scholarly journals Genetic Attenuation of Paraoxonase 1 Activity Induces Proatherogenic Changes in Plasma Proteomes of Mice and Humans

Antioxidants ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1198
Author(s):  
Marta Sikora ◽  
Ewa Bretes ◽  
Joanna Perła-Kaján ◽  
Izabela Lewandowska ◽  
Łukasz Marczak ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Biological Networks ◽  
Immune Cell ◽  
Neurological Diseases ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Paraoxonase 1 ◽  
Cell Trafficking ◽  
Label Free ◽  
Q192r Polymorphism

High-density lipoprotein (HDL), in addition to promoting reverse cholesterol transport, possesses anti-inflammatory, antioxidative, and antithrombotic activities. Paraoxonase 1 (PON1), carried on HDL in the blood, can contribute to these antiatherogenic activities. The PON1-Q192R polymorphism involves a change from glutamine (Q variant) to arginine (R variant) at position 192 of the PON1 protein and affects its enzymatic activity. The molecular basis of PON1 association with cardiovascular and neurological diseases is not fully understood. To get insight into the function of PON1 in human disease, we examined how genetic attenuation of PON1 levels/activity affect plasma proteomes of mice and humans. Healthy participants (48.9 years old, 50% women) were randomly recruited from the Poznań population. Four-month-old Pon1−/− (n = 17) and Pon1+/+ (n = 8) mice (50% female) were used in these experiments. Plasma proteomes were analyzed using label-free mass spectrometry. Bioinformatics analysis was carried out using the Ingenuity Pathway Analysis (IPA) resources. PON1-Q192R polymorphism and Pon1−/− genotype induced similar changes in plasma proteomes of humans and mice, respectively. The top molecular network, identified by IPA, affected by these changes involved proteins participating in lipoprotein metabolism. Other PON1 genotype-dependent proteomic changes affect different biological networks in humans and mice: “cardiovascular, neurological disease, organismal injury/abnormalities” in PON1-192QQ humans and “humoral immune response, inflammatory response, protein synthesis” and “cell-to-cell signaling/interaction, hematological system development/function, immune cell trafficking” in Pon1−/− mice. Our findings suggest that PON1 interacts with molecular pathways involved in lipoprotein metabolism, acute/inflammatory response, and complement/blood coagulation that are essential for blood homeostasis. Modulation of those interactions by the PON1 genotype can account for its association with cardiovascular and neurological diseases.

scholarly journals Integrated analysis of mRNA and protein expression profiling in tubal endometriosis

Reproduction ◽  
2020 ◽  
Vol 159 (5) ◽  
pp. 601-614 ◽  
Author(s):  
Hang Qi ◽  
Huiyu Zhang ◽  
Xiaoya Zhao ◽  
Ya Qin ◽  
Guiling Liang ◽  
...  
Keyword(s):  
Fallopian Tube ◽  
Immune Cell ◽  
Differentially Expressed ◽  
Integrated Analysis ◽  
Cell Trafficking ◽  
Label Free ◽  
Cellular Functions ◽  
Human Fallopian Tube ◽  
Pathway Activation ◽  
Mrna And Protein Expression

Tubal endometriosis (tubal EM) is a subtype of endometriosis (EM) associated with fallopian tube impairments and infertility. Since the molecular mechanism underlying tubal EM is not clear, we assume that an aberrant transcriptome of fallopian tube epithelium and microenvironment changes caused by cytokines in tubal fluid are possible causes. The aim of this study was to identify potential hub mRNAs/proteins of tubal EM through integrated transcriptomic and proteomic analyses and to elucidate significant pathways, cellular functions, and interaction networks during the initiation and progression of tubal EM. We obtained human fallopian tube epithelium and tubal fluid samples from patients with and without tubal EM. Tubal epithelia were analyzed using microarray, and tubal fluid was analyzed using quantitative label-free LC-MS/MS. We identified differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) and determined common mRNAs/protein. We observed 35 commonly deregulated mRNAs/proteins, and IPA indicated that cellular movement, inflammatory response, and immune cell trafficking were significantly activated during the pathogenesis of tubal EM. We also identified acute phase response signaling pathway activation as a unique pathogenesis signature of tubal EM. Our results demonstrate that an integrated analysis of the transcriptome and proteome has the potential to reveal novel disease mechanisms at a molecular level.

scholarly journals A proteomic perspective and involvement of cytokines in SARS-CoV-2 infection

2021 ◽  
Author(s):  
Sarena Banu ◽  
Mohammed M Idris ◽  
Ramakrishnan Nagaraj
Keyword(s):  
Inflammatory Response ◽  
Quantitative Proteomics ◽  
Immune Cell ◽  
Cell Trafficking ◽  
Cytokine Storm ◽  
Proteomics Analysis ◽  
Initial Infection ◽  
Clinical Observations ◽  
Normal Individuals ◽  
Oropharyngeal Swab

Infection with the SARS-CoV-2 virus results in manifestation of several clinical observations from asymptomatic to multi-organ failure. Biochemically, the serious effects are due to what is described as cytokine storm. The initial infection region for COVID-19 is the nasopharyngeal/oropharyngeal region which is the site where samples are taken to examine the presence of virus. We have earlier shown that several defensin genes are down regulated in cells from this region in patients who tested positive in the RTPCR test. We have now carried out detailed proteomic analysis of the nasopharyngeal/oropharyngeal swab samples collected from normal individuals and those tested positive for SARS-CoV-2 by RTPCR, involving high throughput quantitative proteomics analysis. Several proteins like annexins, cytokines and histones were found differentially regulated in the host human cells following SARS-CoV-2 infection. Genes for these proteins were also observed to be differentially regulated when their expression was analyzed. Majority of the cytokine proteins were found to be up regulated in the infected individuals. Cell to Cell signaling interaction, Immune cell trafficking and inflammatory response pathways were found associated with the differentially regulated proteins based on network pathway analysis.

scholarly journals P.1.38 Effects of paraoxonase 1 (PON1) genotype and nanomaterials exposure on heart rate variability

2019 ◽  
Vol 76 (Suppl 1) ◽  
pp. A87.1-A87
Author(s):  
Wei-te Wu ◽  
Saou-Hsing Liou
Keyword(s):  
Density Lipoprotein ◽  
Cross Sectional Study ◽  
Paraoxonase 1 ◽  
Cardiac Events ◽  
Cross Sectional ◽  
Beneficial Effects ◽  
Q192r Polymorphism ◽  
Apparent Relationship ◽  
Blood Specimens ◽  
The Relationship

BackgroundAlthough paraoxonase 1 (PON1) is a high-density lipoprotein (HDL) associated antioxidant enzyme that has beneficial effects on atherosclerosis and cardiovascular disease, whether PON1 Q192R polymorphism have any effect on cardiac autonomic function is yet to be investigated. Moreover, there is limited data regarding the influence of NPs exposure on HRV parameters in humans. The purpose of the study was to exam whether PON1 genotype or NPs exposure has an association with HRV levels.MethodsThis cross-sectional study recruited 235 workers exposed to NM and 185 non-exposed controls from 14 NM handling plants in Taiwan from 2009 to 2011. For each participant, we collected blood specimens to determine the genotype of the PON1 Q192R polymorphism and PON1 paraoxonase and arylesterase activities. In addition, short-term HRV was tested.ResultsThe results showed that PON1 Q192R genotype and PON1 paraoxonase/arylesterase activities associated with HRV, and was particularly noteworthy in RMSSD and HF. The relationship between NPs exposure and HRV was only found in workers exposed to nano-Ag, but the apparent relationship between NPs exposure and HRV is lacking.ConclusionsIt is a novel finding that both RR genotype of PON1 (Q192R) and activities of PON1 increased with HRV levels. PON1 Q192R genotype may play an important role in cardiac protection. Considering the global prevalence of NMs market, further studies of NPs-induced cardiac events and stresses still are required to establish.

scholarly journals OP0040 HIPPOCAMPAL IMMUNE CELL TRAFFICKING AND A MYELOID PREDOMINANT INFLAMMATORY RESPONSE WITH ENHANCED ANTIGEN PRESENTATION AND DECREASED LEVELS OF NEUROTRANSMITTERS UNDERLY THE NEUROPSYCHIATRIC PHENOTYPE OF THE NZW/NZB MURINE LUPUS MODEL

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 21.1-22
Author(s):  
D. Nikolopoulos ◽  
T. Manolakou ◽  
A. Filia ◽  
M. Nakos-Bimpos ◽  
A. Polissidis ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Antigen Presentation ◽  
Rna Sequencing ◽  
Immune Cell ◽  
Myeloid Cells ◽  
Brain Regions ◽  
Cell Trafficking ◽  
Murine Lupus ◽  
Immune Cell Trafficking ◽  
The Brain

Background:Neuropsychiatric events are common in patients with systemic lupus erythematosus (SLE), yet the underlying pathogenesis remains ill-defined, as the access to brain tissue is limited. We have previously shown that NZW/NZB F1 murine lupus model recapitulates the neuropsychiatric lupus phenotype including depressive-like behavior, increased rates of anxiety, cognitive dysfunction and motor disturbances, both at pre-nephritic and nephritic stages of the disease.Objectives:To dissect specific regions in the brain, which account for this phenotype and elucidate inflammatory and non-inflammatory mechanisms involved.Methods:Four distinct brain regions (hippocampus, amygdala, striatum and pre-frontal cortex) were dissected from brains of female C57BL/6 (WT) and NZW/NZB F1 mice at the age of 3 months (pre-nephritic) and 6 months (nephritic stage) (n=5-8/condition/experiment). Since most of the behavioral phenotype corresponds to the hippocampus, we first examined in depth the hippocampal pathology by bulk RNA sequencing, measurements of neurotransmitters levels via high-performance liquid chromatography (HPLC) and by immunophenotyping via flow cytometry analyses. For comparisons, statistical significance was indicated as a two-sided P<0.05.Results:Transcriptomic analysis revealed aberrant immune mediated response in the hippocampus of 6 month-old lupus mice compared to WT. Specifically, inflammatory pathways including both innate and adaptive immune responses, increased cytokine production, increased antigen presentation and immune cell trafficking, along with increased apoptosis and decreased cell proliferation suggest that immune aberrancies may lead to neuronal damage. These aberrancies were present in mice at 3 month-old, yet were progressed with time being more prominent at 6 month of age in lupus hippocampus. The RNA sequencing date were validated by immunophenotyping on lupus hippocampus demonstrating increased reactive GFAP+ astrocytes both at 3 and 6-month old mice. Activated IBA1+ microglia and CD11b+CD45hi CNS myeloid cells were increased only at 6 months of age. Furthermore, increased immune cell infiltration from the periphery including lymphocytes (CD45+CD11b-) mainly T cells (CD4+/CD8+) and monocytes (CD45+CD11b+Ly6G-Ly6C+), was evident only in 6 month-old lupus hippocampus compared to WT. Importantly, microglia cells in lupus hippocampus at 6 but not at 3 month of age, exhibited increased expression of antigen presenting markers including CD80, CD86 and MHC-II indicating that microglia cells may carry out the antigen presentation process seen in transcriptomic data. Low levels of serotonin and noradrenaline were observed at both 3 and 6 months of age in lupus mice; these aberrancies were mainly attributed to decreased serotonin synthesis as evidenced by intact serotonin metabolism (no differences were observed at its metabolite: 5-hydroxyindoleacetic acid). Analysis of the remaining regions of the brain combined with studies of metabolic activities of various brain regions by PET-CT scanning is in progress.Conclusion:Immune cell trafficking from the periphery combined with marked inflammatory response in the hippocampus underlie the neuropsychiatric phenotype in NZW/B murine lupus. Our data indicate increased expression of activated myeloid cells -including microglia- in the hippocampus of lupus mice culminating in increased antigen presentation and decreased neurotransmitter levels.References:[1]Nikolopoulos, D., et al. “THU0223 THE NEUROPSYCHIATRIC PHENOTYPE OF NZB/W LUPUS-PRONE MOUSE MODEL AT PRE-NEPHRITIC AND NEPHRITIC STAGES OF THE DISEASE: MURINE MODEL RECAPITULATES HUMAN DISEASE.” (2020): 334-335.Acknowledgements:This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 742390)Disclosure of Interests:None declared

scholarly journals Association of Paraoxonase-1 Q192R (rs662) Single Nucleotide Variation with Cardiovascular Risk in Coffee Harvesters of Central Colombia

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Fernando Siller-López ◽  
Sandra Garzón-Castaño ◽  
Martha E. Ramos-Márquez ◽  
Iván Hernández-Cañaveral
Keyword(s):  
Cardiovascular Risk ◽  
Pesticide Exposure ◽  
Density Lipoprotein ◽  
Catalytic Efficiency ◽  
Paraoxonase 1 ◽  
Cvd Risk ◽  
Genotype Frequencies ◽  
Q192r Polymorphism ◽  
Ascvd Risk ◽  
Genetic And Environmental Factors

Paraoxonase 1 (PON1), a high-density lipoprotein-associated antioxidant enzyme, hydrolyzes several organophosphate pesticides and oxidized lipids. The PON1 Q192R polymorphism affects the catalytic efficiency and is considered a risk factor for pesticide intoxication and cardiovascular disease (CVD) but the association is not consistent between individuals or populations. We aimed to study the association of PON1 Q192R polymorphism with CVD risk in coffee harvesters of central Colombia. Demographics were collected from 205 subjects via standardized questionnaires. Lipid profiles and serum butyrylcholinesterase (BChE) were measured by standard procedures. The calculated 10-year atherosclerotic CVD (ASCVD) risk was used as the cardiovascular risk estimate. Q192R genotype was determined by real-time PCR. Prevalence of hypertension, hypercholesterolemia, and the 10-year ASCVD risk was 33%, 62%, and 22%, respectively. BChE levels were no indicative of recent pesticide exposure, although a positive correlation was observed with BChE and hypercholesterolemia. The Q192R genotype frequencies were 38% (QQ), 44% (QR), and 18% (RR). We found an association of the 192Q genotype with hypertension. The results of this study signal the importance to evaluate the influence and potential interactions of BChE and PON1 192Q allele with known genetic and environmental factors implicated in the pathogenesis of CVD.

scholarly journals Individuals with increased inflammatory response to ozone demonstrate muted signaling of immune cell trafficking pathways

2012 ◽  
Vol 13 (1) ◽  
pp. 89 ◽  
Author(s):  
Rebecca C Fry ◽  
Julia E Rager ◽  
Haibo Zhou ◽  
Baiming Zou ◽  
June W Brickey ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Immune Cell ◽  
Cell Trafficking ◽  
Immune Cell Trafficking

New Trends in Anti-Cancer Therapy: Combining Conventional Chemotherapeutics with Novel Immunomodulators

2018 ◽  
Vol 25 (36) ◽  
pp. 4758-4784 ◽  
Author(s):  
Amy L. Wilson ◽  
Magdalena Plebanski ◽  
Andrew N. Stephens
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Immune System ◽  
Cancer Therapy ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Tumour Microenvironment ◽  
Immune Checkpoints ◽  
Tumour Regression ◽  
Cell Trafficking

Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1. Although tumour regression is the outcome for some patients following immunotherapy, many patients still do not respond. Furthermore, chemotherapy has been the standard of care for most cancers, but the immunomodulatory capacity of these drugs has only recently been uncovered. The ability of chemotherapy to modulate the immune system through a variety of mechanisms, including immunogenic cell death (ICD), increased antigen presentation and depletion of regulatory immune cells, highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. In addition, recent pre-clinical trials indicate dipeptidyl peptidase (DPP) enzyme inhibition, an enzyme that can regulate immune cell trafficking to the tumour microenvironment, as a novel cancer therapy. The present review focuses on the current immunological approaches for the treatment of cancer, and summarizes clinical trials in the field of immunotherapy as a single treatment and in combination with chemotherapy.

Structure and Function of Angiopoietin-like Protein 3 (ANGPTL3) in Atherosclerosis

2020 ◽  
Vol 27 (31) ◽  
pp. 5159-5174 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
Low Density Lipoprotein ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Structure And Function ◽  
Biological Functions ◽  
Pharmacological Management ◽  
Vascular Growth ◽  
Promising Target ◽  
And Function ◽  
Systematic Appraisal

Background:Angiopoietin-Like Proteins (ANGPTLs) are structurally related to the angiopoietins. A total of eight ANGPTLs (from ANGPTL1 to ANGPTL8) have been identified so far. Most ANGPTLs possess multibiological functions on lipid metabolism, atherosclerosis, and cancer. Among them, ANGPTL3 has been shown to regulate the levels of Very Low-Density Lipoprotein (VLDL) made by the liver and play a crucial role in human lipoprotein metabolism.Method:A systematic appraisal of ANGPTLs was conducted, focusing on the main features of ANGPTL3 that has a significant role in atherosclerosis.Results:Angiopoietins including ANGPTL3 are vascular growth factors that are highly specific for endothelial cells, perform a variety of other regulatory activities to influence inflammation, and have been shown to possess both pro-atherosclerotic and atheroprotective effects.Conclusion:ANGPTL3 has been demonstrated as a promising target in the pharmacological management of atherosclerosis. However, many questions remain about its biological functions.

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