The therapeutic effects of microRNAs in preclinical studies of acute kidney injury: a systematic review protocol.

BACKGROUND: Acute kidney injury (AKI) causes significant morbidity and mortality in humans, and there are currently no effective treatments to enhance renal recovery. MicroRNAs (miRNAs) are short chain nucleotides that regulate protein expression and have been implicated in the pathogenesis of AKI. Recently, preclinical studies in vivo have uncovered a therapeutic role for administration of specific miRNAs in AKI. However, the overall benefits of this strategy in preclinical studies have not been systematically reviewed, and the potential for translation to human studies is unclear. AIM: The primary aim is to conduct a systematic review of the therapeutic properties of miRNAs in preclinical studies of AKI. The secondary aim is to determine potential adverse effects of miRNA administration in these studies. METHODS: A comprehensive search strategy will identify relevant studies in AKI in vivo models, using the MEDLINE, EMBASE, OVID, PUBMED, and Web of Science databases. The search strategy will include terms for mammalian (non-human) AKI models, including injury related to ischemia/reperfusion, nephrotoxicity, sepsis, contrast agents, cardio-pulmonary bypass, and hemorrhagic shock. Interventions will be defined as direct administration of exogenous miRNAs or antagonists of miRNAs, as well as maneuvers that alter expression of miRNAs that are mechanistically linked to AKI outcomes. The primary outcomes will be indices of kidney function and structure, and there will be no restriction on comparator interventions. Two independent investigators will initially screen abstracts, and selected articles that meet eligibility criteria will be reviewed for data abstraction and analysis. The SYRCLE RoB tool for animal studies will determine risk of bias, and meta-analysis will be performed as appropriate. The GRADE methodology will assess the quality of evidence. DISCUSSION: The administration of selective miRNA mimics or antagonists exerts beneficial effects in mammalian models of AKI, although multiple obstacles must be addressed prior to translation to human clinical trials. The proposed systematic review will document key miRNA candidates, and determine effect size estimates and sources of outcome bias. The review will also identify gaps in knowledge and guide future directions in AKI research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128854.

miRNA let-7e modulates the Wnt pathway and early nephrogenic markers in mouse embryonic stem cell differentiation.

This study indicates that embryonic stem cells [ESCs] cultured with retinoic acid and activin A significantly upregulate the miRNA let-7e. This specific miRNA modulates the Wnt pathway and the expression of early nephrogenic markers under these differentiation conditions. The differentiation markers WT1, Pax2 and Wnt4 were downregulated when miRNA let-7e was silenced, thus indicating the role of miRNA let-7e in the differentiation process. PKCß, GSK3ß phosphorylation (GSK3ß(P)) and ß-catenin expression was reduced in differentiated cells and reversed by miRNA let-7e silencing. Addition of a PKCß inhibitor to the miRNA let-7e silenced cells abolished let-7e-derived effects in differentiation markers, and reversed the increase in GSK3ß(P) and ß-catenin, thus indicating that miRNA let-7e is involved in differentiation via the modulation of GSK3ß phosphorylation and ß-catenin production.

Infusion of IL-10-expressing cells protects against renal ischemia through induction of lipocalin-2.

Ischemia/reperfusion injury is a leading cause of acute renal failure triggering an inflammatory response associated with infiltrating macrophages, which determine disease outcome. To repair the inflammation we designed a procedure whereby macrophages that overexpress the anti-inflammatory agent interleukin (IL)-10 were adoptively transferred. These bone marrow-derived macrophages were able to increase their intracellular iron pool that, in turn, augmented the expression of lipocalin-2 and its receptors. Infusion of these macrophages into rats after 1 h of reperfusion resulted in localization of the cells to injured kidney tissue, caused increases in regenerative markers, and a notable reduction in both blood urea nitrogen and creatinine. Furthermore, IL-10 therapy decreased the local inflammatory profile and upregulated the expression of pro-regenerative lipocalin-2 and its receptors. IL-10-mediated protection and subsequent renal repair were dependent on the presence of iron and lipocalin-2, since the administration of a neutralizing antibody for lipocalin-2 or administration of IL-10 macrophages pretreated with the iron chelating agent deferoxamine abrogated IL-10-mediated protective effects. Thus, adoptive transfer of IL-10 macrophages to ischemic kidneys blunts acute kidney injury. These effects are mediated through the action of intracellular iron to induce lipocalin-2.

Salud pública y sistema sanitario. Informe SESPAS 2010 / Public health and the health system. SESPAS Report 2010

Para llevar a cabo un análisis sobre la relación entre la salud pública y el sistema sanitario se plantea la necesidad previa de definir un marco conceptual sobre sistemas sanitarios y seleccionar un contexto que facilite el análisis. El contexto elegido en la presente reflexión es el de la gestión de organizaciones públicas, y teniendo esto presente, al hablar de funciones se asocian, éstas, a los macroprocesos de las organizaciones. Desde este punto de vista se identifican cuáles son las funciones-procesos que debe desarrollar cualquier sistema sanitario y cuáles serían sus objetivos. La actual situación de la salud pública en el sistema sanitario se analiza con el estudio de los presupuestos dedicados a salud pública y el nivel jerárquico que ocupan en los diferentes departamentos sanitarios de las comunidades autónomas. El programa presupuestario «salud pública» representa una media del 1,34% del gasto sanitario de las comunidades autónomas en el año 2010. Por otra parte, más del 20% de las organizaciones de salud pública de las comunidades autónomas tienen un rango inferior a dirección general. Estos datos indican el bajo peso de la salud pública en los sistemas sanitarios en España. Para poder cambiar esta situación se plantea la necesidad de consensuar cuál debe ser la relación con el sistema sanitario, asumir ese consenso y trabajar para mejorar los resultados. Se proponen tres opciones: la salud pública sería una organización que está por encima o fuera del sistema sanitario; la salud pública es sinónimo de sistema sanitario público; y la salud pública es una parte del sistema sanitario con una serie de funciones asignadas. Para finalizar se exponen algunas recomendaciones que contribuyan a definir la relación más efectiva y eficiente entre la salud pública y el sistema sanitario (AU)

Analysis of the relationship between public health and the health system requires definition of a conceptual framework and the choice of a particular context. The chosen context of this discussion is the management of public organizations. With this in mind, functions will be associated with organizational macroprocesses. From this point of view, this article identifies the functions-processes that any health system should develop and their goals. The current situation of public health in the health system is analyzed through the study of public health budgets and the place they occupy in the hierarchy of the health departments of the autonomous communities. The “public health” budget program represents an average of 1.34% of health expenditure in the autonomous communities in 2010. Over 20% of public health organizations of the autonomous communities have a rank lower than general directorate. These data indicate the low weight assigned to public health in the health systems of the Spanish state. To change this situation, consensus must be reached on the desired relationship between public health and the health system. Such a consensus would then have to be accepted and work would have to be undertaken to improve results. Three alternatives are proposed: (i) public health would be an organization that would be above or outside the health system; (ii) public health would be synonymous with the public health system; and (iii) public health would form part of the health system with a range of assigned functions. Finally, we provide some recommendations to help define the most effective and efficient relationship between public health and the health system (AU)

[Public health and the health system. SESPAS Report 2010]. / Salud pública y sistema sanitario. Informe SESPAS 2010.

Analysis of the relationship between public health and the health system requires definition of a conceptual framework and the choice of a particular context. The chosen context of this discussion is the management of public organizations. With this in mind, functions will be associated with organizational macroprocesses. From this point of view, this article identifies the functions-processes that any health system should develop and their goals. The current situation of public health in the health system is analyzed through the study of public health budgets and the place they occupy in the hierarchy of the health departments of the autonomous communities. The "public health" budget program represents an average of 1.34% of health expenditure in the autonomous communities in 2010. Over 20% of public health organizations of the autonomous communities have a rank lower than general directorate. These data indicate the low weight assigned to public health in the health systems of the Spanish state. To change this situation, consensus must be reached on the desired relationship between public health and the health system. Such a consensus would then have to be accepted and work would have to be undertaken to improve results. Three alternatives are proposed: (i) public health would be an organization that would be above or outside the health system; (ii) public health would be synonymous with the public health system; and (iii) public health would form part of the health system with a range of assigned functions. Finally, we provide some recommendations to help define the most effective and efficient relationship between public health and the health system.

Inhibitory action of Wnt target gene osteopontin on mitochondrial cytochrome c release determines renal ischemic resistance.

Certain determinants of ischemic resistance in the Brown Norway rat strain have been proposed, but no studies to date have focused on the role of the Wnt pathway in the ischemic resistance mechanism. We performed a comparative genomic study in Brown Norway vs. Sprague-Dawley rats. Selective manipulations of the Wnt pathway in vivo and in vitro allowed us to study whether the action of the Wnt pathway on apoptosis through the regulation of osteopontin was critical to the maintenance of inherent ischemic resistance mechanisms. The results revealed a major gene upregulation of the Wnt family in Brown Norway rats after renal ischemia-reperfusion. Manipulation of the Wnt signaling cascade by selective antibodies increased mitochondrial cytochrome c release and caspase 3 activity. The antiapoptotic role of Wnt was mediated by osteopontin, a direct Wnt target gene. Osteopontin was reduced by Wnt antibody administration in vivo, and osteopontin gene silencing in vitro significantly increased mitochondrial cytochrome c release. The overexpression of Wnt pathway genes detected in Brown Norway rats is critical in the maintenance of their inherent ischemic resistance. Activation of the Wnt signaling cascade reduces mitochondrial cytochrome c release and caspase 3 activity through the action of osteopontin.

Cisplatin upregulates mitochondrial nitric oxide synthase and peroxynitrite formation to promote renal injury.

The mitochondria are a critical target for cisplatin-associated nephrotoxicity. Though nitric oxide formation has been implicated in the toxicity of cisplatin, this formation has not so far been related to a possible activation of mitochondrial nitric oxide synthase (mNOS). We show here that the upregulation of oxide mNOS and peroxynitrite formation in cisplatin treatment are key events that influence the development of the harmful parameters described in cisplatin-associated kidney failure. We confirm this by isolating the mitochondrial fraction of the kidney and across different access routes such as the use of a specific inhibitor of neuronal NOS, L-NPA, a peroxynitrite scavenger, FeTMPyP, and a peroxynitrite donor, SIN-1. The in vitro studies corroborated the information obtained in the in vivo experiments. The administration of cisplatin reveals a clear upregulation in the transcription of neuronal NOS and an increase in the levels of nitrites in the mitochondrial fractions of the kidneys. The upregulated transcription directly affects the cytoskeleton structure and the apoptosis. The inhibition of neuronal NOS reduces the levels of nitrites, cell death, and cytoskeleton derangement. Peroxynitrite is involved in the mechanism promoting the NOS transcription. In addition, in controls SIN-1 imitates the effects of cisplatin. In summary, we demonstrate that upregulation of mNOS in cisplatin treatment is a key component in both the initiation and the spread of cisplatin-associated damage in the kidney. Furthermore, peroxynitrite formation is directly involved in this process.

[Processes maps in public health organizations: the experience of the Galician Department of Public Health]. / Mapa de procesos en organizaciones de salud pública: la experiencia de la Dirección Xeral de Saúde Pública de Galicia.

To design the processes map of the Galician Department of Public Health, we performed document reviews, held meetings and interviewed persons in charge of programs and departments to identify the processes carried out. The processes were classified into strategic, key and support processes. We defined 4 levels of disaggregation and management and staff were kept informed throughout the process. At level 0, we included 4 key processes that defined the organization's mission. At level 1, 5 strategic, 5 support and 10 key processes were defined. The key processes at level 2 identified the health programs' services. A processes map was obtained by consensus and was then approved by management and staff as a first step in implanting a process management system to improve the organization's performance.

Mapa de procesos en organizaciones de salud pública: la experiencia de la Dirección Xeral de Saúde Pública de Galicia / Processes maps in public health organizations: the experience of the Galician Department of Public Health

Con el objetivo de elaborar el mapa de procesos de la Dirección General de Salud Pública gallega, se realizaron revisiones documentales, reuniones y entrevistas a responsables de programas y jefes de servicio para identificar los procesos realizados, que se clasificaron en estratégicos, clave y de apoyo. Se definieron hasta 4 niveles de desagregación, y seinformó a la dirección y a los trabajadores de todo el proceso. En el nivel 0 se incluyeron los 4 procesos clave que definían la misión de la organización y, en el 1, 5 estratégicos, 5 de apoyo y los 10 clave. Los procesos clave de nivel 2 identifican servicios de los programas de salud. Se obtuvo un mapa de procesos consensuado que contaba con la aprobación de la dirección y de los trabajadores como paso previo para laimplantación de un sistema de gestión de procesos como mejora de la gestión en la organización

To design the processes map of the Galician Department ofPublic Health, we performed document reviews, held meetings and interviewed persons in charge of programs and departments to identify the processes carried out. The processes were classified into strategic, key and support processes. We defined 4 levels of disaggregation and management and staff were kept informed throughout the process. At level 0, we included 4 key processes that defined the organization’s mission. At level 1, 5 strategic, 5 support and 10 key processes were defined. The key processes at level 2 identified the healthprograms’ services. A processes map was obtained byconsensus and was then approved by management and staffas a first step in implanting a process management systemto improve the organization’s performance (AU)

Coordinación. La experiencia de la red de los programas de detección precoz de cáncer de mama / Coordination. The experience of the breast cancer early detection program network

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Role of peroxynitrite on cytoskeleton alterations and apoptosis in renal ischemia-reperfusion.

During renal ischemia-reperfusion (I/R) injury, apoptosis has been reported as a very important contributor to final kidney damage. The determinant role of cytoskeleton derangement in the development of apoptosis has been previously reported, but a clear description of the different mechanisms involved in this process has not been yet provided. The aim of our study was to know the role of peroxynitrite as an inductor of cytoskeleton derangement and apoptosis during renal I/R. Based on a rat kidney I/R model, using experiments in which both the actin cytoskeleton and peroxynitrite generation were pharmacologically manipulated, results indicate that the peroxynitrite produced during the I/R-derived oxidative stress state is able to provoke cytoskeleton derangement and apoptosis development. Thus control of peroxynitrite generation during I/R could be an effective tool for the improvement of cytoskeleton damage and reduction of apoptosis incidence in renal I/R injury.

NO and NOS isoforms in the development of apoptosis in renal ischemia/reperfusion.

Nitric oxide (NO) and the expression of endothelial (eNOS) and inducible (iNOS) isoforms of nitric oxide synthase (NOS) are recognized as important mediators of physiological and pathological processes of renal ischemia/reperfusion (I/R) injury, but little is known about their role in apoptosis. The ability of the eNOS/NO system to regulate the iNOS/NO system and thus promote apoptosis was assessed during experimental renal I/R. Renal caspase-3 activity and the number of TUNEL-positive cells increased with I/R, but decreased when NOS/NO systems were blocked with L-NIO (eNOS), 1400W (iNOS), and N-nitro-l-arginine methyl ester (L-NAME; a nonselective NOS inhibitor). I/R increased renal eNOS and iNOS expression as well as NO production. The NO increase was eNOS- and iNOS-dependent. Blockage of NOS/NO systems with L-NIO or L-NAME also resulted in a lower renal expression of iNOS and iNOS mRNA; in contrast, eNOS expression was not affected by iNOS-specific blockage. In conclusion, two pathways define the role of NOS/NO systems in the development of apoptosis during experimental renal I/R: a direct route, through eNOS overexpression and NO production, and an indirect route, through expression/activation of the iNOS/NO system, induced by eNOS.