scholarly journals PBMC Treatment Significantly Changes Gene Expression Regulation in Horses

2019 ◽  
Author(s):  
Victor C. Mason ◽  
Tosso Leeb ◽  
Vinzenz Gerber
Keyword(s):  
Gene Expression ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Mononuclear Cells ◽  
Reference Genome ◽  
Gene Expression Regulation ◽  
Inflammatory Responses ◽  
Cholesterol Biosynthesis ◽  
Expression Regulation ◽  
Peripheral Blood Mononuclear

AbstractExpression quantitative trait loci (eQTLs) are context dependent, and therefore change between tissues, cell types, and after cell treatment. In addition, SNP positions and RNAseq counts must be updated after assembly of new reference genome sequences. Therefore, we remapped eQTLs with Matrix eQTL using the previously generated and publicly available data from four contexts of peripheral blood mononuclear cells (PBMCs) from European Warmblood horses to the EquCab3.0 reference genome, and used a linear mixed model in R to identify eQTLs with significantly different gene expression regulation in treated PBMCs when compared to no treatment (baseline). We found no evidence that SNPs associated with significant changes in gene expression between MCK and a treatment in PBMCs caused strong opposing regulatory effects. We identified canonical pathways with a significant number of genes in PBMCs with altered gene expression regulation when treated with lipopolysaccharides (LPS) and hay-dust extract (HDE). Significant pathways included RhoA signaling in LPS, as well as histamine degradation, cholesterol biosynthesis, FcγRIIB signaling, and others in HDE. Our results support previous research indicating that pathways altered between baseline and treatment of PBMCs in horses with LPS or HDE affect inflammatory responses through RhoA, B-cell signaling, IL-4 and IFN-γ, and histamine.

scholarly journals Single-cell RNA-sequencing reveals widespread personalized, context-specific gene expression regulation in immune cells.

2021 ◽  
Author(s):  
Roy Oelen ◽  
Dylan H. de Vries ◽  
Harm Brugge ◽  
Gracie Gordon ◽  
Martijn Vochteloo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Gene Expression Regulation ◽  
Specific Gene ◽  
Specific Expression ◽  
Peripheral Blood Mononuclear ◽  
Cell Type Specific Expression ◽  
Context Specific

Gene expression and its regulation can be context-dependent. To dissect this, using samples from 120 individuals, we single-cell RNA-sequenced 1.3M peripheral blood mononuclear cells exposed to three different pathogens at two time points or left unexposed. This revealed thousands of cell type-specific expression changes (eQTLs) and pathogen-induced expression changes (response QTLs) that are influenced by genetic variation. In monocytes, the strongest responder to pathogen stimulations, genetics also affected co-expression of 71.4% of these eQTL genes. For example, the pathogen recognition receptor CLEC12A showed many such co-expression interactions, but only in monocytes after 3h pathogen stimulation. Further analysis linked this to interferon-regulating transcription factors, a finding that we recapitulated in an independent cohort of patients with systemic lupus erythematosus, a condition characterized by increased interferon activity. Altogether, this study highlights the importance of context for gaining a better understanding of the mechanisms of gene regulation in health and disease.

scholarly journals COVID-19-activated SREBP2 disturbs cholesterol biosynthesis and leads to cytokine storm

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Wonhwa Lee ◽  
June Hong Ahn ◽  
Hee Ho Park ◽  
Hong Nam Kim ◽  
Hyelim Kim ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Lung Damage ◽  
Cytokine Storm ◽  
Peripheral Blood Mononuclear ◽  
Terminal Fragment ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

Abstract Sterol regulatory element binding protein-2 (SREBP-2) is activated by cytokines or pathogen, such as virus or bacteria, but its association with diminished cholesterol levels in COVID-19 patients is unknown. Here, we evaluated SREBP-2 activation in peripheral blood mononuclear cells of COVID-19 patients and verified the function of SREBP-2 in COVID-19. Intriguingly, we report the first observation of SREBP-2 C-terminal fragment in COVID-19 patients’ blood and propose SREBP-2 C-terminal fragment as an indicator for determining severity. We confirmed that SREBP-2-induced cholesterol biosynthesis was suppressed by Sestrin-1 and PCSK9 expression, while the SREBP-2-induced inflammatory responses was upregulated in COVID-19 ICU patients. Using an infectious disease mouse model, inhibitors of SREBP-2 and NF-κB suppressed cytokine storms caused by viral infection and prevented pulmonary damages. These results collectively suggest that SREBP-2 can serve as an indicator for severity diagnosis and therapeutic target for preventing cytokine storm and lung damage in severe COVID-19 patients.

scholarly journals Calorie Restriction Improves Physical Performance and Modulates the Antioxidant and Inflammatory Responses to Acute Exercise

Nutrients ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 930 ◽  
Author(s):  
Xavier Capó ◽  
Miquel Martorell ◽  
Miguel D. Ferrer ◽  
Antoni Sureda ◽  
Victoria Pons ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Energy Efficiency ◽  
Physical Performance ◽  
Calorie Restriction ◽  
Acute Exercise ◽  
Stress Proteins ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Peripheral Blood Mononuclear

Our aim was to characterize the effects of calorie restriction on the anthropometric characteristics and physical performance of sportsmen and to evaluate the effects of calorie restriction and acute exercise on mitochondria energetics, oxidative stress, and inflammation. Twenty volunteer taekwondo practitioners undertook a calorie restriction of 30–40% on three alternate days a week for one month. Eleven volunteer sportsmen participated as controls. Both groups performed an energy efficiency test to evaluate physical performance, and samples were taken before and after exercise. The total weight of participants significantly decreased (5.9%) after calorie restriction, while the efficiency of work and the contributions of fat to obtain energy were enhanced by calorie restriction. No significant differences induced by acute exercise were observed in individual non-esterified fatty acid percentage or oxidative stress markers. Calorie restriction downregulated the basal gene expression of nitric oxide synthase, antioxidant enzymes, mitochondrial uncoupling proteins, and repairing stress proteins, but it enhanced the expression of sirtuins in peripheral blood mononuclear cells. In conclusion, one month of calorie restriction decreases body weight and increases physical performance, enhancing energy efficiency, moderating the antioxidant and inflammatory basal gene expression, and influencing its response to acute exercise.

scholarly journals Evaluation of a Gene Expression Biomarker to Identify Operationally Tolerant Liver Transplant Recipients: The LITMUS Trial

2021 ◽  
Author(s):  
Andrzej Chruscinski ◽  
Vanessa Rojas-Luengas ◽  
Sajad Moshkelgosha ◽  
Assaf Issachar ◽  
Jane Luo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Transplant ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Transplant Recipients ◽  
Peripheral Blood Mononuclear ◽  
Operational Tolerance ◽  
Liver Biopsies ◽  
Liver Transplant Recipients

Abstract LITMUS was a single-centre, Phase 2a study designed to investigate whether the gene biomarker FGL2/IFNG previously reported for the identification of tolerance in murine models could identify operationally tolerant liver transplant recipients. Multiplex RT-PCR was used to amplify eight immunoregulatory genes in peripheral blood mononuclear cells (PBMC) from 69 adult liver transplant recipients. Patients with PBMC FGL2/IFNG ≥ 1 and a normal liver biopsy underwent immunosuppression (IS) withdrawal. The primary endpoint was the development of operational tolerance. Secondary endpoints included correlation of tolerance with allograft gene expression and immune cell markers. Twenty-eight of 69 patients (38%) were positive for the PBMC tolerance biomarker and 23 proceeded to IS withdrawal. Nine of the 23 patients had abnormal baseline liver biopsies and were excluded. Of the14 patients with normal biopsies, eight (57%) have achieved operational tolerance and are off IS (range 12-57 months). Additional studies revealed that all of the tolerant patients and only one non-tolerant patient had a liver gene ratio of FOXP3/IFNG ≥1 prior to IS withdrawal. Increased CD4 + T regulatory T cells were detected both in PBMC and livers of tolerant patients following IS withdrawal. Higher expression of SELE (gene for E-selectin) and lower expression of genes associated with inflammatory responses (GZMB, CIITA, UBD, LSP1 and CXCL9) were observed in the pre-withdrawal liver biopsies of tolerant patients by RNA sequencing. These results suggest that measurement of PBMC FGL2/IFNG may enrich for the identification of operationally tolerant liver transplant patients, especially when combined with intragraft measurement of FOXP3/IFNG.

scholarly journals Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nan Xiao ◽  
Meng Nie ◽  
Huanhuan Pang ◽  
Bohong Wang ◽  
Jieli Hu ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Rhesus Macaques ◽  
Fatal Outcome ◽  
Organ Injury ◽  
Cytokine Release ◽  
Serum Samples ◽  
Peripheral Blood Mononuclear

AbstractCytokine release syndrome (CRS) is a major cause of the multi-organ injury and fatal outcome induced by SARS-CoV-2 infection in severe COVID-19 patients. Metabolism can modulate the immune responses against infectious diseases, yet our understanding remains limited on how host metabolism correlates with inflammatory responses and affects cytokine release in COVID-19 patients. Here we perform both metabolomics and cytokine/chemokine profiling on serum samples from healthy controls, mild and severe COVID-19 patients, and delineate their global metabolic and immune response landscape. Correlation analyses show tight associations between metabolites and proinflammatory cytokines/chemokines, such as IL-6, M-CSF, IL-1α, IL-1β, and imply a potential regulatory crosstalk between arginine, tryptophan, purine metabolism and hyperinflammation. Importantly, we also demonstrate that targeting metabolism markedly modulates the proinflammatory cytokines release by peripheral blood mononuclear cells isolated from SARS-CoV-2-infected rhesus macaques ex vivo, hinting that exploiting metabolic alterations may be a potential strategy for treating fatal CRS in COVID-19.

scholarly journals Expression Profiling of Transcriptome and Its Associated Disease Risk in Yang Deficiency Constitution of Healthy Subjects

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Ruoxi Yu ◽  
Yin Yang ◽  
Yuanyuan Han ◽  
Pengwei Hou ◽  
Yingshuai Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Healthy Subjects ◽  
Mononuclear Cells ◽  
Clinical Medicine ◽  
Disease Risk ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Molecular Evidence ◽  
Chinese Han ◽  
Peripheral Blood Mononuclear

Objectives. Differences among healthy subjects and associated disease risks are of substantial interest in clinical medicine. According to the theory of “constitution-disease correlation” in traditional Chinese medicine, we try to find out if there is any connection between intolerance of cold in Yang deficiency constitution and molecular evidence and if there is any gene expression basis in specific disorders. Methods. Peripheral blood mononuclear cells were collected from Chinese Han individuals with Yang deficiency constitution (n=20) and balanced constitution (n=8) (aged 18–28) and global gene expression profiles were determined between them using the Affymetrix HG-U133 Plus 2.0 array. Results. The results showed that when the fold change was ≥1.2 and q ≤ 0.05, 909 genes were upregulated in the Yang deficiency constitution, while 1189 genes were downregulated. According to our research differential genes found in Yang deficiency constitution were usually related to lower immunity, metabolic disorders, and cancer tendency. Conclusion. Gene expression disturbance exists in Yang deficiency constitution, which corresponds to the concept of constitution and gene classification. It also suggests people with Yang deficiency constitution are susceptible to autoimmune diseases, enteritis, arthritis, metabolism disorders, and cancer, which provides molecular evidence for the theory of “constitution-disease correlation.”

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