scholarly journals Different Flavors of Astrocytes: Revising the Origins of Astrocyte Diversity and Epigenetic Signatures to Understand Heterogeneity after Injury

2021 ◽  
Vol 22 (13) ◽  
pp. 6867
Author(s):  
Alejandro Villarreal ◽  
Tanja Vogel
Keyword(s):  
Cellular Response ◽  
Reactive Astrogliosis ◽  
Damage Propagation ◽  
Structural Support ◽  
Disease States ◽  
Pathological Conditions ◽  
Astrocyte Heterogeneity ◽  
Transcriptional Changes ◽  
Epigenetic Signatures ◽  
Type Specification

Astrocytes are a specific type of neuroglial cells that confer metabolic and structural support to neurons. Astrocytes populate all regions of the nervous system and adopt a variety of phenotypes depending on their location and their respective functions, which are also pleiotropic in nature. For example, astrocytes adapt to pathological conditions with a specific cellular response known as reactive astrogliosis, which includes extensive phenotypic and transcriptional changes. Reactive astrocytes may lose some of their homeostatic functions and gain protective or detrimental properties with great impact on damage propagation. Different astrocyte subpopulations seemingly coexist in reactive astrogliosis, however, the source of such heterogeneity is not completely understood. Altered cellular signaling in pathological compared to healthy conditions might be one source fueling astrocyte heterogeneity. Moreover, diversity might also be encoded cell-autonomously, for example as a result of astrocyte subtype specification during development. We hypothesize and propose here that elucidating the epigenetic signature underlying the phenotype of each astrocyte subtype is of high relevance to understand another regulative layer of astrocyte heterogeneity, in general as well as after injury or as a result of other pathological conditions. High resolution methods should allow enlightening diverse cell states and subtypes of astrocyte, their adaptation to pathological conditions and ultimately allow controlling and manipulating astrocyte functions in disease states. Here, we review novel literature reporting on astrocyte diversity from a developmental perspective and we focus on epigenetic signatures that might account for cell type specification.

scholarly journals Identification of drugs for leukaemia differentiation therapy by network pharmacology

2019 ◽  
Author(s):  
Eleni G Christodoulou ◽  
Lin Ming Lee ◽  
Kian Leong Lee ◽  
Tsz Kan Fung ◽  
Eric So ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cellular Reprogramming ◽  
Network Pharmacology ◽  
Differentiation Therapy ◽  
Disease States ◽  
Small Molecule Drugs ◽  
Transcriptional Changes ◽  
Gene Regulatory ◽  
Computational Platform

AbstractAcute leukaemias differ from their normal haematopoietic counterparts in their inability to differentiate. This phenomenon is thought to be the result of aberrant cellular reprogramming involving transcription factors (TFs). Here we leveraged on Mogrify, a network-based algorithm, to identify TFs and their gene regulatory networks that drive differentiation of the acute promyelocytic leukaemia (APL) cell line NB4 in response to ATRA (all-transretinoic acid). We further integrated the detected TF regulatory networks with the Connectivity Map (CMAP) repository and recovered small molecule drugs which induce similar transcriptional changes. Our method outperformed standard approaches, retrieving ATRA as the top hit. Of the other drug hits, dimaprit and mebendazole enhanced ATRA-mediated differentiation in both parental NB4 and ATRA-resistant NB4-MR2 cells. Thus, we provide proof-of-principle of our network-based computational platform for drug discovery and repositioning in leukaemia differentiation therapy, which can be extended to other dysregulated disease states.

scholarly journals Immunoglobulins with Non-Canonical Functions in Inflammatory and Autoimmune Disease States

2020 ◽  
Vol 21 (15) ◽  
pp. 5392 ◽  
Author(s):  
Evgeny A. Ermakov ◽  
Georgy A. Nevinsky ◽  
Valentina N. Buneva
Keyword(s):  
Ivig Therapy ◽  
Intravenous Immunoglobulins ◽  
Innate Immune ◽  
Catalytic Antibodies ◽  
Human Antibody ◽  
Therapeutic Effects ◽  
Innate Immune Responses ◽  
Disease States ◽  
Pathological Conditions ◽  
Classical Immunoglobulin

Immunoglobulins are known to combine various effector mechanisms of the adaptive and the innate immune system. Classical immunoglobulin functions are associated with antigen recognition and the initiation of innate immune responses. However, in addition to classical functions, antibodies exhibit a variety of non-canonical functions related to the destruction of various pathogens due to catalytic activity and cofactor effects, the action of antibodies as agonists/antagonists of various receptors, the control of bacterial diversity of the intestine, etc. Canonical and non-canonical functions reflect the extreme human antibody repertoire and the variety of antibody types generated in the organism: antigen-specific, natural, polyreactive, broadly neutralizing, homophilic, bispecific and catalytic. The therapeutic effects of intravenous immunoglobulins (IVIg) are associated with both the canonical and non-canonical functions of antibodies. In this review, catalytic antibodies will be considered in more detail, since their formation is associated with inflammatory and autoimmune diseases. We will systematically summarize the diversity of catalytic antibodies in normal and pathological conditions. Translational perspectives of knowledge about natural antibodies for IVIg therapy will be also discussed.

scholarly journals Induction of protein aggregation and starvation response by tRNA modification defects

2020 ◽  
Vol 66 (6) ◽  
pp. 1053-1057
Author(s):  
Roland Klassen ◽  
Alexander Bruch ◽  
Raffael Schaffrath
Keyword(s):  
Cellular Response ◽  
Anticodon Loop ◽  
Protein Aggregate ◽  
Starvation Response ◽  
Codon Recognition ◽  
Growth Defects ◽  
Yeast Strains ◽  
Transcriptional Changes ◽  
Decoding Efficiency ◽  
Synthetic Growth

Abstract Posttranscriptional modifications of anticodon loops contribute to the decoding efficiency of tRNAs by supporting codon recognition and loop stability. Consistently, strong synthetic growth defects are observed in yeast strains simultaneously lacking distinct anticodon loop modifications. These phenotypes are accompanied by translational inefficiency of certain mRNAs and disturbed protein homeostasis resulting in accumulation of protein aggregates. Different combinations of anticodon loop modification defects were shown to affect distinct tRNAs but provoke common transcriptional changes that are reminiscent of the cellular response to nutrient starvation. Multiple mechanisms may be involved in mediating inadequate starvation response upon loss of critical tRNA modifications. Recent evidence suggests protein aggregate induction to represent one such trigger.

scholarly journals The many hats of protein kinase Cδ: one enzyme with many functions

2014 ◽  
Vol 42 (6) ◽  
pp. 1529-1533 ◽  
Author(s):  
Nir Qvit ◽  
Daria Mochly-Rosen
Keyword(s):  
Protein Kinase ◽  
Physiological Response ◽  
Cellular Response ◽  
Molecular Event ◽  
Genetic Approach ◽  
Multifunctional Protein ◽  
Protein Substrates ◽  
Pathological Conditions ◽  
The Many ◽  
Protein Kinase Cδ

A large number of protein substrates are phosphorylated by each protein kinase under physiological and pathological conditions. However, it remains a challenge to determine which of these phosphorylated substrates of a given kinase is critical for each cellular response. Genetics enabled the generation of separation-of-function mutations that selectively cause a loss of one molecular event without affecting others, thus providing some tools to assess the importance of that one event for the measured physiological response. However, the genetic approach is laborious and not adaptable to all systems. Furthermore, pharmacological tools of the catalytic site are not optimal due to their non-selective nature. In the present brief review, we discuss some of the challenges in drug development that will regulate the multifunctional protein kinase Cδ (PKCδ).

scholarly journals Acute phase biomarkers of diseases in small ruminants: an overview

2019 ◽  
Vol 22 (1) ◽  
pp. 1-12
Author(s):  
P.T. Iliev ◽  
T.M. Georgieva
Keyword(s):  
Acute Phase ◽  
Serum Amyloid A ◽  
Acute Phase Proteins ◽  
Small Ruminants ◽  
Bacterial Disease ◽  
Disease Treatment ◽  
Aseptic Inflammation ◽  
Amyloid A ◽  
Disease States ◽  
Pathological Conditions

Acute phase proteins (APPs) are a large group of proteins synthesised mainly by the liver. Their production is stimulated in response to disturbances in the systemic homeostasis. It is known that each species has a specific set of APPs. Serum amyloid A and haptoglobin are the main APPs in small ruminants and their plasma concentration is changed most significantly in comparison with minor APPs such as ceruloplasmin. In general, APPs could provide valuable information on the general condition of the organism but cannot point at the exact disease. Therefore, APPs should be included as an additional indicator in clinical diagnosis. Knowledge of APPs behaviour in disease states has a remarkable potential for detecting animals with subclinical infections, determining the prognosis of clinical infection, differentiation between viral and bacterial disease, treatment monitoring, vaccine effectiveness and stress conditions. The aim of this review is to present data on APPs behaviour during some parasitic and infectious diseases as well as pathological conditions leading to aseptic inflammation and stress in sheep and goats.

scholarly journals Sky1 regulates the expression of sulfur metabolism genes in response to cisplatin

Microbiology ◽  
2014 ◽  
Vol 160 (7) ◽  
pp. 1357-1368 ◽  
Author(s):  
Silvia Rodríguez-Lombardero ◽  
Ángel Vizoso-Vázquez ◽  
Luis J. Lombardía ◽  
Manuel Becerra ◽  
M. Isabel González-Siso ◽  
...  
Keyword(s):  
Amino Acids ◽  
Cellular Response ◽  
Dna Microarrays ◽  
Sulfur Metabolism ◽  
Yeast Cells ◽  
Genes Encoding ◽  
Cisplatin Sensitivity ◽  
Transcriptional Changes ◽  
Upregulated Genes ◽  
Sulfur Containing

Cisplatin is commonly used in cancer therapy and yeast cells are also sensitive to this compound. We present a transcriptome analysis discriminating between RNA changes induced by cisplatin treatment, which are dependent on or independent of SKY1 function – a gene whose deletion increases resistance to the drug. Gene expression changes produced by addition of cisplatin to W303 and W303-Δsky1 cells were recorded using DNA microarrays. The data, validated by quantitative PCR, revealed 122 differentially expressed genes: 69 upregulated and 53 downregulated. Among the upregulated genes, those related to sulfur metabolism were over-represented and partially dependent on Sky1. Deletions of MET4 or other genes encoding co-regulators of the expression of sulfur-metabolism-related genes, with the exception of MET28, did not modify the cisplatin sensitivity of yeast cells. One of the genes with the highest cisplatin-induced upregulation was SEO1, encoding a putative permease of sulfur compounds. We also measured the platinum, sulfur and glutathione content in W303, W303-Δsky1 and W303-Δseo1 cells after cisplatin treatment, and integration of the data suggested that these transcriptional changes might represent a cellular response that allowed chelation of cisplatin with sulfur-containing amino acids and also helped DNA repair by stimulating purine biosynthesis. The transcription pattern of stimulation of sulfur-containing amino acids and purine synthesis decreased, or even disappeared, in the W303-Δsky1 strain.

scholarly journals Splicing variants impact in thyroid normal physiology and pathological conditions

2009 ◽  
Vol 53 (6) ◽  
pp. 709-715 ◽  
Author(s):  
Elizabete Rosária de Miranda ◽  
Luiz De Marco ◽  
Maria Marta Sarquis Soares
Keyword(s):  
Rna Splicing ◽  
Protein Localization ◽  
Mrna Translation ◽  
Peptide Sequence ◽  
Disease States ◽  
Pathological Conditions ◽  
Splicing Variants ◽  
Localization Errors ◽  
And Function ◽  
Splicing Patterns

RNA splicing is an essential, precisely regulated process that occurs after gene transcription and before mRNA translation, in which introns may be removed and exons, retained. Variability in splicing patterns is a major source of protein diversity from the genome and function to generate a tremendously diverse proteome from a relatively small number of genes. Changes in splice site choice can determine different effects on the encoded protein. Small changes in peptide sequence can alter ligand binding, enzymatic activity, allosteric regulation, or protein localization. Errors in splicing regulation have been implicated in a number of different disease states. This study reviewed the mechanisms of splicing and their repercussion in endocrinology, emphasizing its importance in some thyroid physiological and pathological conditions.

scholarly journals The CD300 molecules: an emerging family of regulators of the immune system

Blood ◽  
2013 ◽  
Vol 121 (11) ◽  
pp. 1951-1960 ◽  
Author(s):  
Francisco Borrego
Keyword(s):  
Immune Cell ◽  
Published Data ◽  
Biological Processes ◽  
Disease States ◽  
Outer Leaflet ◽  
Pathological Conditions ◽  
Leukocyte Function ◽  
The Family ◽  
Cell Processes ◽  
Human And Mouse

Abstract The CD300 family of molecules modulates a broad and diverse array of immune cell processes via their paired activating and inhibitory receptor functions. The description that CD300 molecules are able to recognize lipids, such as extracellular ceramide, phosphatidylserine, and phosphatidylethanolamine, that are exposed on the outer leaflet of the plasma membrane of dead and activated cells has opened a new field of research. Through their binding to lipids and other ligands, this family of receptors is poised to have a significant role in complex biological processes and in the host response to severe pathological conditions. Indeed, published data have demonstrated their participation in the pathogenesis of several disease states. Moreover, this family of receptors has great potential as targets for diagnosis and therapeutic purposes in infectious diseases, allergies, cancer, and other pathological situations. For instance, one member of the family, CD300a, has been studied as a possible biomarker. Here, a review is provided on the cellular distribution of the human and mouse families of receptors, the stimuli that regulate their expression, their ability to tune leukocyte function and immune responses, their signaling pathways, ligand recognition, and their clinical relevance.

Abstract 7: In vivo Transcriptional Profiling of Endothelial Cells Identifies Vascular Bed-Specific Changes Upon Lps-Induced Endotoxemia

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Audrey Cleuren ◽  
Martijn van der Ent ◽  
Kristina Hunker ◽  
Hui Jiang ◽  
Andrew Yee ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cellular Response ◽  
Inflammatory Responses ◽  
Differential Expression Analysis ◽  
Response To Therapy ◽  
Microbial Pathogens ◽  
P Value ◽  
Transcriptional Changes ◽  
Vascular Beds

Endothelial cells (ECs) form a critical barrier between blood and parenchymal cells and play an important role in many pathologic conditions, including sepsis. ECs are highly adaptive to their microenvironment and also act as a critical responder to microbial pathogens. Though ECs are thought to display extensive heterogeneity, detailed profiling of the in vivo EC gene expression program has been limited by the challenges of isolating ECs from complex tissues and the phenotypic drift associated with manipulation and expansion of ECs in vitro . We applied an in vivo system in which a conditional hemagglutinin-epitope tag is targeted into the mouse ribosomal protein Rpl22 locus and specifically activated in ECs, allowing immunoisolation of endothelial ribosome-associated mRNA. Both EC-selected and total mRNA from tissue lysates (brain, heart, kidney, liver and lung) were subjected to RNA sequencing followed by differential expression analysis to determine EC-enriched transcripts. These analyses were performed under physiologic conditions as well as in LPS injected mice to study transcriptional changes induced in ECs following endotoxin exposure. LPS-induced endotoxemia resulted in striking changes in the EC transcriptome (~800 per tissue), and included transcripts associated with known sepsis related pathophysiology, including impaired hemostasis, leukocyte recruitment and increased vascular permeability. Gene ontology analysis of transcriptional changes shared between ECs of different tissues identified cellular response to LPS among the highest enriched biologic processes (adjusted p-value 5.2E-5), together with immune (2.0E-14) and inflammatory responses (4.4E-12). Novel transcripts not previously associated with ECs or endotoxemia were also identified, as well as a subset of genes uniquely expressed in distinct vascular beds. In conclusion, our findings demonstrate remarkable heterogeneity of the EC transcriptome across multiple vascular beds in vivo . The EC response to endotoxin challenge is also highly heterogeneous across vascular beds and provides new insight into the endothelial response to infectious challenges, as well as identifying potentially useful biomarkers for the onset of sepsis and response to therapy.

scholarly journals Transcriptomic response of Campylobacter jejuni following exposure to acidified sodium chlorite

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Gayani Weerasooriya ◽  
Andrea R. McWhorter ◽  
Samiullah Khan ◽  
Kapil K. Chousalkar
Keyword(s):  
Cellular Response ◽  
Chicken Meat ◽  
Poultry Meat ◽  
Sodium Chlorite ◽  
Meat Industry ◽  
Transcriptomic Response ◽  
Dna Damage And Repair ◽  
Transcriptional Changes ◽  
Poultry Processing ◽  
Contrast Exposure

AbstractChemical decontamination during processing is used in many countries to mitigate the Campylobacter load on chicken meat. Chlorine is a commonly used sanitizer in poultry processing to limit foodborne bacterial pathogens but its efficacy is limited by high bacterial loads and organic material. Acidified sodium chlorite (ASC) is a potential alternative for poultry meat sanitization but little is known about its effects on the cellular response of Campylobacter. In this study, the sensitivity of C. jejuni isolates to ASC was established. RNAseq was performed to characterize the transcriptomic response of C. jejuni following exposure to either chlorine or ASC. Following chlorine exposure, C. jejuni induced an adaptive stress response mechanism. In contrast, exposure to ASC induced higher oxidative damage and cellular death by inhibiting all vital metabolic pathways and upregulating the genes involved in DNA damage and repair. The transcriptional changes in C. jejuni in response to ASC exposure suggest its potential as an effective sanitizer for use in the chicken meat industry.

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