• Journal of Chest Surgery
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• v.50 no.3
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• pp.144-152
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• 2017

Background: The ubiquitin-proteasome system (UPS) is an important pathway of proteolysis in pathologic hypertrophic cardiomyocytes. We hypothesize that MG132, a proteasome inhibitor, might prevent hypertrophic cardiomyopathy (CMP) by blocking the UPS. Nuclear factor kappa-light-chain-enhancer of activated B cells ($NF-{\kappa}B$) and androgen receptor (AR) have been reported to be mediators of CMP and heart failure. This study drew upon pathophysiologic studies and the analysis of $NF-{\kappa}B$ and AR to assess the cardioprotective effects of MG132 in a left ventricular hypertrophy (LVH) rat model. Methods: We constructed a transverse aortic constriction (TAC)-induced LVH rat model with 3 groups: sham (TAC-sham, n=10), control (TAC-cont, n=10), and MG132 administration (TAC-MG132, n=10). MG-132 (0.1 mg/kg) was injected for 4 weeks in the TAC-MG132 group. Pathophysiologic evaluations were performed and the expression of AR and $NF-{\kappa}B$ was measured in the left ventricle. Results: Fibrosis was prevalent in the pathologic examination of the TAC-cont model, and it was reduced in the TAC-MG132 group, although not significantly. Less expression of AR, but not $NF-{\kappa}B$, was found in the TAC-MG132 group than in the TAC-cont group (p<0.05). Conclusion: MG-132 was found to suppress AR in the TAC-CMP model by blocking the UPS, which reduced fibrosis. However, $NF-{\kappa}B$ expression levels were not related to UPS function.

• Food Science and Preservation
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• v.6 no.4
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• pp.506-513
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• 1999

The growth of lactic acid bacteria was investigated in liquid broth medium containing organic germanium compound(Ge-132, carboxyethylgermanium sesquioxide) in the range of 0.01 to 10mg/ml. Most of all lactic acid bacteria tested were tolerant and could grow better to the high Ge-132 concentration. However, the growth of Leuconostoc mesenteroides and Pediococcus pentosaceus were inhibited in the presence of 10mg/m1 Ge-132. Among 22 strains tested, lactic acid bacteria that were grown to a high degree(about 2 times) by addition of Ge-132 (10mg/ml)were Lactococcus lactis, Lc. cremoris, Lc. diacetilactis, Enterococcus faecium and Streptococcus faecalis. The growth of these strains were markedly accelerated in the culture medium supplemented with 1.omg/ml Ge-132 The optimal concentration of glucose for growth of Lc. lactic was found to be high in medium containing Ge-132 as compared with the case of control. During cultivation viscosity in culture broths of Lc. lactis and Lc. cremoris was rapidly elevated by adding Ge-132 to medium containing high concentration of glucose, and then decreased after incubation of long time. However, in the cultivation of Lc. diacetilactis, E, faecium and S. faecalis, viscosity of culture broths was not increased, even though Ge-132 was shown to be an effective stimulant of growth.

• Journal of the Korean Society of Food Science and Nutrition
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• v.22 no.6
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• pp.702-708
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• 1993

The study was attempted to elucidate the mechanism of GE-132(100mg/kg, p.o. for 6 weeks) on the metabolism of bromobenzene (460mg/kg, i.p. bid, for 2 days), which has potent carcinogenicity, mutagenicity and hepatotoxicity. It showed that activities of cytochrome p-450, aminopyrine demethylase and aniline hydroxylase, which have epoxide generating property, were not changed by GE-132 treatment. On the other hand, epoxide hydrolase was not changed but that glutathione S-transferase was significantly increased by GE-132 treatment. And also ${\gamma}-glutamylcysteine$ synthetase was not changed following the GE-132 treatment, but the activity of glutathione reductase was significantly increased. The level of hepatic glutathione which was decreased by bromobenzene recovered markedly by GE-132 pretreatment. It is concluded that the mechanism for the observed effect of GE-132 on bromobenzene metabolism is due to the induction of glutathione S-transferase.

• BMB Reports
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• v.44 no.3
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• pp.182-186
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• 2011

Exogenous stimuli such as nerve growth factor (NGF) exert their effects on neurite outgrowth via Trk neurotrophin receptors. TrkA receptors are known to be ubiquitinated via proteasome inhibition in the presence of NGF. However, the effect of proteasome inhibition on neurite outgrowth has not been studied extensively. To clarify these issues, we investigated signaling events in PC12 cells treated with NGF and the proteasome inhibitor MG132. We found that MG132 facilitated NGF-induced neurite outgrowth and potentiated the phosphorylation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) and phosphatidylinositol-3-kinase (PI3K)/AKT pathways and TrkA receptors. MG132 stimulated internalization of surface TrkA receptor and stabilized intracellular TrkA receptor, and the $Ub^{K63}$ chain was found to be essential for stability. These results indicate that the ubiquitin-proteasome system potentiated neurite formation by regulating the stability of TrkA receptors.

• Molecules and Cells
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• v.40 no.11
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• pp.871-879
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• 2017

Levels of maturation-promoting factor (MPF) in oocytes decline after vitrification, and this decline has been suggested as one of the main causes of low developmental competence resulting from cryoinjury. Here, we evaluated MPF activity in vitrified mouse eggs following treatment with caffeine, a known stimulator of MPF activity, and/or the proteasome inhibitor MG132. Collected MII oocytes were vitrified and divided into four groups: untreated, 10 mM caffeine (CA), $10{\mu}M$ MG132 (MG), and 10 mM caffeine + $10{\mu}M$ MG132 (CA+MG). After warming, the MPF activity of oocytes and their blastocyst formation and implantation rates in the CA, MG, and CA+MG groups were much higher than those in the untreated group. However, the cell numbers in blastocysts did not differ among groups. Analysis of the effectiveness of caffeine and MG132 for improving somatic cell nuclear transfer (SCNT) technology using cryopreserved eggs showed that supplementation did not improve the blastocyst formation rate of cloned mouse eggs. These results suggest that maintaining MPF activity after cryopreservation may have a positive effect on further embryonic development, but is unable to fully overcome cryoinjury. Thus, intrinsic factors governing the developmental potential that diminish during oocyte cryopreservation should be explored.

• Journal of Radiation Protection and Research
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• v.29 no.4
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• pp.237-242
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• 2004

The radioprotective effects of Melatonin and Ge-132 on acute hematopoietic injury was investigated in mice exposed to an acute whole-body radiation dose of 8 Gy. Melatonin was administered intraperitoneally 1 hour before irradiation at a dose of 200 mg/kg, and Ge-132 was administered orally from days 5 to 20 after irradiation at a dose 130 - 150 mg/kg/d. The radioprotective effects were evaluated for spleen using TUNEL assay, and in peripheral blood by counting lymphocyte & WBC. The 4 experimental groups (irradiation-only, melatonin pretreatment, Ge-132 posttreatment, and melatonin pretreatment plus Ge-132 posttreatment) were observed for survival analysis up to 30 days following irradiation. The apoptotic index (47.8% vs 45.9%, p=0.385), and the number of lymphocytes ($97/{\mu}{\ell}\;vs\;101/{\mu}{\ell}$, p=0.898) were not significantly different between the irradiation-only and the melatonin pretreatment group, But the number of WBCs ($147/{\mu}{\ell}\;vs\;306/{\mu}{\ell}$, p=0.010) was higher in the melatonin pretreatment group. The irradiation-only, melatonin, Ge-132, and melatonin plus Ge-132 treatments resulted in survival rate at 30 days of 21.4%, 100%, 35.7%, and 85.7%, respectively. The melatonin pretreatment group in survival analysis between groups was showed significantly higher survival than the irradiation-only(p=0.000), or Ge-132 posttreatment group(p=0.0003). These results indicate that the melatonin may have a potential as an effective radioprotector on acute hematopoietic syndrome following radiation exposure.

• YAKHAK HOEJI
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• v.37 no.1
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• pp.18-29
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• 1993

This study was initiated to investigate the effective action and mechanism of GE-132 (Carboxyethylgermanium sesquioxide)on benzo(a)pyrene, which have strong carcinogenicity and mutagenicity. To confirm desmutagenic effect (inhibition of metabolic processes of benzo(a)pyrene with S9 Mix or inactivation of the mutagenicity of benzo(a)pyrene metabolites) and antimutagenic effect (inhibition of gene-expression of reverted genes) of GE-132 against benzo(a)pyrene using with Salmonella typhimuyium TA98 Ames test was performed. The revertants in desmutagenicity test were decreased significantly in the combined groups of benzo(a)pyrene and GE-132 than benzo(a)pyrene only, without inhibition the metabolism of benzo(a)pyrene by S9 Mix. The ideal combined groups of benzo(a)pyrene and GE-132 were 10 $\mu{M}$ and 10mg, 20 $\mu{M}$ and 20mg, 100 $\mu{M}$ and 30 mg, respectively. Then, the revertants in antimutagenicity test, which was studied the direct action of GE-132 on the induction of revertant cells by Salmonella typhimurium TA98 and activated benzo(a)pyrene were decreased significantly in the treated groups of GE-132 than no treated groups. The number of revertants of Salmonella typhimurium TA98 were reduced with increasing amounts of GE-132. From the above results, it was found that GE-132 inactivated the mutagenic metabolites of benzo(a)pyrene without inhibition of the enzyme action in the S9 Mix, and GE132 showed antimutagenic effect which have inhibitory action of reverted gene expression.

• Journal of the Korean Society of Food Science and Nutrition
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• v.23 no.4
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• pp.581-586
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• 1994

The study was initiated elucidate the mechanism by examining the effect of GE-132 on hepatic glutathione S-transferase (GST) activity. Activity of GST increased with dose-dependent manner in hepatic cytosolic fraction of GE-132 treatment rats. Double reciprocal plotting gave Vmax value 1.4 fold increase by the treatment of GE-132(100mg/kg, p.o.for 6 weeks) compared with control group, but did not change Km value. Ethacryinc acid (85mg/kg, once a day, i.p) was injected to control rat, the GST activity decreased remarkably . However, GE-132 pretreated group, the effect caused by ethacrynic acid was markedly reduced. And activity of ${\gamma}$-glutamylcys- teine synthetase was not changed either by GE-132 treatment , but the activity of glutathione reudctase increased significantly. Decreasing properties of ethacrynic acid decreased level of hepatic glutathione , which was restored to same degree by GE -132 pretreatment . GE-132 protective effect on ethacrynic acid-induced mortality. It is concluded that the efect of GE-132 is partly mediated by increase in hepatic GST activity.

• Biomolecules & Therapeutics
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• v.21 no.2
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• pp.107-113
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• 2013

Plasminogen activator inhibitor-1 (PAI-1) is a member of serine protease inhibitor family, which regulates the activity of tissue plasminogen activator (tPA). In CNS, tPA/PAI-1 activity is involved in the regulation of a variety of cellular processes such as neuronal development, synaptic plasticity and cell survival. To gain a more insights into the regulatory mechanism modulating tPA/PAI-1 activity in brain, we investigated the effects of proteasome inhibitors on tPA/PAI-1 expression and activity in rat primary astrocytes, the major cell type expressing both tPA and PAI-1. We found that submicromolar concentration of MG132, a cell permeable peptide-aldehyde inhibitor of ubiquitin proteasome pathway selectively upregulates PAI-1 expression. Upregulation of PAI-1 mRNA as well as increased PAI-1 promoter reporter activity suggested that MG132 transcriptionally increased PAI-1 expression. The induction of PAI-1 downregulated tPA activity in rat primary astrocytes. Another proteasome inhibitor lactacystin similarly increased the expression of PAI-1 in rat primary astrocytes. MG132 activated MAPK pathways as well as PI3K/Akt pathways. Inhibitors of these signaling pathways reduced MG132-mediated upregulation of PAI-1 in varying degrees and most prominent effects were observed with SB203580, a p38 MAPK pathway inhibitor. The regulation of tPA/PAI-1 activity by proteasome inhibitor in rat primary astrocytes may underlie the observed CNS effects of MG132 such as neuroprotection.

• Environmental Analysis Health and Toxicology
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• v.23 no.4
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• pp.301-306
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• 2008

To investigate the effects of carboxyethylgermanium sesquioxide (Ge-132) on the cyclophosphamide (CY)-induced immunotoxicity, hemagglutinin titer (HA-titer), splenic IgM plaque forming cells (PFC) and contact-delayed type hypersensitivity (CDTH) were assessed in mice. Ge-132 was orally administered alone (single dose of 300, 600, 900 mg/kg b.w.) or with CY (10 or 50 mg/kg, i.p.) to mice on the 2nd day before, simultaneously with, the 2nd day after immunization. Within Ge-132 alone-treated groups, HA-titer and PFC to SRBC were significantly and dose-dependently enhanced when compared with control group. HA-titer and PFC numbers suppressed by the treatment of CY alone were significantly restored by the concomitant treatment of CY and Ge-132. Also, Ge-132 significantly decreased DNFB-induced CDTH and inhibited the CY-enhanced CDTH. These results indicate that Ge-132 may be able to increase humoral immunity and inhibit the immunotoxicity by CY.