摘要
Schistosomiasis is a neglected zoonotic parasitic disease. Currently, praziquantel is the drug of choice for the treatment of schistosomiasis, and is the only effective chemical for treatment of schistosomiasis japonica. Since its introduction in the 1970s, praziquantel has been used for large-scale chemotherapy of schistosomiasis for over 40 years. However, there have been reports pertaining to the resistance to praziquantel in schistosomes. Therefore, development of novel antischistosomal agents as alternatives of praziquantel, is of great need. Histone deacetylases and histone acetyltransferases have been recently reported to play critical roles in the growth, development and reproduction of schistosomes, and are considered as potential drug targets for the treatment of schistosomiasis. This review summarizes the latest advances of histone deacetylase and histone acetyltransferase inhibitors in the research on antischistosomal drugs, so as to provide insights into research and development of novelantischistosomal agents.
摘要
@#Histone acetylation and methylation can affect chromatin conformation and regulate a variety of biological activities. Abnormal histone acetylation and methylation modifications are related to the occurrence and development of a variety of oral diseases. Histone acetylation and methylation increase or decrease in an orderly manner to regulate the development of teeth. Fluoride ions can destroy the balance between histone acetylation and methylation, which may be related to the occurrence of dental fluorosis. In addition, histone acetylation and methylation are involved in the regulation of oral inflammatory diseases. In the inflammatory microenvironment, the expression of histone acetyltransferase GCN5 decreases, and the expression of Dickkopf 1 (DKK1) decreases, activating the Wnt/β-catenin pathway and ultimately inhibiting the osteogenic differentiation of periodontal ligament stem cells. Enhancer of zeste homolog 2 (EZH2) and H3K27me3 levels were decreased in inflamed dental pulp tissues and cells. EZH2 inhibition inhibited the expression of interleukin (IL)-1b, IL-6 and IL-8 in human dental pulp cells under inflammatory stimulation. Histone acetylation/methylation modifications can interact with multiple signaling pathways to promote the occurrence and development of oral tumors and are related to the high invasiveness of salivary gland tumors. Small molecule drugs targeting histone acetylation and methylation-related enzymes can regulate the level of histone methylation/acetylation and have shown potential in the treatment of oral and maxillofacial diseases. For example, the histone deacetylase inhibitor vorinostat can inhibit the secretion of inflammation-related cytokines; it also promotes the maturation of odontoblasts and the formation of dentin-related matrix, demonstrating its potential in pulp preservation. Understanding the role of histone acetylation/methylation modifications in the occurrence and development of oral diseases will help promote research on epigenetic modifications in oral diseases and provide new perspectives for disease diagnosis and treatment.
摘要
Objective To investigate the role of autophagy in contrast-induced acute kidney injury(CI-AKI)in rats and to explore its possible mechanism.Methods SD rats were randomly divided into control group,acute kid-ney injury model group(intravenous injection of contrast medium ioversol via tail vein;model),rapamycin(RAPA)group and hydroxychloroquine(HCQ)group.Blood urea nitrogen(BUN)and serum creatinine(Scr)con-tents were measured and the potential change foun in renal pathology was detected by HE staining and microscopy.Transmission electron microscopy was used to observe auto-phagy-related changes in ultrastructure.Western blot was used to observe the expression of microtubule-associated protein 1 light chain 3(LC3)Ⅱ/LC3Ⅰ,ubiquitin-binding protein p62 and Histone deacetylase 4(HDAC4).The expression of HDAC4 was also observed by RT-qPCR.Results Compared with control group,the level of BUN,Scr and HDAC4 expression in the model and HCQ group was increased(P＜0.01),the proximal tubules of the kidney were significantly damaged.In the model group,auto-phagososomes and autolysosomes increased,accompanied by an increase of LC3Ⅱ/LC3Ⅰ and a decrease in the p62 level(P＜0.05,P＜0.01);Compared with model group,there were more autophagosomes and autolysosomes were found in RAPA group(P＜0.01),accompanied by increased LC3Ⅱ/LC3Ⅰratio and decrease in the p62 and HDAC4(P＜0.05,P＜0.01).In contrast,the number of autophagy related structures decreased in HCQ group(P＜0.01),accompanied by the simultaneous increase of LC3Ⅱ/LC3Ⅰ,p62 and the increase of HDAC4(P＜0.01).Conclusions Ioversol may induce autophagy activation,while enhancing autophagy by RAPA alleviates CI-AKI induced renal dysfunction.The mechanism is potentially atributed to the regulation of HDAC4.
摘要
Objective To analyze the relationship between serum micro RNA(miR)139-5p,histone deacetylase 4(HDAC4)and glial fibrillary acidic protein(GFAP)and the severity of brain injury in neonatal hypoxic-ischemic encephalopathy(HIE).Methods From January 2017 to March 2022,72 HIE neonates born in Guangyuan Central Hospital were collected as research objects(study group),while 75 healthy full-term newborns were the control group.The expression levels of miR-139-5p and HDAC4 in serum were detected by real-time fluorescence quantitative PCR.ELISA was applied to detect serum GFAP level.Binary logistic regression was applied to analyze the factors affecting the occurrence of severe brain injury in children with HIE.Results Compared with the control group,the serum GFAP(1.30±0.37ng/L vs 0.50±0.15 ng/L)and HDAC4 relative expression level(2.05±0.39 vs 1.02±0.21)in the study group were increased,the relative expression level of miR-139-5p(0.63±0.14 vs 1.01±0.22)and the NBNA score(33.20±1.43 score vs 39.85±2.23 score)was decreased,the differences were statistically significant(t=17.304,20.046,12.436,21.424,all P＜0.05).Compared with the mild to moderate group,the serum GFAP level(1.61±0.47ng/L vs 1.16±0.33ng/L),HDAC4 relative expression level(2.43±0.37 vs 1.87±0.40),miR-139-5p(0.38±0.10 vs 0.74±0.16)and NBNA score(30.52±1.54 score vs 34.46±1.38 score)relative expression level in the severe group were increased,and the differences were statistically significant(t=4.690,5.669,9.900,10.884,all P＜0.05).Logistic regression analysis showed that low expression of miR-139-5p,high expression of HDAC4,low NBNA score and low Apgar score within 1 min after birth were risk factors for severe brain injury in HIE children(Wald χ2=5.772～6.969,OR=1.519～1.709,all P＜0.05).Pearson analysis showed that the expression level of serum miR-139-5p was negatively correlated with GFAP,HDAC4(r=-0.416,-0.579,all P＜0.05),while the expression level of serum HDAC4 was positively correlated with GFAP(r= 0.437,P＜0.05).Spearman analysis showed that the expression level of serum miR-139-5p was positively correlated with NBNA score,Apgar score within 1 min after birth,and Apgar score within 5 min after birth(r= 0.398,0.367,0.348,all P＜0.05).Serum HDAC4 expression level was negatively correlated with NBNA score,Apgar score within 1 min after birth,and Apgar score within 5 min after birth(r=-0.364,-0.345,-0.332,all P＜0.05).Conclusion The expression of miR-139-5p in the serum of children with HIE was decreased,and the expression of HDAC4 was increased,miR-139-5p and HDAC4 were associated with the severity of brain injury in children with HIE.
摘要
Acute myeloid leukemia (AML) is a malignant clonal disease of hematopoietic stem cells, characterized by the proliferation of abnormal primordial cells of myeloid origin in bone marrow, blood and other tissues. At present, the standard induction therapy for AML mainly includes “3+7” standard treatment(anthracycline combined with cytarabine), allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and targeted drug therapy. However, AML cells usually express high levels of P-glycoprotein, which mediates the efflux of chemotherapeutic drugs, which makes AML cells resistant to chemotherapy, resulting in many patients who are not sensitive to chemotherapy or relapse after complete remission. And some patients can not tolerate intensive therapy or lack of donors and can not use Allo-HSCT therapy. Therefore, it is of great clinical significance to find new drugs to improve the efficacy of AML patients. Epigenetic disorders play a key role in the pathogenesis of many diseases, especially cancer. Studies have shown that most AML patients have epigenetic regulatory gene mutations, such as DNMT3A, IDH and TET2, and these mutations are potentially reversible, which has become one of the therapeutic targets of AML. Histone deacetylase inhibitors (HDACi) can regulate the balance between histone acetylation and deacetylation, change the expression of proto-oncogenes or tumor suppressor genes that control cancer progression from epigenetics, and play an important role in many kinds of tumor therapy. At present, HDACi has shown the ability to induce differentiation, cell cycle arrest and apoptosis of AML cells. The mechanism may be mainly related to HDACi inducing chromatin conformation opening of tumor suppressor gene by inhibiting HDAC activity, promoting oncogene damage and preventing oncogene fusion protein from recruiting HDAC. Although the preclinical outcome of HDACi is promising, it is not as effective as the conventional therapy of AML. However, the combination strategy with various anticancer drugs is in clinical trials, showing significant anti-AML activity, improving efficacy through key targeting pathways in a typical synergistic or additive way, increasing AML sensitivity to chemotherapy, reducing tumor growth and metastasis potential, inhibiting cell mitotic activity, inducing cell apoptosis, regulating bone marrow microenvironment, which provides a good choice for the treatment of AML. Especially for those AML patients who are not suitable for intensive therapy and drug resistance to chemotherapy. This review introduces the relationship between HDAC and cancer; the classification of HDAC and its function in AML; the correlation between HDAC and AML; the clinical application of five types of HDACi; preclinical research results and clinical application progress of six kinds of HDACi in AML, such as Vrinota, Belinostat, Panobinostat, Valproic acid, Entinostat, and Chidamide, the mechanism of HDACi combined with other anticancer drugs in AML indicates that the current HDACi is mainly aimed at various subtypes of pan-HDAC inhibitors, with obvious side effects, such as fatigue, thrombocytopenia, nausea, vomiting, diarrhea. In recent years, the next generation of HDACi is mainly focused on the selectivity of analogues or isomers. Finding the best combination of HDACi and other drugs and the best timing of administration to balance the efficacy and adverse reactions is a major challenge in the treatment of AML, and the continued development of selective HDACi with less side effects and more accurate location is the key point for the development of this drug in the future. It is expected to provide reference for clinical treatment of AML.
摘要
Objective To investigate the expression of histone deacetylase(HDAC)isoforms in the frontal lobe,hippo-campus and liver of offspring rats delivered by rats with maternal immune activation and their correlation with the efficiency of prepulse inhibition(PPI％).Methods Ten pregnant Sprague-Dawley rats were randomly divided into the model group(n=5)and control group(n=5).The rats in the model group were injected with 10 mg·kg-1 polyinosinic-polycytidylic acid(Poly I:C)via the caudal vein on the 9th day of pregnancy,while rats in the control group were given the same volume of sterile physiological saline.After 3 h,blood was collected from the caudal vein,and the levels of interleukin(IL)-1 β,IL-6 and tumor necrosis factor-α(TNF-α)in the plasma of pregnant rats were detected by enzyme-linked immunosorbent assay to evaluate the immune activation status.The pregnant rats in the two groups were fed until natural delivery,the offspring rats were weaned on the 21st day after birth,and the male offspring rats were fed continuously.A prepulse inhibition test was performed at puberty(the 40th day after birth)to evaluate the spatial recognition memory and sensory gating function of the offspring rats.The expression levels of the HDAC gene family in the hippocampus,frontal lobe and liver of offspring rats were detected by real-time fluorescence quantitative polymerase chain reaction.Results The plasma IL-6,IL-1 β and TNF-α levels in the model group were significantly higher than those in the control group(P＜0.05).When the prepulse stimulation was 75 dB,the PPI％of the offspring rats at puberty in the model group was significantly lower than that in the control group(P＜0.05).When the prepulse stimulation was 80 and 85 dB,there was no significant difference in PPI％between the model group and the control group(P＞0.05).In the frontal lobe,the expression levels of HDAC3,HDAC4,HDAC8,HDAC9,HDAC10 and Sirt mRNA in the offspring rats in the model group were significantly lower than those in the control group(P＜0.05),while the expression level of HDAC5 mRNA was significantly higher than that in the control group(P＜0.05);there were no significant differences in the expression levels of HDAC1,HDAC2,HDAC6,HDAC7 and HDAC11 mRNA between the model group and the control group(P＞0.05).In the hippocampus,the offspring rats in the model group had significantly lower expression levels of HDAC1,HDAC8 and HDAC10 mRNA and significantly higher expression levels of HDAC2 and HDAC5 mRNA than those in the control group(P＜0.05);there were no significant differences in the expression levels of HDAC3,HDAC4,HDAC6,HDAC7,HDAC9,HDAC11 and Sirt mRNA between the model group and control group(P＞0.05).In the liver tissue,the expression levels of HDAC6 and HDAC10 mRNA of the offspring rats in the model group were significantly lower than those in the control group(P＜0.05);there were no significant differences in the expression levels of HDAC1,HDAC2,HDAC3,HDAC4,HDAC5,HDAC7,HDAC8,HDAC9,HDAC11 and Sirt mRNA between the model group and the control group(P＞0.05).The expression level of HDAC2 mRNA in the hippocampus of offspring rats in the two groups was negatively correlated with PPI％at 75 dB(r=-0.965,P＜0.05),the expression levels of HDAC10 and Sirt mRNA in frontal lobe tissues were positively correlated with PPI％at 75dB(r=0.946,0.925;P＜0.05).Conclusion Pregnancy Poly I:C infection has significant effects on the expression of HDAC family proteins in offspring rats,and which is related to the impairment of early sensory gating,this may provide new ideas for the research in pathogenesis and drug treatment of schizophrenia.
摘要
AIM: To elucidate the effect of histone deacetylase(HDAC)inhibitor suberoylanilide hydroxamic acid(SAHA)on the proliferation of choroidal melanoma(CM)cell line C918 and to explore the related mechanism.METHODS: Inverted fluorescence microscope was used to observe the effect of different concentrations of SAHA(0.625, 1.25 or 2.5 μmol/L)on the morphology of C918 cell. The cell viability was detected by cholecystokinin octapeptide(CCK-8)assay. Plate clone formation assay and EdU staining were carried out to measure the effect of SAHA on the cell proliferation. Meanwhile, the expressions of cell proliferation-related proteins including c-Myc, CyclinA2 and CDK2, and histone deacetylase 7(HDAC7)and fibroblast growth factor 18(FGF18)were detected by Western blot.RESULTS: Compared with the control group, the cell density was reduced in SAHA. SAHA could also promote cell shrinkage, and the inhibition on cell was in a concentration-dependent manner. CCK-8 assay showed that SAHA treatment decreased cell viability in a dose-dependent manner and the inhibition rate was 80% when SAHA at 2.5 μmol/L. Compared with the control group, Western blot showed that SAHA could suppress the expression of cell proliferation proteins including c-Myc, CyclinA2 and CDK2 in a dose-dependent manner. In addition, 1.25 μmol/L SAHA significantly decreased the numbers of EdU staining positive cells and cell clones. More importantly, SAHA could dose-dependently decrease the expression of HDAC7 and FGF18 compared with control group.CONCLUSION: SAHA could inhibit the proliferation of CM cell line C918 by inhibiting the HDAC7/FGF18 signaling pathway.
摘要
OBJECTIVES@#Subarachnoid hemorrhage (SAH) is a serious cerebrovascular disease. Early brain injury (EBI) and cerebral vasospasm are the main reasons for poor prognosis of SAH patients. The specific inhibitor of histone deacetylase 6 (HDAC6), tubastatin A (TubA), has been proved to have a definite neuroprotective effect on a variety of animal models of acute and chronic central nervous system diseases. However, the neuroprotective effect of TubA on SAH remains unclear. This study aims to investigate the expression and localization of HDAC6 in the early stage of SAH, and to evaluate the protective effects of TubA on EBI and cerebral vasospasm after SAH and the underlying mechanisms.@*METHODS@#Adult male SD rats were treated with modified internal carotid artery puncture to establish SAH model. In the first part of the experiment, rats were randomly divided into 6 groups: a sham group, a SAH-3 h group, a SAH-6 h group, a SAH-12 h group, a SAH-24 h group, and a SAH-48 h group. At 3, 6, 12, and 24 h after SAH modeling, the injured cerebral cortex of rats in each group was taken for Western blotting to detect the expression of HDAC6. In addition, the distribution of HDAC6 in the cerebral cortex of the injured side was measured by immunofluorescence double staining in SAH-24 h group rats. In the second part, rats were randomly divided into 4 groups: a sham group, a SAH group, a SAH+TubAL group (giving 25 mg/kg TubA), and a SAH+TubAH group (giving 40 mg/kg TubA). At 24 h after modeling, the injured cerebral cortex tissue was taken for Western blotting to detect the expression levels of HDAC6, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining to detect apoptosis, and hematoxylin and eosin (HE) staining to detect the diameter of middle cerebral artery.@*RESULTS@#The protein expression of HDAC6 began to increase at 6 h after SAH (P<0.05), peaked at 24 h (P<0.001), and decreased at 48 h, but there was still a difference compared with the sham group (P<0.05). HDAC6 is mainly expressed in the cytoplasm of the neurons. Compared with the sham group, the neurological score was decreased significantly and brain water content was increased significantly in the SAH group (both P<0.01). Compared with the SAH group, the neurological score was increased significantly and brain water content was decreased significantly in the SAH+TubAH group (both P<0.05), while the improvement of the above indexes was not significant in the SAH+TubAL group (both P>0.05). Compared with the sham group, the expression of eNOS was significantly decreased (P<0.01) and the expressions of iNOS and HDAC6 were significantly increased (P<0.05 and P<0.01, respectively) in the SAH group. Compared with the SAH group, the expression of eNOS was significantly increased, and iNOS and HDAC6 were significantly decreased in the SAH+TubA group (all P<0.05). Compared with the SAH group, the number of TUNEL positive cells was significantly decreased and the diameter of middle cerebral artery was significantly increased in the SAH+TubA group (both P<0.05) .@*CONCLUSIONS@#HDAC6 is mainly expressed in neurons and is up-regulated in the cerebral cortex at the early stage of SAH. TubA has protective effects on EBI and cerebral vasospasm in SAH rats by reducing brain edema and cell apoptosis in the early stage of SAH. In addition, its effect of reducing cerebral vasospasm may be related to regulating the expression of eNOS and iNOS.
Subject(s)
Rats , Male , Animals , Rats, Sprague-Dawley , Subarachnoid Hemorrhage/drug therapy , Vasospasm, Intracranial/metabolism , Histone Deacetylase Inhibitors/therapeutic use , Neuroprotective Agents/therapeutic use , Histone Deacetylase 6/pharmacology , Apoptosis , Brain Injuries/drug therapy摘要
Gliomas are commonly central nervous system tumors. The conventional treatment is surgical resection combined with chemoradiotherapy， but glioma patients often have a poor prognosis. Therefore， there is an urgent need to identify new potential targets in gliomas and develop more effective treatments. Valproic acid has the properties of histone deacetylase inhibitor， which has been proven to have inhibitory effects on various tumors. It is confirmed that valproic acid could promote apoptosis and cell arrest of glioma cells， inhibit cell invasion and glioma stem cells， increase the sensitivity of glioma cells to radiotherapy and chemotherapy by regulating ERK/Akt signaling pathway， Akt/mTOR signaling pathway， and regulating expression levels of RECK， MGMT， Nrf2， PON2， Smad4， GSK3β and other proteins. In addition， valproic acid can also enhance the effectiveness of anticancer drugs by inhibiting the growth of glioma stem cells and inducing their differentiation. In conclusion， valproic acid can inhibit glioma through multiple targeted actions， and may become a new targeted drug for the treatment of glioma.
摘要
Entinostat plus exemestane in hormone receptor-positive (HR+) advanced breast cancer (ABC) previously showed encouraging outcomes. This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemestane in Chinese patients with HR + ABC that relapsed/progressed after ≥1 endocrine therapy. Patients were randomized (2:1) to oral exemestane 25 mg/day plus entinostat (n = 235) or placebo (n = 119) 5 mg/week in 28-day cycles. The primary endpoint was the independent radiographic committee (IRC)-assessed progression-free survival (PFS). The median age was 52 (range, 28-75) years and 222 (62.7%) patients were postmenopausal. CDK4/6 inhibitors and fulvestrant were previously used in 23 (6.5%) and 92 (26.0%) patients, respectively. The baseline characteristics were comparable between the entinostat and placebo groups. The median PFS was 6.32 (95% CI, 5.30-9.11) and 3.72 (95% CI, 1.91-5.49) months in the entinostat and placebo groups (HR, 0.76; 95% CI, 0.58-0.98; P = 0.046), respectively. Grade ≥3 adverse events (AEs) occurred in 154 (65.5%) patients in the entinostat group versus 23 (19.3%) in the placebo group, and the most common grade ≥3 treatment-related AEs were neutropenia [103 (43.8%)], thrombocytopenia [20 (8.5%)], and leucopenia [15 (6.4%)]. Entinostat plus exemestane significantly improved PFS compared with exemestane, with generally manageable toxicities in HR + ABC (ClinicalTrials.gov #NCT03538171).
摘要
@#Objective To explore the correlation between serum levels of histone deacetylase 3(HDAC3) and the signal molecule SMAD family member 3(SMAD3) and the degree of neurological deficit in patients with acute ischemic stroke(AIS). Methods From June 2021 to June 2022,104 patients diagnosed with AIS in our hospital were selected. Using the National Institutes of Health Stroke Scale(NIHSS),they were divided based on the degree of neurological impairment into mild group(32 cases),moderate group(37 cases),and severe group(35 cases). At the same time,98 healthy volunteers from health examination in our hospital were included as the control group. The expression levels of HDAC3,SMAD3,tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),and interleukin-6(IL-6) in serum were measured by using enzyme-linked immunosorbent assay. Pearson correlation analysis was used to analyze the correlation between the expression of HDAC3 and SMAD3.Spearman correlation analysis was used to analyze the correlation between the expression of HDAC3 and SMAD3 and NIHSS score and the degree of neurological deficit. Results Compared with the control group,the AIS group showed significantly higher levels of triglyceride,total cholesterol,low-density lipoprotein cholesterol,fibrinogen,TNF-α,IL-1β,and IL-6 and a significantly lower level of HDL-C(all P<0.05). HDAC3 and SMAD3 levels were significantly higher in the AIS group than in the control group(both P<0.05). HDAC3 and SMAD3 levels in the severe group were significantly higher than those in the moderate and mild groups,and those in the moderate group were significantly higher than those in the mild group(all P<0.05). The Pearson correlation analysis showed that the serum expression levels of HDAC3 and SMAD3 in the AIS patients were positively correlated(P<0.05). The Spearman correlation analysis showed positive correlations between the expression of HDAC3 and SMAD3 and NIHSS score(r=0.339,0.563;both P<0.001)and the degree of neurological impairment(r=0.698,0.572;both P<0.001). Conclusion Serum HDAC3 and SMAD3 levels in patients with AIS were abnormally increased,and both were related to the degree of neurological deficit.
摘要
Objective:To investigate the effect of histone deacetylase inhibitor trichostatin A(TSA) on the lipopolysaccharide(LPS)-induced injury and apoptosis of human microvascular endothelial cell(HMEC).Methods:HMECs were used as research cells to establish LPS-induced septic cell model, which were divided into three groups according to different treatments: control group (150 μL of phosphate buffer), LPS group (150 μL of 5 μg/mL LPS), LPS+ TSA group (150 μL of 5 μg/mL LPS and 500 μg/L TSA). After cells of each group were cultured for 24 h and 48 h, the concentration of lactate dehydrogenase(LDH)in the culture supernatant was detected by enzyme-linked immunosorbent assay and the apoptosis rate of HMECs was detected by Annexin V-FTTC/PI staining, then comparison between different groups were made.Results:Compared with the control group, LDH concentration in LPS group increased significantly at 24 h[(4.67±1.27) ng/L vs. (11.57±0.83) ng/L ] and 48 h[(7.93±0.80) ng/L vs. (12.72±0.89) ng/L ]; Compared with LPS group, LDH concentration in LPS + TSA group decreased significantly at 24 h[(6.01±0.29) ng/L ] and 48 h[(5.96±0.27) ng/L ], and the differences were statistically significant ( P<0.05). Compared with the control group, the apoptosis rates of HMEC cells in LPS group were significantly higher at 24 h[(0.92±0.89)% vs. (1.66±0.09)% ] and 48 h[(1.09±0.14)% vs. (5.01±0.16)%]; Compared with LPS group, the apoptosis rate of HMEC cells in LPS + TSA group significantly decreased at 24 h[(1.36±0.01)% ] and 48 h[(4.19±0.23)% ], the differences were statistically significant ( P<0.05). Conclusion:TSA has the protective effect of reducing cell injury and apoptosis in sepsis.
摘要
Objective:To investigate the relationship between histone deacetylase (HDAC) gene polymorphism and type 2 diabetes mellitus (T2DM) in Bai and Han populations in Dali of Yunnan province.Methods:A total of 148 patients with T2DM of Bai and Han nationalities who received treatment in Dali Bai Autonomous Prefecture People's Hospital from May 2019 to March 2021 were included in the T2DM group. An additional 100 healthy controls of Bai and Han nationalities who concurrently received physical examination in the same hospital from May 2019 to December 2020 were included in the normal control group. The susceptibility genes of T2DM were detected using the Taqman MGB probe method. The susceptibility gene loci were amplified using polymerase chain reaction. The whole sequence of susceptibility gene was sequenced.Results:There were no significant differences in the distribution frequencies of rs2530223 genotype, rs11741808 genotype, rs2547547 genotype, and rs1741981 genotype between Bai and Han populations (all P > 0.05). There was a significant difference in blood lipid level between four loci ( t = -1.06, -0.19, 0.39, -2.12, -2.04, 0.16, 1.47, < 0.01, -0.16, -3.17, -2.93, 0.69, -2.58, -2.33, all P < 0.05). There was a significant difference in homeostasis model assessment of insulin resistance between different states (all P < 0.05). The frequency distributions of each genotype and each allele did not differ significantly between healthy control people of Bai nationality and T2DM patients of Bai nationality and between healthy control people of Han nationality and T2DM patients of Han nationality (all P > 0.05). Logistic regression analysis showed that the polymorphism was not an independent risk factor for T2DM. Conclusion:The relationships between HDAC gene polymorphism and T2DM, obesity and dyslipidemia differ between Bai and Han populations.
摘要
Objective:To evaluate the effect of surgery under propofol anesthesia during mid-pregnancy on the cognitive function and hippocampal histone deacetylase 2 (HDAC2)-cAMP response element-binding protein (CREB)-N-methyl-D-aspartate (NMDA) receptor 2B subunit (NR2B)-containing NMDA receptor (NR2B) signaling pathway in the offspring rats.Methods:Thirty healthy Sprague-Dawley rats at 14 days of gestation were divided into 3 groups ( n=10 each) using a random number table method: propofol anesthesia group (P group), surgery under propofol anesthesia group (S group) and control group (C group). In S group, propofol 20 mg/kg was injected via the caudal vein, and then propofol was continuously infused at a rate of 20 mg·kg -1·h -1 to maintain anesthesia for 4 h, and exploratory laparotomy was performed. Group P received no exploratory laparotomy and the other treatments were similar to those previously described in group S. The equal volume of normal saline was given instead in group C. The learning and memory of the offspring rats was assessed using Morris water maze test on postnatal day 30. The expression of HDAC2, phosphorylated CREB (p-CREB), NR2B, brain-derived neurotriphic factor (BDNF) and phosphorylated tyrosine kinase B (p-TrkB) in offspring′s hippocampi was evaluated by Western blot. Apoptosis in hippocampal neurons was detected by TUNEL staining. Results:Compared with group C, the escape latency was significantly prolonged, the frequency of crossing the original platform was decreased, the time spent in the second quadrant was shortened, the expression of HDAC2 was up-regulated, the expression of p-CREB, NR2B, BDNF and p-TrkB was down-regulated, and the apoptosis rate of the hippocampal neurons was increased in P and S groups ( P<0.05). Compared with P group, the escape latency was significantly prolonged, the frequency of crossing the original platform was decreased, the time spent in the second quadrant was shortened, the expression of HDAC2 was up-regulated, the expression of p-CREB, NR2B, BDNF and p-TrkB was down-regulated, and the apoptosis rate of the hippocampal neurons was increased in S group ( P<0.05). Conclusions:Surgery under propofol anesthesia during mid-pregnancy can decrease the cognitive function of offspring rats, and the mechanism is related to the regulation of HDAC2-CREB-NR2B signaling pathway and the promotion of apoptosis in hippocampal neurons.
摘要
ABSTRACT OBJECTIVE To investigate the effects and mechanism of ginsenoside Rh2 on the proliferation and apoptosis in human glioma U87 and U251 cells. METHODS Using human glioma U87 and U251 cells as subjects， the proliferation and apoptosis， as well as the expression of histone deacetylase 1（HDAC1） protein and apoptosis-related proteins [B cell lymphoma-2（Bcl-2）， Bcl-2-associated X protein （Bax） and cleaved caspase-3] were detected after being treated with different concentrations of ginsenoside Rh2. RESULTS The concentrations of 10，20，30，40，50，60，70，80 μmol/L ginsenoside Rh2 could generally significantly increase the proliferation inhibition rate of U87 and U251 cells （P＜0.05 or P＜0.01）， and the half inhibitory concentrations of this component after 48 hours of action were 51.34 and 55.84 μmol/L， respectively；30，50 μmol/L ginsenoside Rh2 could increase the total apoptotic rate of both types of cells， reduced the protein expressions of HDAC1 and Bcl-2， and increased the protein expressions of Bax and cleaved caspase-3 significantly （P＜0.05 or P＜0.01）. CONCLUSIONS Ginsenoside Rh2 has a significant inhibitory effect on the proliferation of glioma cells and promotes the apoptosis of cells， which may be through reducing the expression of HDAC1 protein and activating the Bcl-2 family protein-mediated apoptosis pathway.
摘要
As an important component of nucleosomes on the chromatin of eukaryotic cells, histones play an important role in the development and progression of tumour diseases by regulating epigenetic post-translational modifications such as acetylation and methylation. In addition, development of inhibitors targeting methyltransferase and deacetylase provides novel therapeutic strategies for cancer treatment. Mass spectrometry-based proteomics can reveal the global changes of histone modifications under the action of drugs during disease progression, which in turn provides important support for revealing drug action mechanism, drug resistance mechanism, and investigating novel drug combination strategies. This article focuses on the progress and status of proteomic research on a variety of histone modifying enzyme inhibitors, including methyltransferase inhibitors and histone deacetylase inhibitors, which will help to understand the current and further utilization of proteomics in studying histone modifications.
摘要
Krüppel-like transcription factor 2 (KLF2) plays a key regulatory role in endothelial inflammation, thrombosis, angiogenesis and macrophage inflammation and polarization, and up-regulation of KLF2 expression has the potential to prevent and treatment atherosclerosis. In this study, trichostatin C (TSC) was obtained from the secondary metabolites of rice fermentation of Streptomyces sp. CPCC 203909 as a KLF2 up-regulator by using a high throughput screening model based on a KLF2 promoter luciferase reporter assay. TSC significantly inhibited the adhesion of tumor necrosis factor-α (TNFα) induced monocytes (THP-1) to human umbilical vein endothelial cells (HUVECs). Western blot results showed that TSC decreased TNFα induced the protein expression increase of vascular cell adhesion molecule-1 (VCAM-1), and thereby inhibited endothelial inflammation. The results of histone deacetylase (HDAC) overexpression and molecular docking experiments showed that TSC upregulated the expression of KLF2 by inhibiting subtypes of HDAC 4/5/7. In conclusion, this study suggests that TSC up-regulates the expression of KLF2 through inhibiting HDAC 4/5/7 and thus inhibits TNFα induced endothelial inflammation, and it has the potential to prevent and treat atherosclerosis.
摘要
Acute lung injury ( ALI) and its most extreme form a-cute respiratory distress syndrome ( ARDS) are lung diseases with high morbidity and mortality. There is no effective therapeutic intervention until now for its complicated pathophysiologi-cal processes and sophisticated regulatory mechanism. Histone deacetylases (HDACs) are a family of proteins with deacetylase activity. Studies have shown that HDACs are involved in the pathophysiological processes of ALI/ARDS, including inflammatory responses,endothelial permeability,oxidative stresses,alveolar fluid clearance and lung tissue repairment. Simultaneously, the use of HDACs inhibitors (HDACIs) can interfere with ALI/ ARDS progression. In this review we describe and summarize the pathophysiological processes and the underlying mechanisms in ALI/ARDS regulated by HDACs and HDACIs in detail, in order to provide the basis for the clinical application of HDACs-targe- ted agents and indicate directions for future study.
摘要
Aim To explore the inhibitory effect of Buyang Huanwu Decoction on the inflammatory response in the hippocampus of brain tissues of CIRI rats by regulating SIRT1 and the underlying mechanism. Methods The middle cerebral artery embolization (MCAO) model was prepared in rats and divided into sham operation group (Sham), model group (MCAO/R), Buyang Huanwu Decoction group (BYHWT),and BYHWT + SIRT1 inhibitor group (BYHWT + EX527). Zea Longa was used to detect the neurological function score of rats in each group; TTC staining was used to determine the volume of cerebral infarction; HE staining was used to observe the pathological damage of the hippocampus; Western blot was used to detect the expression levels of SIRT1 and IL-6; immunohistochemistry was used to detect TNF-α, IL-1β expression level. Results Compared with the sham group,the neurological function score of the MCAO/R group increased (P < 0.05); the volume of cerebral infarction increased (P < 0.05); the nerve cells in hippocampus were severely damaged, arranged disorderly, and the nucleus was broken; Western blot showed that the expression of SIRT1 decreased, IL-6 expression increased (P <0.05); immunohistochemistry showed that TNF-α,IL-1β expression increased (P < 0.05). Compared with the MCAO/R group, the neurological function score of the BYHWT group decreased (P <0.05); the volume of cerebral infarction decreased (P < 0.05); the damage of nerve cells in hippocampus was reduced; Western blot showed that the expression of SIRT1 increased and IL-6 expression decreased (P < 0.05); immunohistochemistry showed that TNF-α, IL-1β expression decreased (P < 0.05). Compared with the BYHWT group, the neurological function score of the BYHWT + EX527 group increased (P < 0.05); the volume of cerebral infarction was raised (P <0.05); the damage of nerve cells in hippocampus was aggravated; Western blot showed that the expression of SIRT1 decreased and IL-6 expression increased (P < 0.05); immunohistochemistry showed that TNF-α, IL-1β expression increased (P < 0.05). Conclusions Preliminary discussion of Buyang Huanwu Decoction can activate SIRT1 in hippocampus of rat brain tissues to reduce the inflammatory response after CIRI and play a role in brain protection.
摘要
Epilepsy is a complex neurological disease and its pathogenesis has not yet been clear. More and more evidence shows that epilepsy is closely related to epigenetic mechanisms such as histone deacetylation. Histone deacetylase inhibitors, a kind of epilepsy targeting drug potentially, are involved in the protection of neurogenesis and the regulation of a variety of neural signal cascade reactions. This article reviews the research progress of histone deacetylation in the pathogenesis of epilepsy and application prospect of histone deacetylase inhibitors in treating epilepsy.