Endotoxin Effects on Synthesis of Phosphatidic Acid and Phosphatidic Acid–Derived Diacylglyceride Species
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
The role of lipids, such as phosphatidylinositides (PI), diacylglycerides (DG), and phosphatidic acid (PA) species in both intracellular homeostatic and inflammatory signaling has been well established for over a decade (reviewed in Refs. 1,2), although initial evidence for the significance of PA-related signaling can be found in research from the period 1950–1955. Given that the recent reviews cited have extensively discussed mechanisms and dynamics of generalized lipid signaling in the context of PA, this chapter will center on aspects of PA and PA-related DG synthesis commensurate with inflammatory signaling that has been associated with endotoxin. The initial discussion will briefly summarize current understanding of PA and connected DG signaling, with analysis of their complex interconnections, and will include a section on the membrane effects of these lipids, which are related to some of their numerous biological activities.
Phosphoinositide Metabolism
Enrique Pimentel in Handbook of Growth Factors, 2017
Choline phospholipids may function as important mediators and modulators of signal transduction.81 The quarternary amine, choline, is an essential nutrient for humans. Choline is present in cell membranes in the form of ubiquitous phospholipids such as phosphatidylcholine, lysophosphatidylcholine, PAF, choline plasmalogen, and sphingomyelin. Calcium-mobilizing agonists can induce the hydrolysis of phosphatidylcholine by phospholipase C and phospholipase D, thus generating 1,2-diacylglycerol and phosphatidic acid, respectively.82,83 Phosphatidic acid may function as an intracellular mediator by itself and is able to activate protein kinase C in many different types of cells, including endothelial cells.84 Phosphatidic acid is degraded by a specific phosphohydrolase to diacylglycerol.
Phosphatidate Phosphohydrolase in Plants and Microorganisms
David N. Brindley, John R. Sabine in Phosphatidate Phosphohydrolase, 2017
Incorporation of radioactivity from 32P-orthophosphate into phospholipids during time-course experiments usually confirms that phosphatidic acid is labeled at high rates initially. This high specific activity then rapidly declines as phosphatidate is dephosphorylated or converted to CDP-diacylglycerol. Two examples of such a set of results are shown in Table 2. Soybean tissue has been quite well studied with regard to its metabolism and it is known that phosphatidylcholine is mainly made by the CDP-base pathway.31 Thus, it can be assumed that a significant proportion of the decline in phosphatidate labeling is due to phosphatidate phosphohydrolase activity which produces the necessary diacylglycerol. (It should be borne in mind that the 32P-labeling of phosphatidylcholine and phosphatidylethanolamine will be via ATP whereas phosphatidylinositol or phosphatidylglycerol will be labeled from phosphatidate which would itself be labeled either from ATP or from other sources such as glycerophosphate). The rapid and transient labeling of phosphatidic acid in maturing soybean32 was also seen in studies with other plants or algae. Data for the marine brown alga, Fucus serratus are included in Table 2 and Bieleski33 showed a similar result with Spirodela oligorhiza L.
Blockade of PLD1 potentiates the antitumor effects of bortezomib in multiple myeloma cells by inhibiting the mTOR/NF-κB signal pathway
Published in Hematology, 2020
Yanfang Wang, Fei Dong, Wei Wan, Zhenhao Zhang, Jing Wang, Hua Wang, Xiaoyan Ke
NF-κB plays a key role in the pathogenesis of MM and is the major regulatory molecule of bortezomib against MM [25]. Increased PLD1 activity could activate various molecular pathways such as the mTOR, Ras-ERK-PI3 K, and Wnt/β-catenin signaling to promote tumor cell proliferation and cell cycle progression [14–17]. In this study, we found that the expressions of both mTOR and NF-κB were significantly decreased when the PLD1-specific inhibitor was combined with bortezomib. Previous reports revealed that Akt activation and NF-κB nuclear translocation could be significantly inhibited by the knockdown of the mTORC2 protein [33], and the activation of mTOR in pulmonary epithelial cells promoted acute lung injury through the downregulation of autophagy and subsequent activation of NF-κB [34]. In addition, phosphatidic acid (PA) is the metabolic product of PLD1 and can bind and activate the mTORC1 as well as of mTORC2 complexes, which could also phosphorylate Akt [35]. NF-κB is a well-known target protein of the PI3K/Akt signaling pathway. Therefore, the absence of PLD1 could impair the activation of the mTOR complex and lead to a defective Akt/NF-κB activation. Our results confirmed that the mTOR activator MHY1485 could counteract the chemosensitizing effect of the PLD1 inhibitor by increasing the expressions of mTOR and NF-κB and promoting MM cell proliferation.
Modulating effect of a new ester, 28-O-phosphatidylbetulin (DAPB), obtained from hen egg yolk lecithin and betulin on lymphocyte subsets and humoral immune response in mice
Published in Immunopharmacology and Immunotoxicology, 2019
Magdalena Lis, Barbara Barycza, Angelika Sysak, Aleksandra Pawlak, Agnieszka Suszko-Pawłowska, Marianna Szczypka, Czesław Wawrzeńczyk, Bożena Obmińska-Mrukowicz
Synthesis of the first ester of betulin with phosphatidic acid (DAPB) was aimed at receiving compounds in which phospholipid part would serve as a carrier of bioactive molecules and its affinity to the cell membrane would facilitate its transport. The similarity to cell membranes would increase the availability of bioactive betulin to target cancer cells. Moreover, the resulting phosphatidyl derivative of betulin would serve as a donor of both biologically active betulin and phosphatidic acid [18,19]. Phosphatidic acids regulated lipid and protein kinases, are the source of 1,2-diacylglycerol and lysophosphatidic acid [20] and participate in exocytosis, endocytosis, cell differentiation, apoptosis, cell aging, formation of vesicles, and transport in the Golgi apparatus [21]. In addition, a phosphatidic acid obtained by enzymatic hydrolysis of phosphatidylcholine from egg yolk is rich in exogenous fatty acids (18:2, 20:4, 22:6), that are necessary for proper body functioning.
Phytic acid-modified manganese dioxide nanoparticles oligomer for magnetic resonance imaging and targeting therapy of osteosarcoma
Published in Drug Delivery, 2023
Qian Ju, Rong Huang, Ruimin Hu, Junjie Fan, Dinglin Zhang, Jun Ding, Rong Li
Aptamers (Niu et al., 2022), diphosphonate (Wu & Wan, 2012), and aspartic acid-related oligopeptides (Ogawa et al., 2017) exhibited good targeting ability to bones. However, their applications were restricted due to sophisticated synthetic methods or unpredictable biosafety. Phytic acid (PA), an organic phosphoric acid compound extracted from plant seeds, has been widely used as food additives (Zhou et al., 2019), antioxidant (Lux et al., 2022), preserving agent (Zhao et al., 2022), and chelating agent (Chen et al., 2018). PA has good biocompatibility since it was detected in mammalian cells. Interestingly, PA showed certain antitumor activities on colon tumor (Vucenik et al., 2020). PA also displayed special bone-targeting capability due to its strong chelating ability to calcium ion of bone. Consequently, PA-modified NPs was employed for targeting treatment of bone tumors (Zhou & Fan et al., 2019; Wang et al., 2020).
Related Knowledge Centers
- Choline
- Fatty Acid
- Glycerol
- Phosphate
- Phosphatidylcholine
- Phospholipase D
- Phospholipid
- Ion
- Lipid-Gated Ion Channels
- Carbon