scholarly journals Physiologic hypoxia and oxygen homeostasis in the healthy intestine. A Review in the Theme: Cellular Responses to Hypoxia

2015 ◽  
Vol 309 (6) ◽  
pp. C350-C360 ◽  
Author(s):  
Leon Zheng ◽  
Caleb J. Kelly ◽  
Sean P. Colgan
Keyword(s):  
Tissue Oxygenation ◽  
Hypoxia Inducible Factor ◽  
Cellular Responses ◽  
The Body ◽  
Functional Responses ◽  
Body Studies ◽  
Oxygen Homeostasis ◽  
Healthy Mucosa ◽  
Countercurrent Exchange ◽  
Small And Large Intestine

In recent years, the intestinal mucosa has proven to be an intriguing organ to study tissue oxygenation. The highly vascularized lamina propria juxtaposed to an anaerobic lumen containing trillions of metabolically active microbes results in one of the most austere tissue microenvironments in the body. Studies to date have determined that a healthy mucosa contains a steep oxygen gradient along the length of the intestine and from the lumen to the serosa. Advances in technology have allowed multiple independent measures and indicate that, in the healthy mucosa of the small and large intestine, the lumen-apposed epithelia experience Po2 conditions of <10 mmHg, so-called physiologic hypoxia. This unique physiology results from a combination of factors, including countercurrent exchange blood flow, fluctuating oxygen demands, epithelial metabolism, and oxygen diffusion into the lumen. Such conditions result in the activation of a number of hypoxia-related signaling processes, including stabilization of the transcription factor hypoxia-inducible factor. Here, we review the principles of mucosal oxygen delivery, metabolism, and end-point functional responses that result from this unique oxygenation profile.

Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis

Blood ◽  
2009 ◽  
Vol 114 (10) ◽  
pp. 2015-2019 ◽  
Author(s):  
Gregg L. Semenza
Keyword(s):  
Blood Cells ◽  
Tissue Oxygenation ◽  
Hypoxia Inducible Factor ◽  
Α Subunit ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Hypoxia Inducible Factor 1 ◽  
Oxygen Homeostasis ◽  
Genes Encoding ◽  
Asparaginyl Hydroxylase

Abstract Red blood cells deliver O2 from the lungs to every cell in the human body. Reduced tissue oxygenation triggers increased production of erythropoietin by hypoxia-inducible factor 1 (HIF-1), which is a transcriptional activator composed of an O2-regulated α subunit and a constitutively expressed β subunit. Hydroxylation of HIF-1α or HIF-2α by the asparaginyl hydroxylase FIH-1 blocks coactivator binding and transactivation. Hydroxylation of HIF-1α or HIF-2α by the prolyl hydroxylase PHD2 is required for binding of the von Hippel-Lindau protein (VHL), leading to ubiquitination and proteasomal degradation. Mutations in the genes encoding VHL, PHD2, and HIF-2α have been identified in patients with familial erythrocytosis. Patients with Chuvash polycythemia, who are homozygous for a missense mutation in the VHL gene, have multisystem pathology attributable to dysregulated oxygen homeostasis. Intense efforts are under way to identify small molecule hydroxylase inhibitors that can be administered chronically to selectively induce erythropoiesis without undesirable side effects.

scholarly journals Basic Biology of Hypoxic Responses Mediated by the Transcription Factor HIFs and Its Implication for Medicine

Biomedicines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 32 ◽  
Author(s):  
Kiichi Hirota
Keyword(s):  
Transcription Factor ◽  
Human Life ◽  
Energy Levels ◽  
Hypoxia Inducible Factor ◽  
Atp Synthesis ◽  
Point Of View ◽  
The Body ◽  
Living Body ◽  
Oxygen Homeostasis ◽  
Multiple Organs

Oxygen (O2) is essential for human life. Molecular oxygen is vital for the production of adenosine triphosphate (ATP) in human cells. O2 deficiency leads to a reduction in the energy levels that are required to maintain biological functions. O2 acts as the final acceptor of electrons during oxidative phosphorylation, a series of ATP synthesis reactions that occur in conjunction with the electron transport system in mitochondria. Persistent O2 deficiency may cause death due to malfunctioning biological processes. The above account summarizes the classic view of oxygen. However, this classic view has been reviewed over the last two decades. Although O2 is essential for life, higher organisms such as mammals are unable to biosynthesize molecular O2 in the body. Because the multiple organs of higher organisms are constantly exposed to the risk of “O2 deficiency,” living organisms have evolved elaborate strategies to respond to hypoxia. In this review, I will describe the system that governs oxygen homeostasis in the living body from the point-of-view of the transcription factor hypoxia-inducible factor (HIF).

Nervous Control of Chromatophores in Teleost Fishes

1964 ◽  
Vol 41 (3) ◽  
pp. 543-552
Author(s):  
J. D. PYE
Keyword(s):  
Local Heating ◽  
Respiratory Rhythm ◽  
Cellular Responses ◽  
The Body ◽  
Adaptive Responses ◽  
Physiological Mechanisms ◽  
Nervous Control ◽  
Temperature Thresholds ◽  
Motor Tracts ◽  
New Hypothesis

1. Observations of earlier workers on the chromatic responses to local heating or cooling of the skin of Phoxinus have been confirmed. They have also been found to hold true for anaesthetized fish, in which finer control and observation are possible. 2. The results of a series of nerve-section experiments are held to exclude any possibility that the responses of the intact fish are mediated by a nervous reflex from thermoreceptors in the skin. 3. The responses of melanophores following section of the chromatic motor tracts, or when isolated from the body, are considered to be independent cellular responses. 4. Normal responses in the intact fish show clear temperature thresholds and are completely dependent upon continuation of the respiratory rhythm. 5. Possible physiological mechanisms for mediating these non-adaptive responses are discussed and a new hypothesis is put forward.

scholarly journals Crosstalk in oxygen homeostasis networks: SKN-1/NRF inhibits the HIF-1 hypoxia-inducible factor in Caenorhabditis elegans

2021 ◽  
Author(s):  
Dingxia Feng ◽  
Zhiwei Zhai ◽  
Zhiyong Shao ◽  
Yi Zhang ◽  
Jo Anne Powell-Coffman
Keyword(s):  
Oxidative Stress ◽  
Hypoxia Inducible Factor ◽  
Regulatory Sequences ◽  
Low Oxygen ◽  
Transcriptional Responses ◽  
C Elegans ◽  
Protein Levels ◽  
Oxygen Homeostasis ◽  
Genome Wide ◽  
A Genome

AbstractDuring development, homeostasis, and disease, organisms must balance responses that allow adaptation to low oxygen (hypoxia) with those that protect cells from oxidative stress. The evolutionarily conserved hypoxia-inducible factors are central to these processes, as they orchestrate transcriptional responses to oxygen deprivation. Here, we employ genetic strategies in C. elegans to identify stress-responsive genes and pathways that modulate the HIF-1 hypoxia-inducible factor and facilitate oxygen homeostasis. Through a genome-wide RNAi screen, we show that RNAi-mediated mitochondrial or proteasomal dysfunction increases the expression of hypoxia-responsive reporter Pnhr-57:GFP in C. elegans. Interestingly, only a subset of these effects requires hif-1. Of particular importance, we found that skn-1 RNAi increases the expression of hypoxia-responsive reporter Pnhr-57:GFP and elevates HIF-1 protein levels. The SKN-1/NRF transcription factor has been shown to promote oxidative stress resistance. We present evidence that the crosstalk between HIF-1 and SKN-1 is mediated by EGL-9, the prolyl hydroxylase that targets HIF-1 for oxygen-dependent degradation. Treatment that induces SKN-1, such as heat, increases expression of a Pegl-9:GFP reporter, and this effect requires skn-1 function and a putative SKN-1 binding site in egl-9 regulatory sequences. Collectively, these data support a model in which SKN-1 promotes egl-9 transcription, thereby inhibiting HIF-1. We propose that this interaction enables animals to adapt quickly to changes in cellular oxygenation and to better survive accompanying oxidative stress.

scholarly journals Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression

2020 ◽  
Vol 21 (21) ◽  
pp. 8162
Author(s):  
Guang Yang ◽  
Rachel Shi ◽  
Qing Zhang
Keyword(s):  
Gene Regulation ◽  
Cancer Progression ◽  
Current Knowledge ◽  
Oxygen Sensing ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylases ◽  
Von Hippel Lindau ◽  
Oxygen Homeostasis ◽  
Jmjc Domain ◽  
Encoding Protein

Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression. The key molecules of the hypoxia/oxygen-sensing signaling include the transcriptional regulator hypoxia-inducible factor (HIF) which widely controls oxygen responsive genes, the central members of the 2-oxoglutarate (2-OG)-dependent dioxygenases, such as prolyl hydroxylase (PHD or EglN), and an E3 ubiquitin ligase component for HIF degeneration called von Hippel–Lindau (encoding protein pVHL). In this review, we summarize the current knowledge about the canonical hypoxia signaling, HIF transcription factors, and pVHL. In addition, the role of 2-OG-dependent enzymes, such as DNA/RNA-modifying enzymes, JmjC domain-containing enzymes, and prolyl hydroxylases, in gene regulation of cancer progression, is specifically reviewed. We also discuss the therapeutic advancement of targeting hypoxia and oxygen sensing pathways in cancer.

scholarly journals Determinants of hypoxia-inducible factor activity in the intestinal mucosa

2017 ◽  
Vol 123 (5) ◽  
pp. 1328-1334 ◽  
Author(s):  
Raphael R. Fagundes ◽  
Cormac T. Taylor
Keyword(s):  
Intestinal Mucosa ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Hypoxia Inducible Factor ◽  
Oxygen Demand ◽  
Intestinal Lumen ◽  
Adaptation To Hypoxia ◽  
Healthy Mucosa ◽  
Microenvironmental Factors ◽  
Anoxic Environment

The intestinal mucosa is exposed to fluctuations in oxygen levels due to constantly changing rates of oxygen demand and supply and its juxtaposition with the anoxic environment of the intestinal lumen. This frequently results in a state of hypoxia in the healthy mucosa even in the physiologic state. Furthermore, pathophysiologic hypoxia (which is more severe and extensive) is associated with chronic inflammatory diseases including inflammatory bowel disease (IBD). The hypoxia-inducible factor (HIF), a ubiquitously expressed regulator of cellular adaptation to hypoxia, is central to both the adaptive and the inflammatory responses of cells of the intestinal mucosa in IBD patients. In this review, we discuss the microenvironmental factors which influence the level of HIF activity in healthy and inflamed intestinal mucosae and the consequences that increased HIF activity has for tissue function and disease progression.

scholarly journals Hypoxia and HIF Signaling: One Axis with Divergent Effects

2020 ◽  
Vol 21 (16) ◽  
pp. 5611 ◽  
Author(s):  
Chiara Corrado ◽  
Simona Fontana
Keyword(s):  
Cellular Response ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Biological Processes ◽  
Oxygen Homeostasis ◽  
Tissue Responses ◽  
Liver And Kidney ◽  
Heterodimeric Complex ◽  
Complex Activities

The correct concentration of oxygen in all tissues is a hallmark of cellular wellness, and the negative regulation of oxygen homeostasis is able to affect the cells and tissues of the whole organism. The cellular response to hypoxia is characterized by the activation of multiple genes involved in many biological processes. Among them, hypoxia-inducible factor (HIF) represents the master regulator of the hypoxia response. The active heterodimeric complex HIF α/β, binding to hypoxia-responsive elements (HREs), determines the induction of at least 100 target genes to restore tissue homeostasis. A growing body of evidence demonstrates that hypoxia signaling can act by generating contrasting responses in cells and tissues. Here, this dual and controversial role of hypoxia and the HIF signaling pathway is discussed, with particular reference to the effects induced on the complex activities of the immune system and on mechanisms determining cell and tissue responses after an injury in both acute and chronic human diseases related to the heart, lung, liver, and kidney.

scholarly journals HIF1α/TET1 Pathway Mediates Hypoxia-Induced Adipocytokine Promoter Hypomethylation in Human Adipocytes

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 134 ◽  
Author(s):  
Mohamed M. Ali ◽  
Shane A. Phillips ◽  
Abeer M. Mahmoud
Keyword(s):  
Dna Methylation ◽  
Interleukin 1 ◽  
Hypoxia Inducible Factor ◽  
Interferon Γ ◽  
The Body ◽  
Human Adipocytes ◽  
Protein Levels ◽  
Factor Α ◽  
Necrosis Factor

Obesity is associated with the accumulation of dysfunctional adipose tissue that secretes several pro-inflammatory cytokines (adipocytokines). Recent studies have presented evidence that adipose tissues in obese individuals and animal models are hypoxic, which may result in upregulation and stabilization of the hypoxia inducible factor HIF1α. Epigenetic mechanisms such as DNA methylation enable the body to respond to microenvironmental changes such as hypoxia and may represent a mechanistic link between obesity-associated hypoxia and upregulated inflammatory adipocytokines. The purpose of this study was to investigate the role of hypoxia in modifying adipocytokine DNA methylation and subsequently adipocytokine expression. We suggested that this mechanism is mediated via the DNA demethylase, ten-eleven translocation-1 (TET1), transcription of which has been shown to be induced by HIF1α. To this end, we studied the effect of hypoxia (2% O2) in differentiated subcutaneous human adipocytes in the presence or absence of HIF1α stabilizer (Dimethyloxalylglycine (DMOG), 500 μM), HIF1α inhibitor (methyl 3-[[2-[4-(2-adamantyl) phenoxy] acetyl] amino]-4-hydroxybenzoate, 30 μM), or TET1-specific siRNA. Subjecting the adipocytes to hypoxia significantly induced HIF1α and TET1 protein levels. Moreover, hypoxia induced global hydroxymethylation, reduced adipocytokine DNA promoter methylation, and induced adipocytokine expression. These effects were abolished by either HIF1α inhibitor or TET1 gene silencing. The major hypoxia-responsive adipocytokines were leptin, interleukin-1 (IL6), IL1β, tumor necrosis factor α (TNFα), and interferon γ (IFNγ). Overall, these data demonstrate an activation of the hydroxymethylation pathway mediated by TET1. This pathway contributes to promoter hypomethylation and gene upregulation of the inflammatory adipocytokines in adipocytes in response to hypoxia.

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