The phosphatidylinositol 3-kinase (PI3K)-Akt pathway suppresses Bax translocation to mitochondria

Bax, a proapoptotic member of the Bcl-2 family, localizes largely in the cytoplasm but redistributes to mitochondria in response to apoptotic stimuli, where it induces cytochrome c release. In this study, we show that the phosphatidylinositol 3-OH kinase (PI3K)-Akt pathway plays an important role in the regulation of Bax subcellular localization. We found that LY294002, a PI3K inhibitor, blocked the effects of serum to prevent Bax translocation to mitochondria and that expression of an active form of PI3K suppressed staurosporine-induced Bax translocation, suggesting that PI3K activity is essential for retaining Bax in the cytoplasm. In contrast, both U0126, a MEK inhibitor, and active MEK had little effect on Bax localization. In respect to downstream effectors of PI3K, we found that expression of active Akt, but not serum and glucocorticoid-induced protein kinase (SGK), suppressed staurosporine-induced translocation of Bax, whereas dominant negative Akt moderately promoted Bax translocation. Expression of Akt did not alter the levels of Bax, Bcl-2, Bcl-X(L), or phosphorylated JNK under the conditions used, suggesting that there were alternative mechanisms for Akt in the suppression of Bax translocation. Collectively, these results suggest that the PI3K-Akt pathway inhibits Bax translocation from cytoplasm to mitochondria and have revealed a novel mechanism by which the PI3K-Akt pathway promotes survival.     

Adenovirus vector-mediated macrophage erythroblast attacher (MAEA) overexpression in primary mouse hepatocytes attenuates hepatic gluconeogenesis

Japanese patients with type 2 diabetes mellitus present a different responsiveness in terms of insulin secretion to glucose and body mass index (BMI) from other populations. The genetic background that predisposes Japanese individuals to type 2 diabetes mellitus is under study. Recent genetic studies demonstrated that the locus mapped in macrophage erythroblast attacher (MAEA) increases the susceptibility to type 2 diabetes mellitus in East Asians, including Japanese individuals. MAEA encodes a protein that plays a role in erythroblast enucleation and in the normal differentiation of erythroid cells and macrophages. However, the contribution of MAEA to type 2 diabetes mellitus remains unknown. In this study, to overexpress MAEA in the mouse liver and primary mouse hepatocytes, we generated a MAEA-expressing adenovirus (Ad) vector using a novel Ad vector exhibiting significantly lower hepatotoxicity (Ad-MAEA). Blood glucose and insulin levels in Ad-MAEA-treated mice were comparable to those in control Ad-treated mice. Primary mouse hepatocytes transduced with Ad-MAEA showed lower levels of expression of gluconeogenesis genes than those transduced with the control Ad vector. Hepatocyte nuclear factor-4α (HNF-4α) mRNA expression in primary mouse hepatocytes was also suppressed by MAEA overexpression. These results suggest that MAEA overexpression attenuates hepatic gluconeogenesis, which could potentially lead to improvement of type 2 diabetes mellitus.     

Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity

Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)amino]nicotinic acid (5a) is a moderately RXRα-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists.     

Selective Transmission of R5 HIV-1 over X4 HIV-1 at the Dendritic Cell–T Cell Infectious Synapse Is Determined by the T Cell Activation State

Dendritic cells (DCs) are essential antigen-presenting cells for the induction of T cell immunity against HIV. On the other hand, due to the susceptibility of DCs to HIV infection, virus replication is strongly enhanced in DC–T cell interaction via an immunological synapse formed during the antigen presentation process. When HIV-1 is isolated from individuals newly infected with the mixture of R5 and X4 variants, R5 is predominant, irrespective of the route of infection. Because the early massive HIV-1 replication occurs in activated T cells and such T-cell activation is induced by antigen presentation, we postulated that the selective expansion of R5 may largely occur at the level of DC–T cell interaction. Thus, the immunological synapse serves as an infectious synapse through which the virus can be disseminated in vivo. We used fluorescent recombinant X4 and R5 HIV-1 consisting of a common HIV-1 genome structure with distinct envelopes, which allowed us to discriminate the HIV-1 transmitted from DCs infected with the two virus mixtures to antigen-specific CD4⁺ T cells by flow cytometry. We clearly show that the selective expansion of R5 over X4 HIV-1 did occur, which was determined at an early entry step by the activation status of the CD4⁺ T cells receiving virus from DCs, but not by virus entry efficiency or productivity in DCs. Our results imply a promising strategy for the efficient control of HIV infection.     

A food‐borne outbreak of gastroenteritis due to genotype G1P[8] rotavirus among adolescents in Japan

Six high school students in Tochigi prefecture, Japan, developed gastroenteritis after eating at a pork cutlet shop. Molecular epidemiologic analyses showed that the causative agent was genotype G1P[8] rotavirus (RV), this being detected in stool samples from both the patients and the asymptomatic food handlers. The detected RV strains were closely related genetically. The only uncooked food that all victims had eaten was raw sliced cabbage. These findings results suggest that uncooked foods contaminated with RV may be sources of infectious gastroenteritis in adolescents.     

Distribution of the Argentine ant, Linepithema humile, along the Seto Inland Sea, western Japan: Result of surveys in 2003–2005

The distribution of the Argentine ant, Linepithema humile, was investigated in 65 cities or towns along the Seto Inland Sea, western Japan in 2003–2005. Our results include all available information of their distribution in Japan until 2005. Argentine ants have invaded Aichi Prefecture (Tahara‐shi), Hyogo Prefecture (Kobe‐shi), Hiroshima Prefecture (Hiroshima‐shi, Fuchu‐cho, Hatsukaichi‐shi, Ono‐cho and Otake‐shi), and Yamaguchi Prefecture (Iwakuni‐shi and Yanai‐shi). The most widespread distribution was found around Hatsukaichi‐shi including the westernmost part of Hiroshima‐shi and the easternmost of Ono‐cho.     

Novel plastocyanin containing phenylalanine-83 from the gymnosperm Ginkgo biloba

Plastocyanin was purified from the gymnosperm Ginkgo biloba L., and its complete amino acid sequence was determined. The protein was shown to contain Phe-83 instead of Tyr-83 conserved in other land plant plastocyanins. This is the first report of the characterization and complete amino acid sequence of a gymnosperm plastocyanin.     

The mechanisms underlying neuromuscular changes in microgravity environment.

We reported that the levels of electromyogram in soleus muscle and the afferent neurogram recorded at L5 segmental level of the spinal cord were instantly decreased in response to exposure to microgravity (micro-G) environment created during a parabolic flight, although these activities were constantly presented at 1-G. It was also observed that the soleus muscle length was passively shortened in micro-G due to the plantarflexion of ankle joint. Similar phenomena were also induced by acute hindlimb suspension at 1-G. Further, the soleus muscle atrophied, if the dorsal root at L5 was transected. These results suggested that the unloading-related effects on muscle are closely associated with the inhibition of the afferent input. However, effects of gravity on most of the cells in the whole body can not be removed, although hindlimb suspension can inhibit the antigravity activity of rat hindlimb muscles. And parabolic flight can create micro-G only for a short period of time. Further, effects of hypergravity before and after micro-G are unavoidable. Therefore, further experiments utilizing space environment are essential.