SWI/SNF mediates polycomb eviction and epigenetic reprogramming of the INK4b-ARF-INK4a locus

Stable silencing of the INK4b-ARF-INK4a tumor suppressor locus occurs in a variety of human cancers, including malignant rhabdoid tumors (MRTs). MRTs are extremely aggressive cancers caused by the loss of the hSNF5 subunit of the SWI/SNF chromatin-remodeling complex. We found previously that, in MRT cells, hSNF5 is required for p16(INK4a) induction, mitotic checkpoint activation, and cellular senescence. Here, we investigated how the balance between Polycomb group (PcG) silencing and SWI/SNF activation affects epigenetic control of the INK4b-ARF-INK4a locus in MRT cells. hSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15(INK4b) and p16(INK4a), but not of p14(ARF). Gene activation by hSNF5 is strictly dependent on the SWI/SNF motor subunit BRG1. SWI/SNF mediates eviction of the PRC1 and PRC2 PcG silencers and extensive chromatin reprogramming. Concomitant with PcG complex removal, the mixed lineage leukemia 1 (MLL1) protein is recruited and active histone marks supplant repressive ones. Strikingly, loss of PcG complexes is accompanied by DNA methyltransferase DNMT3B dissociation and reduced DNA methylation. Thus, various chromatin states can be modulated by SWI/SNF action. Collectively, these findings emphasize the close interconnectivity and dynamics of diverse chromatin modifications in cancer and gene control.     

Fungal proteases induce Th2 polarization through limited dendritic cell maturation and reduced production of IL-12

Allergens are capable of polarizing the T cell immune response toward a Th2 cytokine profile in a process that is mediated by dendritic cells (DCs). Proteases derived from Aspergillus species (Aspergillus proteases; AP) have been shown to induce a Th2-like immune response when administered directly to the airway and without adjuvant or prior priming immunizations at sites remote from the lung in models of allergic airway disease. To explore mechanisms that underlie the Th2 immune response, we have investigated the effect of AP on DC function. We found that human DCs derived from CD14(+) monocytes from healthy donors underwent partial maturation when incubated with AP. Naive allogeneic T cells primed with AP-activated DCs proliferated and displayed enhanced production of IL-4 and reduced expression of IFN-gamma as compared with naive T cells primed with LPS-activated DCs. Global gene expression analysis of DCs revealed relatively low expression of IL-12p40 in AP-activated DCs as compared with those activated by LPS, and this was confirmed at the protein level by ELISA. Exogenous IL-12p70 added to cocultures of DCs and T cells resulted in reduced IL-4 and increased IFN-gamma expression when DCs were activated with AP. When the proteolytic activity of AP was neutralized by chemical inactivation it failed to up-regulate costimulatory molecules on DCs, and these DCs did not prime a Th2 response in naive T cells. These findings provide a mechanism for explaining how proteolytically active allergens could preferentially induce Th2 responses through limited maturation of DCs with reduced production of IL-12.     

Dual protective mechanisms of matrix metalloproteinases 2 and 9 in immune defense against Streptococcus pneumoniae

A localized and effective innate immune response to pathogenic bacterial invasion is central to host survival. Identification of the critical local innate mediators of lung defense against such pathogens is essential for a complete understanding of the mechanism(s) underlying effective host defense. In an acute model of Streptococcus pneumoniae lung infection, deficiency in matrix metalloproteinase (MMP)2 and MMP9 (Mmp2/9(-/-)) conferred a survival disadvantage relative to wild-type mice treated under the same conditions. S. pneumoniae-infected Mmp2/9(-/-) mice recruited more polymorphonuclear leukocytes to the lung but had higher bacterial burdens. Mmp2/9(-/-) mice showed significantly higher levels of IL-17A, IP-10, and RANTES in the lung. Although MMP2-dependent cleavage partially inactivated IL-17A, MMP9 was critical for effective bacterial phagocytosis and reactive oxygen species generation in polymorphonuclear neutrophils. These data demonstrate critical nonredundant and protective roles for MMP2 and MMP9 in the early host immune response against S. pneumoniae infection.     

Sublethal effects of fenazaquin on life table parameters of the predatory mite Amblyseius swirskii (Acari: Phytoseiidae)

Knowledge of the impact of acaricides on predatory mites is crucial for integrated pest management programs. The present study evaluated the sublethal effect of fenazaquin (Pride^® 20 % SC, Behavar, Iran) on life table parameters of the subsequent generation of the predatory mite, Amblyseius swirskii Athias-Henriot (Acari: Phytoseiidae), fed on Tetranychus urticae Koch under laboratory conditions [26 ± 1 °C, 70 ± 3 % RH and 16:8 (L:D) h]. The sublethal concentrations including LC₁₀, LC₂₀ and LC₃₀ were determined using a dose–effect assay. The total development time of both sexes enhanced with an increase in concentration. The oviposition period and total fecundity decreased in dose-dependent manner. The intrinsic rate of increase (r) and finite rate of increase (λ) significantly descended with concentration enhancing from LC₁₀ to LC₃₀, compared with the control. The net reproductive rate (R ₀) ranged between 2.76 and 7.37 offspring. Overall, the results indicated that fenazaquin had negative effects on development and life table parameters of the subsequent generation of A. swirskii. In conclusion, fenazaquin is not a compatible acaricide with A. swirskii and should not be used with this predatory mite in integrated management of T. urticae.     

Antielastin autoimmunity in tobacco smoking-induced emphysema

Chronic obstructive pulmonary disease and emphysema are common destructive inflammatory diseases that are leading causes of death worldwide. Here we show that emphysema is an autoimmune disease characterized by the presence of antielastin antibody and T-helper type 1 (T(H)1) responses, which correlate with emphysema severity. These findings link emphysema to adaptive immunity against a specific lung antigen and suggest the potential for autoimmune pathology of other elastin-rich tissues such as the arteries and skin of smokers.     

A protease-activated pathway underlying Th cell type 2 activation and allergic lung disease

The respiratory allergens that induce experimental Th cell type 2-dependent allergic lung inflammation may be grouped into two functional classes. One class of allergens, in this study termed type I, requires priming with adjuvants remote from the lung to overcome airway tolerogenic mechanisms that ordinarily preclude allergic responses to inhaled Ags. In contrast, the other, or type II, allergen class requires neither remote priming nor additional adjuvants to overcome airway tolerance and elicit robust allergic lung disease. In this study, we show in an experimental model that diverse type II allergens share in common proteolytic activity that is both necessary and sufficient for overcoming airway tolerance and induction of pulmonary allergic disease. Inactivated protease and protease-free Ag fragments showed no allergenic potency, demonstrating that only active protease acting on endogenous substrates was essential. Furthermore, induction of airway tolerance could be aborted and allergic lung disease established by simply adding purified protease to a type I allergen. Thus, exogenous proteases are common to type II allergens and may be generally required to overcome the innate resistance of the airway to Th cell type 2 activation and allergic inflammation, raising concern for their potential contribution to diseases such as asthma.     

Prevalence of restless legs syndrome in pregnant women: a meta-analysis

Sleep and Biological Rhythms - Restless legs syndrome is a neuromotor problem which is more common among pregnant women. Several studies have reported different prevalences for this disorder....     

Proteomic identification of in vivo substrates for matrix metalloproteinases 2 and 9 reveals a mechanism for resolution of inflammation

Clearance of allergic inflammatory cells from the lung through matrix metalloproteinases (MMPs) is necessary to prevent lethal asphyxiation, but mechanistic insight into this essential homeostatic process is lacking. In this study, we have used a proteomics approach to determine how MMPs promote egression of lung inflammatory cells through the airway. MMP2- and MMP9-dependent cleavage of individual Th2 chemokines modulated their chemotactic activity; however, the net effect of complementing bronchoalveolar lavage fluid of allergen-challenged MMP2(-/-)/MMP9(-/-) mice with active MMP2 and MMP9 was to markedly enhance its overall chemotactic activity. In the bronchoalveolar fluid of MMP2(-/-)/MMP9(-/-) allergic mice, we identified several chemotactic molecules that possessed putative MMP2 and MMP9 cleavage sites and were present as higher molecular mass species. In vitro cleavage assays and mass spectroscopy confirmed that three of the identified proteins, Ym1, S100A8, and S100A9, were substrates of MMP2, MMP9, or both. Function-blocking Abs to S100 proteins significantly altered allergic inflammatory cell migration into the alveolar space. Thus, an important effect of MMPs is to differentially modify chemotactic bioactivity through proteolytic processing of proteins present in the airway. These findings provide a molecular mechanism to explain the enhanced clearance of lung inflammatory cells through the airway and reveal a novel approach to target new therapies for asthma.     

Ghrelin attenuates heat-induced degenerative effects in the rat testis

This study was conducted to examine the efficacy of ghrelin in prevention of deleterious effects of heat stress in rat testicular tissue. Forty five adult male rats were scheduled for this study and were divided equally into three groups: heat-saline, heat-ghrelin and control-saline. The scrota of heated-designed rats were immersed once in water bath at 43 °C for 15 min. Immediately upon heating, 2 nmol of ghrelin were given subcutaneously to heat-ghrelin animals every other day up to day 60 and physiological saline to the other two groups using the same method. The animals were sacrificed at 10, 30 and 60 days after heat treatment and their testes were taken for later photomicrograph and immunohistochemical analysis. Testicular histopathology revealed a significant reduction in the means of seminiferous tubules and Sertoli cell nucleus diameters as well as germinal epithelium height on day 10 in both heated groups. Furthermore, other testicular components including miotic index, spermatogenesis rate, presence of spermatocytes and volume densities were dramatically decreased following heat exposure. Notably, ghrelin caused a partial recovery in all of the above-mentioned parameters and accelerated testicular regeneration process by day 30 compared to the heat-saline group (P<0.05). Because of testicular progressive recovery, these indices were similar among groups on day 60 (P>0.05). However, immunohistochemistry evaluation for in situ detection of Bcl-2 protein did not exhibit any germ cells-positive of this factor among groups at different experimental days. In conclusion, the results of the present study indicate for the first time the novel evidences of ghrelin ability in attenuation of heat-induced testicular damage and also that ghrelin therapy may be useful as a suppressor of degenerative effects following testicular hyperthermia.