Euthyroid sick syndrome characterized by reduced levels of thyroid hormones (THs) is observed in patients with meningococcal shock. It has been found that the level of THs reflects disease severity and is predictive for mortality. The present study was conducted to investigate the impact of THs on host defense during meningococcal infection. We found that supplementation of thyroxine to mice infected with Neisseria meningitidis enhanced bacterial clearance, attenuated the inflammatory responses and promoted survival. In vitro studies with macrophages revealed that THs enhanced bacteria-cell interaction and intracellular killing of meningococci by stimulating inducible nitric oxide synthase (iNos)-mediated NO production. TH treatment did not activate expression of TH receptors in macrophages. Instead, the observed TH-directed actions were mediated through nongenomic pathways involving the protein kinases PI3K and ERK1/2 and initiated at the membrane receptor integrin αvβ3. Inhibition of nongenomic TH signaling prevented iNos induction, NO production and subsequent intracellular bacterial killing by macrophages. These data demonstrate a beneficial role of THs in macrophage-mediated N. meningitidis clearance. TH replacement might be a novel option to control meningococcal septicemia.

Aberrant activation of Wnt/β-catenin signaling pathways is closely involved in the occurrence and progression of several types of human malignancies. However, as a fundamental component in this cascade, Wnt3 has not been well understood for the expression level and pathogenic mechanism in gastric carcinogenesis. Here, this research was undertaken to elucidate the important role of Wnt3 in gastric cancer. Wnt3 expression in gastric carcinomas and their respective normal tissues was examined by immunoblotting and immunohistochemistry. In all cases, Wnt3 expression was significantly elevated in gastric carcinomas compared with normal tissues. Knocking down Wnt3 in MGC-803 gastric cancer cells by small interfering RNAs transfection led to an obvious decrease in both transcript and protein levels. Silence of Wnt3 expression in gastric cancer cells inhibited the expression of β-catenin and cyclin D1 genes in Wnt/β-catenin pathway, significantly blocked cellular proliferation, delayed cell cycle, suppressed cell invasion and metastasis, accompanied by a higher apoptosis rate. Together, we conclude that upregulation of Wnt3 plays a crucial role in gastric tumorigenesis by inducing proliferation, migration, and invasion and inhibiting apoptosis of cancer cells, and Wnt3 might be a potential target for the treatment of gastric cancer.

Streptococcal collagen-like protein 1 (Scl1) is a virulence factor on the surface of group A Streptococcus (GAS). We have previously reported that several Scl1 proteins derived from various M-type GAS strains, including M41, can bind to low-density lipoprotein but Scl1 protein derived from M6-type GAS strain can not. Here, we demonstrated that recombinant protein, designated C176, derived from Scl1.41 of GAS M41-type strain also binds both plasma and purified high-density lipoprotein (HDL). Next, we determined that intact non-collagenous region of C176 was necessary and sufficient for HDL binding. C176-HDL interaction could be eliminated by the presence of low concentrations of the nonionic detergent, Tween 20, suggesting hydrophobic character of this interaction. We finally showed that whole GAS cells expressing native Scl1.41 protein absorbed HDL from human plasma in the absence of Tween 20 but M6-type GAS cells did not. Altogether, our results add further evidence to the importance of GAS-lipoprotein binding.

Objective. The aim of this study was to investigate the association between adiponectin gene polymorphisms rs10937273, rs1501299, rs182052, rs2241767, and rs266729 and environmental risk factors of type 2 diabetes mellitus (T2DM) in Hohhot. The study explored different models of gene-environment interactions, aimed at providing approaches for the prevention and control of T2DM in combination with the characteristics of the local population. Methods. A case-control study was conducted including 406 Chinese participants, comprising 203 cases and 203 controls from various hospitals. Adiponectin (ADIPOQ) gene polymorphisms rs10937273, rs1501299, rs182052, rs2241767, and rs266729 were detected using an improved multiple ligation detection reaction technique. Generalized multifactor dimensionality reduction (GMDR) and logistic regression were conducted to analyze the associations between adiponectin gene polymorphisms and T2DM, as well as the interactions between adiponectin gene polymorphisms and environmental factors. Results. ADIPOQ gene polymorphisms rs10937273, rs1501299, rs182052, rs2241767, and rs266729 were associated with type 2 diabetes. Based on the haplotype of the five adiponectin gene single-nucleotide polymorphism (SNP) loci, we found that G-G-A-A-C was a susceptible haplotype of T2DM (P<0.05). Interaction analyses demonstrated associations between rs1501299 and central obesity (consistency=80%, P=0.011) and between rs266729 and rs182052 and central obesity (consistency=70%, P=0.011). Conclusions. Our findings indicate that there is an interaction between the ADIPOQ gene and central obesity, which provides new insights into the prevention and treatment of T2DM.

Activation of macrophages by Toll-like receptors (TLRs) and functionally related proteins is essential for host defense and innate immunity. TLRs recognize a wide variety of pathogen-associated molecules. Here, we demonstrate that the meningococcal outer membrane protein NhhA has immunostimulatory functions and triggers release of proinflammatory cytokines from macrophages. NhhA-induced cytokine release was found to proceed via two distinct pathways in RAW 264.7 macrophages. Interleukin-6 (IL-6) secretion was dependent on activation of TLR4 and required the TLR signaling adaptor protein MyD88. In contrast, release of tumor necrosis factor (TNF) was TLR4 and MyD88 independent. Both pathways involved NF-B-dependent gene regulation. Using a PCR-based screen, we could identify additional targets of NhhA-dependent gene activation such as the cytokines and growth factors IL-1␣, IL-1␤, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). In human monocyte-derived macrophages, G-CSF, GM-CSF, and IL-6 were found to be major targets of NhhA-dependent gene regulation. NhhA induced transcription of IL-6 and G-CSF mRNA via TLR4-dependent pathways, whereas GM-CSF transcription was induced via TLR4-independent pathways. These data provide new insights into the role of NhhA in host-pathogen interaction.

Neisseria meningitidis colonizes the nasopharyngeal mucosa of healthy populations asymptomatically, although the bacterial surface is rich in motifs that activate the host innate immunity. What determines the tolerant host response to this bacterium in asymptomatic carriers is poorly understood. We demonstrated that the conserved meningococcal surface protein NhhA orchestrates monocyte (Mo) differentiation specifically into macrophage-like cells with a CD200Rhi phenotype (NhhA-Mφ). In response to meningococcal stimulation, NhhA-Mφ failed to produce proinflammatory mediators. Instead, they upregulated interleukin-10 (IL-10) and Th2/regulatory T cell (Treg)-attracting chemokines, such as CCL17, CCL18, and CCL22. Moreover, NhhA-Mφ were highly efficient in eliminating bacteria. The in vivo validity of these findings was corroborated using a murine model challenged with N. meningitidis systematically or intranasally. The NhhA-modulated immune response protected mice from septic shock; Mo/Mφ depletion abolished this protective effect. Intranasal administration of NhhA induced an anti-inflammatory response, which was associated with N. meningitidis persistence at the nasopharynx. In vitro studies demonstrated that NhhA-triggered Mo differentiation occurred upon engaged Toll-like receptor 1 (TLR1)/TLR2 signaling and extracellular signal-regulated kinase (ERK) and Jun N-terminal protein kinase (JNK) activation and required endogenously produced IL-10 and tumor necrosis factor alpha (TNF-α). Our findings reveal a strategy that might be adopted by N. meningitidis to maintain asymptomatic nasopharyngeal colonization.

Introduction:The aim of present study was to investigate gender differences in physical fitness indexes in regard to BMI (body mass index) levels among Inner Mongolia medical students in China.Methods:Data on participant characteristics came from basic information contained in the school database. Physical fitness indexes including BMI, vital capacity index, sidestep test, and standing long jump, were conducted.Results:Female students had a higher rate of normal weight than those of males. The obesity rate of males was 5 times higher compared to females. Compared with male students, female students had a higher pass rate in vital capacity index, sidestep and standing long jump. Females were higher 17% than males in the pass rate of the sidestep test. Males performed better than females in the standing long jump. In both the malnutrition and normal weight group, the pass rate of the 3 physical fitness indexes for both male and female students was higher than obese group. The not pass rate was higher than pass rate both male and female students in the vital capacity index in the obese group.Discussion:Males had a poor physical fitness level compared with females. Male students may be more likely to spend more time using computers and it will cut down the time of participating in physical activities. So, in our university, more attention should pay on physical education, especially for males.

Low-density lipoprotein (LDL) binds to group A Streptococcus (GAS) through Sc11 protein, and scavenger receptor CD36 of monocyte mediates the endocytosis of native or modified LDL. Therefore, we hypothesized that LDL might be an opsonin enhancing the phagocytosis of LDL-bound GAS by monocyte. The results showed that LDL could significantly promote U937 cell to phagocytose M28 (ATCC BAA1064) and M41 (ATCC 12373, AM41)-type GAS, and the phagocytosis rates were significantly increased, compared with LDL-free group. LDL, however, did not enhance the phagocytosis of M41 (CMCC 32198, CM41) or M6 (ATCC BAA946)-type GAS since these two strains did not bind to LDL. CD36 was the major scavenger receptor mediating the uptake of LDL-bound GAS by monocyte U937 cells since anti-CD36 antibody abolished the phagocytosis of LDL-opsonized GAS but anti-CD4 antibody did not. Most of AM41-type GAS cells were killed in human blood, whereas only a few CM41-type cells were phagocytosed. Moreover, recombinant Scl1 (rScl1) derived from M41-type GAS could significantly decrease the opsonophagocytosis of AM41 but not CM41-type GAS because the rScl1 competitively blocked the binding of AM41-type GAS to LDL. Therefore, our findings suggest that LDL may be an opsonin to enhance CD36-dependent opsonic phagocytosis of GAS by monocyte.Electronic supplementary materialThe online version of this article (doi:10.1007/s00430-015-0436-8) contains supplementary material, which is available to authorized users.