Regeneration in acute-on-chronic liver failure – the phantom lost its camouflage

Engelmann, Cornelius; Mehta, Gautam; Tacke, Frank

doi:10.1016/j.jhep.2020.01.003

Cited by 11 publications

(12 citation statements)

References 23 publications

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“…Traditional Chinese medicines have received attention worldwide in last few decades because of their satisfactory therapeutic effects, facile availability, and cost-effectiveness (Bajaj et al, 2018;Engelmann et al, 2020). Our previous study confirmed that the treatment with Yi-Qi-Jian-Pi Formula (YQJPF) composed of Huangqi, Taizishen, Baizhu, Chenpi, Danggui, Fulin, Huangqin, and Gancao can ameliorate HBV-ACLF.…”

Section: Introductionsupporting

confidence: 55%

Yi-Qi-Jian-Pi Formula Suppresses RIPK1/RIPK3-Complex-Dependent Necroptosis of Hepatocytes Through ROS Signaling and Attenuates Liver Injury in Vivo and in Vitro

et al. 2021

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Acute-on-chronic liver failure (ACLF) is described as a characteristic of acute jaundice and coagulation dysfunction. Effective treatments for ACLF are unavailable and hence are urgently required. We aimed to define the effect of Yi-Qi-Jian-Pi Formula (YQJPF) on liver injury and further examine the molecular mechanisms. In this study, we established CCl4-, LPS-, and d-galactosamine (D-Gal)-induced ACLF rat models in vivo and LPS- and D-Gal-induced hepatocyte injury models in vitro. We found that YQJPF significantly ameliorates liver injury in vivo and in vitro that is associated with the regulation of hepatocyte necroptosis. Specifically, YQJPF decreased expression of receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3) and pseudokinase mixed lineage kinase domain-like (MLKL) to inhibit the migration of RIPK1 and RIPK3 into necrosome. YQJPF also reduces the expression of inflammatory cytokines IL-6, IL-8, IL-1β, and TNF-α, which were regulated by RIPK3 mediates cell death. RIPK1 depletion was found to enhance the protective effect of YQJPF. Furthermore, we showed that YQJPF significantly downregulates the mitochondrial reactive oxygen species (ROS) production and mitochondrial depolarization, with ROS scavenger, 4-hydroxy-TEMPO treatment recovering impaired RIPK1-mediated necroptosis and reducing the expression of IL-6, IL-8, IL-1β, and TNF-α. In summary, our study revealed the molecular mechanism of protective effect of YQJPF on hepatocyte necroptosis, targeting RIPK1/RIPK3-complex-dependent necroptosis via ROS signaling. Overall, our results provided a novel perspective to indicate the positive role of YQJPF in ACLF.

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Section: Introductionsupporting

confidence: 55%

Yi-Qi-Jian-Pi Formula Suppresses RIPK1/RIPK3-Complex-Dependent Necroptosis of Hepatocytes Through ROS Signaling and Attenuates Liver Injury in Vivo and in Vitro

et al. 2021

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“…Despite the availability of animal models representing liver diseases such as acute liver failure, CLDs, and fulminant hepatic failure ( Shi et al, 2017 ; Nevzorova et al, 2020 ), ACLF remains a severe clinical entity, necessitating the establishment of appropriate and reliable animal model, as the availability of such animal model is crucial to fully understand ACLF disease pathogenesis. The key elements in establishing such a model are to initiate liver fibrosis or its advanced form cirrhosis, which represents the common final pathway of most types of CLDs ( Engelmann et al, 2020 ), followed by acute insult to ultimately develop ACLF. At present, available animal models that accurately mimic ACLF are rare, and the currently available models are inconsistent with ACLF pathophysiology.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomics reveals immune-metabolism disorder in acute-on-chronic liver failure in rats

et al. 2021

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Acute-on-chronic liver failure (ACLF) is clinical syndrome with high mortality rate. This study aimed to perform detailed transcriptomic analysis in liver cirrhosis–based ACLF rats to elucidate ACLF pathogenesis. ACLF was induced by combined porcine serum with D-galactosamine and lipopolysaccharide. Gene expression profile of liver tissues from ACLF rats was generated by transcriptome sequencing to reveal the molecular mechanism. ACLF rats successfully developed with typical characteristics. Total of 2,354/3,576 differentially expressed genes were identified when ACLF was compared to liver cirrhosis and normal control, separately. The functional synergy analysis revealed prominent immune dysregulation at ACLF stage, whereas metabolic disruption was significantly down-regulated. Relative proportions of innate immune–related cells showed significant elevation of monocytes and macrophages, whereas adaptive immune–related cells were reduced. The seven differentially expressed genes underlying the ACLF molecular mechanisms were externally validated, among them THBS1, IL-10, and NR4A3 expressions were confirmed in rats, patient transcriptomics, and liver biopsies, verifying their potential value in the ACLF pathogenesis. This study indicates immune-metabolism disorder in ACLF rats, which may provide clinicians new targets for improving intervention strategies.

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“…This is not, however, entirely consistent with ACLF pathogenesis, and the surgery required for the BDL model is difficult. The clinical situation is often more complex, and different modulating factors may occur concurrently or sequentially[ 86 ]. Typically, 50% of patients develop bacterial infection as an ACLF complication, although the (initial) precipitating event was non-inflammatory[ 87 ].…”

Section: Disadvantages and Challenges Of Aclf Animal Modelsmentioning

confidence: 99%

“…The significant challenge to develop an ACLF model is the ability to unite all the clinical characteristics observed in humans, as this is a multifactorial disease with multiple precipitators and complications and, therefore, varying disease phenotypes and organ failures, making it almost impossible to develop a single experimental model capable of triggering all of the most important clinical features[ 86 ]. In a recent study by Xiang and coworkers (2020), the authors developed a new ACLF model that could sequentially reproduce three important clinical ACLF disease factors.…”

Section: Disadvantages and Challenges Of Aclf Animal Modelsmentioning

confidence: 99%

Animal models applied to acute-on-chronic liver failure: Are new models required to understand the human condition?

Gama¹,

Cardoso²,

Lagrota-Candido³

et al. 2022

WJCC

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The liver is a multifaceted organ; its location and detoxifying function expose this organ to countless injuries. Acute-on-chronic failure liver (ACLF) is a severe syndrome that affects the liver due to acute decompensation in patients with chronic liver disease. An infection environment, ascites, increased liver enzymes and prothrombin time, encephalopathy and fast-evolving multiorgan failure, leading to death, usually accompany this. The pathophysiology remains poorly understand. In this context, animal models become a very useful tool in this regard, as understanding; the disease may be helpful in developing novel therapeutic methodologies for ACLF. However, although animal models display several similarities to the human condition, they do not represent all ACLF manifestations, resulting in significant challenges. An initial liver cirrhosis framework followed by the induction of an acute decompensation by administering lipopolysaccharide and D-GaIN, potentiating liver damage supports the methodologies applied to induce experimental ACLF. The entire methodology has been described mostly for rats. Nevertheless, a quick PubMed database search indicates about 30 studies concerning ACFL models and over 1000 regarding acute liver failure models. These findings demonstrate the clear need to establish easily reproducible ACFL models to elucidate questions about this quickly established and often fatal syndrome.

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Regeneration in acute-on-chronic liver failure – the phantom lost its camouflage

Cited by 11 publications

References 23 publications

Yi-Qi-Jian-Pi Formula Suppresses RIPK1/RIPK3-Complex-Dependent Necroptosis of Hepatocytes Through ROS Signaling and Attenuates Liver Injury in Vivo and in Vitro

Yi-Qi-Jian-Pi Formula Suppresses RIPK1/RIPK3-Complex-Dependent Necroptosis of Hepatocytes Through ROS Signaling and Attenuates Liver Injury in Vivo and in Vitro

Transcriptomics reveals immune-metabolism disorder in acute-on-chronic liver failure in rats

Animal models applied to acute-on-chronic liver failure: Are new models required to understand the human condition?

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