188 research outputs found
The role of gut-derived microbial antigens on liver fibrosis initiation and progression
Intestinal dysbiosis has recently become known as an important driver of gastrointestinal and liver disease. It remains poorly understood, however, how gastrointestinal microbes bypass the intestinal mucosa and enter systemic circulation to enact an inflammatory immune response. In the context of chronic liver disease (CLD), insults that drive hepatic inflammation and fibrogenesis (alcohol, fat) can drastically increase intestinal permeability, hence flooding the liver with gut-derived microbiota. Consequently, this may result in exacerbated liver inflammation and fibrosis through activation of liver-resident Kupffer and stellate cells by bacterial, viral, and fungal antigens transported to the liver via the portal vein. This review summarizes the current understanding of microbial translocation in CLD, the cell-specific hepatic response to intestinal antigens, and how this drives the development and progression of hepatic inflammation and fibrosis. Further, we reviewed current and future therapies targeting intestinal permeability and the associated, potentially harmful anti-microbial immune response with respect to their potential in terms of limiting the development and progression of liver fibrosis and end-stage cirrhosis
Probing the Y2 Receptor on Transmembrane, Intra- and Extra-Cellular Sites for EPR Measurements
The function of G protein-coupled receptors is intrinsically linked to their conformational dynamics. In conjugation with site-directed spin labeling, electron paramagnetic resonance (EPR) spectroscopy provides powerful tools to study the highly dynamic conformational states of these proteins. Here, we explored positions for nitroxide spin labeling coupled to single cysteines, introduced at transmembrane, intra- and extra-cellular sites of the human neuropeptide Y2 receptor. Receptor mutants were functionally analyzed in cell culture system, expressed in Escherichia coli fermentation with yields of up to 10 mg of purified protein per liter expression medium and functionally reconstituted into a lipid bicelle environment. Successful spin labeling was confirmed by a fluorescence assay and continuous wave EPR measurements. EPR spectra revealed mobile and immobile populations, indicating multiple dynamic conformational states of the receptor. We found that the singly mutated positions by MTSL ((1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl) methyl methanesulfonothioate) have a water exposed immobilized conformation as their main conformation, while in case of the IDSL (bis(1-oxyl-2,2,5,5-tetramethyl-3-imidazolin-4-yl) disulfide) labeled positions, the main conformation are mainly of hydrophobic nature. Further, double cysteine mutants were generated and examined for potential applications of distance measurements by double electron–electron resonance (DEER) pulsed EPR technique on the receptor
Hydroxylated derivatives of dimethoxy-1,4-benzoquinone as redox switchable earth-alkaline metal ligands and radical scavengers
Benzoquinones (BQ) have important functions in many biological processes. In alkaline environments, BQs
can be hydroxylated at quinoid ring proton positions. Very little is known about the chemical reaction
leading to these structural transformations as well as about the properties of the obtained hydroxyl
benzoquinones. We analyzed the behavior of the naturally occurring 2,6-dimethoxy-1,4-benzoquinone
under alkaline conditions and show that upon substitution of methoxy-groups, poly-hydroxyl-derivatives
(OHBQ) are formed. The emerging compounds with one or several hydroxyl-substituents on single or fused
quinone-rings exist in oxidized or reduced states and are very stable under physiological conditions. In
comparison with the parent BQs, OHBQs are stronger radical scavengers and redox switchable
earth-alkaline metal ligands. Considering that hydroxylated quinones appear as biosynthetic intermediates
or as products of enzymatic reactions, and that BQs present in food or administered as drugs can be
hydroxylated by enzymatic pathways, highlights their potential importance in biological systems
Incorporation of β-Alanine in Cu(II) ATCUN Peptide Complexes Increases ROS Levels, DNA Cleavage and Antiproliferative Activity
Redox-active Cu(II) complexes are able to form reactive oxygen species (ROS) in the presence of oxygen and reducing agents. Recently, Faller et al. reported that ROS generation by Cu(II) ATCUN complexes is not as high as assumed for decades. High complex stability results in silencing of the Cu(II)/Cu(I) redox cycle and therefore leads to low ROS generation. In this work, we demonstrate that an exchange of the α-amino acid Gly with the β-amino acid β-Ala at position 2 (Gly2→β-Ala2) of the ATCUN motif reinstates ROS production (•OH and H2O2). Potentiometry, cyclic voltammetry, EPR spectroscopy and DFT simulations were utilized to explain the increased ROS generation of these β-Ala2-containing ATCUN complexes. We also observed enhanced oxidative cleavage activity towards plasmid DNA for β-Ala2 compared to the Gly2 complexes. Modifications with positively charged Lys residues increased the DNA affinity through electrostatic interactions as determined by UV/VIS, fluorescence, and CD spectroscopy, and consequently led to a further increase in nuclease activity. A similar trend was observed regarding the cytotoxic activity of the complexes against several human cancer cell lines where β-Ala2 peptide complexes had lower IC50 values compared to Gly2. The higher cytotoxicity could be attributed to an increased cellular uptake as determined by ICP-MS measurements
Meta-modal Information Flow: A Method for Capturing Multimodal Modular Disconnectivity in Schizophrenia
Objective: Multimodal measurements of the same phenomena provide
complementary information and highlight different perspectives, albeit each
with their own limitations. A focus on a single modality may lead to incorrect
inferences, which is especially important when a studied phenomenon is a
disease. In this paper, we introduce a method that takes advantage of
multimodal data in addressing the hypotheses of disconnectivity and dysfunction
within schizophrenia (SZ). Methods: We start with estimating and visualizing
links within and among extracted multimodal data features using a Gaussian
graphical model (GGM). We then propose a modularity-based method that can be
applied to the GGM to identify links that are associated with mental illness
across a multimodal data set. Through simulation and real data, we show our
approach reveals important information about disease-related network
disruptions that are missed with a focus on a single modality. We use
functional MRI (fMRI), diffusion MRI (dMRI), and structural MRI (sMRI) to
compute the fractional amplitude of low frequency fluctuations (fALFF),
fractional anisotropy (FA), and gray matter (GM) concentration maps. These
three modalities are analyzed using our modularity method. Results: Our results
show missing links that are only captured by the cross-modal information that
may play an important role in disconnectivity between the components.
Conclusion: We identified multimodal (fALFF, FA and GM) disconnectivity in the
default mode network area in patients with SZ, which would not have been
detectable in a single modality. Significance: The proposed approach provides
an important new tool for capturing information that is distributed among
multiple imaging modalities
Association between the rs2241883 polymorphism of the fatty acid-binding protein-1 (FABP1) gene and obesity in a population of MASHAD study cohort
Funding Information: We would like to thank Mashhad University of Medical Sciences Research Council for their financial supports.Peer reviewedPublisher PD
Measuring ovarian toxicity in clinical trials: Measuring ovarian toxicity in clinical trials: an American Society of Clinical Oncology research statement
Martini 3 : a general purpose force field for coarse-grained molecular dynamics
The coarse-grained Martini force field is widely used in biomolecular simulations. Here we present the refined model, Martini 3 (http://cgmartini.nl), with an improved interaction balance, new bead types and expanded ability to include specific interactions representing, for example, hydrogen bonding and electronic polarizability. The updated model allows more accurate predictions of molecular packing and interactions in general, which is exemplified with a vast and diverse set of applications, ranging from oil/water partitioning and miscibility data to complex molecular systems, involving protein-protein and protein-lipid interactions and material science applications as ionic liquids and aedamers.Peer reviewe
An EPR and DFT study on the primary radical formed in hydroxylation reactions of 2,6-dimethoxy-1,4-benzoquinone
HDAC7 Is a Repressor of Myeloid Genes Whose Downregulation Is Required for Transdifferentiation of Pre-B Cells into Macrophages
B lymphopoiesis is the result of several cell-commitment, lineage-choice, and differentiation processes. Every differentiation step is characterized by the activation of a new, lineage-specific, genetic program and the extinction of the previous one. To date, the central role of specific transcription factors in positively regulating these distinct differentiation processes to acquire a B cell-specific genetic program is well established. However, the existence of specific transcriptional repressors responsible for the silencing of lineage inappropriate genes remains elusive. Here we addressed the molecular mechanism behind repression of non-lymphoid genes in B cells. We report that the histone deacetylase HDAC7 was highly expressed in pre-B cells but dramatically down-regulated during cellular lineage conversion to macrophages. Microarray analysis demonstrated that HDAC7 re-expression interfered with the acquisition of the gene transcriptional program characteristic of macrophages during cell transdifferentiation; the presence of HDAC7 blocked the induction of key genes for macrophage function, such as immune, inflammatory, and defense response, cellular response to infections, positive regulation of cytokines production, and phagocytosis. Moreover, re-introduction of HDAC7 suppressed crucial functions of macrophages, such as the ability to phagocytose bacteria and to respond to endotoxin by expressing major pro-inflammatory cytokines. To gain insight into the molecular mechanisms mediating HDAC7 repression in pre-B cells, we undertook co-immunoprecipitation and chromatin immunoprecipitation experimental approaches. We found that HDAC7 specifically interacted with the transcription factor MEF2C in pre-B cells and was recruited to MEF2 binding sites located at the promoters of genes critical for macrophage function. Thus, in B cells HDAC7 is a transcriptional repressor of undesirable genes. Our findings uncover a novel role for HDAC7 in maintaining the identity of a particular cell type by silencing lineage-inappropriate genes
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