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The 5-HT(1A) agonist 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) causes inhibition of caspase-3 and apoptosis via the extracellular signal-regulated kinases (ERK1/2) in hippocampal HN2-5 cells. Two 5-HT(1A) agonists, Repinotan hydrochloride (BAY x 3702) and 8-OH-DPAT, block caspase-3 activation and apoptosis caused by anoxia/reoxygenation and H(2)O(2) treatment. This is reversed upon transient expression of dominant negative Ras (N17Ras) and Raf-1 (Raf301), confirming the involvement of Ras and Raf-1 in this 5-HT(1A)-R-->ERK1/2-->caspase-3 pathway. A selective inhibitor of phospholipase Cbeta (PLCbeta) (U73122) but not a general protein kinase C (PKC) inhibitor (GFX) reversed the 5-HT(1A)-R-mediated ERK1/2 stimulation. However, both GFX and the PKCalpha and PKCbeta(1) inhibitor Gö6976 reversed the ERK1/2-mediated inhibition of caspase-3. ERK-dependent activation of only PKCalpha was observed in immunoprecipitates obtained from 5-HT(1A) agonist-treated HN2-5 cells. Finally, transient expression of kinase-negative PKCalpha eliminated the 8-OH-DPAT-evoked block on the H(2)O(2)-triggered caspase-3 stimulation, establishing PKCalpha as a link between ERK and caspase-3 (5-HT(1A)-R-->PLC-->ERK1/2-->PKCalpha-->caspase-3). Our results elucidate a novel yet general, neuroprotective pathway through which G protein-coupled receptors could cause inhibition of effector caspases, such as caspase-3.

Obesity, characterized by chronic activation of inflammatory pathways, is a critical factor contributing to insulin resistance (IR) and type 2 diabetes (T2D). Free fatty acids (FFAs) are increased in obesity and are implicated as proximate causes of IR and induction of inflammatory signaling in adipose, liver, muscle, and pancreas. Cells of the innate immune system produce cytokines, and other factors that affect insulin signaling and result in the development of IR. In the lean state, adipose tissue is populated by adipose tissue macrophage of the anti-inflammatory M2 type (ATM2) and natural killer (NK) cells; this maintains the insulin-sensitive phenotype because ATM2 cells secrete IL10. In contrast, obesity induces lipolysis and release of pro-inflammatory FFAs and factors, such as chemokine (C–C motif) ligand 2 (CCL2) and tumor necrosis factor alpha (TNF-α), which recruit blood monocytes in adipose tissue, where they are converted to macrophages of the highly pro-inflammatory M1-type (ATM1). Activated ATM1 produce large amounts of pro-inflammatory mediators such as TNF-α, interleukin-1β, IL-6, leukotriene B4, nitric oxide (NO), and resistin that work in a paracrine fashion and cause IR in adipose tissue. In the liver, both pro-inflammatory Kupffer cells (M1-KCs) and recruited hepatic macrophages (Ly6Chigh) contribute to decreased hepatic insulin sensitivity. The present mini-review will update the bidirectional interaction between the immune system and obesity-induced changes in metabolism in adipose tissue and liver and the metabolic consequences thereof.

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Fibrillar amyloid beta-protein (Abeta) is the major protein of amyloid plaques in the brains of patients with Alzheimer's disease (AD). The mechanism by which normally produced soluble Abeta gets fibrillized in AD is not clear. We studied the effect of neutral, zwitterionic, and anionic lipids on the fibrillization of Abeta 1-40. We report here that acidic phospholipids such as phosphatidic acid, phosphatidylserine, phosphatidylinositol (PI), PI 4-phosphate, PI 4,5-P2 and cardiolipin can increase the fibrillization of Abeta, while the neutral lipids (diacylglycerol, cholesterol, cerebrosides), zwitterionic lipids (phosphatidylcholine, phosphatidylethanolamine, sphingomyelin) and anionic lipids lacking phosphate groups (sulfatides, gangliosides) do not affect Abeta fibrillization. Abeta was found to increase the fluorescence of 1-acyl-2-[12-[(7-nitro-2-1, 3-benzoxadiazol-4-yl) amino] dodecanoyl]-sn-glycero-3-phosphate (NBD-PA) in a concentration-dependent manner, while no change was observed with 1-acyl-2- [12-[(7-nitro-2-1, 3-benzoxadiazol-4-yl) amino] dodecanoyl]-sn-glycero-3-phosphoethanolamine (NBD-PE). Under similar conditions, other proteins such as apolipoprotein E, gelsolin and polyglutamic acid did not interact with NBD-PA. The order of interaction of amyloid beta-peptides with NBD-PA was Abeta 1-43 = Abeta 1-42 = Abeta 17-42 > Abeta 1-40 = Abeta 17-40. Other Abeta peptides such as Abeta 1-11, Abeta 1-16, Abeta 1-28, Abeta 1-38, Abeta 12-28, Abeta 22-35, Abeta 25-35, and Abeta 31-35 did not increase the NBD-PA fluorescence. These results suggest that phosphate groups, fatty acids, and aliphatic amino acids at the C-terminus end of Abeta 1-40/Abeta 1-42 are essential for the interaction of Abeta with anionic phospholipids, while hydrophilic Abeta segment from 1-16 amino acids does not participate in this interaction. Since positively charged amino acids in Abeta are necessary for the interaction with negatively charged phosphate groups of phospholipids, it is suggested that Lys28 of Abeta may provide anchor for the phosphate groups of lipids, while aliphatic amino acids (Val-Val-Ile-Ala) at the C-terminus of Abeta interact with fatty acids of phospholipids.

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