Compared with Th2 cells, Th1 cytokines, such as IFN-c and IL-12, are involved in antagonism of Th2 cell responses and IgE synthesis to restrain the progress of asthma. In physiological condition, immune responses of Th1 and Th2 cells maintain dynamic balance. Whenever this balance is disturbed, diseases will occur. Therefore, one effective AMN107 treatment for asthma is to try to improve Th1 immune responses and simultaneously inhibit Th2 immune responses to restore Th1/Th2 balance. Signal transducer and activator of transcription proteins are a group of transcription factors that transmit signals from extracellular milieu of cells to nucleus. It has been demonstrated that the activation of STAT4 and STAT6 is pivotal in naive CD4+ T cell differentiate along Th1 and Th2 pathways. Previous studies indicated that immunization of STAT4-deficient mice resulted in a typical Th2-like immune response. In addition, protein content and mRNA levels of STAT6 in asthma patients/models appeared to arise, STAT4 decreased abnormally. T-box expressed in T-cells, a key transcription factor of Th1 cells, has been identified to promote Th1 development and IFN-c production. What’s more, IFN-c has been shown to induce T-bet expression, which results in a potential positive feedback loop during Th1 cell differentiation. GATA-binding protein-3, as a downstream transcriptional factor of STAT6, plays an important role in Th2 cell development by promoting Th2 cytokine expression through binding to a variety of regulatory regions of Th2 cytokines. At the same time, GATA-3 induction inhibits Th1 differentiation both by increasing IL-4 production, and by inhibiting the master Th1 transcription factor T-bet. Thus, biological compounds targeting these molecules may provide an effective therapeutic modality for patients with asthma. Mangiferin, a natural C-glucoside xanthone and its PubChem identification number, is abundantly present in Mangifera indica Linn leaves.. Aqueous extracts of such leaves have been traditionally used for decades as a remedy for respiratory diseases in Chinese medicine. In Cuba, Vimang products are used for treating inflammatory diseases and cancer. Previous published pharmacological studies, both in vitro and in vivo, indicate that mangiferin has pleiotropic bioactivities, including anti-oxidant, anti-tumor, anti-microbial, anti-diabetic, hepato-, cardio- and radioprotective, and anti-allergic activities. Besides, it also exhibits anti-inflammatory and immunomodulatory properties. There has not yet been found any clinical evidence of adverse effects of mangiferin. Therefore, it could become a promising candidate for developing natural medicine. In our previous studies, we reported that mangiferin had beneficial effects on treatment of chronic inflammation and chronic bronchitis. Recently, anti-asthmatic properties of mangiferin have also been initially described by Rivera DG. They reported that mangiferin could inhibit the airway inflammation based on the histological changes and the reduction of IL-4, IL-5 and IgE levels. However, underlying molecular mechanisms of mangiferin, such as the contributions of Th1 vs Th2 responses, on anti-asthma remain unclear.
Month: February 2020
This is likely driven by the epicardial rather than the microvascular association between OEC function and CFR
More recently, patients with exacerbation of idiopathic pulmonary fibrosis were reported to be associated with increased OEC proliferation. In our study, we did not find a relationship between OEC proliferation and CAD severity, although this disparate result may be related to distinct pathogenic mechanisms underlying CAD and pulmonary disease. There are a number of potential reasons for the conflicting results. Firstly, the previous studies relied solely on angiography to assess CAD severity, a technique which may have limited correlation with the physiological significance of disease severity. Although EPC number and functionality are assumed to reflect the endogenous vascular protective capacity, an alternative explanation for these conflicting BMN673 1207456-01-6 results may be that severe CAD results in ischemia and a pro-inflammatory state, thus leading to EPC mobilization. This explanation is supported by studies showing increased EPC number and clonogenic expansion capacity in vitro in patients suffering from acute coronary syndrome. These results support our findings, where we found that higher OEC levels were associated with less severe CAD. Lastly, other potential reasons for the conflicting results include significant variability between studies in the time point at which early EPC counts were performed, ranging from 4 to 12 days post culture, and the fact that EPC levels may exhibit diurnal variation, so that the differing relationships reported may simply reflect different blood collection times. Our study also explored the relationship between EPCs and the physiologic status of the coronary microcirculation, a critical determinant of cardiovascular outcomes. Previous studies on patients with cardiac syndrome X have yielded conflicting results with regards to EPC levels, with one study reporting higher EPC levels, and another reporting decreased levels and adhesive function of circulating EPCs, when compared to normal controls. Another more recent study involving patients post myocardial infarction reported that the presence of OEC was associated with reduced microvascular obstruction and infarct size, as assessed by cardiac magnetic resonance imaging, suggesting that OEC may be a marker of microvascular integrity. Additionally, EPCs have been shown to correlate with the extent of coronary collateralization by qualitative angiography. Apart from the non-uniform EPC definitions, a possible reason for the disparate results between our present study and the previous studies was that the state of the coronary microcirculation was not physiologically assessed in the previous studies. In the studies involving patients with cardiac syndrome X, the diagnosis of microcirculatory dysfunction was presumed on the basis of exclusion. Assessment of coronary microvascular dysfunction by cardiac MRI may also be compounded by the presence of concomitant epicardial coronary disease.
Indeed carnosol exert some discard that some of the nutrients in the RE may have a part in the observed effects
It should be noted that the major difference between the two diets was the presence of diterpenoids which provided a daily intake of these compounds of,40 mg and,70 mg for the lean and obese rats, respectively. We have previously shown that part of the ingested diterpenoids resist gastric and small intestine conditions and reach the large intestine and therefore, it is plausible that these molecules and their derived metabolites may be involved in the observed effects. The evaluation of novel compounds or extracts with potential prebiotic effects should also take into account the effects of such products on digestive enzymes in the upper gut and in the hydrolysis and fermentation by the microbiota in the large bowel. We have previously reported that the intake of RE causes a significant inhibition of a butyrate-esterase activity in the stomach of Zucker rats and it was hypothesized that this may cause a reduction in the digestion and absorption of fat from the diet. Fecal composition analysis in the present work does not support this hypothesis since we did not find significant differences in the % of fat eliminated in the feces between the control and RE supplemented animals. We have now also evaluated the effects of the consumption of the RE on a-amylase activity in the small intestine and on b-glucosidase in the caecum of the rats. However, fermentation in the caecum produces a significant daily quantity of SCFA which are partially assimilated into host carbohydrates and lipids equivalent to 8% to10% of caloric requirements. Inhibition of the enzyme activities involved in this process such as b-glucosidase may contribute to reduce dietary energy extraction and to moderate body weight gain which may be beneficial. b-Glucosidases are also de-glycosylating enzymes that can release a range of aglycones from plant compounds which may exhibit toxic or healthpromoting activities. The inhibition of this activity in the caecum by the RE can thus have an additional impact on health through regulation of bioactive microbial metabolites production. It has been generally recognized that gut microbiota clearly differs between, genetically- or diet-induced, lean and obese phenotypes. Genetic predisposition to obesity associated to leptin or leptin receptor deficiencies appear to shape a microbiota specialized for enhanced dietary energy recovery with elevated abundance of Firmicutes and reduced abundance of Bacteroidetes compared with lean mice. We also examined changes in some of the main caecum microbiota groups following the intake of the RE. The RE caused a moderate but significant reduction of total caecum bacteria. It has been reported that germ-free mice and antibiotictreated mice display enlarged caecum and changes in the proportions of Firmicutes and Bacteroidetes proportions which suggest that the RE might have a strain specific bactericidal and/or bacteriostatic effect in the caecum.
In the offspring of intrauterine retarded rats by uteroplacental insufficiency the hepatic expression of both PCK1 and FBP1 were increased
Some of the affected proteins have previously been associated with effects of prenatal protein undernutrition in mammalian models and will be discussed in more detail. The GLUT proteins are a family of facilitative transport proteins, catalyzing glucose uptake across the plasma membrane, the rate-limiting step in glucose metabolism. In mammals, GLUT1 is expressed ubiquitously and facilitates the basal glucose uptake, which is essential for growth and development in most cells. Expression of GLUT1 has previously been examined in other mammalian models of prenatal undernutrition, but no differences could be detected. Chickens exhibit a peculiar glucose transport and glucose homeostasis, since they are lacking GLUT4, the major insulin-responsive transporter. The mechanism for regulation of blood glucose concentration in chickens is not well understood. Furthermore, no information is available on the roles of the chickens GLUT isoforms in relation to glucose metabolism. Most likely, GLUT1 will act in maintaining basal glucose transport in most chicken cell types as in mammals, however the precise function of GLUT1 in the chicken remains to be elucidated. Chickens maintain an elevated level of blood glucose, which is supported by high rates of gluconeogenesis. In the present study, prenatal protein undernutrition caused an increase in PCK2 protein abundance, as opposite to the decreased FBP1 protein abundance and the decreased glycogen content. The liver glycogen content has previously been shown to change in a reciprocal way to the cytosolic PCK activity. Indeed, there are two forms of PCK found in most species, differing in their cellular localization: cytosolic PCK1 and mitochondrial PCK2. The relative abundance of both isoforms is dependent on the animal species and the growth stage of the animal. In the avian liver, the mitochondrial PCK activity is the most abundant one but during the perinatal period the cytosolic PCK activity increased considerable from a few days before hatching to 4 days after hatching. As PCK1 is the most abundant form in rats and has been linked previously with effects of prenatal protein undernutrition, the expression of both PCK1 and PCK2 was measured. Both genes were present in similar amounts in the liver at hatch, but were not influenced by the applied treatment. Rats and mice have been used extensively to examine the effects of the maternal diet on the programming of the progeny. In rat dams fed a protein-restricted diet an increase in PCK1 mRNA and increased activity was detected in liver of the progeny until 11 months of age, suggesting that programming of the metabolism also extends to the regulation of gene expression. A persistent increase in the gene expression of hepatic PCK, catalyzing the first, committed step of gluconeogenesis, leads to reduced ability of insulin to suppress hepatic glucose output.
suggests that non-immune cells are subjected to a similar mechanism of regulation and chromatin configuration
TALE technology holds great promise in serving as a useful tool to decipher the functionality of genetic elements and in serving as a means to selectively switch on or off genes for therapeutic purpose. In the effort to selectively switch on gene expression using TALE technology, recent studies from two independent laboratories have demonstrated that robust and synergistic gene activation can be achieved using multiple TALE activators. Here we report that this synergistic effect could be further potentiated by up to 11-fold with a novel class of TALEbased activators, TBP-TALE. We demonstrated the potentiation capability of TBP-TALEs using two classical examples of silent, cell-type restricted genes, IL-2 and GM-CSF, in diverse cell lines at both the transcriptional and translational level. These unique TBP-based activators seem to function synergistically with the conventional VP64-TALEs on both genes and on a variety of cell lines that have been tested, indicating their universal potentiation activity in a diverse intracellular environment. The demonstrated potency of TBP-TALEs in synergizing with other VP64 activators to selectively switch on the expression of immunoregulatory genes such as IL-2 and GM-CSF has direct implications for targeted cancer immunotherapy and other similar applications. Although our studies, together with two recent publications, have clearly shown that multiple VP64-TALE activators alone or in combination with TBP-TALE can act synergistically to switch on silenced genes, the detailed mechanism of such a synergistic action has not been fully elucidated. One report has suggested that TALE activators can be designed with negligible regard for chromatin structure. However, based on extensive characterization of both the IL-2 and GM-CSF promoters, it is possible that their proximal and/or core promoter regions require extensive chromatin remodeling to activate gene expression. In supporting this notion, our data indicate that the robust TALE-mediated activation on the IL-2 promoter was in part due to altered chromatin accessibility possibly attributed to the action of VP64-TALE activators in collaboration with TBP-TALE directed initiation of transcription. As transcriptional initiation begins with the recruitment of TBP, it is plausible that targeted binding of TBP-TALE to the TATA box in cytokine gene promoters can bypass this rate limiting initial step of transcription for a silenced gene and facilitate mechanisms directed by VP64-TALEs such as, displacing or repositioning the nucleosome to allow for exclusive access of TALE activators to the promoter regulatory regions. In addition, other cooperative interactions between TBP and VP64-TALEs may also contribute to their synergistic activation on the cytokine genes. Potent transcriptional activators like VP16, in which our study uses four copies of it, interact with multiple components.