Advances in metal-induced oxidative stress and human disease

Objective:To assess the magnitude and direction of associations of depression with C-reactive protein (CRP), interleukin (IL)-1, and IL-6 in community and clinical samples.Methods:Systematic review of articles published between January 1967 and January 2008 in the PubMed and PsycINFO electronic data

Associations of Depression With C-Reactive Protein, IL-1, and IL-6 : A Meta-Analysis

The recent sequencing of the entire genomes of Mycoplasma genitalium and M. pneumoniae has attracted considerable attention to the molecular biology of mycoplasmas, the smallest self-replicating organisms. It appears that we are now much closer to the goal of defining, in molecular terms, the entire machinery of a self-replicating cell. Comparative genomics based on comparison of the genomic makeup of mycoplasmal genomes with those of other bacteria, has opened new ways of looking at the evolutionary history of the mycoplasmas. There is now solid genetic support for the hypothesis that mycoplasmas have evolved as a branch of gram-positive bacteria by a process of reductive evolution. During this process, the mycoplasmas lost considerable portions of their ancestors’ chromosomes but retained the genes essential for life. Thus, the mycoplasmal genomes carry a high percentage of conserved genes, greatly facilitating gene annotation. The significant genome compaction that occurred in mycoplasmas was made possible by adopting a parasitic mode of life. The supply of nutrients from their hosts apparently enabled mycoplasmas to lose, during evolution, the genes for many assimilative processes. During their evolution and adaptation to a parasitic mode of life, the mycoplasmas have developed various genetic systems providing a highly plastic set of variable surface proteins to evade the host immune system. The uniqueness of the mycoplasmal systems is manifested by the presence of highly mutable modules combined with an ability to expand the antigenic repertoire by generating structural alternatives, all compressed into limited genomic sequences. In the absence of a cell wall and a periplasmic space, the majority of surface variable antigens in mycoplasmas are lipoproteins. Apart from providing specific antimycoplasmal defense, the host immune system is also involved in the development of pathogenic lesions and exacerbation of mycoplasma induced diseases. Mycoplasmas are able to stimulate as well as suppress lymphocytes in a nonspecific, polyclonal manner, both in vitro and in vivo. As well as to affecting various subsets of lymphocytes, mycoplasmas and mycoplasma-derived cell components modulate the activities of monocytes/macrophages and NK cells and trigger the production of a wide variety of up-regulating and down-regulating cytokines and chemokines. Mycoplasma-mediated secretion of proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin-1 (IL-1), and IL-6, by macrophages and of up-regulating cytokines by mitogenically stimulated lymphocytes plays a major role in mycoplasma-induced immune system modulation and inflammatory responses.

Molecular Biology and Pathogenicity of Mycoplasmas

Zinc and immune function: the biological basis of altered resistance to infection.

IBD, comprising Crohn's disease and ulcerative colitis, is a chronic immunologically mediated disease at the intersection of complex interactions between genetics, environment and gut microbiota. Established high-prevalence populations of IBD in North America and Europe experienced the steepest increase in incidence towards the second half of the twentieth century. Furthermore, populations previously considered 'low risk' (such as in Japan and India) are witnessing an increase in incidence. Potentially relevant environmental influences span the spectrum of life from mode of childbirth and early-life exposures (including breastfeeding and antibiotic exposure in infancy) to exposures later on in adulthood (including smoking, major life stressors, diet and lifestyle). Data support an association between smoking and Crohn's disease whereas smoking cessation, but not current smoking, is associated with an increased risk of ulcerative colitis. Dietary fibre (particularly fruits and vegetables), saturated fats, depression and impaired sleep, and low vitamin D levels have all been associated with incident IBD. Interventional studies assessing the effects of modifying these risk factors on natural history and patient outcomes are an important unmet need. In this Review, the changing epidemiology of IBD, mechanisms behind various environmental associations and interventional studies to modify risk factors and disease course are discussed.

Epidemiology and risk factors for IBD

MHC class II (MHC-II) molecules are capable of transducing signals with the help of associated molecules. Although the search to find associated molecules over the past few years has been fruitful, it remains clear that not all signaling components and their mechanisms of action have been identified. In this study, we investigated calcium and MAPK signaling pathways using the BJAB and Raji human B cell lines. We demonstrate that calcium mobilization is an isotype-independent event that triggers the dephosphorylation of NFAT. We also show that BCR activation followed by MHC-II ligation increases the activation of NFAT. This signaling pathway differs from MHC-II-mediated MAP activation, where MEK1/2 and ERK1/2 phosphorylation are isotype-specific events, which correspond to the induction of c-Fos and formation of AP-1. Future studies should elucidate the intertwined, intricate signaling cascades triggered by BCR and MHC-II leading to humoral immune responses.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/eji.200838992

MHC class II molecules activate NFAT and the ERK group of MAPK through distinct signaling pathways in B cells

Excessive and permanent cytokine production in response to bacterial LPS causes cell and tissue damage, and hence organ failure during sepsis. We have previously demonstrated that zinc treatment prevents LPS-induced TNF-α expression and production in human monocytes by inhibiting cyclic nucleotide phosphodiesterase (PDE) activity and expression, and subsequent elevation of the cyclic nucleotide cGMP. In the present study, we investigated the molecular mechanism by which cGMP signaling affects the LPS-induced signaling cascade to suppress TNF-α transcription and release from monocytes. Zinc-mediated cGMP elevation led to cross activation of protein kinase A. This zinc-induced protein kinase A activation inhibited Raf-1 activity by phosphorylation at serine 259, preventing activation of Raf-1 by phosphorylation of serine 338. By this mechanism, zinc suppressed LPS-induced activation of IκB kinase β (IKKβ) and NF-κB, and subsequent TNF-α production. Our study shows that PDE inhibition by zinc modulates the monocytic immune response by selectively intervening in the Raf-1/IKKβ/NF-κB pathway, which may constitute a common mechanism for the anti-inflammatory action of PDE inhibitors.

/pdf/zinc-dependent-suppression-of-tnf-a-production-is-mediated-1hbsh7u94w.pdf

Zinc-Dependent Suppression of TNF-α Production Is Mediated by Protein Kinase A-Induced Inhibition of Raf-1, IκB Kinase β, and NF-κB

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MHC class II molecules activate NFAT and the ERK group of MAPK through distinct signaling pathways in B cells

Zinc-Dependent Suppression of TNF-α Production Is Mediated by Protein Kinase A-Induced Inhibition of Raf-1, IκB Kinase β, and NF-κB