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  • However despite medicinal chemistry efforts lead to consider

    2021-12-01

    However, despite medicinal chemistry efforts lead to considerable improvement in potency and selectivity of new HO-1 inhibitors, still have not identified inhibitors in the low nanomolar range. Therefore, due to the possible in vivo non-specific effects at high dosage, novel strategies should be developed with the aim to discover an ideal drug decreasing HO levels and activity with high potency, without affecting other akt inhibitors biological functions.
    Acknowledgments This work was supported by Research Funding for University (Piano per la Ricerca 2016–2018, project code 57722172107).
    Introduction The heme oxygenase (HO) is a stress-responsive enzyme system that can catabolizes free heme into biliverdin, carbon monoxide and iron [1]. Free heme is essential for controlling the expression of numerous proteins such as HO-1, nitric oxide synthase, cytochromes and so on. It also regulates proliferation and differentiation of a variety of akt inhibitors [2]. Besides its physiological importance, heme has a potent oxidative capacity in oxidizing lipids and proteins, and damaging DNA [3]. Excess of heme may be pathogenic because heme catalyzes the formation of reactive oxygen species (ROS), resulting in oxidative stress and subsequent cellular or tissue damage. Furthermore, it is known that chronic oxidative stress promotes inflammatory responses in multifarious immune-mediated diseases and contributes to pathogenesis. Thus, HO enzymes possess a crucial metabolic function by heme bioavailability regulation and turnover in cells or tissues during oxidative stress. HO activity is represented by 3 separate isozymes: an inducible isoform HO-1, and two constitutively expressed isoforms HO-2 and HO-3. The inducible isoform HO-1, exhibited low basal expression levels in most cells and tissue, and expressed highest in the spleen, the site of erythorocyte turnover [4]. HO-1 is undetectable under basal conditions but highly inducible under conditions of stress or inflammation [5]. HO-2, is also an important component of cells that participates in the regulation of various physiological processes [6]. In contrast, the so-called HO-3 form, studies of which are still limited, was proved to be a processed pseudogene derived from an HO-2 transcript [7]. Rheumatic diseases are a range of more than 100 chronic and disabling illnesses seriously affecting people's life. It is featured by inflammation infiltration and loss of function in one or more regions of musculoskeletal system, such as cartilage, joints, muscles, bones, tendons, ligaments, even internal organs [8,9]. Most rheumatic diseases exhibit autoimmune or inflammatory disorders. For instance, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), osteoarthritis are typical rheumatic diseases accompanying with disorders of immune system. Although rheumatic diseases are complex and considerably different in etiology, clinical manifestations and therapies, there is resemblance in pathogenic mechanisms involved. In the last decade, accumulating evidence supported contribution of oxidative stress to the symptoms and progression of inflammatory diseases and common rheumatic diseases [10]. Notably, HO-1 exhibits critical immune-modulatory functions in macrophages, which play essential roles in immune system especially in rheumatic diseases [1]. Some therapies targeting HO-1 in experimental models have been confirmed beneficial for attenuating the severity of these rheumatic diseases. It suggests that the cytoprotective effect of HO-1 against oxidative stress and inflammation has the potential to be a burgeoning therapeutic strategy for a series of immune-related rheumatic diseases. Based on the multiple biological characteristics of HO-1, interest in it continues to grow rapidly (Fig. 1). Nowadays, there have been plenty of publications about the essential role and therapeutic potential of HO-1 in diversified disorders including tumor, vascular diseases, diabetes and obesity. Despite the growing interest in the protective role for HO-1 in rheumatic disease (Fig. 2), the definite function of HO-1 in immunological modulation is only scarcely understood. This review highlights the significant impact of HO-1 in rheumatic diseases and provides a brief overview of rheumatic diseases therapies targeting HO-1 based on the informed researches.