Medicinal Plants Classification Biosynthesis and ... - Index of

Gastroprotective Triterpenoids: Pharmacological Mechanism
The third route involves aspirin and the action of cyclooxygenase (COX-2) and 5-LO
(lipooxygenase) [48]. Endothelial and epithelial cells express COX-2 in response to various
stimuli such as cytokines, hypoxia and bacterial infections [47]. Aspirin covalently modifies,
through acetylation, a serine residue near the active site of COX. In the case of COX-1, this
acetylation occurs in a serine residue near the active site (Ser530) which induces a
conformational change in the enzyme, and then it can no longer oxidize arachidonic acid
[49]. With COX-2 does not occur the same, aspirin also acetylates a serine residue (Ser516),
but COX-2 remains able to metabolize arachidonic acid to 15-(R)-HETE (15-Rhydroxyepitetraenoic
acid) [50]; this compound is released from endothelial and epithelial
cells and transformed by leukocyte 5-LO to 15-epimer lipoxin A4 or aspirin-triggered
lipoxins (ATL) [47]. Those events could occur in endothelial cells from mesentery and
vessels in gastric microcirculation; furthermore, lipoxins exert potent protective actions on
the gastric mucosa. Lipoxin generation in gastric tissue after aspirin administration was
induced throw COX-2 activity; concomitant administration with a COX-2 inhibitor exhibits
greater gastric damage after aspirin administration. These effects may occur in part through
the ability of lipoxins to suppress aspirin-induced leukocyte adherence within the gastric
microcirculation [14]. Lipoxins produce their effects via the FPRL-1 receptor [51], blockade
of this receptor results in a significant increment of the gastric damage effects of aspirin [14].
Besides, lipoxins inhibit LTB4 responses in neutrophils by down-regulating
CD11b/CD18, and then reduce leukocyte adhesion to the endothelium an early step for
gastric damage pathogenesis [52]. Moreover, nitric oxide exhibits its anti-inflammatory
effects in the microcirculation by inhibiting leukocyte-endothelium interactions, and lipoxins
increases nitric oxide synthesis through eNOS and iNOS [53]. In addition, Wallace and
coworkers evaluated the effect of intraperitoneal administration of synthetic LXA4 prior to
oral administration of aspirin to determine if ATL might act to reduce the severity of aspirininduced
gastric mucosal injury. They found that LXA4 dose-dependently reduced aspirininduced
injury in the stomach [14]. The most important event than lipoxins offer to gastric
safety are the increment on mucosal blood flow and the decrement on leukocyte adherence to
the vascular endothelium, an early step on pathogenesis in gastric mucosa induced by
NSAIDs [54].
3.2.4. Resolvins
The essential polyunsaturated fatty acids (PUFA) include arachidonic acid of the ω-6
series, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from the ω-3
series of PUFA [55].
Similar as occurs with lipoxins, aspirin acetylates Ser516 in the internal cavity of COX-2
active site to cause a shift in the position and chirality of oxygen insertion by a change in the
conformation of the omega side chain [56]. It has been reported that aspirin treatment of
COX-2 enhanced the production of 15-R-HETE from araquidonic acid to form lipoxins, 18-
R-HEPE from EPA and 17-R-HDHA from DHA. When 18-R-HEPE and 15-R-HEPE were
incubated with activated human PMN were converted to trihydroxy-containing EPE
compounds, namely 5S,12R,18R-triHEPE (Resolvin E1, RVE1) and 5S,6R,15R-triHEPE (15epi-lipoxin
A5).
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