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Similarities and Distinctions in the Effects of Metformin and Carbon Monoxide in Immunometabolism
Park, Jeongmin,Joe, Yeonsoo,Ryter, Stefan W.,Surh, Young-Joon,Chung, Hun Taeg Korean Society for Molecular and Cellular Biology 2019 Molecules and cells Vol.42 No.4
Immunometabolism, defined as the interaction of metabolic pathways with the immune system, influences the pathogenesis of metabolic diseases. Metformin and carbon monoxide (CO) are two pharmacological agents known to ameliorate metabolic disorders. There are notable similarities and differences in the reported effects of metformin and CO on immunometabolism. Metformin, an anti-diabetes drug, has positive effects on metabolism and can exert anti-inflammatory and anti-cancer effects via adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. CO, an endogenous product of heme oxygenase-1 (HO-1), can exert anti-inflammatory and antioxidant effects at low concentration. CO can confer cytoprotection in metabolic disorders and cancer via selective activation of the protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) pathway. Both metformin and CO can induce mitochondrial stress to produce a mild elevation of mitochondrial ROS (mtROS) by distinct mechanisms. Metformin inhibits complex I of the mitochondrial electron transport chain (ETC), while CO inhibits ETC complex IV. Both metformin and CO can differentially induce several protein factors, including fibroblast growth factor 21 (FGF21) and sestrin2 (SESN2), which maintain metabolic homeostasis; nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of the antioxidant response; and REDD1, which exhibits an anticancer effect. However, metformin and CO regulate these effects via different pathways. Metformin stimulates p53- and AMPK-dependent pathways whereas CO can selectively trigger the PERK-dependent signaling pathway. Although further studies are needed to identify the mechanistic differences between metformin and CO, pharmacological application of these agents may represent useful strategies to ameliorate metabolic diseases associated with altered immunometabolism.
Park, Sin-Aye,Na, Hye-Kyung,Surh, Young-Joon Informa Healthcare 2012 Free radical research Vol.46 No.8
<P>Excess estrogen stimulates the proliferation of mammary epithelial cells and hence represents a major risk factor for breast cancer. Estrogen is subjected to cytochrome P450-catalysed oxidative metabolism to produce an oncogenic catechol estrogen, 4-hydroxyestradiol (4-OHE<SUB>2</SUB>). 4-OHE<SUB>2</SUB> undergoes redox cycling during which reactive oxygen species (ROS) as well as the chemically reactive estrogen semiquinone and quinone intermediates are produced, thereby contributing to hormonal carcinogenesis. Resveratrol (3,4′,5-trihydroxy stilbene), a phytoalexin present in grapes, has been reported to possess chemopreventive and chemotherapeutic activities. In the present study, we examined the inhibitory effects of resveratrol on 4-OHE<SUB>2</SUB>-induced transformation of human breast epithelial MCF-10A cells. Resveratrol inhibited migration and anchorage-independent growth of MCF-10A cells treated with 4-OHE<SUB>2</SUB>. Resveratrol treatment suppressed the 4-OHE<SUB>2</SUB>-induced activation of IκB kinaseβ (IKKβ) and phosphorylation of IκBα, and consequently NF-κB DNA binding activity and cyclooxygenase-2 (COX-2) expression. Resveratrol suppressed ROS production and phosphorylation of Akt and ERK induced by 4-OHE<SUB>2</SUB> treatment. In conclusion, resveratrol blocks activation of IKKβ-NF-κB signalling and induction of COX-2 expression in 4-OHE<SUB>2</SUB>-treated MCF-10A cells, thereby suppressing migration and transformation of these cells.</P>
朴俊緖 연세대학교 신과대학 1993 신학논단 Vol.21 No.-
이상과 같이 제 3계명의 뜻을 포괄적으로 이해할 때, 오늘날 이 계명의 현대적 의미는 무엇인가? 창조주 하나님의 귀한 이름은 찬양과 예배의 대상이 되어야하며, 인간의 다른 목적을 위한 수단으로 이용될 수는 없다. 앞으로는 하나님의 이름을 받들어 내세우면서 뒤로는 인간적인 다른 목적이 숨어있다면, 이것도 제 3계명의 위반이 되는 것이다. 왜냐하며 인간적인 목적을 위한 수단으로 하나님의 이름을 사용한다면, 그것은 하나님의 이름을 도용하는 것이기 때문이다. 다른 사람의 이름ㅇ르 도용하는 것도 사회적으로 범죄행위가 된다. 하물며 두려움없이 하나님의 이름을 도용한다며 ㄴ그 죄는 용서받기 어려운 것이다. 그래서 제 3계명은 이렇게 끝을 맺는다. 「나 야웨는 나의 이름을 오용, 남용, 도용하는 자를 죄없다 아니하리라」