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>

Feasibility of Tissue Engineering Small Vessel Scaffold on Vascular Transplantation

( Chen Huayong ),( Bai Shuling ),( Chen Yingqing ) 한국조직공학·재생의학회 2011 조직공학과 재생의학 Vol.8 No.6

The glycoprotein with α-galactosyl-terminal is a major xenogeneic antigen for hyperacute rejection. In this study, we observed distributive features of α-galactosyl in endothelial and smooth muscle cells for small tissue engineering vessel scaffolds, and for vessels of Wistar rats and Japanese white rabbits. We also aimed to discuss the feasibility of small vessel scaffolds on xenotransplantation. We utilized 30 Wistar rat caudal arteries, non gender specific. Fifteen of caudal arteries were prepared for small acellular vessel scaffolds assigned as small vessel scaffold group, the other 15 caudal arteries were assigned as caudal artery group. We also collected eight Japanese white rabbits, non gender specific, and extracted 15 ear central arteries assigned as central artery group. We added Bandeireae Simplicifolia 1 Isolectin B4 (16 mg/L) to tissue sections for DAB staining, then we detected the positive reaction product of α-galactosyl. The expression of α-galactosyl in central artery group was mainly in membrane and nucleus of endothelial; in caudal artery group, which expressed strong positive in membrane of endothelial. However, in the vessel scaffold group, α-galactosyl expressed weakly or scarcely in the intima of the vessels. The absorbency of caudal artery group was significantly higher than that of central vessel group, and which of vessel scaffold group was significantly lower than that of caudal artery and central artery group, We could conclude xenogeneic antigenicity of endothelial membrane for caudal artery was higher than that for central artery, and we could use acellular small vessel scaffolds for xenogeneic vascular transplantation.

Pterostilbene 4′- <i>β</i> -Glucoside Protects against DSS-Induced Colitis via Induction of Tristetraprolin

Chen, Yingqing,Park, Jeongmin,Joe, Yeonsoo,Park, Hyeok-Jun,Jekal, Seung-Joo,Sato, Daisuke,Hamada, Hiroki,Chung, Hun Taeg Hindawi 2017 Oxidative medicine and cellular longevity Vol.2017 No.-

<P>Pterostilbene, a dimethyl ester analog of resveratrol, has anti-inflammatory and antioxidative effects and alters cell proliferation. Tristetraprolin (TTP) promotes the degradation of proinflammatory mediators via binding to adenosine and uridine- (AU-) rich elements (ARE) located in the 3′-untranslated regions of mRNAs. Here, we utilized pterostilbene 4′-<I>β</I>-glucoside (4-PG), a compound derived from pterostilbene, to investigate whether it has anti-inflammatory effects on dextran sulfate sodium- (DSS-) induced colitis via TTP enhancement. TTP expression was increased in 4-PG dose- and time-dependent manners in RAW264.7 cells. The production of proinflammatory cytokine, such as TNF-<I>α</I>, was reduced by 4-PG in vitro. To investigate the role of TTP in the anti-inflammatory effects of 4-PG, we used DSS–induced colitis in TTP WT and KO mice as models. The expression levels of TTP and proinflammatory cytokines were determined in serum and colon tissue. 4-PG increased the expression of TTP while suppressing proinflammatory cytokines both in vitro and in vivo. These findings suggest that treatment with 4-PG mediates the anti-inflammatory effects of 4-PG on DSS-induced colitis via enhancing TTP expression.</P>

Carbon monoxide attenuates amyloidogenesis via down‐regulation of NF‐κB‐mediated BACE1 gene expression

Kim, Hyo Jeong,Joe, Yeonsoo,Chen, Yingqing,Park, Gyu Hwan,Kim, Uh‐,Hyun,Chung, Hun Taeg John Wiley and Sons Inc. 2019 Aging cell Vol.18 No.1

<P><B>Abstract</B></P><P>Amyloid‐β (Aβ) peptides, the major constituent of plaques, are generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) via β‐secretase (BACE1) and the γ‐secretase complex. It has been proposed that the abnormal secretion and accumulation of Aβ are the initial causative events in the development of Alzheimer's disease (AD). Drugs modulating this pathway could be used for AD treatment. Previous studies indicated that carbon monoxide (CO), a product of heme oxygenase (HO)‐1, protects against Aβ‐induced toxicity and promotes neuroprotection. However, the mechanism underlying the mitigative effect of CO on Aβ levels and BACE1 expression is unclear. Here, we show that CO modulates cleavage of APP and Aβ production by decreasing BACE1 expression in vivo and in vitro. CO reduces Aβ levels and improves memory deficits in AD transgenic mice. The regulation of BACE1 expression by CO is dependent on nuclear factor‐kappa B (NF‐κB). Consistent with the negative role of SIRT1 in the NF‐κB activity, CO fails to evoke significant decrease in BACE1 expression in the presence of the SIRT1 inhibitor. Furthermore, CO attenuates elevation of BACE1 level in brains of 3xTg‐AD mouse model as well as mice fed high‐fat, high‐cholesterol diets. CO reduces the NF‐κB‐mediated transcription of BACE1 induced by the cholesterol oxidation product 27‐hydroxycholesterol or hydrogen peroxide. These data suggest that CO reduces the NF‐κB‐mediated BACE1 transcription and consequently decreases Aβ production. Our study provides novel mechanisms by which CO reduces BACE1 expression and Aβ production and may be an effective agent for AD treatment.</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>

Carbon Monoxide Attenuates Dextran Sulfate Sodium-Induced Colitis via Inhibition of GSK-3 <i><i>β</i></i> Signaling

Uddin, Md. Jamal,Jeong, Sun-oh,Zheng, Min,Chen, Yingqing,Cho, Gyeong Jae,Chung, Hun Taeg,Joe, Yeonsoo Hindawi Publishing Corporation 2013 Oxidative medicine and cellular longevity Vol.2013 No.-

<P>Endogenous carbon monoxide (CO) is produced by heme oxygenase-1 (HO)-1 which mediates the degradation of heme into CO, iron, and biliverdin. Also, CO ameliorates the human inflammatory bowel diseases and ulcerative colitis. However, the mechanism for the effect of CO on the inflammatory bowel disease has not yet been known. In this study, we showed that CO significantly increases survival percentage, body weight, colon length as well as histologic parameters in DSS-treated mice. In addition, CO inhalation significantly decreased DSS induced pro-inflammatory cytokines by inhibition of GSK-3<I><I>β</I></I> in mice model. To support the in vivo observation, TNF-<I><I>α</I></I>, iNOS and IL-10 after CO and LiCl treatment were measured in mesenteric lymph node cells (MLNs) and bone marrow-derived macrophages (BMMs) from DSS treated mice. In addition, we determined that CO potentially inhibited GSK-3<I><I>β</I></I> activation and decreased TNF-<I><I>α</I></I> and iNOS expression by inhibition of NF-<I><I>κ</I></I>B activation in LPS-stimulated U937 and MLN cells pretreated with CO. Together, our findings indicate that CO attenuates DSS-induced colitis via inhibition of GSK-3<I><I>β</I></I> signaling in vitro and in vivo. Importantly, this is the first report that investigated the molecular mechanisms mediated the novel effects of CO via inhibition GSK-3<I><I>β</I></I> in DSS-induced colitis model.</P>

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>

15-Deoxy-Δ^12,14-Prostaglandin J₂ Exerts Proresolving Effects Through Nuclear Factor E2-Related Factor 2-Induced Expression of CD36 and Heme Oxygenase-1

Kim, Wonki,Lee, Ha-Na,Jang, Jeong-Hoon,Kim, Seung Hyeon,Lee, Yeon-Hwa,Hahn, Young-il,Ngo, Hoang-Kieu-Chi,Choi, Yeonseo,Joe, Yeonsoo,Chung, Hun Taeg,Chen, Yingqing,Cha, Young Nam,Surh, Young-Joon Mary Ann Liebert 2017 Antioxidants & redox signaling Vol.27 No.17