Beneficial effects of the activation of the Angiotensin-(1-7) MAS receptor in a murine model of adriamycin-induced nephropathy

Angiotensin-(1-7) [Ang-(1-7)] is a biologically active heptapeptide that may counterbalance the physiological actions of angiotensin II (Ang II) within the renin-angiotensin system (RAS). Here, we evaluated whether activation of the Mas receptor with the oral agonist, AVE 0991, would have renoprotective effects in a model of adriamycin (ADR)-induced nephropathy. We also evaluated whether the Mas receptor contributed for the protective effects of treatment with AT1 receptor blockers. ADR (10 mg/kg) induced significant renal injury and dysfunction that was maximal at day 14 after injection. Treatment with the Mas receptor agonist AVE 0991 improved renal function parameters, reduced urinary protein loss and attenuated histological changes. Renoprotection was associated with reduction in urinary levels of TGF-{beta}. Similar renoprotection was observed after treatment with the AT1 receptor antagonist, Losartan. AT1 and Mas receptor mRNA levels dropped after ADR administration and treatment with losartan reestablished the expression of Mas receptor and increased the expression of ACE2. ADR-induced nephropathy was similar in wild type (Mas(+/+)) and Mas knockout (Mas (-/-)) mice, suggesting there was no endogenous role for Mas receptor activation. However, treatment with Losartan was able to reduce renal injury only in Mas(+/+) , but not in Mas (-/-) mice. Therefore, these findings suggest that exogenous activation of the Mas receptor protects from ADR-induced nephropathy and contributes to the beneficial effects of AT1 receptor blockade. Medications which target specifically the ACE2/Ang-(1-7)/Mas axis may offer new therapeutic opportunities to treat human nephropathies

Preliminary investigation of a novel controlled stiffness proximal femoral prosthesis

Previous studies have suggested that a controlled stiffness prosthesis is required to address the conflicting requirements of minimizing stress shielding and micromotion. The design for a controlled stiffness prosthesis is proposed and a preliminary analytical investigation performed to assess its predicted performance before fabrication of a prototype component. The novel prosthesis consisted of a cobalt–chrome core and a flexible composite outer layer. Varying the composite layer thickness allowed the prosthesis stiffness to be controlled. Three variants of the controlled stiffness prosthesis were critically assessed using the finite element method and their predicted performance compared with those of conventional prosthesis designs. The potential for stress shielding was assessed by examining the periosteal strain energy and the potential for migration assessed by examining the endosteal minimum principal cancellous bone stresses. Both the conventional and controlled stiffness implants performed poorly as press-fit prostheses. All the press-fit prostheses generated high cancellous bone stresses, suggesting that excessive migration of these implants would be likely. The controlled stiffness implants performed better than the conventional implants when bonded to the surrounding bone. Although the controlled stiffness implants did not eliminate stress shielding of the calcar, they produced higher strain energies than the conventional designs. The findings of this study are that osseointegrated controlled stiffness implants may perform better than current osseointegrated cementless prostheses and therefore it is worth while progressing to the next stage, of prototyping an implant

Indole monoterpenes with antichemotactic activity from Psychotria myriantha: Chemotaxonomic significance

The alkaloid extract of the aerial parts of Psychotria myriantha (Rubiaceae) displayed antichemotactic activity on polymorphonuclear leukocytes (PMN) assessed by the Boyden chamber assay. On analysis of the crude extract by LC/APCI/MS and LC/UV/DAD, two major constituents could be detected. In order to rapidly identify the active compounds, a microfractionation was conducted during LC/UV/DAD analysis. By this means, both the collected compounds could be assayed separately in the Boyden chamber and were shown to inhibit PMN chemotaxis. Their isolation was performed by semi-preparative HPLC and their structures elucidated by classical spectroscopic methods, including UV, NMR, MS and HRMS. Both compounds showed characteristics of monoterpene indole glucoside alkaloids; one of them was identified as strictosidinic acid and the other was a new natural product, myrianthosine. The antichemotactic activity of the compounds may be related to an antiacute inflammation activity

Origin of step-like and lobate seafloor features along the continental shelf off Rio de Janeiro State, Santos basin-Brazil

International audienceA combined analysis of seismic and morphological features identified in a set of high-resolution seismic reflection and bathymetric data, shows a systematic relationship between major modern seafloor morphological traces and the basinward migration of Late Pleistocene coastlines along the continental shelf of the Santos basin (Rio de Janeiro State, SE Brazil). Observed fairly continuous and sinuous mid-outer shelf escarpments are related to the sea-level variations and shelf exposure during the Last Glacial cycle. A bathymetric step at - 110 m is an erosional remnant of offlapping detached forced-regressive wedges that spread over 50 km in the shelf-dip direction, probably developed during periods of falling sea level between MIS 3 and 2. A second major escarpment at - 130 m was interpreted as the shoreline during the LGM, at the time of most extensive subaerial exposure of the continental shelf. However, a distal escarpment at - 150 m is expressed as a straight contour feature along the two main shelf-edge embayments that characterize the shelf break. This escarpment is coupled with a basal seaward-inclined and highly eroded ramp, and was interpreted as the erosional action of bottom currents during the last transgression due to the displacement of the southward flowing Brazil Current towards the present-day outer shelf. Previously published articles have regarded the morphological features observed on the modern shelf as indicators of stillstands during the post-LGM transgression. We conclude that, on the contrary, most of these features are actually from earlier parts of the Late Pleistocene and were formed in a regressive scenario under oscillating and relative slow sea-level fall

The effect of amiodarone on the control of hyperthyroidism by propylthiouracil

CommentLetterSCOPUS: le.jFLWNAinfo:eu-repo/semantics/publishe

Mechanisms of the anti-inflammatory actions of the angiotensin type 1 receptor antagonist losartan in experimental models of arthritis

Angiotensin (Ang) II and its AT1 receptors have been implicated in the pathogenesis of Rheumatoid Arthritis. Activation of the counter-regulatory Ang-(1-7)-Mas receptor axis may contribute to some of the effects of AT1 receptor blockers (ARBs). In this study, we have used losartan, an ARB, to investigate the role of and the mechanisms by which AT1 receptors participated in two experimental models of arthritis: antigen-induced arthritis (AIA) in mice and adjuvant-induced arthritis (AdIA) in rats. Treatment with losartan decreased neutrophil recruitment, hypernociception and the production of TNF-α, IL-1β and chemokine (C-X-C motif) ligand 1 in mice subjected to AIA. Histopathological analysis showed significant reduction of tissue injury and inflammation and decreased proteoglycan loss. In addition to decreasing cytokine production, losartan directly reduced leukocyte rolling and adhesion. Anti-inflammatory effects of losartan were not associated to Mas receptor activation and/or Ang-(1-7) production. Anti-inflammatory effects were reproduced in rats subjected to AdIA. This study shows that ARBs have potent anti-inflammatory effects in animal models of arthritis. Mechanistically, reduction of leukocyte accumulation and of joint damage was associated with local inhibition of cytokine production and direct inhibition of leukocyte-endothelium interactions. The anti-inflammatory actions of losartan were accompanied by functional improvement of the joint, as seen by reduced joint hypernociception. These findings support the use of ARBs for the treatment of human arthritis and provide potential mechanisms for the anti-inflammatory actions of these compounds

Anti-inflammatory effects of the activation of the angiotensin-(1-7) receptor, Mas, in experimental models of arthritis

Activation of the renin-angiotensin (Ang) system induces inflammation via interaction between Ang II and type 1 receptor on leukocytes. The relevance of the new arm of the renin-Ang system, namely Ang-converting enzyme-2/Ang-(1-7)/Mas receptor, for inflammatory responses is not known and was investigated in this study. For this purpose, two experimental models were used: Ag-induced arthritis (AIA) in mice and adjuvant-induced arthritis (AdIA) in rats. Male C57BL/6 wild-type or Mas(-/-) mice were subjected to AIA and treated with Ang-(1-7), the Mas agonist AVE 0991, or vehicle. AdIA was performed in female rats that were given AVE 0991 or vehicle. In wild-type mice, Mas protein is expressed in arthritic joints. Administration of AVE 0991 or Ang-(1-7) decreased AIA-induced neutrophil accumulation, hypernociception, and production of TNF-α, IL-1β, and CXCL1. Histopathological analysis showed significant reduction of inflammation. Mechanistically, AVE 0991 reduced leukocyte rolling and adhesion, even when given after Ag challenge. Mas(-/-) mice subjected to AIA developed slightly more pronounced inflammation, as observed by greater neutrophil accumulation and cytokine release. Administration of AVE 0991 was without effect in Mas(-/-) mice subjected to AIA. In rats, administration of AVE 0991 decreased edema, neutrophil accumulation, histopathological score, and production of IL-1β and CXCL1 induced by AdIA. Therefore, activation of Mas receptors decreases neutrophil influx and cytokine production and causes significant amelioration of arthritis in experimental models of arthritis in rats and mice. This approach might represent a novel therapeutic opportunity for arthritis