Vitamin C deficiency increases the binucleation of hepatocytes in SMP30 knock‐out mice

Park, Jin‐Kyu; Hong, Il-Hwa; Ki, Mi-Ran; Chung, Habong; Ishigami, Akihito; Ji, Ae-Ri; Goo, Moon-Jung; Kim, Dong Hwan; Kwak, Ji-Hoon; Min, Chang-Woo; Lee, Seung-Sook; Jeong, Kyu‐Shik

doi:10.1111/j.1440-1746.2010.06239.x

Cited by 13 publications

(14 citation statements)

References 33 publications

(78 reference statements)

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“…2009). These characteristics were observed repeatedly in our own several previous studies (Park et al. 2010a,b), which confirms that vitamin C‐deficient SMP30 mice have a less robust phenotype compared with WT mice.…”

Section: Discussionsupporting

confidence: 84%

Vitamin C deficiency accelerates bone loss inducing an increase in PPAR‐γ expression in SMP30 knockout mice

Park

Lee

Kim

et al. 2012

Int J Experimental Path

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Senescence marker protein (SMP) 30 knockout (KO) mice display symptoms of scurvy, including spontaneous bone fractures, and this was considered to be induced by a failure of collagen synthesis owing to vitamin C deficiency. However, low bone mineral density is also known to be associated with spontaneous bone fracture. Therefore, we investigated the effects of vitamin C deficiency on the balance between osteoblasts and osteoclasts in SMP30 KO mice as evidenced by histopathology. All mice were fed a vitamin C-free diet, and only one group (KV) mice were given water containing 1.5 g/l of vitamin C, whereas wild-type (WT) and KO mice were given normal drinking tap water without vitamin C for 16 weeks. After 16 weeks, all femur samples were removed for histopathological examination. The femurs of KO mice showed significantly reduced bone area and decreased number of osteoblasts compared with those of WT mice and KV mice. KO mice also exhibited the lowest level of alkaline phosphatase (ALP) expression in their femurs. However, KO mice showed the most elevated expression of the receptor activator of nuclear factor kappa-B ligand (RANKL). Moreover, KO mice had the strongest peroxisome proliferator-activated receptor (PPAR)-γ expression level in their osteoblasts and the highest number of TUNEL-positive bone marrow cells. Therefore, we concluded that vitamin C deficiency plays an important role in spontaneous bone fracture by inhibiting osteoblast differentiation and promoting transition of osteoblasts to adipocytes, and this could in turn be related to the increased PPAR-γ expression.

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Section: Discussionsupporting

confidence: 84%

Vitamin C deficiency accelerates bone loss inducing an increase in PPAR‐γ expression in SMP30 knockout mice

Park

Lee

Kim

et al. 2012

Int J Experimental Path

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“…In another study, scavenging of ROS during fetal-neonatal transition resulted in a decrease in the number of binucleated cardiomyocytes (Matsuyama and Kawahara, 2011). A correlative in vivo study was performed in mice, where the authors showed that vitamin C deficiency induces elevated ROS production, which causes oxidative liver injury and the increase of BN hepatocytes (Park et al, 2010). These data indicate a correlation between ROS and BN formation although it is still not known whether there is a direct causal effect.…”

Section: Discussionmentioning

confidence: 91%

Smooth Muscle Cells Isolated from Thoracic Aortic Aneurysms Exhibit Increased Genomic Damage, but Similar Tendency for Apoptosis

Acılan

Serhatlı

Kaçar

et al. 2012

DNA and Cell Biology

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Aortic aneurysms (AA) are characterized by structural deterioration leading to progressive dilation. During the development of AA, two key structural changes are pronounced, one being degradation of extracellular matrix and the other loss of smooth muscle cells (SMCs) through apoptosis. Reactive oxygen species (ROS) are produced above physiological levels in dilated (aneurismal) part of the aorta compared to the nondilated part and they are known to be associated with both the extracellular matrix degradation and the loss of SMCs. In this study, we hypothesized that aneurismal SMCs are more prone to apoptosis and that at least some cells undergo apoptosis due to elevated ROS in the aortic wall. To test this hypothesis, we first isolated SMCs from thoracic aneurismal tissue and compared their apoptotic tendency with normal SMCs in response to H 2 O 2 , oxidized sterol, or UV treatment. Exposed cells exhibited morphological changes characteristic of apoptosis, such as cell shrinkage, membrane blebbing, chromatin condensation, and DNA fragmentation. Terminal deoxynucleotidyl transferased UTP nick end labeling (TUNEL) further confirmed the fragmentation of nuclear DNA in these cells. Vascular SMCs were analyzed for their micronuclei (MN) and binucleate (BN) frequency as indicators of genomic abnormality. These data were then compared to patient parameters, including age, gender, hypertension, or aortic diameter for existing correlations. While the tendency for apoptosis was not significantly different compared to normal cells, both the %MN and %BN were higher in aneurismal SMCs. The data suggest that there is increased DNA damage in TAA samples, which might play a pivotal role in disease development.

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“…In these cases, the increase in binucleation could be linked to hepatic recovery processes following toxic injury 114 and usually as a result of oxidative stress generation 114,115 . Confirming the results that present a role of oxidative stress in liver binucleation, it has been already published that vitamin C deficiency induced an increase of cytochrome P450 2E1 (CYP2E1) expression and elevated ROS production, which causes oxidative liver injury and the elevation of hepatocyte binucleation in senescence marker protein 30 (SMP30) knock-out mice 116 .…”

Section: Binucleation and Chemical-driven Liver Damagementioning

confidence: 53%

Regulation of cytokinesis and its clinical significance

Tormos¹,

Taléns‐Visconti

Sastre³

2015

Critical Reviews in Clinical Laboratory Sciences

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Dysregulation of the cell cycle leads to polyploid cells, which are classified into mononuclear or binuclear polyploid cells depending on the number of nuclei. Polyploidy is common in plants and in animals. Physiologically, polyploidy and binucleation are differentiation markers and also features of the aging process. In fact, although they provide multiple copies of genes required for survival, a negative correlation between growth capacity and polyploidy has been reported, and thus, suppression or reversal of this phenomenon may be a growth advantage. On the other hand, unscheduled polyploidization may cause genomic instability that might lead to neoplastic aneuploidy. The aim of this review is to analyze the mechanisms that lead to polyploidy, and particularly binucleation, and highlight the potential of ploidy as a marker of illness severity or the success of the adaptive response for an injury, with special emphasis in the liver under physiological and pathological conditions. Hepatocyte binucleation occurs in late fetal development and postnatal maturation, especially after weaning via phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt). It also increases upon aging of the liver as well as in liver cirrhosis and cancer. Liver binucleation mainly indicates the severity of the damage. Furthermore, the eventual increase in hepatocyte binucleation points out compensatory proliferation associated with liver injury. Ploidy conveyor would also permit hepatocyte adaptation to xenobiotic or nutritional injury. In contrast, polyploidy is a feature of many human cancers, and it may predispose to genomic instability and generation of aneuploidization that play a major role in carcinogenesis. Finally, a better understanding of the polyploidization process is needed in order to approach clinical research but also, to get deeper knowledge of cell cycle control. The fascinating regulation of cell cycle in liver and the generation and reversal of ploidies will provide more clues for the mystery of liver regeneration.

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Vitamin C deficiency increases the binucleation of hepatocytes in SMP30 knock‐out mice

Abstract: Therefore, it is concluded that vitamin C deficiency induces an increase of CYP2E1 expression and elevated ROS production, which causes oxidative liver injury and the elevation of hepatocyte binucleation in SMP30 KO mice.

Cited by 13 publications

References 33 publications

Vitamin C deficiency accelerates bone loss inducing an increase in PPAR‐γ expression in SMP30 knockout mice

Vitamin C deficiency accelerates bone loss inducing an increase in PPAR‐γ expression in SMP30 knockout mice

Smooth Muscle Cells Isolated from Thoracic Aortic Aneurysms Exhibit Increased Genomic Damage, but Similar Tendency for Apoptosis

Regulation of cytokinesis and its clinical significance

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