Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Introduction: Targeting of inflammatory states with non-steroidal anti-inflammatory drugs (NSAID'S) is an attractive proposition for cancer prevention. There is abundant epidemiological and experimental evidence that NSAID'S can inhibit tumour development in a number of organs and such drugs have given positive results in human intervention studies. It is hoped that problems with side effects can be overcome by development of specific inhibitors of cancer- and inflammation-associated enzymes. NSAID Pharmacology: Starting with the production of aspirin, NSAIDs have received an enormous amount of clinical attention. Inhibitors of the two isoforms of cyclooxygenase (COX) or prostaglanding G/H synthase, they have found widespread application with increasing interest focused on their employment for cancer prevention. Particular attention is now being drawn to specific inhibitors of the inducible C0X-2 rather than the constitutive COX-1 isoform. Mechanisms of Action: NSAIDs appear to act via depression of prostaglandin synthesis through inhibiting COX-2, often overexpressed in cancers, and the resultant suppression of proliferation, possibly through enhancement of apoptosis. Future Prospectives: The possibility of applying NSAIDs in conjunction with other chemopreventive agents and developing specific inhibitors of different stages in the pathways leading to prostaglandin production and functions hold hope for improved drugs/protocols with reduced detrimental side effects for employment in both primary and secondary cancer prevention in the future.
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PMID:NSAIDs as Cancer Preventive Agents. 1271 76

In the present study, we examined the effect of prostaglandin (PG) E2 on interleukin (IL) -12 production in monocytes stimulated with a combination of lipopolysaccharide (LPS) from Actinobacillus actinomycetemcomitans and interferon-gamma (A. actinomycetemcomitans-LPS/IFN-gamma). Indomethacin, a cyclooxygenase inhibitor, enhanced IL-12 production, but inhibited PGE2 generation in A. actinomycetemcomitans-LPS/IFN-gamma-stimulated monocytes. Exogenous PGE2 inhibited IL-12 release in the cells. EP2, EP3 and EP4 receptor mRNA expression was detected in monocytes by reverse transcription-polymerase chain reaction. 11-deoxy-PGE1 (an EP2/EP4 agonist) inhibited IL-12 production in A. actinomycetemcomitans-LPS/IFN-gamma-challenged monocytes, whereas butaprost (an EP2 agonist) or ONO-AP-324 (an EP3 agonist) had no effect on IL-12 production. Dibutyryl cAMP, a cAMP analogue, and forskolin, an adenylate cyclase activator, mimicked depression of IL-12 production by PGE2. From these results, we suggest that PGE2 inhibits IL-12 production via EP4 receptors by cAMP-dependent pathways in A. actinomycetemcomitans-LPS/IFN-gamma-challenged monocytes.
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PMID:Prostaglandin E2 downregulates interleukin-12 production through EP4 receptors in human monocytes stimulated with lipopolysaccharide from Actinobacillus actinomycetemcomitans and interferon-gamma. 1275 65

Lipoxygenases are a family of enzymes which dioxygenate unsaturated fatty acids, thus initiating lipoperoxidation of membranes or the synthesis of signalling molecules, or inducing structural and metabolic changes in the cell. This activity is the basis for the critical role of lipoxygenases in a number of pathophysiological conditions, both in animals and plants. We review the effects of microgravity on the catalytic efficiency of purified soybean (Glycine max) lipoxygenase-1, as well as the modulation of the activity and expression of 5-lipoxygenase in human erythroleukemia K562 cells subjected to altered gravity. We also outline the molecular properties of the lipoxygenase family and discuss its possible involvement in space-related processes, such as apoptosis (programmed cell death) and immuno-depression. Finally, we discuss the modulation of cyclooxygenase activity and expression in K562 cells exposed to altered gravity, because cyclooxygenase catalyzes the oxidation of arachidonate through a pathway different from that catalyzed by lipoxygenase activity.
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PMID:Lipoxygenase activity in altered gravity. 1295 91

The chloroformic crude extract of roots of Bupleurum fruticosum L. (Umbelliferae) showed a concentration-dependent vasorelaxing effect on aortic rings endothelium-deprived and pre-contracted by norepinephrine (NE). The pharmacological effect was not produced through the stimulation of cyclooxygenase, adenyl cyclase, or guanylyl cyclase, since selective inhibitors did not prevent the extract-induced responses. The incubation of the aortic rings with the chloroformic extract (10(-4) g/ml) produced a depression of the concentration-contractile response curve to NE, in normal conditions, and this effect was more evident in Ca2+-free Tyrode solution, suggesting an action on the intracellular mobilization of Ca2+ ions. Moreover, the vasodilator action of Bupleurum fruticosum extract was resistant to the pre-treatment with nifedipine and to the pre-treatment with cyclopiazonic acid (blocker of Ca2+/ATPase). Finally, the chloroformic extract of Bupleurum fruticosum produced a reduction of the contraction obtained by caffeine, an opener of ryanodine-sensitive receptors, suggesting that the plant could elicit the vasorelaxing response by the blockade of ryanodine-sensitive Ca2+ channels of the sarcoplasmic reticulum.
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PMID:Vasorelaxant effects of the chloroformic crude extract of Bupleurum fruticosum L. (Umbelliferae) roots on rat thoracic aorta. 1558 55

Pain after surgery results in significant morbidity, and systemic opioids often fail to provide adequate analgesia without marked sedation and respiratory depression. Intrathecal morphine provides better analgesia, but is limited by delayed respiratory depression. Intrathecal injection of the cyclooxygenase inhibitor, ketorolac, has recently entered clinical trials, and the current study examined the interaction between intrathecal morphine and ketorolac to treat postoperative pain. We also sought to compare these treatments on a commonly used assessment of withdrawal threshold and a new assessment of spontaneous behavior after surgery. Male Sprague Dawley rats and underwent hind paw incision or subcostal laparotomy surgery. Intrathecal morphine, ketorolac, or their combination were injected on the first postoperative day, with outcome measure being return to pre-surgery withdrawal threshold with von Frey filament testing of the paw after paw incision, or return to pre-surgery exploratory activity after laparotomy. Intrathecal morphine completely reversed the effects of surgery in both models, but intrathecal ketorolac only partially reversed them. Ketorolac enhanced the potency of morphine several fold in both models, and did so synergistically after paw incision. In all cases drug potency was greater for spontaneous than elicited responses. These data confirm that spinal opioid receptor and cyclooxygenase enzyme inhibition diminish elicited tactile hypersensitivity after surgery, and that they similarly return spontaneous behavior to normal. Differences in drug potency could reflect fundamental differences in outcome measures or in the surgical procedures themselves. These data support combination study of intrathecal morphine and ketorolac for postoperative pain.
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PMID:Intrathecal morphine and ketorolac analgesia after surgery: comparison of spontaneous and elicited responses in rats. 1566 47

Platelet activation is a hallmark of severe preeclampsia, and platelet PGH synthase 1-derived (PGHS1-derived) thromboxane A(2) (TxA(2)) has been implicated in its pathogenesis. However, genetic disruption of PGHS1 delays parturition. We created hypomorphic PGHS1 (PGHS1(Neo/Neo)) mice, in which the substantial but tissue-dependent variability in the inhibition of PGHS1-derived eicosanoids achieved by low-dose aspirin treatment is mimicked, to assess the relative impact of this strategy on hemostatic and reproductive function. Depression of platelet TxA(2) by 98% in PGHS1(Neo/Neo) mice decreased platelet aggregation and prevented thrombosis. Similarly, depression of macrophage PGE(2) by 75% was associated with selectively impaired inflammatory responses. PGF(2alpha) at 8% WT levels was sufficient to induce coordinated temporal oxytocin receptor (OTR) expression in uterus and normal ovarian luteolysis in PGHS1(Neo/Neo) mice at late gestation, while absence of PGHS1 expression in null mice delayed OTR induction and the programmed decrease of serum progesterone during parturition. Thus, extensive but tissue-dependent variability in PG suppression, as occurs with low-dose aspirin treatment, prevents thrombosis and impairs the inflammatory response but sustains parturition. PGHS1(Neo/Neo) mice provide a model of low-dose aspirin therapy that elucidates how prevention or delay of preeclampsia might be achieved without compromising reproductive function.
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PMID:Differential impact of prostaglandin H synthase 1 knockdown on platelets and parturition. 1577 9

Given the expanding role of ambulatory surgery and the need to facilitate an earlier hospital discharge, improving postoperative pain control has become an increasingly important issue for all anesthesiologists. As a result of the shift from inpatient to outpatient surgery, the use of IV patient-controlled analgesia and continuous epidural infusions has steadily declined. To manage the pain associated with increasingly complex surgical procedures on an ambulatory or short-stay basis, anesthesiologists and surgeons should prescribe multimodal analgesic regimens that use non-opioid analgesics (e.g., local anesthetics, nonsteroidal antiinflammatory drugs, cyclooxygenase inhibitors, acetaminophen, ketamine, alpha 2-agonists) to supplement opioid analgesics. The opioid-sparing effects of these compounds may lead to reduced nausea, vomiting, constipation, urinary retention, respiratory depression and sedation. Therefore, use of non-opioid analgesic techniques can lead to an improved quality of recovery for surgical patients.
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PMID:The changing role of non-opioid analgesic techniques in the management of postoperative pain. 1633 89

Although a putative role has been attributed to inflammation in the pathogenesis of depressive disorders, the relationship of prostaglandins, known mediators of inflammation, and depression has not been elucidated. Clomipramine is an antidepressive drug with a pro-depressive paradoxical effect in adult rats when administrated neonatally. Using this effect as a model of depression, we investigated the differential expression of the cyclooxygenase (COX-2) gene in rat brains. Rats injected neonatally with clomipramine showed depressive-like symptoms in adulthood, as well as decreased levels of the brain-derived neurotrophic factor (BDNF) and a quantitative differential expression of the COX-2 gene (Real Time PCR) and protein (immunohistochemistry) in the hippocampus. As evidenced, the relationship between a key enzyme in the prostaglandin synthesis and biological and behavioral depression-like changes opens an interesting line of investigation regarding the molecular bases of depression and its potential treatment through immunomodulatory drugs.
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PMID:Hippocampal upregulation of the cyclooxygenase-2 gene following neonatal clomipramine treatment (a model of depression). 1656 49

Licofelone is an analogue of arachidonic acid that inhibits 5-lipoxygenase (LOX), cyclooxygenase (COX)-1 and COX-2. We investigated the effects of licofelone on cardiovascular derangements and production of thromboxane (Tx)A(2) induced by the inflammatory agonist n-formyl-methionyl-leucyl-phenylalanine (fMLP) in the rabbit, in comparison with those of aspirin or rofecoxib, inhibitors of COX-1 and COX-2, respectively. In control rabbits, injection of fMLP (30 nmol/kg) in the jugular vein evokes ischemic electrocardiographic (ECG) changes in the first 1-5 min, i.e. a profound depression of the ST segment and inversion of the T wave. Simultaneously, fMLP induces bradycardia and hypotension and increases TxB(2) blood levels. All changes are transient. Licofelone (60 mg/kg/5 days, p.os) prevented fMLP-induced ECG ischemic changes in all treated animals, reverted bradycardia and hypotension, and significantly reduced TxB(2). Aspirin (10 mg/kg/5 days, p.os) prevented ischemic ECG alterations in 2 out of 5 treated animals and did not modify either bradycardia or hypotension. One rabbit died two min after fMLP. In 2 rabbits, aspirin reduced TxB(2) levels by more than 80% respect to mean control values; the remaining two rabbits produced an amount of TxB(2) similar to controls. These two rabbits also showed ischemic ECG changes. Rofecoxib (10 mg/kg/5 days, p.os) did not prevent fMLP-induced ischemic ECG alteration, bradycardia and hypotension, and did not significantly modify the increase of TxB(2). These results indicate that the capacity of licofelone to efficiently suppress TxA(2) production, is responsible for the protection from the cardiovascular derangement triggered by an inflammatory stimulus.
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PMID:The lipoxygenase-cyclooxygenase inhibitor licofelone prevents thromboxane A2-mediated cardiovascular derangement triggered by the inflammatory peptide fMLP in the rabbit. 1692 97

Selective inhibitors of cyclooxygenase (COX)-2 were developed to improve the safety of anti-inflammatory therapy in patients at elevated risk for gastrointestinal complications which are thought to be caused primarily by depression of COX-1 derived mucosal prostanoids. They were not expected to be more efficacious analgesics than compounds acting on both cyclooxygenases, the traditional (t) non-steroidal antiinflammatory drugs (NSAIDs). While these predictions were generally supported by clinical evidence, an elevated rate of severe cardiovascular complications was observed in randomized controlled trials of three chemically distinct COX-2 selective compounds. The cardiovascular hazard is plausibly explained by the depression of COX-2 dependent prostanoids formed in vasculature and kidney; vascular prostacyclin (PGI2) constrains the effect of prothrombotic and atherogenic stimuli, and renal medullary prostacyclin and prostaglandin (PG) E(2) formed by COX-2 contribute to arterial pressure homeostasis. A drug development strategy more closely linking research into the biology of the drug target with clinical drug development may have allowed earlier recognition of these mechanisms and the cardiovascular risk of COX-2 inhibition. Open questions are i) whether the gastrointestinal benefit of COX-2 selective compounds drugs can be conserved by identifying individuals at risk and excluding them from treatment; ii) whether the risk extends to tNSAIDs; iii) and whether alternative strategies to anti-inflammatory therapy with a more advantageous risk-benefit profile can be developed.
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PMID:The pharmacology of selective inhibition of COX-2. 1700 12


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