Authors: Puurunen MK, Hwang SJ, Larson MG, Vasan RS, O'Donnell CJ, Tofler G, Johnson AD.
Journal: J Am Heart Assoc. 2018 Mar 3;7(5). pii: e008522. doi: 10.1161/JAHA.118.008522.
BACKGROUND: Platelet function is associated with adverse events in patients with cardiovascular disease (CVD).
METHODS AND RESULTS: We examined associations of baseline platelet function with incident CVD events in the community-based FHS (Framingham Heart Study). Participants free of prevalent CVD and without recent aspirin treatment with available data in the Framingham Offspring cohort (1991-1995) and Omni cohort (1994-1998) were included. Platelet function was measured with light transmission aggregometry using collagen (1.9 μg/mL), ADP (0.05-15 μmol/L), and epinephrine (0.01-15 μmol/L). We used proportional hazards models to analyze incident outcomes (myocardial infarction/stroke, CVD, and CVD mortality) with respect to platelet measures. The study sample included 2831 participants (average age, 54.3 years; 57% women). During follow-up (median, 20.4 years), we observed 191 composite incident myocardial infarction or stroke events, 432 incident CVD cases, and 117 CVD deaths. Hyperreactivity to ADP and platelet aggregation at ADP concentration of 1.0 μmol/L were significantly associated with incident myocardial infarction/stroke in a multivariable model (hazard ratio, 1.68 [95% confidence interval, 1.13-2.50] [P=0.011] for hyperreactivity across ADP doses; and hazard ratio, 1.16 [95% confidence interval, 1.02-1.33] [P=0.029] for highest quartile of ADP response at 1.0 μmol/L versus others). No association was observed for collagen lag time or any epinephrine measures with incident myocardial infarction or stroke.
CONCLUSIONS: Intrinsic hyperreactivity to low-dose ADP in our community-based sample, who were free of CVD and any antiplatelet therapy, is associated with future arterial thrombosis during a 20-year follow-up. These findings reinforce ADP activation inhibition as a critical treatment paradigm and encourage further study of ADP inhibitor-refractive populations.
Authors: Motamedi V, Kanefsky R, Matsangas P, Mithani S, Jeromin A, Brock MS, Mysliwiec V, Gill J.
Journal: Sleep Med. 2018 Mar;43:71-76. doi: 10.1016/j.sleep.2017.11.1121. Epub 2017 Nov 24.
Obstructive sleep apnea (OSA) is characterized by apneas and hypopneas that result in hypoxia, cerebral hypoperfusion, endothelial dysfunction, inflammation, and oxidative stress. These pathophysiologic processes likely contribute to neuronal damage. Tau is a protein that stabilizes microtubules and, along with amyloid beta (Aβ), is associated with neurodegenerative processes. We sought to determine if tau and other biomarkers of inflammation were related to OSA severity. Concentrations of tau, Aβ40, Aβ42, c-reactive protein (CRP), TNF-α, interleukin (IL)-6, and IL-10 were measured in blood and compared between participants with moderate-severe OSA (n = 28), those with mild OSA (n = 22), and healthy controls (n = 24). The cohort included relatively young, primarily male active duty military personnel without a history of traumatic brain injury or neurodegenerative disease. Total biomarker concentrations were determined from plasma samples using an ultra-sensitive detection method, SimoaTM, and CRP was assayed by ELISA. Total tau and IL-6 concentrations were elevated in participants with moderate-severe OSA, with a mean apnea-hypopnea index (AHI) of 26.1/h, compared to those with mild OSA (mean AHI 8.6/h) and healthy controls (mean AHI 2.1/h). Tau concentrations were also significantly correlated with the AHI (r = 0.342, p = 0.004). Our findings show that tau is elevated in the blood of young patients with moderate-severe OSA, suggesting that this degree of sleep-disordered breathing is a contributing factor in the development of neurodegenerative disorders. The finding of increased IL-6 further suggests that inflammatory biomarkers are present early in the course of this chronic disease.
Authors: Hooper LG, Young MT, Keller JP, Szpiro AA, O'Brien KM, Sandler DP, Vedal S, Kaufman JD, London SJ.
Journal: Environ Health Perspect. 2018 Feb 6;126(2):027005. doi: 10.1289/EHP2199.
BACKGROUND: Limited evidence links air pollution exposure to chronic cough and sputum production. Few reports have investigated the association between long-term exposure to air pollution and classically defined chronic bronchitis.
OBJECTIVES: Our objective was to estimate the association between long-term exposure to particulate matter (diameter <10 μm, PM10; <2.5μm, PM2.5), nitrogen dioxide (NO2), and both incident and prevalent chronic bronchitis.
METHODS: We estimated annual average PM2.5, PM10, and NO2 concentrations using a national land-use regression model with spatial smoothing at home addresses of participants in a prospective nationwide U.S. cohort study of sisters of women with breast cancer. Incident chronic bronchitis and prevalent chronic bronchitis, cough and phlegm, were assessed by questionnaires.
RESULTS: Among 47,357 individuals with complete data, 1,383 had prevalent chronic bronchitis at baseline, and 647 incident cases occurred over 5.7-y average follow-up. No associations with incident chronic bronchitis were observed. Prevalent chronic bronchitis was associated with PM10 [adjusted odds ratio (aOR) per interquartile range (IQR) difference (5.8 μg/m3)=1.07; 95% confidence interval (CI): 1.01, 1.13]. In never-smokers, PM2.5 was associated with prevalent chronic bronchitis (aOR=1.18 per IQR difference; 95% CI: 1.04, 1.34), and NO2 was associated with prevalent chronic bronchitis (aOR=1.10; 95% CI=1.01, 1.20), cough (aOR=1.10; 95% CI: 1.05, 1.16), and phlegm (aOR=1.07; 95% CI: 1.01, 1.14); interaction p-values (nonsmokers vs. smokers) <0.05.
CONCLUSIONS: PM10 exposure was related to chronic bronchitis prevalence. Among never-smokers, PM2.5 and NO2 exposure was associated with chronic bronchitis and component symptoms. Results may have policy ramifications for PM10 regulation by providing evidence for respiratory health effects related to long-term PM10 exposure.
Authors: Christensen CH, Rostron B, Cosgrove C, Altekruse SF, Hartman AM, Gibson JT, Apelberg B, Inoue-Choi M, Freedman ND.
Journal: JAMA Intern Med. 2018 Feb 19. doi: 10.1001/jamainternmed.2017.8625. [Epub ahead of print]
IMPORTANCE: Tobacco products have changed in recent years. Contemporary mortality risk estimates of combustible tobacco product use are needed.
OBJECTIVE: To investigate the mortality risks associated with current and former use of cigars, pipes, and cigarettes.
DESIGN, SETTING, AND PARTICIPANTS: The National Longitudinal Mortality Study is a longitudinal population-based, nationally representative health survey with mortality follow-up that includes demographic and other information from the Current Population Survey, tobacco product use information from the Tobacco Use Supplement, and mortality data from the National Death Index. In this study, participants provided tobacco use information at baseline in surveys starting from 1985 and were followed for mortality through the end of 2011. The study includes 357 420 participants who reported exclusively using cigar, pipes, or cigarettes or reported never using any type of tobacco product.
EXPOSURES: Current or former exclusive use of any cigar (little cigar, cigarillos, large cigar), traditional pipe, or cigarette and never tobacco use. Information on current daily and nondaily use was also collected. Estimates adjusted for age, sex, race/ethnicity, education, and survey year.
MAIN OUTCOMES AND MEASURES: All-cause and cause-specific mortality as identified as the primary cause of death from death certificate information.
RESULTS: Of the 357 420 persons included in the analysis, the majority of current and former cigar and pipe smokers were male (79.3%-98.0%), and smokers were more evenly divided by sex (46% of current daily smokers were male). There were 51 150 recorded deaths during follow-up. Exclusive current cigarette smokers (hazard ratio [HR], 1.98; 95% CI, 1.93-2.02) and exclusive current cigar smokers (HR, 1.20; 95% CI, 1.03-1.38) had higher all-cause mortality risks than never tobacco users. Exclusive current cigarette smokers (HR, 4.06; 95% CI, 3.84-4.29), exclusive current cigar smokers (HR, 1.61; 95% CI, 1.11-2.32), and exclusive current pipe smokers (HR, 1.58; 95% CI, 1.05-2.38) had an elevated risk of dying from a tobacco-related cancer (including bladder, esophagus, larynx, lung, oral cavity, and pancreas). Among current nondaily cigarette users, statistically significant associations were observed with deaths from lung cancer (HR, 6.24; 95% CI, 5.17-7.54), oral cancer (HR, 4.62; 95% CI, 1.84-11.58), circulatory death (HR, 1.43; 95% CI, 1.30-1.57), cardiovascular death (HR, 1.24; 95% CI, 1.11-1.39), cerebrovascular death (stroke) (HR, 1.39; 95% CI, 1.12-1.74), and chronic obstructive pulmonary disease (HR, 7.66; 95% CI, 6.09-9.64) as well as for daily smokers.
CONCLUSIONS AND RELEVANCE: This study provides further evidence that exclusive use of cigar, pipes, and cigarettes each confers significant mortality risks.
Authors: Pillon MC, Sobhanhy M, Stanley RE
Journal: RNA. 2018 Feb 9. pii: rna.065037.117. doi: 10.1261/rna.065037.117. [Epub ahead of print]
Grc3 is an essential well-conserved eukaryotic polynucleotide kinase (PNK) that cooperates with the endoribonuclease Las1 to process the pre-ribosomal RNA (rRNA). Aside from being dependent upon Las1 for coordinated kinase and nuclease function, little is known about Grc3 substrate specificity and the molecular mechanisms governing kinase activity. Here we characterize the kinase activity of Grc3 and identify key similarities and differences between Grc3 and other polynucleotide kinase family members. In contrast to other PNK family members, Grc3 has distinct substrate preferences for RNA substrates in vitro. By disrupting conserved residues found at the Grc3 kinase active site, we identified specific residues required to support Grc3-directed Las1-mediated pre-rRNA cleavage in vitro and in vivo. The exquisite crosstalk between Grc3 and Las1 ensures the direct coupling of cleavage and phosphorylation during pre-rRNA processing. Taken together, our studies provide key insight into the polynucleotide kinase activity of the essential enzyme Grc3 and its molecular crosstalk with the endoribonuclease Las1.
Authors: Howard BH, Hirai TH, Russanova VR.
Journal: PLoS One. 2018 Feb 21;13(2):e0191033. doi: 10.1371/journal.pone.0191033.
Substantial evidence has accumulated linking epigenome change to alterations in stem cell function during postnatal development and aging. Yet much remains to be learned about causal relationships, and large gaps remain in our understanding of epigenome-transcriptome interactions. Here we investigate structural features of large histone H3K27me3-enriched regions in human stem cell-like monocytes and their dendritic cell derivatives, where the H3K27me3 modification is considered to demarcate Polycomb (PcG) domains. Both differentiation- and postnatal development-related change are explored, initially by confirming expected reciprocal relationships between transcript abundance and span of PcG domains overlapping transcribed regions. PcG-associated postnatal transcriptome change specific to the stem cell-like monocytes is found to be incompletely explained by conventional measures of PcG region structure. To address this, we introduce algorithms that quantify local nucleosome-scale conservation of PcG-region topology. It is shown that topology-based comparisons can reveal broad statistical linkage between postnatal gene down-regulation and epigenome remodeling; further, such comparisons provide access to a previously unexplored dimension of epigenome architecture.
Authors: Yano H, Cai NS, Xu M, Verma RK, Rea W, Hoffman AF, Shi L, Javitch JA, Bonci A, Ferré S.
Journal: Nat Commun. 2018 Feb 5;9(1):486. doi: 10.1038/s41467-017-02606-w.
The two highly homologous subtypes of stimulatory G proteins Gαs (Gs) and Gαolf (Golf) display contrasting expression patterns in the brain. Golf is predominant in the striatum, while Gs is predominant in the cortex. Yet, little is known about their functional distinctions. The dopamine D1 receptor (D1R) couples to Gs/olf and is highly expressed in cortical and striatal areas, making it an important therapeutic target for neuropsychiatric disorders. Using novel drug screening methods that allow analysis of specific G-protein subtype coupling, we found that, relative to dopamine, dihydrexidine and N-propyl-apomorphine behave as full D1R agonists when coupled to Gs, but as partial D1R agonists when coupled to Golf. The Gs/Golf-dependent biased agonism by dihydrexidine was consistently observed at the levels of cellular signaling, neuronal function, and behavior. Our findings of Gs/Golf-dependent functional selectivity in D1R ligands open a new avenue for the treatment of cortex-specific or striatum-specific neuropsychiatric dysfunction.
Authors: Rath BH, Waung I, Camphausen K, Tofilon PJ.
Journal: Mol Cancer Ther. 2018 Feb 26. pii: molcanther.1053.2017. doi: 10.1158/1535-7163.MCT-17-1053. [Epub ahead of print]
The processes mediating the repair of DNA double strand breaks (DSBs) are critical determinants of radiosensitivity and provide a source of potential targets for tumor radiosensitization. Among the events required for efficient DSB repair are a variety of post-translational histone modifications including methylation. Because trimethylation of histone H3 on lysine 27 (H3K27me3) has been associated with chromatin condensation, which can influence DSB repair, we determined the effects of radiation on H3K27me3 levels in tumor and normal cell lines. Irradiation of tumor cells resulted in a rapid loss of H3K27me3, which was prevented by the siRNA-mediated knockdown of the H3K27 demethylase UTX. Knockdown of UTX also enhanced the radiosensitivity of each tumor cell line. Treatment of tumor cells with the H3K27 demethylase inhibitor GSKJ4 immediately before irradiation prevented the radiation-induced decrease in H3K27me3 and enhanced radiosensitivity. As determined by neutral comet analysis and γH2AX expression, this GSKJ4 treatment protocol inhibited the repair of radiation-induced DSBs. Consistent with in vitro results, treatment of mice bearing leg tumor xenografts with GSKJ4 significantly enhance radiation-induce tumor growth delay. In contrast to results generated from tumor cell lines, radiation had no effect on H3K27me3 levels in normal fibroblast cell lines and GSKJ4 did not enhance their radiosensitivity. These data suggest that H3K27me3 demethylation contributes to DSB repair in tumor cells and that UTX, the demethylase responsible, provides a target for selective tumor cell radiosensitization.
Authors: Marosi K, Moehl K, Navas-Enamorado I, Mitchell SJ, Zhang Y, Lehrmann E, Aon MA, Cortassa S, Becker KG, Mattson MP
Journal: FASEB J. 2018 Feb 27:fj201701378RR. doi: 10.1096/fj.201701378RR. [Epub ahead of print]
Evolutionary considerations suggest that the body has been optimized to perform at a high level in the food-deprived state when fatty acids and their ketone metabolites are a major fuel source for muscle cells. Because controlled food deprivation in laboratory animals and intermittent energy restriction in humans is a potent physiologic stimulus for ketosis, we designed a study to determine the impact of intermittent food deprivation during endurance training on performance and to elucidate the underlying cellular and molecular mechanisms. Male mice were randomly assigned to either ad libitum feeding or alternate-day food deprivation (ADF) groups, and half of the mice in each diet group were trained daily on a treadmill for 1 mo. A run to exhaustion endurance test performed at the end of the training period revealed superior performance in the mice maintained on ADF during training compared to mice fed ad libitum during training. Maximal O2 consumption was increased similarly by treadmill training in mice on ADF or ad libitum diets, whereas respiratory exchange ratio was reduced in ADF mice on food-deprivation days and during running. Analyses of gene expression in liver and soleus tissues, and metabolomics analysis of blood suggest that the metabolic switch invoked by ADF and potentiated by exercise strongly modulates molecular pathways involved in mitochondrial biogenesis, metabolism, and cellular plasticity. Our findings demonstrate that ADF engages metabolic and cellular signaling pathways that result in increased metabolic efficiency and endurance capacity.
Authors: Choi SH, Arai AL, Mou Y, Kang B, Yen CC, Hallenbeck J, Silva AC.
Journal: Stroke. 2018 Feb 13. pii: STROKEAHA.117.019664. doi: 10.1161/STROKEAHA.117.019664. [Epub ahead of print]
BACKGROUND AND PURPOSE: MAGL (monoacylglycerol lipase) is an enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol and regulates the production of arachidonic acid and prostaglandins-substances that mediate tissue inflammatory response. Here, we have studied the effects of the selective MAGL inhibitors JZL184 and MJN110 and their underlying molecular mechanisms on 3 different experimental models of focal cerebral ischemia.
METHODS: SHR (spontaneously hypertensive rats) and normotensive WKY (Wistar Kyoto) rats were subject to an intracortical injection of the potent vasoconstrictor endothelin-1, permanent occlusion of a distal segment of the middle cerebral artery via craniectomy, or transient occlusion of the middle cerebral artery by the intraluminal suture method. JZL184 or MJN110 was administered 60 minutes after focal cerebral ischemia. Infarct volumes, hemispheric swelling, and functional outcomes were assessed between days 1 to 28 by magnetic resonance imaging, histology, and behavioral tests.
RESULTS: Pharmacological inhibition of MAGL significantly attenuated infarct volume and hemispheric swelling. MAGL inhibition also ameliorated sensorimotor deficits, suppressed inflammatory response, and decreased the number of degenerating neurons. These beneficial effects of MAGL inhibition were not fully abrogated by selective antagonists of cannabinoid receptors, indicating that the anti-inflammatory effects are caused by inhibition of eicosanoid production rather than by activation of cannabinoid receptors.
CONCLUSIONS: Our results suggest that MAGL may contribute to the pathophysiology of focal cerebral ischemia and is thus a promising therapeutic target for the treatment of ischemic stroke.