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.

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.

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.

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.