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Marine-Based Carbohydrates as a Valuable Resource for Nutraceuticals and Biotechnological Application
Published in Se-Kwon Kim, Marine Biochemistry, 2023
Rajni Kumari, V. Vivekanand, Nidhi Pareek
Alkaline phosphatase plays a vital role in bone formation. Its activation results in phosphorus, mineralization of protomers, and a decrease in the concentration of extracellular pyrophosphate (inhibitor of mineralization). Acceptance of fucoidan at a dosage of 2 mg/mL increases bone mineralization by raising alkaline phosphatase activity by 35%. (Boskey et al., 1998). Osteocalcin advances bone development, speeding up the development of hydroxyapatite crystals (Min et al., 2012). Fucoidan expanded the discharge of osteocalcin in 7F2 cells and the worth of its mineralization in a portion subordinate way. Apart from these applications, fucoidan play a vital role in various biological activities that has been summarized in Table 1.3 along with mechanism of action.
Microbial Pathways of Lipid A Biosynthesis
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Paul D. Rick, Christian R. H. Raetz
As shown in Figure 2, a portion of the lipid A moieties found in wild-type E. coli K-12 may be substituted with a pyrophosphate residue at position 1 rather than with the more abundant monophosphate (111). The origin of this pyrophosphate is unknown. Recent studies in mutants with reduced levels of the MsbA protein (125) (an ABC transporter involved in lipid A transfer across the inner membrane) suggest that the formation of the pyrophosphate occurs in conjunction with transport (126). When MsbA levels are low, hexa-acylated lipid A moieties on nascent LPS accumulate in the inner membrane, but only the monophosphate form is present (126). If the extra phosphate is indeed added on the periplasmic surface of the inner membrane or in the outer membrane, then ATP is unlikely to be the phosphate donor. Other high-energy compounds, such as bactroprenyl pyrophosphate (3) or diacylgycerol pyrophosphate (129), would have to be considered, since they are more likely to gain access to the outer layers of the cell envelope.
Glycogenosis type I – von Gierke disease
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The microsomal glucose-6-phosphate transport protein (T1; translocase) was recognized through the study of glycogenosis type Ib. T1 catalyzes the transport of glucose-6-phosphate into the lumens of hepatic microsomes [76, 77]. In its absence, the liver is unable to release glucose from glucose-6-phosphate. The glucose-6-phosphatase catalytic protein is normal and can be assayed if membranous elements of the liver cell are disrupted by freezing or treatment with detergents, but in situ the system is nonfunctional [3, 78, 79]. The defect is also demonstrable in leukocytes, which have impaired uptake of glucose [80] in type Ib, and this may provide a way to test for the disorder. Activity against pyrophosphate and carbamylphosphate is not impaired.
Experimental study on preparation and anti-tumor efficiency of nanoparticles targeting M2 macrophages
Published in Drug Delivery, 2021
Zheng Zeng, Yu Liu, Qinglian Wen, Yixian Li, Jing Yu, Qiang Xu, Wenwu Wan, Yu He, Chen Ma, Yan Huang, Helin Yang, Ou Jiang, Fuyu Li
Imidazole group can aggregate isopentene pyrophosphate by inhibiting -ferric pyrophosphate synthase and thereby it can lead to cell apoptosis (Gu et al., 2015). Imidazole-based drugs possess remarkable anticancer activities, due to their ability to hinder cell growth and cell division. It is an important part of the molecular structure of many drugs including anti-tumor drugs, dacarbazine, temozolomide, zoledronic acid, mercaptopurine, nilotinib, tipifarnib, etc., which has been reported for the effect of cytotoxicity and anti-cancer properties (Ali et al., 2017). As a kind of synthetic pyrophosphate in which the basic molecular structure is ‘P-C-P’, etidronic acid cannot be metabolized by biological cell and then accumulate in the cell after entering cell. Pyrophosphate can inhibit the activity of some enzymes of cells, especially farnesyl pyrophosphate synthase, and lead to cell apoptosis (Brown & Holen, 2009).
Calciphylaxis-as a drug induced adverse event
Published in Expert Opinion on Drug Safety, 2019
Ignacio Portales-Castillo, Daniela Kroshinsky, Cindy K. Malhotra, Roberta Culber-Costley, Mario Gennaro Cozzolino, Shelly Karparis, Charles L. Halasz, Jeremy Goverman, Harold J. Manley, Rajeev Malhotra, Sagar U. Nigwekar
In addition to MGP, another relevant calcification inhibitor is the α2–Heremans-Schmid glycoprotein, also known as fetuin-A. Fetuin-A inhibits basic calcium-phosphate (the precursor of apatite) by forming soluble colloid spheres known as ‘calciprotein particles’ (CPP) [30]. Fetuin-A is decreased in the serum of patients that develop vascular calcification and decreases in the presence of inflammation [31,32]. Knock out models of this protein in mice develop spontaneous ectopic calcification, including vascular calcification. Sodium thiosulfate which is used in the treatment of calciphylaxis has been observed to increase the functional levels of fetuin-A [33]. Pyrophosphate is another important inhibitor of hydroxyapatite formation. Deficiency of the enzyme ectonucleotide pyrophosphatase phosphodiesterase (NPP1), necessary for its synthesis, has been found in a fatal form of arterial calcification in infants [34,35]. In patients with end stage renal disease, there are decreased levels of pyrophosphate. In experimental models, knock out of the enzyme NPP1 results in ectopic calcification, especially in the presence of high phosphorus diets. A recent experiment used nephrectomized rats fed with a high phosphorus diet. Gene markers relevant to vascular calcification were measured and it was found that elevations of Dkk1 and tissue nonspecific alkaline phosphatase, which decreases the activity of pyrophosphate, preceded osteogenesis [19,36]. These three enzymes exemplify the balance of calcification mediated by enzymes with the influence of vitamin D, calcium, phosphorus [37] and medications.
PT-112 induces immunogenic cell death and synergizes with immune checkpoint blockers in mouse tumor models
Published in OncoImmunology, 2020
Takahiro Yamazaki, Aitziber Buqué, Tyler D. Ames, Lorenzo Galluzzi
Platinum-based chemotherapeutics such as cisplatin (CDDP), carboplatin and oxaliplatin have extensively been used for the clinical management of numerous neoplasms, including (but not limited to) pulmonary, ovarian and colorectal tumors.1-3 However, platinum derivatives are associated with considerable toxicity and a high incidence of acquired resistance,4,5 calling for the identification of improved chemical entities. R,R-1,2 cyclohexanediamine-pyrophosphato-platinum(II) (PT-112, Figure 1a) has been developed in this setting, with the specific aim of altering the cellular mechanisms of action of the drug to improve its efficacy and at the same limit its toxicity.6-10 From a chemical perspective, PT-112 differs from other platinum derivatives as Pt2+ ions are chelated by diaminocyclohexane and pyrophosphate moieties. Pyrophosphate exists in the plasma in a di-anionic state, providing PT-112 with improved pharmacokinetic and pharmacodynamic properties, including a considerable tendency to accumulate in the lung, liver and bones (in mice).7,11-13 In line with this notion, multiple individual patients with primary or metastatic lesions in these organs, who failed several lines of conventional and/or experimental therapy, have experienced robust and durable responses upon systemic administration of PT-112 in the context of ongoing, dose-escalation, Phase I clinical trials (NCT02266745, NCT03409458).11,12,14 In particular, PT-112 monotherapy enabled durable responses in three patients with solid tumors, including two individuals who progressed on immune checkpoint blocker (ICB)-based immunotherapy.11,12 Moreover, heavily pretreated men with castration resistant prostate cancer exhibited serologic and radiographic responses to PT-112, employed as standalone therapeutic agent11,12 or combined with avelumab,14 an ICB specific for CD274 (best known as PD-L1)15,16 that is poorly active in such patients.17 Together with existing preclinical data,7,13 these observations suggest that PT-112 treatment may elicit, or at least be compatible with, a tumor-targeting immune response that can be potentiated by ICBs.18,19