Dynamic Regulation of APE1/Ref-1 as a Therapeutic Target Protein / 전남의대학술지

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein that plays a central role in the cellular response to DNA damage and redox regulation against oxidative stress. APE1/Ref-1 functions in the DNA base excision repair pathway, the redox regulation of several transcription factors, and the control of intracellular redox status through the inhibition of reactive oxygen species (ROS) production. APE1/Ref-1 is predominantly localized in the nucleus; however, its subcellular localization is dynamically regulated and it may be found in the mitochondria or elsewhere in the cytoplasm. Studies have identified a nuclear localization signal and a mitochondrial target sequence in APE1/Ref-1, as well as the involvement of the nuclear export system, as determinants of APE1/Ref-1 subcellular distribution. Recently, it was shown that APE1/Ref-1 is secreted in response to hyperacetylation at specific lysine residues. Additionally, post-translational modifications such as phosphorylation, S-nitrosation, and ubiquitination appear to play a role in fine-tuning the activities and subcellular localization of APE1/Ref-1. In this review, we will introduce the multifunctional role of APE1/Ref-1 and its potential usefulness as a therapeutic target in cancer and cardiovascular disease.

Rescue of Heart Failure by Mitochondrial Recovery / 대한배뇨장애요실금학회지

Heart failure (HF) is a multifactorial disease brought about by numerous, and oftentimes complex, etiological mechanisms. Although well studied, HF continues to affect millions of people worldwide and current treatments can only prevent further progression of HF. Mitochondria undoubtedly play an important role in the progression of HF, and numerous studies have highlighted mitochondrial components that contribute to HF. This review presents an overview of the role of mitochondrial biogenesis, mitochondrial oxidative stress, and mitochondrial permeability transition pore in HF, discusses ongoing studies that attempt to address the disease through mitochondrial targeting, and provides an insight on how these studies can affect future research on HF treatment.

Dynamic Regulation of APE1/Ref-1 as a Therapeutic Target Protein / 전남의대학술지

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein that plays a central role in the cellular response to DNA damage and redox regulation against oxidative stress. APE1/Ref-1 functions in the DNA base excision repair pathway, the redox regulation of several transcription factors, and the control of intracellular redox status through the inhibition of reactive oxygen species (ROS) production. APE1/Ref-1 is predominantly localized in the nucleus; however, its subcellular localization is dynamically regulated and it may be found in the mitochondria or elsewhere in the cytoplasm. Studies have identified a nuclear localization signal and a mitochondrial target sequence in APE1/Ref-1, as well as the involvement of the nuclear export system, as determinants of APE1/Ref-1 subcellular distribution. Recently, it was shown that APE1/Ref-1 is secreted in response to hyperacetylation at specific lysine residues. Additionally, post-translational modifications such as phosphorylation, S-nitrosation, and ubiquitination appear to play a role in fine-tuning the activities and subcellular localization of APE1/Ref-1. In this review, we will introduce the multifunctional role of APE1/Ref-1 and its potential usefulness as a therapeutic target in cancer and cardiovascular disease.

Targeting the Peroxisome Proliferator-Activated Receptor-gamma to Counter the Inflammatory Milieu in Obesity

Adipose tissue, which was once viewed as a simple organ for storage of triglycerides, is now considered an important endocrine organ. Abnormal adipose tissue mass is associated with defects in endocrine and metabolic functions which are the underlying causes of the metabolic syndrome. Many adipokines, hormones secreted by adipose tissue, regulate cells from the immune system. Interestingly, most of these adipokines are proinflammatory mediators, which increase dramatically in the obese state and are believed to be involved in the pathogenesis of insulin resistance. Drugs that target peroxisome proliferator-activated receptor-gamma have been shown to possess anti-inflammatory effects in animal models of diabetes. These findings, and the link between inflammation and the metabolic syndrome, will be reviewed here.

The role of O-GlcNAc modification in glutamine-induced myocardial heat shock protein 70 expression in a rat model of endotoxic shock / 中华麻醉学杂志

Objective To investigate the role of O-linked N-acetylglutamine (O-GlcNAc) modification in glutamine-induced myocardial heat shock protein (HSP70) expression in a rat model of endotoxic shock. Methods Thirty-two 8 weeks old male SD rats weighing 250-300 g were randomly divided into 4 groups (n = 8 each):group Ⅰ control (group C); group Ⅱ LPS; group Ⅲ G+ LPS and group glutamine + LPS (group A + G + LPS). Endotoxic shock was induced by iv administration of LPS 10 mg/kg in group Ⅱ , Ⅲ and Ⅳ.Glutamine 0.75 g/kg was administered iv at 1 h before iv LPS in group Ⅲ and Ⅳ . Alloxan (an inhibitor ofO-linked N-acetylglucosamine transferase) 50 mg/kg was administered iv together with glutamine at 1 h before LPS in group Ⅳ. The animals were sacrificed at 6 h after iv LPS administration. Their hearts were removed for determination of the expression of O-GlcNAc and HSP70 in myocardium. Results Intravenous LPS significantly up-regulated the expression of O-GlcNAc and HSP70. Glutamine pretreatment further increased the expression of O-GlcNAc and HSP70. The glutamine pretreatment induced increase in O-GlcNAc and HSP70 expression was abolished by concomitant administration of alloxan. Conclusion O-GlcNAc modification may be involved in glutamine-induced myocardial HSP70 expression in endotoxic shock.

Effects of O-GIcNAc modification on glutamine-induced heat shock protein 70 expression in LPS-treated rat cardiomyocytes / 中华麻醉学杂志

Objective To investigate the effects of O-GlcNAc modification on gintamine (Glu)-induced heat shock protein 70 (HSP70) expression in LPS-treated rat cardiomyocytes.Methods Primary cultures of neonatal rat cardiomyocytes were randomly divided into 6 groups:group Ⅰ control(group C);group Ⅱ Glu;group Ⅲ LPS;group Ⅳ Glu+LPS;group Ⅴ Glu+LPS+Alloxan and group Ⅵ Gln+LPS+PUGNAc.In group C double distilled water 25 μl was added.In group Ⅱ-Ⅵ the cells were exposed to the sanle concentrations of Glu (5 mmol/L)and LPS(4 μg/ml) except Alloxan (an inhibiter of O-linked β-N-acetyl glucosamine transferase/OGT) (1 mmol/L) and PUGNAc (an inhibitor of O-linked β-N-acetyl glucosaminidase/OGA)(100μmol/L).After being incubated for 6 h,cardiomyocyte viability,O-GlcNAc modification level and HSP70 expression level were measured.Results There was no significant difference in cell viability among the six groups.The levels of O-GlcNAc modification and HSP70 expression were significantly higher in group Ⅱ-Ⅵ than in group Ⅰ,were significantly higher in group Ⅳ and group Ⅵ than in group Ⅲ,were significantly lower in group Ⅴ and higher in group Ⅵ than in group Ⅳ.Conclusion O-GlcNAc modification may be involved in Glu-induced HSPT0 expression in LPS-treated cardiomyocytes.

Cytokeratin 8 and cancer / 国际肿瘤学杂志

Cytokeratin 8 ( CK8 ) belongs to the keratin family of intermediate filament cytoskeletal proteins. A lot of researches have demonstrated that abnormal expression or post-translational modifications of CK8 may affect its activity and consequently affect the development and progression of tumors. Therefore, investigating the role of CK8 in tumorigenesis may contribute to the prevention and treatment of tumors.

Stathmin: a potential tumor biomarker / 肿瘤

Stathmin, a ubiquitously expressed cytosolic protein(Mr=19×10~3), is also called oncogene protein 18 (Op18). Stathmin is involved in the assembly of microtubule (MT) and spindle by binding the tubulin protein. It plays a key role in cell proliferation, differentiation, regeneration, and migration and has regulatory effects on the signal transduction. Recently, it is reported that stathmin is overexpressed in a variety of human malignancies. It induces tumor cell migration and invasion by regulating MT depolymeri-zation. Its post-translational modification influences the interaction with p53 protein and is involved in the initiation and progression of malignant tumor. Stathmin alone or in combination with chemotherapeutics has been used for tumor therapy. The internal association of stathmin with cancer etiology is still unknown. So, further studies are needed to determine the role of stathmin as potential tumor biomarker and a drug target in tumor therapy.

Overexpression of nicotinamide N-methyltransferase in gastric cancer tissues and its potential post-translational modification

Gastric cancer is one of the most common cancers worldwide. The purpose of this study was to find out potential markers for gastric cancer. Tumor and normal tissues from 152 gastric cancer cases were analyzed by two-dimensional gel electrophoresis (2-DE). The images of silver stained gels were analyzed and statistical analysis of spot intensities revealed that spot 4262 showed higher expression (5.7-fold increase) in cancer tissues than in normal tissues (P< 0.001). It was identified by peptide mass fingerprinting as nicotinamide N-methyltransferase (NNMT). A monoclonal antibody with a detection limit down to 10 ng was produced against NNMT in mouse. Using the prepared monoclonal antibody, western blot analysis of NNMT was performed for gastric tissues from 15 gastric cancer patients and two gastric ulcer patients. The results corroborated those of 2-DE experiments. A single spot was detected in gastric ulcer tissues while four to five spots were detected in gastric cancer tissues. In cancer tissues, two additional spots of acidic and basic form were mainly detected on 2-DE gels. This suggests that NNMT receives a post-translational modification in cancer- specific manner.

Effects of alcoholic extracts of seven traditional Chinese medicines and psoralen on tyrosinase in human YUGEN8 melanoma cell / 中华皮肤科杂志

Objective To explore the effects of alcoholic extracts of traditional Chinese medicines on the post-translational processing and trafficking of tyrosinase.Methods Human YUGEN8 amelanotic melanoma cells were grown in vitro;the cells were incubated with one of the seven traditional Chinese medicines,including Rhizoma Chuanxiong and psoralen.Protein analysis with Western blot,enzymolysis with endoglycosidase H (Endo H),and subcellular localization with laser confocal microscopy were per- formed.The expression,maturity and export from endoplasmic reticulum (ER) of tyrosinase in the treated cells were compared with those in the untreated controls.Results Compared with controls,an approximate- ly 80-kDa,Endo H-resistant tyrosinase doublet,which represented mature glycoform of tyrosinase,was in- creased in melanocytes treated with Semen Cuscutae,and in those treated with Semen Persicae.Within those cells,tyrosinase was distributed outside ER resident protein calnexin.Conclusion Both Semen Cus- cutae and Semen Persicae could induce tyrosinase maturation,stability and export from ER to distal site.