Alda-1 Ameliorates Liver Ischemia-Reperfusion Injury by Activating Aldehyde Dehydrogenase 2 and Enhancing Autophagy in Mice

Li, Meng; Xu, Min; Li, Jichang; Chen, Lili; Xu, Dongwei; Tong, Ying; Zhang, Jianjun; Wu, Hailong; Kong, Xiaoni; Xia, Qiang

doi:10.1155/2018/9807139

Cited by 17 publications

(13 citation statements)

References 35 publications

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“…For example, several groups have demonstrated a protective role of autophagy during hepatic ischemia/reperfusion injury [[53], [54], [55]]. Moreover, a recent study also demonstrated that Alda-1 enhanced autophagy in a model of hepatic ischemia/reperfusion injury by increasing LC3II and p62 degradation [56]. In line with these results, here we found that Alda-1 significantly decreased p62 protein expression in the HFD + VC group (Fig.…”

Section: Discussionsupporting

confidence: 90%

Vinyl chloride-induced interaction of nonalcoholic and toxicant-associated steatohepatitis: Protection by the ALDH2 activator Alda-1

et al. 2019

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Vinyl chloride (VC), an abundant environmental contaminant causes steatohepatitis at high levels, but is considered safe at lower (i.e., sub-OSHA) levels. However, we have previously shown that even lower VC levels exacerbate experimental nonalcoholic fatty liver disease (NAFLD) caused by high-fat diet (HFD). Mitochondrial oxidative injury and subsequent metabolic dysfunction appeared to play key roles in mediating this interaction. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) serves as a key line of defense against endogenous and exogenous reactive aldehydes. The current study therefore tests the hypothesis that allosteric activation of ALDH2 with Alda-1 will protect against VC-enhanced NAFLD. Mice were exposed to low VC concentrations (<1 ppm), or room air for 6 h/day, 5 days/week for 12 weeks, while on HFD or low-fat control diet (LFD). Some mice received Alda-1 (20 mg/kg i.p., 3 × /week) for the last 3 weeks of diet/VC exposure. Indices of liver injury, oxidative stress, metabolic and mitochondrial (dys)function were measured. As observed previously, low-dose VC did not cause liver injury in control mice; while liver injury caused by HFD was enhanced by VC. VC decreased hepatic ALDH2 activity of mice fed HFD. Alda-1 attenuated oxidative stress, liver injury, and dysmetabolism in mice exposed to HFD+VC under these conditions. Importantly, alterations in mitochondrial function caused by VC and HFD were diminished by Alda-1. Previous studies have indicated that liver injury caused by HFD is mediated, at least in part, by enhanced mitochondrial autophagy (mitophagy). Here, Alda-1 suppressed PINK1/PARKIN-mediated mitophagy. Taken together, these results support the hypothesis that ALDH2 is a critical defense against mitochondrial injury caused by VC in experimental NAFLD. The ALDH2 activator Alda-1 conferred protection against liver damage under these conditions, most likely via increasing clearance of aldehydes and preserving mitochondrial respiratory function.

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Section: Discussionsupporting

confidence: 90%

Vinyl chloride-induced interaction of nonalcoholic and toxicant-associated steatohepatitis: Protection by the ALDH2 activator Alda-1

et al. 2019

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“…Aldehyde dehydrogenase-2 (ALDH2), a liver mitochondrial enzyme that was initially implicated in the liver alcohol metabolism, has been associated with the pathophysiology of ischemia–reperfusion injury in several organs, including the liver [ 22 , 23 , 24 ]. Several authors reported that the use of Alda-1 (an activator of ALDH2) protects against liver ischemia–reperfusion injury (IRI) in the rat [ 25 , 26 ], but currently, no evidence exists on the direct PEG35 effect as a regulator of mitochondrial ALDH2 in cold old ischemic preservation strategies, although its cytoprotective action was indirectly evidenced when different organ preservation solutions were used for cold storage of fatty liver grafts [ 23 , 24 ]. ALDH2 could play a constitutive housekeeping role essential for the development and regulation of recycling and survival processes as those occurring in cold ischemia preservation [ 22 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Role of PEG35, Mitochondrial ALDH2, and Glutathione in Cold Fatty Liver Graft Preservation: An IGL-2 Approach

Bardallo

Silva

Carbonell

et al. 2021

IJMS

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The total damage inflicted on the liver before transplantation is associated with several surgical manipulations, such as organ recovery, washout of the graft, cold conservation in organ preservation solutions (UW, Celsior, HTK, IGL-1), and rinsing of the organ before implantation. Polyethylene glycol 35 (PEG35) is the oncotic agent present in the IGL-1 solution, which is an alternative to UW and Celsior solutions in liver clinical transplantation. In a model of cold preservation in rats (4 °C; 24 h), we evaluated the effects induced by PEG35 on detoxifying enzymes and nitric oxide, comparing IGL-1 to IGL-0 (which is the same as IGL-1 without PEG). The benefits were also assessed in a new IGL-2 solution characterized by increased concentrations of PEG35 (from 1 g/L to 5 g/L) and glutathione (from 3 mmol/L to 9 mmol/L) compared to IGL-1. We demonstrated that PEG35 promoted the mitochondrial enzyme ALDH2, and in combination with glutathione, prevented the formation of toxic aldehyde adducts (measured as 4-hydroxynonenal) and oxidized proteins (AOPP). In addition, PEG35 promoted the vasodilator factor nitric oxide, which may improve the microcirculatory disturbances in steatotic grafts during preservation and revascularization. All of these results lead to a reduction in damage inflicted on the fatty liver graft during the cold storage preservation. In this communication, we report on the benefits of IGL-2 in hypothermic static preservation, which has already been proved to confer benefits in hypothermic oxygenated dynamic preservation. Hence, the data reported here reinforce the fact that IGL-2 is a suitable alternative to be used as a unique solution/perfusate when hypothermic static and preservation strategies are used, either separately or combined, easing the logistics and avoiding the mixture of different solutions/perfusates, especially when fatty liver grafts are used. Further research regarding new therapeutic and pharmacological insights is needed to explore the underlying mitochondrial mechanisms exerted by PEG35 in static and dynamic graft preservation strategies for clinical liver transplantation purposes.

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“…Although the exact role of autophagy in I/R injury is still under debate, we and other groups have demonstrated that autophagy plays a positive role in protecting I/R injury. 37 , 44 , 45 , 46 , 47 In this study, we showed that elevated autophagy levels are required for the protective effect in Dj-1 deficiency hepatocytes, because inhibition of autophagy by 3-MA and CQ counteracted the hepatoprotective function of Dj-1 deficiency during hepatic I/R injury. Interestingly, like PINK1 and PARKIN, which are frequently mutated in many cases of early-onset familial PD, some DJ-1 mutations also lead to early-onset PD.…”

Section: Discussionmentioning

confidence: 66%

DJ-1 Deficiency in Hepatocytes Improves Liver Ischemia-Reperfusion Injury by Enhancing Mitophagy

Hang

Hao

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims DJ-1 is universally expressed in various tissues and organs and is involved in the physiological processes in various liver diseases. However, the role of DJ-1 in liver ischemia-reperfusion (I/R) injury is largely unknown. Methods In this study, we first examined the DJ-1 expression changes in the liver tissues of mice and clinical donor after hepatic I/R by both quantitative polymerase chain reaction and Western blotting assays. Then we investigated the role of DJ-1 in I/R injury by using a murine liver I/R model. Results We demonstrated that DJ-1 down-regulation in both human and mouse liver tissues in response to I/R injury and Dj-1 deficiency in hepatocytes but not in myeloid cells could significantly ameliorate I/R induced liver injury and inflammatory responses. This hepatoprotective effect was dependent on enhanced autophagy in Dj-1 knockout mice, because inhibition of autophagy by 3-methyladenine and chloroquine could reverse the protective effect on hepatic I/R injury in Dj-1 knockout mice. Conclusions Dj-1 deficiency in hepatocytes significantly enhanced mitochondrial accumulation and protein stability of PARKIN, which in turn promotes the onset of mitophagy resulting in elevated clearance of damaged mitochondria during I/R injury.

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Alda-1 Ameliorates Liver Ischemia-Reperfusion Injury by Activating Aldehyde Dehydrogenase 2 and Enhancing Autophagy in Mice

Cited by 17 publications

References 35 publications

Vinyl chloride-induced interaction of nonalcoholic and toxicant-associated steatohepatitis: Protection by the ALDH2 activator Alda-1

Vinyl chloride-induced interaction of nonalcoholic and toxicant-associated steatohepatitis: Protection by the ALDH2 activator Alda-1

Role of PEG35, Mitochondrial ALDH2, and Glutathione in Cold Fatty Liver Graft Preservation: An IGL-2 Approach

DJ-1 Deficiency in Hepatocytes Improves Liver Ischemia-Reperfusion Injury by Enhancing Mitophagy

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