No abstract

The gut microbiota is reported to be related to obesity, and visceral fat is reported to be strongly associated with cardiovascular disease and overall mortality. However, the association between the gut microbiota and obesity has mainly been studied using body mass index (BMI) as a proxy for obesity. We investigated the relationship of both visceral fat and BMI with the gut microbiota stratified by sex in a population-based cross-sectional study of Japanese men and women 20–76 years of age (n = 1001). Women with a higher visceral fat area (VFA) harboured a higher relative abundance of the Firmicutes phylum (P for trend <0.001) and a lower relative abundance of the Bacteroidetes phylum (P for trend 0.030), whereas men with higher VFA harboured a lower relative abundance of the Firmicutes phylum (P for trend 0.076) and a higher relative abundance of the Bacteroidetes phylum (P for trend 0.013). Similar results were obtained using BMI as an index, but the differences were not significant in men. At the genus level, Blautia was the only gut microbe significantly and inversely associated with VFA regardless of sex. In conclusion, at the genus level we found that Blautia was the only gut microbe significantly and inversely associated with VFA, regardless of sex.

Purpose: The RNA interference effect is an alternative to antisense DNA as an experimental method of downregulating a specific target protein. Although the RNA interference effect, which is mediated by small interfering RNA (siRNA) or micro-RNA, has potential application to human therapy, the hydrodynamic method usually used for rapid administration of oligonucleotides is unsuitable for use in humans. In this study, we have investigated the antitumor activity of a synthetic siRNA, B717, which is sequence specific for the human bcl-2 oncogene, complexed with a novel cationic liposome, LIC-101.Experimental Design: In a mouse model of liver metastasis, we administered B717/LIC-101 by bolus intravenous injection, adjusting the rate and volume of administration to what is feasible in human therapy. In a mouse model bearing prostate cancer in which the cells were inoculated under the skin, B717/LIC-101 was administered subcutaneously around the tumor.Results: The B717/LIC-101 complex inhibited the expression of bcl-2 protein and the growth of tumor cell lines in vitro in a sequence-specific manner in the concentration range of 3 to 100 nmol/L. Furthermore, the complex had a strong antitumor activity when administered intravenously in the mouse model of liver metastasis. B717 (siRNA) was shown to be delivered to tumor cells in the mouse liver, but only when complexed with LIC-101. The complex also inhibited tumor cell growth in the mouse model bearing prostate cancer.Conclusions: By combining siRNA with our cationic liposome, we overcame the difficulty of administering siRNA to animals in ways that can be applied in human therapy. Although our siRNA/liposome complex is not yet in clinical trials, it is expected to provide a novel siRNA therapy for cancer patients.

Background/Objectives:Brown adipose tissue (BAT) is a potential therapeutic target against obesity and diabetes through thermogenesis and substrate disposal with cold exposure. The role of BAT in energy metabolism under thermoneutral conditions, however, remains controversial. We assessed the contribution of BAT to energy expenditure (EE), particularly diet-induced thermogenesis (DIT), and substrate utilization in human adults.Methods:In this cross-sectional study, BAT activity was evaluated in 21 men using 18F-fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography (18F-FDG-PET/CT) after cold exposure (19 °C). The subjects were divided into BAT-positive (n=13) and BAT-negative (n=8) groups according to the 18F-FDG-PET/CT findings. Twenty-four hour EE, DIT and respiratory quotient were measured using a whole-room indirect calorimeter at 27 °C.Results:Body composition, blood metabolites and 24-h EE did not differ between groups. DIT (%), calculated as DIT divided by total energy intake, however, was significantly higher in the BAT-positive group (BAT-positive: 9.7±2.5%, BAT-negative: 6.5±4.0%, P=0.03). The 24-h respiratory quotient was significantly lower (P=0.03) in the BAT-positive group (0.861±0.027) than in the BAT-negative group (0.889±0.024).Conclusion:DIT and fat utilization were higher in BAT-positive subjects compared to BAT-negative subjects, suggesting that BAT has a physiologic role in energy metabolism.

The recent explosion in genome sequencing has revealed the great diversity of the cadherin superfamily. Within the superfamily, protocadherins, which are expressed mainly in the nervous system, constitute the largest subgroup. Nevertheless, the structures of only the classical cadherins are known. Thus, to broaden our understanding of the adhesion repertoire of the cadherin superfamily, we determined the structure of the N-terminal first extracellular cadherin domain of the cadherin-related neuronal receptor/protocadherin-␣4. The hydrophobic pocket essential for homophilic adhesiveness in the classical cadherins was not found, and the functional significance of this structural domain was supported by exchanging the first extracellular cadherin domains of protocadherin and classical cadherin. Moreover, potentially crucial variations were observed mainly in the loop regions. These included the protocadherin-specific disulfide-bonded Cys-X 5 -Cys motif, which showed Ca 2؉ -induced chemical shifts, and the RGD motif, which has been suggested to be involved in heterophilic cell adhesion via the active form of ␤1 integrin. Our findings reveal that the adhesion repertoire of the cadherin superfamily is far more divergent than would be predicted by studying the classical cadherins alone.In recent years, the cadherins have emerged as an important superfamily, and their structures and biological functions are proving to be complex. Originally thought of as calcium-dependent cell adhesion molecules, the cadherin superfamily molecules are now known to be involved in many biological processes, including cell recognition, cell signaling, cell communication during embryogenesis, and the formation of neural circuits in the central nervous system (1-3).The cadherin superfamily can be divided into several subgroups (4): the classical (type I) and closely related type II cadherins, the desmosomal cadherins, and the protocadherins (see Fig. 1A). Most of the previous functional and structural analyses have been of the classical cadherins. These studies revealed homophilic adhesive binding interfaces localized primarily within the N-terminal first extracellular cadherin (EC) 6 domain, which is conserved among the classical (type I), type II, and desmosomal cadherins (5-13).However, the classical cadherins account for only a fraction of the cadherin superfamily, which has a multitude of diverse members. Protocadherins are now known to constitute the largest subgroup within the cadherin superfamily (see Fig. 1A) (4,9,11,14). Most protocadherins have a divergent cytoplasmic domain and six or seven EC domains, with low sequence similarities to the EC domains of the classical cadherin group (15). Here, we have focused on one of the major cluster-type protocadherins, the cadherin-related neuronal receptor/protocadherin-␣ (CNR/Pcdh␣) family. The CNR/Pcdh␣ genome is organized into an unusual gene cluster that is similar to the organization of the immunoglobulin and T-cell receptor genes 6 The abbreviations used are: EC, extracellular cadhe...