RATIONALE:Acute coronary syndrome (ACS) is a leading cause of death worldwide. Immune functions play a vital role in ACS development, however, whether epigenetic modulation contributes to the ...regulation of blood immune cells in this disease has not been investigated.
OBJECTIVE:We conducted an epigenome-wide analysis with circulating immune cells to identify differentially methylated genes in ACS.
METHODS AND RESULTS:We examined genome-wide methylation of whole blood in 102 ACS patients and 101 controls using HumanMethylation450 array, and externally replicated significant discoveries in 100 patients and 102 controls. For the replicated loci, we further analyzed their association with ACS in six purified leukocyte subsets, their correlation with the expressions of annotated genes, and their association with cardiovascular traits/risk factors. We found novel and reproducible association of ACS with blood methylation at 47 CpGs (discoveryFDR<0.005; replicationBonferroni corrected P<0.05). The association of these CpGs with ACS was further validated in at least one of the six leukocyte subsets, with predominant contributions from in CD8+T, CD4+T and B cells. Blood methylation of 26 replicated CpGs showed significant correlation with expressions of annotated genes (including IL6R, FASLG and CCL18, P<5.9×10), and differential gene expression in case vs. controls corroborated the observed differential methylation. The replicated loci suggested a role in ACS-relevant functions including chemotaxis, coronary thrombosis and T cell-mediated cytotoxicity. Functional analysis using the top ACS-associated methylation loci in purified T and B cells revealed vital pathways related to atherogenic signaling and adaptive immune response. Furthermore, we observed a significant enrichment of the replicated CpGs associated with smoking and low-density lipoprotein cholesterol (Penrichment≤1×10).
CONCLUSIONS:Our study identified novel blood methylation alterations associated with ACS and provided potential clinical biomarkers and therapeutic targets. Our results may suggest that immune signaling and cellular functions might be regulated at an epigenetic level in ACS.
Heat shock protein 60 kDa (Hsp60) is a chaperone classically believed to be involved in assisting the correct folding of other mitochondrial proteins. Hsp60 also plays a role in cytoprotection ...against cell stressors, displaying for example, antiapoptotic potential. Despite the plethora of studies devoted to the mechanism of Hsp60's function, especially in prokaryotes, fundamental issues still remain unexplored, including the definition of its role in cancer. Key questions still unanswered pertain to the differences in structure-function features that might exist between the well-studied prokaryotic GroEL and the largely unexplored eukaryotic Hsp60 proteins. In this article we discuss these differences in sequence, structure, and roles of Hsp60, focusing on the human ortholog with the view of devising compounds to block its ability to favour tumor-cell growth and survival. Compounds currently known to directly or indirectly affect Hsp60 functions, such as protein folding, HIF-1α accumulation, or Hsp60-induced cell proliferation, are discussed along with strategies that might prove effective for developing Hsp60-targeting drugs for anticancer therapy.
Chaperonins mediate protein folding in a cavity formed by multisubunit rings. The human CCT has eight non-identical subunits and the His147Arg mutation in one subunit, CCT5, causes neuropathy. ...Knowledge is scarce on the impact of this and other mutations upon the chaperone's structure and functions. To make progress, experimental models must be developed. We used an archaeal mutant homolog and demonstrated that the His147Arg mutant has impaired oligomeric assembly, ATPase activity, and defective protein homeostasis functions. These results establish for the first time that a human chaperonin gene defect can be reproduced and studied at the molecular level with an archaeal homolog. The major advantage of the system, consisting of rings with eight identical subunits, is that it amplifies the effects of a mutation as compared with the human counterpart, in which just one subunit per ring is defective. Therefore, the slight deficit of a non-lethal mutation can be detected and characterized.
In this minireview we focus on Hsp60 as a target for anticancer therapy. We discuss the new concepts of chaperonopathies and chaperonotherapy and present information on Hsp60 localization in the cell ...membrane of human tumor cells. We describe novel mechanisms for Hsp60 reaching the extracellular environment that involve membrane-associated stages, as well as data on anti-Hsp60 antibodies found in human sera, both in normal subjects and patients affected by autoimmune diseases. Finally, we discuss possible therapeutic applications of anti-Hsp60 antibodies in cancer treatment, evaluating also side effects on non-tumor cells. In conclusion, the way for investigating Hsp60-targeted anti-tumor therapy is open, at least for those tumors that express Hsp60 on its surface and/or secrete it outside the cell, as is the search for the molecular mechanisms involved in Hsp60 translocation from cytosol to cell membrane: elucidation of this mechanism will greatly facilitate the optimization of chaperonotherapy centered on Hsp60 with anti-tumor efficacy and minimal side effects.
Hereditary Tyrosinemia type 1 (HT1) is a metabolic liver disease caused by genetic defects of fumarylacetoacetate hydrolase (FAH), an enzyme necessary to complete the breakdown of tyrosine. The ...severe hepatic dysfunction caused by the lack of this enzyme is prevented by the therapeutic use of NTBC (2-2-nitro-4-(trifluoromethyl)benzoyl cyclohexane-1,3-dione). However despite the treatment, chronic hepatopathy and development of hepatocellular carcinoma (HCC) are still observed in some HT1 patients. Growing evidence show the important role of heat shock proteins (HSPs) in many cellular processes and their involvement in pathological diseases including cancer. Their survival-promoting effect by modulation of the apoptotic machinery is often correlated with poor prognosis and resistance to therapy in a number of cancers. Here, we sought to gain insight into the pathophysiological mechanisms associated with liver dysfunction and tumor development in a murine model of HT1. Differential gene expression patterns in livers of mice under HT1 stress, induced by drug retrieval, have shown deregulation of stress and cell death resistance genes. Among them, genes coding for HSPB and HSPA members, and for anti-apoptotic BCL-2 related mitochondrial proteins were associated with the hepatocarcinogenetic process. Our data highlight the variation of stress pathways related to HT1 hepatocarcinogenesis suggesting the role of HSPs in rendering tyrosinemia-affected liver susceptible to the development of HCC.
Untreated HT1 rapidly degenerates into very severe liver complications often resulting in liver cancer. The molecular basis of the pathogenic process in HT1 is still unclear. The murine model of ...FAH-deficiency is a suitable animal model, which represents all phenotypic and biochemical manifestations of the human disease on an accelerated time scale. After removal of the drug 2-(2-N-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), numerous signaling pathways involved in cell proliferation, differentiation and cancer are rapidly deregulated in FAH deficient mice. Among these, the Endoplasmic reticulum (ER) pathway, the heat stress response (HSR), the Nrf2, MEK and ERK pathways, are highly represented. The p21 and mTOR pathways critical regulators of proliferation and tumorigenesis have also been found to be dysregulated. The changes in these pathways are described and related to the development of liver cancer.
Hereditary tyrosinemia type 1 (HT1) is caused by the lack of fumarylacetoacetate hydrolase (FAH), the last enzyme of the tyrosine catabolic pathway. Up to now, around 100 mutations in the FAH gene ...have been associated with HT1, and despite many efforts, no clear correlation between genotype and clinical phenotype has been reported. At first, it seems that any mutation in the gene results in HT1. However, placing these mutations in their molecular context allows a better understanding of their possible effects. This chapter presents a closer look at the FAH gene and its corresponding protein in addition to provide a complete record of all the reported mutations causing HT1.
Abstract
Study Objectives:
Prospective evidence on the association of sleep duration and midday napping with metabolic syndrome (MetS) is limited. We aimed to examine the associations of sleep ...duration and midday napping with risk of incidence and reversion of MetS and its components among a middle-aged and older Chinese population.
Methods:
We included 14,399 subjects from the Dongfeng-Tongji (DFTJ) Cohort Study (2008–2013) who were free of coronary heart disease, stroke, and cancer at baseline. Baseline data were obtained by questionnaires and health examinations. Odds ratios (ORs) and 95% confidence interval (CI) were derived from multivariate logistic regression models.
Results:
After controlling for potential covariates, longer sleep duration (≥ 9 h) was associated with a higher risk of MetS incidence (OR, 1.29; 95% CI, 1.08–1.55) and lower reversion of MetS (OR, 0.80; 95% CI, 0.66–0.96) compared with sleep duration of 7 to < 8 h; whereas shorter sleep duration (< 6 h) was not related to incidence or reversion of MetS. For midday napping, subjects with longer napping (≥ 90 min) was also associated with a higher risk of MetS incidence and a lower risk of MetS reversion compared with those with napping of 1 to < 30 min (OR, 1.48; 95% CI, 1.05–2.10 and OR, 0.70; 95% CI, 0.52–0.94, respectively). Significance for incidence or reversion of certain MetS components remained in shorter and longer sleepers but disappeared across napping categories.
Conclusions:
Both longer sleep duration and longer midday napping were potential risk factors for MetS incidence, and concurrently exert adverse effects on MetS reversion.
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