Recently I found that glycosidase inhibitors such as castanospermine, deoxynojirimycin, swainsonine, 2-acetamindo 2,3-dideoxynojirimycin, and deoxymannojirimycin change the N-glycan structure of root glycoproteins, and that the glucosidase inhibitors castanospermine and deoxynojirimycin suppress the growth of Raphanus sativus seedlings (Mega, T., J. Biochem., 2004). The present study undertook to see whether the growth suppression is due to the inhibition of glucose trimming in endoplasmic reticulum (ER). The study, using three glucosidase inhibitors, castanospermine, N-methyl deoxynojirimycin, and deoxynojirimycin, upon the growth of R. sativus foliage leaf, made clear that glucose trimming is indispensable for plant growth, because the inhibition of glucose trimming correlated with leaf growth. On the other hand, processing inhibition in the Golgi apparatus by other glycosidase inhibitors had little effect on plant growth, although N-glycan processing was disrupted depending on inhibitor specificity. These results suggest that N-glycan processing after glucosidase processing is dispensable for plant growth and cell differentiation.

01 Nov 2000·Heart and VesselsQ4 · MEDICINE

N-Methyl-1-deoxynojirimycin (MOR-14), an α-glucosidase inhibitor, markedly improves postischemic left ventricular dysfunction

Q4 · MEDICINE

Article

Author: Shinya Minatoguchi ; Xue-Hai Chen ; Yoshio Nishida ; Masazumi Arai ; H. Fujiwara ; Kazuaki Hashimoto ; Genzou Takemura ; Ningyuan Wang ; Yoshihiro Uno ; Takako Fujiwara

We examined whether pharmacological inhibition of glycogenolysis by N-methyl-1-deoxynojirimycin (MOR-14), a new compound which reduces the glycogenolytic rate by inhibiting the alpha-1,6-glucosidase activity of the glycogen-debranching enzyme, can protect the heart against postischemic left ventricular dysfunction. The hearts of male Sprague-Dawley rats were excised, and perfused on a Langendorff apparatus with Krebs-Henseleit solution with a gas mixture of 95% O2 and 5% CO2. The hearts were paced at 320 beats/min except during the ischemia. Left ventricular developed pressure (LVDP, mmHg), +/-dP/dt (mmHg/s), and coronary flow (ml/min) were continuously monitored. All hearts were perfused for a total of 120 min including a 30-min preischemic period followed by a 30-min episode of global ischemia and 60 min reperfusion. with or without 0.5 or 2 mM of MOR-14 during the 30-min preischemic period or the first 30 min of reperfusion. In another series of experiments, the myocardial content of glycogen and lactate was measured during the 30-min episode of ischemia in groups treated with and without 2mM of MOR-14. Preischemic but not postischemic treatment with MOR-14 significantly improved LVDP and +/-dP/dt without altering coronary flow during reperfusion in a dose-dependent manner. MOR-14 significantly preserved the glycogen content and significantly attenuated the lactate accumulation during the 30-min episode of ischemia. Preischemic treatment with MOR-14 is protective against postischemic left ventricular dysfunction through the inhibition of glycogenolysis in the isolated rat heart.

01 Jan 1999·Biochemical JournalQ3 · BIOLOGY

Secretion and apparent activation of human hepatic lipase requires proper oligosaccharide processing in the endoplasmic reticulum

Q3 · BIOLOGY

Article

Author: JANSEN, Hans ; NEVE, Bernadette P. ; VERHOEVEN, Adrie J. M.

Human hepatic lipase (HL) is a glycoprotein with four N-linked oligosaccharide side chains. The importance of glycosylation for the secretion of catalytically active HL was studied in HepG2 cells by using inhibitors of intracellular trafficking, N-glycosylation and oligosaccharide processing. Secretion of HL was inhibited by carbonyl cyanide m-chlorophenylhydrazone (CCCP), monensin, brefeldin A (BFA), tunicamycin, castanospermine and N-methyldeoxynojirimycin, but not by 1-deoxymannojirimycin. Secretion of α1-antitrypsin, an unrelated N-glycoprotein, was also inhibited by monensin, BFA and tunicamycin, but not by CCCP, castanospermine or N-methyldeoxynojirimycin. Intracellular HL activity decreased with CCCP, tunicamycin, castanospermine and N-methyldeoxynojirimycin, but increased with monensin and BFA. In the absence of protein synthesis de novo, HL activity secreted into the medium was 7.8±2.1-fold higher (mean±S.D., n = 7) than the simultaneous fall in intracellular HL activity. In cells pretreated with monensin or BFA, this factor decreased to 1.3±0.5, indicating that the apparent increase in HL activity had already occurred within these cells. After chromatography on Sepharose–heparin, the specific triacylglycerol hydrolase activity of secreted HL was only 1.7±0.3-fold higher than that of intracellular HL, indicating that the secretion-coupled increase in HL activity is only partly explained by true activation. We conclude that oligosaccharide processing by glucosidases in the endoplasmic reticulum is necessary for the transport of newly synthesized human HL, but not α1-antitrypsin, to the Golgi, where the catalytic activity of HL is unmasked.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus	Preclinical	JP	Nippon Shinyaku Co., Ltd.	-
Reperfusion Injury	Preclinical	JP	Nippon Shinyaku Co., Ltd.	-
Thromboembolism	Preclinical	JP	Nippon Shinyaku Co., Ltd.	-

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