Integrative Survival Response Evoked by Heme Oxygenase-1 and Heme Metabolites

Heme oxygenase (HO) catalyzes the rate-limiting step in heme degradation to produce carbon monoxide (CO), iron, and biliverdin. Biliverdin is subsequently converted to bilirubin by its reductase, and iron is recycled for heme synthesis. The inducible HO isoform, HO-1, is involved in the protection of multiple tissues and organs. The mechanism of protective actions of HO-1 has not been completely elucidated, but recent evidence suggests that one or more of heme metabolites can mediate the protective effects of HO-1. Particularly, CO mimics the antioxidant, anti-inflammatory, anti-apoptotic and antiproliferative actions of HO-1. Many of these effects of CO depend on the production of cyclic guanosine monophosphate (cGMP), and the modulation of mitogen-activated protein kinase (MAPK) pathways. The transcription factors, including nuclear factor E2-related factor-2 (Nrf2), and their upstream kinases, including MAPK pathway, play an important regulatory role in HO-1 expression by dietary antioxidants and drugs. This review attempts to concisely summarize the molecular and biochemical characteristics of HO-1, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by dietary antioxidants and drugs. In addition, the cytoprotective roles of HO-1 shall be discussed from the perspective of each of the metabolic by-products

Okanin, a chalcone found in the genus Bidens, and 3-penten-2-one inhibit inducible nitric oxide synthase expression via heme oxygenase-1 induction in RAW264.7 macrophages activated with lipopolysaccharide

Excess production of nitric oxide by activated macrophages via inducible nitric oxide synthase leads to the development of various inflammatory diseases. Heme oxygenase-1 expression via activation of nuclear factor-erythroid 2-related factor 2 inhibits nitric oxide production and inducible nitric oxide synthase expression in activated macrophages. Okanin is one of the most abundant chalcones found in the genus Bidens (Asteraceae) that is used as various folk medications in Korea and China for treating inflammation. Here, we found that okanin (possessing the α-β unsaturated carbonyl group) induced heme oxygenase-1 expression via nuclear factor-erythroid 2-related factor 2 activation in RAW264.7 macrophages. 3-Penten-2-one, of which structure, as in okanin, possesses the α-β unsaturated carbonyl group, also induced nuclear factor-erythroid 2-related factor 2-dependent heme oxygenase-1 expression, while both 2-pentanone (lacking a double bond) and 2-pentene (lacking a carbonyl group) were virtually inactive. In lipopolysaccharide-activated RAW264.7 macrophages, both okanin and 3-penten-2-one inhibited nitric oxide production and inducible nitric oxide synthase expression via heme oxygenase-1 expression. Collectively, our findings suggest that by virtue of its α-β unsaturated carbonyl functional group, okanin can inhibit nitric oxide production and inducible nitric oxide synthase expression via nuclear factor-erythroid 2-related factor 2-dependent heme oxygenase-1 expression in lipopolysaccharide-activated macrophages

Therapeutic Roles of Heme Oxygenase-1 in Metabolic Diseases: Curcumin and Resveratrol Analogues as Possible Inducers of Heme Oxygenase-1

Metabolic diseases, such as insulin resistance, type II diabetes, and obesity, are associated with a low-grade chronic inflammation (inflammatory stress), oxidative stress, and endoplasmic reticulum (ER) stress. Because the integration of these stresses is critical to the pathogenesis of metabolic diseases, agents and cellular molecules that can modulate these stress responses are emerging as potential targets for intervention and treatment of metabolic diseases. It has been recognized that heme oxygenase-1 (HO-1) plays an important role in cellular protection. Because HO-1 can reduce inflammatory stress, oxidative stress, and ER stress, in part by exerting antioxidant, anti-inflammatory, and antiapoptotic effects, HO-1 has been suggested to play important roles in pathogenesis of metabolic diseases. In the present review, we will explore our current understanding of the protective mechanisms of HO-1 in metabolic diseases and present some emerging therapeutic options for HO-1 expression in treating metabolic diseases, together with the therapeutic potential of curcumin and resveratrol analogues that have their ability to induce HO-1 expression

Antidiabetic Potential of the Heme Oxygenase-1 Inducer Curcumin Analogues

Although there is a therapeutic treatment to combat diabetes, the identification of agents that may deal with its more serious aspects is an important medical field for research. Diabetes, which contributes to the risk of cardiovascular disease, is associated with a low-grade chronic inflammation (inflammatory stress), oxidative stress, and endoplasmic reticulum (ER) stress. Because the integration of these stresses is critical to the pathogenesis of diabetes, agents and cellular molecules that can modulate these stress responses are emerging as potential targets for intervention and treatment of diabetic diseases. It has been recognized that heme oxygenase-1 (HO-1) plays an important role in cellular protection. Because HO-1 can reduce oxidative stress, inflammatory stress, and ER stress, in part by exerting antioxidant, anti-inflammatory, and antiapoptotic effects, HO-1 has been suggested to play important roles in pathogenesis of diabetes. In the present review, we will explore our current understanding of the protective mechanisms of HO-1 in diabetes and present some emerging therapeutic options for HO-1 expression in treating diabetic diseases, together with the therapeutic potential of curcumin analogues that have their ability to induce HO-1 expression