Identification of the Flavonoid Luteolin as a Repressor of the Transcription Factor Hepatocyte Nuclear Factor 4α

Hepatocyte nuclear factor 4α (HNF4α) is a nuclear receptor that regulates the expression of genes involved in the secretion of apolipoprotein B (apoB)-containing lipoproteins and in glucose metabolism. In the present study, we identified a naturally occurring flavonoid, luteolin, as a repressor of HNF4α by screening for effectors of the human microsomal triglyceride transfer protein (MTP) promoter. Luciferase reporter gene assays revealed that the activity of the MTP gene promoter was suppressed by luteolin and that the mutation of HNF4α-binding element abolished luteolin responsiveness. Luteolin treatment caused a significant decrease in the mRNA levels of HNF4α target genes in HepG2 cells and inhibited apoB-containing lipoprotein secretion in HepG2 and differentiated Caco2 cells. The interaction between luteolin and HNF4α was demonstrated using absorption spectrum analysis and luteolin-immobilized beads. Luteolin did not affect the DNA binding of HNF4α to the promoter region of its target genes but suppressed the acetylation level of histone H3 in the promoter region of certain HNF4α target genes. Short term treatment of mice with luteolin significantly suppressed the expression of HNF4α target genes in the liver. In addition, long term treatment of mice with luteolin significantly suppressed their diet-induced obesity and improved their serum glucose and lipid parameters. Importantly, long term luteolin treatment lowered serum VLDL and LDL cholesterol and serum apoB protein levels, which was not accompanied by fat accumulation in the liver. These results suggest that the flavonoid luteolin ameliorates an atherogenic lipid profile in vivo that is likely to be mediated through the inactivation of HNF4α.     

Where is the origin of the Japanese gamecocks?

The tradition of cockfighting is widespread throughout the world. There is no doubt that the gamecock has evolved together with the human culture of cockfighting for a long time. In Japan, there is a group of gamecocks called "Shamo" that are used specifically for cockfighting. However, the process of the geographic distribution of cockfighting and the influx route of gamecocks into Japan are totally unclear. The molecular evolutionary study of gamecocks is obviously useful to gain profound insight into the understanding of not only the evolutionary origin of "Shamo" but also the distribution process of cockfighting as a culture. In this study, we collected blood samples of gamecocks from 11 different prefectures in Japan. Then, a phylogenetic tree was constructed using a total of 42 mtDNAs (D-loop, 1100 bp) sequenced. It showed that Japanese Shamo was clearly separated into two different groups: One group contains the samples from the island of Okinawa and the other group is composed of the samples mainly from Kyushu and Honshu of Japan. It suggests that Japanese Shamo must have been brought to Japan from two different origins. Our examination of historical records showed that the results of the phylogenetic analysis is consistent with the view that Japanese Shamo was originated from Southeast Asia and the mainland China independently, but was geographically a bit mixed afterwards.     

Does it matter who pulls the switch? Perceptions of intentions in the trolley dilemma

This research examines the automatic moral and intentional inferences that third parties generate as a function of outcomes for the actor. Participants were asked about the moral acceptability of redirecting a train to save five lives by sacrificing one, as well as the intentions of the person directing the train, and the consequences of doing so. Actor position was varied with respect to whether the person redirecting the train stood to benefit by doing so. Across four studies in international and US samples, participants rated the redirection as less morally acceptable or more punishable when the actor redirecting the train was saving their own life in the process. The implications of these findings for moral claims are discussed.     

Ubiquitin Binding in Endocytosis – How Tight Should It Be and Where Does It Happen?

Ubiquitin is an important tag in membrane transport. From studies in yeast, monoubiquitin has been considered sufficient to elicit uptake of cell surface transporters and receptors into endosomes. Two articles in the current issue of Traffic (Hawryluk et al. and Barriere et al.) indicate that stronger binding is required to retain and concentrate cargo in endocytic microdomains of the plasma membrane. High avidity interactions can be obtained by tandemly arrayed ubiquitin interaction motifs (UIM), in proteins such as the endocytic adaptors epsin and Eps15, interacting with polyubiquitin or by UIM-containing proteins binding several ubiquitins brought together through oligomerization of receptors. A controversial issue has been where such interactions take place. One view is that the association of epsin with ubiquitinated cargo is negatively regulated by its interaction with clathrin (Chen H and De Camilli P. Proc Natl Acad Sci USA 2005;102:2766-2771). This contention is now challenged by the articles of Hawryluk et al. and Barriere et al. Hawryluk et al. demonstrate that epsin and Eps15 consistently co-localize with clathrin but never with caveolin.     

Where is the root of the universal tree of life?

The currently accepted universal tree of life based on molecular phylogenies is characterised by a prokaryotic root and the sisterhood of archaea and eukaryotes. The recent discovery that each domain (bacteria, archaea, and eucarya) represents a mosaic of the two others in terms of its gene content has suggested various alternatives in which eukaryotes were derived from the merging of bacteria and archaea. In all these scenarios, life evolved from simple prokaryotes to complex eukaryotes. We argue here that these models are biased by overconfidence in molecular phylogenies and prejudices regarding the primitive nature of prokaryotes. We propose instead a universal tree of life with the root in the eukaryotic branch and suggest that many prokaryotic features of the information processing mechanisms originated by simplification through gene loss and non-orthologous displacement.     

Phospholipase D1 Has a Pivotal Role in Interleukin-1β-Driven Chronic Autoimmune Arthritis through Regulation of NF-κB,Hypoxia-Inducible Factor 1α, and FoxO3a

Interleukin-1β (IL-1β) is a potent proinflammatory and immunoregulatory cytokine playing an important role in the progression of rheumatoid arthritis (RA). However, the signaling network of IL-1β in synoviocytes from RA patients is still poorly understood. Here, we show for the first time that phospholipase D1 (PLD1), but not PLD2, is selectively upregulated in IL-1β-stimulated synoviocytes, as well as synovium, from RA patients. IL-1β enhanced the binding of NF-κB and ATF-2 to the PLD1 promoter, thereby enhancing PLD1 expression. PLD1 inhibition abolished the IL-1β-induced expression of proinflammatory mediators and angiogenic factors by suppressing the binding of NF-κB or hypoxia-inducible factor 1α to the promoter of its target genes, as well as IL-1β-induced proliferation or migration. However, suppression of PLD1 activity promoted cell cycle arrest via transactivation of FoxO3a. Furthermore, PLD1 inhibitor significantly suppressed joint inflammation and destruction in IL-1 receptor antagonist-deficient (IL-1Ra^−/−) mice, a model of spontaneous arthritis. Taken together, these results suggest that the abnormal upregulation of PLD1 may contribute to the pathogenesis of IL-1β-induced chronic arthritis and that a selective PLD1 inhibitor might provide a potential therapeutic molecule for the treatment of chronic inflammatory autoimmune disorders.     

Metapopulation dynamics: Does it help to have more of the same?

With the interest in conservation biology shifting towards processes from patterns, and to populations from communities, the theory of metapopulation dynamics is replacing the equilibrium theory of island biogeography as the population ecology paradigm in conservation biology. The simplest models of metapopulation dynamics make predictions about the effects of habitat fragmentation - size and isolation of habitat patches - on metapopulation persistence. The simple models may be enriched by considerations of the effects of demographic and environmental stochasticity on the size and extinction probability of local populations. Environmental stochasticity affects populations at two levels: it makes local extinctions more probable, and it also decreases metapopulation persistence time by increasing the correlation of extinction events across populations. Some controversy has arisen over the significance of correlated extinctions, and how they may affect the optimal subdivision of metapopulations to maximize their persistence time.     

Diversity in the circumsporozoite protein of Plasmodium vivax: Does it matter?

Since the gene encoding the malarial circumsporozoite surface protein was characterized a decade ago, the corresponding protein has been considered an important vaccine candidate. Victoria Mann, Michael Good and Allan Saul here discuss molecular variation in the circumsporozoite surface protein of Plasmodium vivax in this context. There is still doubt about the degree and importance of polymorphisms in non-repetitive regions of the molecule. The degree of polymorphisms and data on naturally occurring protective responses suggests there has been minimal immunological pressure; the authors contend that antigenic diversity is unlikely to be a major factor in the use of this antigen as a vaccine for P. vivax.     

Could a Factor That Does Not Affect Egg Recognition Influence the Decision of Rejection?

Rejection of the parasitic egg is the most important defence of hosts against brood parasites. However, this response is variable among and within species, and egg discrimination is not always followed by egg rejection. Low risk of parasitism and high risk of rejection costs may lead to the acceptance of the parasitic egg even if it has been previously recognized. The main aim of this paper is to answer a relevant question: can a single egg trait provoke the acceptance of an experimental egg previously recognized as foreign? Increased egg mass should hamper the ejection of an egg that has been discriminated because ejection of a heavy egg may imply higher rejection costs for hosts. We have tested this prediction by experimentally parasitizing natural nests of Common Blackbirds (Turdus merula) with non-mimetic model eggs of different mass (heavy, normal-weight, and light) while controlling for potential confounding factors such as egg size and colour. Our results showed that blackbirds more frequently accepted heavy eggs, even when previously recognized. This differential acceptance may be related to insufficient motivation to assume the higher costs that the ejection of a heavy egg could impose.     

Does Phospholipid Methylation Play a Role in the Primary Mechanism of Action of Nerve Growth Factor?

Nerve growth factor (NGF)-untreated (naive) and neurite-bearing NGF-treated ("primed") PC12 rat pheochromocytoma cells were used as model system to study the role of phospholipid methylation in the NGF mechanism of action. The neurite-bearing cultures were deprived of NGF for 3 h before experimentation. Under both experimental conditions, the cells were labelled with [methyl-3H]methionine and then challenged with NGF for time periods ranging from 5 s to 30 min. Methylated phospholipids were extracted and then resolved and identified by TLC as phosphatidyl mono-, di-, and trimethyl ethanolamine. Quantification of the amount of radioactivity incorporated into each of the phospholipids indicated that NGF does not significantly alter phospholipid methylation either in naive or in neurite-bearing cells. Furthermore, using a methyltransferase inhibitor, it was found that neurite outgrowth still occurs when phospholipid methylation is almost completely blocked. These results indicate that phospholipid methylation does not play a primary role in the mechanism of action of NGF.