Physiological and pharmacological implications of AT1 versus AT2 receptors

Physiological and pharmacological implications of AT1versus AT2receptors. Angiotensin II (Ang II) has diverse physiological actions that lead, for instance, to increases in extracellular volume and peripheral vascular resistance and blood pressure, and it has also been implicated in the regulation of cell growth and differentiation. Molecular cloning and pharmacological studies have defined two major classes of Ang II receptors, designated AT1 and AT2. Most effects of Ang II are mediated by AT1 receptors. Much less is known about the physiological role of AT2 receptors. Recent evidence suggests involvement of AT2 receptors in development, cell differentiation, apoptosis, and regeneration in various tissues. AT1 and AT2 receptors have been shown to exert counteracting effects on cellular growth and differentiation, vascular tone, and the release of arginine vasopressin. In each condition, the AT2 receptor appears to down-modulate actions mediated by the AT1 receptor, resulting in decreased cellular proliferation, decreased levels of serum arginine vasopressin levels, or decreased vasoconstrictor responses. In addition, in neuronal cell lines, the AT2 receptor exerts antiproliferative actions and promotes neurite outgrowth, an effect accompanied by significant changes in the expression pattern of growth/differentiation-related genes

Shareholder Litigation Rights and Corporate Acquisitions

We examine the effect of shareholder litigation rights on managers’ acquisition decisions. Our experimental design exploits a U.S. Ninth Circuit Court of Appeals ruling on July 2, 1999 that resulted in a reduction in shareholder class actions. We find that, since the ruling, firms in Ninth Circuit states acquire larger targets. Furthermore, acquirers’ returns are lower in these states, especially for those with weaker corporate governance. Further analysis shows that value destruction is the result of managers’ freedom to conduct empire-building acquisitions using overvalued equity. Overall, our findings indicate the importance of shareholder litigation as an external governance mechanism

Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force

Background: Therapeutic targets have been defined for diseases like diabetes, hypertension or rheumatoid arthritis and adhering to them has improved outcomes. Such targets are just emerging for spondyloarthritis (SpA). Objective: To define the treatment target for SpA including ankylosing spondylitis and psoriatic arthritis (PsA) and develop recommendations for achieving the target, including a treat-to-target management strategy. Methods: Based on results of a systematic literature review and expert opinion, a task force of expert physicians and patients developed recommendations which were broadly discussed and voted upon in a Delphi-like process. Level of evidence, grade and strength of the recommendations were derived by respective means. The commonalities between axial SpA, peripheral SpA and PsA were discussed in detail. Results: Although the literature review did not reveal trials comparing a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated the development of recommendations. The group agreed on 5 overarching principles and 11 recommendations; 9 of these recommendations related commonly to the whole spectrum of SpA and PsA, and only 2 were designed separately for axial SpA, peripheral SpA and PsA. The main treatment target, which should be based on a shared decision with the patient, was defined as remission, with the alternative target of low disease activity. Follow-up examinations at regular intervals that depend on the patient's status should safeguard the evolution of disease activity towards the targeted goal. Additional recommendations relate to extra-articular and extramusculoskeletal aspects and other important factors, such as comorbidity. While the level of evidence was generally quite low, the mean strength of recommendation was 9-10 (10: maximum agreement) for all recommendations. A research agenda was formulated. Conclusions: The task force defined the treatment target as remission or, alternatively, low disease activity, being aware that the evidence base is not strong and needs to be expanded by future research. These recommendations can inform the various stakeholders about expert opinion that aims for reaching optimal outcomes of SpA

Quaternary structure of a G-protein coupled receptor heterotetramer in complex with Gi and Gs

Background: G-protein-coupled receptors (GPCRs), in the form of monomers or homodimers that bind heterotrimeric G proteins, are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways. Different GPCRs may also interact to form heteromers that are novel signaling units. Despite the exponential growth in the number of solved GPCR crystal structures, the structural properties of heteromers remain unknown. Results: We used single-particle tracking experiments in cells expressing functional adenosine A1-A2A receptors fused to fluorescent proteins to show the loss of Brownian movement of the A1 receptor in the presence of the A2A receptor, and a preponderance of cell surface 2:2 receptor heteromers (dimer of dimers). Using computer modeling, aided by bioluminescence resonance energy transfer assays to monitor receptor homomerization and heteromerization and G-protein coupling, we predict the interacting interfaces and propose a quaternary structure of the GPCR tetramer in complex with two G proteins. Conclusions: The combination of results points to a molecular architecture formed by a rhombus-shaped heterotetramer, which is bound to two different interacting heterotrimeric G proteins (Gi and Gs). These novel results constitute an important advance in understanding the molecular intricacies involved in GPCR function

Comparison of anti-oxidant activities of seventy herbs that have been used in Korean traditional medicine

Many herbs have been used as therapeutics in Korean traditional medicine. In view of their clinical indications, anti-oxidant activity may contribute to their pharmacological effects. However, anti-oxidant information on these plants has not been available. In this study, seventy herbs which have been used in Korean traditional medicine were selected and screened for anti-oxidant activity using their water extracts. The anti-oxidant activity was assessed by their ability to inhibit three oxidation reactions; luminol/Fenton reagent, 2, 7-dichlorodihydrofluorescein (DCHF)/Fenton reagent and DCHF/peroxynitrite. In each assay, 70 herbs were divided into two groups; anti-oxidant group which inhibited the respective oxidation reaction and was majority (about 60 herbs), and pro-oxidant group which enhanced the oxidation reaction but was minority (more or less 10 herbs). When the herbs were listed in the order of their anti-oxidant strength, the orders obtained from each assay were found to be quite similar. The upper top rankers (more or less 10 herbs) in each assay showed strong activity compared to the others. The uppermost rankers in each assay were Rubus coreanus Miquel/ Rubus schizostylus, Schisandra chinensis Baillon/ Schizandra chinensis and Terminalia chebula Retzius/ Terminalia chebula. Of the pro-oxidant herbs, about 4-5 herbs were strongly pro-oxidant, which enhanced the control oxidation reactions to 150-300%. But the meaning of this observation is not known since few of them in one assay were also anti-oxidant in other assays. The results obtained in the present study may serve as information for understanding pharmacological effects of these herbs and developing new drugs from them

Extracellular MRP8/14 is a regulator of β2 integrin-dependent neutrophil slow rolling and adhesion

Myeloid-related proteins (MRPs) 8 and 14 are cytosolic proteins secreted from myeloid cells as proinflammatory mediators. Currently, the functional role of circulating extracellular MRP8/14 is unclear. Our present study identifies extracellular MRP8/14 as an autocrine player in the leukocyte adhesion cascade. We show that E-selectin-PSGL-1 interaction during neutrophil rolling triggers Mrp8/14 secretion. Released MRP8/14 in turn activates a TLR4-mediated, Rap1-GTPase-dependent pathway of rapid beta 2 integrin activation in neutrophils. This extracellular activation loop reduces leukocyte rolling velocity and stimulates adhesion. Thus, we identify Mrp8/14 and TLR4 as important modulators of the leukocyte recruitment cascade during inflammation in vivo

Extracellular MRP8/14 is a regulator of β2 integrin-dependent neutrophil slow rolling and adhesion

Myeloid-related proteins (MRPs) 8 and 14 are cytosolic proteins secreted from myeloid cells as proinflammatory mediators. Currently, the functional role of circulating extracellular MRP8/14 is unclear. Our present study identifies extracellular MRP8/14 as an autocrine player in the leukocyte adhesion cascade. We show that E-selectin-PSGL-1 interaction during neutrophil rolling triggers Mrp8/14 secretion. Released MRP8/14 in turn activates a TLR4-mediated, Rap1-GTPase-dependent pathway of rapid beta 2 integrin activation in neutrophils. This extracellular activation loop reduces leukocyte rolling velocity and stimulates adhesion. Thus, we identify Mrp8/14 and TLR4 as important modulators of the leukocyte recruitment cascade during inflammation in vivo