Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration

Viswanathan, Preeti; Sharma, Yogeshwar; Gupta, Prem K.; Gupta, Sanjeev

doi:10.1111/cpr.12445

Cited by 22 publications

(22 citation statements)

References 57 publications

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“…As preservation of MMP is an excellent indicator of mitochondrial health, this property was examined first. Use of JC-1 dye for elucidating effect of oxidative stress, as previously demonstrated for other cell types, 45 indicated MMP levels in BOS-treated LSEC, even under basal conditions, were greater than control LSEC (Fig. 3A).…”

Section: Mitochondrial Viability and The Atm Pathway Were Affected Bysupporting

confidence: 68%

“…Importantly, inflammatory cytokines and growth factors may regulate the ATM pathway, along with other related events and processes during liver injury. 45,48,49 For instance, deficiency of ATM is responsible for damage to mitochondria, and characterizes a significant mechanism for failed liver regeneration in acute liver failure. 45 As loss of LSEC is integral to such liver injuries, restoring health to EC with drugs should be highly significant.…”

Section: Discussionmentioning

confidence: 99%

“…45,48,49 For instance, deficiency of ATM is responsible for damage to mitochondria, and characterizes a significant mechanism for failed liver regeneration in acute liver failure. 45 As loss of LSEC is integral to such liver injuries, restoring health to EC with drugs should be highly significant. The ability of drug-modified LSEC for reconstitution of liver will be significant for potential cell therapy applications in hepatic injury.…”

Section: Discussionmentioning

confidence: 99%

“…In DNA damage settings, the ATM pathway regulates cell survival and proliferation. 45 Recently, ATM and partners were found to be critical for mitochondrial biogenesis and also function. 39,40,46,47 To identify whether these processes were involved in ET A/B antagonism, phosphorylated ATM was localized, along with NBS1, a component of MRE11/ RAD50/NBS1 complex in DNA double-strand breaks, and Chk2 kinase, a downstream ATM transducer and mitosis inhibitor after DNA damage.…”

Section: Mitochondrial Viability and The Atm Pathway Were Affected Bymentioning

confidence: 99%

“…[35][36][37][38] Recently, ataxia telangiectasia mutated (ATM) protein, which oversees DNA protection, has been associated with mitochondrial homeostasis. [39][40][41] This molecular context should be significant for the role of ET-1 in transplanted cells.…”

Section: Introductionmentioning

confidence: 99%

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Efficient Reconstitution of Hepatic Microvasculature by Endothelin Receptor Antagonism in Liver Sinusoidal Endothelial Cells

et al. 2019

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Reconstitution of healthy endothelial cells in vascular beds offers opportunities for mechanisms in tissue homeostasis, organ regeneration, and correction of deficient functions. Liver sinusoidal endothelial cells express unique functions, and their transplantation is relevant for disease models and for cell therapy. As molecular targets for improving transplanted cell engraftment and proliferation will be highly significant, this study determined whether ET A/B receptor antagonism by the drug bosentan could overcome cell losses due to cell transplantation-induced cytotoxicity. Cell engraftment and proliferation assays were performed with healthy wild-type liver sinusoidal endothelial cells transplanted into the liver of dipeptidylpeptidase IV knockout mice. Transplanted cells were identified in tissues by enzyme histochemistry. Cells with prospective ET A/B antagonism engrafted significantly better in hepatic sinusoids. Moreover, these cells underwent multiple rounds of division under liver repopulation conditions. The gains of ET A/B antagonism resulted from benefits in cell viability and membrane integrity. Also, in bosentan-treated cells, mitochondrial homeostasis was better maintained with less oxidative stress and DNA damage after injuries. Intracellular effects of ET A/B antagonism were transduced by conservation of ataxia telangiectasia mutated protein, which directs DNA damage response. Therefore, ET A/B antagonism in donor cells will advance vascular reconstitution. Extensive experience with ET A/B antagonists will facilitate translation in people.

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Section: Mitochondrial Viability and The Atm Pathway Were Affected Bysupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mitochondrial Viability and The Atm Pathway Were Affected Bymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficient Reconstitution of Hepatic Microvasculature by Endothelin Receptor Antagonism in Liver Sinusoidal Endothelial Cells

et al. 2019

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Liver regeneration after injury: Mechanisms, cellular interactions and therapeutic innovations

Liu,

Wang,

et al. 2024

Clinical & Translational Med

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The liver possesses a distinctive capacity for regeneration within the human body. Under normal circumstances, liver cells replicate themselves to maintain liver function. Compensatory replication of healthy hepatocytes is sufficient for the regeneration after acute liver injuries. In the late stage of chronic liver damage, a large number of hepatocytes die and hepatocyte replication is blocked. Liver regeneration has more complex mechanisms, such as the transdifferentiation between cell types or hepatic progenitor cells mediated. Dysregulation of liver regeneration causes severe chronic liver disease. Gaining a more comprehensive understanding of liver regeneration mechanisms would facilitate the advancement of efficient therapeutic approaches. This review provides an overview of the signalling pathways linked to different aspects of liver regeneration in various liver diseases. Moreover, new knowledge on cellular interactions during the regenerative process is also presented. Finally, this paper explores the potential applications of new technologies, such as nanotechnology, stem cell transplantation and organoids, in liver regeneration after injury, offering fresh perspectives on treating liver disease.

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EGR1 is crucial for the chlorogenic acid–provided promotion on liver regeneration and repair after APAP-induced liver injury

Wei

et al. 2023

Cell Biol Toxicol

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Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration

Abstract: Cell cycle lesions following mitochondrial and DNA damage led to failure of hepatic regeneration in acetaminophen toxicity but their reversibility offers molecular targets for treating acute liver failure.

Cited by 22 publications

References 57 publications

Efficient Reconstitution of Hepatic Microvasculature by Endothelin Receptor Antagonism in Liver Sinusoidal Endothelial Cells

Efficient Reconstitution of Hepatic Microvasculature by Endothelin Receptor Antagonism in Liver Sinusoidal Endothelial Cells

Liver regeneration after injury: Mechanisms, cellular interactions and therapeutic innovations

EGR1 is crucial for the chlorogenic acid–provided promotion on liver regeneration and repair after APAP-induced liver injury

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