RESUMEN
Stroke represents the leading cause of disability and mortality amongst the elderly worldwide. Multiple risk factors, including both genetic and non-genetic components, as well as their interactions, are proposed as etiological factors involved in the development of ischemic stroke (IS). Promoter polymorphisms of the IL-6-174G/C (rs1800795) and TNF-α-308G/A (rs1800629) genes have been considered as predictive risk factors of IS; however, these have not yet been evaluated in a Thai population. The aims of this study were to investigate the association of IL-6-174G/C and TNF-α-308G/A polymorphisms with IS. Genomic DNA from 200 patients with IS and 200 controls were genotyped for IL-6-174G/C and TNF-α-308G/A polymorphisms using TaqMan™ SNP genotyping and quantitative PCR-high resolution melting analysis, respectively. It was found that the TNF-α-308 A allele was significantly associated with an increased risk of IS development compared with the G allele [odds ratio (OR)=2.044; 95% CI=1.154-3.620; P=0.014]. Moreover, the IS risk was significantly higher in the presence of TNF-α-308 GA or AA genotypes compared with that in the presence of GG genotypes with a dominant inheritance (OR=1.971; 95% CI=1.080-3.599; P=0.027). However, there was no association between IL-6-174G/C and the risk of IS development. The interaction study demonstrated that IL-6-174 GG and TNF-α-308 GG genotypes enhanced IS susceptibility when combined with hypertension, hyperlipidemia and alcohol consumption. Hypertensive and hyperlipidemic subjects with the TNF-α-308 GA and AA genotypes were more likely to develop IS compared with those who did not have these two conditions and had the GG genotype. In a matched study design (1:1), the IL-6-174 GC genotype was associated with higher IL-6 levels in the control group. Collectively, the present results highlight the utility of the TNF-α-308G/A polymorphism as a predictive genetic risk factor for development of IS.
RESUMEN
Trienones are curcuminoid analogues and are minor constituents in the rhizomes of numerous Curcuma plant species. Studies investigating the biological activities of trienones, particularly their antiinflammatory activities, are limited. In the present study, the trienone 1,7bis(4hydroxy3methoxyphenyl)1,4,6heptatrien3one (HMPH) was structurally modified from curcumin using a novel and concise method. HMPH was shown to exhibit potential antiinflammatory effects on lipopolysaccharide (LPS)activated RAW264.7 macrophages. Furthermore, LPSinduced nitric oxide secretion in RAW264.7 cells was markedly and dosedependently inhibited by HMPH; in addition, HMPH had a greater efficacy compared with curcumin. This inhibition was accompanied by the suppression of inducible nitric oxide synthase and cyclooxygenase2 expression, as well as proinflammatory cytokine secretion. To elucidate the molecular mechanism underlying the antiinflammatory effects of HMPH, the effects of this compound on nuclear factorκB (NFκB) translocation were assessed. HMPH significantly inhibited the translocation of p65 NFκB into the nucleus to a greater extent than curcumin, thus indicating that HMPH has more potent antiinflammatory activity than curcumin. In addition, an in silico modelling study revealed that HMPH possessed stronger binding energy to myeloid differentiation factor 2 (MD2) compared with that of curcumin, and indicated that the antiinflammatory effects of HMPH may be through upstream inhibition of the inflammatory pathway. In conclusion, HMPH may be considered a promising compound for reducing inflammation via targeting p65 NFκB translocation and interfering with MD2 binding.
Asunto(s)
Curcumina/análogos & derivados , Lipopolisacáridos/toxicidad , Antígeno 96 de los Linfocitos , Macrófagos/metabolismo , Factor de Transcripción ReIA , Animales , Curcumina/farmacología , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Antígeno 96 de los Linfocitos/química , Antígeno 96 de los Linfocitos/metabolismo , Macrófagos/patología , Ratones , Células RAW 264.7 , Factor de Transcripción ReIA/química , Factor de Transcripción ReIA/metabolismoRESUMEN
The assessment of muscle strength by hand grip strength (HGS) is used to evaluate muscle weakness and wasting among stroke patients. This study aimed to investigate the association of oxidative stress/oxidative damage and inflammatory biomarkers with muscle strength and wasting, as evaluated by HGS, among community-dwelling post-stroke patients. The HGS of both paretic and non-paretic limbs was negatively associated with modified Rankin scale (mRS) values. The serum levels of catalase activity and malondialdehyde (MDA), and plasma tumor necrosis factor (TNF)-α levels were significantly increased in post-stroke patients compared with non-stroke controls. Further analysis highlighted that hydrogen peroxide was positively correlated with HGS in the paretic limbs. Interestingly, an elevated MDA level, excluding advanced age and high mRS, increased the risk of low HGS in the non-paretic limbs of stroke patients. This study suggests that there is a detrimental association between MDA and muscle strength and early muscle wasting among post-stroke patients. Hence, MDA is a potentially useful biomarker of muscle weakness and wasting in post-stroke patients living in the community.