Makoto Naito

Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas

PTEN is a tumor suppressor gene mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP system to generate a hepatocyte-specific null mutation of Pten in mice (AlbCrePten(flox/flox) mice). AlbCrePten(flox/flox) mice showed massive hepatomegaly and steatohepatitis with triglyceride accumulation, a phenotype similar to human nonalcoholic steatohepatitis. Adipocyte-specific genes were induced in mutant hepatocytes, implying adipogenic-like transformation of these cells. Genes involved in lipogenesis and beta-oxidation were also induced, possibly as a result of elevated levels of the transactivating factors PPARgamma and SREBP1c. Importantly, the loss of Pten function in the liver led to tumorigenesis, with 47% of AlbCrePten(flox/flox) livers developing liver cell adenomas by 44 weeks of age. By 74-78 weeks of age, 100% of AlbCrePten(flox/flox) livers showed adenomas and 66% had hepatocellular carcinomas. AlbCrePten(flox/flox) mice also showed insulin hypersensitivity. In vitro, AlbCrePten(flox/flox) hepatocytes were hyperproliferative and showed increased hyperoxidation with abnormal activation of protein kinase B and MAPK. Pten is thus an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver.

Differentiation and function of Kupffer cells.

Kupffer cells are the largest population of tissue macrophages. They are predominantly distributed in the lumen of hepatic sinusoids and exhibit endocytic activity against blood-borne materials entering the liver. Macrophage colony-stimulating factor and other growth factors regulate Kupffer cell differentiation in the fetal and adult period. Because of the unique attributes of tissue, Kupffer cells play essential roles not only in host defense but also in the homeostatic responses of tissue. Macrophage scavenger receptors and heme oxygenase are expressed in Kupffer cells from an early stage of ontogeny. Scavenger receptors are involved not only in the lipid metabolism but also in the bactericidal mechanism. Heme oxygenase in Kupffer cells is essential to the production of bilirubin. In this review, the developmental mechanism and functional activities of Kupffer cells are described. Evidence suggests that Kupffer cells represent a distinct cell population with unique differentiation mechanisms, metabolic functions, and responsiveness to inflammatory agents.

AIM inhibits apoptosis of T cells and NKT cells in corynebacterium-induced granuloma formation in mice

Apoptosis inhibitor expressed by macrophages (AIM) inhibits apoptosis of CD4(+)CD8(+) (CD4/CD8) double-positive thymocytes, and supports the viability of these cells on the thymic selection. However, pleiotropic functions of AIM have been suggested. In this study, heat-killed Corynebacterium parvum (C. parvum) was injected into mice carrying the homozygous mutation (AIM(-/-)) and wild-type (AIM(+/+)) mice, to investigate the role of AIM in the formation of hepatic granulomas. In AIM(-/-) mice, the size and the number of hepatic granulomas were larger, and the resorption of granulomas was more delayed than in AIM(+/+) mice. The production of interleukin-12 was more prominent in AIM(-/-) mice than in AIM(+/+) mice. In the liver of AIM(+/+) mice, expression of AIM messenger ribonucleic acid (mRNA) increased after C. parvum injection. In situ hybridization demonstrated that AIM mRNA was expressed in Kupffer cells and exudate macrophages in the liver, especially in granulomas. Larger numbers of T cells and natural killer T (NKT) cells underwent apoptosis in the granulomas of AIM(-/-) mice, suggesting that AIM prevents apoptosis of NKT cells and T cells in C. parvum-induced inflammation. Recombinant AIM (rAIM) protein significantly inhibited apoptosis of NKT cells and T cells obtained from C. parvum-stimulated livers in vitro. These results indicate that AIM functions to induce resistance to apoptosis within NKT cells and T cells, and supports the host defense in granulomatous inflammation.

Epidemiology of Human Influenza A and B Viruses in Myanmar from 2005 to 2007

Objectives: To perform genetic analysis of influenza A and B viruses in Myanmar from 2005 to 2007 and to determine the prevalence of amantadine-resistant influenza A viruses. Methods: Phylogenies of the HA and NA genes were analyzed and mutations in M2 that confer resistance to amantadine were screened. Results: Influenza in Myanmar exhibited seasonality, which coincided during the rainy season from June to August. Out of 2,618 samples, 76 influenza A and 132 influenza B viruses were isolated. Phylogenetic analysis showed that in 2005, 11 A/H1N1 isolates formed one cluster with A/Solomon Islands/3/2006 and were amantadine-sensitive strains. One A/H3N2 isolate was amantadine-resistant harboring S31N mutation in M2 and possessing S193F and D225N substitutions in HA (clade N), similar to A/Wisconsin/67/2005. No viruses were isolated in 2006 due to sample storage failure. In 2007, all 64 A/H3N2 isolates were amantadine-resistant and similar to A/Brisbane/10/2007. For influenza B, 3 Yamagata-lineage and 17 Victoria-lineage isolates were detected in 2005 and 112 Victoria-lineage viruses were isolated in 2007. All Victoria-lineage isolates were reassortants possessing NA derived from the Yamagata lineage. Conclusion: Continuous surveillance in tropical countries is important for elucidating the seasonality of influenza and determining the molecular characteristics of circulating strains.

Rare influenza A (H3N2) variants with reduced sensitivity to antiviral drugs.

In 2007 and 2008 in Myanmar, we detected influenza viruses A (H3N2) that exhibited reduced sensitivity to both zanamivir and amantadine. These rare and naturally occurring viruses harbored a novel Q136K mutation in neuraminidase and S31N mutation in M2.

Delayed emergence of oseltamivir‐resistant seasonal influenza A (H1N1) and pandemic influenza A(H1N1)pdm09 viruses in Myanmar

Please cite this paper as: Dapat et al. (2012) Delayed emergence of oseltamivir‐resistant seasonal influenza A (H1N1) and pandemic influenza A(H1N1)pdm09 viruses in Myanmar. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12030.