Inhibition Of Lysosomal Oxidation Of Ldl Prevents Lysosomal Dysfunction, Cellular Senescence, Secretion Of Pro-Inflammatory Cytokines In Human Macrophages And Reduces Atherosclerosis In Mice

2019 ◽  
Vol 287 ◽  
pp. e16
Author(s):  
F. Ahmad ◽  
D. Leake
Keyword(s):  
Inflammatory Cytokines ◽  
Cellular Senescence ◽  
Human Macrophages ◽  
Lysosomal Dysfunction ◽  
Pro Inflammatory Cytokines

Abstract 1123: Critical Role Of Adipose Senescence In Insulin Resistance And Vascular Dysfunction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Masayuki Orimo ◽  
Tohru Minamino ◽  
Hideyuki Miyauchi ◽  
Kaoru Tateno ◽  
Sho Okada ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Inflammatory Cytokines ◽  
Cellular Senescence ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Serum Levels ◽  
P53 Expression ◽  
Deficient Mice ◽  
Pro Inflammatory Cytokines

Cellular senescence is originally described as the finite replicative lifespan of human somatic cells in culture. As a consequence of semi-conservative DNA replication, the extreme terminals of the chromosomes are not duplicated completely, resulting in successive shortening of telomeres with each cell division. Telomerase is a ribonucleoprotein that adds telomeres to the ends of chromosomes. Critically short telomeres are thought to trigger DNA damage response, thereby inducing cellular senescence. Accumulating evidence has suggested that senescent cells promote aging phenotypes or age-related pathologies. Here we show that adipose senescence is critically involved in the regulation of insulin resistance that underlies age-associated cardiovascular disease. The later generation of telomerase-deficient mice with short telomeres exhibited insulin resistance and vascular dysfunction when fed on a high-calorie diet. Adipose tissue of these mice revealed senescence-like phenotypes such as an increase in neutral β galactosidase activity and upregulation of p53 and pro-inflammatory cytokines. Serum levels of pro-inflammatory cytokines were markedly elevated in telomerase-deficient mice and treatment of these mice with a neutralizing antibody against TNF-α significantly improved insulin and glucose intolerance. Removal of senescent adipose tissue reduced serum levels of pro-inflammatory cytokines and thereby improved insulin resistance in telomerase-deficient mice. Conversely, implantation of senescent adipose tissue to wild-type mice impaired insulin sensitivity and glucose tolerance in recipients. Introduction of telomere dysfunction to young adipose tissue markedly upregulated p53 expression and increased the production of pro-inflammatory cytokines. Inhibition of p53 activity significantly improved senescence-like phenotypes of adipose tissue, insulin resistance, and vascular dysfunction in telomerase-deficient mice. These results disclose a novel mechanism of insulin resistance and suggest that adipose senescence is a potential therapeutic target for the treatment of diabetes and diabetic vasculopathy.

scholarly journals Ku70 and Ku80 participate in LPS-induced pro-inflammatory cytokines production in human macrophages and monocytes

Aging ◽  
2020 ◽  
Vol 12 (20) ◽  
pp. 20432-20444
Author(s):  
Hong Sun ◽  
Quan Li ◽  
Gang Yin ◽  
Xi Ding ◽  
Jing Xie
Keyword(s):  
Inflammatory Cytokines ◽  
Human Macrophages ◽  
Pro Inflammatory Cytokines

scholarly journals ANTI-CELL SENESCENT EFFECTS OF RAPAMYCIN AND THEIR ROLE IN DISEASES, INCLUDING ALZHEIMER’S

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S370-S370
Author(s):  
Viviana I Perez
Keyword(s):  
Mouse Models ◽  
Inflammatory Cytokines ◽  
Cellular Senescence ◽  
Selective Removal ◽  
Current Work ◽  
Loss Of Function ◽  
Age Related ◽  
The Brain ◽  
Pro Inflammatory Cytokines

Abstract Senescent cells contribute to age-related pathology and loss of function, and their selective removal improves physiology and extends longevity. We have shown that deficiency in Nrf2 in young Nrf2KO mice leads to an increase in senescent cells, with increased levels of pro-inflammatory cytokines in various tissues, including the brain. Both the cellular senescence and SASP decrease significantly when these mice are treated with rapamycin. Our current work focuses on determining whether cellular senescence contributes to premature AD-like pathogenesis in mouse models of AD. Indeed, it has been shown that Nrf2 deficiency in mouse models for AD leads to exacerbated pathology, suggesting that increased inflammation, due in part to the increased SASP-producing senescent cells, might be contribute to this phenotype. We are testing whether the burden of senescent cells in the brain on mouse models of AD can be reverted by rapamycin.

scholarly journals 4-Octyl Itaconate Activates Nrf2 Signaling to Inhibit Pro-Inflammatory Cytokine Production in Peripheral Blood Mononuclear Cells of Systemic Lupus Erythematosus Patients

2018 ◽  
Vol 51 (2) ◽  
pp. 979-990 ◽  
Author(s):  
Chun Tang ◽  
Xiaohua Wang ◽  
Yingying Xie ◽  
Xiaoyan Cai ◽  
Na Yu ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Nuclear Factor ◽  
Systemic Lupus ◽  
Peripheral Blood Mononuclear ◽  
Human Macrophages ◽  
Tnf Α ◽  
Blood Mononuclear Cells ◽  
Pro Inflammatory Cytokines

Background/Aims: Increased production of multiple pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, plays an essential pathogenic role in the progression of systemic lupus erythematosus (SLE). Recent studies have characterized itaconate as a novel and potent nuclear-factor-E2-related factor 2 (Nrf2) activator that activates Nrf2 signaling by alkylating cysteine residues on Keap1 (Kelch-like ECH-associated protein 1). Methods: THP-1 human macrophages and peripheral blood mononuclear cells (PBMCs) of SLE patients were treated with 4-octyl itaconate (OI). Nrf2 signaling activation was tested by qPCR assay and western blotting. mRNA expression and the production of multiple pro-inflammatory cytokines were tested by qPCR and enzyme-linked immunosorbent assays, respectively. Nuclear factor (NF)-κB activation was tested by the p65 DNA-binding assay. Results: We demonstrated that OI, the cell-permeable derivative of itaconate, induced Keap1-Nrf2 dissociation, Nrf2 protein accumulation, and nuclear translocation, which enabled the transcription and expression of multiple Nrf2-dependentantioxidant enzymes (heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase modifier subunit) in THP-1 human macrophages. OI also induced significant Nrf2 activation in SLE patient-derived PBMCs. OI pretreatment inhibited mRNA expression and the production of multiple pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in SLE patient-derived PBMCs and lipopolysaccharide (LPS)-activated THP-1 cells. OI potently inhibited NF-κB activation in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Importantly, Nrf2 silencing (by targeted short hairpin RNA) or knockout (by CRISPR/Cas9 gene-editing method) almost abolished OI-induced anti-oxidant and anti-inflammatory actions in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Conclusion: OI activates Nrf2 signaling to inhibit the production of pro-inflammatory cytokines in human macrophages and SLE patient-derived PBMCs. OI and itaconate could have important therapeutic value for the treatment of SLE.

scholarly journals FTIR spectroscopic analysis and effect of Diplotaxis Acri’s flower extract on pro-inflammatory cytokines in THP-1 human macrophages

2020 ◽  
Vol 11 (4) ◽  
pp. 5282-5286
Author(s):  
Nasser Fahad Alotaibi
Keyword(s):  
Inflammatory Cytokines ◽  
Spectroscopic Analysis ◽  
Biological Activities ◽  
Natural Compounds ◽  
Mediating Effect ◽  
Active Constituent ◽  
Human Macrophages ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Plants and natural compounds are extensively reported for diverse biological activities, including their effects on the inflammation pathway. The annual winter herb Diplotaxis Acris (D.Acris) is found only slopes of sandy and stony valleys in the desert. This research is intended to make a contribution to the literature regarding the employment of the species of plant ethnomedicinally by undertaking FTIR spectroscopic analysis and examining several concentrations of the plant's extract for anti-inflammatory activity in vitro with activated THP-1 human macrophages to examine its mediating effect on inflammation. Cell viability was also evaluated, and there was no severe cytotoxic effect from D.Acris extract with any of the concentrations being assessed on cells. ELISA was used to assess the pro-inflammatory cytokines and chemo kines that were produced. It has been noted that the plant extract led to a significant decrease in levels of the pro-inflammatory cytokines, including interleukin (IL)-1β, tumour necrosis factor (TNF)- α and IL-6. Inhibition of pro-inflammatory cytokines indicates the anti-inflammatory trends of D.Acris. This plant can be investigated further by isolation of natural compounds from the extract and effects of these compounds can be evaluated on the same inflammatory markers to show the main active constituent responsible for anti-inflammatory activities.

Dysbalance of cytokines in schizophrenia and strategies for restoration of immune functions

2020 ◽  
pp. 1-4
Keyword(s):  
Monoclonal Antibodies ◽  
Immune System ◽  
Inflammatory Cytokines ◽  
Cumulative Effect ◽  
Theoretical Explanation ◽  
Psychotropic Medications ◽  
Immune Functions ◽  
Human Macrophages ◽  
Individualized Approach ◽  
Pro Inflammatory Cytokines

We discuss the cumulative effect of different cytokines in veterans with schizophrenia. Previously we reported that the chemoattractant G-CSF, MCP, MDC and GRO, which activates human macrophages, monocytes, neutrophils and basophils that these factors were significantly increased compared to control subjects and also that levels NF-γ and IL-17 and Il-2 were significantly decreased as compared to controls. Based on these results we hypothesize that the immune system with schizophrenia is trying to restore the balance of their immune system by reducing the amounts of pro-inflammatory cytokines and increasing the amounts of anti-inflammatory and regulating cytokines. We decided to use an unorthodox approach by clustering the cytokines in four groups according to their predominant functions and analyzing the effect of cumulative amounts of cytokines in each group. This hypothetical approach provided theoretical explanation about the changes of cytokines in patients with schizophrenia. We suggest an individualized approach for treatment of psychosis in patients with schizophrenia by augmenting psychotropic medications with the help of monoclonal antibodies which block the excessive amounts of specific proinflammatory cytokines.

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