Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential cation channel that is critical for transducing environmental irritant stimuli into nociceptor activity. Moreover, we find that pain and acute vascular reactions, including neurogenic inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers new insights into the pathogenesis of pain and neurovascular responses during bacterial infections and opens novel avenues for their treatment.

Ghrelin, the endogenous ligand of the GH secretagogue receptor, acts at central level to elicit GH release and regulate food intake. To elucidate the neural circuit that exerts its effects, we measured the expression of hypothalamic neuropeptides involved in weight regulation and GH secretion after ghrelin administration. Adult male rats, fed or fasted for 72 h, were treated centrally (intracerebroventicularly) with a single dose of ghrelin (5 micro g). After 2, 4, and 6 or 8 h, agouti-related peptide, melanin-concentrating hormone, neuropeptide Y, prepro-orexin, GHRH, and somatostatin mRNA levels were measured by in situ hybridization. We found that ghrelin increased agouti-related peptide and neuropeptide Y expression in the arcuate nucleus of the hypothalamus of fed and fasted rats. In contrast, no change was demonstrated in the mRNA levels of the other neuropeptides studied at any time evaluated. Finally, we examined the effect of ghrelin on GHRH and somatostatin mRNA levels in GH-deficient (dwarf) rats. Our results show that ghrelin increases somatostatin mRNA levels in the hypothalamus of these rats. This study furthers our understanding of the molecular basis and mechanisms involved in the effect of ghrelin on food intake and GH secretion.

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0 -AMP-activated protein kinase (AMPK) is an energy sensor that controls cell metabolism, and it has been related to apoptosis and cell-cycle arrest. Although its role in metabolic homeostasis is well documented, its function in cancer is much less clear. In this study, we examined the role of AMPK in a mouse model of astrocytoma driven by oncogenic H-Ras V12 and/or with PTEN deletion based on the common constitutive activation of the Raf/MEK/ERK and PI3K/AKT cascades in human astrocytomas. We also evaluated the activity and role of AMPK in human glioblastoma cells and xenografts. AMPK was constitutively activated in astrocytes expressing oncogenic H-Ras V12 in parallel with high cell division rates. Genetic deletion of AMPK or attenuation of its activity in these cells was sufficient to reduce cell proliferation. The levels of pAMK were always related to the levels of phosphorylated retinoblastoma (Rb) at Ser804, which may indicate an AMPKmediated phosphorylation of Rb. We confirmed this AMPK-Rb relationship in human glioblastoma cell lines and xenografts. In clinical specimens of human glioblastoma, elevated levels of activated AMPK appeared especially in areas of high proliferation surrounding the blood vessels. Together, our findings indicate that the initiation and progression of astrocytic tumors relies upon AMPK-dependent control of the cell cycle, thereby identifying AMPK as a candidate therapeutic target in this setting. Cancer Res; 73(8); 2628-38. Ó2013 AACR.

leptin is synthesized as a single molecular variant identical to human recombinant leptin in human placentae at delivery.