Adenosine kinase inhibition protects mice from abdominal aortic aneurysm via epigenetic modulation of VSMC inflammation.

AIM: Abdominal aortic aneurysm (AAA) is a common, serious vascular disease with no effective pharmacological treatment. The nucleoside adenosine plays an important role in modulating vascular homeostasis, which prompted us to determine whether adenosine kinase (ADK), an adenosine metabolizing enzyme, modulates AAA formation via control of intracellular adenosine level, and to investigate the underlying mechanisms. METHODS AND RESULTS: We used a combination of genetic and pharmacological approaches in murine models of AAA induced by calcium chloride (CaCl2) application or angiotensin II (Ang II) infusion to study the role of ADK in the development of AAA. In vitro functional assays were performed by knocking down ADK with adenovirus-short hairpin RNA in human vascular smooth muscle cells (VSMCs), and the molecular mechanisms underlying ADK function were investigated using RNA-sequencing, isotope tracing and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). Heterozygous deficiency of Adk protected mice from CaCl2- and Ang II-induced AAA formation. Moreover, specific knockout of Adk in VSMCs prevented Ang II-induced AAA formation, as evidenced by reduced aortic extracellular elastin fragmentation, neovascularization and aortic inflammation. Mechanistically, ADK knockdown in VSMCs markedly suppressed the expression of inflammatory genes associated with AAA formation, and these effects were independent of adenosine receptors. Metabolic flux and ChIP-qPCR results showed that ADK knockdown in VSMCs decreased S-adenosylmethionine (SAM)-dependent transmethylation, thereby reducing H3K4me3 binding to the promoter regions of the genes that are associated with inflammation, angiogenesis and extracellular elastin fragmentation. Furthermore, the ADK inhibitor ABT702 protected mice from CaCl2-induced aortic inflammation, extracellular elastin fragmentation and AAA formation. CONCLUSION: Our findings reveal a novel role for ADK inhibition in attenuating AAA via epigenetic modulation of key inflammatory genes linked to AAA pathogenesis.

Blockade of endothelial adenosine receptor 2 A suppresses atherosclerosis in vivo through inhibiting CREB-ALK5-mediated endothelial to mesenchymal transition.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and morbidity and mortality rates continue to rise. Atherosclerosis constitutes the principal etiology of CVDs. Endothelial injury, inflammation, and dysfunction are the initiating factors of atherosclerosis. Recently, we reported that endothelial adenosine receptor 2 A (ADORA2A), a G protein-coupled receptor (GPCR), plays critical roles in neovascularization disease and cerebrovascular disease. However, the precise role of endothelial ADORA2A in atherosclerosis is still not fully understood. Here, we showed that ADORA2A expression was markedly increased in the aortic endothelium of humans with atherosclerosis or Apoe-/- mice fed a high-cholesterol diet. In vivo studies unraveled that endothelial-specific Adora2a deficiency alleviated endothelial-to-mesenchymal transition (EndMT) and prevented the formation and instability of atherosclerotic plaque in Apoe-/- mice. Moreover, pharmacologic inhibition of ADORA2A with KW6002 recapitulated the anti-atherogenic phenotypes observed in genetically Adora2a-deficient mice. In cultured human aortic endothelial cells (HAECs), siRNA knockdown of ADORA2A or KW6002 inhibition of ADORA2A decreased EndMT, whereas adenoviral overexpression of ADORA2A induced EndMT. Mechanistically, ADORA2A upregulated ALK5 expression via a cAMP/PKA/CREB axis, leading to TGFß-Smad2/3 signaling activation, thereby promoting EndMT. In conclusion, these findings, for the first time, demonstrate that blockade of ADORA2A attenuated atherosclerosis via inhibition of EndMT induced by the CREB1-ALK5 axis. This study discloses a new link between endothelial ADORA2A and EndMT and indicates that inhibiting endothelial ADORA2A could be an effective novel strategy for the prevention and treatment of atherosclerotic CVDs.

STRIPAK regulation of katanin microtubule severing in the Caenorhabditis elegans embryo.

Microtubule severing plays important role in cell structure and cell division. The microtubule severing protein katanin, composed of the MEI-1/MEI-2 subunits in Caenorhabditis elegans, is required for oocyte meiotic spindle formation; however, it must be inactivated for mitosis to proceed as continued katanin expression is lethal. Katanin activity is regulated by 2 ubiquitin-based protein degradation pathways. Another ubiquitin ligase, HECD-1, the homolog of human HECTD1/HECT domain E3 ubiquitin protein ligase 1, regulates katanin activity without affecting katanin levels. In other organisms, HECD-1 is a component of the striatin-interacting kinase phosphatase complex, which affects cell proliferation and a variety of signaling pathways. Here we conducted a systematic screen of how mutations in striatin-interacting kinase phosphatase components affect katanin function in C. elegans. Striatin-interacting kinase phosphatase core components (FARL-11, CASH-1, LET-92, and GCK-1) were katanin inhibitors in mitosis and activators in meiosis, much like HECD-1. By contrast, variable components (SLMP-1, OTUB-2) functioned as activators of katanin activity in mitosis, indicating they may function to alter striatin-interacting kinase phosphatase core function. The core component CCM-3 acted as an inhibitor at both divisions, while other components (MOB-4, C49H3.6) showed weak interactions with katanin mutants. Additional experiments indicate that katanin may be involved with the centralspindlin complex and a tubulin chaperone. HECD-1 shows ubiquitous expression in the cytoplasm throughout meiosis and early development. The differing functions of the different subunits could contribute to the diverse functions of the striatin-interacting kinase phosphatase complex in C. elegans and other organisms.

Deficiency of Myeloid Pfkfb3 Protects Mice From Lung Edema and Cardiac Dysfunction in LPS-Induced Endotoxemia.

Sepsis, a pathology resulting from excessive inflammatory response that leads to multiple organ failure, is a major cause of mortality in intensive care units. Macrophages play an important role in the pathophysiology of sepsis. Accumulating evidence has suggested an upregulated rate of aerobic glycolysis as a key common feature of activated proinflammatory macrophages. Here, we identified a crucial role of myeloid 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3), a glycolytic activator in lipopolysaccharide (LPS)-induced endotoxemia in mice. Pfkfb3 expression is substantially increased in bone marrow derived macrophages (BMDMs) treated with LPS in vitro and in lung macrophages of mice challenged with LPS in vivo. Myeloid-specific knockout of Pfkfb3 in mice protects against LPS-induced lung edema, cardiac dysfunction and hypotension, which were associated with decreased expression of interleukin 1 beta (Il1b), interleukin 6 (Il6) and nitric oxide synthase 2 (Nos2), as well as reduced infiltration of neutrophils and macrophages in lung tissue. Pfkfb3 ablation in cultured macrophages attenuated LPS-induced glycolytic flux, resulting in a decrease in proinflammatory gene expression. Mechanistically, Pfkfb3 ablation or inhibition with a Pfkfb3 inhibitor AZ26 suppresses LPS-induced proinflammatory gene expression via the NF-κB signaling pathway. In summary, our study reveals the critical role of Pfkfb3 in LPS-induced sepsis via reprogramming macrophage metabolism and regulating proinflammatory gene expression. Therefore, PFKFB3 is a potential target for the prevention and treatment of inflammatory diseases such as sepsis.

Cancer killers in the human gut microbiota: diverse phylogeny and broad spectra.

Cancer as a large group of complex diseases is believed to result from the interactions of numerous genetic and environmental factors but may develop in people without any known genetic or environmental risks, suggesting the existence of other powerful factors to influence the carcinogenesis process. Much attention has been focused recently on particular members of the intestinal microbiota for their potential roles in promoting carcinogenesis. Here we report the identification and characterization of intestinal bacteria that exhibited potent anti-malignancy activities on a broad range of solid cancers and leukemia. We collected fecal specimens from healthy individuals of different age groups (preschool children and university students), inspected their effects on cancer cells, and obtained bacteria with potent anti-malignancy activities. The bacteria mostly belonged to Actinobacteria but also included lineages of other phyla such as Proteobacteria and Firmicutes. In animal cancer models, sterile culture supernatant from the bacteria highly effectively inhibited tumor growth. Remarkably, intra-tumor administration of the bacterial products prevented metastasis and even cleared cancer cells at remote locations from the tumor site. This work demonstrates the prevalent existence of potent malignancy-killers in the human intestinal microbiota, which may routinely clear malignant cells from the body before they form cancers.

Systematic review of studies evaluating urinary iodine concentration as a predictor of 24-hour urinary iodine excretion for estimating population iodine intake.

OBJECTIVE: To examine the usefulness of "spot" urine iodine concentrations (UICs) in predicting 24-hour urine iodine excretion (UIE) for estimating average population iodine intake. METHODS: An electronic literature search was conducted for articles published through 19 May 2013 in MEDLINE (from 1950), EMBASE (from 1980), and the Cochrane Library (from 1993) using the terms "urinary excretion (timed or spot or random) and (24 h or 24 hour), iodine (iodine deficiency), iodine (intake)," and "urine (timed, spot, random, 24-hour)." Full-text articles about studies that examined > 40 healthy human subjects and measured UIE using the 24-hour urine collection method and UIC and/or UIE using one alternative method (spot (random), timed, and "overnight" (first morning urine), fasting or not fasting) were selected and reviewed. RESULTS: The review included data from 1 434 participants across the six studies that met the inclusion criteria. The main statistical methods for comparing data from the 24-hour urine collections with the values obtained from the alternative method(s) were either regression (ß) or correlation (r) coefficients and concordance analysis through Bland-Altman plots. The urine samples collected using the alternative methods were subject to greater intra-individual and inter-individual variability than the 24-hour urine collections. There was a wide range in coefficient values for the comparisons between 24-hour URE measured in 24-hour urine collection and 24-hour UIE estimated using the alternative sampling methods. No alternative sampling method (spot, timed, or "overnight") was appropriate for estimating 24-hour UIE. CONCLUSIONS: The results of this systematic review suggest current data on UICs as a means of predicting 24-hour UIE for estimating population sodium intake are inadequate and highlight the need for further methodological investigations.

Systematic review of studies evaluating urinary iodine concentration as a predictor of 24-hour urinary iodine excretion for estimating population iodine intake / Revisión sistemática de estudios que evalúan la concentración urinaria de yodo como factor predictivo de la excreción urinaria de yodo de 24 horas para calcular la ingesta de yodo en la población

OBJECTIVE: To examine the usefulness of "spot" urine iodine concentrations (UICs) in predicting 24-hour urine iodine excretion (UIE) for estimating average population iodine intake. METHODS: An electronic literature search was conducted for articles published through 19 May 2013 in MEDLINE (from 1950), EMBASE (from 1980), and the Cochrane Library (from 1993) using the terms "urinary excretion (timed or spot or random) and (24 h or 24 hour), iodine (iodine deficiency), iodine (intake)," and "urine (timed, spot, random, 24-hour)." Full-text articles about studies that examined > 40 healthy human subjects and measured UIE using the 24-hour urine collection method and UIC and/or UIE using one alternative method (spot (random), timed, and "overnight" (first morning urine), fasting or not fasting) were selected and reviewed. RESULTS: The review included data from 1 434 participants across the six studies that met the inclusion criteria. The main statistical methods for comparing data from the 24-hour urine collections with the values obtained from the alternative method(s) were either regression (β) or correlation (r) coefficients and concordance analysis through Bland-Altman plots. The urine samples collected using the alternative methods were subject to greater intra-individual and inter-individual variability than the 24-hour urine collections. There was a wide range in coefficient values for the comparisons between 24-hour URE measured in 24-hour urine collection and 24-hour UIE estimated using the alternative sampling methods. No alternative sampling method (spot, timed, or "overnight") was appropriate for estimating 24-hour UIE. CONCLUSIONS: The results of this systematic review suggest current data on UICs as a means of predicting 24-hour UIE for estimating population sodium intake are inadequate and highlight the need for further methodological investigations.

OBJETIVO: Analizar la utilidad de la concentraciones urinarias de yodo en una muestra puntual de orina como predicción de la excreción urinaria de yodo de 24 horas para calcular la ingesta promedio de yodo en la población. MÉTODOS: Se realizó una búsqueda de bibliografía electrónica de artículos publicados hasta el 19 de mayo del 2013 en MEDLINE (desde 1950), EMBASE (desde 1980) y la Biblioteca Cochrane (desde 1993) que utilizaran los términos "urinary excretion (timed or spot or random) y (24 h or 24 hour)", "iodine (iodine deficiency)", "iodine (intake)", y "urine (timed, spot, random, 24-hour)" ("excreción urinaria [programada o puntual o aleatoria] y [24 h o 24 horas]", "yodo [carencia de yodo]", "yodo [ingesta]", y "orina [programada, puntual, aleatoria, 24 horas]"). Se seleccionaron y analizaron artículos de texto completo acerca de estudios que hubieran examinado como mínimo a 40 personas sanas y medido la excreción urinaria de yodo mediante la recolección de orina de 24 horas, y la concentración urinaria de yodo o la excreción urinaria de yodo mediante un método alternativo (recolección puntual [aleatoria], programada y "de toda la noche" [primera orina de la mañana], en ayunas o no). RESULTADOS: La revisión incluyó datos de 1 434 participantes de los seis estudios que reunieron los criterios de inclusión. Los principales métodos estadísticos utilizados para comparar los datos de las recolecciones de orina de 24 horas con los valores obtenidos a partir de los métodos alternativos fueron los coeficientes de regresión (β) o correlación (r) y los análisis de concordancia mediante el gráfico de Bland-Altman. Las muestras de orina recolectadas mediante métodos alternativos presentaron una mayor variabilidad interpersonal y para una misma persona que las recolecciones de orina de 24 horas. Se observó una amplia gama de valores de los coeficientes en las comparaciones entre la excreción urinaria de yodo de 24 horas medida mediante la recolección de orina de 24 horas y la excreción urinaria de yodo de 24 horas calculada mediante métodos de muestreo alternativos. Ningún método de muestreo alternativo (puntual, programado o "de toda la noche") resultó apropiado para calcular la excreción urinaria de yodo de 24 horas. CONCLUSIONES: Los resultados de esta revisión sistemática indican que los datos actuales en cuanto a la concentración urinaria de yodo como factor predictivo de la excreción urinaria de yodo de 24 horas para calcular la ingesta de yodo en la población son inadecuados y subrayan la necesidad de nuevas investigaciones metodológicas.

Systematic review of studies evaluating urinary iodine concentration as a predictor of 24-hour urinary iodine excretion for estimating population iodine intake / Revisión sistemática de estudios que evalúan la concentración urinaria de yodo como factor predictivo de la excreción urinaria de yodo de 24 horas para calcular la ingesta de yodo en la población

Objective. To examine the usefulness of ”spot” urine iodine concentrations (UICs) in predicting 24-hour urine iodine excretion (UIE) for estimating average population iodine intake. Methods. An electronic literature search was conducted for articles published through 19 May 2013 in MEDLINE (from 1950), EMBASE (from 1980), and the Cochrane Library (from 1993) using the terms “urinary excretion (timed or spot or random) and (24 h or 24 hour),” “iodine (iodine deficiency),” “iodine (intake),” and “urine (timed, spot, random, 24-hour).” Full-text articles about studies that examined ≥ 40 healthy human subjects and measured UIE using the 24-hour urine collection method and UIC and/or UIE using one alternative method (spot (random), timed, and “overnight” (first morning urine), fasting or not fasting) were selected and reviewed. Results. The review included data from 1 434 participants across the six studies that met the inclusion criteria. The main statistical methods for comparing data from the 24-hour urine collections with the values obtained from the alternative method(s) were either regression (β) or correlation (r) coefficients and concordance analysis through Bland–Altman plots. The urine samples collected using the alternative methods were subject to greater intra-individual and inter-individual variability than the 24-hour urine collections. There was a wide range in coefficient values for the comparisons between 24-hour URE measured in 24-hour urine collection and 24-hour UIE estimated using the alternative sampling methods. No alternative sampling method (spot, timed, or “overnight”) was appropriate for estimating 24-hour UIE. Conclusions. The results of this systematic review suggest current data on UICs as a means of predicting 24-hour UIE for estimating population sodium intake are inadequate and highlight the need for further methodological investigations.

Objetivo. Analizar la utilidad de la concentraciones urinarias de yodo en una muestra puntual de orina como predicción de la excreción urinaria de yodo de 24 horas para calcular la ingesta promedio de yodo en la población. Métodos. Se realizó una búsqueda de bibliografía electrónica de artículos publicados hasta el 19 de mayo del 2013 en MEDLINE (desde 1950), EMBASE (desde 1980) y la Biblioteca Cochrane (desde 1993) que utilizaran los términos “urinary excretion (timed or spot or random) y (24 h or 24 hour)”, “iodine (iodine deficiency)”, “iodine (intake)”, y “urine (timed, spot, random, 24-hour)” (“excreción urinaria [programada o puntual o aleatoria] y [24 h o 24 horas]”, “yodo [carencia de yodo]”, “yodo [ingesta]”, y “orina [programada, puntual, aleatoria, 24 horas]”). Se seleccionaron y analizaron artículos de texto completo acerca de estudios que hubieran examinado como mínimo a 40 personas sanas y medido la excreción urinaria de yodo mediante la recolección de orina de 24 horas, y la concentración urinaria de yodo o la excreción urinaria de yodo mediante un método alternativo (recolección puntual [aleatoria], programada y “de toda la noche” [primera orina de la mañana], en ayunas o no). Resultados. La revisión incluyó datos de 1 434 participantes de los seis estudios que reunieron los criterios de inclusión. Los principales métodos estadísticos utilizados para comparar los datos de las recolecciones de orina de 24 horas con los valores obtenidos a partir de los métodos alternativos fueron los coeficientes de regresión (β) o correlación (r) y los análisis de concordancia mediante el gráfico de Bland-Altman. Las muestras de orina recolectadas mediante métodos alternativos presentaron una mayor variabilidad interpersonal y para una misma persona que las recolecciones de orina de 24 horas. Se observó una amplia gama de valores de los coeficientes en las comparaciones entre la excreción urinaria de yodo de 24 horas medida mediante la recolección de orina de 24 horas y la excreción urinaria de yodo de 24 horas calculada mediante métodos de muestreo alternativos. Ningún método de muestreo alternativo (puntual, programado o “de toda la noche”) resultó apropiado para calcular la excreción urinaria de yodo de 24 horas. Conclusiones. Los resultados de esta revisión sistemática indican que los datos actuales en cuanto a la concentración urinaria de yodo como factor predictivo de la excreción urinaria de yodo de 24 horas para calcular la ingesta de yodo en la población son inadecuados y subrayan la necesidad de nuevas investigaciones metodológicas.

Healthy food procurement policies and their impact.

Unhealthy eating is the leading risk for death and disability globally. As a result, the World Health Organization (WHO) has called for population health interventions. One of the proposed interventions is to ensure healthy foods are available by implementing healthy food procurement policies. The objective of this systematic review was to evaluate the evidence base assessing the impact of such policies. A comprehensive review was conducted by searching PubMed and Medline for policies that had been implemented and evaluated the impact of food purchases, food consumption, and behaviors towards healthy foods. Thirty-four studies were identified and found to be effective at increasing the availability and purchases of healthy food and decreasing purchases of unhealthy food. Most policies also had other components such as education, price reductions, and health interventions. The multiple gaps in research identified by this review suggest that additional research and ongoing evaluation of food procurement programs is required. Implementation of healthy food procurement policies in schools, worksites, hospitals, care homes, correctional facilities, government institutions, and remote communities increase markers of healthy eating. Prior or simultaneous implementation of ancillary education about healthy eating, and rationale for the policy may be critical success factors and additional research is needed.

Social constraints, genetic vulnerability, and mental health following collective stress.

A repeat-length polymorphism of the serotonin promoter gene (5-HTTLPR) has been associated with depression and posttraumatic stress disorder (PTSD) in trauma-exposed individuals reporting unsupportive social environments. We examine the contributions of the triallelic 5-HTTLPR genotype and social constraints to posttraumatic stress (PTS) symptoms in a national sample following the September 11, 2001 (9/11) terrorist attacks. Saliva was collected by mail from 711 respondents (European American subsample n = 463) of a large national probability sample of 2,729 adults. Respondents completed web-based assessments of pre-9/11 mental and physical health, acute stress 9 to 23 days post-9/11, PTS symptoms, and social constraints on disclosure regarding fears of future terrorist attacks 2-3 years post-9/11. Social constraints were positively associated with PTS symptoms 2-3 years post-9/11. The triallelic 5-HTTLPR genotype was not directly associated with PTS symptoms, but it interacted with social constraints to predict PTS symptoms 2-3 years post-9/11: Social constraints were more strongly associated with PTS symptoms for individuals with any s/lg allele than for homozygous la/la individuals. Constraints on disclosing fears about future terrorism moderate the 5-HTTLPR genotype-PTS symptom association even when indirectly exposed to collective stress.