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( Augustine M. K. Choi ) 대한내과학회 2015 대한내과학회 추계학술대회 Vol.2015 No.2
Claude Bernard, a brilliant French physiologist, had proclaimed that hospitals are entrance to scientific medicine and medical science is a laboratory where one can seek explanations of life in the normal and pathological states by means of experimental analysis. Hence, in medicine, the desire to combine scientific observation with a clinical perspective has a long tradition with roots going back to classical antiquity. Physician scientists are uniquely capable of asking clinically relevant questions in research settings and bringing rigorous scientific inquiry to the care of patients. We will review both tangible and intangible reasons to pursue biomedical research among physicians, and how the advancements in research have impacted the healthcare and well being of patients. We will also review the similarities and differences in the infrastructure of Korean and Amercian physician scientist training during medical school and clinical training, and the impact in the respective healthcare system.
Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins
Ryter, Stefan W.,Choi, Augustine M.K.,Kim, Hong Pyo Canadian Science Publishing 2014 Biochemistry and cell biology Vol.92 No.5
<P> Fibrosis underlies the pathogenesis of several human diseases, which can lead to severe injury of vital organs. We previously demonstrated that caveolin-1 expression is reduced in experimental fibrosis and that caveolin-1 exerts antiproliferative and antifibrotic effects in lung fibrosis models. The signal transducers and activators of transcription (STAT) proteins, STAT1 and STAT3, can be activated simultaneously. STAT1 can inhibit cell growth and promote apoptosis while STAT3 inhibits apoptosis. Here, we show that caveolin-1-deficient (cav-1<SUP>−</SUP><SUP>/</SUP><SUP>−</SUP>) lung fibroblasts display dramatically upregulated STAT3 activation in response to platelet-derived growth factor-BB and transforming growth factor-β stimuli, whereas STAT1 activation is undetectable. Downregulation of protein tyrosine phosphatase-1B played a role in the preferential activation of STAT3 in cav-1<SUP>−</SUP><SUP>/</SUP><SUP>−</SUP> fibroblasts. Genetic deletion of STAT3 by siRNA modulated the expression of genes involved in cell proliferation and fibrogenesis. Basal expression of α-smooth muscle actin was prominent in cav-1<SUP>−</SUP><SUP>/</SUP><SUP>−</SUP> liver and kidney, consistent with deposition of collagen in these organs. Collectively, we demonstrate that the antiproliferative and antifibrogenic properties of caveolin-1 in vitro are mediated by the balance between STAT1 and STAT3 activation. Deregulated STAT signaling associated with caveolin-1 deficiency may be relevant to proliferative disorders such as tissue fibrosis. </P>
Carbon monoxide: present and future indications for a medical gas
Stefan W. Ryter,Augustine M. K. Choi 대한내과학회 2013 The Korean Journal of Internal Medicine Vol.28 No.2
Gaseous molecules continue to hold new promise in molecular medicine as experimental and clinical therapeutics. The low molecular weight gas carbon monoxide (CO), and similar gaseous molecules (e.g., H2S, nitric oxide) have been implicated as potential inhalation therapies in inf lammatory diseases. At high concentration, CO represents a toxic inhalation hazard, and is a common component of air pollution. CO is also produced endogenously as a product of heme degradation catalyzed by heme oxygenase enzymes. CO binds avidly to hemoglobin, causing hypoxemia and decreased oxygen delivery to tissues at high concentrations. At physiological concentrations, CO may have endogenous roles as a signal transduction molecule in the regulation of neural and vascular function and cellular homeostasis. CO has been demonstrated to act as an effective antiinf lammatory agent in preclinical animal models of inf lammation, acute lung injury, sepsis, ischemia/reperfusion injury, and organ transplantation. Additional experimental indications for this gas include pulmonary fibrosis, pulmonary hypertension, metabolic diseases, and preeclampsia. The development of chemical CO releasing compounds constitutes a novel pharmaceutical approach to CO delivery with demonstrated effectiveness in sepsis models. Current and pending clinical evaluation will determine the usefulness of this gas as a therapeutic in human disease.
Autophagy: A Critical Regulator of Cellular Metabolism and Homeostasis
Stefan W. Ryter,Suzanne M. Cloonan,Augustine M. K. Choi 한국분자세포생물학회 2013 Molecules and cells Vol.36 No.1
Autophagy is a dynamic process by which cytosolic mate-rial, including organelles, proteins, and pathogens, are sequestered into membrane vesicles called autopha-gosomes, and then delivered to the lysosome for degra-dation. By recycling cellular components, this process provides a mechanism for adaptation to starvation. The regulation of autophagy by nutrient signals involves a com- plex network of proteins that include mammalian target of rapamycin, the class III phosphatidylinositol-3 kinase/Be-clin 1 complex, and two ubiquitin-like conjugation systems. Additionally, autophagy, which can be induced by multiple forms of chemical and physical stress, including endo-plasmic reticulum stress, and hypoxia, plays an integral role in the mammalian stress response. Recent studies indicate that, in addition to bulk assimilation of cytosol, autophagy may proceed through selective pathways that target distinct cargoes to autophagosomes. The principle homeostatic functions of autophagy include the selective clearance of aggregated protein to preserve proteostasis, and the selective removal of dysfunctional mitochondria (mitophagy). Additionally, autophagy plays a central role in innate and adaptive immunity, with diverse functions such as regulation of inflammatory responses, antigen presen-tation, and pathogen clearance. Autophagy can preserve cellular function in a wide variety of tissue injury and disease states, however, maladaptive or pro-pathogenic outcomes have also been described. Among the many diseases where autophagy may play a role in-clude proteo-pathies which involve aberrant accumulation of proteins (e.g., neurodegenerative disorders), infectious diseases, and metabolic disorders such as diabetes and metabolic syndrome. Targeting the autophagy pathway and its regu-latory components may eventually lead to the develop-ment of therapeutics.
Mitochondrial Dysfunction Induces Formation of Lipid Droplets as a Generalized Response to Stress
Lee, Seon-Jin,Zhang, Jinglan,Choi, Augustine M. K.,Kim, Hong Pyo Hindawi Publishing Corporation 2013 Oxidative medicine and cellular longevity Vol.2013 No.-
<P>Lipid droplet (LD) formation is a hallmark of cellular stress. Cells attempt to combat noxious stimuli by switching their metabolism from oxidative phosphorylation to glycolysis, sparing resources in LDs for generating cellular reducing power and for anabolic biosynthesis. Membrane phospholipids are also a source of LDs. To elucidate the formation of LDs, we exposed mice to hyperoxia, hypoxia, myocardial ischemia, and sepsis induced by cecal ligation and puncture (CLP). All the above-mentioned stressors enhanced the formation of LDs, as assessed by transmission electron microscopy, with severe mitochondrial swelling. Disruption of mitochondria by depleting mitochondrial DNA (<I><I>ρ</I></I>0 cells) significantly augmented the formation of LDs, causing transcriptional activation of fatty acid biosynthesis and metabolic reprogramming to glycolysis. Heme oxygenase (HO)-1 counteracts CLP-mediated septic shock in mouse models. In HO-1-deficient mice, LD formation was not observed upon CLP, but a concomitant decrease in “LD-decorating proteins” was observed, implying a link between LDs and cytoprotective activity. Collectively, LD biogenesis during stress can trigger adaptive LD formation, which is dependent on mitochondrial integrity and HO-1 activity; this may be a cellular survival strategy, apportioning energy-generating substrates to cellular defense.</P>
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>
Hyun, Dong-Wook,Min, Hyun Jin,Kim, Min-Soo,Whon, Tae Woong,Shin, Na-Ri,Kim, Pil Soo,Kim, Hyun Sik,Lee, June Young,Kang, Woorim,Choi, Augustine M. K.,Yoon, Joo-Heon,Bae, Jin-Woo American Society for Microbiology 2018 Infection and immunity Vol.86 No.4
<P>Abnormalities in the human microbiota are associated with the etiology of allergic diseases. Although disease site-specific microbiota may be associated with disease pathophysiology, the role of the nasal microbiota is unclear. We sought to characterize the microbiota of the site of allergic rhinitis, the inferior turbinate, in subjects with allergic rhinitis (n = 20) and healthy controls (n = 12) and to examine the relationship of mucosal microbiota with disease occurrence, sensitized allergen number, and allergen-specific and total IgE levels. Microbial dysbiosis correlated significantly with total IgE levels representing combined allergic responses but not with disease occurrence, the number of sensitized allergens, or house dust mite allergen-specific IgE levels. Compared to the populations in individuals with low total IgE levels (group IgE(low)), low microbial biodiversity with a high relative abundance of Firmicutes phylum (Staphylococcus aureus) and a low relative abundance of Actinobacteria phylum (Propionibacterium acnes) was observed in individuals with high total serum IgE levels (group IgE(high)). Phylogeny-based microbial functional potential predicted by the 16S rRNA gene indicated an increase in signal transduction-related genes and a decrease in energy metabolism-related genes in group IgE(high) as shown in the microbial features with atopic and/or inflammatory diseases. Thus, dysbiosis of the inferior turbinate mucosa microbiota, particularly an increase in S. aureus and a decrease in P. acnes, is linked to high total IgE levels in allergic rhinitis, suggesting that inferior turbinate microbiota may be affected by accumulated allergic responses against sensitized allergens and that site-specific microbial alterations play a potential role in disease pathophysiology.</P>