SummaryInflammatory bowel disease (IBD), a chronic intestinal inflammatory condition that affects millions of people worldwide, results in high morbidity and exorbitant health-care costs. The critical features of both innate and adaptive immunity are to control inflammation and dysfunction in this equilibrium is believed to be the reason for the development of IBD. miR-155, a microRNA, is up-regulated in various inflammatory disease states, including IBD, and is a positive regulator of T-cell responses.
Staphylococcal enterotoxin B (SEB) is a potent superantigen produced by Staphylococcus aureus that triggers a strong immune response, characterized by cytokine storm, multi‐organ failure, and often death. When inhaled, SEB can cause acute lung injury (ALI) and respiratory failure. In this study, we investigated the effect of resveratrol (RES), a phytoallexin, on SEB‐driven ALI and mortality in mice. We used a dual‐exposure model of SEB in C3H/HeJ mice, which caused 100% mortality within the first 5 days of exposure, and treatment with RES resulted in 100% survival of these mice up to 10 days post‐SEB exposure. RES reduced the inflammatory cytokines in the serum and lungs, as well as T cell infiltration into the lungs caused by SEB. Treatment with RES also caused increased production of transforming growth factor‐beta (TGF‐β) in the blood and lungs. RES altered the miRNA profile in the immune cells isolated from the lungs. Of these, miR‐193a was strongly induced by SEB and was down‐regulated by RES treatment. Furthermore, transfection studies and pathway analyses revealed that miR‐193a targeted several molecules involved in TGF‐β signalling (TGFβ2, TGFβR3) and activation of apoptotic pathways death receptor‐6 (DR6). Together, our studies suggest that RES can effectively neutralize SEB‐mediated lung injury and mortality through potential regulation of miRNA that promote anti‐inflammatory activities.
These results represent the first patient-reported dataset on hypoglycemia in the participating countries and confirm that hypoglycemia is under-reported and more widespread than previously believed. Although the incidence of hypoglycemia was variable among patients on different treatment regimens, there were substantial impacts on both productivity and healthcare utilization following an episode of hypoglycemia. This trial is registered at clinicaltrials.gov: NCT02306681.
Primary immunodeficiencies are heritable disorders of immune function. CD19 is a B cell co-receptor important for B cell development, and CD19 deficiency is a known genetic risk factor for a rare form of primary immunodeficiency known as “common variable immunodeficiency” (CVID); an antibody deficiency resulting in low levels of serum IgG and IgA. Enteropathies are commonly observed in CVID patients but the underlying reason for this is undefined. Here, we utilize CD19−/− mice as a model of CVID to test the hypothesis that antibody deficiency negatively impacts gut physiology under steady-state conditions. As anticipated, immune phenotyping experiments demonstrate that CD19−/− mice develop a severe B cell deficiency in gut-associated lymphoid tissues that result in significant reductions to antibody concentrations in the gut lumen. Antibody deficiency was associated with defective anti-commensal IgA responses and the outgrowth of anaerobic bacteria in the gut. Expansion of anaerobic bacteria coincides with the development of a chronic inflammatory condition in the gut of CD19−/− mice that results in an intestinal malabsorption characterized by defects in lipid metabolism and transport. Administration of the antibiotic metronidazole to target anaerobic members of the microbiota rescues mice from disease indicating that intestinal malabsorption is a microbiota-dependent phenomenon. Finally, intestinal malabsorption in CD19−/− mice is a gluten-sensitive enteropathy as exposure to a gluten-free diet also significantly reduces disease severity in CD19−/− mice. Collectively, these results support an effect of antibody deficiency on steady-state gut physiology that compliment emerging data from human studies linking IgA deficiency with non-infectious complications associated with CVID. They also demonstrate that CD19−/− mice are a useful model for studying the role of B cell deficiency and gut dysbiosis on gluten-sensitive enteropathies; a rapidly emerging group of diseases in humans with an unknown etiology.
Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), which is thought to result from immune-mediated inflammatory disorders, leads to high morbidity and health care cost. Fatty acid amide hydrolase (FAAH) is an enzyme crucially involved in the modulation of intestinal physiology through anandamide (AEA) and other endocannabinoids. Here we examined the effects of an FAAH inhibitor (FAAH-II), on dextran sodium sulphate (DSS)-induced experimental colitis in mice. Treatments with FAAH-II improved overall clinical scores by reversing weight loss and colitis-associated pathogenesis. The frequencies of activated CD4+ T cells in spleens, mesenteric lymph nodes (MLNs), Peyer's patches (PPs), and colon lamina propiria (LP) were reduced by FAAH inhibition. Similarly, the frequencies of macrophages, neutrophils, natural killer (NK), and NKT cells in the PPs and LP of mice with colitis declined after FAAH blockade, as did concentrations of systemic and colon inflammatory cytokines. Microarray analysis showed that 26 miRNAs from MLNs and 217 from PPs had a 1.5-fold greater difference in expression after FAAH inhibition. Among them, 8 miRNAs were determined by reverse-transcription polymerase chain reaction (RT-PCR) analysis to have anti-inflammatory properties. Pathway analysis demonstrated that differentially regulated miRNAs target mRNA associated with inflammation. Thus, FAAH-II ameliorates experimental colitis by reducing not only the number of activated T cells but also the frequency of macrophages, neutrophils, and NK/NKT cell, as well as inflammatory miRNAs and cytokine at effector sites in the colon. These studies demonstrate for the first time that FAAH-II inhibitor may suppress colitis through regulation of pro-inflammatory miRNAs expression.
Chemokines (CXCR3) and their ligands (CXCL9, CXCL10, and CXCL11) exert exquisite control over T-cell trafficking and are critical for activation, differentiation and effector T cell function. CXCR3 is important for CD4 Th1 cells, CD8 effectors, memory cells, and for the function of natural killer and natural killer T cells. The presence of high cytotoxic CXCR3 ligand expression on CD8 T cells in colorectal cancerous tissue has been well documented in the past. CXCR3 and its ligands are differentially expressed at sites of inflammation and within the tumors. Further, the expression of CXCR3 and its ligands has been correlated with both the presence of effector T cells within tumor tissue and disease-free survival of patients. However, effector T cell infiltration into primary and metastatic tumors is highly variable and, in fact, often absent. Thus, understanding why T cells fail to infiltrate into tumors and determining the way to improve effector T cell entry into tumors would be important advances in efforts to harness the power of the immune system to fight cancer. To this end, the recent exciting discovery that CXCR3 is functionally expressed on regulatory T cells and also induces the differentiation of peripheral CD4 T cells into regulatory T cells, might address the novel clinically relevant question of the therapeutic potential of the CXCR3 system. This is also coupled with the fact that increases in CXCR3 expression also improves effector T cell function. This review describes the differential role of CXCR3 induction on peripheral and tumor microenvironment inflammation. Further, this review, tied with important findings from our laboratory, demonstrates that polyphenols induce CXCR3 expression on regulatory T cells and increases CXCR3 ligands in the tumor microenvironment, which act together to suppress colorectal cancer through a differential mechanism discussed herewith.
Background: Previous research has found that African American (AA) vegetarians/vegans have a significantly lower body mass index and risk of hypertension compared to omnivores. Objectives: The Nutritious Eating with Soul (NEW Soul) study partnered with local soul food restaurants/chefs to deliver two behavioral nutrition interventions to AA adults. NEW Soul examines the impact of two different culturally tailored diets (vegan and omnivorous low-fat) on changes in risk factors for cardiovascular disease (CVD). Methods: AA adults with overweight or obesity are recruited from the community in the Midlands of South Carolina. Eligible participants are randomized to follow one of two different culturally-adapted, soul food diets: a vegan diet emphasizing minimally-processed whole foods from plants or a low-fat omnivorous diet. Participants attend weekly group classes for the first six months, biweekly for the next six months, and monthly meetings for the last year. In addition to face-to-face content, participants also have access to private Facebook groups for their diet, podcasts, and online newsletters starting at six months. Primary outcomes include changes in body weight and CVD risk factors (lipids, blood pressure, glucose, and insulin) at 12 months. Secondary outcomes include changes in dietary intake. Participants complete assessments at baseline and at months 6, 12, and 24. Conclusions: The NEW Soul study is an innovative intervention aimed at improving dietary intake while maintaining traditional AA cultural food choices. Primary outcomes are expected by 2021.
Parasitic isopods (family Bopyridae) and burrowing barnacles (family Trypetesidae) infesting hermit crabs were investigated from shallow subtidal collections made along the southeastern coast of Spain in 2009. A total of 713 specimens of Clibanarius erythropus (Latreille, 1818) and 82 Calcinus tubularis (L., 1767) were examined. Gastropod shells and worm tubes inhabited by hermit crabs were collected by hand while snorkeling and were cracked to determine host species, size, sex and presence of eggs. Two species of bopyrid isopods were found on C. erythropus: the branchial parasite Bopyrissa fraiseii (Carayon, 1943) and the abdominal parasite Parathelges cardonae Codreanu and Codreanu in Codreanu, 1968. Among all C. erythropus examined, Bopyrissa fraiseii was found on 0.6% of hermit crabs and P. cardonae was found on 0.3%. A redescription of P. cardonae is provided and the species is documented with light and scanning electron microscopy for the first time. No Calcinus tubularis harbored parasitic isopods, but one specimen was parasitized by an unidentified rhizocephalan barnacle of the genus Septosaccus (1.2%). The burrowing barnacle Trypetesa lampas (Hancock, 1849) was found associated with both hermit crab species and evidence of predation on host eggs by this barnacle is shown for the first time. Trypetesa lampas was found in 4.2% of the shells collected. The present study expands our knowledge of the parasite fauna of hermit crabs from the Mediterranean Sea and indicates that additional research is needed to determine the impact of trypetesid egg predators on hermit crab populations.
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