The gastrointestinal tract is an active player of the human immune system, participating in the innate and adaptive immune responses, keeping the homeostasis of the human being in a healthy status. ...However, most intestinal conditions are associated with an altered immune response, which implies the activation of CD4+ T helper (Th) cells. Based on their cytokine secretion, transcription factor expression and immunological functions, the differentiated Th cells were initially subdivided into different lineages: Th1 (that express the transcription factor T-box (T-bet), secrete interferon (IFN)-γ and protect the host against intracellular infections) and Th2 (that express GATA binding protein 3 (GATA-3), secrete interleukin (IL)-4, IL-5 and IL-13, and mediate host defense against helminths). Later, a new subset was identified, the Th17, which selectively produces IL-17A and is crucial for host defense against extracellular pathogens. More recently, a functional plasticity between the Th1 and Th17 lineages has been described, a process sometimes controversial that seems to play a key role in different inflammatory conditions, including those affecting the gastrointestinal system. This review will summarize the current knowledge regarding the regulation and functional role of Th17 cells in the gut, focusing on these newly identified features of this T cell subset, including plasticity, their relationship with regulatory T cells and their heterogeneity in the inflammatory microenvironment. A better understanding of these issues is critical to elucidate the role of Th17 cells in intestine immunity, and so for the design of novel therapeutic approaches for intestinal diseases specifically targeting Th17 cells.
As for other aromatic plants, there are many analytical methods for the determination of volatile compounds in lavender essential oils. Alternatively, in this study RP–HPLC–DAD–QTOF–MS was used for ...the profiling of the phytochemical constituents of hydromethanolic extracts of L. stoechas and L. dentata, which were obtained by pressurized liquid extraction. The spectrometric data revealed complex profiles constituted of a wide range of polar and semi‐polar phytochemicals, mainly, phenolic compounds (68). Most phenolic compounds (55) have not been previously reported in Lavandula; such is the case of caffeic acid‐based oligomers. Moreover, the analytical method was validated for the determination of phenolic compounds. Our findings showed both qualitative and quantitative differences between the extracts. In this sense, while hydroxycinnamic acids made up the largest class in both extracts, flavones were the most abundant class, accounting for 10.44 g (L. dentata) and 4.85 g (L. stoechas) per 100 g of dry extract. In conclusion, this analytical method provided essential information about the phytochemical composition of the studied medicinal plants, revealing novel constituents that were probably hidden for others. In addition, these results may help to understand the anti‐inflammatory properties of these extracts.
•This study evaluates iron and manganese metabolism and the haematological changes provoked by treating rats with BMOV.•It presents the first evaluation of hepcidin mRNA expression in rats exposed to ...BMOV.•Exposure to BMOV increased hepcidin mRNA expression.•Exposure to BMOV increased levels of pro-inflammatory cytokines IL-6 and TNFα.•Exposure to BMOV caused an anaemic state, associated with Fe overload and inflammatory disorder.
The aim of this study was to examine whether alterations in iron homeostasis, caused by exposure to vanadium, are related to changes in the gene expression of hepatic hepcidin. Two groups of rats were examined: control and vanadium-exposed. Vanadium, as bis(maltolato)oxovanadium(IV) was supplied in the drinking water. The experiment had a duration of five weeks. Iron and manganese were measured in excreta, serum and tissues. Leptin, ferritin, IL-1β, IL-6, TNF-α, red blood cells, haemoglobin and haematocrit were determined. Protein carbonyl group levels and hepcidin gene expression were determined in the liver. In the vanadium-exposed rats, iron absorption, serum iron and leptin and all haematological parameters decreased. Levels of IL-6, TNF-α and ferritin in serum and of iron in the liver, spleen and heart increased. In the liver, levels of protein carbonyl groups and hepcidin mRNA were also higher in the vanadium-exposed group. Exposure to vanadium did not modify manganese homeostasis. The results obtained from this study provide the first evidence that bis(maltolato)oxovanadium(IV) produces an increase in the gene expression of the hepcidin, possibly caused by an inflammatory process. Both factors could be the cause of alterations in Fe homeostasis and the appearance of anaemia. However, Mn homeostasis was not affected.
Background
Drug‐induced maculopapular exanthemas (MPEs) are mediated by Th1 CD4+ T cells. One of the mechanisms of control of Th1 cells in homeostasis is the interaction between the checkpoint ...inhibitor Tim3 and its physiological ligand galectin‐9 (Gal9). Disorders affecting this axis may be responsible for various autoimmune and immunological diseases. The aim of this study was to determinate the influence of the Tim3‐Gal9 axis on the development of MPE induced by drugs.
Methods
Frequencies of different cell subsets and the expression of Tim3 and Gal9 were measured in peripheral blood by flow cytometry and in skin biopsies by immunohistochemistry. Gal9 expression was assessed by RT‐qPCR; its release was measured by multiplex assay. The effects of blocking or enhancing the Tim3‐Gal9 axis on monocyte‐derived dendritic cell (moDC) maturation and T‐cell proliferation were determined by flow cytometry.
Results
The expression of Tim3 was significantly reduced in peripheral blood Th1 cells and in the skin of MPE patients vs controls. Gal9 expression and release were significantly reduced in patient peripheral blood and moDCs, respectively. The addition of exogenous Gal9 significantly reduced Tim3+ Th1 proliferation, although Treg proliferation increased.
Conclusion
This study showed the involvement of the Tim3‐Gal9 axis in MPE. The reduced expression of Tim3 in Th1 cells together with the impaired expression of Gal9 in PBMCs and DCs appears to have a role in the development of the disease. The potential of Gal9 to suppress Th1 and enhance Treg proliferation makes it a promising tool for treating these reactions.
The reduced level of the checkpoint molecule Tim3 in Th1 cells together with the impaired expression of Gal9 in PBMCs and dendritic cells hampers the control of Th1 cell numbers in patients with drug‐induced maculopapular exanthema (MPE). The reduced expression of Gal9 in patients with drug‐induced MPE could be responsible for the low frequencies of Treg cells in these patients. Exogenous administration of Gal9 could be a potential therapeutic tool able to suppress Th1 and enhance Treg differentiation in patients with drug‐induced MPE.
Probiotics have been used as alternative therapies in intestinal inflammatory disorders. Many studies have shown that different bacterial probiotic strains possess immuno-modulatory and ...anti-inflammatory properties. However, there is an increasing interest in the use of non-viable bacteria to reduce the risk of microbial translocation and infection. The aim of this study was to evaluate whether the viability of L. fermentum CECT5716 is essential to exert its intestinal anti-inflammatory effect. We compared the preventative effects of viable and non-viable probiotic in the TNBS model of rat colitis. In vitro studies were also performed in Caco-2 and RAW 264.7 cells to evaluate the probiotic effects on IL-8, IL-1β and nitrite production, and p44/42 and p38 MAP kinase protein expressions. In vitro results revealed a decrease in the stimulated production of pro-inflammatory mediators regardless of the viability of the probiotic. Likewise, both forms of the probiotic administered to colitic rats produced a significant reduction of IL-1β and TNF-α levels and colonic iNOS expression. In conclusion, both live and dead L. fermentum CECT5716 have been demonstrated to attenuate the inflammatory process and diminish the production of some of the inflammatory mediators. In fact, the viability of this probiotic did not affect its immuno-modulatory and anti-inflammatory properties.
Nitric-oxide synthase, the enzyme responsible for mammalian nitric oxide generation, and cytochrome P450, the major enzymes involved in drug metabolism, share striking similarities. Therefore, it ...makes sense that cytochrome P450 drug mediated biotransformations might play an important role in the pharmacological modulation of nitric oxide synthase. In this work, we have undertaken an integrated
assessment of the hepatic metabolism and nitric oxide modulation of previously described dual inhibitors (imidazoles and macrolides) of these enzymes in order assess the implication of CYP450 activities over production of nitric oxide.
systems based in human liver microsomes and activated mouse macrophages were developed for these purposes. Additionally
production the hepatic metabolites of dual inhibitor, roxithromycin, was investigated achieving the identification and isolation of main hepatic biotransformation products. Our results suggested that for some macrolide compounds, the cytochrome P450 3A4 derived drug metabolites have an important effect on nitric oxide production and might critically contribute to the pharmacological immunomodulatory activity observed.
Scope
Much of the knowledge about gene expression during anaphylaxis comes from candidate gene studies. Despite their potential role, expression changes in dendritic cells (DCs) have not been studied ...in this context using high throughput methods. The molecular mechanisms underlying food‐antigen‐induced anaphylaxis are investigated using DCs from an animal model.
Methods and results
RNA sequencing is used to study gene expression in lymph‐node‐derived DCs from anaphylactic mice sensitized intranasally with the major peach allergen Pru p 3 during the acute reaction phase, induced intraperitoneally. In total, 237 genes changed significantly, 181 showing at least twofold changes. Almost three‐quarters of these increase during anaphylaxis. A subset is confirmed using RT‐PCR in a second set of samples obtained from a new batch of mice. Enrichment analysis shows an overrepresentation of genes involved in key immune system and inflammatory processes, including TGF‐β signaling. Comparison with a study using anaphylactic human subjects show significant overlap.
Conclusions
The findings provide a comprehensive overview of the transcriptional changes occurring in DCs during anaphylaxis and help elucidate the mechanisms involved. They add further weight to the putative role of these cells in anaphylaxis and highlight genes that may represent potential therapeutic targets.
Mice are sensitized to the major peach allergen Pru p 3 using a previously published protocol. Upon challenge with the specific allergen, they underwent an anaphylactic reaction. Dendritic cells are isolated from their lymph nodes, from which RNA is extracted and sequenced, comparing the results to non‐anaphylactic, non‐sensitized mice to look for differences in gene expression in a high‐throughput manner. Differential expression is found for over 200 genes and multiple immune pathways, including complement activation, LPS signaling, and TGF‐β pathways.
Aim
High blood pressure (BP) is associated with gut microbiota dysbiosis. The aim of this study was to investigate whether changes in gut microbiota induced by exchanging the gut microbiota between ...spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto (WKY) alter the gut‐immune system interaction inducing changes in vascular function and BP.
Methods
Twenty‐week‐old recipient WKY and SHR were orally gavaged with donor faecal contents from WKY or SHR. In additional experiments, we used a design to determine whether blockade of B7‐dependent costimulation with CTLA4‐Ig or blockade of IL‐17 with IL‐17‐neutralizing antibody could prevent hypertension caused by faecal microbiota transplantation (FMT) from SHR to WKY.
Results
Correlation analyses identified the bacterial abundance of Turicibacter and S24‐7_g that, respectively, positively and negatively correlated with systolic BP. FMT from WKY rats to SHR rats reduced basal systolic BP, restored the imbalance between Th17/Treg in mesenteric lymph nodes (MLNs) and aorta, and improved endothelial dysfunction and vascular oxidative status found in SHR transplanted with SHR faeces. FMT from SHR to WKY increased CD80 and CD86 mRNA levels and T cells activation in MLNs, circulating T cells, aortic T cell infiltration, impaired endothelial function and increased basal SBP. These effects were abolished by blockade of B7‐dependent costimulation with CTLA4‐Ig. IL‐17a neutralizing antibody reduced SBP and improved endothelial dysfunction induced by FMT from SHR to WKY.
Conclusion
Gut microbiota is an important factor involved in the control of BP, as a consequence of its effect in T‐cell activation in gut immune system and vascular T‐cells accumulation.
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