Browse > Article
http://dx.doi.org/10.14348/molcells.2019.0016

Similarities and Distinctions in the Effects of Metformin and Carbon Monoxide in Immunometabolism  

Park, Jeongmin (Department of Biological Sciences, University of Ulsan)
Joe, Yeonsoo (Department of Biological Sciences, University of Ulsan)
Ryter, Stefan W. (Joan and Sanford I. Weill Department of Medicine, and Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical Center)
Surh, Young-Joon (Tumor microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University)
Chung, Hun Taeg (Department of Biological Sciences, University of Ulsan)
Publication Information
Molecules and Cells / v.42, no.4, 2019 , pp. 292-300 More about this Journal
Abstract
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.
Keywords
heme oxygenase-1; metabolic diseases; metabolic homeostasis; mitochondrial ROS; PERK;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Jamal Uddin, M., Joe, Y., Kim, S.K., Oh, J., S., Ryter, S.W., Pae, H.O. and Chung, H.T. (2016). IRG1 induced by heme oxygenase-1/carbon monoxide inhibits LPS-mediated sepsis and pro-inflammatory cytokine production. Cell Mol. Immunol. 13, 170-179.   DOI
2 Jing, Y., Wu, F., Li, D., Yang, L., Li, Q. and Li, R. (2018). Metformin improves obesity-associated inflammation by altering macrophages polarization. Mol. Cell Endocrinol. 461, 256-264.   DOI
3 Joe, Y., Kim, S., Kim, H.J., Park, J., Chen, Y., Park, H.J., Jekal, S.J., Ryter, S.W., Kim, U.H. and Chung, H.T. (2018). FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway. FASEB J. 32, 2630-2643.   DOI
4 Kalender, A., Selvaraj, A., Kim, S.Y., Gulati, P., Brule, S., Viollet, B., Kemp, B.E., Bardeesy, N., Dennis, P., Schlager, J.J., et al. (2010). Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 11, 390-401.   DOI
5 Kim, E.K., Lee, S.H., Lee, S.Y., Kim, J.K., Jhun, J.Y., Na, H.S., Kim, S.Y., Choi, J.Y., Yang, C.W., Park, S.H., et al. (2018a). Metformin ameliorates experimental-obesity-associated autoimmune arthritis by inducing FGF21 expression and brown adipocyte differentiation. Exp. Mol. Med. 50, e432.   DOI
6 Kim, H.J., Joe, Y., Kim, S.K., Park, S.U., Park, J., Chen, Y., Kim, J., Ryu, J., Cho, G.J., Surh, Y.J., et al. (2017). Carbon monoxide protects against hepatic steatosis in mice by inducing sestrin-2 via the PERKeIF2alpha-ATF4 pathway. Free Radic. Biol. Med. 110, 81-91.   DOI
7 Kim, H.J., Joe, Y., Surh, Y.J. and Chung, H.T. (2018b). Metabolic signaling functions of the heme oxygenase/CO system in metabolic diseases. Cell Mol. Immunol. 15, 1085-1087.   DOI
8 Copps, K.D. and White, M.F. (2012). Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55, 2565-2582.   DOI
9 Chen, C.Y., Jang, J.H., Li, M.H. and Surh, Y.J. (2005). Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells. Biochem. Biophys. Res. Commun. 331, 993-1000.   DOI
10 Chen, S.C., Brooks, R., Houskeeper, J., Bremner, S.K., Dunlop, J., Viollet, B., Logan, P.J., Salt, I.P., Ahmed, S.F. and Yarwood, S.J. (2017). Metformin suppresses adipogenesis through both AMP-activated protein kinase (AMPK)-dependent and AMPK-independent mechanisms. Mol. Cell. Endocrinol. 440, 57-68.   DOI
11 Dandona, P., Aljada, A., Ghanim, H., Mohanty, P., Tripathy, C., Hofmeyer, D. and Chaudhuri, A. (2004). Increased plasma concentration of macrophage migration inhibitory factor (MIF) and MIF mRNA in mononuclear cells in the obese and the suppressive action of metformin. J. Clin. Endocrinol. Metab. 89, 5043-5047.   DOI
12 de Oliveira, S., Houseright, R.A., Graves, A.L., Golenberg, N., Korte, B.G., Miskolci, V. and Huttenlocher, A. (2019). Metformin modulates innate immune-mediated inflammation and early progression of NAFLD-associated hepatocellular carcinoma in zebrafish. J. Hepatol. 70, 710-721.   DOI
13 DeFronzo, R., Fleming, G.A., Chen, K. and Bicsak, T.A. (2016). Metformin-associated lactic acidosis: current perspectives on causes and risk. Metabolism 65, 20-29.   DOI
14 Deng, W., Cha, J., Yuan, J., Haraguchi, H., Bartos, A., Leishman, E., Viollet, B., Bradshaw, H.B., Hirota, Y. and Dey, S.K. (2016). p53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing. J. Clin. Invest. 126, 2941-2954.   DOI
15 Chawla, A., Nguyen, K.D. and Goh, Y.P. (2011). Macrophage-mediated inflammation in metabolic disease. Nat. Rev. Immunol. 11, 738-749.   DOI
16 Shoshani, T., Faerman, A., Mett, I., Zelin, E., Tenne, T., Gorodin, S., Moshel, Y., Elbaz, S., Budanov, A., Chajut, A., et al. (2002). Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis. Mol. Cell Biol. 22, 2283-2293.   DOI
17 Shaw, R.J., Lamia, K.A., Vasquez, D., Koo, S.H., Bardeesy, N., Depinho, R.A., Montminy, M. and Cantley, L.C. (2005). The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642-1646.   DOI
18 Sheikh, V., Zamani, A., Mahabadi-Ashtiyani, E., Tarokhian, H., Borzouei, S. and Alahgholi-Hajibehzad, M. (2018). Decreased regulatory function of CD4(+)CD25(+)CD45RA(+) T cells and impaired IL-2 signalling pathway in patients with type 2 diabetes mellitus. Scand. J. Immunol. 88, e12711.   DOI
19 Shen, L., Chng, M.H., Alonso, M.N., Yuan, R., Winer, D.A. and Engleman, E.G. (2015). B-1a lymphocytes attenuate insulin resistance. Diabetes 64, 593-603.   DOI
20 Siavash, M., Tabbakhian, M., Sabzghabaee, A.M. and Razavi, N. (2017). Severity of gastrointestinal side effects of metformin tablet compared to metformin capsule in type 2 diabetes mellitus patients. J. Res. Pharm. Pract. 6, 73-76.   DOI
21 Szabo, M.E., Gallyas, E., Bak, I., Rakotovao, A., Boucher, F., de Leiris, J., Nagy, N., Varga, E. and Tosaki, A. (2004). Heme oxygenase-1-related carbon monoxide and flavonoids in ischemic/reperfused rat retina. Invest. Ophthalmol. Vis. Sci. 45, 3727-3732.   DOI
22 Takagi, T., Naito, Y., Tanaka, M., Mizushima, K., Ushiroda, C., Toyokawa, Y., Uchiyama, K., Hamaguchi, M., Handa, O. and Itoh, Y. (2018). Carbon monoxide ameliorates murine T-cell-dependent colitis through the inhibition of Th17 differentiation. Free Radic. Res. 52, 1328-1335.   DOI
23 Kumar, V. (2018). T cells and their immunometabolism: A novel way to understanding sepsis immunopathogenesis and future therapeutics. Eur. J. Cell Biol. 97, 379-392.   DOI
24 Schertzer, J.D. and Steinberg, G.R. (2014). Immunometabolism: the interface of immune and metabolic responses in disease. Immunol. Cell Biol. 92, 303.   DOI
25 Kim, J., Kwak, H.J., Cha, J.Y., Jeong, Y.S., Rhee, S.D., Kim, K.R. and Cheon, H.G. (2014). Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction. J. Biol. Chem. 289, 23246-23255.   DOI
26 Kim, K.H., Jeong, Y.T., Kim, S.H., Jung, H.S., Park, K.S., Lee, H.Y. and Lee, M.S. (2013a). Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation. Biochem. Biophys. Res. Commun. 440, 76-81.   DOI
27 Kim, K.H., Jeong, Y.T., Oh, H., Kim, S.H., Cho, J.M., Kim, Y.N., Kim, S.S., Kim, D.H., Hur, K.Y., Kim, H.K., et al. (2013b). Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19, 83-92.   DOI
28 Kim, K.M., Pae, H.O., Zheng, M., Park, R., Kim, Y.M. and Chung, H.T. (2007). Carbon monoxide induces heme oxygenase-1 via activation of protein kinase R-like endoplasmic reticulum kinase and inhibits endothelial cell apoptosis triggered by endoplasmic reticulum stress. Circ. Res. 101, 919-927.   DOI
29 Foresti, R., Hammad, J., Clark, J.E., Johnson, T.R., Mann, B.E., Friebe, A., Green, C.J. and Motterlini, R. (2004). Vasoactive properties of CORM-3, a novel water-soluble carbon monoxide-releasing molecule. Br. J. Pharmacol. 142, 453-460.   DOI
30 Diaz, A., Romero, M., Vazquez, T., Lechner, S., Blomberg, B.B. and Frasca, D. (2017). Metformin improves in vivo and in vitro B cell function in individuals with obesity and Type-2 Diabetes. Vaccine 35, 2694-2700.   DOI
31 Foretz, M., Hebrard, S., Leclerc, J., Zarrinpashneh, E., Soty, M., Mithieux, G., Sakamoto, K., Andreelli, F. and Viollet, B. (2010). Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, 2355-2369.   DOI
32 Fullerton, M.D., Steinberg, G.R. and Schertzer, J.D. (2013). Immunometabolism of AMPK in insulin resistance and atherosclerosis. Mol. Cell. Endocrinol. 366, 224-234.   DOI
33 Gopoju, R., Panangipalli, S. and Kotamraju, S. (2018). Metformin treatment prevents SREBP2-mediated cholesterol uptake and improves lipid homeostasis during oxidative stress-induced atherosclerosis. Free Radic. Biol. Med. 118, 85-97.   DOI
34 Gotlieb, W.H., Saumet, J., Beauchamp, M.C., Gu, J., Lau, S., Pollak, M.N. and Bruchim, I. (2008). In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecol. Oncol. 110, 246-250.   DOI
35 Griffin, S.J., Leaver, J.K. and Irving, G.J. (2017). Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia 60, 1620-1629.   DOI
36 Li, C., Xu, M.M., Wang, K., Adler, A.J., Vella, A.T. and Zhou, B. (2018). Macrophage polarization and meta-inflammation. Transl. Res. 191, 29-44.   DOI
37 Laban, S., Suwandi, J.S., van Unen, V., Pool, J., Wesselius, J., Hollt, T., Pezzotti, N., Vilanova, A., Lelieveldt, B.P.F. and Roep, B.O. (2018). Heterogeneity of circulating CD8 T-cells specific to islet, neo-antigen and virus in patients with type 1 diabetes mellitus. PLoS One 13, e0200818.   DOI
38 Lee, J.M., Seo, W.Y., Song, K.H., Chanda, D., Kim, Y.D., Kim, D.K., Lee, M.W., Ryu, D., Kim, Y.H., Noh, J.R., et al. (2010). AMPK-dependent repression of hepatic gluconeogenesis via disruption of CREB.CRTC2 complex by orphan nuclear receptor small heterodimer partner. J. Biol. Chem. 285, 32182-32191.   DOI
39 Alberti, K.G., Eckel, R.H., Grundy, S.M., Zimmet, P.Z., Cleeman, J.I., Donato, K.A., Fruchart, J.C., James, W.P., Loria, C.M., Smith, S.C., et al. (2009). Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; american heart association; world heart federation; international atherosclerosis society; and international association for the study of obesity. Circulation 120, 1640-1645.   DOI
40 Lee, Y.H., Petkova, A.P. and Granneman, J.G. (2013). Identification of an adipogenic niche for adipose tissue remodeling and restoration. Cell Metab. 18, 355-367.   DOI
41 Liu, L., Wise, D.R., Diehl, J.A. and Simon, M.C. (2008). Hypoxic reactive oxygen species regulate the integrated stress response and cell survival. J. Biol. Chem. 283, 31153-31162.   DOI
42 Manieri, E. and Sabio, G. (2015). Stress kinases in the modulation of metabolism and energy balance. J. Mol. Endocrinol. 55, R11-22.   DOI
43 Mathis, D. and Shoelson, S.E. (2011). Immunometabolism: an emerging frontier. Nat. Rev. Immunol. 11, 81.   DOI
44 McNally, S.J., Harrison, E.M., Ross, J.A., Garden, O.J. and Wigmore, S.J. (2007). Curcumin induces heme oxygenase 1 through generation of reactive oxygen species, p38 activation and phosphatase inhibition. Int. J. Mol. Med. 19, 165-172.
45 Witters, L.A. (2001). The blooming of the French lilac. J. Clin. Invest. 108, 1105-1107.   DOI
46 Grisouard, J., Timper, K., Radimerski, T.M., Frey, D.M., Peterli, R., Kola, B., Korbonits, M., Herrmann, P., Krahenbuhl, S., Zulewski, H., et al. (2010). Mechanisms of metformin action on glucose transport and metabolism in human adipocytes. Biochem. Pharmacol. 80, 1736-1745.   DOI
47 Uysal, K.T., Wiesbrock, S.M., Marino, M.W. and Hotamisligil, G.S. (1997). Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389, 610-614.   DOI
48 Weyer, C., Bogardus, C., Mott, D.M. and Pratley, R.E. (1999). The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J. Clin. Invest. 104, 787-794.   DOI
49 Wolf, Y., Boura-Halfon, S., Cortese, N., Haimon, Z., Sar Shalom, H., Kuperman, Y., Kalchenko, V., Brandis, A., David, E., Segal-Hayoun, Y., et al. (2017). Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure. Nat. Immunol. 18, 665-674.   DOI
50 Wu, H. and Ballantyne, C.M. (2017). Skeletal muscle inflammation and insulin resistance in obesity. J. Clin. Invest. 127, 43-54.   DOI
51 Xu, X., So, J.S., Park, J.G. and Lee, A.H. (2013). Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP. Semin. Liver Dis. 33, 301-311.   DOI
52 Yamamoto-Oka, H., Mizuguchi, S., Toda, M., Minamiyama, Y., Takemura, S., Shibata, T., Cepinskas, G. and Nishiyama, N. (2018). Carbon monoxide-releasing molecule, CORM-3, modulates alveolar macrophage M1/M2 phenotype in vitro. Inflammopharmacology 26, 435-445.   DOI
53 Ben Sahra, I., Regazzetti, C., Robert, G., Laurent, K., Le Marchand-Brustel, Y., Auberger, P., Tanti, J.F., Giorgetti-Peraldi, S. and Bost, F. (2011). Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 71, 4366-4372.   DOI
54 Morse, D., Pischke, S.E., Zhou, Z., Davis, R.J., Flavell, R.A., Loop, T., Otterbein, S.L., Otterbein, L.E. and Choi, A.M. (2003). Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1. J. Biol. Chem. 278, 36993-36998.   DOI
55 Motterlini, R., Clark, J.E., Foresti, R., Sarathchandra, P., Mann, B.E. and Green, C.J. (2002). Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities. Circ. Res. 90, E17-24.
56 Motterlini, R., Sawle, P., Hammad, J., Bains, S., Alberto, R., Foresti, R. and Green, C.J. (2005). CORM-A1: a new pharmacologically active carbon monoxide-releasing molecule. FASEB J. 19, 284-286.   DOI
57 Yang, Y.C., Huang, Y.T., Hsieh, C.W., Yang, P.M. and Wung, B.S. (2014). Carbon monoxide induces heme oxygenase-1 to modulate STAT3 activation in endothelial cells via S-glutathionylation. PLoS One 9, e100677.   DOI
58 Zakikhani, M., Dowling, R., Fantus, I.G., Sonenberg, N. and Pollak, M. (2006). Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 66, 10269-10273.   DOI
59 Grundy, S.M., Brewer, H.B., Jr., Cleeman, J.I., Smith, S.C., Jr., Lenfant, C., American Heart, A., National Heart, L. and Blood, I. (2004). Definition of metabolic syndrome: report of the national heart, lung, and blood institute/american heart association conference on scientific issues related to definition. Circulation 109, 433-438.   DOI
60 Ashabi, G., Khalaj, L., Khodagholi, F., Goudarzvand, M. and Sarkaki, A. (2015). Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia. Metab. Brain Dis. 30, 747-754.   DOI
61 Boucher, J., Kleinridders, A. and Kahn, C.R. (2014). Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect. Biol. 6.
62 Bray, G.A. (2004). Medical consequences of obesity. J. Clin. Endocrinol. Metab. 89, 2583-2589.   DOI
63 Hosick, P.A., AlAmodi, A.A., Storm, M.V., Gousset, M.U., Pruett, B.E., Gray, W., 3rd, Stout, J. and Stec, D.E. (2014). Chronic carbon monoxide treatment attenuates development of obesity and remodels adipocytes in mice fed a high-fat diet. Int. J. Obes. (Lond) 38, 132-139.   DOI
64 Gunton, J.E., Delhanty, P.J., Takahashi, S. and Baxter, R.C. (2003). Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J. Clin. Endocrinol. Metab. 88, 1323-1332.   DOI
65 Hanahan, D. and Weinberg, R.A. (2011). Hallmarks of cancer: the next generation. Cell 144, 646-674.   DOI
66 Hausberger, F.X. (1966). Pathological changes in adipose tissue of obese mice. Anat. Rec. 154, 651-660.   DOI
67 Hotamisligil, G.S. (2017). Foundations of immunometabolism and implications for metabolic health and disease. Immunity 47, 406-420.   DOI
68 Howell, J.J., Hellberg, K., Turner, M., Talbott, G., Kolar, M.J., Ross, D.S., Hoxhaj, G., Saghatelian, A., Shaw, R.J. and Manning, B.D. (2017). Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab. 25, 463-471.   DOI
69 Ismailova, A., Kuter, D., Bohle, D.S. and Butler, I.S. (2018). An overview of the potential therapeutic applications of CO-releasing molecules. Bioinorg. Chem. Appl. 2018, 8547364.
70 Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001). Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167-1174.   DOI
71 Cao, J., Meng, S., Chang, E., Beckwith-Fickas, K., Xiong, L., Cole, R.N., Radovick, S., Wondisford, F.E. and He, L. (2014). Low concentrations of metformin suppress glucose production in hepatocytes through AMP-activated protein kinase (AMPK). J. Biol. Chem. 289, 20435-20446.   DOI
72 Brugarolas, J., Lei, K., Hurley, R.L., Manning, B.D., Reiling, J.H., Hafen, E., Witters, L.A., Ellisen, L.W. and Kaelin, W.G. (2004). Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893-2904.   DOI
73 Bugianesi, E., Moscatiello, S., Ciaravella, M.F. and Marchesini, G. (2010). Insulin resistance in nonalcoholic fatty liver disease. Curr. Pharm. Des. 16, 1941-1951.   DOI
74 Caballero, A.E., Delgado, A., Aguilar-Salinas, C.A., Herrera, A.N., Castillo, J.L., Cabrera, T., Gomez-Perez, F.J. and Rull, J.A. (2004). The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J. Clin. Endocrinol. Metab. 89, 3943-3948.   DOI
75 Onken, B. and Driscoll, M. (2010). Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PLoS One 5, e8758.   DOI
76 Otterbein, L.E., Bach, F.H., Alam, J., Soares, M., Tao Lu, H., Wysk, M., Davis, R.J., Flavell, R.A. and Choi, A.M. (2000). Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat. Med. 6, 422-428.   DOI
77 Otterbein, L.E., Foresti, R. and Motterlini, R. (2016). Heme oxygenase-1 and carbon monoxide in the heart: the balancing act between danger signaling and pro-survival. Circ. Res. 118, 1940-1959.   DOI
78 Otterbein, L.E., Mantell, L.L. and Choi, A.M. (1999). Carbon monoxide provides protection against hyperoxic lung injury. Am. J. Physiol. 276, L688-694.   DOI
79 Zhou, Z.Y., Ren, L.W., Zhan, P., Yang, H.Y., Chai, D.D. and Yu, Z.W. (2016). Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling. Acta Pharmacol. Sin. 37, 1063-1075.   DOI
80 Zuckerbraun, B.S., Chin, B.Y., Bilban, M., d'Avila, J.C., Rao, J., Billiar, T.R. and Otterbein, L.E. (2007). Carbon monoxide signals via inhibition of cytochrome c oxidase and generation of mitochondrial reactive oxygen species. FASEB J. 21, 1099-1106.   DOI
81 Otterbein, L.E., Soares, M.P., Yamashita, K. and Bach, F.H. (2003). Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol. 24, 449-455.   DOI
82 Pae, H.O., Oh, G.S., Choi, B.M., Chae, S.C., Kim, Y.M., Chung, K.R. and Chung, H.T. (2004). Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. J. Immunol. 172, 4744-4751.   DOI
83 Pekala, P., Kawakami, M., Vine, W., Lane, M.D. and Cerami, A. (1983). Studies of insulin resistance in adipocytes induced by macrophage mediator. J. Exp. Med. 157, 1360-1365.   DOI
84 Prado-Garcia, H. and Sanchez-Garcia, F.J. (2017). Editorial: immuno-metabolism in tumor microenvironment. Front. Immunol. 8, 374.
85 Quentin, T., Steinmetz, M., Poppe, A. and Thoms, S. (2012). Metformin differentially activates ER stress signaling pathways without inducing apoptosis. Dis. Model. Mech. 5, 259-269.   DOI