High‐Mobility Group Box‐1 and Liver Disease

Gaskell, Harriet; Ge, Xiaodong; Nieto, Natalia

doi:10.1002/hep4.1223

Cited by 79 publications

(83 citation statements)

References 175 publications

(434 reference statements)

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“…Recent study has shown that hepatic inflammation and fibrogenesis are closely associated with hepatocellular necrosis and apoptosis (Lee & Friedman, ). Consistently, it has been well‐documented that danger signals such as high‐mobility group box‐1 and IL‐33 released from dying cells are critical activators in sterile inflammation that enhances the severity of several liver diseases (Gaskell, Ge, & Nieto, ; Neumann, Schiller, & Tiegs, ). Furthermore, proinflammatory cytokines such as IL‐1β and TNF‐α are closely associated with the progression of ALI because antagonizing these cytokines ameliorates the severity of liver damages induced by CCl 4 exposure (Sato et al, ; Zhu et al, ).…”

Section: Discussionmentioning

confidence: 76%

Dietary zerumbone, a sesquiterpene, ameliorates hepatotoxin‐mediated acute and chronic liver injury in mice

Kim

Yang

Jeong

et al. 2019

Phytotherapy Research

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Acute liver injury (ALI) is a life‐threatening clinical syndrome. Long‐lasting liver injury can lead to chronic hepatic inflammation and fibrogenic responses. Zerumbone (ZER), the main constituent of rhizomes of Zingiber zerumbet Smith, has a variety of functions including anticancer activity. We investigated the role of ZER on the progression of hepatotoxin‐induced liver injury. Single or repeated injection of CCl4 was used to induce acute or chronic liver injury, respectively. Mice were orally administered with ZER (10, 50 mg/kg) during the experimental period. Histopathologic analysis and serum biochemical levels revealed that ZER had hepatoprotective activities against ALI. Similar effects of ZER on injured livers were confirmed by analyses of inflammation and apoptosis‐related genes. Western blot analysis showed that protein levels of apoptotic molecules were decreased, whereas antiapoptotic protein levels were conversely increased in injured livers treated with ZER. Furthermore, chronic liver injury and its associated fibrogenesis in mice were reduced by ZER treatment. These findings from our in vivo experiments further indicate that ZER could alleviate hepatocellular toxicity and inhibit activation of primary hepatic stellate cells. Our results suggest that ZER might have potential as a safe and prophylactic alternative to prevent acute and chronic liver injury.

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Section: Discussionmentioning

confidence: 76%

Dietary zerumbone, a sesquiterpene, ameliorates hepatotoxin‐mediated acute and chronic liver injury in mice

Kim

Yang

Jeong

et al. 2019

Phytotherapy Research

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“…In addition it is equally important to investigate either one of the HMGB1 isoform dominates or regulates the activity of other isoforms (Gaskell et al . ) which is essential to elucidate the importance of HMGB1 in epileptogenesis and to design HMGB1 targeted therapies that specifically focus each HMGB1 isoform.…”

Section: Future Perspective Of Hmgb1mentioning

confidence: 99%

“…Moreover, future HMGB1 antagonist should be designed in a way that it would selectively block to harmful disulfide isoform of HMGB1 overcoming the limitation of currently available HMGB1 antagonist which binds to all the three isoforms of HMGB1 ). In addition it is equally important to investigate either one of the HMGB1 isoform dominates or regulates the activity of other isoforms (Gaskell et al 2018) which is essential to elucidate the importance of HMGB1 in epileptogenesis and to design HMGB1 targeted therapies that specifically focus each HMGB1 isoform.…”

Section: Future Perspective Of Hmgb1mentioning

confidence: 99%

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

Paudel

Semple

Jones

et al. 2019

Journal of Neurochemistry

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Epilepsy is a serious neurological condition exhibiting complex pathology and deserving of more serious attention. More than 30% of people with epilepsy are not responsive to more than 20 anti‐epileptic drugs currently available, reflecting an unmet clinical need for novel therapeutic strategies. Not much is known about the pathogenesis of epilepsy, but evidence indicates that neuroinflammation might contribute to the onset and progression of epilepsy following acquired brain insults. However, the molecular mechanisms underlying these pathophysiological processes are yet to be fully understood. The emerging research suggests that high‐mobility group box protein 1 (HMGB1), a DNA‐binding protein that is both actively secreted by inflammatory cells and released by necrotic cells, might contribute to the pathogenesis of epilepsy. HMGB1 as an initiator and amplifier of neuroinflammation, and its activation is implicated in the propagation of seizures in animal models. The current review will highlight the potential role of HMGB1 in the pathogenesis of epilepsy, and implications of HMGB1‐targeted therapies against epilepsy. HMGB1 in this context is an emerging concept deserving further exploration. Increased understanding of HMGB1 in seizures and epilepsy will pave the way in designing novel and innovative therapeutic strategies that could modify the disease course or prevent its development.

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“…HMGB1 is a non-histone nuclear protein that facilitates the binding of regulatory proteins to DNA and typically enhances transcriptional activation 10 . When released extracellularly, HMGB1 can binds to one of its receptors, such as RAGE or TLR4 36 . In our previous study, Atg7-/- mice develop hepatic tumors at 9-month old in the liver, which could be inhbited by the deletion of either Hmgb1 or Rage 2 .…”

Section: Resultsmentioning

confidence: 99%

The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors

Khambu

Hong

Liu

et al. 2019

Preprint

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AbstractAutophagy is an intracellular lysosomal degradative pathway important for tumor surveillance. Autophagy deficiency can lead to tumorigenesis. Autophagy is also known to be important for the aggressive growth of tumors, yet the mechanism that sustains the growth of autophagy-deficient tumors is not known. We previously reported that progression of hepatic tumors developed in autophagy-deficient livers required high mobility group box 1 (HMGB1) that is released from autophagy-deficient hepatocytes. However, the mechanism by which HMGB1 promotes hepatic tumorigenesis is not understood. In this study we examined the pathological features of the hepatic tumors and the mechanism of HMGB1-mediated tumorigenesis using liver-specific autophagy-deficient (Atg7-/-) and Atg7-/-/Hmgb1-/- mice. We found that in Atg7-/- mice the tumors cells were still deficient in autophagy and could also release HMGB1. Histological analysis using cell-specific markers suggested that fibroblast and ductular cells were present only outside the tumor whereas macrophages were present both inside and outside the tumor. Genetic deletion of HMGB1 or one of its receptors, receptor for advanced glycated end product (Rage), retarded liver tumor development. In addition, we found that expression of RAGE was only on ductual cells and Kupffer’s cells but not on hepatoctyes, which suggested that HMGB1 might promote hepatic tumor growth through a paracrine mode that altered the tumor microenvironment. Furthermore, HMGB1 and RAGE enhanced the proliferation capability of the autophagy-deficient hepatocytes and tumors. Finally, RNAseq analysis of the tumors indicated that HMGB1 induced a much broad changes in tumors. In particular, genes related to mitochondrial structures or functions were enriched among those differentially expressed in tumors in the presence or absence of HMGB1, revealing a potential key role of mitochondria in sustaining the growth of autophagy-deficient liver tumors via HMGB1 stimulation.

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High‐Mobility Group Box‐1 and Liver Disease

Cited by 79 publications

References 175 publications

Dietary zerumbone, a sesquiterpene, ameliorates hepatotoxin‐mediated acute and chronic liver injury in mice

Dietary zerumbone, a sesquiterpene, ameliorates hepatotoxin‐mediated acute and chronic liver injury in mice

High mobility group box 1 (HMGB1) as a novel frontier in epileptogenesis: from pathogenesis to therapeutic approaches

The HMGB1-RAGE axis modulates the growth of autophagy-deficient hepatic tumors

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