HIF-α Prolyl Hydroxylase Inhibitors and Their Implications for Biomedicine: A Comprehensive Review

Oxygen is essential for the maintenance of the body. Living organisms have evolved systems to secure an oxygen environment to be proper. Hypoxia-inducible factor (HIF) plays an essential role in this process; it is a transcription factor that mediates erythropoietin (EPO) induction at the transcriptional level under hypoxic environment. After successful cDNA cloning in 1995, a line of studies were conducted for elucidating the molecular mechanism of HIF activation in response to hypoxia. In 2001, cDNA cloning of dioxygenases acting on prolines and asparagine residues, which play essential roles in this process, was reported. HIF-prolyl hydroxylases (PHs) are molecules that constitute the core molecular mechanism of detecting a decrease in the partial pressure of oxygen, or hypoxia, in the cells; they can be called oxygen sensors. In this review, I discuss the process of molecular cloning of HIF and HIF-PH, which explains hypoxia-induced EPO expression; the development of HIF-PH inhibitors that artificially or exogenously activate HIF by inhibiting HIF-PH; and the significance and implications of medical intervention using HIF-PH inhibitors.

Download Full-text

Erythrocytosis: the HIF pathway in control

Blood ◽

10.1182/blood-2013-01-478065 ◽

2013 ◽

Vol 122 (7) ◽

pp. 1122-1128 ◽

Cited By ~ 48

Author(s):

Kristin Franke ◽

Max Gassmann ◽

Ben Wielockx

Keyword(s):

Transcription Factor ◽

Ubiquitin Ligase ◽

Hypoxia Inducible Factor ◽

The Body ◽

Partial Pressure Of Oxygen ◽

Prolyl Hydroxylases ◽

Von Hippel Lindau ◽

Sensing System ◽

Oxygen Sensitive ◽

Hif Pathway

Abstract Organisms living under aerobic conditions need oxygen for the metabolic conversion of nutrition into energy. With the appearance of increasingly complex animals, a specialized transport system (erythrocytes) arose during evolution to provide oxygen to virtually every single cell in the body. Moreover, in case of low environmental partial pressure of oxygen, the number of erythrocytes automatically increases to preserve sustained oxygen delivery. This process relies predominantly on the cytokine erythropoietin (Epo) and its transcription factor hypoxia inducible factor (HIF), whereas the von Hippel-Lindau (VHL) ubiquitin ligase as well as the oxygen-sensitive prolyl hydroxylases (PHDs) represent essential regulators of this oxygen-sensing system. Deregulation of particular members of this pathway (eg, PHD2, HIF2α, VHL) lead to disorders in blood homeostasis as a result of insufficient (anemia) or excessive (erythrocytosis) red blood cell production.

Download Full-text

HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α–induced excessive erythropoiesis

Blood ◽

10.1182/blood-2012-08-449181 ◽

2013 ◽

Vol 121 (8) ◽

pp. 1436-1445 ◽

Cited By ~ 40

Author(s):

Kristin Franke ◽

Joanna Kalucka ◽

Soulafa Mamlouk ◽

Rashim Pal Singh ◽

Antje Muschter ◽

...

Keyword(s):

Protective Factor ◽

Hypoxia Inducible Factor ◽

The Body ◽

Entire System ◽

Mouse Line ◽

Prolyl Hydroxylases ◽

Oxygen Sensitive ◽

New Treatments ◽

First Time ◽

Deficient Mice

Abstract Erythropoiesis must be tightly balanced to guarantee adequate oxygen delivery to all tissues in the body. This process relies predominantly on the hormone erythropoietin (EPO) and its transcription factor hypoxia inducible factor (HIF). Accumulating evidence suggests that oxygen-sensitive prolyl hydroxylases (PHDs) are important regulators of this entire system. Here, we describe a novel mouse line with conditional PHD2 inactivation (cKO P2) in renal EPO producing cells, neurons, and astrocytes that displayed excessive erythrocytosis because of severe overproduction of EPO, exclusively driven by HIF-2α. In contrast, HIF-1α served as a protective factor, ensuring survival of cKO P2 mice with HCT values up to 86%. Using different genetic approaches, we show that simultaneous inactivation of PHD2 and HIF-1α resulted in a drastic PHD3 reduction with consequent overexpression of HIF-2α-related genes, neurodegeneration, and lethality. Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2α–dependent erythrocytosis, whereas HIF-1α protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia.

Download Full-text

Hypoxia response and acute lung and kidney injury: possible implications for therapy of COVID-19

Clinical Kidney Journal ◽

10.1093/ckj/sfaa149 ◽

2020 ◽

Vol 13 (4) ◽

pp. 494-499

Author(s):

Lucia Del Vecchio ◽

Francesco Locatelli

Keyword(s):

Hypoxia Inducible Factor ◽

Kidney Injury ◽

The Body ◽

Inflammatory Factors ◽

Tubular Damage ◽

Prolyl Hydroxylases ◽

Viral Spread ◽

Proximal Tubular ◽

Bodies Of Evidence ◽

Hif Pathway

Abstract Coronavirus disease 2019 (COVID-19) is a pandemic of unprecedented severity affecting millions of people around the world and causing several hundred thousands of deaths. The presentation of the disease ranges from asymptomatic manifestations through to acute respiratory distress syndrome with the necessity of mechanical ventilation. Cytokine storm and maladaptive responses to the viral spread in the body could be responsible for the severity of disease. Many patients develop acute kidney injury (AKI) during the course of their disease, especially in more severe cases. Many factors could cause kidney damage during infection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It is still unclear whether direct viral damage or the overexpression of cytokines and inflammatory factors are preeminent. According to autoptic studies, in most of the cases, AKI is due proximal tubular damage. However, cases of collapsing focal segmental glomerulosclerosis were reported as well in the absence of signs of direct viral infection of the kidney. Considering that severe hypoxia is a hallmark of severe SARS-CoV-2 infection, the involvement of the hypoxia-inducible factor (HIF) system is very likely, possibly influencing the inflammatory response and outcome in both the lungs and kidneys. Several bodies of evidence have shown a possible role of the HIF pathway during AKI in various kidney disease models. Similar observations were made in the setting of acute lung injury. In both organs, HIF activation by means of inhibition of the prolyl-hydroxylases domain (PHD) could be protective. Considering these promising experimental data, we hypothesize that PHD inhibitors could be considered as a possible new therapy against severe SARS-CoV-2 infection.

Download Full-text

Neutral Lipids of Oats Fruit (Avena Sativa L.)

Drug development & registration ◽

10.33380/2305-2066-2020-9-4-40-43 ◽

2020 ◽

Vol 9 (4) ◽

pp. 40-43

Author(s):

N. K. Yuldasheva ◽

S. D. Gusakova ◽

D. Kh. Nurullaeva ◽

N. T. Farmanova ◽

R. P. Zakirova ◽

...

Keyword(s):

Avena Sativa ◽

Neutral Lipids ◽

The Body ◽

Biologically Active ◽

Absorption Bands ◽

Vital Functions ◽

The Republic ◽

Living Organisms ◽

Main Components ◽

Active Substances

Introduction. Lipids are a widespread group of biologically active substances in nature, making up the bulk of the organic substances of all living organisms. They accumulate in plants in seeds, as well as in fruits and perform a number of vital functions: they are the main components of cell membranes and the energy reserve for the body.Aim. Study of neutral lipids of sown oats (Avena sativa L.).Materials and methods. The objects of the study were fruits (grains) of oats of the sown variety "Tashkent 1," harvested in the Republic of Uzbekistan. Results and discussions. Neutral lipids of oat grains have been found to contain 13 fatty acids with a predominance of the sum of oleic, linolenic and linoleic acids. The total degree of unsaturation was almost 78%. Absorption bands characteristic of these substances were observed in the IR spectrum of MEGC.Conclusion. According to the results of the NL analysis, oat grains consisted of triacylglycerides and free LCDs, which were accompanied by hydrocarbons, phytosterols, triterpenoids and tocopherols.

Download Full-text

miR-29a sensitizes the response of glioma cells to temozolomide by modulating the P53/MDM2 feedback loop

Cellular & Molecular Biology Letters ◽

10.1186/s11658-021-00266-9 ◽

2021 ◽

Vol 26 (1) ◽

Author(s):

Qiudan Chen ◽

Weifeng Wang ◽

Shuying Chen ◽

Xiaotong Chen ◽

Yong Lin

Keyword(s):

Molecular Mechanism ◽

Feedback Loop ◽

Glioma Cells ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Transcriptional Level ◽

Aberrant Expression ◽

Altered Expression ◽

P53 Signaling

AbstractRecently, pivotal functions of miRNAs in regulating common tumorigenic processes and manipulating signaling pathways in brain tumors have been recognized; notably, miR‐29a is closely associated with p53 signaling, contributing to the development of glioma. However, the molecular mechanism of the interaction between miR-29a and p53 signaling is still to be revealed. Herein, a total of 30 glioma tissues and 10 non-cancerous tissues were used to investigate the expression of miR‐29a. CCK-8 assay and Transwell assay were applied to identify the effects of miR-29a altered expression on the malignant biological behaviors of glioma cells in vitro, including proliferation, apoptosis, migration and invasion. A dual-luciferase reporter assay was used to further validate the regulatory effect of p53 or miR-29a on miR-29a or MDM2, respectively, at the transcriptional level. The results showed that miR-29a expression negatively correlated with tumor grade of human gliomas; at the same time it inhibited cell proliferation, migration, and invasion and promoted apoptosis of glioma cells in vitro. Mechanistically, miR-29a expression was induced by p53, leading to aberrant expression of MDM2 targeted by miR-29a, and finally imbalanced the activity of the p53-miR-29a-MDM2 feedback loop. Moreover, miR-29a regulating p53/MDM2 signaling sensitized the response of glioma cells to temozolomide treatment. Altogether, the study demonstrated a potential molecular mechanism in the tumorigenesis of glioma, while offering a possible target for treating human glioma in the future.

Download Full-text

Roles of HIF and 2-Oxoglutarate-Dependent Dioxygenases in Controlling Gene Expression in Hypoxia

Cancers ◽

10.3390/cancers13020350 ◽

2021 ◽

Vol 13 (2) ◽

pp. 350

Author(s):

Julianty Frost ◽

Mark Frost ◽

Michael Batie ◽

Hao Jiang ◽

Sonia Rocha

Keyword(s):

Gene Expression ◽

Hypoxia Inducible Factor ◽

Transcriptional Regulator ◽

Hydroxylase Activity ◽

Control Of Gene Expression ◽

Prolyl Hydroxylases ◽

Chromatin Organisation ◽

Sense And Respond ◽

Almost All ◽

And Function

Hypoxia—reduction in oxygen availability—plays key roles in both physiological and pathological processes. Given the importance of oxygen for cell and organism viability, mechanisms to sense and respond to hypoxia are in place. A variety of enzymes utilise molecular oxygen, but of particular importance to oxygen sensing are the 2-oxoglutarate (2-OG) dependent dioxygenases (2-OGDs). Of these, Prolyl-hydroxylases have long been recognised to control the levels and function of Hypoxia Inducible Factor (HIF), a master transcriptional regulator in hypoxia, via their hydroxylase activity. However, recent studies are revealing that dioxygenases are involved in almost all aspects of gene regulation, including chromatin organisation, transcription and translation. We highlight the relevance of HIF and 2-OGDs in the control of gene expression in response to hypoxia and their relevance to human biology and health.

Download Full-text

Dealing with PET radiometabolites

EJNMMI Research ◽

10.1186/s13550-020-00692-4 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Krishna Kanta Ghosh ◽

Parasuraman Padmanabhan ◽

Chang-Tong Yang ◽

Sachin Mishra ◽

Christer Halldin ◽

...

Keyword(s):

Pet Imaging ◽

Distribution Patterns ◽

The Body ◽

Analysis Process ◽

Pet Tracer ◽

Positron Emission ◽

Structural Identity ◽

Available Technology ◽

Living Organisms ◽

Entire Amount

Abstract Positron emission tomography (PET) offers the study of biochemical, physiological, and pharmacological functions at a cellular and molecular level. The performance of a PET study mostly depends on the used radiotracer of interest. However, the development of a novel PET tracer is very difficult, as it is required to fulfill a lot of important criteria. PET radiotracers usually encounter different chemical modifications including redox reaction, hydrolysis, decarboxylation, and various conjugation processes within living organisms. Due to this biotransformation, different chemical entities are produced, and the amount of the parent radiotracer is declined. Consequently, the signal measured by the PET scanner indicates the entire amount of radioactivity deposited in the tissue; however, it does not offer any indication about the chemical disposition of the parent radiotracer itself. From a radiopharmaceutical perspective, it is necessary to quantify the parent radiotracer’s fraction present in the tissue. Hence, the identification of radiometabolites of the radiotracers is vital for PET imaging. There are mainly two reasons for the chemical identification of PET radiometabolites: firstly, to determine the amount of parent radiotracers in plasma, and secondly, to rule out (if a radiometabolite enters the brain) or correct any radiometabolite accumulation in peripheral tissue. Besides, radiometabolite formations of the tracer might be of concern for the PET study, as the radiometabolic products may display considerably contrasting distribution patterns inside the body when compared with the radiotracer itself. Therefore, necessary information is needed about these biochemical transformations to understand the distribution of radioactivity throughout the body. Various published review articles on PET radiometabolites mainly focus on the sample preparation techniques and recently available technology to improve the radiometabolite analysis process. This article essentially summarizes the chemical and structural identity of the radiometabolites of various radiotracers including [11C]PBB3, [11C]flumazenil, [18F]FEPE2I, [11C]PBR28, [11C]MADAM, and (+)[18F]flubatine. Besides, the importance of radiometabolite analysis in PET imaging is also briefly summarized. Moreover, this review also highlights how a slight chemical modification could reduce the formation of radiometabolites, which could interfere with the results of PET imaging. Graphical abstract

Download Full-text

Enzymes, Reacting with Organophosphorus Compounds as Detoxifiers: Diversity and Functions

International Journal of Molecular Sciences ◽

10.3390/ijms22041761 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1761

Author(s):

Ilya Lyagin ◽

Elena Efremenko

Keyword(s):

Phylogenetic Analysis ◽

Future Development ◽

Organophosphorus Compounds ◽

The Body ◽

Chemical Transformations ◽

Negative Consequences ◽

Biological Targets ◽

Oxidation Reduction ◽

Structural Differences ◽

Living Organisms

Organophosphorus compounds (OPCs) are able to interact with various biological targets in living organisms, including enzymes. The binding of OPCs to enzymes does not always lead to negative consequences for the body itself, since there are a lot of natural biocatalysts that can catalyze the chemical transformations of the OPCs via hydrolysis or oxidation/reduction and thereby provide their detoxification. Some of these enzymes, their structural differences and identity, mechanisms, and specificity of catalytic action are discussed in this work, including results of computational modeling. Phylogenetic analysis of these diverse enzymes was specially realized for this review to emphasize a great area for future development(s) and applications.

Download Full-text

A MicroRNA Signature of Hypoxia

Molecular and Cellular Biology ◽

10.1128/mcb.01395-06 ◽

2006 ◽

Vol 27 (5) ◽

pp. 1859-1867 ◽

Cited By ~ 711

Author(s):

Ritu Kulshreshtha ◽

Manuela Ferracin ◽

Sylwia E. Wojcik ◽

Ramiro Garzon ◽

Hansjuerg Alder ◽

...

Keyword(s):

Expression Profiles ◽

Hypoxia Inducible Factor ◽

Tumor Formation ◽

Low Oxygen ◽

Functional Link ◽

Factors Affecting ◽

Cellular Processes ◽

Hypoxic Environment ◽

Tumorigenic Transformation ◽

First Time

ABSTRACT Recent research has identified critical roles for microRNAs in a large number of cellular processes, including tumorigenic transformation. While significant progress has been made towards understanding the mechanisms of gene regulation by microRNAs, much less is known about factors affecting the expression of these noncoding transcripts. Here, we demonstrate for the first time a functional link between hypoxia, a well-documented tumor microenvironment factor, and microRNA expression. Microarray-based expression profiles revealed that a specific spectrum of microRNAs (including miR-23, -24, -26, -27, -103, -107, -181, -210, and -213) is induced in response to low oxygen, at least some via a hypoxia-inducible-factor-dependent mechanism. Select members of this group (miR-26, -107, and -210) decrease proapoptotic signaling in a hypoxic environment, suggesting an impact of these transcripts on tumor formation. Interestingly, the vast majority of hypoxia-induced microRNAs are also overexpressed in a variety of human tumors.

Download Full-text