University of Aberdeen

About: University of Aberdeen is a education organization based out in Aberdeen, United Kingdom. It is known for research contribution in the topics: Population & Health care. The organization has 21174 authors who have published 49962 publications receiving 2105479 citations. The organization is also known as: Aberdeen University.

New insights into the molecular mechanisms of action of bisphosphonates.

Abstract: Bisphosphonates are currently the most important and effective class of anti-resorptive drugs available, but the exact molecular mechanisms by which they inhibit osteoclast-mediated bone resorption have only recently been identified. Due to the targeting of bisphosphonates to bone mineral and the ability of osteoclasts to release bone-bound bisphosphonate, a direct effect on mature osteoclasts appears to be the most important route of action. As a result of recent discoveries concerning their molecular mechanism of action, bisphosphonates can be grouped into two classes. The simple bisphosphonates that closely resemble PPi (such as clodronate, etidronate and tiludronate) can be metabolically incorporated into non-hydrolysable analogues of ATP that accumulate intracellularly in osteoclasts, resulting in induction of osteoclast apoptosis. By contrast, the more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. Loss of bone-resorptive activity and osteoclast apoptosis is due primarily to loss of geranylgeranylated small GTPases. Identification of FPP synthase as the target of nitrogen-containing bisphosphonates has also helped explain the molecular basis for the adverse effects of these agents in the GI tract and on the immune system.

Anandamide and vanilloid TRPV1 receptors

Abstract: A large body of evidence now exists to substantiate that the endocannabinoid, anandamide, activates TRPV1 receptors. It is a low intrinsic efficacy TRPV1 agonist that behaves as a partial agonist in tissues with a low receptor reserve, while in tissues with high receptor reserve and in circumstances associated with certain disease states, it behaves as a full agonist. The efficacy of anandamide as a TRPV1 agonist is influenced by a succession of factors including receptor reserve, phosphorylation, metabolism and uptake, CB1 receptor activation, voltage, temperature, pH and bovine serum albumin. There are indications that the endocannabinoid system may play a role in the modulation of TRPV1 receptor activation. The activation of TRPV1 receptors by anandamide has potential implications in the treatment of inflammatory, respiratory and cardiovascular disorders. The relative importance of anandamide as a physiological and/or pathophysiological TRPV1 receptor agonist in comparison to other potential candidates has yet to be revealed.