Transfer of H2O2 from Mitochondria to the endoplasmic reticulum via Aquaporin-11.

Some aquaporins (AQPs) can transport H2O2 across membranes, allowing redox signals to proceed in and between cells. Unlike other peroxiporins, human AQP11 is an endoplasmic reticulum (ER)-resident that can conduit H2O2 to the cytosol. Here, we show that silencing Ero1α, an ER flavoenzyme that generates abundant H2O2 during oxidative folding, causes a paradoxical increase in luminal H2O2 levels. The simultaneous AQP11 downregulation prevents this increase, implying that H2O2 reaches the ER from an external source(s). Pharmacological inhibition of the electron transport chain reveals that Ero1α downregulation activates superoxide production by complex III. In the intermembrane space, superoxide dismutase 1 generates H2O2 that enters the ER channeled by AQP11. Meanwhile, the number of ER-mitochondria contact sites increases as well, irrespective of AQP11 expression. Taken together, our findings identify a novel interorganellar redox response that is activated upon Ero1α downregulation and transfers H2O2 from mitochondria to the ER via AQP11.

Adipose-Derived Exosomes as Possible Players in the Development of Insulin Resistance.

Adipose tissue (AT) is an endocrine organ involved in the management of energy metabolism via secretion of adipokines, hormones, and recently described secretory microvesicles, i.e., exosomes. Exosomes are rich in possible biologically active factors such as proteins, lipids, and RNA. The secretory function of adipose tissue is affected by pathological processes. One of the most important of these is obesity, which triggers adipose tissue inflammation and adversely affects the release of beneficial adipokines. Both processes may lead to further AT dysfunction, contributing to changes in whole-body metabolism and, subsequently, to insulin resistance. According to recent data, changes within the production, release, and content of exosomes produced by AT may be essential to understand the role of adipose tissue in the development of metabolic disorders. In this review, we summarize actual knowledge about the possible role of AT-derived exosomes in the development of insulin resistance, highlighting methodological challenges and potential gains resulting from exosome studies.

Aquaporins in insulin resistance and diabetes: More than channels!

Aquaporins (AQPs) are part of the family of the integral membrane proteins. Their function is dedicated to the transport of water, glycerol, ammonia, urea, H2O2, and other small molecules across the biological membranes. Although for many years they were scarcely considered, AQPs have a relevant role in the development of many diseases. Recent discoveries suggest, that AQPs may play an important role in the process of fat accumulation and regulation of oxidative stress, two crucial aspects of insulin resistance and type-2 diabetes (T2D). Insulin resistance (IR) and T2D are multi-faceted systemic diseases with multiple connections to obesity and other comorbidities such as hypertension, dyslipidemia and metabolic syndrome. Both IR and T2D transcends different tissues and organs, creating the maze of mutual relationships between adipose fat depots, skeletal muscle, liver and other insulin-sensitive organs. AQPs with their heterogenous properties, distinctive tissue distribution and documented involvement in both the lipid metabolism and regulation of the oxidative stress appear to be feasible candidates in the search for the explanation to this third-millennium plague. A lot of research has been assigned to adipose tissue AQP7 and liver tissue AQP9, clarifying their relationship and coordinated work in the induction of hepatic insulin resistance. Novel research points also to other aquaporins, such as AQP11 which may be associated with the induction of insulin resistance and T2D through its involvement in hydrogen peroxide transport. In this review we collected recent discoveries in the field of AQP's involvement in the insulin resistance and T2D. Novel paths which connect AQPs with metabolic disorders can give new fuel to the research on obesity, insulin resistance and T2D - one of the most worrying problems of the modern society.

Proline oxidase silencing inhibits p53-dependent apoptosis in MCF-7 breast cancer cells.

Proline oxidase (POX) is mitochondrial proline-degrading enzyme of dual apoptosis/survival function. POX expression and proline availability are considered an underlying mechanism for differential POX functions. The mechanism for POX-dependent regulation of cell death/survival was studied in wild-type (MCF-7WT) and shRNA POX-silenced breast cancer cells (MCF-7iPOX). Proline concentration and proteomic analyses were determined by LC/MS/QTOF and LC/MS/ORBITRA, respectively. Inhibition of collagen biosynthesis (proline utilizing process) by 2-methoxyestradiol (2ME) contributed to induction of apoptosis in MCF-7WT cells, as detected by increase in the expression of active caspase-3, -9 and p53. The process was not shown in MCF-7iPOX. In MCF-7iPOX cells prolidase activity and expression as well as proline concentration were drastically increased, compared to MCF-7WT cells. Down-regulation of p53 in MCF-7iPOX cells was corroborated by proteomic analysis showing decrease in the expression of p53-related proteins. The mechanism for down-regulation of p53 expression in MCF-7iPOX cells was found at the level of p53-PEPD complex formation that was counteracted by hydrogen peroxide treatment. In this study, we found that silencing POX modulate pro-survival phenotype of MCF-7 cells and suggest that the mechanism of this process undergoes through down-regulation of p53-dependent signaling.

Select Polyphenol-Rich Berry Consumption to Defer or Deter Diabetes and Diabetes-Related Complications.

Berries are considered "promising functional fruits" due to their distinct and ubiquitous therapeutic contents of anthocyanins, proanthocyanidins, phenolic acids, flavonoids, flavanols, alkaloids, polysaccharides, hydroxycinnamic, ellagic acid derivatives, and organic acids. These polyphenols are part of berries and the human diet, and evidence suggests that their intake is associated with a reduced risk or the reversal of metabolic pathophysiologies related to diabetes, obesity, oxidative stress, inflammation, and hypertension. This work reviewed and summarized both clinical and non-clinical findings that the consumption of berries, berry extracts, purified compounds, juices, jams, jellies, and other berry byproducts aided in the prevention and or otherwise management of type 2 diabetes mellitus (T2DM) and related complications. The integration of berries and berries-derived byproducts into high-carbohydrate (HCD) and high-fat (HFD) diets, also reversed/reduced the HCD/HFD-induced alterations in glucose metabolism-related pathways, and markers of oxidative stress, inflammation, and lipid oxidation in healthy/obese/diabetic subjects. The berry polyphenols also modulate the intestinal microflora ecology by opposing the diabetic and obesity rendered symbolic reduction of Bacteroidetes/Firmicutes ratio, intestinal mucosal barrier dysfunction-restoring bacteria, short-chain fatty acids, and organic acid producing microflora. All studies proposed a number of potential mechanisms of action of respective berry bioactive compounds, although further mechanistic and molecular studies are warranted. The metabolic profiling of each berry is also included to provide up-to-date information regarding the potential anti-oxidative/antidiabetic constituents of each berry.

Human aquaporin-11 guarantees efficient transport of H2O2 across the endoplasmic reticulum membrane.

Hydrogen peroxide (H2O2) is an essential second intracellular messenger. To reach its targets in the cytosol, H2O2 must cross a membrane, a feat that requires aquaporins (AQP) endowed with 'peroxiporin' activity (AQP3, AQP8, AQP9). Here, we exploit different organelle-targeted H2O2-sensitive probes to show that also AQP11 efficiently conduits H2O2. Unlike other peroxiporins, AQP11 is localized in the endoplasmic reticulum (ER), accumulating partly in mitochondrial-associated ER membranes (MAM). Its downregulation severely perturbs the flux of H2O2 through the ER, but not through the mitochondrial or plasma membranes. These properties make AQP11 a potential regulator of ER redox homeostasis and signaling.

A persulfidation-based mechanism controls aquaporin-8 conductance.

Upon engagement of tyrosine kinase receptors, nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases release H2O2 in the extracellular space. We reported previously that aquaporin-8 (AQP8) transports H2O2 across the plasma membrane and is reversibly gated during cell stress, modulating signal strength and duration. We show that AQP8 gating is mediated by persulfidation of cysteine 53 (C53). Treatment with H2S is sufficient to block H2O2 entry in unstressed cells. Silencing cystathionine ß-synthase (CBS) prevents closure, suggesting that this enzyme is the main source of H2S. Molecular modeling indicates that C53 persulfidation displaces a nearby histidine located in the narrowest part of the channel. We propose that H2O2 molecules transported through AQP8 sulfenylate C53, making it susceptible to H2S produced by CBS. This mechanism tunes H2O2 transport and may control signaling and limit oxidative stress.

AQP8 transports NOX2-generated H2O2 across the plasma membrane to promote signaling in B cells.

H2O2 acts as a second messenger in key signaling circuits, transiently modulating tyrosine phosphatases and kinases. We investigated its origin, membrane transport, and functional role during B cell activation and differentiation. Our data identified NADPH-oxidase 2 as the main source of H2O2 and aquaporin 8 as a transport facilitator across the plasma membrane. On aquaporin 8 silencing, inducible B lymphoma cells responded poorly to TLR and BCR stimulation. Their differentiation was severely impaired, as demonstrated by retarded onset of IgM polymerization, low amounts of IgM secretion, and prolonged BCR expression on the cell surface. A silencing-resistant aquaporin 8 rescued responsiveness, confirming that the import of H2O2 across the membrane is essential for B cell activation. The addition of exogenous catalase to primary B splenocytes severely impaired the tyrosine phosphorylation induced by BCR cross-linking, as did the absence of NOX2 in a murine model of chronic granulomatous disease. Importantly, re-expression of gp91phox through gene therapy restored the specific B cell signaling deficiency in NOX2-/- cells. Thus, efficient induction of B cell activation and differentiation requires intact H2O2 fluxes across the plasma membrane for signal amplification.

Estudo de algumas variáveis físicas como fatores de influência nas lesões em judocas / Study of the some physicals variables how factors of the influence in judoistics lesions

Este estudo, descritivo de tendência longitudinal, objetivou analisar a influência do tempo de prática, dagraduação judoística e do condicionamento físico nas lesões sofridas pelos judocas em 12 meses. Participaram 42 judocas na primeira avaliação; 18 na segunda e 8 na última. O grupo apresentou média de idade de 23,7 ± 7,4 anos, com média de tempo de prática de 6,7± 6,3 anos, sendo dez faixas brancas; uma azul; quatro amarelas; cinco laranjas; cinco verdes; três roxas; oito marrons e seis pretas. A coleta de dados, realizada no local da prática, com aplicação de testes de avaliação física e medidas antropométricas. Os dados foram analisados mediante a estatísticadescritiva, teste Qui-Quadrado, teste "t" de Student, análise de variância - ANOVA - ONE WAY e análise deRegressão Múltipla. Os resultados indicam que: o grupo apresentou 42 lesões; não se encontrou associação (p<0,05) entre graduação e número de lesões (c2c = 3,71), e entre tempo de prática e número de lesões (c2c = 0,12); só encontrou-se diferença significativa, entre a primeira e a segunda avaliação, em relação à força de braço, (t c = -3,66) e na aplicação do ANOVA - ONE WAY, não se encontrou diferença significativa em nenhuma das variáveis. A equação de regressão múltipla (Coeficiente de determinação r2 = 0,63174), representou que para 63,17% dos judocas, as lesões podem ser explicadas pelo efeito das variáveis citadas. Concluiu-se que tanto o tempo de prática como a graduação, não interferiram no número de lesões; no entanto, houve a interferência da maioria das variáveis inerentesao condicionamento físico...

This descriptive study of the longitudinal tendency had the objective of analysing the influence of practice time of the judoistic gradation and the physical preparation in the lesions suffered by the judoists in 12 months. Fortytwojudoists participated in the first evaluation, 18 in the second and 8 in the last. The average age of the group wasbetween 23,7 7,4, with na average practive time of 6,7 6,3 years; tem white belts, one blue, four yellow, five orange, five green, three purple, eight brown and six black belts. The gathering of the data took place at the practive site by applying physical evaluation tests and anthropometrical measures. The data was analysed according to a descriptive statistic, Chi-Square test, "t" the Student test, variance analysis - ANOVA ONE WAY and Multiple Regression analysis. The results indicate that: the group presentes 42 lesions; no association (p<0,05) was found between gradation and the number of lesions (c2c = 3,71), and between practive time and number of lesion (c2c = 0,12); the only significant difference found was between the first and second evaluation in relation to the strength of the arm, (tc = -3,66), and in the ANOVA ONE WAY application no significant difference was found in any of the variables. The multiple regression equation (r2 = 0,63174), showed that for 63,17% of the judoists the lesions can be explained by the effects of the aforementioned variables. The conclusion was that neither the pratice time nor the gradation interferedin the number of lesions; however, there was interference in most of the variables inherent to physical preparation...