Dose-Related Induction of Hepatic Preneoplastic Lesions by Diethylnitrosamine in C57BL/6 Mice

Kushida, Masahiko; Kamendulis, Lisa M.; Peat, Tyler J.; Klaunig, James E.

doi:10.1177/0192623311409596

Cited by 40 publications

(36 citation statements)

References 27 publications

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“…The naked mole rat is not an inbred strain, but breeding occurs between related individuals. C57BL/6 mice are a standard inbred strain, and have low susceptibility to tumors [23,24]. Therefore, the inbred C57BL/6 mouse strain was used in this comparative study.…”

Section: Discussionmentioning

confidence: 99%

High Autophagy in the Naked Mole Rat may Play a Significant Role in Maintaining Good Health

Zhao

Lin

Kan

et al. 2014

Cell Physiol Biochem

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Background/Aims: The maximum lifespan of the naked mole rat is over 28.3 years, which exceeds that of any other rodent species, suggesting that age-related changes in its body composition and functionality are either attenuated or delayed in this extraordinarily long-lived species. However, the mechanisms underlying the aging process in this species are poorly understood. In this study, we investigated whether long-lived naked mole rats display more autophagic activity than short-lived mice. Methods: Hepatic stellate cells isolated from naked mole rats were treated with 50 nM rapamycin or 20 mM 3-methyladenine (3-MA) for 12 or 24 h. Expression of the autophagy marker proteins LC3-II and beclin 1 was measured with western blotting and immunohistochemistry. The induction of apoptosis was analyzed by flow cytometry. Results: Our results demonstrate that one-day-old naked mole rats have higher levels of autophagy than one-day-old short-lived C57BL/6 mice, and that both adult naked mole rats (eight months old) and adult C57BL/6 mice (eight weeks old) have high basal levels of autophagy, which may be an important mechanism inhibiting aging and reducing the risk of age-related diseases. Conclusion: Here, we report that autophagy facilitated the survival of hepatic stellate cells from the naked mole rat, and that treatment with 3-MA or rapamycin increased the ratio of apoptotic cells to normal hepatic stellate cells.

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Section: Discussionmentioning

confidence: 99%

High Autophagy in the Naked Mole Rat may Play a Significant Role in Maintaining Good Health

Zhao

Lin

Kan

et al. 2014

Cell Physiol Biochem

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“…These can be considered as a spectrum of pre-neoplastic and neoplastic lesions. The pre-neoplastic lesions (foci of cellular alteration, non-regenerative and regenerative hyperplastic nodules) have been used as early markers of hepatic carcinogenesis in the mouse in short and medium-term carcinogenicity studies [20]. …”

Section: Methodsmentioning

confidence: 99%

A Multi-Mineral Natural Product Inhibits Liver Tumor Formation in C57BL/6 Mice

Aslam

Bergin

Naik

et al. 2012

Biol Trace Elem Res

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C57BL/6 mice were maintained for up to 18-months on high-fat and low-fat diets with or without a multi-mineral-supplement derived from the skeletal remains of the red marine algae Lithothamnion calcareum. Numerous grossly observable liver masses were visible in animals on the “western-style” high-fat diet sacrificed at 12 and 18 months. The majority of the masses were in male mice (20 out of 100 males versus 3 out of 100 females; p=0.0002). There were more liver masses in animals on the high-fat diet than on the low-fat diet (15 out of 50 on high-fat versus 5 out of 50 on low-fat; p=0.0254). The multi-mineral supplement reduced the number of liver masses in mice on both diets (3 out of 25 male mice in the low-fat diet group without the supplement versus 1 out of 25 mice with supplement; 12 of 25 male mice in the high-fat diet group without the supplement versus 3 of 25 mice with supplement [p=0.0129]). Histological evaluation revealed a total of 17 neoplastic lesions (9 adenomas and 8 hepatocellular carcinomas), and 18 pre-neoplastic lesions. Out of 8 hepatocellular carcinomas, 7 were found in unsupplemented diet groups. Steatosis was widely observed in livers with and without grossly observable masses, but the multi-mineral supplement had no effect on the incidence of steatosis or its severity. Taken together, these findings suggest that a multi-mineral-rich natural product can protect mice against neoplastic and pre-neoplastic proliferative liver lesions that may develop in the face of steatosis.

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“…The physiological roles of NNT are more complicated than previously thought. C57BL/6J mice are protected from chemical carcinogenesis than other mouse strains, in terms of initiation and growth of preneoplastic and neoplastic lesions [15], [16], [17]. It is speculative that NNT may play a growth-regulatory role in cancer.…”

Section: Introductionmentioning

confidence: 99%

Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation

Lin

et al. 2017

Redox Biology

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To study the physiological roles of NADH and NADPH homeostasis in cancer, we studied the effect of NNT knockdown on physiology of SK-Hep1 cells. NNT knockdown cells show limited abilities to maintain NAD+ and NADPH levels and have reduced proliferation and tumorigenicity. There is an increased dependence of energy production on oxidative phosphorylation. Studies with stable isotope tracers have revealed that under the new steady-state metabolic condition, the fluxes of TCA and glycolysis decrease while that of reductive carboxylation increases. Increased [α-ketoglutarate]/[succinate] ratio in NNT-deficient cells results in decrease in HIF-1α level and expression of HIF-1α regulated genes. Reduction in NADPH level leads to repression of HDAC1 activity and an increase in p53 acetylation. These findings suggest that NNT is essential to homeostasis of NADH and NADPH pools, anomalies of which affect HIF-1α- and HDAC1-dependent pathways, and hence retrograde response of mitochondria.

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Dose-Related Induction of Hepatic Preneoplastic Lesions by Diethylnitrosamine in C57BL/6 Mice

Cited by 40 publications

References 27 publications

High Autophagy in the Naked Mole Rat may Play a Significant Role in Maintaining Good Health

High Autophagy in the Naked Mole Rat may Play a Significant Role in Maintaining Good Health

A Multi-Mineral Natural Product Inhibits Liver Tumor Formation in C57BL/6 Mice

Nicotinamide nucleotide transhydrogenase (NNT) deficiency dysregulates mitochondrial retrograde signaling and impedes proliferation

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