The present study investigates the effect of strawberry antioxidants in beverage form on meal-induced postprandial inflammatory and insulin responses in human subjects. Overweight adults (n 24) consumed a high-carbohydrate, moderate-fat meal (HCFM) accompanied by either a strawberry or a placebo beverage in a cross-over design. Postprandial changes in plasma anthocyanins, their metabolites, insulin, glucose and inflammatory markers were assessed for 6 h. The postprandial concentrations of pelargonidin sulfate and pelargonidin-3-O-glucoside were significantly increased when the strawberry beverage was consumed concurrently with the HCFM compared with the placebo beverage (P,0·001). The strawberry beverage significantly attenuated the postprandial inflammatory response as measured by high-sensitivity C-reactive protein and IL-6 (P,0·05) induced by the HCFM. It was also associated with a reduction in postprandial insulin response (P,0·05). Collectively, these data provide evidence for favourable effects of strawberry antioxidants on postprandial inflammation and insulin sensitivity.

Objective-Proinflammatory mediators influence atherosclerosis by inducing adhesion molecules (eg, VCAM-1) on endothelial cells (ECs) via signaling intermediaries including p38 MAP kinase. Regions of arteries exposed to high shear stress are protected from inflammation and atherosclerosis, whereas low-shear regions are susceptible. Here we investigated whether the transcription factor Nrf2 regulates EC activation in arteries. Methods and Results-En face staining revealed that Nrf2 was activated in ECs at an atheroprotected region of the murine aorta where it negatively regulated p38 -VCAM-1 signaling, but was expressed in an inactive form in ECs at an atherosusceptible site. Treatment with sulforaphane, a dietary antioxidant, activated Nrf2 and suppressed p38 -VCAM-1 signaling at the susceptible site in wild-type but not Nrf2 Ϫ/Ϫ animals, indicating that it suppresses EC activation via Nrf2. Studies of cultured ECs revealed that Nrf2 inactivates p38 by suppressing an upstream activator MKK3/6 and by enhancing the activity of the negative regulator MKP-1. Key Words: Nrf2 Ⅲ arterial endothelium Ⅲ shear stress Ⅲ sulforaphane Ⅲ proinflammatory activation Ⅲ p38 Ⅲ MKK3/6 Ⅲ MKP-1 E arly atherosclerotic lesions contain monocytes and T-lymphocytes which are recruited from the circulation by adhesion to activated vascular endothelial cells (ECs). 1 This process is triggered by proinflammatory mediators (eg, TNF␣) which induce cellular adhesion molecules (eg, VCAM-1) via signaling intermediaries including p38 mitogen-activated protein (MAP) kinase, which is activated by phosphorylation by MAP kinase kinases 3 and 6 (MKK 3/6). 2,3 Vascular inflammation and atherosclerosis develop predominantly at distinct sites of the arterial tree located near branches and bends which are exposed to nonuniform blood flow, which exerts relatively low shear stress on vascular endothelium, whereas regions of arteries that are exposed to unidirectional high shear stress are protected. 4 -6 Proinflammatory activation of ECs is reduced at high-shear sites compared to low-shear regions, thus providing a potential explanation for the distinct spatial localization of vascular inflammation and lesion formation. 5,7-10 Similarly, the application of unidirectional high shear stress can suppress proinflammatory activation of cultured ECs, whereas low or oscillatory shear can act as a positive regulator of EC activation. 5,10 -15 The molecular mechanisms underlying the antiinflammatory effects of shear stress are uncertain, but previous studies of cultured cells have suggested a role for the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). 16 -20 In unstimulated cells, Nrf2 is suppressed by kelch-like ECH-associated protein 1 (Keap1) which targets it for ubiquitination and proteasomal processing. Nrf2 can be activated by shear stress, dietary antioxidants (eg, sulforaphane) and other physiological stimuli which disrupt Keap1-Nrf2 interactions leading to stabilization and nuclear translocation of Nrf2. 16 -22 A previous study...

A variety of mouse models have been used to study the pathogenesis of pulmonary emphysema/chronic obstructive pulmonary disease. The effect of cigarette smoke (CS) is believed to be strain dependent, because certain mouse strains are more susceptible or resistant to development of emphysema. However, the molecular basis of susceptibility of mouse strains to effects of CS is not known. We investigated the effect of CS on lungs of most of the commonly used mouse strains to study the molecular mechanism of susceptibility to effects of CS. C57BL/6J, A/J, AKR/J, CD-1, and 129SvJ mice were exposed to CS for 3 consecutive days, and various parameters of inflammatory and oxidative responses were assessed in lungs of these mice. We found that the C57BL/6J strain was highly susceptible, the A/J, AKR/J, and CD-1 strains were moderately susceptible, and the 129SvJ strain was resistant to lung inflammatory and oxidant responses to CS exposure. The mouse strain that was more susceptible to effects of CS showed augmented lung inflammatory cell influx, activation of NF-kappaB and p38 MAPK, and increased levels of matrix metalloproteinase-9 and NF-kappaB-dependent proinflammatory cytokines compared with resistant mouse strains. Similarly, decreased levels of glutathione were associated with increased levels of lipid peroxidation products in susceptible mouse strains compared with resistant strains. Hence, we identified the susceptible and resistant mouse strains on the basis of the pattern of inflammatory and oxidant responses. Identification of sensitive and resistant mouse strains could be useful for studying the molecular mechanisms of effects of CS on inflammation and pharmacological interventional studies in CS-exposure mouse models.

A sustained pro-inflammatory state is a major contributing factor in chronic disease development, progression, and complication, including the most commonly known diseases: cardiovascular disease, Alzheimer's, and type 2 diabetes. Fruits, such as berries, contain polyphenol compounds purported to have anti-inflammatory activity in humans. Among the most notable polyphenols in berries are anthocyanins, responsible for their distinctive colors of red, blue, and purple. Berries have been studied widely for their antioxidant properties; however, preclinical data suggest important effects on inflammatory pathways. Correspondingly, the effects of berries, including extracts and purified anthocyanins, have been the subject of a number of human trials. This review aims to evaluate the current state of the human science on berry (products) as a source of dietary polyphenols, particularly anthocyanins, to modulate inflammatory status. Identifying dietary strategies that manage the modern-day inflammatory burden has important implications for chronic disease risk reduction and informing dietary guidelines aimed at achieving and maintaining health.

Underlying etiological factors in the development of obesity-related chronic diseases are long-term imbalances of oxidative and inflammatory stress leading to tissue dysfunction, damage, and ultimately failure. Poor dietary quality contributes significantly to the oxidative and inflammatory status of an individual. Conversely, various dietary approaches, including specific dietary factors can mitigate or prevent the occurrence of these risk-conferring imbalances brought about by modern lifestyle. Plant-derived polyphenolic compounds are well known for their antioxidant properties. Recent evidence indicates these compounds may confer anti-inflammatory and/or inflammatory response stabilizing activities, which would have important implications in health maintenance and disease risk reduction. Commonly consumed fruits, such as grapes, berries, and oranges/orange juice, contain polyphenolic compounds that have been studied for their effects on inflammation, but the nature and extent of their effects in humans remain unclear. Therefore, this article aims to provide a comprehensive overview of human clinical trials investigating the acute and chronic (feeding) effect of polyphenols from commonly consumed fruits or their derived products on inflammation.

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Oxidative stress has been implicated in the pathogenesis of several inflammatory lung disorders including chronic obstructive pulmonary disease (COPD) due to its effect on pro-inflammatory gene transcription. Cigarette smoke-mediated oxidative stress activates NF-κB-dependent transcription of pro-inflammatory mediators either through activation of inhibitor κB-α kinase (IKK) and/or the enhanced recruitment and activation of transcriptional co-activators. Enhanced NF-κB-co-activator complex formation results in targeted increase in chromatin modifications, such as histone acetylation leading to inflammatory gene transcription. NF-κB-dependent gene expression, at least in part, is regulated by changes in deacetylases such as histone deacetylases (HDACs) and sirtuins. Cigarette smoke and oxidants also alter the levels/activity of HDAC by post-translational modifications and in doing so further induces gene expression of pro-inflammatory mediators. In addition, cigarette smoke/oxidants can reduce glucocorticoid sensitivity by attenuating HDAC2 activity and expression, which may account for the glucocorticoid insensitivity in patients with COPD. Understanding the mechanisms of NF-κB regulation, and the balance between histone acetylation and deacetylation may lead to the development of novel therapies based on the pharmacological manipulation of IKK and deacetylases in lung inflammation and injury.

Cigarette smoke (CS) induces abnormal and sustained lung inflammation; however, the molecular mechanism underlying sustained inflammation is not known. It is well known that activation of I kappaB kinase beta (IKK beta) leads to transient translocation of active NF-kappaB (RelA/p65-p50) in the nucleus and transcription of pro-inflammatory genes, whereas the role of IKK alpha in perpetuation of sustained inflammatory response is not known. We hypothesized that CS activates IKK alpha and causes histone acetylation on the promoters of pro-inflammatory genes, leading to sustained transcription of pro-inflammatory mediators in mouse lung in vivo and in human monocyte/macrophage cell line (MonoMac6) in vitro. CS exposure to C57BL/6J mice resulted in activation of IKK alpha, leading to phosphorylation of ser10 and acetylation of lys9 on histone H3 on the promoters of IL-6 and MIP-2 genes in mouse lung. The increased level of IKK alpha was associated with increased acetylation of lys310 RelA/p65 on pro-inflammatory gene promoters. The role of IKK alpha in CS-induced chromatin modification was confirmed by gain and loss of IKK alpha in MonoMac6 cells. Overexpression of IKK alpha was associated with augmentation of CS-induced pro-inflammatory effects, and phosphorylation of ser10 and acetylation of lys9 on histone H3, whereas transfection of IKK alpha dominant-negative mutants reduced CS-induced chromatin modification and pro-inflammatory cytokine release. Moreover, phosphorylation of ser276 and acetylation of lys310 of RelA/p65 was augmented in response to CS extract in MonoMac6 cells transfected with IKK alpha. Taken together, these data suggest that IKK alpha plays a key role in CS-induced pro-inflammatory gene transcription through phospho-acetylation of both RelA/p65 and histone H3.