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Nature, Function, and Biosynthesis of Surfactant Lipids
Published in Jacques R. Bourbon, Pulmonary Surfactant: Biochemical, Functional, Regulatory, and Clinical Concepts, 2019
Most of the studies dealing with the regulation of PG and PI biosyntheses have been carried out in the developing lung. Two different regulatory mechanisms have been evidenced. A role of cytidine monophosphate (CMP) has been postulated for the regulation of the biosynthesis of PG in the developing lung.307 Indeed, the concentration of CMP in lung tissue was found to increase during lung development, concomitant with the surge of surfactant, and this change appeared to be organ and nucleotide specific.307 CMP, the product of the reaction catalyzed by choline phosphotransferase, would rise as a consequence of increased PC production in maturing lung. CMP regulatory activity would involve the promotion of the reverse reaction catalyzed by CDP-diacylglycerol:inositol phosphatidyltransferase, thus leading to increased CDP-diacylglycerol availability.307 CMP also enhances glycerol-3-phosphate incorporation into PG and PG-phosphate through activation of the reaction catalyzed by CDP-diacylglycerol:glycerol-3-phosphate phosphatidyltransferase.308 Taken together, these data lead one to consider CMP as an important factor for promoting PG synthesis in the developing lung at the expense of PI synthesis.
Interaction of Drugs of Dependence With Receptors
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
Neuro transmitters are present in nerve terminals in a bound form, mainly confined within ultramicroscopic particles termed synaptic vesicles. In the case of ACh, these are about 400 A in diameter and contain from 104 to 105 ACh molecules. Little is known about the exact content of NE molecules. It is uncertain whether ACh exists in a free solution within its vesicles or bound to a macromolecule. Smythies et al.2 considered that ACh is bound to “a stacked array of cytidine monophosphate molecules stabilized by divalent cations.” NE is bound to an ATP-protein (chromogranin?) complex which is released in its entirety upon nerve stimulation. Smythies et al.2 believed that 5-HT is stored in a similar manner.
Other diseases (transverse myelitis, tropical spastic paraparesis, progressive multifocal leukoencephalopathy, Lyme’s disease)
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
Idiopathic or HTLV-1 associated progressive spastic paraparesis does not have a clear treatment. Cartier et al.36 assessed the effects of a medication containing cytidine monophosphate (CMP), uridine triphosphate, and vitamin B12 in the treatment of progressive spasticity. Patients with the disease were randomly assigned to receive the Nucleus CMP forte (containing disodium CMP 5 mg, trisodium uridine triphosphate 3 mg, and hydroxocobalamin 2 mg) three times a day or placebo for 6 months. Gait, spasticity, degree of neurogenic bladder, and SSEPs were assessed during treatment. Results: Forty-six patients aged 25 to 79 years old were studied, 24 were females and 29 were HTLV-1 positive. Twenty-two were treated with the drug and the rest with placebo. Gait and spasticity improved in 7 of 22 patients receiving the drug and 1 of 24 receiving placebo (p < .05). Neurogenic bladder improved in 10 of 22 receiving the drug and 4 of 24 receiving placebo (normal saline). SSEPs improved in four of seven patients treated with the drug and in two of seven treated with placebo. The medication resulted in a modest improvement in patients with progressive spastic paraparesis and was free of side effects.
Research progress of nanocarriers for gene therapy targeting abnormal glucose and lipid metabolism in tumors
Published in Drug Delivery, 2021
Xianhu Zeng, Zhipeng Li, Chunrong Zhu, Lisa Xu, Yong Sun, Shangcong Han
In addition to its regulatory role in cancer cells, miR-130b is also involved in the regulation of normal human cells. For example, miR-130b can inhibit the proliferation of myoblasts and the differentiation of corresponding stem cells. miR-130b plays a key role in muscle replacement (Wang et al. 2021), and miR-130b modulates tumor progression and increases tumor sensitivity radiotherapy and chemotherapy. Inoue’s study demonstrated that increased miR-130b expression in clinical oropharyngeal squamous cell carcinoma resulted in significantly longer progression-free survival and overall survival (Inoue et al. 2021). Clinically, chemical drugs such as cisplatin face huge drug resistance barriers in the treatment of gastric cancer and other solid tumors, and the therapeutic effect is greatly reduced. We know that the high expression of cytidine monophosphate kinase 1 (CMPK1) is also closely related to the therapeutic effect of 5-fluorouracil (5-FU). MiR-130b, a key epigenetic regulator of CMPK1, can downregulate CMPK1 and increase patient sensitivity to 5-FU in the treatment of gastric cancer (Hashimoto et al. 2020; Wang et al. 2020; 2020; Chu et al. 2021). There is sufficient evidence that miR-130b can be used as a potential target for tumor growth inhibition and new therapeutic approaches (Wang et al. 2020).
Comprehensive manipulation of glycosylation profiles across development scales
Published in mAbs, 2019
Sven Loebrich, Elisa Clark, Kristina Ladd, Stefani Takahashi, Anna Brousseau, Seth Kitchener, Robert Herbst, Thomas Ryll
Supplementation with galactose increased levels of galactosylated species, as expected. However, compared to the drastic decreases seen after glucosamine feeding, the increases are modest, in line with findings from others.15 Uridine supplementation increased all galactosylated glycoforms, and decreased G0, G0F, and Man5 species. In our hands, uridine was a stronger modulator of G1F species than galactose, indicating that the synthesis of UDP-galactose was limited by uridine, and that the cells could produce the galactose moiety from other carbon sources, likely from glucose via UDP-galactose 4-epimerase. Supplementation of molecular precursors, while greatly raising intracellular nucleotide sugar levels, has not resulted in significant increases of the desired glycoform. Hills and coworkers reported a 5-fold increase in UDP-galactose levels in response to feeding with galactose, but only a 6% rise in actual galactosylation.15 We observed only modest increases in galactosylation after galactose feeding, and no increases in sialylation in response to either NANA or ManNAc. Similarly, Hills and coworkers reported that even though cytidine-monophosphate-sialic acid (CMP-SA) levels were increased 44-fold after feeding of 20 mM ManNAc, no increase in sialylation followed. These findings are in line with observations from non-mAb biologics, such as tissue inhibitor of metalloproteinase 1,17 and interferon gamma,18,22 (reviewed in ref. 11).
RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment
Published in Expert Opinion on Investigational Drugs, 2019
Beatrice Balboni, Btissame El Hassouni, Richard J. Honeywell, Dzjemma Sarkisjan, Elisa Giovannetti, Julie Poore, Callie Heaton, Christine Peterson, Ely Benaim, Young B. Lee, Deog J. Kim, Godefridus J. Peters
The activation enzyme UCK exists in two forms, UCK1 and UCK2 [23]. Using UCK-siRNAs transfections, UCK2-siRNA could completely downregulate UCK2 at the mRNA and protein-level, protecting cells from the RX-3117 cytotoxicity [24]. On the contrary, UCK1-siRNA was ineffective in protecting cells against RX-3117. Moreover, expression of UCK2 (activity, protein, and mRNA) correlated with cellular sensitivity to RX-3117. As a positive control ethynylcytidine was also investigated, known to be a specific substrate for UCK2 [8]. UCK1 downregulation with siRNA did not affect the sensitivity to both ethynylcytidine and RX-3117. Interestingly, UCK2 expression is low in human normal tissues, in comparison with cancer cells which are sensitive to RX-3117 [24]. Subsequent metabolism of RX-3117 to its diphosphate (RX-3117-DP) and triphosphate (RX-3117-TP) is possibly mediated by uridine monophosphate kinase (UMPK) and cytidine monophosphate kinase (CMPK) and Nucleoside diphosphate kinase (NDPK), respectively, but no definite proof has been obtained for involvement of these enzymes. However, the formation of these nucleotides has been demonstrated by the use of radioactive RX-3117 [12] and by the use of a sensitive LC-MS-MS [25]. Accumulation of these ribonucleotides appeared to be correlated to the sensitivity of RX-3117 in several cancer cell lines [12]. No proof has been obtained that RX-3117-DP is reduced to its deoxynucleotide derivative dRX-3117-DP by ribonucleotide reductase and subsequently to dRX-3117-TP. Analysis of the cellular nucleotide content after incubation of several non-small cell lung cancer (NSCLC) cell lines, did not show any trace of the formation of deoxyribonucleotides, despite the use of a sensitive LC-MS-MS assay. Moreover, the deoxy form of RX-3117, 2ʹ-deoxy-fluoropentenylcytosine (RX-3128), did not exhibit any cytotoxicity to cancer cells (Table 1). Furthermore, inhibition of ribonucleotide reductase by a specific inhibitor triapine did not reduce the incorporation of radiolabelled RX-3117 into DNA (unpublished data). These data question the nature of the derivative of RX-3117 incorporated into DNA, and it is hypothesized that RX-3117 has not to be converted to its deoxyribonucleotide in order to be incorporated into DNA.