Effect of angiotensin II and small GTPase Ras signaling pathway inhibition on early renal changes in a murine model of obstructive nephropathy

This is an open access article distributed under the Creative Commons Attribution License.Tubulointerstitial fibrosis is a major feature of chronic kidney disease. Unilateral ureteral obstruction (UUO) in rodents leads to the development of renal tubulointerstitial fibrosis consistent with histopathological changes observed in advanced chronic kidney disease in humans. The purpose of this study was to assess the effect of inhibiting angiotensin II receptors or Ras activation on early renal fibrotic changes induced by UUO. Animals either received angiotensin II or underwent UUO. UUO animals received either losartan, atorvastatin, and farnesyl transferase inhibitor (FTI) L-744,832, or chaetomellic acid A (ChA). Levels of activated Ras, phospho-ERK1/2, phospho-Akt, fibronectin, and α-smooth muscle actin were subsequently quantified in renal tissue by ELISA, Western blot, and/or immunohistochemistry. Our results demonstrate that administration of angiotensin II induces activation of the small GTPase Ras/Erk/Akt signaling system, suggesting an involvement of angiotensin II in the early obstruction-induced activation of renal Ras. Furthermore, upstream inhibition of Ras signalling by blocking either angiotensin AT1 type receptor or by inhibiting Ras prenylation (atorvastatin, FTI o ChA) reduced the activation of the Ras/Erk/Akt signaling system and decreased the early fibrotic response in the obstructed kidney. This study points out that pharmacological inhibition of Ras activation may hold promise as a future strategy in the prevention of renal fibrosis.This study was supported by grants from Ministerio de Economía y Competitividad (Grant SAF2010-15881 and Red de Investigacion Cooperativa en Enfermedades Renales REDINREN RD12/0021/0032), Junta de Castilla y León (Grant SA 001/C05 and Excellence Group GR100), and REDINREN which is an initiative of the Instituto de Salud Carlos III of Spain supported by FEDER funds. When performing the present study, Ana B. Rodríguez-Pena was a fellow of the Fundacion Renal “Iñigo Ávarez de Toledo” and Neil G. Docherty was a fellow ofThe Marie Curie Programme, EU.Peer Reviewe

HIVconsv Vaccines and Romidepsin in Early-Treated HIV-1-Infected Individuals: Safety, Immunogenicity and Effect on the Viral Reservoir (Study BCN02)

Kick&kill strategies combining drugs aiming to reactivate the viral reservoir with therapeutic vaccines to induce effective cytotoxic immune responses hold potential to achieve a functional cure for HIV-1 infection. Here, we report on an open-label, single-arm, phase I clinical trial, enrolling 15 early-treated HIV-1-infected individuals, testing the combination of the histone deacetylase inhibitor romidepsin as a latency-reversing agent and the MVA.HIVconsv vaccine. Romidepsin treatment resulted in increased histone acetylation, cell-associated HIV-1 RNA, and T-cell activation, which were associated with a marginally significant reduction of the viral reservoir. Vaccinations boosted robust and broad HIVconsv-specific T cells, which were strongly refocused toward conserved regions of the HIV-1 proteome. During a monitored ART interruption phase using plasma viral load over 2,000 copies/ml as a criterium for ART resumption, 23% of individuals showed sustained suppression of viremia up to 32 weeks without evidence for reseeding the viral reservoir. Results from this pilot study show that the combined kick&kill intervention was safe and suggest a role for this strategy in achieving an immune-driven durable viremic control

Endoglin regulates renal ischaemia-reperfusion injury

14 páginas, 10 figuras -- PAGS nros. 2106-2119Background. Renal ischaemia–reperfusion (I–R) can cause acute tubular necrosis and chronic renal deterioration. Endoglin, an accessory receptor for Transforming Growth Factor-β1 (TGF-β1), is expressed on activated endothelium during macrophage maturation and implicated in the control of fibrosis, angiogenesis and inflammation. Methods. Endoglin expression was monitored over 14 days after renal I–R in rats. As endoglin-null mice are not viable, the role of endoglin in I–R was studied by comparing renal I–R injury in haploinsufficient mice (Eng+/−) and their wild-type littermates (Eng+/+). Renal function, morphology and molecular markers of acute renal injury and inflammation were compared. Results. Endoglin mRNA up-regulation in the post-ischaemic kidneys of rats occurred at 12 h after I–R; endoglin protein levels were elevated throughout the study period. Expression was initially localized to the vascular endothelium, then extended to fibrotic and inflamed areas of the interstitium.  Two days after I–R, plasma creatinine elevation and acute tubular necrosis were less marked in Eng+/− than in Eng+/+ mice. Significant up-regulation of endoglin protein was found only in the post-ischaemic kidneys of Eng+/+ mice and coincided with an increased mRNA expression of the TGF-β1 and collagen IV (α1) chain genes. Significant increases in vascular cell adhesion molecule-1 (VCAM-1) and inducible nitric oxide synthase (iNOS) expression, nitrosative stress, myeloperoxidase activity and CD68 staining for macrophages were evident in post-ischaemic kidneys of Eng+/+, but not Eng+/− mice, suggesting that impaired endothelial activation and macrophage maturation may account for the reduced injury in post-ischaemic kidneys of Eng+/− mice. Conclusions. Endoglin is up-regulated in the post-ischaemic kidney and endoglin-haploinsufficient mice are protected from renal I–R injury. Endoglin may play a primary role in promoting inflammatory responses following renal I–R.This study was supported by grants from Ministerio de Ciencia y Tecnología (SAF2001-1701) and Junta de Castilla y León (SA22/03)Peer reviewe

In operando evidence of deoxygenation in ionic liquid gating of YBa2Cu3O7-X

Field-effect experiments on cuprates using ionic liquids have enabled the exploration of their rich phase diagrams [Leng X, et al. (2011) Phys Rev Lett 107(2):027001]. Conventional understanding of the electrostatic doping is in terms of modifications of the charge density to screen the electric field generated at the double layer. However, it has been recently reported that the suppression of the metal to insulator transition induced in VO by ionic liquid gating is due to oxygen vacancy formation rather than to electrostatic doping [Jeong J, et al. (2013) Science 339(6126):1402-1405]. These results underscore the debate on the true nature, electrostatic vs. electrochemical, of the doping of cuprates with ionic liquids. Here, we address the doping mechanism of the high-temperature superconductor YBaCuO (YBCO) by simultaneous ionic liquid gating and X-ray absorption experiments. Pronounced spectral changes are observed at the Cu K-edge concomitant with the superconductor-to-insulator transition, evidencing modification of the Cu coordination resulting from the deoxygenation of the CuO chains, as confirmed by first-principles density functional theory (DFT) simulations. Beyond providing evidence of the importance of chemical doping in electric double-layer (EDL) gating experiments with superconducting cuprates, our work shows that interfacing correlated oxides with ionic liquids enables a delicate control of oxygen content, paving the way to novel electrochemical concepts in future oxide electronics.A.M.G. was supported partially by US National Science Foundation Award DMR-1420013 through the Minnesota Materials Research Science and Engineering Center and by US National Science Foundation Award DMR-1209578. J.G.-B. acknowledges support from the Ministerio de Economía, Industria y Competitividad (MINECO) through the Ramon y Cajal Program and through MINECO Award PCIN-2013-061. Calculations were performed using computer resources from Genci Grand Équipement National de Calcul Intensif under Centre Informatique National de l’Enseignement Suprieur Grants c2015097211 and c2016097211. Work at Universidad Complutense de Madrid was supported by the Spanish MINECO through Grants MAT2014-52405-C02-01 and Consolider Ingenio 2010-CSD2009-00013 (Imagine) and by Comunidad Autonoma de Madrid (CAM) through Grant CAM S2013/MIT-2740. The SpLine beamline is supported financially by the Spanish MINECO and Consejo Superior de Investigaciones Cientificas under Grant PIE 2010 6 OE 013. P.S. acknowledges the support from Fundação de Amparo à Pesquisa do Estado de São Paulo Projects 2012/18397-2 and 2013/12537-9

In operando evidence of deoxygenation in ionic liquid gating of YBa<SUB>2</SUB>Cu<SUB>3</SUB>O<SUB>7-X</SUB>

International audienceIn this work, we investigate the origin of the charge induced in a high-temperature superconducting cuprate film, incorporated in an electric double-layer transistor. Using X-ray spectroscopic measurements made while operating the transistor, together with simulations based on density functional theory, we find that the accumulated charge in the cuprate is due to the depletion of oxygen from specific sites in its unit cell. These results constitute direct evidence of the microscopic mechanism of charge modification. The systematic control of the oxygen content in complex oxides such as the cuprates allows for the study of complex phase diagrams and opens up a route for the design of new complex oxide compounds and devices with improved functionalities

Polyoxazoline‐Based Nanovaccine Synergizes with Tumor‐Associated Macrophage Targeting and Anti‐PD‐1 Immunotherapy against Solid Tumors

Abstract Immune checkpoint blockade reaches remarkable clinical responses. However, even in the most favorable cases, half of these patients do not benefit from these therapies in the long term. It is hypothesized that the activation of host immunity by co‐delivering peptide antigens, adjuvants, and regulators of the transforming growth factor (TGF)‐β expression using a polyoxazoline (POx)‐poly(lactic‐co‐glycolic) acid (PLGA) nanovaccine, while modulating the tumor‐associated macrophages (TAM) function within the tumor microenvironment (TME) and blocking the anti‐programmed cell death protein 1 (PD‐1) can constitute an alternative approach for cancer immunotherapy. POx‐Mannose (Man) nanovaccines generate antigen‐specific T‐cell responses that control tumor growth to a higher extent than poly(ethylene glycol) (PEG)‐Man nanovaccines. This anti‐tumor effect induced by the POx‐Man nanovaccines is mediated by a CD8+‐T cell‐dependent mechanism, in contrast to the PEG‐Man nanovaccines. POx‐Man nanovaccine combines with pexidartinib, a modulator of the TAM function, restricts the MC38 tumor growth, and synergizes with PD‐1 blockade, controlling MC38 and CT26 tumor growth and survival. This data is further validated in the highly aggressive and poorly immunogenic B16F10 melanoma mouse model. Therefore, the synergistic anti‐tumor effect induced by the combination of nanovaccines with the inhibition of both TAM‐ and PD‐1‐inducing immunosuppression, holds great potential for improving immunotherapy outcomes in solid cancer patients