Prostaglandins
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 F2α (PGF2α)
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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Sources
(1) http://www.ncbi.nlm.nih.gov/pubmed/12432919
(2) http://www.ncbi.nlm.nih.gov/pubmed/8665768
(3) http://www.ncbi.nlm.nih.gov/pubmed/21508345
(4) http://www.ncbi.nlm.nih.gov/pubmed/22021672
(5) http://www.ncbi.nlm.nih.gov/pubmed/23231886
(6) http://www.ncbi.nlm.nih.gov/pubmed/22505934
(7) http://www.ncbi.nlm.nih.gov/pubmed/20353998
(8) http://www.ncbi.nlm.nih.gov/pubmed/19082453
(9) http://www.researchgate.net/publication/51685919_Caspase-3_and_prostaglandins_signal_for_tumor_regrowth_in_cancer_therapy
(10) http://www.ncbi.nlm.nih.gov/pubmed/17988207
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