alcoholic hepatitis patients was compared to healthy counterparts. The obtained results revealed that a higher amount of exosomes exists in alcoholic hepatitis with distinct miRNA profiles (Momen-Heravi et al. 2015). Hepatocyte-derived exosomes can potentially mediate the regenerative and reparative effect of hepatocytes in vitro and liver regeneration in vivo (Nojima et al. 2016). The regenerative potency could be rooted in the exosome-mediated delivery of neutral ceramidase and sphingosine kinase 2 (SK2) towards hepatocytes. This transfer could induce the higher production of sphingosine-1-phosphate (S1P) inside the hepatocytes. The sphingomyelin-ceramide pathway is crucial for exosome production (Trajkovic et al. 2008). This can address the increased circulating exosomal levels after liver injury. The exosomes derived from other liver cells did not have the same effect. These exosomes lack the key SK2 cargo and are incapable of evoking the proliferation of hepatocytes. These observations affirm the particular features of hepatocyte exosomes. Consistently, Ying dong et al. showed the hepato-protective impacts of exosomes derived from human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs-Exo) on hepatic IRI (Du et al. 2017).
Ceramide pathway: A novel approach to cancer chemotherapy
Published in Egyptian Journal of Basic and Applied Sciences, 2018
Mahdi Mashhadi Akbar Boojar, Masoud Mashhadi Akbar Boojar, Sepide Golmohammad
The ceramide present within the cytoplasm or in the lysosome can be broken down under the influence of various isoforms of the ceramidase enzyme and converted to the sphingosine and its free fatty acid [16]. So that not only the cell will be saved from the death mediated by ceramide, but its sphingosine base also converts to phosphorylated form, and the cells are directed to the survival and mitogenic condition [34]. Consequently, inhibitors of this enzyme can be considered as tumor suppressor agents [35].