Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy

Wang, Qiuming; Yin, Xueying; Duan, Zhijun; Guo, Shi‐Bin; Sun, Xiaoyu

doi:10.3892/mmr.2013.1472

Cited by 12 publications

(8 citation statements)

References 38 publications

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“…The reasons for these differences results may be that HO-1 exerts different roles during the progression of liver fibrosis ( 43 ) and that protection is restricted to a narrow HO-1 expression threshold ( 44 ). In the early stages of liver fibrosis, low HO-1 induction may exert a protective action ( 45 ), but in the end stages of cirrhosis with portal hypertension, excessive HO-1 expression deteriorates liver function and aggravates liver cirrhosis ( 43 , 46 , 47 ).…”

Section: Discussionmentioning

confidence: 99%

Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression

Guo

Duan

et al. 2014

Molecular Medicine Reports

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The aim of the present study was to investigate the effects of octreotide treatment on hepatic heme oxygenase-1 (HO-1) expression, together with the influence of altered hepatic HO-1 expression levels on hepatic function and fibrosis in bile duct-ligated rats. The rats were divided randomly into sham, cirrhotic, cobalt protoporphyrin and octreotide treatment groups. The expression levels of hepatic HO-1 mRNA were measured by reverse-transcription polymerase chain reaction, while the protein expression was determined by western blotting and immunohistochemical analysis. Hematoxylin and eosin, and Van Gieson’s staining, along with determination of the hydroxyproline content in the liver, were performed to determine the degree of liver fibrosis. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and carboxyhemoglobin (COHb) in arterial blood, and the mean arterial pressure and portal vein pressure were also measured. As compared with the sham group, hepatic HO-1 mRNA and protein expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood, hydroxyproline and collagen type I content were all significantly increased in the cirrhotic group. As compared with the cirrhotic group, the octreotide-treated group exhibited significantly reduced hepatic HO-1 expression levels, serum levels of ALT, AST and TBIL, COHb in arterial blood and the extent of hepatic fibrosis, whereas the cobalt protoporphyrin group exhibited significantly increased hepatic HO-1 expression levels, as well as aggravated hepatic function and fibrosis (P<0.05). In conclusion, octreotide inhibited hepatic HO-1 overexpression in cirrhotic rats, reduced hepatic HO-1 expression levels to relieve liver injury and attenuated liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression

Guo

Duan

et al. 2014

Molecular Medicine Reports

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“…In line with this, elevated HO-1 protein levels and deranged iron homeostasis are features of the aging brain 19 and overexpression of HO-1 in astrocytes induces senescence 15 and is associated with behavioural abnormalities in mice 20 . Upregulation of HO-1 was also shown in ammonia-treated cultured rat astrocytes 21 , in different animal models for HE 21 22 23 and in post mortem human brain samples of patients with liver cirrhosis and HE 24 . However, whether upregulation of HO-1 contributes to ammonia-induced astrocyte senescence in HE is currently unknown.…”

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confidence: 84%

Ammonia-induced miRNA expression changes in cultured rat astrocytes

Oenarto

Karababa

Castoldi

et al. 2016

Sci Rep

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Hepatic encephalopathy is a neuropsychiatric syndrome evolving from cerebral osmotic disturbances and oxidative/nitrosative stress. Ammonia, the main toxin of hepatic encephalopathy, triggers astrocyte senescence in an oxidative stress-dependent way. As miRNAs are critically involved in cell cycle regulation and their expression may be regulated by oxidative stress, we analysed, whether astrocyte senescence is a consequence of ammonia-induced miRNA expression changes. Using a combined miRNA and gene microarray approach, 43 miRNA species which were downregulated and 142 genes which were upregulated by NH4Cl (5 mmol/l, 48 h) in cultured rat astrocytes were found. Ammonia-induced miRNA and gene expression changes were validated by qPCR and 43 potential miRNA target genes, including HO-1, were identified by matching upregulated mRNA species with predicted targets of miRNA species downregulated by ammonia. Inhibition of HO-1 targeting miRNAs which were downregulated by NH4Cl strongly upregulated HO-1 mRNA and protein levels and inhibited astrocyte proliferation in a HO-1-dependent way. Preventing ammonia-induced upregulation of HO-1 by taurine (5 mmol/l) as well as blocking HO-1 activity by tin-protoporphyrine IX fully prevented ammonia-induced proliferation inhibition and senescence. The data suggest that ammonia induces astrocyte senescence through NADPH oxidase-dependent downregulation of HO-1 targeting miRNAs and concomitant upregulation of HO-1 at both mRNA and protein level.

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“…Interestingly, a recent study showed that systemic application of the HO1 inhibitor Zinc Protoporphyrin (ZnPP) diminished oxidative stress and ameliorated behavioral abnormalities in brain of rats fed with an ammoniumcontaining diet. 53 However, further studies are required to exclude that side effects of ZnPP account for the observed anti-oxidative effects in brain and normalization of behavior in hyperammonemic rats. 53 Besides ammonia, also hypoosmolarity-induced astrocyte swelling triggers ROS formation, 14 upregulation of HO1 37 and senescence 37 in astrocytes.…”

Section: Ho1 and Ammonia-induced Astrocyte Senescencementioning

confidence: 99%

“…53 However, further studies are required to exclude that side effects of ZnPP account for the observed anti-oxidative effects in brain and normalization of behavior in hyperammonemic rats. 53 Besides ammonia, also hypoosmolarity-induced astrocyte swelling triggers ROS formation, 14 upregulation of HO1 37 and senescence 37 in astrocytes. This again underlines the fundamental role of osmotic and oxidative stress in astrocytes for the pathogenesis of HE (Figure 2).…”

Section: Ho1 and Ammonia-induced Astrocyte Senescencementioning

confidence: 99%

Hepatic Encephalopathy and Astrocyte Senescence

Görg

Karababa

Häussinger

2018

Journal of Clinical and Experimental Hepatology

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Hepatic Encephalopathy (HE) is a severe complication of acute or chronic liver diseases with a broad spectrum of neurological symptoms including motor disturbances and cognitive impairment of different severity. Contrary to former beliefs, a growing number of studies suggest that cognitive impairment may not fully reverse after an acute episode of overt HE in patients with liver cirrhosis. The reasons for persistent cognitive impairment in HE are currently unknown but recent observations raise the possibility that astrocyte senescence may play a role here. Astrocyte senescence is closely related to oxidative stress and correlate with irreversible cognitive decline in aging and neurodegenerative diseases. In line with this, surrogate marker for oxidative stress and senescence were upregulated in ammonia-exposed cultured astrocytes and in post mortem brain tissue from patients with liver cirrhosis with but not without HE. Ammonia-induced senescence in astrocytes involves glutamine synthesis-dependent formation of reactive oxygen species (ROS), p53 activation and upregulation of cell cycle inhibitory factors p21 and GADD45a. More recent studies also suggest a role of ROS-induced downregulation of Heme Oxygenase (HO)1-targeting micro RNAs and upregulation of HO1 for ammonia-induced proliferation inhibition in cultured astrocytes. Further studies are required to identify the precise sequence of events that lead to astrocyte senescence and to elucidate functional implications of senescence for cognitive performance in patients with liver cirrhosis and HE.

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Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy

Cited by 12 publications

References 38 publications

Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression

Octreotide attenuates liver fibrosis by inhibiting hepatic heme oxygenase-1 expression

Ammonia-induced miRNA expression changes in cultured rat astrocytes

Hepatic Encephalopathy and Astrocyte Senescence

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