Finerenone protects against progression of kidney and cardiovascular damage in a model of type 1 diabetes through modulation of proinflammatory and osteogenic factors.

The non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone (FIN) improves kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) in type 2 diabetes (T2D). We explored the effect of FIN in a novel model of type 1 diabetic Munich Wistar Frömter (MWF) rat (D) induced by injection of streptozotocin (15 mg/kg) and additional exposure to a high-fat/high-sucrose diet. Oral treatment with FIN (10 mg/kg/day in rat chow) in diabetic animals (D-FIN) was compared to a group of D rats receiving no treatment and a group of non-diabetic untreated MWF rats (C) (n = 7-10 animals per group). After 6 weeks, D and D-FIN exhibited significantly elevated blood glucose levels (271.7 ± 67.1 mg/dl and 266.3 ± 46.8 mg/dl) as compared to C (110.3 ± 4.4 mg/dl; p < 0.05). D showed a 10-fold increase of kidney damage markers Kim-1 and Ngal which was significantly suppressed in D-FIN. Blood pressure, pulse wave velocity (PWV) and arterial collagen deposition were lower in D-FIN, associated to an improvement in endothelial function due to a reduction in pro-contractile prostaglandins, as well as reactive oxygen species (ROS) and inflammatory cytokines (IL-1, IL-6, TNFα and TGFß) in perivascular and perirenal adipose tissue (PVAT and PRAT, respectively). In addition, FIN restored the imbalance observed in CKD between the procalcifying BMP-2 and the nephroprotective BMP-7 in plasma, kidney, PVAT, and PRAT. Our data show that treatment with FIN improves kidney and vascular damage in a new rat model of DKD with T1D associated with a reduction in inflammation, fibrosis and osteogenic factors independently from changes in glucose homeostasis.

Beneficial Effect of Bariatric Surgery on Abnormal MMP-9 and AMPK Activities: Potential Markers of Obesity-Related CV Risk.

Bariatric surgery (BS) results in sustained weight loss and may reverse inflammation, metabolic alterations, extracellular matrix remodeling and arterial stiffness. We hypothesize that increased stiffening in omental arteries from obese patients might be associated with an increase in MMP activity and a decrease in p-AMPK, together with systemic oxidative stress and inflammation. Moreover, BS could contribute to reversing these alterations. This study was conducted with 38 patients of Caucasian origin: 31 adult patients with morbid obesity (9 men and 22 women; mean age 46 years and BMI = 42.7 ± 1.0 kg/m2) and 7 non-obese subjects (7 women; mean age 45 years and BMI = 22.7 ± 0.6 kg/m2). Seventeen obese patients were studied before and 12 months after BS. The stiffness index ß, an index of intrinsic arterial stiffness, was determined in omental arteries and was significantly higher in obese patients. Levels of phosphorylated AMPK (p-AMPKThr-172) and SIRT-1 were significantly lower in peripheral blood mononuclear cells (PBMCs) from obese patients than those from non-obese patients (p < 0.05) and were normalized after BS. Total and active MMP-9 activities, LDH, protein carbonyls and uric acid were higher in obese patients and reduced by BS. Moreover, there was a correlation between plasmatic LDH levels and the stiffness index ß. BS has a beneficial effect on abnormal MMP-9, LDH and AMPK activities that might be associated with the development of arterial stiffness in obese patients. Since these parameters are easily measured in blood samples, they could constitute potential biomarkers of cardiovascular risk in morbid obesity.

Role of PVAT in coronary atherosclerosis and vein graft patency: friend or foe?

Perivascular adipose tissue (PVAT) releases numerous factors and adipokines with paracrine effects on both vascular structure and function. These effects are variable as they depend on regional differences in PVAT among blood vessels and vary with changes in adiposity. There is considerable evidence demonstrating an association between coronary PVAT and the development and progression of coronary artery disease, which is associated with inflammation, oxidative stress, angiogenesis, vascular remodelling and blood clotting. However, PVAT also has a protective role in vascular grafts, especially the no-touch saphenous vein, in patients undergoing coronary artery bypass. This beneficial influence of PVAT involves factors such as adipocyte-derived relaxing factor, nitric oxide (NO), leptin, adiponectin, prostanoids, hydrogen sulphide and neurotransmitters, as well as mechanical protection. This article aims to highlight and compare the dual role of PVAT in the development and progression of coronary atherosclerosis, as well as in increased graft patency. Different deleterious and protective mechanisms of PVAT are also discussed and the inside-outside signalling paradigm of atherosclerosis development re-evaluated. The bidirectional communication between the arterial and venous wall and their surrounding PVAT, where signals originating from the vascular wall or lumen can affect PVAT phenotype, has been shown to be very complex. Moreover, signals from PVAT also influence the structure and function of the vascular wall in a paracrine manner. LINKED ARTICLES: This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.

Vascular AMPK as an attractive target in the treatment of vascular complications of obesity.

The key for the survival of all organisms is the regulation and control of energy metabolism. Thus, several strategies have evolved in each tissue in order to balance nutrient supply with energy demand. Adenosine monophosphate-activated protein kinase (AMPK) is now recognized as a key participant in energy metabolism. It ensures an appropriate energetic supply by promoting energy conserving pathways in detriment of anabolic processes not essential for cell survival. Vascular AMPK plays a critical role in the regulation of blood flow and vascular tone through several mechanisms, including vasodilation by stimulating nitric oxide release in endothelial cells. Since obesity leads to endothelial damage and AMPK dysregulation, AMPK activation might be an important strategy to restore vascular function in cardiometabolic alterations. In the present review we focus on the role of vascular AMPK in both endothelial and smooth muscle cells, paying special attention to its dysregulation in obesity- and high-fat diet-related complications, as well as to the mechanisms and benefits of vascular AMPK activation.

Mild caloric restriction reduces blood pressure and activates endothelial AMPK-PI3K-Akt-eNOS pathway in obese Zucker rats.

Genetic obesity models exhibit endothelial dysfunction associated to adenosine monophosphate-activated protein kinase (AMPK) dysregulation. This study aims to assess if mild short-term caloric restriction (CR) restores endothelial AMPK activity leading to an improvement in endothelial function. Twelve-week old Zucker lean and obese (fa/fa) male rats had access to standard chow either ad libitum (AL, n=8) or 80% of AL (CR, n=8) for two weeks. Systolic blood pressure was significantly higher in fa/fa AL rats versus lean AL animals, but was normalized by CR. Endothelium-dependent relaxation to acetylcholine (ACh, 10(-9) to 10(-4) M) was reduced in fa/fa AL compared to control lean AL rats (p<0.001), and restored by CR. The AMPK activator AICAR (10(-5) to 8·10(-3) M) elicited a lower relaxation in fa/fa AL rings that was normalized by CR (p<0.001). Inhibition of PI3K (wortmannin, 10(-7) M), Akt (triciribine, 10(-5) M), or eNOS (L-NAME, 10(-4) M) markedly reduced AICAR-induced relaxation in lean AL, but not in fa/fa AL rats. These inhibitions were restored by CR in Zucker fa/fa rings. These data show that mild short-term CR improves endothelial function and lowers blood pressure in obesity due to the activation of the AMPK-PI3K-Akt-eNOS pathway.

[Influence of climate, according to Koppën classification and Lang's index, on gross rate mortality associated with prostate cancer in the geographical area of Spain]. / Influencia de la climatología, según la clasificación de Koppën e índice de Lang, sobre la tasa bruta de mortalidad asociada al cancer de próstata en el área geográfica de España.

OBJECTIVE: To evaluate if the climatic factors of temperature and rainfall influence mortality associated with prostate cancer for a period of five years. MATERIAL AND METHODS: The mortality trends associated with prostate cancer will be evaluated in the period ranging from 1st january 1998 to 31st december 2002, in the geographical area of Spain. The demographic and mortality data were obtained from the National Institute of Statistics and the climatologically data on temperature and rainfall were obtained from the National Meteorology Institute applying the values registered in 2002. Based on the meteorological data, the different provinces are classified in accordance with Koppën climate classification and climatic index of Lang that defines them from the mean annual and monthly temperature and rainfall data. Mortality rates will be expressed by 100.000 men year, applying for their study the Kruskall-Wallis test for "n" independent samples through the SPSS v12.0 Windows software. RESULTS: Three main climatic areas are obtained, one area with type B climate, which accounts for 13% of the total population, a Csa climate, and a Csb, accounting for 67 and 20% respectively. The mortality found is higher in the Csb type for prostate cancer (p= 0.007), as compared to the other two climatic areas. CONCLUSION: Mortality associated with prostate cancer is significantly higher in the regions with a lower sun exposure. However, randomized prospective studies confirming these findings are warranted.

Influencia de la climatología, según la clasificación de Koppën e índice de Lang, sobre la tasa bruta de mortalidad asociada al cáncer de próstata en el área geográfica de España / Influence of climate, according to Koppën classification and Lang´s index, on gross rate mortality associated with prostate cancer in the geographical area of Spain

Objetivo: Evaluar si los factores climatológicos de temperaturas y precipitaciones influyen sobre la mortalidad asociada al cáncer de próstata a lo largo de un periodo de cinco años. Material y Métodos: Se evalúan las tendencias de mortalidad asociada al cáncer de próstata en el periodo comprendido entre el 1 de enero de 1998 y el 31 de diciembre de 2002, en el área geográfica de España. Los datos demográficos y de mortalidad se obtuvieron del Instituto Nacional de Estadística y los datos climatológicos de temperaturas y precipitaciones se obtuvieron del Instituto Nacional de Meteorología aplicándose los valores registrados en el año 2002. A partir de los datos meteorológicos se clasifican las diferentes provincias de acuerdo a la clasificación climática de Koppën, que los define a partir de los valores medios anuales y mensuales de temperatura y precipitación. Las tasas de mortalidad serán expresadas por 100.000 habitantes y año (100.000 varones año en el caso del cáncer de próstata) aplicándose para su estudio el test de Kruskall-Wallis para “n” muestras independientes mediante el software SPSS v12.0 para Windows. Resultados: Se obtienen tres áreas climáticas fundamentales, un área con clima tipo B que representa el 13 % de la población total, un clima Csa y otro Csb que representan el 67 y el 20 % respectivamente. La mortalidad hallada para el cáncer de próstata es mayor de forma estadísticamente significativa en el área climática Csb (p= 0,007), cuando se compara con las otras dos áreas climáticas. Conclusión: La mortalidad asociada al cáncer de próstata es significativamente superior en las regiones con menor exposición solar. No obstante se requieren estudios prospectivos randomizados que confirmen estos hallazgos (AU)

Objective: To evaluate if the climatic factors of temperature and rainfall influence mortality associated with prostate cancer for a period of five years. Material and methods: The mortality trends associated with prostate cancer will be evaluated in the period ranging from 1st january 1998 to 31st december 2002, in the geographical area of Spain. The demographic and mortality data were obtained from the National Institute of Statistics and the climatologically data on temperature and rainfall were obtained from the National Meteorology Institute applying the values registered in 2002. Based on the meteorological data, the different provinces are classified in accordance with Koppën climate classification and climatic index of Lang that defines them from the mean annual and monthly temperature and rainfall data. Mortality rates will be expressed by 100.000 men year, applying for their study the Kruskall-Wallis test for “n” independent samples through the SPSS v12.0 Windows software. Results: Three main climatic areas are obtained, one area with type B climate, which accounts for 13% of the total population, a Csa climate, and a Csb, accounting for 67 and 20% respectively. The mortality found is higher in the Csb type for prostate cancer (p= 0.007), as compared to the other two climatic areas. Conclusion: Mortality associated with prostate cancer is significantly higher in the regions with a lower sun exposure. However, randomized prospective studies confirming these findings are warranted (AU)

Specific dose-dependent damage of Lieberkühn crypts promoted by large doses of type 2 ribosome-inactivating protein nigrin b intravenous injection to mice.

Nigrin b is a non-toxic type 2 ribosome-inactivating protein as active as ricin at ribosomal level but 10(5) and 5 x 10(3) times less toxic for animal cell cultures and mice, respectively, than ricin. The purpose of the present study was to analyze the effects of intravenous injection of large amounts of nigrin b to the mouse. Injection through the tail vein of 16 mg/kg body weight killed all mice studied before 2 days. Analysis of several major tissues by light microscopy did not reveal gross nigrin b-promoted changes, except in the intestines which appeared highly damaged. As a consequence of the injury, the villi and crypt structures of the small intestine disappeared, leading to profuse bleeding and death. In contrast, intravenous injection of 5 mg/kg body weight was not lethal to mice but did trigger reversible toxic effects. In both cases, lethal and sub-lethal doses, the target of nigrin b appeared to be the highly proliferating stem cells of the intestinal crypts, which had undergone apoptotic changes. In contrast to nigrin b, the injection of 3 mug/kg of ricin kills all mice in 5 days but does not trigger apoptosis in the crypts. Therefore, the effect seen with sub-lethal nigrin b concentrations seems to be specific. Nigrin b killed COLO 320 human colon adenocarcinoma cells with an IC(50) of 3.1 x 10(-8) M and the effect was parallel to the extent of DNA fragmentation of these cells. Accordingly, despite the low general toxicity exerted by nigrin b as compared with ricin, intravenous injection of large amounts of nigrin b is able to kill mouse intestinal stem cells without threatening the lives of the animals, thereby opening a door for its use for the targeting of intestinal stem cells.

Expression and functional properties of group I metabotropic glutamate receptors in bovine chromaffin cells.

We demonstrate the presence and functional properties of Group I metabotropic glutamate receptors (mGluRs) expressed in chromaffin cells. Immunocytochemical techniques revealed that two mGluR subtypes (mGluR1alpha and mGluR5) are expressed in chromaffin cells, located in both the cytoplasmic membrane and the cytosol surrounding the nucleus. These mGluRs are functionally active on catecholamine (CA) secretion in chromaffin cells because both (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD) and the specific agonist of Group I mGluRs, (S)-3,5-dihydroxyphenylglycine (DHPG), were able to stimulate the release of CAs (adrenaline and noradrenaline) in a dose-response manner. These effects were specifically reversed by L-(+)-2-amino-3-phosphonopropionic acid (L-AP3), a selective antagonist of the Group I metabotropic glutamate receptors. t-ACPD induced an increase in CA secretion in both the presence and absence of extracellular calcium, the former effect being accompanied by cell membrane depolarization. Noradrenaline (NA) release was higher in the presence of extracellular calcium than in its absence, whereas adrenaline release was of the same order under both conditions. These results indicate that different subtypes of Group I mGluRs are present in noradrenergic and adrenergic cells. Fluorescence imaging techniques in single cells showed different t-ACPD-induced increases in intracellular calcium in different chromaffin cells: in chromaffin cells, 67% expressed functional metabotropic glutamate receptors and with nicotinic receptors, whereas the remaining 33% expressed only nicotinic receptors. In the absence of external calcium, only about 25% of cells responded to t-ACPD-increased intracellular calcium by increasing inositol 1,4,5-trisphosphate (IP(3)) concentration and subsequent calcium mobilization from intracellular stores, whereas the remaining 75% increased intracellular calcium by promoting Ca(2+) influx from the extracellular medium through L- and N- but not P/Q voltage-dependent calcium channels.

[A benign retroperitoneal schwannoma: a review of the literature and a report of a new case]. / Schwanoma retroperitoneal benigno: revisión de la literatura y aportación de un nuevo caso.

In a 42-years-old woman, an abdominal sonography was done, and a 10 x 9-cm solid cystic tumor on the left kidney appeared. Abdominal CT and arteriography showed a retroperitoneal heterogeneous mass surrounding and obstructing the ureteropelvic left junction. Tumor was removed under open surgery and the pathological study showed a benign schwannoma. We present this case because of its rarity 1%-10% of all primary retroperitoneal tumors.

[Female urethral caruncle. A thrombosis of the dorsal venous complex?]. / Carúncula uretral femenina. Trombosis del complejo venoso dorsal?

Five 72-86 years old women complaining of vaginal bleeding and genital discomfort during the last three weeks. Physical examination show an urethral mass of 1 cm diameter with a black, hard and painful area inside. Blood test was normal, and clinical diagnosis of caruncle urethral thrombosis was done. Topic treatment was develop with good results. We discuss the pathogenic and clinical presentation as well as the treatment of this unusual lesion.

[Renal tuberculosis associated with renal adenocarcinoma: unusual association]. / Tuberculosis renal asociada a adenocarcinoma renal: una asociación poco frecuente.

We present a patient 50 years old, complaining of right lumbar pain and miccional syndrome for three weeks. After analytic and x-ray studies, renal tuberculosis and renal cell carcinoma was the diagnosis. We started with specific antibiotic therapy and a radical nephrectomy was developed. According with the literature revised, just three cases has been published before. Because is an unusual clinic presentation we present these clinical note, we discuss the pathogenic and therapeutic procedures.

Expression of interferon-gamma receptors on murine oligodendrocytes and its regulation by cytokines and mitogens.

Interferon-gamma (IFN-gamma) is a cytokine known to exert an important immunological role on astrocytes and oligodendrocytes. As a receptor for IFN-gamma has been demonstrated on murine astrocytes, we have searched for a specific receptor on the cell surface of pure mouse oligodendrocytes maintained in tissue culture. Using recombinant murine IFN-gamma labelled with 125I, we have established the basic physicochemical parameters of the binding. A single receptor was found with a Kd of 1 x 10(-9) M. The number of receptors per cell was 3000-4000 and its molecular weight, as determined by cross-linking experiments, is 87,000. The binding of IFN-gamma to its oligodendrocyte receptor is saturable, specific and temperature-dependent. The receptor-IFN-gamma complex is quickly endocytosed at 37 degrees (the half-time of maximal internalization is around 1 min). Some cytokines, such as interleukin-1 alpha and interleukin-6, up-regulated the expression of the oligodendrocyte receptor, but others, such as tumour necrosis factor-alpha, did not. A dramatic increase in receptor expression is induced by lipopolysaccharide but it is not detectable after treatment with concanavalin A.

The receptor for tumor necrosis factor on murine astrocytes: characterization, intracellular degradation, and regulation by cytokines and Theiler's murine encephalomyelitis virus.

Previous reports have shown that tumor necrosis factor (TNF) exerts a role on the physiology of astrocytes under inflammatory situations. The signalling for biological effects of this and other cytokines are usually exerted through cell surface receptors. In this study, we have demonstrated the presence of a surface TNF alpha receptor type I in murine astrocytes of both SJL/J and BALB/c origin, using 125I-labelled recombinant mouse TNF alpha. A linear Scatchard plot indicates the presence of only one type of receptor with a MW of 58 kDa (Type I TNF receptor) that binds the ligand with a Kd of 1 x 10(-9) M. There are 3,000 copies of this receptor on untreated astrocytes. The results also indicate that receptor-bound TNF is rapidly internalized at 37 degrees C and degraded intracellularly to a principal molecular species which elutes from HPLC reverse-phase columns at 38% acetonitrile rather than at 60%, as native TNF alpha does. The binding is up-regulated by increasing the number of receptors (but not its affinity) by treatments with Theiler's murine encephalomyelitis virus (TMEV), Con A and inflammatory cytokines such as IL-1 alpha, IL-6, and INF-gamma. It is not influenced by vaccinia virus, IL-2, or LPS. This receptor may contribute to the initiation of perpetuation of the immune response which mediates the demyelinating inflammation induced by Theiler's virus.

[Liver glycogen, blood glucose, somatotropic hormone, and hypophyseal thyrotropin in neonatal rats treated with cortisol and in malnourished ones]. / Glucógeno hepático, glucemia, hormona somatotropa y tirotropa hipofisaria en ratas neonatales tratadas con cortisol y malnutridas.

A population of rats treated with a single dose of cortisol on their first day of life and a population of rats underfed since day sixteen of gestation until sacrificed have been studied. Body, brain and liver glycogen content have been measured at eight, twelve and twenty-two days of life and compared to controls of the same age. Pituitary growth hormone and thyrotrophin content have also been measured in the same population of animals and at the same stages of life. Results are compared to those found in "neo-T4" rats -- which receive 30 micrograms T4 in 5 doses during the first days of life -- at the same ages.