急性白血病组蛋白乙酰化修饰及其对错配修复基因表达的调控作用

 目的　探讨急性白血病患者组蛋白乙酰化修饰规律,并探索组蛋白乙酰化对错配修复基因hMSH2 和hMLH1差异表达的调控作用。方法　用反转录-聚合酶链反应（RT-PCR）方法检测56例急性白血病患者和30名健康志愿者单个核细胞（MNC）的错配修复基因hMSH2 和hMLH1 mRNA的表达,用Western blot法检测组蛋白H3、H4、去乙酰化酶（HDAC1）、hMSH2 和hMLH1基因的蛋白表达情况。用组蛋白去乙酰转移酶抑制剂（TSA）诱导30例白血病患者MNC乙酰化,并检测处理后MNC的组蛋白H3、H4、HDAC1、hMSH2 和hMLH1的表达状态变化。结果　急性白血病组的hMSH2 和hMLH1、组蛋白H3、H4的蛋白表达量分别为0.4610±0.1211、0.4013±0.1143、0.4103±0.1241和0.4251±0.1081,均明显低于健康志愿者组的蛋白表达量（0.9461±0.1841、0.9960±0.2021、0.8971±0.1194、0.9513±0.1953）,差异均有统计学意义（t值分别为3.341、3.935、2.843、3.575,P＜0.05）;而急性白血病患者组的HDAC1表达（0.8841±0.2018）高于健康志愿者组的表达量（0.5142±0.1340）,差异有统计学意义（t＝2.634,P＜0.05）;TSA作用于白血病单个核细胞后,组蛋白H3、H4、hMSH2 和hMLH1的表达上调,分别比阴性对照组表达上调2.9倍、3.4倍、1.5倍和1.6倍,而HDAC1的蛋白表达出现明显的抑制,表达下调为阴性对照组的40 %。结论　急性白血病患者的组蛋白乙酰化呈低表达现象,组蛋白乙酰化在急性白血病患者中对错配修复基因差异表达具有调控作用。     

Active extracts of wild fruiting bodies of <Emphasis Type="Italic">Antrodia camphorata</Emphasis> (EEAC) induce leukemia HL 60 cells apoptosis partially through histone hypoacetylation and synergistically promote anticancer effect of trichostatin A

The endemic species of Antrodia camphorate (AC) is a promising chemotherapeutic drug for cancer. We found that the ethanol extract from wild fruiting bodies of Antrodia camphorata (EEAC) could induce HL 60 cells apoptosis via histone hypoacetylation, up-regulation of histone deacetyltransferase 1 (HDAC 1), and down-regulation of histone acetyltransferase activities including GCN 5, CBP and PCAF in dose-dependent manner. In combination with histone deacetylase inhibitor, trichostatin A (TSA), did not block EEAC-induced apoptosis. Interestingly, combined treatment (100 nM of TSA and 100 μg/ml EEAC) caused synergistic inhibition of cell growth and increase of apoptotic induction. EEAC could effectively increase the cytotoxic sensitivity of TSA through the up-regulation of DR5 and NFκB activation. In this present study, bioassay-guided fractionation of EEAC led to a major active compound, zhankuic acid A, as the bioactive marker. Moreover, our findings may represent an experimental basis for developing EEAC as a potential chemotherapeutic adjuvant. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity

Formaldehyde has been previously shown to play a dominant role in promoting synergy between doxorubicin (Dox) and formaldehyde-releasing butyric acid (BA) prodrugs in killing cancer cells. In this work, we report that these prodrugs also protect neonatal rat cardiomyocytes and adult mice against toxicity elicited by Dox. In cardiomyocytes treated with Dox, the formaldehyde releasing prodrugs butyroyloxymethyl diethylphosphate (AN-7) and butyroyloxymethyl butyrate (AN-1), but not the corresponding acetaldehyde-releasing butyroyloxydiethyl phosphate (AN-88) or butyroyloxyethyl butyrate (AN-11), reduced lactate dehydrogenase leakage, prevented loss of mitochondrial membrane potential (DeltaPsim) and attenuated upregulation of the proapoptotic gene Bax. In Dox-treated mice, AN-7 but not AN-88 attenuated weight-loss and mortality, and increase in serum lactate dehydrogenase. These findings show that BA prodrugs that release formaldehyde and augment Dox anticancer activity also protect against Dox cardiotoxicity. Based on these observations, clinical applications of these prodrugs for patients treated with Dox warrant further investigation.     

Effect of Pectin Type and Plasticizer on In Vitro Mucoadhesion of Free Films

The objective was to measure and compare the specific and general mucin interaction of plasticized and unplasticized pectin films. The pectin types differed in the type and degree of substitution. Mucoadhesive properties were measured by using a texture analyzer. Pectin with an intermediate degree of methoxylation (36%) displayed substantially higher general and specific mucin interaction than amidated, acetylated, and high methoxylated pectin. This was explained with extensive hydrogen bonding in addition to favorable wetting properties. When comparing all plasticized films to all unplasticized films, a consistent and statistically significant increase in the peak force was observed on adding an effective plasticizer.     

消化道肿瘤组蛋白乙酰化与甲基化的研究进展

组蛋白乙酰化、甲基化及磷酸化等共价修饰以及染色质的其他改变如DNA甲基化和ATP依赖的染色质重组在肿瘤形成的多阶段过程中发挥重要作用。消化道肿瘤是我国的常见肿瘤。主要探讨组蛋白共价修饰中乙酰化和甲基化在消化道肿瘤形成过程中的作用。对了解消化道肿瘤的发病机制、细胞免疫与防御、细胞分化以及预防治疗等方面具有十分重要的意义。     

Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8

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Chronic adjunction of 1-deoxynojirimycin protects from age-related behavioral and biochemical changes in the SAMP8 mice

Several studies have indicated that a caloric restriction mimetic or treatment for type 2 diabetes may reverse brain aging. Therefore, we investigated the effect of 1-deoxynojirimycin (DNJ), an alkaloid acting as an inhibitor of α-glucosidase, on age-related behavioral and biochemical changes. SAMP8 mice were randomly assigned to a control group labeled “old” or to the 10- or 20-mg/kg/day DNJ groups. The mice in the DNJ groups were administered DNJ orally from 3 to 9 months of age, and then, a “young” control group was added to analyze the age effect. The old controls exhibited significant declines in sensorimotor ability, open-field anxiety, spatial and nonspatial memory abilities, and age-related biochemical changes, including decreased serum insulin level; increased levels of insulin-like growth factor 1 receptor, presynaptic protein synaptotagmin-1, and astrocyte activation; and decreased levels of insulin receptor, brain-derived neurotrophic factor, presynaptic protein syntaxin-1, and acetylation of histones H4 at lysine 8 in the dorsal hippocampus. Significant correlations exist between the age-related behavioral deficits and the serological and histochemical data. Chronic DNJ treatment alleviated these age-related changes, and the 20-mg/kg/day DNJ group showed more significant improvement. Thus, DNJ may have the potential to maintain successful brain aging.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-015-9839-0) contains supplementary material, which is available to authorized users.     

Serum CathepsinD in pregnancy: Relation with metabolic and inflammatory markers and effects of fish oils and probiotics

Background and aimsElevated circulating levels of CathepsinD (CatD) have been linked to metabolic deviations including liver inflammation. We investigated 1) whether supplementation with probiotics and/or fish oil affects CatD and 2) whether the CatD concentration would associate with gestational diabetes (GDM), low-grade inflammation, lipid metabolism, body fat % and dietary composition.Methods and resultsOverweight/obese pregnant women (n = 438) were randomized into fish oil + placebo, probiotics + placebo, fish oil + probiotics or placebo + placebo groups. Fish oil contained 1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid and probiotics were Lacticaseibacillus rhamnosus HN001 (formerly Lactobacillus rhamnosus HN001) and Bifidobacterium animalis ssp. lactis 420, 10¹⁰ colony-forming units each). Serum CatD levels were analysed by ELISA, GlycA and lipid metabolites by NMR, high sensitive C-reactive protein (hsCRP) by immunoassay, and intakes of energy yielding nutrients and n-3 and n-6 fatty acids from food diaries at both early and late pregnancy. GDM was diagnosed by OGTT. CatD concentrations did not differ between the intervention groups or by GDM status. Multivariable linear models revealed that body fat % and GlycA affected CatD differently in healthy women and those with GDM.ConclusionThe serum CatD concentration of pregnant women was not modified by this dietary intervention. Serum CatD was influenced by two parameters, body fat and low grade inflammation, which were dependent on the woman's GDM status.Clinical trial reg. noNCT01922791, clinicaltrials.gov (secondary analysis).     

Acetylated histones contribute to the immunostimulatory potential of neutrophil extracellular traps in systemic lupus erythematosus

In addition to disturbed apoptosis and insufficient clearance of apoptotic cells, there is recent evidence for a role of neutrophils in the aetiopathogenesis of systemic lupus erythematosus (SLE). In response to various stimuli, neutrophils can rapidly release DNA fibres decorated with citrullinated histones and anti-microbial peptides. These structures are referred to as neutrophil extracellular traps (NETs). In addition to apoptotic cell-derived microparticles, these NETs may comprise a further source of autoantigens, able to drive the autoimmune response in SLE. Our group recently identified specific histone modifications occurring during apoptosis that play an important role in the autoimmune response in SLE. In the current study, we evaluated the presence and immunostimulatory potential of these previously identified histone modifications in NETs. Compared to NETs from healthy donors, the histones present in NETs formed by SLE-derived neutrophils contain increased amounts of acetylated and methylated residues, which we previously observed to be associated with apoptosis and SLE. Treatment of neutrophils with histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), prior to induction of NETosis, induced NETs containing hyperacetylated histones, endowed with an increased capacity to activate macrophages. This implies that specific histone modifications, in particular acetylation, might enhance the immunostimulatory potential of NETs in SLE.