• Journal of Chest Surgery
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• 제50권3호
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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.

• 한국식품저장유통학회지
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• 제6권4호
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• pp.506-513
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• 1999

유기게르마늄(Ge-132, carboxyethylgermanium)에 의한 22가지 젖산균의 성장 효과를 0.01~10mg/m1의 농도로 첨가된 GPYS 액체배지에서 조사하였다. 시험한 대부분의 젖산균은 고농도의 게르마늄에서도 내성이 있었고, 게르마늄의 농도가 높을수록 성장을 더욱 촉진시키는 효과가 나타났다. 게르마늄이 10mg/m1의 농도로 첨가된 GPYS배지에서 Lactococcus factis, Lc. cremoris, Lc. diacetilactis, Enterococus faecium 및 Streptococcus faecalis는 2배 이상 생육촉진의 효과를 나타내었으나, Leuconostoc mesenteroides와 Pediococcus pentosareus는 저해를 나타내었다. Lc. lactic와 Lc. cremoris의 경우, 배양액의 점도는 게르마늄이 첨가된 GPYS배지에서 급격히 증가되었지만, 장시간 배양에 의해서는 약간 감소되었다. 그러나 Lc. diacetilactis, E. faecium와 S. faecalis의 경우, 게르마늄의 첨가에 의하여 생육은 현저하게 촉진되었지만, 배양중의 점도는 증가되지 않았다.

• 한국식품영양과학회지
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• 제22권6호
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• pp.702-708
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• 1993

Bromobenzene투여시 GE-132의 해독기전을 추구할 목적으로 epoxide생성계와 해독계 효소 및 glutathione 관련 효소계의 활성에 GE-132가 어떤 영향을 주는가를 검토하여 다음과 같은 실험 결과를 얻었다. GE-132(100mg/kg)의 전처리로 cytochrome P-450, amino=pyrine demethylase 및 aniline hydroxylase와 해독계 효소인 epoxide hydrolase활성에는 영향을 미치지 않았으나, glutathions S-transferase활성은 증가 하였다. Bromobenzene(460mg/kg)을 주사하였을때 glutathione S-transferase의 활성이 현저히 감소되던 것이 GE-132의 투여로 대조군 수준으로 증가되었다. 조직내 glutathione의 함량변동도 bromobenzene 투여로 감소되던 것이 GE-132의 전처리로 bromobenzene단독 투여군보다 증가되었으며 ${\gamma}-glutamylcystein$ synthtase의 활성은 각 실험군에서 별다른 영향이 없는데 비해 glutathione reductase의 활성은 bromobenzene투여로 억제 되던 것이 GE-132의 전처리로 대조군 수준으로 활성을 유지하고 있었다.

• BMB Reports
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• 제44권3호
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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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• 제40권11호
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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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• 제29권4호
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• pp.237-242
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• 2004

방사선피폭 후 급성조혈계 손상에 대한 Melatonin과 Ge-132의 방어효과를 8 Gy의 선량으로 급성, 전신피폭 된 마우스에서 연구하였다. Melatonin은 피폭 1시간 전에 200 mg/kg의 용량으로 복강 내 주사하였고, Ge-132는 130 - 150 mg/kg/d의 용량으로 피폭 후 5일째부터 20일째까지 경구복용 시켰다. 방사선방어 효과를 평가하기 위해 비장에서 TUNEL assay를 실시하였고 혈액 내 림프구와 총 백혈구 수치를 측정하였다. 피폭 후 30일째까지의 생존분석을 위해 4 실험군들 (피폭단독군, melatonin 전처치군, Ge-132 후처치군, melatonin 전처치 및 Ge-132 후처치군)에서 날짜경과에 따른 사망을 측정하였다. 피폭단독군과 melatonin 전처치군 간에 세포고사지수 (47.8% vs 45.9%, p=0.385)와 림프구 수치 ($97/{\mu}{\ell}\;vs\;101/{\mu}{\ell}$, p=0.898)에서 차이가 없었으나, 총 백혈구 수치는 melatonin 전처치군에서 유의하게 높은 수치 ($147/{\mu}{\ell}\;vs\;306/{\mu}{\ell}$, p=0.010)를 보였다. 피폭 후 30일째의 생존율은 피폭단독군, melatonin 전처치군, Ge-132 후처치군, 그리고 melatonin 전처치 및 Ge-132 후처치군에서 각각 21.4%, 100%, 35.7%, 그리고 85.7%였다. 실험군들 간의 생존분석에서 melatonin 전처치 군은 피폭단독군(p=0.000)이나 Ge-132 후처치군(p=0.0003)에 유의하게 높은 생존을 보였다. 본 연구결과는 방사선피폭 후 급성조혈계증후군에 대하여 melatonin이 방사선방어제로서 효능을 지님을 보여주고 있다.

• 약학회지
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• 제37권1호
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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.

• 한국식품영양과학회지
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• 제23권4호
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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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• 제21권2호
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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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• 제23권4호
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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.