HIGH GLUCOSE-INDUCED INHIBITION OF 2-DEOXYGLUCOSE UPTAKE IS MEDIATED BY cAMP, PROTEIN KINASE C, OXIDATIVE STRESS AND MITOGEN-ACTIVATED PROTEIN KINASES IN MOUSE EMBRYONIC STEM CELLS

Han, Ho Jae,Heo, Jung Sun,Lee, Yun Jung,Min, Jung Jun,Park, Kwang Sung Blackwell Science Pty 2006 Clinical and Experimental Pharmacology & Physiolog Vol.33 No.3

<P>SUMMARY</P><OL TYPE='1'><li level='1'>Abnormally high glucose levels may play an important role in early embryo development and function. In the present study, we investigated the effect of high glucose on 2-deoxyglucose (2-DG) uptake and its related signalling pathway in mouse embryonic stem (ES) cells.</LI><li level='1'>2-Deoxyglucose uptake was maximally inhibited by 25 mmol/L glucose after 24 h treatment. However, 25 mmol/L mannitol and dextran did not affect 2-DG uptake. Indeed, 25 mmol/L glucose decreased GLUT-1 mRNA and protein levels. The glucose (25 mmol/L)-induced inhibition of 2-DG uptake was blocked by pertussis toxin (a G<SUB>i</SUB>-protein inhibitor; 2 ng/mL), SQ 22536 (an adenylate cyclase inhibitor; 10<SUP>-6</SUP> mol/L) and the protein kinase (PK) A inhibitor myristoylated PKI amide-(14–22) (10<SUP>-6</SUP> mol/L). Indeed, 25 mmol/L glucose increased intracellular cAMP content.</LI><li level='1'>Furthermore, 25 mmol/L glucose-induced inhibition of 2-DG uptake was prevented by 10<SUP>-4</SUP> mol/L neomycin or 10<SUP>-6</SUP> mol/L U 73122 (phospholipase C (PLC) inhibitors) and staurosporine or bisindolylmaleimide I (protein kinase (PK) C inhibitors). At 25 mmol/L, glucose increased translocation of PKC from the cytoplasmic fraction to the membrane fraction. The 25 mmol/L glucose-induced inhibition of 2-DG uptake and GLUT-1 protein levels was blocked by SQ 22536, bisindolylmaleimide I or combined treatment. In addition, 25 mmol/L glucose increased cellular reactive oxygen species and the glucose-induced inhibition of 2-DG uptake were blocked by the anti-oxidants <I>N</I>-acetylcysteine (NAC; 10<SUP>-5</SUP> mol/L) or taurine (2 ¥ 10<SUP>-3</SUP> mol/L).</LI><li level='1'>Glucose (25 mmol/L) activated p38 mitogen-activated protein kinase (MAPK) and p44/42 MAPK. Staurosporine (10<SUP>-6</SUP> mol/L), NAC (10<SUP>-5</SUP> mol/L) and PD 98059 (10<SUP>-7</SUP> mol/L) attenuated the phosphorylation of p44/42 MAPK. Both SB 203580 (a p38 MAPK inhibitor; 10<SUP>-7</SUP> mol/L) and PD 98059 (a p44/42 MAPK inhibitor; 10<SUP>-7</SUP> mol/L) blocked 25 mmol/L glucose-induced inhibition of 2-DG uptake.</LI><li level='1'>In conclusion, high glucose inhibits 2-DG uptake through cAMP, PLC/PKC, oxidative stress or MAPK in mouse ES cells.</LI></OL>

Endoplasmic reticulum stress (ER-stress) by 2-deoxy-D-glucose (2DG) reduces cyclooxygenase-2 (COX-2) expression and N-glycosylation and induces a loss of COX-2 activity via a Src kinase-dependent pathway in rabbit articular chondrocytes

Yu, Seon-Mi,Kim, Song-Ja Korean Society for Biochemistry and Molecular Bion 2010 Experimental and molecular medicine Vol.42 No.11

Endoplasmic reticulum (ER) stress regulates a wide range of cellular responses including apoptosis, proliferation, inflammation, and differentiation in mammalian cells. In this study, we observed the role of 2-deoxy-D-glucose (2DG) on inflammation of chondrocytes. 2DG is well known as an inducer of ER stress, via inhibition of glycolysis and glycosylation. Treatment of 2DG in chondrocytes considerably induced ER stress in a dose- and time-dependent manner, which was demonstrated by a reduction of glucose regulated protein of 94 kDa (grp94), an ER stress-inducible protein, as determined by a Western blot analysis. In addition, induction of ER stress by 2DG led to the expression of COX-2 protein with an apparent molecular mass of 66-70kDa as compared with the normally expressed 72-74 kDa protein. The suppression of ER stress with salubrinal (Salub), a selective inhibitor of eif2-alpha dephosphorylation, successfully prevented grp94 induction and efficiently recovered 2DGmodified COX-2 molecular mass and COX-2 activity might be associated with COX-2 N-glycosylation. Also, treatment of 2DG increased phosphorylation of Src in chondrocytes. The inhibition of the Src signaling pathway with PP2 (Src tyrosine kinase inhibitor) suppressed grp94 expression and restored COX-2 expression, N-glycosylation, and PGE2 production, as determined by a Western blot analysis and PGE2 assay. Taken together, our results indicate that the ER stress induced by 2DG results in a decrease of the transcription level, the molecular mass, and the activity of COX-2 in rabbit articular chondrocytes via a Src kinase-dependent pathway.

Endoplasmic reticulum stress (ER-stress) by 2-deoxy-D-glucose (2DG) reduces cyclooxygenase-2 (COX-2) expression and N-glycosylation and induces a loss of COX-2 activity via a Src kinase-dependent pathway in rabbit articular chondrocytes

유선미,Song-Ja Kim 생화학분자생물학회 2010 Experimental and molecular medicine Vol.42 No.11

Endoplasmic reticulum (ER) stress regulates a wide range of cellular responses including apoptosis, proliferation,inflammation, and differentiation in mammalian cells. In this study, we observed the role of 2-deoxy-D-glucose (2DG) on inflammation of chondrocytes. 2DG is well known as an inducer of ER stress,via inhibition of glycolysis and glycosylation. Treatment of 2DG in chondrocytes considerably induced ER stress in a dose- and time-dependent manner, which was demonstrated by a reduction of glucose regulated protein of 94 kDa (grp94), an ER stress-inducible protein,as determined by a Western blot analysis. In addition,induction of ER stress by 2DG led to the expression of COX-2 protein with an apparent molecular mass of 66-70kDa as compared with the normally expressed 72-74 kDa protein. The suppression of ER stress with salubrinal (Salub), a selective inhibitor of eif2-alpha dephosphorylation, successfully prevented grp94 induction and efficiently recovered 2DGmodified COX-2 molecular mass and COX-2 activity might be associated with COX-2 N-glycosylation. Also,treatment of 2DG increased phosphorylation of Src in chondrocytes. The inhibition of the Src signaling pathway with PP2 (Src tyrosine kinase inhibitor) suppressed grp94 expression and restored COX-2 expression,N-glycosylation, and PGE2 production, as determined by a Western blot analysis and PGE2assay. Taken together, our results indicate that the ER stress induced by 2DG results in a decrease of the transcription level, the molecular mass, and the activity of COX-2 in rabbit articular chondrocytes via a Src kinase-dependent pathway.

The Mechanism of Hematoxylin on Glucose Metabolism Improvement in Sciatic Nerves from Streptozotocin-induced Diabetic Rats.

정명규(Chung, Myung-Kiu),강순국(Kang, Soon-Kuk) 한국산학기술학회 2011 한국산학기술학회논문지 Vol.12 No.7

Hematoxylin은 한국의 남부지방에서 당뇨합병증을 치료하기 위하여 사용해오던 민간약제인 Hematoxylon campechianum의 주성분이다. 본 논문에서는 hematoxylin의 혈당저하 메커니즘을 연구하기 위하여 3개 군의 흰쥐-정상군, 당뇨군, hematoxylin 처치군-에서 분리한 대퇴신경을 대상으로 2-deoxyglucose 수송능과 인지질 대사능을 조사였다. 실험 결과 hematoxylin은 당뇨군에서 혈당치를 현저하게 감소시키는 것으로 나타났다. 또한 무게단위의 기준으로 당뇨군의 신 경조직의 경우, 총 인지질의 양은 20% 감소하였으나 상대적으로 phosphatidylinositide의 감소는 작은 것으로 나타났다. 이 경우, hematoxylin을 처치하면 2-[3H] myo-inositol이 총 phosphoinositids로 대사되는 비율이 증가하는 것으로 밝혀졌 다. 이러한 효과는 낮은 농도의 hematoxylin 처치군보다 높은 농도의 처치군에서 훨씬 큰 것으로 나타났다. 이상의 실험결 과는 hematoxylin의 당뇨개선 메커니즘이 myo-inositol 대사를 증가시킴으로써 체내 당 수송과 인지질 대사를 정상화시킨 다는 점을 제시하고 있다. 따라서 본 연구결과를 토대로 저자들은 hematoxylin은 향후 당뇨 치료제로서 후보 물질이 될 수 있음을 제시하고자 한다. Hematoxylin is the main component of Hematoxylon campechianum which has been utilized in the southern provinces of Korea as a folk remedy for diabetic complications. In the present study, to investigate the hypoglycemic mechanism of hematoxylin, the 2-deoxyglucose uptake and phospholipid metabolism were examined in sciatic nerves from three groups of rats : normal control, diabetic control, diabetic hematoxylin-treated group. Hematoxylin significantly reduced blood glucose levels in diabetic control rats. On a wet weight basis, the nerves from diabetic rats showed a 20% decrease in total phospholipid from that of controls and a relative decrease in phosphatidylinositide. Hematoxylin treatment increased the incorporation rate of 2-[3H] myo-inositol into total phosphoinositids in diabetic rat. The effectiveness were more potent in higher dose hematoxylin-treated rats than lower dose hematoxylin-treated rats. These results suggest that hematoxylin increases glucose transport and lipid metabolism by partially normalizing concerned with myo-inositol metabolism in diabetic rat. Therefore we propose that hematoxylin can be a promising candidate for diabetes medication.

전침자극(電針刺戟)에 의한 흰쥐 중추신경계(中樞神經系)내 대사활성(代謝活性) 변화(變化)의 영상화(映像化) 연구(硏究)

손영주,원란,정혁상,김용석,박영배,손낙원,Sohn, Young-Joo,Won, Ran,Jung, Hyuk-Sang,Kim, Yong-Suk,Park, Young-Bae,Sohn, Nak-Won 대한침구의학회 2001 대한침구의학회지 Vol.18 No.3

Objective : Functional brain mapping study on acupuncture stimulation using the [14C]2-deoxyglucose([14C]2-DG) autoradiography provides quantitative data and visualized pathway in central nervous system(CNS). We aimed to investigate the neural pathway and spatial distribution of metabolic activity elicited in CNS on electroacupuncture stimulation using [14C]2-DG autoradiography. Methods : The study were divided into three groups by stimulation times. 45-mins stimulation group according to Sokoloffs method, 5-mins stimulation group according to Duncun's method, and 15-mins stimulation group. ;A venous catheter was equipped into right jugular vein. The rats (Sprague-Dawley rats, 230-260g) were kept fastened loosely on a holding platform without anesthesia. Electroacupuncture stimulation (5 ms, 2 Hz, 1~3 mA) were applied on the left Zusanli (ST36) acupoint and [14C]2-DG ($25{\mu}Ci/rat$) injection was performed through the catheter. After sacrifice, the brain and the spinal cord were made to sections for film image. The film images were digitalized as the isotope concentration based upon comparison of optical densities with that of the standards and normalized by the optical density of corpus callosum. Results : 1. 15-mins stimulation group was most effective among 3 experiments. 2. On 15-mins stimulation group, medial geniculate nucleus, intetpeduncular nucleus intermedius, ventral periolivary nucleus, caudal periolivary nucleus, medial superior olive, lateral paragigantocellular nucleus, including hypothalamic arcuate nucleus were increased by more than 25% (at least, p<0.05) by electroacupuncture stimulation. 3. Especially, the metabolism in hypothalamic arcuate nucleus was increased by 90% (p<0.05). 4. The fact that arcuate nucleus of hypothalamus might play a role of interconnection area between ascending and descending pathway of acupuncture stimulation was demonstrated visually. Conclusions : Advanced study on electroacupuncture stimulation elicited significant increase of metabolic activity in various nuclei of hypothalamus will provide the important experimental basis in research of the relationship between electroacupuncture stimulation and internal visceral functions.

실험적 뇌경색에 미치는 Insulin, 2-Deoxyglucose 및 Dichloroacetate의 효과에 대한 연구

정흥섭,박윤관,이훈갑,이기찬,주정화 고려대학교 의과대학 1991 고려대 의대 잡지 Vol.28 No.1

Hyperglycemia has been reported to worsen the tolerance of the brain to ischemia, and it has therefore been recommended that patient undergoing neurosurgical procedures not receive glucose-containing solutions. Since ischeruc events lead to increased lactate production and accumulation and hence neuronal damage, the present study was designed to test the effect of insulin-induced hypoglycemia and decreased lactate accumulation by 2-Deoxyglucose and Dichloroacetate on focal cerebral ischemia in rats. Although the pre and post-ischemic blood glucose levels of control group and Dichloroacetate group showed no change, the blood glucose level of 2-Deoxyglucose group showed a significant increase(p=0.001), and insulin group a significant decrease(p=0.004). The reducing effects on the infarct zone in these three treated groups were found with statistical significance. As compared with control group, the tissue lactate levels of treated groups were decreased in both infarct zone and border zone but these data did not show statistical significance. From these observations, it is suggested that reduction of lactate production and accumulation could be beneficial by affording neuronal protection in ischemic tissues.

실험적 뇌경색에 미치는 Insulin, 2-Deoxyglucose 및 Dichloroacetate의 효과에 대한 연구

정흥섭,박윤관,이훈갑,이기찬,주정화 대한신경외과학회 1991 Journal of Korean neurosurgical society Vol.20 No.5

Hyperglycemia has been reported to worsen the tolerance of the brain to ischemia, and it has therefore been recommended that patient undergoing neurosurgical procedures not receive glucose-containing solutions. Since ischemic events lead to increased lactate production and accumulation and hence neruonal damage, the present study was designed to test the effect of insulin-induced hypoglycemia and decreased lactate accumulation by 2-Deoxyglucose and Dichloroacetate on focal cerebral ischemia in rats. Although the pre and post-ischemic blood glucose level of 2-Deoxyglucose group showed a significant increase (p=0.001), and insulim group a significant decrease(p=0.004). The reducing effects on the infarct zone in these three treated groups were found with statistical significance. As compared with control group, the tissue lactate levels of treated groups were decreased in both infarct zone and border zone but these data did not show statistical significance. From these observations, it is suggested that reduction of lactate production and accumulation could be beneficial by affording neuronal protection in ischemic tissues.

실험연구 : 토끼의 격리폐 모델에서 안지오텐신이 저산소성 폐혈관 수축에 미치는 영향

박금숙 ( Kum Suk Park ),안원식 ( Won Sik Ahn ),함병문 ( Byung Moon Ham ) 대한마취과학회 2003 Korean Journal of Anesthesiology Vol.45 No.4

¹???F-fluoro-2-deoxyglucose uptake on PET CT and glucose transporter 1 expression in colorectal adenocarcinoma.

Hong, Ran,Lim, Sung-Chul WJG Press 2012 World journal of gastroenterology Vol.18 No.2

<P>To evaluate the correlation between the level of (18)F-fluoro-2-deoxyglucose ((18)F-FDG) uptake and glucose transporter 1 (GLUT1) expression in colorectal adenocarcinoma (CRA).</P>

Synthesis of Novel Flavone-O-2-Deoxyglucopyranosides via One - Pot Enzymatic ReactionApproach

Rit Bahadur GURUNG,Thi Tuoi LE,Ramesh Prasad PANDEY,Niranjan KOIRALA,Pakash PARAJULI,Joo-Ho LEE,Hye Jin JUNG,Jae Kyung SOHNG 한국생물공학회 2014 한국생물공학회 학술대회 Vol.2014 No.4