Biochemical Markers in Ophthalmology
Ching-Yu Cheng, Tien Yin Wong in Ophthalmic Epidemiology, 2022
Metabolomic studies in diabetes have identified altered levels of several biomarkers. This includes cytidine, which has been thought to have the highest sensitivity and specificity of those investigated potential metabolites. One study that analyzed vitreous samples from patients with diabetes and proliferative disease revealed dysregulation of arginine, proline, citrulline, methionine, allantoin, and octanoylcarnitine in patients with proliferative diabetic retinopathy [136]. In the retina, arginine is metabolized by the arginase pathway to ornithine and urea and by nitric oxide synthase to citrulline and nitric oxide. It is possible that hyperactivity of the arginase pathway may result in reduced nitric oxide availability, impaired vasodilation, endothelial dysfunction, increased generation of oxygen and nitrogen reactive species, characteristic for DR [117].
Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
5-Azacytidine is a chemical analog of cytidine (a nucleoside component of DNA and RNA), and becomes incorporated into genomic DNA. It is used, along with its deoxy derivative decitabine (DacogenTM) (Figure 5.110) for the treatment of myelodysplastic syndrome for which it received approval from the FDA in 2004. Both agents were first synthesized in Czechoslovakia as potential antimetabolite agents. In two pivotal randomized controlled clinical trials comparing azacitidine to supportive treatment, 16% of patients with myelodysplastic syndrome who received azacitidine had a complete or partial normalization of bone marrow morphology and blood cell counts compared to 0% who received supportive care. Importantly, approximately two-thirds of patients who would normally require blood transfusions did not need one after azacitidine treatment. 5-Azacytidine is also sometimes used for the treatment of acute myeloid leukemia.
Extrahepatic Synthesis of Acute Phase Proteins
Andrzej Mackiewicz, Irving Kushner, Heinz Baumann in Acute Phase Proteins, 2020
Cystatin C is the extracellular brain protein with the highest ratio of the concentration in cerebrospinal fluid over that in blood plasma (for data on the human, see Reference 107). The primary structure of the cDNA has been reported for human cystatin C.108 Oligonucleotide probes were synthesized based on the sequence of human cystatin C cDNA and found to cross-hybridize with the corresponding mRNA in the rat.109,110 In the rat, the tissue with the highest cystatin C mRNA level was found to be the choroid plexus.109 Cystatin C mRNA was also detected in lower levels in other areas of the brain, in testis, epididymis, seminal vesicles, prostate, ovary, submandibular gland, and, in trace amounts, in liver.109 Choroid plexus pieces incubated with radioactive leucine secreted radioactive cystatin C.109 Possibly, the function of cystatin C is the inhibition of extracellular proteinases, such as those released from destroyed or dying cells. Thus, cystatin C could be important in maintaining the integrity of cell-surface proteins in the brain. The presence of large numbers of lysosomes, cell organelles rich in proteinases, has been described for neuronal cells.111
An integrated analytical strategy to decipher the metabolic profile of alkaloids in Compound Kushen injection based on UHPLC-ESI-QTOF/MSE
Published in Xenobiotica, 2023
Li Zhang, Ruijuan Li, Ting Zheng, Huan Wu, Yanyan Yin
Take matrine (P18) and N-methylcytisine (P12) as examples to illustrate the process of prototype alkaloid identification. P18 with tR of 12.97 min that showed an adduct ion at m/z 249.1965 [M + H]+. It had a molecular formula of C15H25N2O. The molecular formula and its tR were consistent with that of matrine in our chemical database. Furthermore, fragment ions at 218.1552, 190.1585, 176.1442, 162.1292, 150.1281, 148.1117, 134.0970, and 122.0977 were observed (Figure S2). Among these fragments, m/z 218.1552 was the product ion of m/z 249.1965 removal of a molecule of CH3NH2. Then m/z 218.1552 lost CO and C2H2O to form fragment ions m/z 190.1585 and m/z 176.1442, respectively. m/z 190.1585 continuously lost C2H4 to generate fragment ions of m/z 162.1292 and m/z 134.0970. m/z 176.1442 lost C2H2 and C2H4 to form fragment ions m/z 150.1281 and m/z 148.1117, respectively. The cleavage behaviour is consistent with the cleavage mode of matrine. Consequently, P18 was identified as matrine according to its tR, quasi-molecular ion and product ions. This result was also verified using the reference substance of matrine.
Gastroprotective effects of water extract of domesticated Amauroderma rugosum against several gastric ulcer models in rats
Published in Pharmaceutical Biology, 2022
Yanzhen Mai, Siyuan Xu, Ru Shen, Bairu Feng, Hong He, Yifei Xu
Dried domesticated A. rugosum was purchased from Longmen Maling Ganoderma lucidum planting base (Huizhou, China) and identified by morphological, microscopic and gene sequencing (the internal transcribed spacer (ITS). Sequence analysis showed that the similarity between the sample (GenBank accession number: MK660145) and A. rugosum (GenBank accession number: MG021113.1) was 99%. The authenticated voucher specimen (voucher 20-07-02) was kept in Huizhou Health Sciences Polytechnic. Dried domesticated A. rugosum mycelia powder as above was extracted for 1 h in hot water (98 °C) in proportion (1:17, w/v) by heating reflux, thrice. The extracting solution was mixed, filtered, concentrated and lyophilized to obtain WEA. The powder of WEA was dissolved in appropriate distilled water to prepare the extract solution (1 mL equivalent to 1 g of A. rugosum mycelia powder) for test. The polysaccharide content was determined according to Chinese Pharmacopoeia (version 2020) based on the method of Ganoderma lucidum (Curtis: Fr.) P. Karst. (Ganodermataceae) polysaccharide quantification. The nucleosides were determined by high-performance liquid chromatography (HPLC). The total polysaccharides of WEA were analysed by anthrone-sulphuric acid colorimetry at 625 nm. The contents of four nucleosides, namely, including cytidine, uridine, guanosine and adenosine, were determined by HPLC.
The preclinical discovery and development of molnupiravir for the treatment of SARS-CoV-2 (COVID-19)
Published in Expert Opinion on Drug Discovery, 2022
Pasquale Pagliano, Carmine Sellitto, Tiziana Ascione, Giuliana Scarpati, Veronica Folliero, Ornella Piazza, Gianluigi Franci, Amelia Filippelli, Valeria Conti
Molnupiravir (MOV) is also known as EIDD-2801 or MK4482. It is a broad-spectrum oral antiviral agent active against several RNA viruses. It is an isopropyl ester prodrug, which needs to be cleaved by host esterase in plasma to β-D-N4-hydroxycytidine or EIDD-1931 and converted to its 5’ metabolite. The latter is incorporated instead of Uracil or Cytidine into the growing viral RNA chain, causing mutagenesis during transcription [17] (Figure 1). Before MOV was proposed for COVID-19 treatment, it was investigated against many RNA viruses in in vitro and in vivo studies that hypothesized its use as a possible treatment against influenza viruses and some etiologic agents of epidemic encephalitis (encephalitic alphaviruses such as Venezuelan, Eastern, and Western equine encephalitic viruses). Preliminary investigations on SARS-CoV-2 infection demonstrated that MOV administration was associated with an improvement in pulmonary functions in a human airway epithelial cell culture system and the ferret model [18].
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