Monday, 16 December 2013

The Effects of Hormone Prostaglandins(1)

Prostaglandins, are a group of lipid mediators, found and isolated from human semen in the 1930s by Ulf von Euler of Sweden, responsible for inflammation features, such as swelling, pain, stiffness, redness and warmth. The hormones are produced by almost all nucleated cells and synthesized in the cell from the essential fatty acids (EFAs), include prostacyclin I2 (PGI2), prostaglandin E2 (PGE2), and prostaglandin F (PGF)
1. Prostaglandins and other lipid mediators in Alzheimer's disease
In the central nervous system (CNS), prostaglandin (PG) and other bioactive lipids regulate vital aspects of neural membrane biology, including protein-lipid interactions, trans-membrane and trans-synaptic signaling. According to the study by Louisiana State University Health Sciences Center, showed that biochemical mechanisms of PLA2 overactivation and its pathophysiological consequences on CNS structure and function have been extensively studied using animal models and brain cells in culture triggered with PLA2 inducers, PGs, cytokines, and related lipid mediators. Moreover, the expression of both COX-2 and PLA2 appears to be strongly activated during Alzheimer's disease (AD), indicating the importance of inflammatory gene pathways as a response to brain injury. How brain PLA2 and brain PGs are early and key players in acute neural trauma and in brain-cell damage associated with chronic neurodegenerative diseases such as AD.(1).

2. Prostaglandins in labor and delivery
Prostaglandins are produced by almost every tissue in the body and serve as important messengers or effectors in a wide variety of functions. The pivotal role of prostaglandins in contraction of the smooth muscle of the uterus and the biophysical changes associated with cervical ripening, however, point to a major problem with their clinical use.  According to the study of the role of prostaglandins in labor and delivery by University of South Florida College of Medicine, found that unlike oxytocin which requires an induction of receptors that does not usually occur until the later part of pregnancy, prostaglandins receptors always are present in myometrial tissue. This allows for the use of prostaglandins in usual doses throughout pregnancy. Although both F and E series prostaglandins result in uterine contractions, E series prostaglandins are relatively more uteroselective and are clearly superior to F series prostaglandins in producing cervical ripening. Modification of the naturally occurring prostaglandins by blocking the sites that are affected during their usual rapid metabolism, results in products with much longer durations of action, efficacy at much lower concentrations, and a potential for significant savings in cost(2).

3. Prostaglandins and inflammation
Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase isoenzymes, and their biosynthesis is blocked by nonsteroidal antiinflammatory drugs, including those selective for inhibition of cyclooxygenase-2. Despite the clinical efficacy of nonsteroidal antiinflammatory drugs, prostaglandins may function in both the promotion and resolution of inflammation, according to the study by University of Pennsylvania(3).

4.  Brain prostaglandins that promote neuroinflammation
Phospholipase A(2)(PLA(2)) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)-mediated biosynthesis of prostaglandins. According to the study in MAGL-disrupted animals, showed that a distinct pathway exists in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins(4).

5. Prostaglandins and human glioma cells
In many types of cancer, prostaglandin E2 (PGE2) is associated with tumour related processes including proliferation, migration, angiogenesis and apoptosis. In the study on the proliferative, migratory, and apoptotic effects of PGE1, PGE2 and Ibuprofen (IBP) observed in the T98G human glioma cell line in vitro, found that treatments which alter PGE1 and PGE2 metabolism influence the proliferative and apoptotic indices of T98G glioma cells. The migratory capacity of the cells was also significantly affected by the change in prostaglandin metabolism. Modifying PG metabolism remains an interesting target for future studies in gliomas(5).

6. Prostaglandins in cancer cell adhesion, migration, and invasion
Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. According to the study by the University of Texas MD Anderson Cancer Center, cyclooxygenase-2 (COX-2) and microsomal prostaglandin E(2) synthase-1 (mPGES-1) are upregulated in inflammation and cancer. This results in the production of prostaglandin E(2) (PGE(2)), which binds to and activates G-protein-coupled prostaglandin E(1-4) receptors (EP(1-4)). Selectively targeting the COX-2/mPGES-1/PGE(2)/EP(1-4) axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Combining the use of COX-2/mPGES-1/PGE(2)/EP(1-4) axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy(6).

7. Prostaglandin E2 promotes lung cancer cell migration
Many human cancers express elevated levels of cyclooxygenase-2 (COX-2), an enzyme responsible for the biosynthesis of prostaglandins. Available clinical data establish the protective effect of COX-2 inhibition on human cancer progression. According to the study by Medical College of Georgia, showed that the COX-2 product prostaglandin E(2) (PGE(2)) acts on cognate receptor EP4 to promote the migration of A549 lung cancer cells. Treatment with PGE(2) enhances tyrosine kinase c-Src activation, and blockade of c-Src activity represses the PGE(2)-mediated lung cancer cell migration. PGE(2) affects target cells by activating four receptors named EP1 to EP4. Use of EP subtype-selective ligand agonists suggested that EP4 mediates prostaglandin-induced A549 lung cancer cell migration, and this conclusion was confirmed using a short hairpin RNA approach to specifically knock down EP4 expression(7).

8. Prostaglandins and hepatocellular carcinoma cells
Prostaglandin E2 has been implicated in cell growth and metastasis in many types of cancers. According to the study by Nanjing Medical University, showed that PGE2 treatment significantly increased the cell adhesion, migration, and invasion in hepatocellular carcinoma (HCC) cells. In addition, the effects of PGE2 were found to be associated with focal adhesion kinase (FAK). PGE2 treatment increased the phosphorylation and synthesis of FAK in a dose-dependent manner. RNA interference targeting FAK suppressed PGE2-mediated cell adhesion and migration. Furthermore, the downstream proteins of FAK, paxillin and Erk2, were also activated by PGE2. PGE2 treatment increased the phosphorylation and synthesis of paxillin in a dose-dependent manner. PGE2 treatment also induced the phosphorylation of Erk2(8).

9. Caspase-3 and prostaglandins in cancer regrowth
Chemo- and radio-therapeutic regimens frequently kill cancer cells by inducing apoptosis, a cell-death subroutine that involves the activation of a particular class of proteases called caspases.   According to the study of Caspase-3 and prostaglandins signal for tumor regrowth in cancer therapy,. indicated in a recent issue of Nature Medicine, Huang et al. (2011) show that caspase activation in dying tumor cells causes the release of soluble lipid messengers, notably prostaglandin E(2), that stimulate tumor cell proliferation(9).

10. Physiological regulation of prostaglandins in the kidney
Cyclooxygenase-derived prostanoids exert complex and diverse functions within the kidney. The biological effect of each prostanoid is controlled at multiple levels, including (a) enzymatic reactions catalyzed sequentially by cyclooxygenase and prostanoid synthase for the synthesis of bioactive prostanoid and (b) the interaction with its receptors that mediate its functions. Cyclooxygenase-derived prostanoids act in an autocrine or a paracrine fashion and can serve as physiological buffers, protecting the kidney from excessive functional changes during physiological stress. According to the study by Vanderbilt University, and Veterans Affair Medical Center, alhrough these actions, prostanoids play important roles in maintaining renal function, body fluid homeostasis, and blood pressure. Renal cortical COX2-derived prostanoids, particularly PGI2 and PGE2, play critical roles in maintaining blood pressure and renal function in volume-contracted states. Renal medullary COX2-derived prostanoids appear to have an antihypertensive effect in individuals challenged with a high-salt diet. Loss of EP2 or IP receptor is associated with salt-sensitive hypertension. COX2 also plays a role in maintaining renal medullary interstitial cell viability in the hypertonic environment of the medulla. Cyclooxygenase-derived prostanoids also are involved in certain pathological processes. The cortical COX2-derived PGI2 participates in the pathogenesis of renal vascular hypertension through stimulating renal renin synthesis and release. COX-derived prostanoids also appear to be involved in the pathogenesis of diabetic nephropathy(10).
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