Chronic heart failure(CHF) has become a worldwide public health problem due to its high morbidity and mortality, which seriously endangers people's lifespan and quality of life. In recent years, the treatment strategy of CHF has shifted its emphasis on short-term improvement and transformation of hemodynamics to long-term repair as well as improvement of the biological properties of heart failure. At present, with the continuous deepening of medical research, it has been found that histone acetylation is closely related to the occurrence and development of CHF. Traditional Chinese medicine, via regulating histone acetylation, delays ventricular remodeling, improves energy metabolism, inhibits fibrosis and cardiomyocyte hypertrophy, and intervenes in the development process of heart failure, thus reducing the mortality and the readmission rate and ultimately improving long-term prognosis. Therefore, this study reviewed the mechanism of histone acetylation in the treatment of heart failure as well as its prevention and treatment with traditional Chinese medicine, to provide reference for clinical treatment of CHF.
Humans ; Medicine, Chinese Traditional ; Histones/therapeutic use* ; Acetylation ; Quality of Life ; Heart Failure/prevention & control*

OBJECTIVE: To explore the effect of CXCR4 on the treatment response and prognosis of Carfilzomib (CFZ) in multiple myeloma. METHODS: Dataset GSE69078 based on microarray data from two CFZ-resistant MM cell lines and their corresponding parental cell lines (KMS11-KMS11/CFZ and KMS34-KMS34/CFZ) were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified, and Protein-protein interaction (PPI) network was established to identify the key genes involved in CFZ resistance acquisition. Finally, the prognostic roles of the CFZ risistance key genes in MM using MMRF-CoMMpass data study was verified. RESULTS: 44 up-regulated and 46 down-regulated DEGs were identified. Top 10 hub genes (CCND1, CXCR4, HGF, PECAM1, ID1, HEY1, TCF4, HIST1H4J, HIST1H2BD and HIST1H2BH) were identified via Protein-protein interaction (PPI) network analysis. The CoMMpass data showed that high CXCR4 expression showed correlation to relative higher relapse and progress rates and the overall survival was significant decreased in high CXCR4 patients (P=0.013). CONCLUSION CXCR4 perhaps plays a crucial role in CFZ acquired resistance, which might help identifying potential CFZ-sensitive patients before treatment and providing a new therapeutic target in CFZ-resistant MM.
Histones ; Humans ; Multiple Myeloma/genetics* ; Neoplasm Recurrence, Local ; Oligopeptides/therapeutic use* ; Prognosis ; Receptors, CXCR4

OBJECTIVE: To observe the effects of histones on lung injury and von Willebrand factor (vWF) and fibrinogen (FIB) levels in mice, and to explore the protective effect of heparin. METHODS: Twenty-four male C57BL/6 mice aged 6-10 weeks were divided into control group, histone group and histone+heparin group according to random number table method with 8 mice in each group. The mice in the histone group were injected with histone (50 mg/kg) via the tail vein, and the mice in the histone+heparin group were injected with unfractionated heparin (400 U/kg) via the tail vein at 1 hour after administration of histone, and those in the control group were given the same amount of normal saline. Four hours after histone injection, the lungs of the mice were harvested and the lung wet/dry weight ratio (W/D) and the pulmonary water contents were measured. The pathological changes in lung tissue were observed by hematoxylin and eosin (HE) staining under microscope, and the extent of lung injury was evaluated. The positive expression of vWF which was the marker of endothelial cell injury was observed by immunohistochemistry. The real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the expression level of FIB mRNA in lung tissue. RESULTS: The lung W/D ratio and pulmonary water contents in the histone group were significantly higher than those in the control group [lung W/D ratio: 6.19±0.53 vs. 4.54±0.25, pulmonary water contents: (82.59±2.03)% vs. (78.52±1.51)%, both P < 0.01]. The lung W/D ratio and pulmonary water contents in the histone+heparin group were significantly lower than those in the histone group [lung W/D ratio: 4.84±0.35 vs. 6.19±0.53, pulmonary water contents: (79.21±1.48)% vs. (82.59±2.03)%, both P < 0.01], indicating that the heparin could reduce histone-induced pulmonary edema. Histological examination showed that the alveolar structure of the control group was intact, and the alveolar cavity was clean without exudation. In the histone group, the lungs were significantly damaged. The alveolar wall was thickened, infiltrated by inflammatory cells and focally alveolar hemorrhage, edema, associated with alveolar fibrin deposition and micro-thrombus formation. The lung histopathological score in the histone group was significantly higher than that in the control group (5.15±0.87 vs. 0.18±0.17, P < 0.01). All of the pathological changes were significantly alleviated in the histone+heparin group, and the histopathological score of the lung was significantly lower than that in the histone group (2.28±0.72 vs. 5.15±0.87, P < 0.01), indicating that the histone-induced lung injury was improved by heparin. Immunohistochemistry showed that high vWF expressions of lung tissue were observed in the histone group while there was almost no positive expression in the control group, and the vWF expression in the histone+heparin group was significantly reduced, indicating that heparin protected mice against histone-induced endothelial cell injury. The FIB mRNA expression of lung tissue in the histone group was about 49.82 times of the control group (2^-ΔΔCT: 55.30±18.84 vs. 1.11±0.45, P < 0.01), and the expression of FIB mRNA in the histone+heparin group was decreased, which was 23.87 times of the control group (2^-ΔΔCT: 26.50±9.97 vs. 1.11±0.45, P < 0.01), but it was significantly lower than that in the histone group (2^-ΔΔCT: 26.50±9.97 vs. 55.30±18.84, P < 0.01), indicating that heparin could inhibit histone-induced hypercoagulable environment in lung. CONCLUSIONS Histone causes pulmonary edema, endothelial cell injury and coagulation activation. Heparin could effectively attenuate histone-induced lung injury and coagulation activation.
Animals ; Fibrinogen/metabolism* ; Fibrinolytic Agents/therapeutic use* ; Heparin/therapeutic use* ; Histones ; Lung/metabolism* ; Male ; Mice ; Mice, Inbred C57BL ; von Willebrand Factor/metabolism*

OBJECTIVETo examine the effect of icariin (ICA) on the cognitive impairment induced by traumatic brain injury (TBI) in mice and the underlying mechanisms related to changes in hippocampal acetylation level.

METHODSThe modifified free-fall method was used to establish the TBI mouse model. Mice with post-TBI cognitive impairment were randomly divided into 3 groups using the randomised block method (n=7): TBI (vehicle-treated), low-dose (75 mg/kg) and high-dose (150 mg/kg) of ICA groups. An additional sham-operated group (vehicle-treated) was employed. The vehicle or ICA was administrated by gavage for 28 consecutive days. The Morris water maze (MWM) test was conducted. Acetylcholine (ACh) content, mRNA and protein levels of choline acetyltransferase (ChAT), and protein levels of acetylated H3 (Ac-H3) and Ac-H4 were detected in the hippocampus.

RESULTSCompared with the sham-operated group, the MWM performance, hippocampal ACh content, mRNA and protein levels of ChAT, and protein levels of Ac-H3 and Ac-H4 were signifificantly decreased in the TBI group (P<0.05). High-dose of ICA signifificantly ameliorated the TBI-induced weak MWM performance, increased hippocampal ACh content, and mRNA and protein levels of ChAT, as well as Ac-H3 protein level compared with the TBI group (P<0.05).

CONCLUSIONICA improved post-TBI cognitive impairment in mice by enhancing hippocampal acetylation, which improved hippocampal cholinergic function and ultimately improved cognition.

Acetylation ; Acetylcholine ; metabolism ; Animals ; Brain Injuries, Traumatic ; complications ; Choline O-Acetyltransferase ; genetics ; metabolism ; Cognitive Dysfunction ; drug therapy ; etiology ; Flavonoids ; chemistry ; pharmacology ; therapeutic use ; Hippocampus ; pathology ; Histones ; metabolism ; Homeostasis ; drug effects ; Male ; Maze Learning ; drug effects ; Mice ; RNA, Messenger ; genetics ; metabolism

OBJECTIVETo investigate the protective effect of histone acetylation against hypoxic-ischemic cortical injury in neonatal rats.

METHODSA total of 90 neonatal rats aged 3 days were divided into three groups: sham-operation, cortical injury model, and sodium butyrate (a histone deacetylase inhibitor) treatment. The rats in the model and the sodium butyrate treatment groups were intraperitoneally injected with lipopolysaccharide (0.05 mg/kg), and then right common carotid artery ligation was performed 2 hours later and the rats were put in a hypoxic chamber (oxygen concentration 6.5%) for 90 minutes. The rats in the sham-operation group were intraperitoneally injected with normal saline and the right common carotid artery was only separated and exposed without ligation or hypoxic treatment. The rats in the sodium butyrate treatment group were intraperitoneally injected with sodium butyrate (300 mg/kg) immediately after establishment of the cortical injury model once a day for 7 days. Those in the sham-operation and the model groups were injected with the same volume of normal saline. At 7 days after establishment of the model, Western blot was used to measure the protein expression of histone H3 (HH3), acetylated histone H3 (AH3), B-cell lymphoma/leukemia-2 (Bcl-2), Bcl-2-associated X protein (BAX), cleaved caspase-3 (CC3), and brain-derived neurotrophic factor (BDNF). Immunofluorescence assay was used to measure the expression of 5-bromo-2'-deoxyuridine (BrdU) as the cortex cell proliferation index.

RESULTSThe sodium butyrate treatment group had a significantly lower HH3/AH3 ratio than the model group (P<0.05), which suggested that the sodium butyrate treatment group had increased acetylation of HH3. Compared with the model group, the sodium butyrate treatment group had a significant increase in Bcl-2/Bax ratio, a significant reduction in CC3 expression, and a significant increase in BDNF expression (P<0.05). The sodium butyrate treatment group had a significant increase in the number of BrdU-positive cells in the cortex compared with the model group (P<0.05), and BrdU was mainly expressed in the neurons.

CONCLUSIONSIncreased histone acetylation may protect neonatal rats against cortical injury by reducing apoptosis and promoting regeneration of neurons. The mechanism may be associated with increased expression of BDNF.

Acetylation ; Animals ; Animals, Newborn ; Apoptosis ; drug effects ; Brain-Derived Neurotrophic Factor ; analysis ; Butyric Acid ; therapeutic use ; Cerebral Cortex ; pathology ; Female ; Histones ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley

SUV39H1 is a histone 3 lysine 9 (H3K9)-specific methyltransferase that is important for heterochromatin formation and the regulation of gene expression. Chaetocin specifically inhibits SUV39H1, resulted in H3K9 methylation reduction as well as reactivation of silenced genes in cancer cells. Histone deacetylase (HDAC) inhibitors inhibit deacetylases and accumulate high levels of acetylation lead to cell cycle arrest and apoptosis. In this study, we demonstrated that treatment with chaetocin enhanced apoptosis in human leukemia HL60, KG1, Kasumi, K562, and THP1 cells. In addition, chaetocin induced the expression of cyclin-dependent kinase inhibitor 2B (p15), E-cadherin (CDH1) and frizzled family receptor 9 (FZD9) through depletion of SUV39H1 and reduced H3K9 methylation in their promoters. Co-treatment with chaetocin and HDAC inhibitor trichostatin A (TSA) dramatically increased apoptosis and produced greater activation of genes. Furthermore, this combined treatment significantly increased loss of SUV39H1 and reduced histone H3K9 trimethylation responses accompanied by increased acetylation. Importantly, co-treatment with chaetocin and TSA produced potent antileukemic effects in leukemia cells derived from patients. These in vitro findings suggest that combination therapy with SUV39H1 and HDAC inhibitors may be of potential value in the treatment of leukemia.
Acetylation/drug effects ; Adolescent ; Adult ; Aged ; Apoptosis/*drug effects ; Cadherins/metabolism ; Cell Line, Tumor ; Cyclin-Dependent Kinase Inhibitor p15/metabolism ; DNA Methylation/drug effects ; Enzyme Inhibitors/therapeutic use/*toxicity ; Frizzled Receptors/metabolism ; Gene Expression Regulation/drug effects ; HL-60 Cells ; Histone Deacetylase Inhibitors/therapeutic use/*toxicity ; Histone-Lysine N-Methyltransferase/*antagonists & inhibitors/metabolism ; Histones/genetics/metabolism ; Humans ; Hydroxamic Acids/therapeutic use/*toxicity ; K562 Cells ; Leukemia/drug therapy/metabolism/pathology ; Leukemia, Myeloid, Acute/genetics/metabolism/pathology ; Male ; Middle Aged ; Piperazines/therapeutic use/toxicity ; Promoter Regions, Genetic ; Young Adult

Alzheimer's disease (AD) is a neurodegenerative disorder characteristic of neurons reducing, senile plaques, neurofibrillary tangles and so on, and the most common cause of dementia among the elderly. Many efforts have been made to understand the epigenetic mechanisms involved in the development of AD, such as gene methylation and histone acetylation, although the exact mechanisms are not yet entirely clear. Here, we provide a review of the epigenetic mechanisms and related research in AD, which may provide a new direction for the research as well as the development of the epigenetic drugs.
Acetylation ; Alzheimer Disease ; drug therapy ; genetics ; Animals ; DNA Methylation ; genetics ; Epigenesis, Genetic ; Histone Deacetylase Inhibitors ; therapeutic use ; Histones ; genetics ; metabolism ; Humans ; MicroRNAs ; metabolism

Epigenetic abnormalities not only associated with carcinogenesis, they may also influence the curative effect and prognosis of anticancer drugs through modifying pharmacokinetic genes related to drug absorption, distribution, metabolism, excretion and pharmacodynamic genes related to signaling pathways and targets. That drugs through regulating epigenetic factors pocessing anti-cancer effect is becoming a research hot spot. We summarized and analyzed the realtionship of DNA methylation, miRNA, and histone modification with antitumor drug effect, aiming at promoting rational use of antitumor drugs and providing new ideas on developing epi-drugs.
Antineoplastic Agents ; therapeutic use ; DNA Methylation ; Epigenesis, Genetic ; Histones ; genetics ; metabolism ; Humans ; MicroRNAs ; metabolism ; Neoplasms ; drug therapy ; genetics

BACKGROUND/AIMS: DNA double strand breaks (DSB) is one of the critical types of DNA damage. If unrepaired, DSB is accumulated in the nucleus of cells, the cells become apoptotic or transform to tumor by way of genomic instability. Some of malignant cancers and its premalignant lesions were proven to have DSB in their nuclei. There was no report that Helicobacter pylori (H. pylori), the gastric carcinogen, induce DNA DSB in gastric epithelium in vivo. The aim of this study was to investigate whether H. pylori induce DSB in the gastric epithelial cells of chronic gastritis. METHODS: Immunohistochemical stains were performed for the DSB markers, phospho-53BP1 and gammaH2AX, in the gastric epithelium derived from 44 peptic ulcer disease patients before and after H. pylori eradication. DNA fragmentation assay was performed in the cell line to investigate the DNA damage by H. pylori infection. RESULTS: The mean expression score of gammaH2AX was significantly higher in the H. pylori infected gastric epithelium as compared to the H. pylori eradicated gastric epithelium (8.8+/-5.5 vs. 6.2+/-5.3 respectively; p=0.008). The expression score of phospho-53BP1 between before and after eradication of H. pylori was not statistically different, but tended to be higher in H. pylori infection. DNA fragmentation was developed significantly more in the cell lines after infection with H. pylori. CONCLUSIONS: DSB of DNA damage was typical feature of H. pylori infection in the gastric epithelium.
Adult ; Aged ; Aged, 80 and over ; Anti-Bacterial Agents/therapeutic use ; Cell Line, Tumor ; DNA/metabolism ; *DNA Breaks, Double-Stranded ; Female ; Gastric Mucosa/*metabolism ; Helicobacter Infections/drug therapy/*metabolism ; Helicobacter pylori/*drug effects/pathogenicity ; Histones/genetics/metabolism ; Humans ; Immunohistochemistry ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; Male ; Middle Aged ; Peptic Ulcer/genetics/pathology

Histone modification is an important mechanism in oncogenesis and development of hematologic malignancies. Acetylation of lysine residues on histones and opening chromatin are correlated with activation of genes, whereas lysine residues methylation can result in either activation or repression on expressions of chromatin. The main point of all is deacetylation of histone mediated by histone deacetylases (HDACs). HDAC inhibitors are divided into 4 categories: short-chain fatty acids, hydroxamic acids, cyclic tetrapeptides and benzamides, owning different mechanisms in HDAC inhibition. Many kinds of I/II phase clinical tests showed that all these HDAC inhibitors have obviously therapeutic efficacies in treatment of hematologic malignancies with low poisons. Combination of HDAC inhibitors with DNA demethylation drugs can decrease DNA methylation, increase histone acetylation and recover antioncogene expression. As important parts of epigenetics, histone acetylation and HDAC inhibitors possess positive prospects in treatment of hematologic malignancies. In this review the advances of study on mechanisms of histone modification, HDAC inhibitors and their use in treatment of hematologic malignancies are summarized.
Acetylation ; Hematologic Neoplasms ; drug therapy ; Histone Deacetylase Inhibitors ; therapeutic use ; Histone Deacetylases ; genetics ; Histones ; chemistry ; genetics ; metabolism