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Obesity is a multifactorial chronic inflammatory metabolic disorder, with pathogenesis influenced by genetic and non-genetic factors such as environment and diet. Intestinal microbes and their metabolites play significant roles in the occurrence and development of obesity by regulating energy metabolism, inducing chronic inflammation, and impacting intestinal hormone secretion. Epigenetics, which involves the regulation of host gene expression without changing the nucleotide sequence, provides an exact direction for us to understand how the environment, lifestyle factors, and other risk factors contribute to obesity. DNA methylation, as the most common epigenetic modification, is involved in the pathogenesis of various metabolic diseases. The epigenetic modification of the host is induced or regulated by the intestinal microbiota and their metabolites, linking the dynamic interaction between the microbiota and the host genome. In this review, we examined recent advancements in research, focusing on the involvement of intestinal microbiota and DNA methylation in the etiology and progression of obesity, as well as potential interactions between the two factors, providing novel perspectives and avenues for further elucidating the pathogenesis, prevention, and treatment of obesity.

Bacterial infection remains one of the leading causes of death worldwide due to the continuous rise of multiple antibiotic-resistant bacteria. Focusing solely on bacteria as the drug targets is a major limitation inherent in the conventional antibiotic therapy. Recently, host-directed therapies have become such an innovative approach to modulate the host defense system and the interplay of innate and adaptive immunity. Our previous studies showed that memantine (MEM), an α7 nAChR antagonist, could efficiently block multi-drug resistant Escherichia coli-caused bacteremia and meningitis in a mouse model. However, the underlying mechanisms that govern the antibacterial effects of MEM are still unknown. In this study, we demonstrated that MEM is able to significantly suppress E. coli infection by enhancing E. coli-induced formation and release of NETs in vitro and in vivo. MEM could promote the trapping and bactericidal activities of the polymorphonuclear neutrophils (PMNs) in a manner dependent on α7 nAChR, since knockdown of this receptor noticeably reduces the survival ability of bacteria in PMNs while MEM no longer affects the survival of bacteria in PMNs. Our results also showed that when the expression of S100A9, an antiseptic protein, is inhibited, pathogen survival rates in PMNs increase significantly. MEM reverses this effect in a concentration-dependent manner. MEM stimulates the production of MPO, S100A9, and DNA in PMNs and accelerates the release of depolymerized chromatin fibers into the extracellular space, suggesting the formation of NETs. Taken together, our data suggest that MEM effectively blocks bacterial infection through the promotion of the antibacterial function of NETs induced by E. coli.

BACKGROUND:NF-κB activation, pathogen invasion, polymorphonuclear leukocytes (PMN) transmigration (PMNT) across the blood-brain barrier (BBB) are the pathogenic triad hallmark features of bacterial meningitis, but the mechanisms underlying these events remain largely unknown. Vimentin, which is a novel NF-κB regulator, is the primary receptor for the major Escherichia coli K1 virulence factor IbeA that contributes to the pathogenesis of neonatal bacterial sepsis and meningitis (NSM). We have previously shown that IbeA-induced NF-κB signaling through its primary receptor vimentin as well as its co-receptor PTB-associated splicing factor (PSF) is required for pathogen penetration and leukocyte transmigration across the BBB. This is the first in vivo study to demonstrate how vimentin and related factors contributed to the pathogenic triad of bacterial meningitis. METHODOLOGY/PRINCIPAL FINDINGS:The role of vimentin in IbeA+ E. coli K1-induced NF-κB activation, pathogen invasion, leukocyte transmigration across the BBB has now been demonstrated by using vimentin knockout (KO) mice. In the in vivo studies presented here, IbeA-induced NF-κB activation, E. coli K1 invasion and polymorphonuclear neutrophil (PMN) transmigration across the BBB were significantly reduced in Vim-/- mice. Decreased neuronal injury in the hippocampal dentate gyrus was observed in Vim-/- mice with meningitis. The major inflammatory regulator α7 nAChR and several signaling molecules contributing to NF-κB activation (p65 and p-CamKII) were significantly reduced in the brain tissues of the Vim-/- mice with E. coli meningitis. Furthermore, Vim KO resulted in significant reduction in neuronal injury and in α7 nAChR-mediated calcium signaling. CONCLUSION/SIGNIFICANCE:Vimentin, a novel NF-κB regulator, plays a detrimental role in the host defense against meningitic infection by modulating the NF-κB signaling pathway to increase pathogen invasion, PMN recruitment, BBB permeability and neuronal inflammation. Our findings provide the first evidence for Vim-dependent mechanisms underlying the pathogenic triad of bacterial meningitis.

Puerarin, the main isoflavone glycoside extracted from Radix Puerariae, is an isoflavone traditional Chinese herb. Previous studies have demonstrated that puerarin could regulate osteoblast proliferation and differentiation to promote bone formation. However, the effect of puerarin on the process of human osteoblasts (hOBs) apoptosis is still unclear. In this study, we detected the function of puerarin on serum-free-induced cell apoptosis using ELISA and TUNEL arrays and then found that the mortality of hOBs was significantly decreased after exposure to 10−10–10−6 M puerarin and reached the maximal antiapoptotic effect at the concentration of 10−8 M. In addition, compared with the control group, puerarin notably increased the Bcl-2 protein levels while it decreased the Bax protein levels in the hOBs in a dose-dependent way. 10−7 M puerarin decreased the Bax/Bcl-2 ratio with a maximal decrease to 0.08. Moreover, puerarin activated ERK signaling pathways in hOBs, and the antiapoptotic effect induced by puerarin was abolished by incubation of ERK inhibitor PD98059. Similarly, the estrogen receptor antagonist ICI182780 also suppressed the inhibitory effect of puerarin on hOBs apoptosis. In conclusion, puerarin could prevent hOBs apoptosis via ERK signaling pathway, which might be effective in providing protection against bone loss and bone remolding associated with osteoporosis.

Background: Cryptococcal meningitis is the most common fungal infection of the central nervous system (CNS) in HIV/AIDS. HIV-1 virotoxins (e.g., gp41) are able to induce disorders of the blood-brain barrier (BBB), which mainly consists of BMEC. Our recent study suggests that α7 nAChR is an essential regulator of inflammation, which contributes to regulation of NF-κB signaling, neuroinflammation and BBB disorders caused by microbial (e.g., HIV-1 gp120) and non-microbial [e.g., methamphetamine (METH)] factors. However, the underlying mechanisms for multiple comorbidities are unclear. Methods: In this report, an aggravating role of α7 nAChR in host defense against CNS disorders caused by these comorbidities was demonstrated by chemical [inhibitor: methyllycaconitine (MLA)] and genetic (α7-/- mice) blockages of α7 nAChR. Results: As shown in our in vivo studies, BBB injury was significantly reduced in α7-/- mice infected with C. neoformans. Stimulation by the gp41 ectodomain peptide (gp41-I90) and METH was abolished in the α7-/- animals. C. neoformans and gp41-I90 could activate NF-κB. Gp41-I90- and METH-induced monocyte transmigration and senescence were significantly inhibited by MLA and CAPE (caffeic acid phenethyl ester, an NF-κB inhibitor). Conclusions: Collectively, our data suggest that α7 nAChR plays a detrimental role in the host defense against C. neoformans- and HIV-1 associated comorbidity factors-induced BBB injury and CNS disorders. [ABSTRACT FROM AUTHOR]

After successful pilot projects, Zhejiang Province, China, decided to systematically scale-up health promoting schools (HPS) over the entire province of 47 million. This study describes the interventions and self-reported changes in attitudes, knowledge and behavior during the first phase of scaling-up. Group interviews were conducted with a sample of 191 participants (school administrators, teachers, students and parents) from nine schools with a total of 15 200 students. Grounded theory guided data analysis. Schools implemented all HPS components (school health policy, physical school environment, psychosocial school environment, health education, health services, nutrition services, counseling/mental health, physical exercise, health promotion for staff and outreach to families and communities), adapted to local circumstances. Participants reported a range of changes in attitudes (paying more attention to health, attaining better 'psychological quality' and confidence, forming friendships between teachers and students and feeling more relaxed), knowledge and concepts (increasing knowledge about various health issues, developing a broader concept of health and gaining better understanding about the HPS concept) and behavior (actively participating, increasing physical activity, improving sanitary habits, reducing or quitting smoking, eating more nutritiously, increasing safety behavior, sustaining less injuries and improving parent-child communication). This qualitative study shows the feasibility and efficacy of implementing HPS in Zhejiang Province, China. [ABSTRACT FROM AUTHOR]