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Enzymatic Amino Acid Deprivation Therapies Targeting Cancer
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Carla S. S. Teixeira, Henrique S. Fernandes, Sérgio F. Sousa, Nuno M. F. S. A. Cerqueira
Arginase I (ArgI) is the only of the two isozyme types with demonstrated anti-cancer therapeutic potential. It is a cytosolic enzyme found predominantly in liver hepatocytes, where it catalyses the hydrolysis of l-ARG to l-ornithine and urea. This is the final cytosolic step of the urea cycle, which detoxifies ammonia in mammals (Krebs, 1973). l-ornithine can be further metabolized to polyamines via ornithine decarboxylase (ODC). Then, it can generate l-proline via ornithine aminotransferase (OAT), or it can be converted to citrulline by ornithine transcarbamylase (OTC) (Morris Jr., 2002).
The Current State of Non-Viral Vector–Based mRNA Medicine Using Various Nanotechnology Applications
Published in Yashwant V. Pathak, Gene Delivery Systems, 2022
Kshama Patel, Preetam Dasika, Yashwant V. Pathak
Another type of illness that has a potential solution with mRNA technology are various kinds of deficiencies resulting from the body not generating the necessary hormones, biomolecules, or substrate to successfully trigger enzymes. One illness that falls in this category is type 2 diabetes, where the cells of the body can’t take up the sugar put into the body because the cells have become resistant to insulin and the pancreas can’t produce enough insulin to overcome the tolerance. From a study in Germany that ran a clinical trial on the drug AZD8601 with 42 men (ages 18 to 65) with type 2 diabetes, it was shown that the test groups for the drug had increased blood flow and cell permeability.10 In addition to this, the blood vessels had grown in size and number, which is important for diabetic patients, who often have health complications as a result of constrictive blood vessels.10 There were no concerning side effects, and the treatment effects were observed between 4 and 24 hours after administering the treatment.10 What allowed for this duration of protein detention was, once again, a liposomal package that kept the synthesized genetic material safe from the body’s immune system, as well as proteins that mimicked natural RNA identifiers.10 Another study used mice to test the effectiveness of mRNA in being able to supplement deficiencies in organisms such as mice, and this study also references the use of a liposomal package to protect the synthetic mRNA from the immune system. In particular, the deficiency that needed to be supported was a lack of ornithine transcarbamylase (OTC), which is an enzyme that is important in the urea cycle (hydrolysis and expulsion of nitrogen from the body).10 Allowing this deficiency to go untreated leads to high concentrations of ammonia in the blood, of which the toxicity can affect the nervous system. The results of the experiments showed that their treatment accounted for the OTC deficiency and that uptake of the mRNA by the liver (where the deficiency would be identified) was increased by about 200 percent in the first dosage alone over 10 days.10 Using these data, the researchers also generated a model for humans which suggested that mRNA encoded for this particular deficiency would account for about 35 percent of the normal levels found in humans, most likely with the same delivery system using lipid nanoparticles.10
Gene Therapy in Tissue Engineering: Prospects and Challenges
Published in Rajesh K. Kesharwani, Raj K. Keservani, Anil K. Sharma, Tissue Engineering, 2022
In the period between the years 1990 and 2000, numerous attempts related to gene therapy were made involving more than thousands of patients (Abbott, 1992; Blaese et al., 1995). Claudio Bordignon, while working at the Vita-Salute San Raffaele University in 1992, successfully performed the first gene therapy procedure in which hematopoietic stem cells were used as vectors to deliver genes with the intention of correcting hereditary diseases. Jesse Gelsinger, one such patient, had ornithine transcarbamylase deficiency, an X-linked genetic disease of the liver, the symptoms of which include an inability to metabolize ammonia, a byproduct of protein breakdown. He was injected with an adenoviral vector carrying a corrected gene on 13th September, 1999. He died 4 days later due to massive immune response triggered by the use of the viral vector. This was a major setback for gene therapy research in the US (Stolberg, 1999). In 2002, gene therapy was used to treat sickle cell anemia in mice (Wilson, 2002). The year 2003 proved very promising with liposome-aided gene insertion in the brain being performed successfully (Ananthaswamy, 2003). In March 2006, two adult patients for X-linked chronic granulomatous disease (a disease which affects myeloid cells and impairs the immune system) were treated by gene therapy (Ott et al., 2006). In November 2006, VRX496, a gene-based immunotherapy, was successfully employed for the treatment of HIV. Lentiviral vector was used in this case to deliver an antisense gene against the HIV envelope (Levine et al., 2006). The first gene therapy trial for inherited retinal disease was done in 2007 (Ghosh, 2007). In 2010, an 18-year-old male patient in France with beta-thalassemia major was successfully treated (Cavazzana-Calvo et al., 2010). In 2011, Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for vascular endothelial growth factor (VEGF) (Deev et al., 2015). In 2013, scientists reported successful treatment of hemophilia patients using adenovirus-based vectors (Nathwani et al., 2014). The period between 2013 onward has seen immense research being carried out around the world with many successful attempts in certain diseases such as sickle cell disease (Romero et al., 2013), acute lymphoblastic leukemia (ALL) (Qasim et al., 2017), non-Hodgkin lymphoma (Avanzi et al., 2017), Hunter syndrome (Sestito et al., 2018), and many other diseases.
Hepatic proteomic assessment of oral ingestion of titanium dioxide nano fiber (TDNF) in Sprague Dawley rats
Published in Journal of Environmental Science and Health, Part A, 2022
Worlanyo E. Gato, Ji Wu, Isaac Appiah, Olivia Smith, Haresh Rochani
To explore the effects of TDNF ingestion in Sprague Dawley rats, a proteomics approach was used. Proteomics is a useful tool to evaluating the complete structure and function of proteins in an organism.[22] More than 400 hundred proteins were identified to be involved in TDNF effects in the liver. Some of these include Acyl-coenzyme A synthetase ACSM2, mitochondrial (Accession#: O70490), Betaine–homocysteine S-methyltransferase 1 (Accession#: O09171), Acyl-CoA dehydrogenase family member 11 (Accession#: B3DMA2) and Ornithine transcarbamylase, mitochondrial precursor (Accession#: P00481) among many more. These proteins are involved in such processes as catalysis of fatty acids by CoA, homocysteine metabolism, beta oxidation and the condensation of carbamoyl phosphate in the urea cycle.[23–25]