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RISS 인기검색어
- 검색키워드
- 저자 : ( Kiichi Nakahira ) (검색결과 4 건)
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Circulating Mitochondrial DNA as a Predictor of Mortality in Critically ill Patients
( Sun Young Kyung ),( Kiichi Nakahira ),( Augustine Mk Choi ) 대한결핵 및 호흡기학회 2012 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.114 No.-
Background: Multiple scoring systems based on commonly measured clinical parameters help to predict of prognosis of patients admitted to intensive care units. Despite these scoring systems it is needed to develop biomarkers that improve risk prediction in critically ill patients. Mitochondrial DNA (mtDNA) is a critical activator of the inflammasome-dependent inflammation. We evaluated the predictive value of mtDNA level on mortality in critically ill patients. Methods: Circulating cell-free mtDNA levels were measured in plasma from observational cohort study (the Brigham and Women`s Hospital registry of Critical Illness, BWH RoCI, n=200). MtDNA levels in plasma were assessed by measuring copy number of the NADH dehydrogenase 1 (mt-ND1) gene by quantitative real-time PCR. Results: The levels of mt-ND1 were significantly higher in patients with sepsis, and in patients who died. For every 100 copy increase of mt-ND1, there is a 0.09 unit increase in APACHE II score (p=0.0004). The elevated mt-ND1 level (≥400 copies/μL plasma) was associated with increased in-hospital mortality (p=0.0001). Conclusions: Increased levels of circulating mtDNA are associated with sepsis, and in-hospital mortality. The mtDNA could be a plasma biomarker as a predictor of mortality in critically ill patients.
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NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages
Moon, Jong-Seok,Nakahira, Kiichi,Chung, Kuei-Pin,DeNicola, Gina M,Koo, Michael Jakun,Pabó,n, Maria A,Rooney, Kristen T,Yoon, Joo-Heon,Ryter, Stefan W,Stout-Delgado, Heather,Choi, Augustine M K Nature Publishing Group, a division of Macmillan P 2016 Nature medicine Vol.22 No.9
<P>Altered metabolism has been implicated in the pathogenesis of inflammatory diseases. NADPH oxidase 4 (NOX4), a source of cellular superoxide anions, has multiple biological functions that may be of importance in inflammation and in the pathogenesis of human metabolic diseases, including diabetes. However, the mechanisms by which NOX4-dependent metabolic regulation affect the innate immune response remain unclear. Here we show that deficiency of NOX4 resulted in reduced expression of carnitine palmitoyltransferase 1A (CPT1A), which is a key mitochondrial enzyme in the fatty acid oxidation (FAO) pathway. The reduced FAO resulted in less activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome in human and mouse macrophages. In contrast, NOX4 deficiency did not inhibit the activation of the NLR family, CARD-domain-containing 4 (NLRC4), the NLRP1 or the absent in melanoma 2 (AIM2) inflammasomes. We also found that inhibition of FAO by etomoxir treatment suppressed NLRP3 inflammasome activation. Furthermore, Nox4-deficient mice showed substantial reduction in caspase-1 activation and in interleukin (IL)-1b and IL-18 production, and there was improved survival in a mouse model of NLRP3-mediated Streptococcus pneumoniae infection. The pharmacologic inhibition of NOX4 by either GKT137831, which is currently in phase 2 clinical trials, or VAS-2870 attenuated NLRP3 inflammasome activation. Our results suggest that NOX4-mediated FAO promotes NLRP3 inflammasome activation.</P>
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Lee, Seonmin,Lee, Seon-Jin,Coronata, Anna A.,Fredenburgh, Laura E.,Chung, Su Wol,Perrella, Mark A.,Nakahira, Kiichi,Ryter, Stefan W.,Choi, Augustine M.K. Mary Ann Liebert 2014 Antioxidants & redox signaling Vol.20 No.3
<P>Sepsis, a systemic inflammatory response to infection, represents the leading cause of death in critically ill patients. However, the pathogenesis of sepsis remains incompletely understood. Carbon monoxide (CO), when administered at low physiologic doses, can modulate cell proliferation, apoptosis, and inflammation in pre-clinical tissue injury models, though its mechanism of action in sepsis remains unclear.</P>
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Carbon monoxide regulates glycolysis-dependent NLRP3 inflammasome activation in macrophages
Lee, Do won,Shin, Ha young,Jeong, Ji Hun,Han, Jaeseok,Ryu, Seongho,Nakahira, Kiichi,Moon, Jong-Seok Elsevier 2017 Biochemical and biophysical research communication Vol.493 No.2
<P><B>Abstract</B></P> <P>Low dose of carbon monoxide (CO) has anti-inflammatory role through various signaling pathways. Cellular metabolism has been implicated in the activation of inflammation in immune cells. However, the mechanisms by which CO-dependent metabolic regulation affect the immune response remain unclear. Here we show that CO-dependent metabolic pathway regulates the activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome. CO-releasing molecule-3 (CORM-3) resulted in reduced glycolysis-dependent NLRP3 inflammasome activation in macrophages. The reduced mTORC1 activation by CORM-3 resulted in less glycolysis during NLRP3 inflammasome activation. CORM-3 suppressed caspase-1 activation and the secretion of interleukin (IL)-1β and IL-18 in macrophages in response to lipopolysaccharide (LPS) and ATP. Moreover, CORM-3 inhibits the oligomerization of the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which is required for NLRP3-dependent caspase-1 activation. Furthermore, CORM-3-treated mice showed substantial reduction in IL-1β production by hyperglycemia in a mouse model of streptozotocin (STZ)-induced diabetes. Our results suggest that CO regulates glycolysis-dependent NLRP3 inflammasome activation and may provide a therapeutic approach for inflammation in metabolic diseases.</P> <P><B>Highlights</B></P> <P> <UL> <LI> CO regulates glycolysis-dependent NLRP3 inflammasome activation. </LI> <LI> CO suppresses the activation of glycolysis. </LI> <LI> CO prevents hyperglycemia-induced inflammation in vivo. </LI> </UL> </P>
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