Influence of non-steroidal anti-inflammatory drugs on Drosophila melanogaster longevity.
ABSTRACT: Most age-related diseases and aging itself are associated with chronic inflammation. Thus pharmacological inhibition of inflammatory processes may be effective antiaging strategy. In this study we demonstrated that treatment of Drosophila melanogaster with 10 non-steroidal anti-inflammatory drugs (NSAIDs: CAY10404, aspirin, APHS, SC-560, NS-398, SC-58125, valeroyl salicylate, trans-resveratrol, valdecoxib, licofelone) leads to extension of lifespan, delays age-dependent decline of locomotor activity and increases stress resistance. The effect of the lifespan increase was associated with decrease of fecundity. Depending on the concentration, NSAIDs demonstrated both anti- and pro-oxidant properties in Drosophila tissues. However, we failed to identify clear correlation between antioxidant properties of NSAIDs and their pro-longevity effects. The lifespan extending effects of APHS, SC-58125, valeroyl salicylate, trans-resveratrol, valdecoxib, and licofelone were more pronounced in males, valdecoxib and aspirin - in females. We demonstrated that lifespan extension effect of NSAIDs was abolished in flies with defective genes involved in Pkh2-ypk1-lem3-tat2 pathway.
Project description:Compared with other non-steroid anti-inflammatory drugs (NSAIDs), aspirin is not correlated to hypertension. It has been shown that aspirin has unique vasodilator action in vivo, offering an explanation for the unique blood pressure effect of aspirin. In the present study, we investigate the mechanism whereby salicylates (aspirin and sodium salicylate) dilate blood vessels.Rat aortic or mesenteric arterial rings were used to test the vascular effect of salicylates and other NSAIDs. RhoA translocation and the phosphorylation of MYPT1, the regulatory subunit of myosin light chain phosphatase, were measured by western blot, as evidenced for RhoA/Rho-kinase activation. Salicylates, but not other NSAIDs, relaxed contraction induced by most tested constrictors except for calyculin A, indicating that RhoA/Rho-kinase-mediated calcium sensitization is involved. The involvement of RhoA/Rho kinase in vasodilation by salicylates was confirmed by measurements of RhoA translocation and MYPT1 phosphorylation. The calculated half maximal inhibitory concentration (IC(50)) of vasodilation was apparently higher than that of cyclooxygenase inhibition, but comparable to that of proline-rich tyrosine kinase 2 (PYK2) inhibition. Over-expression of PYK2 induced RhoA translocation and MYPT1 phosphorylation, and these effects were markedly inhibited by sodium salicylate treatment. Consistent with the ex vitro vascular effects, sodium salicylate acutely decreased blood pressure in spontaneous hypertensive rats but not in Wistar Kyoto rats.Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation and thus lower blood pressure.
Project description:Substantial efforts are underway for prevention of early stages or recurrence of colorectal cancers (CRC) or new polyp formation by chemoprevention strategies. Several epidemiological, clinical and preclinical studies to date have supported the chemopreventive potentials of several targeted drug classes including non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin, naproxen, sulindac, celecoxib, and licofelone), statins and other natural agents-both individually, and in combinations. Most preclinical trials although were efficacious, only few agents entered clinical trials and have been proven to be potential chemopreventive agents for colon cancer. However, there are limitations for these agents that hinder their approval by the food and drug administration for chemoprevention use in high-risk individuals and in patients with early stages of CRC. In this review, we update the recent advancement in pre-clinical and clinical development of selected anti-inflammatory agents (aspirin, naproxen, sulindac, celecoxib, and licofelone) and their combinations for further development as novel colon cancer chemopreventive drugs. We provide further new perspectives from this old research, and insights into precision medicine strategies to overcome unwanted side-effects and overcoming strategies for colon cancer chemoprevention.
Project description:Tetraploidy constitutes a genomically metastable state that can lead to aneuploidy and genomic instability. Tetraploid cells are frequently found in preneoplastic lesions, including intestinal cancers arising due to the inactivation of the tumor suppressor adenomatous polyposis coli (APC). Using a phenotypic screen, we identified resveratrol as an agent that selectively reduces the fitness of tetraploid cells by slowing down their cell cycle progression and by stimulating the intrinsic pathway of apoptosis. Selective killing of tetraploid cells was observed for a series of additional agents that indirectly or directly stimulate AMP-activated protein kinase (AMPK) including salicylate, whose chemopreventive action has been established by epidemiological studies and clinical trials. Both resveratrol and salicylate reduced the formation of tetraploid or higher-order polyploid cells resulting from the culture of human colon carcinoma cell lines or primary mouse epithelial cells lacking tumor protein p53 (TP53, best known as p53) in the presence of antimitotic agents, as determined by cytofluorometric and videomicroscopic assays. Moreover, oral treatment with either resveratrol or aspirin, the prodrug of salicylate, repressed the accumulation of tetraploid intestinal epithelial cells in the Apc(Min/+) mouse model of colon cancer. Collectively, our results suggest that the chemopreventive action of resveratrol and aspirin involves the elimination of tetraploid cancer cell precursors.
Project description:BACKGROUND AND PURPOSE: Deletion of the cyclooxygenase-2 (COX-2) gene causes impairment of kidney development, but the effect of selective inhibitors of COX-2 (coxibs) or the non-selective inhibitors of COX (the classical non-steroidal anti-inflammatory drugs; NSAIDs) on kidney development was less well described. EXPERIMENTAL APPROACH: We assessed the effects of equipotent analgesic doses of celecoxib, rofecoxib, valdecoxib, etoricoxib and lumiracoxib and of the NSAIDs, diclofenac and naproxen, on postpartum kidney development in mice, from postnatal day 1 (P1) to P21. KEY RESULTS: All the COX inhibitors, at the doses used, blocked COX-2 activity by more than 80% as assayed by PGE(2) synthesis in lipopolysaccharide-stimulated mouse blood samples. Rofecoxib, etoricoxib and lumiracoxib exerted the most marked impairment of postpartum kidney development, demonstrated by attenuation of kidney growth, reduction in size of glomeruli, increase in immature superficial glomeruli, thinning of subcapsular cortical mass and reduction in size of juxtamedullary glomeruli. These defects were less severe than those in kidneys from COX-2(-/-) mice. Administration of diclofenac and naproxen revealed renal defects similar to those after coxib treatment, but both NSAIDs induced greater arrest of immature superficial glomeruli in the outer cortex and increased the number of undifferentiated proliferating cell nuclear antigen-positive cells. Treatment with celecoxib or valdecoxib caused only minimal changes in renal morphology. CONCLUSIONS AND IMPLICATIONS: Classical NSAIDs cause similar or even stronger nephrodysgenesis than the coxibs. Also, the ranking of coxibs regarding adverse effects on renal development, using equi-analgesic doses, is rofecoxib = etoricoxib = lumiracoxib > valdecoxib > celecoxib.
Project description:Although studies have examined the association between nonsteroidal anti-inflammatory drugs (NSAIDs) use and central nervous system (CNS) tumors risk, the results are inconclusive. Here, we conducted a dose-response meta-analysis in order to investigate the correlation between NSAIDs use and CNS tumors risk. Up to July 2017, 12 studies were included in current meta-analysis. NSAIDs use was significantly associated with a lower risk of CNS tumors. Furthermore, non-aspirin NSAIDs or aspirin use are significantly associated with a lower risk of CNS tumors. Additionally, NSAIDs use was associated with significantly a lower risk of glioma, glioblastoma but not meningioma. Subgroup analysis showed consistent findings. Furthermore, a significant dose-response relationship was observed between NSAIDs use and CNS tumors risk. Increasing cumulative 100 defined daily dose of NSAIDs use was associated with a 5% decrement of CNS tumors risk, increasing NSAIDs or non-aspirin NSAIDs or aspirin use (per 3 prescriptions increment) was associated with a 7%, 7%, 10% decrement of CNS tumors risk, increasing per 2 year of duration of NSAIDs or non-aspirin NSAIDs or aspirin use was associated with a 6%, 8%, 6% decrement of CNS tumors risk. Considering these promising results, NSAIDs use might provide helpful for reducing CNS tumors risk. Large sample size and different ethnic population are warranted to validate this association.
Project description:Salicylate, a plant product, has been in medicinal use since ancient times. More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both of which are rapidly broken down to salicylate in vivo. At concentrations reached in plasma after administration of salsalate or of aspirin at high doses, salicylate activates adenosine monophosphate-activated protein kinase (AMPK), a central regulator of cell growth and metabolism. Salicylate binds at the same site as the synthetic activator A-769662 to cause allosteric activation and inhibition of dephosphorylation of the activating phosphorylation site, threonine-172. In AMPK knockout mice, effects of salicylate to increase fat utilization and to lower plasma fatty acids in vivo were lost. Our results suggest that AMPK activation could explain some beneficial effects of salsalate and aspirin in humans.
Project description:<label>BACKGROUND</label>Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used despite their risk of gastrointestinal bleeding or cardiovascular events. We report the profile of people taking NSAIDs in Spain, and we include demographic factors, health-related behaviours and cardiovascular disease history.<label>METHODS</label>Four thousand sixtyparticipants were selected using a pseudorandom number list from Family Practice lists in 12 Spanish provinces. They completed a face-to-face computerized interview on their NSAID consumption, demographic characteristics, body mass index, alcohol and tobacco consumption and medical history. In addition, participants completed a self-administered food-frequency and alcohol consumption questionnaire. Factors associated with ever and current NSAID consumption were identified by logistic regression.<label>RESULTS</label>Women consumed more non-aspirin NSAIDs (38.8% [36.7-41.0]) than men (22.3 [20.5-24.2]), but men consumed more aspirin (11.7% [10.3-13.2]) than women (5.2% [4.3-6.3]). Consumption of non-aspirin NSAIDs decrease with age from 44.2% (39.4-49.1) in younger than 45 to 21.1% (18.3-24.2) in older than 75, but the age-pattern for aspirin usage was the opposite. Aspirin was reported by about 11% patients, as being twice as used in men (11.7%) than in women (5.2%); its consumption increased with age from 1.7% (<?45 years old) to 12.4% (?75 years old). Aspirin was strongly associated with the presence of cardiovascular risk factors or established cardiovascular disease, reaching odds ratios of 15.2 (7.4-31.2) in women with acute coronary syndrome, 13.3 (6.2-28.3) in women with strokes and 11.1 (7.8-15.9) in men with acute coronary syndrome. Participants with cardiovascular risk factors or diseases consumed as much non-aspirin NSAID as participants without such conditions.<label>CONCLUSIONS</label>Non-aspirin NSAIDs were more consumed by women and aspirin by men. The age patterns of aspirin and non-aspirin NSAIDs were opposite: the higher the age, the lower the non-aspirin NSAIDs usage and the higher the aspirin consumption. People with cardiovascular risk factors or diseases consumed more aspirin, but they did not decrease their non-aspirin NSAIDs usage.
Project description:There is little evidence on whether non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin interact in secondary cardiovascular prevention in type 2 diabetic patients. This is an observational study using data from the Action to Control Cardiovascular Risk in Diabetes and Follow-on studies. Hazard ratios (HRs) for mortality with 95% confidence intervals (95% CIs) were calculated using Cox proportional hazard models to compare time to death in patients using and not using aspirin who were simultaneously using or not using NSAIDs. A total of 3600 type 2 diabetic patients with cardiovascular disease were included. During a mean follow-up period of 8.8 years, 948 patients died. After adjustments, the risk of all-cause mortality in patients not using NSAIDs was significantly lower in those using aspirin than in those not using aspirin (HR, 0.81; 95% CI, 0.70-0.93; P = 0.004). The risk in patients using NSAIDs did not differ significantly between the two groups. There was a significant interaction between aspirin use and NSAIDs use. In type 2 diabetic patients with cardiovascular disease, aspirin use was not beneficial for those using NSAIDs.
Project description:Use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of gastric or oesophageal adenocarcinomas. We examined the association between self-reported use of aspirin or non-aspirin NSAIDs in the earlier 12 months and gastric non-cardia (N=182), gastric cardia (N=178), and oesophageal adenocarcinomas (N=228) in a prospective cohort (N=311 115) followed for 7 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) come from Cox models adjusted for potential confounders. Use of any aspirin (HR, 95% CI: 0.64, 0.47-0.86) or other NSAIDs (0.68, 0.51-0.92) was associated with a significantly lower risk of gastric non-cardia adenocarcinoma. Neither aspirin (0.86, 0.61-1.20) nor other NSAIDs (0.91, 0.67-1.22) had a significant association with gastric cardia cancer. We found no significant association between using aspirin (1.00, 0.73-1.37) or other NSAIDs (0.90, 69-1.17) and oesophageal adenocarcinoma. We also performed a meta-analysis of the association between the use of NSAIDs and risk of gastric and oesophageal adenocarcinoma. In this analysis, aspirin use was inversely associated with both gastric and oesophageal adenocarcinomas, with summary odds ratios (95% CI) for non-cardia, cardia, and oesophageal adenocarcinomas of 0.64 (0.52-0.80), 0.82 (0.65-1.04), and 0.64 (0.52-0.79), respectively. The corresponding numbers for other NSAIDs were 0.68 (0.57-0.81), 0.80 (0.67-0.95), and 0.65 (0.50-0.85), respectively.
Project description:Abnormal vascular smooth muscle cell (VSMC) proliferation contributes to occlusive and proliferative disorders of the vessel wall. Salicylate and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit VSMC proliferation by an unknown mechanism unrelated to anti-inflammatory activity. In search for this mechanism, we have studied the effects of salicylate and other NSAIDs on subcellular Ca(2+) homeostasis and Ca(2+)-dependent cell proliferation in rat aortic A10 cells, a model of neointimal VSMCs. We found that A10 cells displayed both store-operated Ca(2+) entry (SOCE) and voltage-operated Ca(2+) entry (VOCE), the former being more important quantitatively than the latter. Inhibition of SOCE by specific Ca(2+) released-activated Ca(2+) (CRAC/Orai) channels antagonists prevented A10 cell proliferation. Salicylate and other NSAIDs, including ibuprofen, indomethacin, and sulindac, inhibited SOCE and thereby Ca(2+)-dependent, A10 cell proliferation. SOCE, but not VOCE, induced mitochondrial Ca(2+) uptake in A10 cells, and mitochondrial depolarization prevented SOCE, thus suggesting that mitochondrial Ca(2+) uptake controls SOCE (but not VOCE) in A10 cells. NSAIDs depolarized mitochondria and prevented mitochondrial Ca(2+) uptake, suggesting that they favor the Ca(2+)-dependent inactivation of CRAC/Orai channels. NSAIDs also inhibited SOCE in rat basophilic leukemia cells where mitochondrial control of CRAC/Orai is well established. NSAIDs accelerate slow inactivation of CRAC currents in rat basophilic leukemia cells under weak Ca(2+) buffering conditions but not in strong Ca(2+) buffer, thus excluding that NSAIDs inhibit SOCE directly. Taken together, our results indicate that NSAIDs inhibit VSMC proliferation by facilitating the Ca(2+)-dependent inactivation of CRAC/Orai channels which normally is prevented by mitochondria clearing of entering Ca(2+).