Molecular mechanism investigation of cycloheximide-induced hepatocyte apoptosis in rat livers by morphological and microarray analysis

Ito, Kazumi; Kiyosawa, Naoki; Kumagai, Kazuyoshi; Manabe, Sunao; Matsunuma, Naochika; Yamoto, Takashi

doi:10.1016/j.tox.2005.11.017

Cited by 37 publications

(33 citation statements)

References 51 publications

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“…Cycloheximide was capable of inducing macrophage cell death, but in contrast to everolimus, apoptosis and not autophagy was induced. This finding confirms earlier studies demonstrating that cycloheximide, independently of other stimuli, is capable of triggering apoptotic cell death in both cultured cells (Martin et al, 1990;Blom et al, 1999;Wu et al, 2004) and tissue (Ledda-Columbano et al, 1992;Alessenko et al, 1997;Higami et al, 2000;Ito et al, 2006). Cycloheximide is widely used in cell death research, but the detailed mechanism of cycloheximide-induced apoptosis re- jpet.aspetjournals.org mains unclear.…”

Section: Discussionsupporting

confidence: 88%

Selective Clearance of Macrophages in Atherosclerotic Plaques by the Protein Synthesis Inhibitor Cycloheximide

Croons¹,

Martinet²,

Herman³

et al. 2006

J Pharmacol Exp Ther

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Macrophages are an essential component of unstable atherosclerotic plaques and play a pivotal role in the destabilization process. We have demonstrated previously that local delivery of the mammalian target of rapamycin (mTOR) inhibitor everolimus selectively clears macrophages in rabbit plaques. Because mTOR controls mRNA translation, inhibition of protein synthesis might induce selective macrophage cell death. We therefore investigated in the present study the effect of the protein synthesis inhibitor cycloheximide on macrophage and smooth muscle cell (SMC) viability. In vitro studies with cultured macrophages and SMCs showed that cycloheximide induced selective apoptosis of macrophages in a concentration-and time-dependent manner. Moreover, macrophages could be selectively depleted in rabbit carotid artery rings with collarinduced atherosclerotic plaques after in vitro treatment with cycloheximide. Local in vivo administration of cycloheximide via osmotic minipumps to rabbit carotid arteries with collarinduced atherosclerotic plaques significantly reduced the macrophage but not the SMC content. Cycloheximide-treated plaques showed signs of apoptosis (increased terminal deoxynucleotidyl transferase end labeling and fluorescein isothiocyanate-Val-Ala-DL-Asp(O-methyl)-fluoromethylketone labeling) that did not colocalize with SMCs. Organ chamber studies demonstrated that the functionality of SMCs and the endothelium were not influenced by cycloheximide treatment. All together, these findings demonstrate that cycloheximide decreases the macrophage load in atherosclerotic plaques by induction of apoptosis without changing SMC content or contractility.

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Section: Discussionsupporting

confidence: 88%

Selective Clearance of Macrophages in Atherosclerotic Plaques by the Protein Synthesis Inhibitor Cycloheximide

Croons¹,

Martinet²,

Herman³

et al. 2006

J Pharmacol Exp Ther

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“…Consistent with this hypothesis, administration of variously proposed second hits (e.g. endotoxin and prooxidants) results in significantly greater liver damage and lethality in obese mice with fatty liver compared to lean mice with healthy livers [16][17][18]. Furthermore, in humans, the severity of steatosis is one of the strongest predictors of the development of NASH [19].…”

Section: Two-hit Hypothesismentioning

confidence: 77%

The role of fatty acids in the development and progression of nonalcoholic fatty liver disease

Gentile

Pagliassotti

2008

The Journal of Nutritional Biochemistry

204

156

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“…b-cell apoptosis ensues from strong prolonged triggers for ER stress in vitro including exposure to chemicals that directly cause protein misfolding such as tunicamycin (inhibitor of N-glycosylation in the ER) and thapsigargin (disturbs SERCA-mediated Ca 2C retention in the ER) or environmental factors such as cytokines and glucolipotoxicity (Oyadomari et al 2002, Contreras et al 2003, Cardozo et al 2005, Endo et al 2006, Ito et al 2006, Cunha et al 2008, Papa 2012, Yang et al 2013. There are several mechanisms by which UPR signalling that is above a threshold drives b-cell apoptosis with the most important being PERK/ATF4-mediated activation of CHOP and IRE1a/TRAF2/ASK1-mediated activation of JNK (reviewed in Papa (2012)).…”

Section: Intrinsic Er Functionsmentioning

confidence: 99%

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes

Hasnain¹,

Prins²,

McGuckin³

2015

Journal of Molecular Endocrinology

220

180

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The inability of pancreatic b-cells to make sufficient insulin to control blood sugar is a central feature of the aetiology of most forms of diabetes. In this review we focus on the deleterious effects of oxidative stress and endoplasmic reticulum (ER) stress on b-cell insulin biosynthesis and secretion and on inflammatory signalling and apoptosis with a particular emphasis on type 2 diabetes (T2D). We argue that oxidative stress and ER stress are closely entwined phenomena fundamentally involved in b-cell dysfunction by direct effects on insulin biosynthesis and due to consequences of the ER stress-induced unfolded protein response. We summarise evidence that, although these phenomenon can be driven by intrinsic b-cell defects in rare forms of diabetes, in T2D b-cell stress is driven by a range of local environmental factors including increased drivers of insulin biosynthesis, glucolipotoxicity and inflammatory cytokines. We describe our recent findings that a range of inflammatory cytokines contribute to b-cell stress in diabetes and our discovery that interleukin 22 protects b-cells from oxidative stress regardless of the environmental triggers and can correct much of diabetes pathophysiology in animal models. Finally we summarise evidence that b-cell dysfunction is reversible in T2D and discuss therapeutic opportunities for relieving oxidative and ER stress and restoring glycaemic control.

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Molecular mechanism investigation of cycloheximide-induced hepatocyte apoptosis in rat livers by morphological and microarray analysis

Cited by 37 publications

References 51 publications

Selective Clearance of Macrophages in Atherosclerotic Plaques by the Protein Synthesis Inhibitor Cycloheximide

Selective Clearance of Macrophages in Atherosclerotic Plaques by the Protein Synthesis Inhibitor Cycloheximide

The role of fatty acids in the development and progression of nonalcoholic fatty liver disease

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes

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