Gene expression is affected by modifications to histone core proteins within chromatin. Changes in these modifications, or epigenetic reprogramming, can dictate cell fate and promote susceptibility ...to disease. The goal of this study was to determine the extent of epigenetic reprogramming in response to chronic stress that occurs following ablation of MIST1 (Mist1(-/-) ), which is repressed in pancreatic disease. Chromatin immunoprecipitation for trimethylation of lysine residue 4 on histone 3 (H3K4Me3) in purified acinar cells from wild type and Mist1(-/-) mice was followed by Next Generation sequencing (ChIP-seq) or ChIP-qPCR. H3K4Me3-enriched genes were assessed for expression by qRT-PCR in pancreatic tissue before and after induction of cerulein-induced pancreatitis. While most of H3K4Me3-enrichment is restricted to transcriptional start sites, >25% of enrichment sites are found within, downstream or between annotated genes. Less than 10% of these sites were altered in Mist1(-/-) acini, with most changes in H3K4Me3 enrichment not reflecting altered gene expression. Ingenuity Pathway Analysis of genes differentially-enriched for H3K4Me3 revealed an association with pancreatitis and pancreatic ductal adenocarcinoma in Mist1(-/-) tissue. Most of these genes were not differentially expressed but several were readily induced by acute experimental pancreatitis, with significantly increased expression in Mist1(-/-) tissue relative to wild type mice. We suggest that the chronic cell stress observed in the absence of MIST1 results in epigenetic reprogramming of genes involved in promoting pancreatitis to a poised state, thereby increasing the sensitivity to events that promote disease.
Angiogenesis is a critical step during cancer progression. The VEGF is a major stimulator for angiogenesis and is predominantly contributed by cancer cells in tumors. Inhibition of the VEGF signaling ...pathway has shown promising therapeutic benefits for cancer patients, but adaptive tumor responses are often observed, indicating the need for further understanding of VEGF regulation. We report that a novel G protein-coupled receptor, GPR56, inhibits VEGF production from the melanoma cell lines and impedes melanoma angiogenesis and growth, through the serine threonine proline-rich segment in its N-terminus and a signaling pathway involving protein kinase Cα. We also present evidence that the two fragments of GPR56, which are generated by autocatalyzed cleavage, played distinct roles in regulating VEGF production and melanoma progression. Finally, consistent with its suppressive roles in melanoma progression, the expression levels of GPR56 are inversely correlated with the malignancy of melanomas in human subjects. We propose that components of the GPR56-mediated signaling pathway may serve as new targets for antiangiogenic treatment of melanoma.
Heat shock proteins (HSPs) are developmentally conserved families of protein found in both prokaryotic and eukaryotic organisms. HSPs are engaged in a diverse range of physiological processes, ...including molecular chaperone activity to assist the initial protein folding or promote the unfolding and refolding of misfolded intermediates to acquire the normal or native conformation and its translocation and prevent protein aggregation as well as in immunity, apoptosis, and autophagy. These molecular chaperonins are classified into various families according to their molecular size or weight, encompassing small HSPs (e.g., HSP10 and HSP27), HSP40, HSP60, HSP70, HSP90, and the category of large HSPs that include HSP100 and ClpB proteins. The overexpression of HSPs is induced to counteract cell stress at elevated levels in a variety of solid tumors, including anticancer chemotherapy, and is closely related to a worse prognosis and therapeutic resistance to cancer cells. HSPs are also involved in anti-apoptotic properties and are associated with processes of cancer progression and development, such as metastasis, invasion, and cell proliferation. This review outlines the previously mentioned HSPs and their significant involvement in diverse mechanisms of tumor advancement and metastasis, as well as their contribution to identifying potential targets for therapeutic interventions.
The on-going SARS-CoV-2 causing COVID-19 discovered in December 2019, is responsible for a global pandemic. The virus belongs to the group of enveloped viruses containing linear, non-segmented, ...single stranded, positive sense strand RNA as genetic material. Already six different strains Coronaviruses are being reported to infect humans, however the seventh one is genetically similar to the SARS Coronavirus and termed as SARS-CoV-2. Specific crucial macromolecules such as membrane, nuclear, spike and enveloped proteins including HE esterase are present in the virus that interact with ACE2, APN, NEU-5, 9SC2 moiety of humans plays significant role in occurrence and transmission of the devastating disease. This review article summarizes the structure, histopathology, transmission of novel Coronavirus, its symptoms with preventive measures & currently prescribed drugs. Though various drugs and therapy have been administrated or implemented to restrict COVID-19, however it is imperative to develop an antidote against SARS-CoV-2 by the scientific or research community to save life.
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•(i) SARS-CoV2 is highly mutated strain.•Antiviral targets may be highly conserved combinational therapy may prescribed.•COVID-19 infection was reduced by plasma cytokines and chemokine including IL-1, 2, 4, 7, 10, 12, 13, 17, GCSF, Macrophage Colony-Stimulating Factor (MCSF), IP-10, MCP-1, MIP-1α, Hepatocyte Growth Factor (HGF), IFN-γ and TNF-α.
The nematode Caenorhabditis elegans is a popular model system in genetics, not least because a majority of human disease genes are conserved in C. elegans. To generate a comprehensive inventory of ...its expressed proteome, we performed extensive shotgun proteomics and identified more than half of all predicted C. elegans proteins. This allowed us to confirm and extend genome annotations, characterize the role of operons in C. elegans, and semiquantitatively infer abundance levels for thousands of proteins. Furthermore, for the first time to our knowledge, we were able to compare two animal proteomes (C. elegans and Drosophila melanogaster). We found that the abundances of orthologous proteins in metazoans correlate remarkably well, better than protein abundance versus transcript abundance within each organism or transcript abundances across organisms; this suggests that changes in transcript abundance may have been partially offset during evolution by opposing changes in protein abundance.
Understanding how proteins and their complex interaction networks convert the genomic information into a dynamic living organism is a fundamental challenge in biological sciences. As an important ...step towards understanding the systems biology of a complex eukaryote, we cataloged 63% of the predicted Drosophila melanogaster proteome by detecting 9,124 proteins from 498,000 redundant and 72,281 distinct peptide identifications. This unprecedented high proteome coverage for a complex eukaryote was achieved by combining sample diversity, multidimensional biochemical fractionation and analysis-driven experimentation feedback loops, whereby data collection is guided by statistical analysis of prior data. We show that high-quality proteomics data provide crucial information to amend genome annotation and to confirm many predicted gene models. We also present experimentally identified proteotypic peptides matching approximately 50% of D. melanogaster gene models. This library of proteotypic peptides should enable fast, targeted and quantitative proteomic studies to elucidate the systems biology of this model organism.
Protein modifications play a major role for most biological processes in living organisms. Amino-terminal acetylation of proteins is a common modification found throughout the tree of life: the ...N-terminus of a nascent polypeptide chain becomes co-translationally acetylated, often after the removal of the initiating methionine residue. While the enzymes and protein complexes involved in these processes have been extensively studied, only little is known about the biological function of such N-terminal modification events. To identify common principles of N-terminal acetylation, we analyzed the amino-terminal peptides from proteins extracted from Drosophila Kc167 cells. We detected more than 1,200 mature protein N-termini and could show that N-terminal acetylation occurs in insects with a similar frequency as in humans. As the sole true determinant for N-terminal acetylation we could extract the (X)PX rule that indicates the prevention of acetylation under all circumstances. We could show that this rule can be used to genetically engineer a protein to study the biological relevance of the presence or absence of an acetyl group, thereby generating a generic assay to probe the functional importance of N-terminal acetylation. We applied the assay by expressing mutated proteins as transgenes in cell lines and in flies. Here, we present a straightforward strategy to systematically study the functional relevance of N-terminal acetylations in cells and whole organisms. Since the (X)PX rule seems to be of general validity in lower as well as higher eukaryotes, we propose that it can be used to study the function of N-terminal acetylation in all species.
Autophagy is a lysosomal-mediated degradation process that promotes cell survival during nutrient-limiting conditions. However, excessive autophagy results in cell death. In Drosophila, autophagy is ...regulated nutritionally, hormonally and developmentally in several tissues, including the fat body, a nutrient-storage organ. Here, we use a proteomics approach to identify components of starvation-induced autophagic responses in the Drosophila fat body. Using cICAT
TM
labeling and mass spectrometry, differences in protein expression levels of normal compared to starved fat bodies were determined. Candidates were analyzed genetically for their involvement in autophagy in fat bodies deficient for the respective genes. One of these genes, Desat1, encodes a lipid desaturase. Desat1 mutant cells fail to induce autophagy upon starvation. The desat1 protein localizes to autophagic structures after nutrient depletion and is required for fly development. Lipid analyses revealed that Desat1 regulates the composition of lipids in Drosophila. We propose that Desat1 exerts its role in autophagy by controlling lipid biosynthesis and/or signaling necessary for autophagic responses.
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•Chitosan and guargum based film were prepared by solvent casting method.•Film containing Ag-ZnONP and Tranexamic acid possessed high tensile strength.•Ag-ZnONP content of the film ...enhanced its therapeutic potential.•The nanocomposite film exhibited excellent antibacterial and antibiofilm properties.•The film promotes rapid hemostasis and facilitates cell proliferation and migration.
Modern wound care requires multifunctional dressings that can efficiently control bleeding and subsequent infection, facilitating faster healing which reduces the healthcare costs. Our study aimed to develop a nanocomposite biopolymeric film composed of Ag doped ZnO nanoparticle and drug tranexamic acid (TRA) loaded into chitosan guargum matrix (CGT/AgZnO) for obtaining improved antibacterial, antibiofilm and haemostatic properties, along with potential wound healing effects.The films were developed via solution casting method and characterized by various standard biophysical techniques such as X-ray diffraction, infrared spectroscopy, electron microscopy imaging etc. The polymeric nanocomposite films exhibited strong antibacterial efficacy against bacteria such as E. coli, P. aeruginosa, S. aureus and B. subtilis. The films loaded with 3 wt% of nanoparticles (CGT/AgZnO3) exhibited remarkable growth inhibition i.e. 90% and 94% against gram-negative and gram-positive bacteria, respectively. These films also demonstrated excellent antibiofilm activity, with CGT/AgZnO3 inhibiting over 80% of bacterial biofilm formation after 72 h. The nanocomposite films exhibited a strong hemostatic effect as indicated by their blood clotting index (BCI) value. The in vitro hemocompatibility and cytocompatibility study (against the mouse fibroblast cells- L929 cell line) showed the films were highly biocompatible. The wound closure potential of the films was evaluated using in vitro scratch assays, exhibiting enhanced cell migration (100%) after 24 h, as compared to the control groups (66%). These findings confirmed that the developed CGT/AgZnO films have the potential as an excellent wound dressing material with high antibacterial, hemostatic, and wound healing properties.
The end-to-end (EE) assembly of gold nanorods (Au-NRs) is of immense interest as it offers great electro-optical properties. This assembly is mainly produced in solution via replacing the ...cetyltrimethylammonium bromide (CTAB) molecules from as-synthesized Au-NR tips with thiolated linker molecules. However, this replacement demands a centrifugation-driven two-step ligand exchange reaction, till date, which is cumbersome, demands a few hours to even a day to occur, and often hampers the stability of Au-NRs during the process. Herein, we present a simple and fast one-step strategy that relies on the ferric chloride–mediated longitudinal oxidation of Au-NRs as an innovative mode to facilitate the in situ exchange of CTAB with thiols at the Au-NR tips to produce the Au-NR EE-assembly in an aqueous medium. We find that the temperature has a strong impact on our approach and it does not require any prior washing of as-synthesized Au-NRs via conventional centrifugation or any other modes. Our principle observation is that incubation of as-synthesized Au-NRs and thiolated linkers (e.g., cysteine, glutathione) in an acidic solution (pH = 1.3) in the presence of FeCl
3
for just 10 min at 75 °C is sufficient to achieve EE-nanoassemblies. We also notice that it is easy to control the extent of assembly by modulating either the FeCl
3
amount or temperature. To assess this assembly, we have used Vis–NIR absorption spectroscopy, dynamic light scattering study, and transmission electron microscopy. Such rapid and one-step fabrication of EE-assembly of Au-NRs is indeed rare in the literature and establishes the novelty of this work.
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