KAT8/MOF-Mediated Anti-Cancer Mechanism of Gemcitabine in Human Bladder Cancer Cells

Histone acetylation is a well-characterized epigenetic modification controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalanced histone acetylation has been observed in many primary cancers. Therefore, efforts have been made to find drugs or small molecules such as HDAC inhibitors that can revert acetylation levels to normal in cancer cells. We observed dose-dependent reduction in the endogenous and exogenous protein expression levels of KAT8 (also known as human MOF), a member of the MYST family of HATs, and its corresponding histone acetylation at H4K5, H4K8, and H4K16 in chemotherapy drug gemcitabine (GEM)-exposed T24 bladder cancer (BLCA) cells. Interestingly, the reduction in MOF and histone H4 acetylation was inversely proportional to GEM-induced γH2AX, an indicator of chemotherapy drug effectiveness. Furthermore, pGL4-MOF-Luc reporter activities were significantly inhibited by GEM, thereby suggesting that GEM utilizes an MOF-mediated anti-BLCA mechanism of action. In the CCK-8, wound healing assays and Transwell ® experiments, the additive effects on cell proliferation and migration were observed in the presence of exogenous MOF and GEM. In addition, the promoted cell sensitivity to GEM by exogenous MOF in BLCA cells was confirmed using an Annexin V-FITC/PI assay. Taken together, our results provide the theoretical basis for elucidating the anti-BLCA mechanism of GEM.

Explore the occurrence and development of β cell dysfunction and insulin resistance according to the stratification on normal glucose tolerance / 中华内分泌代谢杂志

After the stratification of the normal glucose tolerance, the changes of insulin resistance and βcell function in the development of type 2 diabetes mellitus were investigated. A retrospective analysis on data of 275 cases with oral glucose insulin releasing tests. The area under the insulin curve (AUCINS ) 108. 43 mU/ L was taken as the critical value of diagnosis. Normal glucose tolerance subjects were divided into the NGT-a group(AUCINS<108. 43 mU/ L) and the NGT-b group(AUCINS≥108. 43 mU/ L). The plasma glucose, insulin, insulin sensitivity, and β cell function were compared among the 4 groups: NGT-a group (n=96), NGT-b group (n=49), prediabetes group (n=71), and type 2 diabetes mellitus group ( n = 59). Among the fasting insulin, 2 h insulin, AUCINS , early-phase insulin secretion index(△I30 / △G30), the ratio of total insulin area under curve, and total glucose area under curve, disposition index, homeostasis model assessment for insulin resistance, and Matsuda insulin sensitivity index, the relationship as follows: NGT-b group>prediabetes group>NGT-a group>type 2 diabetes mellitus group. The NGT-b group was always the highest, prediabetes group was lower, NGT-a group and type 2 diabetes mellitus group were the lowest, there were significant differences (all P<0. 05). Making the NGT-a group as the basic state, in the NGT-b group, β cell function has begun to appear compensation and insulin resistance, and β cell function compensation reached the peak, the β cell function in the prediabetes group was beginning to compensate for the deficiency, the function of β cell in type 2 diabetes mellitus group decreased further. These findings suggest that the development process of type 2 diabetes mellitus could be the following four stages according to the function of β cell: β cell function normal, β cell functional compensation, β cell function loss of compensation, and finally β cell function failure.

Explore the occurrence and development of β cell dysfunction and insulin resistance according to the stratification on normal glucose tolerance / 中华内分泌代谢杂志

After the stratification of the normal glucose tolerance, the changes of insulin resistance and βcell function in the development of type 2 diabetes mellitus were investigated. A retrospective analysis on data of 275 cases with oral glucose insulin releasing tests. The area under the insulin curve (AUCINS ) 108. 43 mU/ L was taken as the critical value of diagnosis. Normal glucose tolerance subjects were divided into the NGT-a group(AUCINS<108. 43 mU/ L) and the NGT-b group(AUCINS≥108. 43 mU/ L). The plasma glucose, insulin, insulin sensitivity, and β cell function were compared among the 4 groups: NGT-a group (n=96), NGT-b group (n=49), prediabetes group (n=71), and type 2 diabetes mellitus group ( n = 59). Among the fasting insulin, 2 h insulin, AUCINS , early-phase insulin secretion index(△I30 / △G30), the ratio of total insulin area under curve, and total glucose area under curve, disposition index, homeostasis model assessment for insulin resistance, and Matsuda insulin sensitivity index, the relationship as follows: NGT-b group>prediabetes group>NGT-a group>type 2 diabetes mellitus group. The NGT-b group was always the highest, prediabetes group was lower, NGT-a group and type 2 diabetes mellitus group were the lowest, there were significant differences (all P<0. 05). Making the NGT-a group as the basic state, in the NGT-b group, β cell function has begun to appear compensation and insulin resistance, and β cell function compensation reached the peak, the β cell function in the prediabetes group was beginning to compensate for the deficiency, the function of β cell in type 2 diabetes mellitus group decreased further. These findings suggest that the development process of type 2 diabetes mellitus could be the following four stages according to the function of β cell: β cell function normal, β cell functional compensation, β cell function loss of compensation, and finally β cell function failure.

Potential coordination role between O-GlcNAcylation and epigenetics

Dynamic changes of the post-translational O-GlcNAc modification (O-GlcNAcylation) are controlled by O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) and the glycoside hydrolase O-GlcNAcase (OGA) in cells. O-GlcNAcylation often occurs on serine (Ser) and threonine (Thr) residues of the specific substrate proteins via the addition of O-GlcNAc group by OGT. It has been known that O-GlcNAcylation is not only involved in many fundamental cellular processes, but also plays an important role in cancer development through various mechanisms. Recently, accumulating data reveal that O-GlcNAcylation at histones or non-histone proteins can lead to the start of the subsequent biological processes, suggesting that O-GlcNAcylation as 'protein code' or 'histone code' may provide recognition platforms or executive instructions for subsequent recruitment of proteins to carry out the specific functions. In this review, we summarize the interaction of O-GlcNAcylation and epigenetic changes, introduce recent research findings that link crosstalk between O-GlcNAcylation and epigenetic changes, and speculate on the potential coordination role of O-GlcNAcylation with epigenetic changes in intracellular biological processes.

Human INO80/YY1 chromatin remodeling complex transcriptionally regulates the BRCA2- and CDKN1A-interacting protein (BCCIP) in cells

The BCCIP (BRCA2- and CDKN1A-interacting protein) is an important cofactor for BRCA2 in tumor suppression. Although the low expression of BCCIP is observed in multiple clinically diagnosed primary tumor tissues such as ovarian cancer, renal cell carcinoma and colorectal carcinoma, the mechanism of how BCCIP is regulated in cells is still unclear. The human INO80/YY1 chromatin remodeling complex composed of 15 subunits catalyzes ATP-dependent sliding of nucleosomes along DNA. Here, we first report that BCCIP is a novel target gene of the INO80/YY1 complex by presenting a series of experimental evidence. Gene expression studies combined with siRNA knockdown data locked candidate genes including BCCIP of the INO80/YY1 complex. Silencing or over-expressing the subunits of the INO80/YY1 complex regulates the expression level of BCCIP both in mRNA and proteins in cells. Also, the functions of INO80/YY1 complex in regulating the transactivation of BCCIP were confirmed by luciferase reporter assays. Chromatin immunoprecipitation (ChIP) experiments clarify the enrichment of INO80 and YY1 at +0.17 kb downstream of the BCCIP transcriptional start site. However, this enrichment is significantly inhibited by either knocking down INO80 or YY1, suggesting the existence of both INO80 and YY1 is required for recruiting the INO80/YY1 complex to BCCIP promoter region. Our findings strongly indicate that BCCIP is a potential target gene of the INO80/YY1 complex.

Screening study on high-risk population of type 2 diabetes in normal glucose tolerance / 中华内分泌代谢杂志

[Summary] The high-risk subjects of type 2 diabetes mellitus ( T2DM) in normal glucose tolerance ( NGT) were screened. The subjects with NGT at baseline were divided into high-risk and low-risk groups according to the diagnostic threshold of insulin area under the curve ( AUCINS ) 108. 43 mU/L. The incidence of prediabetes and/or T2DM was significantly increased in high risk group in comparison with low risk group ( 29. 41 vs 2. 21%, P<0. 01). The result suggests that the diagnosis threshold for AUCINS≥108. 43 mU/L can be used to screen the high-risk subjects of T2DM in NGT.

The relationship between total IgE and atopic dermatitis in maternal serum and neonatal umbilical cord blood and allergen testing / 天津医药

Objective To explore the correlation of total IgE and childhood atopic dermatitis (AD) in maternal serum and newborn cord blood, as well as its clinical significance of allergen testing. Methods Thirty-five cases diagnosed as AD (AD group) were selected, and other 35 children who were not diagnosed as AD (control group) were randomly selected from a birth cohort established in 2009—2011. The total IgE levels were detected by ELISA in maternal serum and newborn cord blood. The serum specific IgE antibody level was detected by quantitative immunoblotting method. Results The serum total IgE level was significantly higher in mother and newborn cord blood in AD group than that in control group (χ2=16.568 and 14.933, P<0.01). Compared to control group, there was a significantly higher positive rate of mother serum allergen includ?ing dust mites, house dust, ragweed pollen, song kind of pollen, poplar, surname and elm pollen, mould, shrimp, marine fish, in AD group (P<0.05). There was a significantly higher positive rate of artemisia pollen and fungi IgE in newborn cord blood in AD group (P<0.05). Conclusion The increased total IgE in maternal serum may play a predictive effect on infants suf?fering from AD. There is no obvious consistency in allergic state between mothers and infants.

STUDIES ON ANTI-ULCER EFFECT OF DICARBOXYETHYL GERMANIUM SESQUIOXIDE AND ITS MECHANISMS OF ACTION / 中国药理学通报

Dicarboxyethyl Germanium Sesquioxide ( DEG ) is a organic germanium compound of artificial synthesis. It could inhibite gastric lesions in pylorus-tightened rats, increased the levels of PGE2 and markedly reduced pepsin activity and free acid of gastric juice. DEG also inhibited formation of indomethacine, pentagastrin and alcohol induced ulcer. It could accelerate the healing of acetic acid ulcer, but couldn't against acute stress and reserpin produced gastric ulcer. The secretory reaction of chief cell of DEG groups were reduced markedly than control. To sum up, the prineiple mechanism of anti-gastric ulcer of DEG may be by raising the levels of PGE2 in gastric juice and inhibiting pepsinia and promoting synthesis of protein.