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Lysosomal Storage Disorders and Enzyme Replacement Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
The Pompe disease (PD) was first characterized by the Dutch pathologist Joannes Cassianus Pompe in 1932 and is also known as glycogen storage disease type II (the only glycogen storage disease with a defect in lysosomal metabolism), caused by a deficiency of the lysosomal acid alpha-glucosidase (α-1,4-glucosidase, acid maltase; AAG, GAA) enzyme that leads to an accumulation of glycogen in the lysosome. Glycogen formed during glycogenesis is a multi-branched polysaccharide built from glucose units and serves as an energy storage molecule in many different organisms (humans, fungi, bacteria, etc.); functional α-1,4-glucosidase catalyzes the cleavage of terminal α1-4 and α1-6 linked glucose molecules from glycogen. PD affects an estimated 1 in 40,000 people worldwide (Genezyme, 2014). The disease is associated among others with progressive muscle myopathy including the heart muscle, hypotonia and respiratory distress. According to results of investigations performed by Raval et al. (2015) the cause of hypertrophic cardiomyopathy in infantile-onset Pompe disease is probably due to a glycan processing abnormality and shares features with hypertrophic cardiomyopathies observed in the congenital disorders of glycosylation. The late-onset milder form differs from the infantile form in that cardiac involvement is less pronounced.
Toxicity of the neonicotinoid insecticides thiamethoxam and imidacloprid to tadpoles of three species of South American amphibians and effects of thiamethoxam on the metamorphosis of Rhinella arenarum
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Shirley Vivian Daniela Fonseca Peña, Guillermo Sebastián Natale, Julie Céline Brodeur
According to van der Sluijs et al. (2015), short-term toxicity is not a relevant predictor of neonicotinoid-related chronic mortality in most vertebrate taxa, as sublethal effects dominate. Sublethal exposures of frogs and fish to TIA or IMI were reported to affect red and white blood cell counts (Gavel et al. 2019, 2021; Paunescu et al. 2022), endocrine systems (Zhu et al. 2019; Crayton et al. 2020; Gavel et al. 2019, 2021), glycogenesis and blood glucose levels (Delfino Vieira et al. 2018; Paunescu et al. 2022; Stoyanova et al. 2015, 2016), oxidative stress and antioxidant response (Delfino Vieira et al. 2018; Wang et al. 2018; Yan et al. 2020, 2015), the escape response to predators (Lee‐Jenkins and Robinson 2018; Sweeney et al. 2021), as well as DNA damage and genotoxicity (Delfino Vieira et al. 2018; Feng et al. 2004; Iturburu et al. 2017; Moe 2017; Pérez-Iglesias et al. 2014; Ruiz et al. 2014; Yan et al. 2015). For its part, clothianidin was found to induce oxidative stress and alter the leukocyte profile in tadpoles of the frog Rana pipiens (Gavel et al. 2019, 2021; Robinson et al. 2021); although it did not affect the susceptibility of larval leopard frogs to infection by trematode parasites (Robinson et al. 2019).
Chronic exposure to environmentally relevant levels of simvastatin disrupts zebrafish brain gene signaling involved in energy metabolism
Published in Journal of Toxicology and Environmental Health, Part A, 2020
Susana Barros, Ana M. Coimbra, Nélson Alves, Marlene Pinheiro, José Benito Quintana, Miguel M. Santos, Teresa Neuparth
Similar to mammals, fish brain relies mostly on glucose metabolism for the production of acetyl-CoA, essential for the tricarboxylic acid cycle. Nowis et al. (2014) reported that in cultured human muscle cells SIM, as well as other statins, were able to alter gene transcription of glut1b limiting glucose transport to the brain. Our results showed that transcription of glut1b was altered at the intermediate SIM concentrations, 40 ng/L and/or 200 ng/L (a downregulation in males and an upregulation in females) which suggests that glucose uptake may be altered in brain cells. These findings are supported by the noted alterations in gapdh mRNA levels. gapdh is known to be a multifunctional protein, involved in several biological processes, essential for glucose metabolism by its implication in glycolysis and glycogenesis (Figure 1) (Kadmiri et al. 2014; Zala et al. 2013). When glucose is reduced, brain cells also rely on fatty acid β-oxidation to obtain energy through the acetyl-CoA that participates in the TCA cycle (Lyssimachou et al. 2015; Soengas and Aldegunde 2002)(Figure 1). Data demonstrated that acadm, involved in the fatty acid β-oxidation, exhibited altered transcription levels, indicating a potential modulation of glucose metabolism.