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  • In the present study BACH downregulation did not correlate w


    In the present study, BACH1 downregulation did not correlate with nuclear accumulation of NRF2, suggesting that these changes were triggered via an independent mechanism. BACH1 is a transcriptional repressor that is regulated by heme. Heme binding to the BACH1 C-terminal domain inhibits BACH1 DNA binding activity, triggers its export from the nucleus, and induces its ubiquitination and subsequent degradation [25]. Heme has been proposed to bind to the CP motif of BACH1, an area that contains dipeptide sequences of cysteine and proline [32]. Multiple studies reported that protein-bound heme further binds gas molecules, such as NO, oxygen, and carbon monoxide. Therefore, the interaction of heme with the cysteine residue of the CP motif could serve as a potential target for NO. The assumption that heme binds more strongly to BACH1 in the presence of higher NO concentrations, however, could not be explained by current models and requires further investigation. tBHQ has been reported to induce the L002 of of tyrosine 486 of BACH1, thereby enhancing its nuclear export in a CRM1-dependent manner [33]. Additionally, diamide, a sulfhydryl oxidizing agent, was reported to induce the dissociation of BACH1 from AREs. During this process, it is thought that the cysteine residue of BACH1 (C574) acts as a sensor of redox status [34]. In the case of NO, the cysteine residue of BACH1 (C578) can serve as a target of nitrosylation to induce nuclear export of BACH1. In the present study, however, BACH1 degradation induced by the combination of NO and S1PC was observed in the nucleus. The observed nuclear degradation of BACH1 is inconsistent with previously reported findings [22,33,35], and our findings suggested a novel mechanism for BACH1 downregulation. Some cysteine residues of BACH1 are likely to be targets of nitrosylation, and this modification can induce conformational changes and subsequent degradation of BACH1. Similarly, S1PC could interact with the S-nitrosothiols of BACH1 to influence protein stability. The mechanisms underlying these interactions require further investigation. Various sulfur compounds derived from several sulfur-containing amino acids originally found in raw garlic are responsible for the characteristic properties of garlic supplements [36]. S1PC and SAC isolated from aged garlic extracts have been demonstrated to exhibit remarkable oral bioavailability [4,5]. In the present study, S1PC was observed to uniquely interact with NO to modulate the expression of ARE-regulated genes. In contrast, SAC, a stereoisomer of S1PC, did not affect the expression of ARE-regulated genes. Additionally, a recent study indicated that S1PC, but not SAC, increases immunoglobulin A production in vivo and in vitro [37]. The above results indicate that the structure of S-1-propenyl is critical for the unique physiological effects of S1PC. The above findings also provide evidence that the unique feature of the sulfur atom in the S-1-propenyl moiety is responsible for the stereospecific activity of S1PC in the context of BACH1 degradation. Although Bach1 is expressed in diverse cell types, no clear defects are observed in Bach1-deficient mice under normal conditions [10]. Bach1-deficient mice also exhibit elevated disease tolerance in various models, including atherosclerosis in ApoE double-knockout mice [38], lung damage after high oxygen exposure [39], osteoarthritis [40], and chemically induced colitis [41]. Multiple studies have demonstrated the involvement of Hmox1 in this resistance. This protein is highly expressed in diverse tissues in Bach1-deficient mice. Additionally, recent studies have reported that Bach1 is a critical regulator of the immune system, specifically in the context of macrophage polarization. Genetic ablation of Bach1 was found to promote the activation of M2 macrophages and ameliorate lupus nephritis in mice [42]. The above results indicate that downregulation of BACH1 levels and upregulation of HMOX1 levels may provide promising therapeutic approaches for the treatment of inflammatory diseases.