Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0344307 (
analgesia
)
28,200
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Two enzymes, cyclo-oxygenase (COX) and 5-lipoxygenase, act upon arachidonic acids to produce prostaglandins and leukotrienes. Inhibition of COX-2 by non-steroidal anti-inflammatory drugs (NSAIDs) lowers synthesis of proinflammatory prostaglandins and produces
analgesia
. COX-2 is highly inducible by endotoxin, IL-1, hypoxia,
epidermal growth factor
(
EGF
), benzo[a]pyrene, and transforming growth factor beta 1(TGF-beta 1). COX-1 in constitutively expressed. Conventional NSAIDs also inhibit the synthesis of cytoprotective prostaglandins by COX-1 in the gastrointestinal tract. Surplus arachidonic acids accumulate and enhance the generation of leukotrienes via the lipoxygenase pathway inducing neutrophil adhesion to endothelium and vasoconstriction. The NSAIDs harboring a carboxyl group also inhibit oxidative phosphorylation (OXPHOS) lowering adenosine-triphosphate (ATP) generation leading to loss of mucosal cell tight junctions and increased mucosal permeability. Administration of NSAIDs that do not interfere with OXPHOS, and concomitant use of prostaglandin analogues to restore cytoprotection reduces complications of NSAID use. However, no NSAID that lacks potential for serious gastrointestinal toxicity is currently available. Selective inhibitors of COX-2 and 5-lipoxygenase are newer, promising drugs. Surprisingly, COX-2 null mice are able to mount an inflammatory response, suffering however, from kidney dysfunction and a shortened life span. Results of clinical studies on the long-term use of NSAID drugs such as selective inhibitors are still pending.
...
PMID:Adverse effects of nonsteroidal anti-inflammatory drugs on the gastrointestinal system. 955 45
Inhibition of cyclooxygenase (Cox) enzymatic activity by non-steroidal anti-inflammatory drugs (NSAIDs) provides the molecular basis of
analgesia
following wounding or surgery. This study investigated the role of Cox activity in the regulation of vascular endothelial growth factor (VEGF) expression in keratinocytes and the formation of new blood vessels in acute wounds in mice. To this end, human HaCaT keratinocytes were stimulated with
epidermal growth factor
(
EGF
).
EGF
increased Cox-1 mRNA in the presence of the constitutively expressed Cox-1 protein in keratinocytes.
EGF
coinduced Cox-2 and VEGF
165
mRNA and protein expression and an accumulation of prostaglandin E
2
(PGE
2
) in cell culture supernatants. Inhibition of Cox isozyme activity by Cox-1 and -2 siRNA or ibuprofen reduced PGE
2
and VEGF
165
release from keratinocytes. In a mouse model of excisional wound healing, Cox-2 and VEGF
165
expression were colocalized in the granulation tissue of acute wounds. Oral treatment of mice with the Cox-1 and -2 inhibitor diclofenac was associated with reduced levels of VEGF
165
protein and an impaired blood vessel formation in acute wound tissue. In summary, our data suggest that a reduction of PGE
2
-triggered VEGF
165
protein expression in wound keratinocytes is likely to contribute to the observed impairment of wound neovascularisation upon Cox inhibition.
...
PMID:Inhibition of cyclooxygenase-1 and -2 activity in keratinocytes inhibits PGE
2
formation and impairs vascular endothelial growth factor release and neovascularisation in skin wounds. 2667 12
