scholarly journals Colonic Epithelial miR-31 Associates with the Development of Crohn’s Phenotypes

2018 ◽  
Author(s):  
Benjamin P. Keith ◽  
Jasmine B. Barrow ◽  
Takahiko Toyonaga ◽  
Nevzat Kazgan ◽  
Michelle Hoffner O’Connor ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Cell Types ◽  
Adult Patients ◽  
Small Rna Sequencing ◽  
Cellular Mechanisms ◽  
Cellular Processes ◽  
Treatment Naïve ◽  
History Of ◽  
Mucosa Cell ◽  
Ileal Disease

AbstractCrohn’s disease (CD) is highly heterogeneous, due in large part to variability in cellular processes that underlie the natural history of CD, thereby confounding effective therapy. There is a critical need to advance understanding of the cellular mechanisms that drive CD heterogeneity. In this study, small RNA-sequencing and microRNA profiling in the colon revealed two distinct molecular subtypes, each with different clinical associations, in both adult and treatment-naïve pediatric CD patients. Notably, we found that microRNA-31 (miR-31) expression by itself can stratify patients into these two subtypes. Through detailed analysis of several colonic mucosa cell types from adult patients, we found that differential levels of miR-31 are particularly pronounced in epithelial cells. We generated patient crypt-derived epithelial colonoids and showed that miR-31 expression differences preserved in this ex-vivo system. In adult patients, low colonic miR-31 expression levels at the time of surgery are associated with post-operative recurrence of ileal disease. In pediatric patients, lower miR-31 expression at the time of diagnosis is associated with the future development of fibrostenotic ileal CD requiring surgery. These findings represent an important step forward in designing more effective clinical trials and developing personalized therapies for CD.

scholarly journals Chemogenetic Tools for Causal Cellular and Neuronal Biology

2018 ◽  
Vol 98 (1) ◽  
pp. 391-418 ◽  
Author(s):  
Deniz Atasoy ◽  
Scott M. Sternson
Keyword(s):  
G Protein ◽  
Ex Vivo ◽  
Cell Types ◽  
Cell Populations ◽  
Specific Cell ◽  
Cellular Processes ◽  
Distinct Cell ◽  
G Protein Coupled ◽  
Pharmacological Control

Chemogenetic technologies enable selective pharmacological control of specific cell populations. An increasing number of approaches have been developed that modulate different signaling pathways. Selective pharmacological control over G protein-coupled receptor signaling, ion channel conductances, protein association, protein stability, and small molecule targeting allows modulation of cellular processes in distinct cell types. Here, we review these chemogenetic technologies and instances of their applications in complex tissues in vivo and ex vivo.

scholarly journals Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1627 ◽  
Author(s):  
Anita Thyagarajan ◽  
Mamdouh Salman A. Alshehri ◽  
Kelly L.R. Miller ◽  
Catherine M. Sherwin ◽  
Jeffrey B. Travers ◽  
...  
Keyword(s):  
Survival Rates ◽  
Suppressor Cells ◽  
Cell Types ◽  
Therapeutic Agents ◽  
Ductal Adenocarcinoma ◽  
Cancer Therapies ◽  
Myeloid Derived Suppressor Cells ◽  
Tumor Resistance ◽  
Cellular Mechanisms ◽  
Immunosuppressive Cell

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating human malignancy with poor prognosis and low survival rates. Several cellular mechanisms have been linked with pancreatic carcinogenesis and also implicated in inducing tumor resistance to known therapeutic regimens. Of various factors, immune evasion mechanisms play critical roles in tumor progression and impeding the efficacy of cancer therapies including PDAC. Among immunosuppressive cell types, myeloid-derived suppressor cells (MDSCs) have been extensively studied and demonstrated to not only support PDAC development but also hamper the anti-tumor immune responses elicited by therapeutic agents. Notably, recent efforts have been directed in devising novel approaches to target MDSCs to limit their effects. Multiple strategies including immune-based approaches have been explored either alone or in combination with therapeutic agents to target MDSCs in preclinical and clinical settings of PDAC. The current review highlights the roles and mechanisms of MDSCs as well as the implications of this immunomodulatory cell type as a potential target to improve the efficacy of therapeutic regimens for PDAC.

scholarly journals Mitochondrial Glucocorticoid Receptors and Their Actions

2021 ◽  
Vol 22 (11) ◽  
pp. 6054
Author(s):  
Ioanna Kokkinopoulou ◽  
Paraskevi Moutsatsou
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptors ◽  
Mitochondrial Gene ◽  
Cell Types ◽  
Ros Generation ◽  
Mitochondrial Gene Expression ◽  
Mitochondrial Energy Metabolism ◽  
Bcl2 Family ◽  
Cellular Processes ◽  
Almost All

Mitochondria are membrane organelles present in almost all eukaryotic cells. In addition to their well-known role in energy production, mitochondria regulate central cellular processes, including calcium homeostasis, Reactive Oxygen Species (ROS) generation, cell death, thermogenesis, and biosynthesis of lipids, nucleic acids, and steroid hormones. Glucocorticoids (GCs) regulate the mitochondrially encoded oxidative phosphorylation gene expression and mitochondrial energy metabolism. The identification of Glucocorticoid Response Elements (GREs) in mitochondrial sequences and the detection of Glucocorticoid Receptor (GR) in mitochondria of different cell types gave support to hypothesis that mitochondrial GR directly regulates mitochondrial gene expression. Numerous studies have revealed changes in mitochondrial gene expression alongside with GR import/export in mitochondria, confirming the direct effects of GCs on mitochondrial genome. Further evidence has made clear that mitochondrial GR is involved in mitochondrial function and apoptosis-mediated processes, through interacting or altering the distribution of Bcl2 family members. Even though its exact translocation mechanisms remain unknown, data have shown that GR chaperones (Hsp70/90, Bag-1, FKBP51), the anti-apoptotic protein Bcl-2, the HDAC6- mediated deacetylation and the outer mitochondrial translocation complexes (Tom complexes) co-ordinate GR mitochondrial trafficking. A role of mitochondrial GR in stress and depression as well as in lung and hepatic inflammation has also been demonstrated.

scholarly journals Interactome Analysis of KIN (Kin17) Shows New Functions of This Protein

2021 ◽  
Vol 43 (2) ◽  
pp. 767-781
Author(s):  
Vanessa Pinatto Gaspar ◽  
Anelise Cardoso Ramos ◽  
Philippe Cloutier ◽  
José Renato Pattaro Junior ◽  
Francisco Ferreira Duarte Junior ◽  
...  
Keyword(s):  
Dna Replication ◽  
Protein Interactions ◽  
Ribosome Biogenesis ◽  
Cell Metabolism ◽  
Cell Types ◽  
Protein Protein Interactions ◽  
Cellular Mechanisms ◽  
Cancerous Cell ◽  
First Time

KIN (Kin17) protein is overexpressed in a number of cancerous cell lines, and is therefore considered a possible cancer biomarker. It is a well-conserved protein across eukaryotes and is ubiquitously expressed in all cell types studied, suggesting an important role in the maintenance of basic cellular function which is yet to be well determined. Early studies on KIN suggested that this nuclear protein plays a role in cellular mechanisms such as DNA replication and/or repair; however, its association with chromatin depends on its methylation state. In order to provide a better understanding of the cellular role of this protein, we investigated its interactome by proximity-dependent biotin identification coupled to mass spectrometry (BioID-MS), used for identification of protein–protein interactions. Our analyses detected interaction with a novel set of proteins and reinforced previous observations linking KIN to factors involved in RNA processing, notably pre-mRNA splicing and ribosome biogenesis. However, little evidence supports that this protein is directly coupled to DNA replication and/or repair processes, as previously suggested. Furthermore, a novel interaction was observed with PRMT7 (protein arginine methyltransferase 7) and we demonstrated that KIN is modified by this enzyme. This interactome analysis indicates that KIN is associated with several cell metabolism functions, and shows for the first time an association with ribosome biogenesis, suggesting that KIN is likely a moonlight protein.

scholarly journals Characterization of an Ex Vivo Equine Endometrial Tissue Culture Model Using Next-Generation RNA-Sequencing Technology

Animals ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1995
Author(s):  
Maithê R. Monteiro de Barros ◽  
Mina C. G. Davies-Morel ◽  
Luis A. J. Mur ◽  
Christopher J. Creevey ◽  
Roger H. Alison ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Ex Vivo ◽  
Prostaglandin F2α ◽  
Principal Component ◽  
Differentially Expressed ◽  
Temporal Window ◽  
Cellular Processes ◽  
Persistent Inflammation ◽  
Uterine Inflammation ◽  
Tissue Culture Model

Persistent mating-induced endometritis is a major cause of poor fertility rates in the mare. Endometritis can be investigated using an ex vivo equine endometrial explant system which measures uterine inflammation using prostaglandin F2α as a biomarker. However, this model has yet to undergo a wide-ranging assessment through transcriptomics. In this study, we assessed the transcriptomes of cultured endometrial explants and the optimal temporal window for their use. Endometrium harvested immediately post-mortem from native pony mares (n = 8) were sampled (0 h) and tissue explants were cultured for 24, 48 and 72 h. Tissues were stored in RNALater, total RNA was extracted and sequenced. Differentially expressed genes (DEGs) were defined using DESeq2 (R/Bioconductor). Principal component analysis indicated that the greatest changes in expression occurred in the first 24 h of culture when compared to autologous biopsies at 0 h. Fewer DEGs were seen between 24 and 48 h of culture suggesting the system was more stable than during the first 24 h. No genes were differentially expressed between 48 and 72 h but the low number of background gene expression suggested that explant viability was compromised after 48 h. ESR1, MMP9, PTGS2, PMAIP1, TNF, GADD45B and SELE genes were used as biomarkers of endometrial function, cell death and inflammation across tissue culture timepoints. STRING assessments of gene ontology suggested that DEGs between 24 and 48 h were linked to inflammation, immune system, cellular processes, environmental information processing and signal transduction, with an upregulation of most biomarker genes at 24 h. Taken together our observations indicated that 24–48 h is the optimal temporal window when the explant model can be used, as explants restore microcirculation, perform wound healing and tackle inflammation during this period. This key observation will facilitate the appropriate use of this as a model for further research into the equine endometrium and potentially the progression of mating-induced endometritis to persistent inflammation between 24 and 48 h.

scholarly journals Molecular and Cellular Mechanisms Underlying Temperature-Dependent Sex Determination in Turtles

2021 ◽  
pp. 1-9
Author(s):  
Horacio Merchant-Larios ◽  
Verónica Díaz-Hernández ◽  
Diego Cortez
Keyword(s):  
Animal Models ◽  
Sex Determination ◽  
Incubation Temperature ◽  
State Of The Art ◽  
Current Understanding ◽  
Temperature Dependent ◽  
Cellular Mechanisms ◽  
Male Phenotype ◽  
History Of ◽  
Reptilian Species

The discovery in mammals that fetal testes are required in order to develop the male phenotype inspired research efforts to elucidate the mechanisms underlying gonadal sex determination and differentiation in vertebrates. A pioneer work in 1966 that demonstrated the influence of incubation temperature on sexual phenotype in some reptilian species triggered great interest in the environment’s role as a modulator of plasticity in sex determination. Several chelonian species have been used as animal models to test hypotheses concerning the mechanisms involved in temperature-dependent sex determination (TSD). This brief review intends to outline the history of scientific efforts that corroborate our current understanding of the state-of-the-art in TSD using chelonian species as a reference.

scholarly journals Implications of hematopoietic stem cells heterogeneity for gene therapies

Gene Therapy ◽  
2021 ◽  
Author(s):  
Jeremy Epah ◽  
Richard Schäfer
Keyword(s):  
Immune Cell ◽  
Ex Vivo ◽  
Bone Marrow Failure ◽  
Cell Types ◽  
Blood Disorders ◽  
Hematopoietic Stem ◽  
Therapeutic Concept ◽  
Gene Therapies ◽  
Bone Marrow Failure Syndromes ◽  
Immunodeficiency Syndrome

AbstractHematopoietic stem cell transplantation (HSCT) is the therapeutic concept to cure the blood/immune system of patients suffering from malignancies, immunodeficiencies, red blood cell disorders, and inherited bone marrow failure syndromes. Yet, allogeneic HSCT bear considerable risks for the patient such as non-engraftment, or graft-versus host disease. Transplanting gene modified autologous HSCs is a promising approach not only for inherited blood/immune cell diseases, but also for the acquired immunodeficiency syndrome. However, there is emerging evidence for substantial heterogeneity of HSCs in situ as well as ex vivo that is also observed after HSCT. Thus, HSC gene modification concepts are suggested to consider that different blood disorders affect specific hematopoietic cell types. We will discuss the relevance of HSC heterogeneity for the development and manufacture of gene therapies and in exemplary diseases with a specific emphasis on the key target HSC types myeloid-biased, lymphoid-biased, and balanced HSCs.

scholarly journals The Hexosamine Biosynthetic Pathway as a Therapeutic Target after Cartilage Trauma: Modification of Chondrocyte Survival and Metabolism by Glucosamine Derivatives and PUGNAc in an Ex Vivo Model

2021 ◽  
Vol 22 (14) ◽  
pp. 7247
Author(s):  
Jana Riegger ◽  
Julia Baumert ◽  
Frank Zaucke ◽  
Rolf E. Brenner
Keyword(s):  
Biosynthetic Pathway ◽  
Ex Vivo ◽  
Type Ii Collagen ◽  
Cartilage Explants ◽  
Uridine Diphosphate ◽  
Cell Protection ◽  
Ex Vivo Model ◽  
Human Cartilage ◽  
Hexosamine Biosynthetic Pathway ◽  
Cellular Processes

The hexosamine biosynthetic pathway (HBP) is essential for the production of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the building block of glycosaminoglycans, thus playing a crucial role in cartilage anabolism. Although O-GlcNAcylation represents a protective regulatory mechanism in cellular processes, it has been associated with degenerative diseases, including osteoarthritis (OA). The present study focuses on HBP-related processes as potential therapeutic targets after cartilage trauma. Human cartilage explants were traumatized and treated with GlcNAc or glucosamine sulfate (GS); PUGNAc, an inhibitor of O-GlcNAcase; or azaserine (AZA), an inhibitor of GFAT-1. After 7 days, cell viability and gene expression analysis of anabolic and catabolic markers, as well as HBP-related enzymes, were performed. Moreover, expression of catabolic enzymes and type II collagen (COL2) biosynthesis were determined. Proteoglycan content was assessed after 14 days. Cartilage trauma led to a dysbalanced expression of different HBP-related enzymes, comparable to the situation in highly degenerated tissue. While GlcNAc and PUGNAc resulted in significant cell protection after trauma, only PUGNAc increased COL2 biosynthesis. Moreover, PUGNAc and both glucosamine derivatives had anti-catabolic effects. In contrast, AZA increased catabolic processes. Overall, “fueling” the HBP by means of glucosamine derivatives or inhibition of deglycosylation turned out as cells and chondroprotectives after cartilage trauma.

scholarly journals Comparative AAV-eGFP Transgene Expression Using Vector Serotypes 1–9, 7m8, and 8b in Human Pluripotent Stem Cells, RPEs, and Human and Rat Cortical Neurons

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Thu T. Duong ◽  
James Lim ◽  
Vidyullatha Vasireddy ◽  
Tyler Papp ◽  
Hung Nguyen ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Transgene Expression ◽  
Fluorescent Protein ◽  
Ex Vivo ◽  
Cell Types ◽  
Egfp Expression ◽  
Cell Type ◽  
Egfp Gene ◽  
Rat Cortical Neurons

Recombinant adeno-associated virus (rAAV), produced from a nonpathogenic parvovirus, has become an increasing popular vector for gene therapy applications in human clinical trials. However, transduction and transgene expression of rAAVs can differ acrossin vitroand ex vivo cellular transduction strategies. This study compared 11 rAAV serotypes, carrying one reporter transgene cassette containing a cytomegalovirus immediate-early enhancer (eCMV) and chicken beta actin (CBA) promoter driving the expression of an enhanced green-fluorescent protein (eGFP) gene, which was transduced into four different cell types: human iPSC, iPSC-derived RPE, iPSC-derived cortical, and dissociated embryonic day 18 rat cortical neurons. Each cell type was exposed to three multiplicity of infections (MOI: 1E4, 1E5, and 1E6 vg/cell). After 24, 48, 72, and 96 h posttransduction, GFP-expressing cells were examined and compared across dosage, time, and cell type. Retinal pigmented epithelium showed highest AAV-eGFP expression and iPSC cortical the lowest. At an MOI of 1E6 vg/cell, all serotypes show measurable levels of AAV-eGFP expression; moreover, AAV7m8 and AAV6 perform best across MOI and cell type. We conclude that serotype tropism is not only capsid dependent but also cell type plays a significant role in transgene expression dynamics.

The role of exploratory mechanisms in evolution

1995 ◽  
Vol 349 (1329) ◽  
pp. 297-297
Keyword(s):  
Dynamic Instability ◽  
Specific Mechanism ◽  
Cellular Mechanisms ◽  
Selection Processes ◽  
Wide Range ◽  
Rapid Changes ◽  
Neuronal Processes ◽  
History Of ◽  
Variation And Selection

Many cellular mechanisms use a process of variation and selection to generate specific patterns. Among these, dynamic instability of microtubules has been shown to employ a specific mechanism to intentionally generate variation. In many systems the growth of neurons or neuronal processes is excessive, the final connections being established by stabilization of functional interactions. When changes in neuronal networks take place, such as in metamorphosis, use is made of the plasticity of neuronal connectivity. In the immune system, specific responses are generated by variation and selection. Processes that explore a wide range of conditions and a wide range of structures can be called exploratory processes. These are very robust and capable of responding to damage, variability in the environment and ontogenic changes in the organisms. Such robustness would be useful for adapting to changes that occur during phylogenetic changes as well. Given the extensive history of extinction and radiation in evolution, it may be supposed that these mechanisms have themselves been selected for their capacity to survive rapid changes in the organism and for their ability to generate cellular variation.

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