Monthly Archives: April 2019

Important role in the trafficking and stabilization of AMPA receptors at the synapse

For example, we have previously reported that there is a smaller Atractylenolide-III population of GluA2 a ached to N-linked high mannose containing glycans in dorsolateral prefrontal cortex in patients with schizophrenia, which we interpreted as consistent with accelerated forward trafficking of the GluA2-containing AMPA receptors. Glycosylation may also affect neurodevelopment: GluA2 in mouse hippocampus expresses the human natural killer-1 glycol-epitope, which may be essential for dendritic spine morphogenesis in developing neurons. Studies aimed at understanding the function of mammalian brain have predominantly used rodent models. However, given the Benzoylpaeoniflorin significant evolutionary distance between rodents and humans, it remains unclear to what extent data from rodent studies can be used to understand human disorders associated with abnormalities of glutamate neurotransmission. In the current study, we asked if one can use findings from animal models to uncover roles that glycans/glycoproteins may play in normal brain and begin to address dysfunction of glycosylation in pathological conditions, given the rapid rate of human brain evolution and the estimated rate of change in the brain- specific glycoproteome. To that end, we compared N-glycosylation in brain of GluA1-4 between four mammalian species, with the hypothesis that we would observe evolutionarily distinct pa erns of glycosylation of AMPA receptors, which in turn might reflect intrinsic differences in biosynthesis, processing, trafficking, or interaction of the receptor subunits with cellular and extracellular partners. In this study, we characterized the glycosylation of AMPA receptor subunits in the frontal cortex from four mammalian species using Western blot analysis, following enzymatic deglycosylation and by lectin binding assays. As we have previously shown in the human, we found that two AMPA receptor subunits, GluA2 and GluA4, are sensitive to deglycosylation with Endo H and PNGase F, consistent with large molecular masses of glycans a ached to these subunits. When we enriched for glycosylated proteins using lectin binding assay, we were able to detect glycans a ached to all four AMPA receptor subunits. We also noted species-specific pa erns of glycosylation, although these were generally modest differences. N-linked glycosylation occurs in the ER with subsequent modification in the Golgi apparatus; movement of the AMPA subunits through the ER and Golgi can be inferred by their sensitivity to Endo H. Glycoproteins that contain high mannose and hybrid chains are sensitive to Endo H-driven deglycosylation while they are in the ER and in proximal regions of the Golgi complex. In the mid Golgi apparatus, glycans are modified to more complex structures which become Endo H insensitive. However, all N-linked glycans are sensitive to PNGase F, and only the addition of a1,3fucose in invertebrates and plants has been described to confer resistance to this glycosidase. This study is consistent with our previous findings that in the human frontal cortex, GluA2 and GluA4 are the only subunits sensitive to deglycosylation by Endo H and PNGase F. Analysis of deglycosylation pa erns revealed that a larger population of GluA2 in human and macaque contained Endo H-sensitive high mannose or hybrid glycans.

Demonstrates that the SLRP family member PRELP seems to be exclusively expressed in CLL cells

First, both coactivators are expressed by developing and mature photoreceptors, and physically interact with the key photoreceptor transcription factor CRX. Second, during photoreceptor development, both factors are found on the promoter/enhancer regions of CRX-regulated photoreceptor genes after CRX binds. These events are followed by acetylation of histone H3 and H4 on these promoters, recruitment of additional photoreceptor-specific transcription factors, and transcriptional activation of the associated genes. Increases in H3 acetylation have also been associated with activation by NRL. Third, in the absence of CRX, recruitment of CBP to target gene promoters and acetylated histone H3/H4 levels are reduced, correlating with decreased transcription. To examine the role of p300/CBP in CRX-regulated photoreceptor gene expression, we conditionally knocked out Ep300 and/or Cbp in rods or cones of the mouse retina using either a rhodopsin or cone opsin promoter to drive Cre recombinase expression. Here we report that loss of both p300 and CBP, but neither alone, causes detrimental defects in rod/cone structure and function, maintenance of photoreceptor gene Artemisinic-acid expression and cell identity. These defects are accompanied by drastically reduced acetylation of histone H3/H4 on photoreceptor genes, and loss of the nuclear chromatin organization pattern characteristic of mouse photoreceptors. During postnatal mouse retinal development between P10 and P21, post-mitotic opsin-positive photoreceptors undergo terminal differentiation and maturation. At the cellular level, they elaborate outer segments containing the phototransduction machinery, and make synaptic connections to inner neurons. At the molecular level, expression of many photoreceptor genes increases to adult levels during this time. These results agree with findings from a study of postmitotic mouse brain neurons, that loss of either p300 or CBP alone does not affect cell viability or cause severe defects. However, these investigators found modest memory and transcriptional deficits after brain-specific knockout of either Ep300 or Cbp.FMOD is a member of the small leucine-rich proteoglycan family and is normally expressed in collagen-rich tissues. We demonstrated that FMOD was expressed at the gene and protein level in CLL and mantle cell lymphoma. This unexpected finding of an aberrantly expressed extracellular matrix protein raised the question whether also other SLRP family members might be expressed in CLL. Overexpression of genes in tumor cells might be due to epigenetic regulations, which may span a cluster of closely located genes. The function of PRELP is unclear, but the interactions between PRELP and collagen type I and II as well as heparin and heparan sulphate suggest that PRELP may be a molecule anchoring basement membranes to connective tissue. Following our previous studies on FMOD and ROR1 in CLL, both located on chromosome 1, the present study was undertaken to explore the gene and protein expression of PRELP in CLL and other hematological malignancies, in our endeavour to explore uniquely expressed molecules in CLL which may play a role in the Glycitin pathobiology of the disease.

DNA methylation frequently becomes drastically aberrantly altered in cancer cells.

Hypomethylation of oncogene promoters and hypermethylation of tumor suppressor gene promoters are pivotal alterations in cancer development. The CpG island methylator phenotype is a methylation status when a large number of gene loci are simultaneously hypermethylated, probably as consequence of mutations of methyltransferases or histone-modifying proteins, aging, virus exposure, chronic inflammation or other underlying factors. Reportedly, CIMP was observed in many tumors, including colorectal cancer, adrenocortical carcinomas, gastric tumors, liver cancer, esophagus cancer, ovarian cancers and acute myelogenous leukemia. In different tumors, CIMP of the whole tumor Anemarsaponin-BIII genome affects different specific genes and functions differently, either as favorable or unfavorable predictors for patients. Poorer outcome was observed in Ursolic-acid patients who suffered adrenocortical carcinomas with the existence of CIMP. Nevertheless, according to previous research, in gastric carcinoma, the prognosis of the patients without CIMP was significantly worse compared with that of patients with CIMP. Such evidence confirms the fact that hypermethylation of the whole cancer genome does not necessarily mean better or worse outcomes for patients. Instead, it is the specific genes that are aberrantly methylated that determine outcomes. G-CIMP is enriched in a subgroup of glioma, the proneural subgroup, according to the TCGA classification scheme for glioma. In G-CIMP-positive samples, a large number of CpG island loci located in specific gene promoters are hypermethylated and patients usually have better outcomes. According to our research and data analysis, hypermethylation of the SOCS3 promoter is highly associated with G-CIMP-positive samples and predicts improved outcomes for patients, but is not a predictor for G-CIMP-negative patients. Therefore, we conclude that SOCS3 hypermethylation status has favorable prognostic value in GBM patients because of its whole genome methylation status. SOCS3 functions as a tumor suppressor in many cancers including GBM. According to the bio-effects of the genetic hypermethylation process, hypermethylation of tumor suppressor gene promoters theoretically is aversive for tumorigenesis or progression. Furthermore, many studies have confirmed the effect of SOCS3 in GBM samples. In G-CIMP-positive samples, as our data showed above, the SOCS3 promoter is hypermethylated along with a variety of other loci. The hypermethylation of the SOCS3 promoter is just a part of the whole genome methylation status and its negative effect on tumorigenesis or progression may be neutralized by the comprehensive genome hypermethylation. This hypothesis may explain why hypermethylation of the SOCS3 promoter predicts favorable prognosis in GBM patients. In addition, other potential signaling pathways may be uncovered for which hypermethylation of the SOCS3 promoter serves as a better prognosticator. Because this single gene alteration accompanies whole genome hypermethylation, SOCS3 can be regarded as a pivotal gene that functions as a predictor for the whole genome methylation status. As we revealed in this research, SOCS3 hypermethylation is a de novo indicator for G-CIMP and predicts better patients’ outcomes.

Glucose intolerance during pregnancy is associated with an increased risk for cardiovascular

Since pGDM exhibit many features of the Cardio-metabolic Gentiopicrin Syndrome, including hyperglycemia and hyperinsulinemia we hypothesized that cardiac steatosis might present an early sign of cardiac vulnerability and can be detected in these women with impaired glucose tolerance and early diabetes. Therefore, the aim of this study was to investigate myocardial lipid content and cardiac function and its relations to other features of the Cardio-metabolic Syndrome, such as fatty liver, insulin insensitivity and altered insulin secretion in women with prior gestational diabetes, when compared to healthy controls. The current study aimed to assess whether women with prior gestational diabetes – at different stages of glucose intolerance – already exhibit features of incident cardiac steatosis, predisposing them for the development of cardiomyopathy. According to our data, neither myocardial lipid content nor left ventricular function differed between pGDM and healthy controls. In addition, none of the groups showed evidence of cardiac steatosis or cardiac dysfunction, indicating that metabolic disturbances might not influence cardiac morbidity in this relatively young female population. In contrast to prior investigations in 10-Gingerol patients with diabetes, we could not detect a link between MYCL and diastolic function, assessed by the E/A-ratio. Our results are also in contrast to a prior investigation, which reported increased MYCL in women with diabetes. However, in both studies male patients were over-represented and, moreover, the study populations were about 10�C15 years older than ours. Assuming that the development of cardiomyopathy in patients with diabetes may take years and furthermore be accelerated by the co-existence of arterial hypertension and coronary artery disease, our study population might be too young to detect cardiac abnormalities. In addition, myocardial lipid content was independent of medication intake and not associated with insulin sensitivity, described by OGIS. This is in line with our prior studies, in which we also could not find a link between insulin resistance and myocardial lipid accumulation in healthy women. Furthermore, we have previously shown that combined hyperglycemia and hyperinsulinemia increase myocardial lipid content in both, healthy men and women, and that myocardial lipid accumulation tightly relates to hyperinsulinemia. However, MYCL was not associated with insulin sensitivity, calculated by the M-value during the clamp, and its increase comparable between male and female subjects. In contrast to our findings, another group has described a link between insulin resistance and cardiac steatosis in sedentary, obese women; subsequently we assume that this might be related to increased adiposity in those women with a mean BMI of 33 kg/m2. This assumption is supported by our data, which showed a positive correlation between BMI and MYCL in the CON- and NGT-group, both with normal glucose tolerance. Thus, the co-existence of obesity might accelerate myocardial lipid accumulation due to increased endogenous fatty acids and insulin supply, at least in women without disturbed glucose metabolism.

Several proinflammatory cytokines and monocyte chemotactic protein activated platelets into the aortic wall

These early events are followed by extracellular matrix destruction and remodelling, vascular smooth muscle cell depletion and dysfunction. Experiments had demonstrated that Hcy stimulates chemokine and cytokine secretion from cultured human monocytes and has been implicated in suppressing regulatory T-cell function. A recent interesting study by Liu Z et al., within an angiotensin II induced AAA mouse model suggests that hyper-Hcy exaggerates adventitial inflammation, promoting AAA. Hcy induces the synthesis of serine elastase in arterial smooth muscle cells, causing elastolysis by degradation of the extracellular matrix and release of reactive oxygen species, which are implicated in AAA pathogenesis. Whether Hcy plays a role in aneurysm formation and/or in aneurysm expansion or Hcy is simply a marker of the condition need to be investigated. Plasma Hcy levels are also influenced by several factors such as genetic factors, plasma folate and vitamin B12 concentrations. Selhub and colleagues have suggested that inadequate plasma concentrations of one or more B vitamins are contributing factors in approximately two thirds of all cases of hyperhomocysteinaemia and that vitamin supplementation can normalise high homocysteine concentrations. As lack of well-designed RCTs, we were unable to perform a meta-analysis of the clinical effects of Hcy-lowering therapy among the limited studies because of the in consistent outcomes. Hcy-lowering therapy by folic acid, vitamins B6 and B12 supplement will help to reduce rates of AAA or not, the answer maybe urgent in the development of interventions to prevent AAA. More well-design RCTs are needed to test the effects of Hcy-lowering therapy on the AAA incident. Although we only included the case-control studies in the analysis, there are still several potential limitations. First, because of the cross-sectional design, the studies are unable to determine if the altered parameters are causally related to the presence of AAA. Second, we only included the study in English and Chinese, and some relevant studies might be not included in the review. There was a low risk of publication bias in studies of Hcy concentrations in relation to all AAA, as suggested by asymmetrical funnel plot on visual inspection and Egger’s linear regression test. Third, there was significant heterogeneity among the included studies. Another potential source of heterogeneity was the lack of uniform definition of subjects. Forth, a major limitation was the possibility of uncontrolled confounding, and the individual studies did not adjust for potential risk factors in a consistent way. A wide spectrum of diseases was associated with elevated plasma Hcy concentrations, such as cardiovascular 9-methoxycamptothecine disease, stroke and cognitive impairment. These diseases were also associated with AAA; some residual confounding factors still affected the Salvianolic-acid-B results. None of the analyzed studies seems to have adjusted Hcy levels for its most important covariate, glomerular filtration rate, and this is a major problem for the outcome. The lack of adjustment for these confounding factors might have resulted in a slight over estimation of the OR. Finally, the studies of Wong YYE and the Brunelli T contained only men, and that may make the findings have only limited relevance to AAA in women. Chronic, low-grade inflammation in adipose tissue induced by obesity is characterized by an aberrant release of hormones, cytokines and chemokines. These factors affect insulin sensitivity not only in an auto-/paracrine fashion in adipose tissue but also in an endocrine manner in liver and skeletal muscle.