1 Inflammmatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leucocyte infiltration and upregulation of proinflammatory cytokines. In this study, we have investigated the protective effects of curcumin, an anti-inflammatory and antioxidant food derivative, on 2,4,6-trinitrobenzene sulphonic acid-induced colitis in mice, a model for IBD. 2 Intestinal lesions (judged by macroscopic and histological score) were associated with neutrophil infiltration (measured as increase in myeloperoxidase activity in the mucosa), increased serine protease activity (may be involved in the degradation of colonic tissue) and high levels of malondialdehyde (an indicator of lipid peroxidation). 3 Dose -response studies revealed that pretreatment of mice with curcumin (50 mg kg À1 daily i.g. for 10 days) significantly ameliorated the appearance of diarrhoea and the disruption of colonic architecture. Higher doses (100 and 300 mg kg À1 ) had comparable effects. 4 In curcumin-pretreated mice, there was a significant reduction in the degree of both neutrophil infiltration (measured as decrease in myeloperoxidase activity) and lipid peroxidation (measured as decrease in malondialdehyde activity) in the inflamed colon as well as decreased serine protease activity. 5 Curcumin also reduced the levels of nitric oxide (NO) and O 2 À associated with the favourable expression of Th1 and Th2 cytokines and inducible NO synthase. Consistent with these observations, nuclear factor-kB activation in colonic mucosa was suppressed in the curcumin-treated mice. 6 These findings suggest that curcumin or diferuloylmethane, a major component of the food flavour turmeric, exerts beneficial effects in experimental colitis and may, therefore, be useful in the treatment of IBD.

Leishmania donovani parasites are the cause of visceral leishmaniasis and are transmitted by bites from phlebotomine sand flies. A prominent feature of vector-transmitted Leishmania is the persistence of neutrophils at bite sites, where they protect captured parasites, leading to enhanced disease. Here, we demonstrate that gut microbes from the sand fly are egested into host skin alongside Leishmania parasites. The egested microbes trigger the inflammasome, leading to a rapid production of interleukin-1β (IL-1β), which sustains neutrophil infiltration. Reducing midgut microbiota by pretreatment of Leishmania-infected sand flies with antibiotics or neutralizing the effect of IL-1β in bitten mice abrogates neutrophil recruitment. These early events are associated with impairment of parasite visceralization, indicating that both gut microbiota and IL-1β are important for the establishment of Leishmania infections. Considering that arthropods harbor a rich microbiota, its potential egestion after bites may be a shared mechanism that contributes to severity of vector-borne disease.

Background: How glucocorticoids affect ER-positive breast cancer cell proliferation is unclear.Results: GR occupies ERα-binding regions (EBRs) via tethering to AP1 and ERα.Conclusion: Interaction of GR with EBRs via ERα and AP1 inhibits E2-ERα activity.Significance: Breast tumors with ERα and AP1 expression will be responsive to glucocorticoid therapy; the study establishes a foundation for personalized medicine for BC.

Leishmaniasis is a neglected tropical disease caused by Leishmania protozoa transmitted by infected sand flies. Vaccination through leishmanization with live Leishmania major has been used successfully but is no longer practiced because it resulted in occasional skin lesions. A second generation leishmanization is described here using a CRISPR genome edited L. major strain ( LmCen −/− ). Notably, LmCen −/− is a genetically engineered centrin gene knock-out mutant strain that is antibiotic resistant marker free and does not have detectable off-target mutations. Mice immunized with LmCen −/− have no visible lesions following challenge with L. major -infected sand flies, while non-immunized animals develop large and progressive lesions with a 2-log fold higher parasite burden. LmCen −/− immunization results in protection and an immune response comparable to leishmanization. LmCen −/− is safe since it is unable to cause disease in immunocompromised mice, induces robust host protection against vector sand fly challenge and because it is marker free, can be advanced to human vaccine trials.

Multiple factors influence estrogen receptor ␣ (ER␣) transcriptional activity. Current models suggest that the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor functions within a histone deactylase-containing protein complex that binds to antiestrogen-bound ER␣ and contributes to negative regulation of gene expression. In this report, we demonstrate that SMRT is required for full agonistdependent ER␣ activation. Chromatin immunoprecipitation assays demonstrate that SMRT, like ER␣ and the SRC-3 coactivator, is recruited to an estrogen-responsive promoter in estrogen-treated MCF-7 cells. Depletion of SMRT, but not histone deacetylases 1 or 3, negatively impacts estradiol-stimulated ER␣ transcriptional activity, while exogenous expression of SMRT's receptor interaction domains blocks ER␣ activity, indicating a functional interaction between this corepressor and agonist-bound ER␣. Stimulation of estradiol-induced ER␣ activity by SMRT overexpression occurred in HeLa and MCF-7 cells, but not HepG2 cells, indicating that these positive effects are cell type specific. Similarly, the ability of SMRT depletion to promote the agonist activity of tamoxifen was observed for HeLa but not MCF-7 cells. Furthermore, impairment of agoniststimulated activity by SMRT depletion is specific to ER␣ and not observed for receptors for vitamin D, androgen, or thyroid hormone. Nuclear receptor corepressor (N-CoR) depletion increased the transcriptional activity of all four tested receptors. SMRT is required for full expression of the ER␣ target genes cyclin D1, BCL-2, and progesterone receptor but not pS2, and its depletion significantly attenuated estrogen-dependent proliferation of MCF-7 cells. Taken together, these data indicate that SMRT, in conjunction with gene-specific and cell-dependent factors, is required for positively regulating agonist-dependent ER␣ transcriptional activity.Estrogens are potent mitogens in a number of target tissues, including the mammary gland, where they play a pivotal role in the development and progression of breast tumorigenesis. The effects of estrogen are mediated via estrogen receptor ␣ (ER␣) and ER␤, which are nuclear receptors that belong to a superfamily of ligand-regulated transcription factors (61). Subsequent to estradiol (E2) binding to ER␣, the receptor undergoes a conformational change, dimerizes, and either binds directly to DNA via estrogen response elements (EREs) or indirectly binds DNA via interactions with other DNA-bound transcription factors, such as Sp1 or AP-1 (41, 61, 68). Although ER␣ binds within the promoter regions of some estrogen-sensitive target genes, it has been estimated that only ϳ4% of ER␣ binding sites lie within 1 kb of proximal promoter regions, and the good correlation of ER␣ binding sites within 50 kb of the transcriptional start sites of estrogen-induced genes suggests that ER␣ can regulate the expression of these genes from a substantial distance (7-9, 42). The central involvement of estrogens in the genesis and progression of b...