Cilostazol attenuates murine hepatic ischemia and reperfusion injury via heme oxygenase-dependent activation of mitochondrial biogenesis

Joe, Yeonsoo,Zheng, Min,Kim, Hyo Jeong,Uddin, Md. Jamal,Kim, Seul-Ki,Chen, Yingqing,Park, Jeongmin,Cho, Gyeong Jae,Ryter, Stefan W.,Chung, Hun Taeg American Physiological Society 2015 American journal of physiology, Gastrointestinal a Vol.309 No.1

<P>Hepatic ischemia-reperfusion (I/R) can cause hepatocellular injury associated with the inflammatory response and mitochondrial dysfunction. We studied the protective effects of the phosphodiesterase inhibitor cilostazol in hepatic I/R and the roles of mitochondria and the Nrf2/heme oxygenase-1 (HO-1) system. Wild-type, <I>Hmox1</I><SUP><I>−/−</I></SUP>, or <I>Nrf2</I><SUP><I>−/−</I></SUP> mice were subjected to hepatic I/R in the absence or presence of cilostazol followed by measurements of liver injury. Primary hepatocytes were subjected to cilostazol with the HO-1 inhibitor ZnPP, or Nrf2-specific siRNA, followed by assessment of mitochondrial biogenesis. Preconditioning with cilostazol prior to hepatic I/R protected against hepatocellular injury and mitochondrial dysfunction. Cilostazol reduced the serum levels of alanine aminotransferase, TNF-α, and liver myeloperoxidase content relative to control I/R-treated mice. In primary hepatocytes, cilostazol increased the expression of HO-1, and markers of mitochondrial biogenesis, PGC-1α, NRF-1, and TFAM, induced the mitochondrial proteins COX III and COX IV and increased mtDNA and mitochondria content. Pretreatment of primary hepatocytes with ZnPP inhibited cilostazol-induced PGC-1α, NRF-1, and TFAM mRNA expression and reduced mtDNA and mitochondria content. Genetic silencing of Nrf2 prevented the induction of HO-1 and mitochondrial biogenesis by cilostazol in HepG2 cells. Cilostazol induced hepatic HO-1 production and mitochondrial biogenesis in wild-type mice, but not in <I>Hmox1</I><SUP><I>−/−</I></SUP> or <I>Nrf2</I><SUP><I>−/−</I></SUP> mice, and failed to protect against liver injury in <I>Nrf2</I><SUP><I>−/−</I></SUP> mice. These results suggest that I/R injury can impair hepatic mitochondrial function, which can be reversed by cilostazol treatment. These results also suggest that cilostazol-induced mitochondrial biogenesis was mediated by an Nrf-2- and HO-1-dependent pathway.</P>

Salvianolic acid B exerts vasoprotective effects through the modulation of heme oxygenase-1 and arginase activities.

Joe, Yeonsoo,Zheng, Min,Kim, Hyo Jeong,Kim, Sena,Uddin, Md Jamal,Park, Chul,Ryu, Do Gon,Kang, Shin Sung,Ryoo, Sungwoo,Ryter, Stefan W,Chang, Ki Churl,Chung, Hun Taeg Williams Wilkins 2012 The Journal of pharmacology and experimental thera Vol.341 No.3

<P>Salvia miltiorrhiza (Danshen), a traditional Chinese herbal medicine, is commonly used for the prevention and treatment of cardiovascular disorders including atherosclerosis. However, the mechanisms responsible for the vasoprotective effects of Danshen remain largely unknown. Salvianolic acid B (Sal B) represents one of the most bioactive compounds that can be extracted from the water-soluble fraction of Danshen. We investigated the effects of Danshen and Sal B on the inflammatory response in murine macrophages. Danshen and Sal B both induced the expression of heme oxygenase-1 (HO-1) and inhibited nitric oxide (NO) production and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-activated RAW 264.7 cells. Inhibition of HO activity using Sn-protoporphyrin-IX (SnPP) abolished the inhibitory effect of Sal B on NO production and iNOS expression. Sal B increased macrophage arginase activity in a dose-dependent manner and diminished LPS-inducible tumor necrosis factor-관 production. These effects were also reversed by SnPP. These data suggest that HO-1 expression plays an intermediary role in the anti-inflammatory effects of Sal B. In contrast to the observations in macrophages, Sal B dose-dependently inhibited arginase activity in murine liver, kidney, and vascular tissue. Furthermore, Sal B increased NO production in isolated mouse aortas through the inhibition of arginase activity and reduction of reactive oxygen species production. We conclude that Sal B improves vascular function by inhibiting inflammatory responses and promoting endothelium-dependent vasodilation. Taken together, we suggest that Sal B may represent a potent candidate therapeutic for the treatment of cardiovascular diseases associated with endothelial dysfunction.</P>

FGF21 induced by carbon monoxide mediates metabolic homeostasis <i>via</i> the PERK/ATF4 pathway

Joe, Yeonsoo,Kim, Sena,Kim, Hyo Jeong,Park, Jeongmin,Chen, Yingqing,Park, Hyeok-Jun,Jekal, Seung-Joo,Ryter, Stefan W.,Kim, Uh Hyun,Chung, Hun Taeg Federation of American Societies for Experimental 2018 The FASEB Journal Vol. No.

<P>The prevalence of metabolic diseases, including type 2 diabetes, obesity, and cardiovascular disease, has rapidly increased, yet the molecular mechanisms underlying the metabolic syndrome, a primary risk factor, remain incompletely understood. The small, gaseous molecule carbon monoxide (CO) has well-known anti-inflammatory, antiproliferative, and antiapoptotic effects in a variety of cellular- and tissue-injury models, whereas its potential effects on the complex pathways of metabolic disease remain unknown. We demonstrate here that CO can alleviate metabolic dysfunction <I>in vivo</I> and <I>in vitro</I>. We show that CO increased the expression and section of the fibroblast growth factor 21 (FGF21) in hepatocytes and liver. CO-stimulated PERK activation and enhanced the levels of FGF21 <I>via</I> the eIF2α–ATF4 signaling pathway. The induction of FGF21 by CO attenuated endoreticulum stress- or diet-induced, obesity-dependent hepatic steatosis. Moreover, CO inhalation lowered blood glucose levels, enhanced insulin sensitivity, and promoted energy expenditure by stimulating the emergence of beige adipose cells from white adipose cells. In conclusion, we suggest that CO acts as a potent inducer of FGF21 expression and that CO critically depends on FGF21 to regulate metabolic homeostasis.—Joe, Y., Kim, S., Kim, H. J., Park, J., Chen, Y., Park, H.-J., Jekal, S.-J., Ryter, S. W., Kim, U. H., Chung, H. T. FGF21 induced by carbon monoxide mediates metabolic homeostasis <I>via</I> the PERK/ATF4 pathway.</P>

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.

Endoplasmic reticulum stress is sufficient for the induction of IL-1β production via activation of the NF-κB and inflammasome pathways

Kim, Sena,Joe, Yeonsoo,Jeong, Sun Oh,Zheng, Min,Back, Sung Hoon,Park, Sang Won,Ryter, Stefan W,Chung, Hun Taeg SAGE Publications 2014 Innate immunity Vol.20 No.8

<P>The mechanisms underlying pathophysiological states such as metabolic syndrome and obesity include endoplasmic reticulum (ER) stress and aberrant inflammatory responses. ER stress results from the accumulation of misfolded proteins during stress conditions. However, the precise mechanisms by which ER stress modulates inflammation remain incompletely understood. In this study, we hypothesized that ER stress alone could represent a sufficient signal for the modulation of inflammasome-dependent cytokine responses. We found that several ER stress-inducing chemicals and the free fatty acid palmitate can trigger IL-1 secretion in various cell types, including monocytic leukemia cells, primary macrophages and differentiated adipocytes. We show that ER stress primes cells for the expression of pro-IL-1 via NF-B activation and promotes IL-1 secretion. Enhanced IL-1 secretion depended on the activation of the NLRP3 inflammasome through a mechanism involving reactive oxygen species formation and activation of thioredoxin-interacting protein. Chemical chaperone treatment and the pharmacological application of carbon monoxide inhibited IL-1 secretion in response to ER stress. Our results provide a mechanistic link between ER stress and the regulation of inflammation, and suggest that modulation of ER stress may provide a therapeutic opportunity to block progression of low grade chronic inflammation to metabolic syndrome.</P>

Induction of endoplasmic reticulum stress under endotoxin tolerance increases inflammatory responses and decreases <i>Pseudomonas aeruginosa</i> pneumonia

Kim, Sena,Joe, Yeonsoo,Park, Se-Ung,Jeong, Sun Oh,Kim, Jin-Kyung,Park, Seong Hoon,Pae, Hyun-Ock,Surh, Young-Joon,Shin, Jaekyoon,Chung, Hun Taeg Wiley (John WileySons) 2018 Journal of leukocyte biology Vol.104 No.5

Endoplasmic Reticulum Stress–Induced IRE1α Activation Mediates Cross-Talk of GSK-3β and XBP-1 To Regulate Inflammatory Cytokine Production

Kim, Sena,Joe, Yeonsoo,Kim, Hyo Jeong,Kim, You-Sun,Jeong, Sun Oh,Pae, Hyun-Ock,Ryter, Stefan W.,Surh, Young-Joon,Chung, Hun Taeg The American Association of Immunologists, Inc. 2015 JOURNAL OF IMMUNOLOGY Vol.194 No.9

<P>IL-1 beta and TNF-alpha are important proinflammatory cytokines that respond to mutated self-antigens of tissue damage and exogenous pathogens. The endoplasmic reticulum (ER) stress and unfolded protein responses are related to the induction of proinflammatory cytokines. However, the detailed molecular pathways by which ER stress mediates cytokine gene expression have not been investigated. In this study, we found that ER stress-induced inositol-requiring enzyme (IRE) 1a activation differentially regulates proinflammatory cytokine gene expression via activation of glycogen synthase kinase (GSK)-3 beta and X-box binding protein (XBP)-1. Surprisingly, IL-1 beta gene expression was modulated by IRE1 alpha-mediated GSK-3 beta activation, but not by XBP-1. However, IRE1 alpha-mediated XBP-1 splicing regulated TNF-alpha gene expression. SB216763, a GSK-3 inhibitor, selectively inhibited IL-1 beta gene expression, whereas the IRE1 alpha RNase inhibitor STF083010 suppressed only TNF-alpha production. Additionally, inhibition of GSK-3 beta greatly increased IRE1 alpha-dependent XBP-1 splicing. Our results identify an unsuspected differential role of downstream mediators GSK-3 beta and XBP-1 in ER stress-induced IRE1 alpha activation that regulates cytokine production through signaling cross-talk. These results have important implications in the regulation of inflammatory pathways during ER stress, and they suggest novel therapeutic targets for diseases in which meta-inflammation plays a key role.</P>

Differential Regulation of Toll-Like Receptor-Mediated Cytokine Production by Unfolded Protein Response

Kim, Sena,Joe, Yeonsoo,Surh, Young-Joon,Chung, Hun Taeg Hindawi 2018 Oxidative medicine and cellular longevity Vol.2018 No.-

<P>The ability of the host immune response is largely mediated by the proinflammatory cytokine production. Physiological and pathological conditions of endoplasmic reticulum (ER) trigger unfolded protein response and contribute to the development or pathology of inflammatory diseases. Under ER stress, unfolded protein response (UPR) signaling pathways participate in upregulating inflammatory cytokine production via NF-kappaB, MAPK, and GSK-3<I>β</I>. Moreover, it has been suggested that ER stress crosstalks with toll-like receptor (TLR) signaling pathway to promote the production of proinflammatory cytokines. In addition, TLR stimulation can lead to UPR activation to promote inflammation. In this review, we will cover how proinflammatory cytokine production by UPR signaling can be induced or amplified in the presence or absence of TLR activation.</P>

Carbon monoxide induces the assembly of stress granule through the integrated stress response

Chen, Yingqing,Joe, Yeonsoo,Park, Jeongmin,Song, Hyun-Chul,Kim, Uh-Hyun,Chung, Hun Taeg Elsevier 2019 Biochemical and biophysical research communication Vol.512 No.2

<P><B>Abstract</B></P> <P>Stress granules (SGs) are membraneless and phase-dense organelles that form transiently in response to a variety of harmful stimuli, including oxidative, heat, osmotic, ultraviolet light and chemotoxic stresses, and thus providing protective effects, allowing survivals. Carbon monoxide (CO), a gaseous second messenger, is synthesized by heme-oxygenases, and exerts anti-inflammatory, anti-proliferative and anti-apoptotic effects in a variety of cellular- and tissue-injury models. Several reports indicate that low levels of mitochondrial reactive oxygen species (mtROS) generated by CO can selectively activate PERK-eIF2α integrated stress response (ISR) to preserve the cellular homeostasis. Hence, CO can confer protection against cellular stresses. However, the mechanisms underlying the cyto-protective effects of CO against various harmful stimuli remain to be elucidated. Here, we sought to examine whether CO induces the SG assembly, and uncover its molecular mechanisms. We treated WI-38 cells and primary mouse embryonic fibroblasts (MEFs) with CO-releasing molecule 2 (CORM2) or CO gas, and found the SG assemblies were gradually increased in time and dose dependent manners. Next, we used Mito-TEMPO, an mtROS scavenger, to explore if mtROS might be involved in the CO-induced SG assembly. Furthermore, we confirmed the involvement of ISR consisted of PERK-eIF2α signaling pathway induced by CO for the SGs assembly. Finally, the inhibition of SG assembly by ISR inhibitor further verified CO-induced ISR might be responsible for SG. Taken together, in this study, we first demonstrated that CO is a novel SG inducer by activating ISR. Moreover, mtROS might be an initiator for the CO-induced ISR responsible for SG assembly.</P> <P><B>Highlights</B></P> <P> <UL> <LI> CO as a product of HO-1 protects cells from stresses. </LI> <LI> CO activates integrated stress response (ISR) via mtROS production. </LI> <LI> CO-PERK- eIF2α signaling pathway induces stress granules (SC) assembly. </LI> </UL> </P>

Filbertone reduces α-synuclein accumulation in neuroblastoma cells by modulating autophagy-lysosomal pathway

Jeong-Hun Gong,Yeonsoo Joe,Byungyong Ahn,Rina Yu 한국식품영양과학회 2021 한국식품영양과학회 학술대회발표집 Vol.2021 No.10

Dysregulation of autophagy-lysosomal pathway is closely associated with the neurodegeneration observed in synucleinopathies such as Parkinson’s disease. The protein kinase R-like endoplasmic reticulum (ER) kinase (PERK) can activate autophagy-lysosomal pathway, and reduces protein aggregation associated neuropathies. Filbertone, a main aroma compound of hazelnuts, elicits anti-obesity, anti-inflammatory, and neuroprotective properties. In this study, we investigated whether filbertone has a potential to alter the accumulation of α-synuclein in neuroblastoma cells. Filbertone increased expression of autophagy markers and decreased α-synuclein accumulation in neuroblastoma cells. Filbertone promoted the activation of PERK-eIF2-ATF4 axis in the neuroblastoma cells. Using siRNA against TFEB, we confirmed that filbertone-induced autophagy was mediated through TFEB nuclear translocation. These results indicate that filbertone activates autophagy-lysosomal pathway by acting as a PERK activator, leading to the reduction of α-synuclein accumulation in the neuroblastoma cells. Filbertone may have a potential to ameliorate synucleinopathies in Parkinson’s disease.