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Inflammation is a hallmark of many diseases, such as atherosclerosis, chronic obstructive pulmonary disease, arthritis, infectious diseases, and cancer. Although steroids and cyclooxygenase inhibitors are effective antiinflammatory therapeutical agents, they may cause serious side effects. Therefore, developing unique antiinflammatory agents without significant adverse effects is urgently needed. Vinpocetine, a derivative of the alkaloid vincamine, has long been used for cerebrovascular disorders and cognitive impairment. Its role in inhibiting inflammation, however, remains unexplored. Here, we show that vinpocetine acts as an antiinflammatory agent in vitro and in vivo. In particular, vinpocetine inhibits TNF-[alpha]-induced NF-[kappa]B activation and the subsequent induction of proinflammatory mediators in multiple cell types, including vascular smooth muscle cells, endothelial cells, macrophages, and epithelial cells. We also show that vinpocetine inhibits monocyte adhesion and chemotaxis, which are critical processes during inflammation. Moreover, vinpocetine potently inhibits TNF-[alpha]- or LPS-induced up-regulation of proinflammatory mediators, including TNF-[alpha], IL-1[beta], and macrophage inflammatory protein-2, and decreases interstitial infiltration of polymorphonudear leukocytes in a mouse model of TNF-[alpha]- or LPS-induced lung inflammation. Interestingly, vinpocetine inhibits NF-[kappa]B-dependent inflammatory responses by directly targeting IKK, independent of its well-known inhibitory effects on phosphodiesterase and [Ca.sup.2+] regulation. These studies thus identify vinpocetine as a unique antiinflammatory agent that may be repositioned for the treatment of many inflammatory diseases. vinpocetine | inflammation | NF-[kappa]B | IKK www.pnas.org/cgi/doi/10.1073/pnas.0914414107

Long-term administration of angiotensin II causes myocardial loss and cardiac fibrosis. We previously found iron deposition in the heart of the angiotensin II-infused rat, which may promote angiotensin II-induced cardiac damage. In the present study, we have investigated whether an iron chelator (deferoxamine) and a free radical scavenger (T-0970) affect the angiotensin II-induced upregulation of transforming growth factor-[beta]1 (TGF-[beta]1). Angiotensin II infusion for 7 days caused a robust increase in TGF-[beta]1 mRNA expression in vascular smooth muscle cells, myofibroblast-like cells, and migrated monocytes/macrophages. T-0970 and deferoxamine suppressed the upregulation of TGF-[beta]1 mRNA and reduced the extent of cardiac fibrosis in the heart of rats treated with angiotensin II. These agents blocked the angiotensin II-induced upregulation of heine oxygenase-1, a potent oxidative and cellular stress-responsive gene, but they did not significantly affect systolic blood pressure or plasma levels of aldosterone. In addition, T-0970 and deferoxamine suppressed the angiotensin II-induced upregulation of monocyte chemoattractant protein-1 in the heart. These results collectively suggest that iron and the iron-mediated generation of reactive oxygen species may contribute to angiotensin II-induced upregulation of profibrotic and proinflammatory genes, such as TGF-[beta]1 and monocyte chemoattractant protein-1. fibrosis; iron chelator; oxidative stress; aldosterone

For normal glucose homeostasis, insulin release by the pancreatic [Beta] cell is vital. Until recently, it was thought that glucose-induced ionic events, such as closure of the ATP-sensitive [K.sup.+] ([K.sub.ATP]) channels, membrane depolarization, activation of the L-type voltage-dependent [Ca.sup.2+] channels, [Ca.sup.2+] influx and elevation of cytosolic free [Ca.sup.2+], constitute the main signalling pathway in [Beta]-cell stimulus-secretion coupling. However, since the discovery of 'non-ionic' glucose actions in the [Beta] cell by the Aizawa and Henquin laboratories in 1991, data have accumulated that strongly indicate the physiological relevance of this signalling pathway. In this review, Toru Aizawa and colleagues discuss how the [K.sub.ATP] channel-[Ca.sup.2+] hypothesis was formulated, what was overlooked in the hypothesis, and then provide a comprehensive view of stimulus-secretion coupling in the [Beta] cell, with an emphasis on non-ionic glucose actions.