scholarly journals Chronic and Cycling Hypoxia: Drivers of Cancer Chronic Inflammation through HIF-1 and NF-κB Activation. A Review of the Molecular Mechanisms

2021 ◽  
Vol 22 (19) ◽  
pp. 10701
Author(s):  
Jan Korbecki ◽  
Donata Simińska ◽  
Magdalena Gąssowska-Dobrowolska ◽  
Joanna Listos ◽  
Izabela Gutowska ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Hypoxia Inducible Factor ◽  
Nuclear Factor Κb ◽  
Low Grade ◽  
Hypoxia Inducible Factor 1 ◽  
Mapk Cascades ◽  
Oxide Synthase ◽  
Low Grade Inflammation ◽  
Tumor Associated Neutrophils

Chronic (continuous, non-interrupted) hypoxia and cycling (intermittent, transient) hypoxia are two types of hypoxia occurring in malignant tumors. They are both associated with the activation of hypoxia-inducible factor-1 (HIF-1) and nuclear factor κB (NF-κB), which induce changes in gene expression. This paper discusses in detail the mechanisms of activation of these two transcription factors in chronic and cycling hypoxia and the crosstalk between both signaling pathways. In particular, it focuses on the importance of reactive oxygen species (ROS), reactive nitrogen species (RNS) together with nitric oxide synthase, acetylation of HIF-1, and the action of MAPK cascades. The paper also discusses the importance of hypoxia in the formation of chronic low-grade inflammation in cancerous tumors. Finally, we discuss the effects of cycling hypoxia on the tumor microenvironment, in particular on the expression of VEGF-A, CCL2/MCP-1, CXCL1/GRO-α, CXCL8/IL-8, and COX-2 together with PGE2. These factors induce angiogenesis and recruit various cells into the tumor niche, including neutrophils and monocytes which, in the tumor, are transformed into tumor-associated neutrophils (TAN) and tumor-associated macrophages (TAM) that participate in tumorigenesis.

Periodontal Pathogens and Neuropsychiatric Health

2020 ◽  
Vol 20 (15) ◽  
pp. 1353-1397 ◽  
Author(s):  
Abhishek Wadhawan ◽  
Mark A. Reynolds ◽  
Hina Makkar ◽  
Alison J. Scott ◽  
Eileen Potocki ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Low Grade ◽  
Periodontal Pathogens ◽  
Synergistic Interactions ◽  
Brain Vasculature ◽  
Micro Rnas ◽  
Clinical Conditions ◽  
Low Grade Inflammation ◽  
Neuropsychiatric Illness

Increasing evidence incriminates low-grade inflammation in cardiovascular, metabolic diseases, and neuropsychiatric clinical conditions, all important causes of morbidity and mortality. One of the upstream and modifiable precipitants and perpetrators of inflammation is chronic periodontitis, a polymicrobial infection with Porphyromonas gingivalis (P. gingivalis) playing a central role in the disease pathogenesis. We review the association between P. gingivalis and cardiovascular, metabolic, and neuropsychiatric illness, and the molecular mechanisms potentially implicated in immune upregulation as well as downregulation induced by the pathogen. In addition to inflammation, translocation of the pathogens to the coronary and peripheral arteries, including brain vasculature, and gut and liver vasculature has important pathophysiological consequences. Distant effects via translocation rely on virulence factors of P. gingivalis such as gingipains, on its synergistic interactions with other pathogens, and on its capability to manipulate the immune system via several mechanisms, including its capacity to induce production of immune-downregulating micro-RNAs. Possible targets for intervention and drug development to manage distal consequences of infection with P. gingivalis are also reviewed.

Hypoxia-Inducible Factor 1 Alpha (HIF1A) Stimulates Neuronal Nitric Oxide Synthase (NOS1) Transcription by Binding to Multiple Enhancers

2017 ◽  
Vol 152 (5) ◽  
pp. S565-S566 ◽  
Author(s):  
Siva Arumugam Saravanaperumal ◽  
Jeong Heon Lee ◽  
Sabriya A. Syed ◽  
Yujiro Hayashi ◽  
Aditya V. Bhagwate ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Hypoxia Inducible Factor ◽  
Neuronal Nitric Oxide Synthase ◽  
Hypoxia Inducible Factor 1 ◽  
Oxide Synthase

Abstract 353: Chronic Polarization of Low-grade Inflammatory Monocytes During the Pathogenesis of Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Liwu Li ◽  
Shuo Geng
Keyword(s):  
High Fat Diet ◽  
Immunohistochemical Staining ◽  
Molecular Mechanisms ◽  
Molecular Switches ◽  
Low Grade ◽  
High Fat ◽  
Inflammatory Monocytes ◽  
Severe Atherosclerosis ◽  
Low Grade Inflammation ◽  
Deficient Mice

Background: Chronic inflammation mediated by low-grade inflammatory monocytes may serve as a key culprit for atherosclerosis. However, the cellular and molecular mechanisms responsible for the low-grade inflammatory polarization of monocytes are not well understood. We hypothesize that the selective clearance of homeostatic molecular switches may pre-dispose innate monocytes for the establishment of non-resolving low-grade inflammation. Methods and Results: By comparing high-fat-diet (HFD) fed ApoE deficient mice chronically challenged with either PBS or a subclinical dose endotoxin, we observed that subclinical endotoxin potently induced the establishment of low-grade inflammation, as manifested in elevated levels of systemic inflammatory mediators, accumulation of low-grade inflammatory circulating monocytes and neutrophils, as well as lipids. Immunohistochemical staining of liver and aorta tissues revealed significantly elevated steatosis and atherosclerosis in ApoE deficient mice chronically challenged with subclinical dose of endotoxin. At the mechanistic level, the polarization of low-grade inflammatory monocytes were due to the down-regulation and removal of key homeostatic molecules such as IRAK-M and Tollip. ApoE and IRAK-M double deficient mice had enhanced inflammatory polarization of innate monocytes, and developed severe atherosclerosis. Conclusions: Our data suggest that the clearance of homeostatic suppressors such as IRAK-M and Tollip may cause the memory establishment of low-grade inflammatory monocytes that are conducive for the chronic pathogenesis of atherosclerosis. Key words: Low-grade inflammation, monocyte polarization, innate memory, atherosclerosis

IL-6 as a Surrogate Biomarker: The IL-6 Clinical Value for the Diagnosis of Insulin Resistance and Type 2 Diabetes.

2021 ◽  
pp. 1-13
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Molecular Mechanisms ◽  
Diagnostic Value ◽  
Low Grade ◽  
Clinical Value ◽  
Insulin Resistant ◽  
Tnf Α ◽  
Low Grade Inflammation

1. Abstract Insulin Resistance is the leading cause of Type 2 diabetes mellitus (T2D). It occurs as a result of lipid disorders and increased levels of circulating free fatty acids (FFAs). FFAs accumulate within the insulin sensitive tissues such as muscle, liver and adipose tissues exacerbating different molecular mechanisms. Increased levels fatty acid has been documented to be strongly associated with insulin resistant states and obesity causing inflammation that eventually causes type 2-diabetes. Among the biomarkers that are accompanying low grade inflammation include IL-1β, IL-6 and TNF-α. The current review point out the importance of measuring the inflammatory biomarkers especially focusing on the conductance and measurement for IL-6 as a screening laboratory test and its diagnostic value in clinical practice.

scholarly journals HIF-1–dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia

2005 ◽  
Vol 202 (11) ◽  
pp. 1493-1505 ◽  
Author(s):  
Holger K. Eltzschig ◽  
Parween Abdulla ◽  
Edgar Hoffman ◽  
Kathryn E. Hamilton ◽  
Dionne Daniels ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Nucleoside Transporter ◽  
In Vivo Models ◽  
Equilibrative Nucleoside Transporter ◽  
Hypoxia Inducible Factor 1 ◽  
And Function

Extracellular adenosine (Ado) has been implicated as central signaling molecule during conditions of limited oxygen availability (hypoxia), regulating physiologic outcomes as diverse as vascular leak, leukocyte activation, and accumulation. Presently, the molecular mechanisms that elevate extracellular Ado during hypoxia are unclear. In the present study, we pursued the hypothesis that diminished uptake of Ado effectively enhances extracellular Ado signaling. Initial studies indicated that the half-life of Ado was increased by as much as fivefold after exposure of endothelia to hypoxia. Examination of expressional levels of the equilibrative nucleoside transporter (ENT)1 and ENT2 revealed a transcriptionally dependent decrease in mRNA, protein, and function in endothelia and epithelia. Examination of the ENT1 promoter identified a hypoxia inducible factor 1 (HIF-1)–dependent repression of ENT1 during hypoxia. Using in vitro and in vivo models of Ado signaling, we revealed that decreased Ado uptake promotes vascular barrier and dampens neutrophil tissue accumulation during hypoxia. Moreover, epithelial Hif1α mutant animals displayed increased epithelial ENT1 expression. Together, these results identify transcriptional repression of ENT as an innate mechanism to elevate extracellular Ado during hypoxia.

L-arginine Administration Reverses Anemia of Renal Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1631-1631
Author(s):  
Shigehiko Imagawa ◽  
Takahisa Tarumoto ◽  
Makoto Kobayashi ◽  
Keiya Ozawa
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Adverse Effects ◽  
Renal Disease ◽  
Hypoxia Inducible Factor ◽  
Deficiency Anemia ◽  
Uremic Toxin ◽  
Limited Data ◽  
Hypoxia Inducible Factor 1 ◽  
Oxide Synthase

Abstract Erythropoietin (EPO) gene expression is positively regulated by hypoxia-inducible factor-1, which binds to the 3′ enhancer of the EPO gene. EPO expression is negatively regulated by GATA, which binds to the GATA site in the 5′ promoter. Anemia of renal disease is believed to be caused by damage to the EPO-producing cells in the kidney as a result of renal failure. However, even mild renal failure can reduce the serum concentrations of EPO, suggesting that, in addition to the damage to EPO-producing kidney cells, uremic toxin(s) may play an important role in the pathogenesis of the anemia of renal disease. NG-monomethyl-L-arginine (L-NMMA), which competes with L-arginine as a substrate for nitric oxide synthase (NOS), is undetectable in nonuremic subjects, but is markedly elevated in patients with chronic renal failure. We have previously shown in the Hep3B cell line that L-NMMA suppresses EPO expression by upregulating GATA through the suppression of NOS activity, and that inhibition of EPO production with NG -nitro-L-arginine methyl ester (L-NAME) is reversed by pretreatment with L-arginine in mice. In this study, eight patients with anemia of renal disease, who were in the predialysis state of chronic renal failure, were enrolled in a nonrandomized study. All patients were anemic, and had hemoglobin (Hb) levels ranging between 7.9 and 10.8 g/dL. Patients with iron deficiency anemia, hemolytic anemia, and hematological malignancies were excluded. Blood urea nitorgen (BUN) levels were 29.7–90.1 mg/dL, and creatinine (Cre) levels were 1.1–3.8 mg/dL. Eight patients with anemia of renal disease were treated orally with L-arginine at 1.3 g/day for 8 to 22 wks. During this period, patients did not receive blood transfusions, or treatment with iron, vitamins or recombinant human EPO. Six patients responded to the treatment with increased levels of Hb and EPO, and three of these showed improved renal function. The EPO concentrations decreased in two nonresponders. There were no significant adverse effects. These limited data suggest that oral administration of 1.3 g/day of L-arginine can significantly improve EPO production and reverse anemia without adverse effects in patients with anemia of renal disease who are in the predialysis state of chronic renal failure. More studies including younger patients with severe renal dysfunction are in progress.

scholarly journals Xenon Upregulates Hypoxia Inducible Factor 1 Alpha in Neonatal Rat Brain under Normoxic Conditions

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Simona Valleggi ◽  
Chirag B. Patel ◽  
Andrea O. Cavazzana ◽  
Daqing Ma ◽  
Francesco Giunta ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Hypoxia Inducible Factor ◽  
Neonatal Rat ◽  
Transcript Analysis ◽  
Sprague Dawley ◽  
Organ Protection ◽  
Minute Exposure ◽  
Hypoxia Inducible Factor 1 ◽  
Significant Difference

Xenon can induce cell and organ protection through different molecular mechanisms related to oxygen level. We explored the effect of xenon on oxygen-related signalling in the central nervous system via hypoxia inducible factor 1 alpha (HIF-1α) and mammalian target of rapamycin (mTOR). Methods. Postnatal day 7 (P7) Sprague Dawley rats were exposed to 25% oxygen/75% nitrogen (air group) or 25% oxygen/75% xenon (treatment group) for 120 min. Brains were collected immediately (transcript analysis—relative real-time polymerase chain reaction) or 24 hours (protein analysis—immunohistochemistry) after the 120-minute exposure period; peak anesthetic preconditioning has been previously identified at 24 hours post-exposure. Results. HIF-1α transcript and protein levels were found to be increased in xenon-exposed compared to air-exposed brains. Sustained nuclear translocation of the protein, accounting for an increased activity of HIF-1α, was also noted. mTOR transcript analysis revealed no significant difference between xenon-exposed and air-exposed brains immediately after the 120-minute exposure. Conclusion. Our data suggest that xenon induces the upregulation of HIF-1α transcription and translation, which may contribute to xenon's neuroprotective preconditioning effect. However, given that xenon exposure did not affect mTOR transcription, further investigation into other signalling cascades mediating xenon’s effects on HIF-1α in developing brain is warranted.

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