Proceedings of the Japan Academy, Series B

Review

Hepatitis C virus utilizes lipid droplet for production of infectious virus

Kazuya OGAWA, Takayuki HISHIKI, Yuko SHIMIZU, Kenji FUNAMI, Kazuo SUGI ...

2009 Volume 85 Issue 7 Pages 217-228
Published: 2009
Released on J-STAGE: July 31, 2009

DOIhttps://doi.org/10.2183/pjab.85.217

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Hepatitis C virus (HCV) establishes a persistent infection and causes chronic hepatitis. Chronic hepatitis patients often develop hepatic cirrhosis and progress to liver cancer. The development of this pathological condition is linked to the persistent infection of the virus. In other words, viral replication/multiplication may contribute to disease pathology. Accumulating clinical studies suggest that HCV infection alters lipid metabolism, and thus causes fatty liver. It has been reported that this abnormal metabolism exacerbates hepatic diseases. Recently, we revealed that lipid droplets play a key role in HCV replication. Understanding the molecular mechanism of HCV replication will help elucidate the pathogenic mechanism and develop preventive measures that inhibit disease manifestation by blocking persistent infection. In this review, we outline recent findings on the function of lipid droplets in the HCV replication cycle and describe the relationship between the development of liver diseases and virus replication.

(Communicated by Takao SEKIYA, M.J.A.)

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Original Papers

Accumulation of radium in ferruginous protein bodies formed in lung tissue: association of resulting radiation hotspots with malignant mesothelioma and other malignancies

Eizo NAKAMURA, Akio MAKISHIMA, Kyoko HAGINO, Kazunori OKABE

2009 Volume 85 Issue 7 Pages 229-239
Published: 2009
Released on J-STAGE: July 31, 2009

DOIhttps://doi.org/10.2183/pjab.85.229

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While exposure to fibers and particles has been proposed to be associated with several different lung malignancies including mesothelioma, the mechanism for the carcinogenesis is not fully understood. Along with mineralogical observation, we have analyzed forty-four major and trace elements in extracted asbestos bodies (fibers and proteins attached to them) with coexisting fiber-free ferruginous protein bodies from extirpative lungs of individuals with malignant mesothelioma. These observations together with patients’ characteristics suggest that inhaled iron-rich asbestos fibers and dust particles, and excess iron deposited by continuous cigarette smoking would induce ferruginous protein body formation resulting in ferritin aggregates in lung tissue. Chemical analysis of ferruginous protein bodies extracted from lung tissues reveals anomalously high concentrations of radioactive radium, reaching millions of times higher concentration than that of seawater. Continuous and prolonged internal exposure to hotspot ionizing radiation from radium and its daughter nuclides could cause strong and frequent DNA damage in lung tissue, initiate different types of tumour cells, including malignant mesothelioma cells, and may cause cancers.

(Communicated by Takashi SUGIMURA, M.J.A.)

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Recovery of cell nuclei from 15,000 years old mammoth tissues and its injection into mouse enucleated matured oocytes

Hiromi KATO, Masayuki ANZAI, Tasuku MITANI, Masahiro MORITA, Yui NISHI ...

2009 Volume 85 Issue 7 Pages 240-247
Published: 2009
Released on J-STAGE: July 31, 2009

DOIhttps://doi.org/10.2183/pjab.85.240

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Here, we report the recovery of cell nuclei from 14,000-15,000 years old mammoth tissues and the injection of those nuclei into mouse enucleated matured oocytes by somatic cell nuclear transfer (SCNT). From both skin and muscle tissues, cell nucleus-like structures were successfully recovered. Those nuclei were then injected into enucleated oocytes and more than half of the oocytes were able to survive. Injected nuclei were not taken apart and remained its nuclear structure. Those oocytes did not show disappearance of nuclear membrane or premature chromosome condensation (PCC) at 1 hour after injection and did not form pronuclear-like structures at 7 hours after injection. As half of the oocytes injected with nuclei derived from frozen-thawed mouse bone marrow cells were able to form pronuclear-like structures, it might be possible to promote the cell cycle of nuclei from ancient animal tissues by suitable pre-treatment in SCNT. This is the first report of SCNT with nuclei derived from mammoth tissues.

(Contributed by Akira IRITANI, M.J.A.)

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The A^y allele at the agouti locus reduces the size and alters the shape of the mandible in mice

Jun-ichi SUTO

2009 Volume 85 Issue 7 Pages 248-257
Published: 2009
Released on J-STAGE: July 31, 2009

DOIhttps://doi.org/10.2183/pjab.85.248

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To confirm my previous findings that the A^y allele at the agouti locus reduced the mandible size and therefore altered the mandible shape in a KK mouse strain background, I further investigated the effects of the A^y allele on mandible morphology on different strain backgrounds, DDD and B6. Principal component analysis revealed that the mandible was significantly smaller in A^y mice (DDD-A^y and B6-A^y) than in corresponding non-A^y mice (DDD and B6, respectively). Discriminant and canonical discriminant analyses revealed that most mice were classified correctly in their own strains, and misclassification was not observed between DDD (-A^y) and B6 (-A^y). The results confirmed that the A^y allele reduced the mandible size and altered the mandible shape regardless of the strain background. However, the difference in mandible morphology between A^y mice and the corresponding non-A^y mice within a strain was not as large as that which intrinsically underlay the two strains. Possible mechanisms of the A^y action are discussed.

(Edited by Akira IRITANI, M.J.A.)

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Regulation of succinate-ubiquinone reductase and fumarate reductase activities in human complex II by phosphorylation of its flavoprotein subunit

Eriko TOMITSUKA, Kiyoshi KITA, Hiroyasu ESUMI

2009 Volume 85 Issue 7 Pages 258-265
Published: 2009
Released on J-STAGE: July 31, 2009

DOIhttps://doi.org/10.2183/pjab.85.258

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Complex II (succinate-ubiquinone reductase; SQR) is a mitochondrial respiratory chain enzyme that is directly involved in the TCA cycle. Complex II exerts a reverse reaction, fumarate reductase (FRD) activity, in various species such as bacteria, parasitic helminths and shellfish, but the existence of FRD activity in humans has not been previously reported. Here, we describe the detection of FRD activity in human cancer cells. The activity level was low, but distinct, and it increased significantly when the cells were cultured under hypoxic and glucose-deprived conditions. Treatment with phosphatase caused the dephosphorylation of flavoprotein subunit (Fp) with a concomitant increase in SQR activity, whereas FRD activity decreased. On the other hand, treatment with protein kinase caused an increase in FRD activity and a decrease in SQR activity. These data suggest that modification of the Fp subunit regulates both the SQR and FRD activities of complex II and that the phosphorylation of Fp might be important for maintaining mitochondrial energy metabolism within the tumor microenvironment.

(Communicated by Takashi SUGIMURA, M.J.A.)

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