CB2 Cannabinoid Receptors Contribute to Bacterial Invasion and Mortality in Polymicrobial Sepsis

BACKGROUND:Sepsis is a major healthcare problem and current estimates suggest that the incidence of sepsis is approximately 750,000 annually. Sepsis is caused by an inability of the immune system to eliminate invading pathogens. It was recently proposed that endogenous mediators produced during sepsis can contribute to the immune dysfunction that is observed in sepsis. Endocannabinoids that are produced excessively in sepsis are potential factors leading to immune dysfunction, because they suppress immune cell function by binding to G-protein-coupled CB(2) receptors on immune cells. Here we examined the role of CB(2) receptors in regulating the host's response to sepsis. METHODS AND FINDINGS:The role of CB(2) receptors was studied by subjecting CB(2) receptor wild-type and knockout mice to bacterial sepsis induced by cecal ligation and puncture. We report that CB(2) receptor inactivation by knockout decreases sepsis-induced mortality, and bacterial translocation into the bloodstream of septic animals. Furthermore, CB(2) receptor inactivation decreases kidney and muscle injury, suppresses splenic nuclear factor (NF)-kappaB activation, and diminishes the production of IL-10, IL-6 and MIP-2. Finally, CB(2) receptor deficiency prevents apoptosis in lymphoid organs and augments the number of CD11b(+) and CD19(+) cells during CLP. CONCLUSIONS:Taken together, our results establish for the first time that CB(2) receptors are important contributors to septic immune dysfunction and mortality, indicating that CB(2) receptors may be therapeutically targeted for the benefit of patients suffering from sepsis

Search for top-down and bottom-up drivers of latitudinal trends in insect herbivory in oak trees in Europe

AimThe strength of species interactions is traditionally expected to increase toward the Equator. However, recent studies have reported opposite or inconsistent latitudinal trends in the bottom‐up (plant quality) and top‐down (natural enemies) forces driving herbivory. In addition, these forces have rarely been studied together thus limiting previous attempts to understand the effect of large‐scale climatic gradients on herbivory.LocationEurope.Time period2018–2019.Major taxa studiedQuercus robur.MethodsWe simultaneously tested for latitudinal variation in plant–herbivore–natural enemy interactions. We further investigated the underlying climatic factors associated with variation in herbivory, leaf chemistry and attack rates in Quercus robur across its complete latitudinal range in Europe. We quantified insect leaf damage and the incidence of specialist herbivores as well as leaf chemistry and bird attack rates on dummy caterpillars on 261 oak trees.ResultsClimatic factors rather than latitude per se were the best predictors of the large‐scale (geographical) variation in the incidence of gall‐inducers and leaf‐miners as well as in leaf nutritional content. However, leaf damage, plant chemical defences (leaf phenolics) and bird attack rates were not influenced by climatic factors or latitude. The incidence of leaf‐miners increased with increasing concentrations of hydrolysable tannins, whereas the incidence of gall‐inducers increased with increasing leaf soluble sugar concentration and decreased with increasing leaf C : N ratios and lignins. However, leaf traits and bird attack rates did not vary with leaf damage.Main conclusionsThese findings help to refine our understanding of the bottom‐up and top‐down mechanisms driving geographical variation in plant–herbivore interactions, and indicate the need for further examination of the drivers of herbivory on trees.</p

Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness

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Adenosine signalling in diabetes mellitus--pathophysiology and therapeutic considerations

Adenosine is a key extracellular signalling molecule that regulates several aspects of tissue function by activating four G-protein-coupled receptors, A1, A2A, A2B and A1 adenosine receptors. Accumulating evidence highlights a critical role for the adenosine system in the regulation of glucose homeostasis and the pathophysiology of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Although adenosine signalling is known to affect insulin secretion, new data indicate that adenosine signalling also contributes to the regulation of β-cell homeostasis and activity by controlling the proliferation and regeneration of these cells as well as the survival of β cells in inflammatory microenvironments. Furthermore, adenosine is emerging as a major regulator of insulin responsiveness by controlling insulin signalling in adipose tissue, muscle and liver; adenosine also indirectly mediates effects on inflammatory and/or immune cells in these tissues. This Review critically discusses the role of the adenosine-adenosine receptor system in regulating both the onset and progression of T1DM and T2DM, and the potential of pharmacological manipulation of the adenosinergic system as an approach to manage T1DM, T2DM and their associated complications

Immunity, inflammation and cancer: a leading role for adenosine

Cancer is a complex disease that is dictated by both cancer cell-intrinsic and cell-extrinsic processes. Adenosine is an ancient extracellular signalling molecule that can regulate almost all aspects of tissue function. As such, several studies have recently highlighted a crucial role for adenosine signalling in regulating the various aspects of cell-intrinsic and cell-extrinsic processes of cancer development. This Review critically discusses the role of adenosine and its receptors in regulating the complex interplay among immune, inflammatory, endothelial and cancer cells during the course of neoplastic disease