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Green Tea Polyphenols as an Anti-Oxidant and Anti-Inflammatory Agent for Cardiovascular Protection

Our review aims to examine the cellular and molecular mechanisms of cardiovascular protection of green tea polyphenols, particularly epigallocatechin gallate (EGCG), which focuses on the anti-oxidative and anti-inflammatory effects. EGCG is the major and the most active component in green tea. Studies have shown that EGCG protects cellular damage by inhibiting DNA damage and oxidation of LDL. One of the protective properties of EGCG is its ability to scavenge free radicals. EGCG can also reduce the inflammatory response associated with local tissue injuries such as the hepatocellular necrosis in acute liver injury induced by carbon tetrachloride. The protective effect of EGCG is due to its ability to decrease lipid peroxidation, oxidative stress and the production of nitric oxide (NO) radicals by inhibiting the expression of iNOS. EGCG also ameliorates the overproduction of pro-inflammatory cytokines and mediators, reduces the activity of NF-kappaB and AP-1 and the subsequent formation of peroxynitrite with NO and reactive oxygen species. Thus, EGCG effectively mitigates cellular damage by lowering the inflammatory reaction and reducing the lipid peroxidation and NO generated radicals leading to the oxidative stress. Green tea is proposed to be a dietary supplement in the prevention of cardiovascular diseases in which oxidative stress and proinflammation are the principal causes.

Epigallocatechin-3-gallate (EGCG) reduces liver inflammation, oxidative stress and fibrosis in carbon tetrachloride (CCl4)-induced liver injury in mice

The anti-inflammatory and antioxidant effects of epigallocatechin-3-gallate (EGCG) are considered important forces in attenuate liver injury and fibrosis. The aim of the study was to investigate the effect of EGCG on the expression of fibrogenic factors and whether EGCG attenuates the severity of oxidative stress and inflammatory response in chronic liver injury. Mice were administered with CCl(4) together with or without EGCG for 8 weeks (n=6-8 per group). Histopathological and biochemical analyses were carried out. The mRNA expression levels of TNF-alpha, COX-2, iNOS, alpha-smooth muscle actin (alpha-SMA), transforming growth factor (TGF-beta(1)), pro-collagen-I, matrix metalloproteinases (MMP-2, -9) and their inhibitors (TIMP-1, -2) were determined by RT-PCR. The collagen deposited in the liver was detected by Sirius Red staining. The formation of nitrotyrosine was measured as a marker of oxidative stress. The activity level of NF-kappaB and the expression level of C/EBP were also assessed. Chronic CCl(4) treatment caused liver injury, oxidative stress and nitrosative stress, and collagen accumulation in the liver. The expression levels of pro-inflammatory and pro-fibrotic mediators and the activity of NF-kappaB were increased. Treatment with EGCG significantly reduced liver injury, oxidative stress and the inflammatory response. EGCG also significantly reduced the formation of collagen in the liver, the expression of alpha-SMA and all of the assayed pro-fibrogenic markers except TIMP-2 and MMP-9. EGCG significantly attenuated the severity of CCl(4)-induced liver injury and the progression of liver fibrosis. The protective effect of EGCG may in part be a consequence of the reduction in oxidative stress and the pro-inflammatory response.

Effects of combination of angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist on inflammatory cellular infiltration and myocardial interstitial fibrosis after acute myocardial infarction.

OBJECTIVES The goal of this study was to compare the relative efficacy of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) in suppressing the histopathologic changes that lead to ventricular remodeling after an acute myocardial infarction (AMI). BACKGROUND Myocardial interstitial fibrosis in the noninfarcted region is a major histologic landmark resulting in cardiac dysfunction after AMI. However, the relative potency of an ACE inhibitor and ARB on suppressing the histopathologic changes was unclear. METHODS Rats with AMI were randomized to fosinopril, valsartan or a combination of the two drugs for two or four weeks. The total, type I and type III collagen and activated fibroblasts and macrophages were quantified by histomorphometry. The expression of transforming growth factor-beta 1 (TGF-beta 1) messenger ribonucleic acid (mRNA) was determined by reverse transcription polymerase chain reaction. RESULTS Acute myocardial infarction resulted in significant elevation of total (p < 0.001) and type I (p < 0.001) collagen and a twofold increase in TGF-beta 1 mRNA expression (p < 0.001) in the septum at two and four weeks. Macrophages and activated myofibroblasts infiltrated extensively in the infarct zone. Treatment with valsartan or combination therapy normalized the total and type I collagen (p < 0.001) as well as TGF-beta 1 mRNA level (p < 0.01) in the septum and was associated with the suppression of macrophages and myofibroblasts in the infarct zone (p < 0.01). Fosinopril was less effective than valsartan or combination therapy. CONCLUSIONS The use of valsartan, especially combined with fosinopril, was more effective than fosinopril in the suppression of histopathologic changes resulting in cardiac remodeling after AMI. This study has important therapeutic implications in pharmacotherapy of clinical practice.

Inhaled fluticasone in bronchiectasis: a 12 month study

Background: The clinical efficacy of inhaled corticosteroid (ICS) treatment has not been evaluated in bronchiectasis, despite the presence of chronic airway inflammation. Methods: After three consecutive weekly visits, 86 patients were randomised to receive either fluticasone 500 μg twice daily (n = 43, 23F, mean (SD) age 57.7 (14.4) years) or matched placebo (n = 43, 34F, 59.2 (14.2) years) and reviewed regularly for 52 weeks in a double blind fashion. Results: 35 and 38 patients in the fluticasone and placebo groups completed the study. Significantly more patients on ICS than on placebo showed improvement in 24 hour sputum volume (OR 2.5, 95% CI 1.1 to 6.0, p = 0.03) but not in exacerbation frequency, forced expiratory volume in 1 second, forced vital capacity, or sputum purulence score. Significantly more patients with Pseudomonas aeruginosa infection receiving fluticasone showed improvement in 24 hour sputum volume (OR 13.5, 95% CI 1.8 to 100.2, p = 0.03) and exacerbation frequency (OR 13.3, 95% CI 1.8 to 100.2, p = 0.01) than those given placebo. Logistic regression models revealed a significantly better response in sputum volume with fluticasone treatment than with placebo among subgroups of patients with 24 hour sputum volume <30 ml (p = 0.04), exacerbation frequency ⩽2/year (p = 0.04), and sputum purulence score >5 (p = 0.03). Conclusions: ICS treatment is beneficial to patients with bronchiectasis, particularly those with P aerurginosa infection.

Exhaled nitric oxide: the effects of age, gender and body size.

Since little is known of the effects of age, gender, and body size on exhaled nitric oxide (NO) production, we have conducted a prospective study to examine these factors in a healthy nonsmoking women (mean age +/- SD 47.7 +/- 15.8, range 20-79 years). Exhaled NO was measured by an automatic chemiluminescence analyzer (Sievers NO Analyser 280) at steady expiration. Men had significantly higher exhaled NO levels than women (p = 0.001). Although exhaled NO levels did not correlate with age (r = 0.12, p = 0.17), it correlated significantly with height (r = 0.23, p = 0.02), weight (r = 0.34, p

Bone Morphogenic Protein-4 Impairs Endothelial Function Through Oxidative Stress–Dependent Cyclooxygenase-2 Upregulation. Implications on Hypertension

Rationale: Bone morphogenic protein (BMP)4 can stimulate superoxide production and exert proinflammatory effects on the endothelium. The underlying mechanisms of how BMP4 mediates endothelial dysfunction and hypertension remain elusive. Objective: To elucidate the cellular pathways by which BMP4-induced endothelial dysfunction is mediated through oxidative stress–dependent upregulation of cyclooxygenase (COX)-2. Methods and Results: Impaired endothelium-dependent relaxations, exaggerated endothelium-dependent contractions, and reactive oxygen species (ROS) production were observed in BMP4-treated mouse aortae, which were prevented by the BMP4 antagonist noggin. Pharmacological inhibition with thromboxane prostanoid receptor antagonist or COX-2 but not COX-1 inhibitor prevented BMP4-induced endothelial dysfunction, which was further confirmed with the use of COX-1−/− or COX-2−/− mice. Noggin and knockdown of BMP receptor 1A abolished endothelium-dependent contractions and COX-2 upregulation in BMP4-treated aortae. Apocynin and tempol treatment were effective in restoring endothelium-dependent relaxations, preventing endothelium-dependent contractions and eliminating ROS overproduction and COX-2 overexpression in BMP4-treated aortae. BMP4 increased p38 mitogen-activated protein kinase (MAPK) activity through a ROS-sensitive mechanism and p38 MAPK inhibitor prevented BMP4-induced endothelial dysfunction. COX-2 inhibition blocked the effect of BMP4 without affecting BMP4-induced ROS overproduction and COX-2 upregulation. Importantly, renal arteries from hypertensive rats and humans showed higher levels of COX-2 and BMP4 accompanied by endothelial dysfunction. Conclusions: We show for the first time that ROS serve as a pathological link between BMP4 stimulation and the downstream COX-2 upregulation in endothelial cells, leading to endothelial dysfunction through ROS-dependent p38 MAPK activation. This BMP4/ROS/COX-2 cascade is important in the maintenance of endothelial dysfunction in hypertension.

Lycium barbarum polysaccharides protect mice liver from carbon tetrachloride-induced oxidative stress and necroinflammation

ETHNOPHARMACOLOGICAL RELEVANCE Lycium barbarum has been used as a traditional Chinese medicine to nourish liver, kidneys and the eyes. AIM OF THE STUDY We investigated the protective mechanisms of Wolfberry, Lycium barbarum polysaccharides (LBP) in carbon tetrachloride (CCl(4))-induced acute liver injury. MATERIALS AND METHODS Mice were intraperitoneally injected with a 50 μl/kg CCl(4) to induce acute hepatotoxicity (8h) and were orally fed with LBP 2 h before the CCl(4) injection. There were six experimental groups of mice (n=7-8 per group), namely: control mice (vehicle only; 1 mg/kg LBP or 10 mg/kg LBP), CCl(4)-treated mice and CCl(4)+LBP treated mice (1 mg/kg LBP or 10 mg/kg LBP). RESULTS Pre-treatment with LBP effectively reduced the hepatic necrosis and the serum ALT level induced by CCl(4) intoxication. LBP remarkably inhibited cytochrome P450 2E1 expression and restored the expression levels of antioxidant enzymes. It also decreased the level of nitric oxide metabolism and lipid peroxidation induced by CCl(4). LBP attenuated hepatic inflammation via down-regulation of proinflammatory mediators and chemokines. Furthermore, LBP promoted liver regeneration after CCl(4) treatment. The protective effects of LBP against hepatotoxicity were partly through the down-regulation of nuclear factor kappa-B activity. CONCLUSION LBP is effective in reducing necroinflammation and oxidative stress induced by a chemical toxin, thus it has a great potential use as a food supplement in the prevention of hepatic diseases.

Hyperinduction of Cyclooxygenase-2-Mediated Proinflammatory Cascade: A Mechanism for the Pathogenesis of Avian Influenza H5N1 Infection

The mechanism for the pathogenesis of H5N1 infection in humans remains unclear. This study reveals that cyclooxygenase-2 (COX-2) was strongly induced in H5N1-infected macrophages in vitro and in epithelial cells of lung tissue samples obtained during autopsy of patients who died of H5N1 disease. Novel findings demonstrated that COX-2, along with tumor necrosis factor alpha and other proinflammatory cytokines were hyperinduced in epithelial cells by secretory factors from H5N1-infected macrophages in vitro. This amplification of the proinflammatory response is rapid, and the effects elicited by the H5N1-triggered proinflammatory cascade are broader than those arising from direct viral infection. Furthermore, selective COX-2 inhibitors suppress the hyperinduction of cytokines in the proinflammatory cascade, indicating a regulatory role for COX-2 in the H5N1-hyperinduced host proinflammatory cascade. These data provide a basis for the possible development of novel therapeutic interventions for the treatment of H5N1 disease, as adjuncts to antiviral drugs.

Suppression of Microglial Activation Is Neuroprotective in a Mouse Model of Human Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a photoreceptor-degenerative disease caused by various mutations and is characterized by death of rod photoreceptor cell followed by gradual death of cone photoreceptors. The molecular mechanisms that lead to rod and cone death are not yet fully understood. Neuroinflammation contributes to the progression of many chronic neurodegenerative disorders. However, it remains to be determined how microglia contribute to photoreceptor disruption in RP. In this study, we explored the role of microglia as a contributor to photoreceptor degeneration in the rd10 mouse model of RP. First, we demonstrated that microglia activation was an early alteration in RP retinas. Inhibition of microglia activation by minocycline reduced photoreceptor apoptosis and significantly improved retinal structure and function and visual behavior in rd10 mice. Second, we identified that minocycline exerted its neuroprotective effects through both anti-inflammatory and anti-apoptotic mechanisms. Third, we found that Cx3cr1 deficiency dysregulated microglia activation and subsequently resulted in increased photoreceptor vulnerability in rd10 mice, suggesting that the Cx3cl1/Cx3cr1 signaling pathway might protect against microglia neurotoxicity. We concluded that suppression of neuroinflammatory responses could be a potential treatment strategy aimed at improving photoreceptor survival in human RP.

Overexpression of matrix metalloproteinase‐8 and ‐9 in bronchiectatic airways in vivo

The progressive bronchial dilatation in bronchiectasis is likely to be the result of continued airway matrix destruction, although little is known about the role of neutrophil matrix metalloproteinases (MMPs) in this process. Immunohistochemistry has been used to investigate the expression and cellular localisation of MMP‐8 and MMP‐9 in bronchiectatic airways in vivo. Endobronchial biopsies were taken from 25 bronchiectatic patients, and from the right lower lobe in 14 control subjects. MMP‐8, MMP‐9, neutrophils and macrophages were stained with monoclonal antibodies and quantified as positive cell·mm−2 of the lamina propria by using an image analysis system. There were significantly higher densities of MMP‐8 and MMP‐9 positive cells in the lamina propria of bronchiectatic than control airways. In bronchiectatic airways, the densities of MMP‐8 and MMP‐9 positive cells correlated with each other and with neutrophil density, but not with macrophage density. In control airways, a significant correlation was found between MMP‐8 with neutrophil and MMP‐9 with macrophage densities. An overexpression of neutrophil matrix metalloproteinases in bronchiectatic airways could help explain the continuation of airway destruction in bronchiectasis. In view of the clinical availability of matrix metalloproteinase antagonists, the results presented here could have a significant impact on the development of novel therapies of this untreatable disease.