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Structure, Function and Evolutionary Aspects of Mitochondria
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Puja Agarwal, Mehali Mitra, Sujit Roy
Mitochondrial matrix contains a wide variety of metabolites. Pyruvate, acetyl CoA, acyl CoA, α-ketoglutarate, isocitrate, succinyl CoA, succinate, malate, fumarate and oxaloacetate are involved in citric acid cycle. L-citrulline, L-ornithine and carbamoyl phosphate are used in urea cycle. Mitochondria DNA, RNA and transfer RNA are used for protein synthesis. Another ions like Ca+2, K+, Mg+2 are also present in the matrix. Moreover CO2, H2O, O2, ATP, ADP and inorganic phosphate are present as metabolites. Enzymes like citrate synthase, Pyruvate dehydrogenase, isocitrate dehydrogenase, aconitase, α-ketoglutarate dehydrogenase, succinyl CoA synthetase, fumerase and malate dehydrogenase facilitates the TCA cycle. Transaminase facilitates amino acid production. β-oxidation uses pyruvate carboxylase, acyl CoA dehydrogenase and β-ketothiolase. The urea cycle is facilitated by carbamoyl phosphate synthetase I and ornithine transcarboxylase.
Fermented whey modulated AFB1 and OTA-induced hepatotoxicity and nephrotoxicity in vivo. A relative and absolute quantification about sex differences
Published in Toxicology Mechanisms and Methods, 2023
Massimo Frangiamone, Alexander Yemelin, Alessandra Cimbalo, Guillermina Font, Eckhard Thines, Lara Manyes
For in vivo toxicological studies concerning mycotoxins, a main aspect to take into account is the sex-dependent response. For instance, in mice, chickens, and humans, the liver carcinogenicity of AFB1 is greater in males than in females. Similarly, OTA prompted kidney tumors much more frequently in male rats than in females (Soler and Oswald 2018; EFSA 2020a; EFSA 2020b). The beneficial effects of probiotics have been also reported to show sex-related responses (He et al. 2019; Myles et al. 2020). Furthermore, the findings achieved with animal models can be extrapolated to humans by using biological biomarkers (Kraus 2018). In this sense, carbamoyl phosphate synthetase-1 (CPS1), the most abundant protein in liver mitochondria, represents a robust biomarker to detect hepatic diseases in humans and rats (Weerasinghe et al. 2014). Likewise, kidney injury molecule 1 (KIM-1) has been accepted by the Food and Drug Administration and European Medicines Agency as a highly sensitive and specific biomarker to monitor chemical-induced kidney injury in preclinical studies (Griffin et al. 2019).
Novel considerations on drug safety in epilepsy
Published in Expert Opinion on Drug Safety, 2021
Various genes have also been identified which are associated with some of the more severe adverse effects of valproate. The T1405 polymorphism variant in the carbamoyl phosphate synthetase 1 (CPS1) was found to be a significant risk factor for the occurrence of hyperammonemia with valproate.A retrospective study in Japanese patients showed that the Val16Ala polymorphism of the Superoxide Dismutase2 (SOD2) gene has an impact on the relationship between valproate exposure and GT elevation [13].Weight gain, a common adverse reaction of valproate, has been associated with leptin receptor (LEPR) and ankyrin repeat kinase domain containing 1 (ANKK1) gene polymorphisms in a cohort of Han Chinese people with epilepsy.In a pediatric cohort, it was found that CYP2C9 variant-guided treatment significantly reduced valproate misdosing [13].
Liver-directed gene-based therapies for inborn errors of metabolism
Published in Expert Opinion on Biological Therapy, 2021
Pasquale Piccolo, Alessandro Rossi, Nicola Brunetti-Pierri
AAV vectors can accommodate sequences up to 4.5–5 kb in size whereas the inclusion of sequences greater than 5 kb reduces significantly the in vivo potency [34]. This limited cargo capacity is a hurdle for few diseases, such as hemophilia A, Wilson disease, and carbamoyl phosphate synthetase-1 (CPS1) deficiency that are due to defects in large genes. In hemophilia A and Wilson disease, smaller versions of the genes encoding functionally active proteins have been developed to overcome this obstacle. Alternatively, a method has been developed to reconstitute upon co-infection of the same cell, expression of the full-length gene via intermolecular recombination between multiple AAV vector genomes containing large transgenes split into two or more separate portions (dual or triple AAV) [35–38].