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Biologic Drug Substance and Drug Product Manufacture
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Ajit S. Narang, Mary E. Krause, Shelly Pizarro, Joon Chong Yee
The nutritional requirements of the auxotrophs form the basis of selection of cells post-transfection for those expressing exogenous proteins and has been utilized to also increase the transgene copy number and expression levels. Commonly used auxotrophs of CHO cells are the DG44 and DUKXB-11 host cell lines that are deficient in the dihydrofolate reductase (DHFR) enzyme. This enzyme reduces dihydrofolic acid to tetrahydrofolic acid, an essential cellular biochemical product for purine and thymidylate synthesis. Cells lacking the DHFR enzyme require glycine, hypoxanthine, and thymidine to grow (and are thus called triple auxotrophs). This property is utilized for the expression of a heterologous gene by co-transfection with a functional copy of the DHFR gene, such that the transfected cells do not require exogenously supplied glycine, hypoxanthine, and thymidine in the growth medium. Hence, cell culture in a deficient growth medium allows the selection of transfected cells. Another recombinant DNA expression strategy is the glutamine synthetase (GS) system utilized in GS deficient CHO cells. GS catalyzes the production of glutamine, an essential amino acid required for cellular metabolism, from glutamate and ammonia. Upon co-transfection of the recombinant gene and GS into host cells, the cells are cultivated in glutamine-free media to select for producing clones.
Prognostic value of neutrophil to lymphocyte ratio in the diagnosis of neurotoxicity after glufosinate ammonium poisoning
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Joochan Kim, Byeong Jo Chun, Jeong Mi Moon, Yongsoo Cho
Glufosinate ammonium irreversibly inhibits glutamine synthetase which catalyzes the synthesis of glutamine from glutamate and ammonia. Glutamine synthetase inhibition leads to the accumulation of intracellular ammonia (Takano and Dayan 2020). As serum ammonia levels increase, uptake of ammonia by the brain also rises (Sorensen 2013). Elevated brain ammonia levels may induce activation of N-methyl-D-aspartate receptors, which increase intracellular calcium ions and nitric oxide. Therefore, a rise in ammonia levels in the brain following glufosinate ammonium poisoning may elevate intracellular calcium ion and nitric oxide levels. This effect might inhibit glutamine synthetase in nearby astrocytes, increasing consumption and reducing synthesis of adenosine triphosphate with consequent neurotoxicity eventually leading to cell death (Rodrigo et al. 2009).
Synthesis and characterization of new bis(fluoroalkyl) phosphoramidates bearing sulfoximine groups
Published in Journal of Sulfur Chemistry, 2021
Hanen Mechi, M.A.K. Sanhoury, F. Laribi, M. T. Ben Dhia
Sulfoximines are considered as the monoaza analogs of sulfones and their stability has led to versatile chemistry [17,18]. In synthetic organic chemistry [19,20], the acidic α-hydrogen is one of the properties they share but the nitrogen atom offers the possibility for functionalization of molecules through nucleophilic reactions [21]. The widespread interest in the chemistry of sulfoximines is mainly due to the versatility of their applications in stereochemical studies [22–24]; they have been explored as building blocks in bioactive molecules [25,26] and often have very high efficiency in asymmetric metal catalysis [27]. In the literature some patents can be found on substituted sulfoximines for use as agrochemicals [28], detergents, additives, bacterial, antifungal compounds and auspicious bioisosteres in medicinal chemistry [29]. Some sulfoximine phosphoramidates are known for their important biological role [30–34]. For example, the active form of methionine sulfoximine, which efficiently inhibits glutamine synthetase, is methionine sulfoximine phosphate [30]. In addition, two nucleoside sulfoximine-containing phosphoramidates were shown to be potent inhibitors of human asparagine synthetase (hASNS) [31–33]. However, research studies on N-phosphorylated sulfoximines are still relatively rare and limited to a few examples [34,35–37]. As far as we are aware and despite the above mentioned interest in sulfoximine derived phosphoramidates and the versatile influence of inclusion of fluorine atoms on molecule properties [38–40], no reports on fluoroalkyl analogs have been yet described.
Reactive astrogliosis in the dentate gyrus of mice exposed to active volcanic environments
Published in Journal of Toxicology and Environmental Health, Part A, 2021
A. Navarro, M. García, A.S. Rodrigues, P.V. Garcia, R. Camarinho, Y. Segovia
It is well known the CNS is highly susceptible to the harmful effects of reactive oxygen species (ROS) (Pałasz et al. 2019), another group of molecules described by Sofroniew and Vinters (2010) as capable of triggering astrogliosis. Several investigators suggested that NO synthesized by the neural NOS (nNOS) deactivate the GS enzyme (Görg et al. 2005; McBean et al. 1995; Miñana et al. 1997) and attenuate glutamate uptake by astrocytes (Suárez, Bodega, and Fernández 2002), leading to reactive astrogliosis. It is known that astrocytes are responsible for 80–90% of glutamate uptake (Rose et al. 2018; Rose, Verkhratsky, and Parpura 2013) to protect neurons from excitotoxic damage by rapidly converting glutamate to glutamine, using GS enzyme (Muse et al. 2001). The activity and expression of this enzyme might be diminished in the presence of TNFα (Kazazoglou et al. 1996; Zou et al. 2010). Data demonstrated that TNFα affects glutamate uptake by astrocytes through the negative regulation of glutamate transporters (Sitcheran et al. 2005; Wang et al. 2003). If glutamate uptake is adversely affected, apart from the toxicity derived from reaching a high level of extracellular glutamate, many metabolic pathways might be impaired and thus, uptake is a critical step for a well-functioning brain.