Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
that in humans is encoded by the ''NFE2L2''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
NRF2 is a
basic leucine zipper (bZIP) protein that may regulate the expression of
antioxidant proteins that protect against
oxidative damage
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal r ...
triggered by injury and inflammation, according to preliminary research.
In vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology ...
, NRF2 binds to antioxidant response elements (AREs) in the promoter regions of genes encoding
cytoprotective proteins.
NRF2 induces the expression of
heme oxygenase 1
''HMOX1'' (heme oxygenase 1 gene) is a human gene that encodes for the enzyme heme oxygenase 1 (). Heme oxygenase (abbreviated HMOX or HO) mediates the first step of heme catabolism, it cleaves heme to form biliverdin.
The ''HMOX'' gene is locat ...
''in vitro'' leading to an increase in
phase II enzymes.
NRF2 also inhibits the
NLRP3
NLR family pyrin domain containing 3 (NLRP3) (previously known as NACHT, LRR and PYD domains-containing protein 3 ALP3and cryopyrin), is a protein that in humans is encoded by the ''NLRP3'' gene located on the long arm of chromosome 1.
NLRP3 is ...
inflammasome
Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses. Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-in ...
.
NRF2 appears to participate in a complex regulatory network and performs a pleiotropic role in the regulation of metabolism, inflammation, autophagy, proteostasis, mitochondrial physiology, and immune responses. Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress.
A mechanism for hormetic dose responses is proposed in which Nrf2 may serve as an hormetic mediator that mediates a vast spectrum of chemopreventive processes.
Structure
NRF2 is a basic leucine zipper (bZip
The Basic Leucine Zipper Domain (bZIP domain) is found in many DNA binding eukaryotic proteins. One part of the domain contains a region that mediates sequence specific DNA binding properties and the leucine zipper that is required to hold tog ...
) transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
with a Cap “n” Collar (CNC) structure. NRF2 possesses seven highly conserved domains called NRF2-ECH homology (Neh) domains. The Neh1 domain is a CNC-bZIP domain that allows Nrf2 to heterodimerize with small Maf
Small may refer to:
Science and technology
* SMALL, an ALGOL-like programming language
* Small (anatomy), the lumbar region of the back
* ''Small'' (journal), a nano-science publication
* <small>, an HTML element that defines smaller text
...
proteins (MAFF MAFF may refer to:
* MAFF (gene), a transcription factor
* Malmö Arab Film Festival, held in Malmö (Sweden), the largest Arabic film festival in Europe
* Ministry of Agriculture, Fisheries and Food (United Kingdom), a former department of UK gov ...
, MAFG
Transcription factor MafG is a bZip Maf transcription factor protein that in humans is encoded by the ''MAFG'' gene.
MafG is one of the small Maf proteins, which are basic region and leucine zipper (bZIP)-type transcription factors. The HUGO G ...
, MAFK #REDIRECT MAFK
{{R from alternative capitalization
...
). The Neh2 domain allows for binding of NRF2 to its cytosolic repressor Keap1.
The Neh3 domain may play a role in NRF2 protein stability and may act as a transactivation domain, interacting with component of the transcriptional apparatus.
The Neh4 and Neh5 domains also act as transactivation domains, but bind to a different protein called cAMP Response Element Binding Protein (CREB
CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first de ...
), which possesses intrinsic histone acetyltransferase
Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring ...
activity.
The Neh6 domain may contain a degron that is involved in a redox-insensitive process of degradation of NRF2. This occurs even in stressed cells, which normally extend the half-life of NRF2 protein relative to unstressed conditions by suppressing other degradation pathways.
The "Neh7" domain is involved in the repression of Nrf2 transcriptional activity by the retinoid X receptor α through a physical association between the two proteins.
Localization and function
NFE2L2 and other genes, such as NFE2
__NOTOC__
Transcription factor NF-E2 45 kDa subunit is a protein that in humans is encoded by the ''NFE2'' gene.
It is involved in megakaryocyte production.
Interactions
NFE2 has been shown to interact with CREB-binding protein
Cyclic aden ...
, NFE2L1
Nuclear factor erythroid 2-related factor 1 (Nrf1) also known as nuclear factor erythroid-2-like 1 (NFE2L1) is a protein that in humans is encoded by the ''NFE2L1'' gene. Since NFE2L1 is referred to as Nrf1, it is often confused with nuclear resp ...
and NFE2L3
Nuclear factor (erythroid 2)-like factor 3, also known as NFE2L3 or 'NRF3', is a transcription factor that in humans is encoded by the ''Nfe2l3'' gene.
Nrf3 is a basic leucine zipper (bZIP) transcription factor belonging to the Cap ‘n’ Collar ...
, encode basic leucine zipper
A leucine zipper (or leucine scissors) is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amin ...
(bZIP
The Basic Leucine Zipper Domain (bZIP domain) is found in many DNA binding eukaryotic proteins. One part of the domain contains a region that mediates sequence specific DNA binding properties and the leucine zipper that is required to hold tog ...
) transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s. They share highly conserved regions that are distinct from other bZIP families, such as JUN and FOS, although remaining regions have diverged considerably from each other.
Under normal or unstressed conditions, NRF2 is kept in the cytoplasm by a cluster of proteins that degrade it quickly. Under oxidative stress, NRF2 is not degraded, but instead travels to the nucleus where it binds to a DNA promoter and initiates transcription of antioxidative genes and their proteins.
NRF2 is kept in the cytoplasm by Kelch like-ECH-associated protein 1 (KEAP1
Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the ''Keap1'' gene.
Structure
Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 res ...
) and Cullin 3
Cullin 3 is a protein that in humans is encoded by the ''CUL3'' gene.
Cullin 3 protein belongs to the family of cullins which in mammals contains eight proteins (Cullin 1, Cullin 2, Cullin 3, Cullin 4A, Cullin 4B, Cullin 5, Cullin 7 and Cullin 9) ...
, which degrade NRF2 by ubiquitination
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
. Cullin 3 ubiquitinates NRF2, while Keap1 is a substrate adaptor protein that facilitates the reaction. Once NRF2 is ubiquitinated, it is transported to the proteasome, where it is degraded and its components recycled. Under normal conditions, NRF2 has a half-life of only 20 minutes. Oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
or electrophilic stress disrupts critical cysteine residues in Keap1, disrupting the Keap1-Cul3 ubiquitination system. When NRF2 is not ubiquitinated, it builds up in the cytoplasm, and translocates into the nucleus. In the nucleus, it combines (forms a heterodimer) with one of small Maf
Small may refer to:
Science and technology
* SMALL, an ALGOL-like programming language
* Small (anatomy), the lumbar region of the back
* ''Small'' (journal), a nano-science publication
* <small>, an HTML element that defines smaller text
...
proteins (MAFF MAFF may refer to:
* MAFF (gene), a transcription factor
* Malmö Arab Film Festival, held in Malmö (Sweden), the largest Arabic film festival in Europe
* Ministry of Agriculture, Fisheries and Food (United Kingdom), a former department of UK gov ...
, MAFG
Transcription factor MafG is a bZip Maf transcription factor protein that in humans is encoded by the ''MAFG'' gene.
MafG is one of the small Maf proteins, which are basic region and leucine zipper (bZIP)-type transcription factors. The HUGO G ...
, MAFK #REDIRECT MAFK
{{R from alternative capitalization
...
) and binds to the antioxidant response element (ARE) in the upstream promoter region
In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of ...
of many antioxidative genes, and initiates their transcription.
Target genes
Activation of NRF2 induces the transcription of genes encoding cytoprotective proteins. These include:
* NAD(P)H quinone oxidoreductase 1 (Nqo1
NAD(P)H dehydrogenase uinone1 is an enzyme that in humans is encoded by the ''NQO1'' gene. This protein-coding gene is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a 2-electron reductase (enzyme). This FAD-binding protein ...
) is a prototypical NRF2 target protein which catalyzes the reduction and detoxification of highly reactive quinones
The quinones are a class of organic compounds that are formally "derived from aromatic compounds uch as benzene or naphthalene">benzene.html" ;"title="uch as benzene">uch as benzene or naphthalene] by conversion of an even number of –CH= group ...
that can cause redox cycling and oxidative stress
Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
.
* Glutamate-cysteine ligase catalytic subunit (GCLC
Glutamate—cysteine ligase catalytic subunit is an enzyme that in humans is encoded by the ''GCLC'' gene.
Function
Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase is the first rate limiting enzyme of glutathione syn ...
) and glutamate-cysteine ligase regulatory subunit (GCLM
Glutamate-cysteine ligase regulatory subunit is an enzyme that in humans is encoded by the ''GCLM'' gene.
Glutamate-cysteine ligase, also known as gamma-glutamylcysteine synthetase, is the first rate limiting enzyme of glutathione synthesis. Th ...
) form a heterodimer, which is the rate-limiting step in the synthesis of glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...
(GSH), a very powerful endogenous antioxidant. Both Gclc and Gclm are characteristic NRF2 target genes, which establish NRF2 as a regulator of glutathione, one of the most important antioxidants in the body.
* Sulfiredoxin 1 (SRXN1
Sulfiredoxin-1 is a protein that in humans is encoded by the ''SRXN1'' gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth' ...
) and Thioredoxin reductase
Thioredoxin reductases (TR, TrxR) () are enzymes that reduce thioredoxin (Trx). Two classes of thioredoxin reductase have been identified: one class in bacteria and some eukaryotes and one in animals. In bacteria TrxR also catalyzes the reduction ...
1 (TXNRD1
Thioredoxin reductase 1, cytoplasmic is an enzyme that in humans is encoded by the ''TXNRD1'' gene.
This gene encodes a member of the family of pyridine nucleotide oxidoreductases. This protein reduces thioredoxins as well as other substrates, and ...
) support the reduction and recovery of peroxiredoxins, proteins important in the detoxification of highly reactive peroxides, including hydrogen peroxide
Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...
and peroxynitrite
Peroxynitrite (sometimes called peroxonitrite) is an ion with the formula ONOO−. It is a structural isomer of nitrate,
Preparation
Peroxynitrite can be prepared by the reaction of superoxide with nitric oxide:
:
It is prepared by the react ...
.
* Heme oxygenase-1 (HMOX1
''HMOX1'' (heme oxygenase 1 gene) is a human gene that encodes for the enzyme heme oxygenase 1 (). Heme oxygenase (abbreviated HMOX or HO) mediates the first step of heme catabolism, it cleaves heme to form biliverdin.
The ''HMOX'' gene is locat ...
, HO-1) is an enzyme that catalyzes the breakdown of heme
Heme, or haem (pronounced / hi:m/ ), is a precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, heme is a coordination complex "consis ...
into the antioxidant biliverdin
Biliverdin (latin for green bile) is a green tetrapyrrolic bile pigment, and is a product of heme catabolism.Boron W, Boulpaep E. Medical Physiology: a cellular and molecular approach, 2005. 984-986. Elsevier Saunders, United States. It is the ...
, the anti-inflammatory agent carbon monoxide
Carbon monoxide (chemical formula CO) is a colorless, poisonous, odorless, tasteless, flammable gas that is slightly less dense than air. Carbon monoxide consists of one carbon atom and one oxygen atom connected by a triple bond. It is the simple ...
, and iron. HO-1 is a NRF2 target gene that has been shown to protect from a variety of pathologies, including sepsis
Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...
, hypertension, atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
, acute lung injury, kidney injury, and pain. In a recent study, however, induction of HO-1 has been shown to exacerbate early brain injury after intracerebral hemorrhage.
* The glutathione S-transferase
Glutathione ''S''-transferases (GSTs), previously known as ligandins, are a family of eukaryotic and prokaryotic phase II metabolic isozymes best known for their ability to catalyze the conjugation of the reduced form of glutathione (GSH) ...
(GST) family includes cytosolic, mitochondrial, and microsomal
In cell biology, microsomes are heterogeneous vesicle-like artifacts (~20-200 nm diameter) re-formed from pieces of the endoplasmic reticulum (ER) when eukaryotic cells are broken-up in the laboratory; microsomes are not present in healthy, liv ...
enzymes that catalyze the conjugation of GSH with endogenous and xenobiotic
A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
electrophile
In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carrie ...
s. After detoxification by glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...
(GSH) conjugation catalyzed by GSTs, the body can eliminate potentially harmful and toxic compounds. GSTs are induced by NRF2 activation and represent an important route of detoxification.
* The UDP-glucuronosyltransferase
Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is ...
(UGT) family catalyze the conjugation of a glucuronic acid moiety to a variety of endogenous and exogenous substances, making them more water-soluble and readily excreted. Important substrates for glucuronidation
Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...
include bilirubin and acetaminophen. NRF2 has been shown to induce UGT1A1 and UGT1A6.
* Multidrug resistance-associated proteins (Mrps) are important membrane transporters that efflux various compounds from various organs and into bile or plasma, with subsequent excretion in the feces or urine, respectively. Mrps have been shown to be upregulated by NRF2 and alteration in their expression can dramatically alter the pharmacokinetics and toxicity of compounds.
* Kelch-like ECH-associated protein 1 is also a primary target of NFE2L2. Several interesting studies have also identified this hidden circuit in NRF2 regulations. In the mouse Keap1 (INrf2) gene, Lee and colleagues found that an AREs located on a negative strand can subtly connect Nrf2 activation to Keap1 transcription. When examining NRF2 occupancies in human lymphocytes, Chorley and colleagues identified an approximately 700 bp locus within the KEAP1 promoter region was consistently top rank enriched, even at the whole-genome scale. These basic findings have depicted a mutually influenced pattern between NRF2 and KEAP1. NRF2-driven KEAP1 expression characterized in human cancer contexts, especially in human squamous cell cancers, implicated a new perspective in understanding NRF2 signaling regulation.
Tissue distribution
NRF2 is ubiquitously expressed with the highest concentrations (in descending order) in the kidney, muscle, lung, heart, liver, and brain.
Clinical relevance
Dimethyl fumarate
Dimethyl fumarate (DMF) is the methyl ester of fumaric acid and is named after the earth smoke plant (''Fumaria officinalis''). Dimethyl fumarate combined with three other fumaric acid esters (FAEs) is solely licensed in Germany as an oral thera ...
, marketed as Tecfidera by Biogen Idec
Biogen Inc. is an American multinational biotechnology company based in Cambridge, Massachusetts, specializing in the discovery, development, and delivery of therapies for the treatment of neurological diseases to patients worldwide.
History
...
, was approved by the Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
in March 2013 following the conclusion of a Phase III clinical trial
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
which demonstrated that the drug reduced relapse rates and increased time to progression of disability in people with multiple sclerosis.[ The mechanism of action of dimethyl fumarate is not well understood. Dimethyl fumarate (and its metabolite, monomethyl fumarate) activates the NRF2 pathway and has been identified as a nicotinic acid receptor agonist in vitro.][ For label updates se]
FDA index page for NDA 204063
/ref> The label includes warnings about the risk of anaphylaxis and angioedema, progressive multifocal leukoencephalopathy (PML), lymphopenia
Lymphocytopenia is the condition of having an abnormally low level of lymphocytes in the blood. Lymphocytes are a white blood cell with important functions in the immune system. It is also called lymphopenia. The opposite is lymphocytosis, which ...
, and liver damage
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the si ...
; other adverse effects include flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain.[
The dithiolethiones are a class of organosulfur compounds, of which ]oltipraz
Oltipraz is an organosulfur compound belonging to the dithiolethione class. It acts as a schistosomicide and has been shown in rodent models to inhibit the formation of cancers in the bladder, blood, colon, kidney, liver, lung, pancreas, stomac ...
, an NRF2 inducer, is most well understood. Oltipraz inhibits cancer formation in rodent organs, including the bladder, blood, colon, kidney, liver, lung, pancreas, stomach, and trachea, skin, and mammary tissue. However, clinical trials of oltipraz have not demonstrated efficacy and have shown significant side effects, including neurotoxicity and gastrointestinal toxicity. Oltipraz also generates superoxide radical
In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of th ...
s, which can be toxic.
Associated pathology
Genetic activation of NRF2 may promote the development of ''de novo'' cancerous tumors as well as the development of atherosclerosis by raising plasma cholesterol levels and cholesterol content in the liver.[ It has been suggested that the latter effect may overshadow the potential benefits of antioxidant induction afforded by NRF2 activation.]
Interactions
NFE2L2 has been shown to interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with MAFF MAFF may refer to:
* MAFF (gene), a transcription factor
* Malmö Arab Film Festival, held in Malmö (Sweden), the largest Arabic film festival in Europe
* Ministry of Agriculture, Fisheries and Food (United Kingdom), a former department of UK gov ...
, MAFG
Transcription factor MafG is a bZip Maf transcription factor protein that in humans is encoded by the ''MAFG'' gene.
MafG is one of the small Maf proteins, which are basic region and leucine zipper (bZIP)-type transcription factors. The HUGO G ...
, MAFK #REDIRECT MAFK
{{R from alternative capitalization
...
, C-jun, CREBBP
Cyclic adenosine monophosphate Response Element Binding protein Binding Protein (CREB-binding protein), also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the ''CREBBP'' gene in humans, located on chromosome 16p13.3. CBP has intri ...
, EIF2AK3
Eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), is an enzyme that in humans is encoded by the ''EIF2AK3'' gene.
Function
The protein encoded by this gene ...
,[ ]KEAP1
Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the ''Keap1'' gene.
Structure
Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 res ...
, and UBC
The University of British Columbia (UBC) is a public research university with campuses near Vancouver and in Kelowna, British Columbia. Established in 1908, it is British Columbia's oldest university. The university ranks among the top three ...
.
See also
* Heme oxygenase
Heme oxygenase, or haem oxygenase, (HMOX, commonly abbreviated as HO) is an enzyme that catalyzes the degradation of heme to produce biliverdin, ferrous ion, and carbon monoxide.
There are many heme degrading enzymes in nature. In general, onl ...
* Carbon monoxide-releasing molecules
Carbon monoxide-releasing molecules (CORMs) are chemical compounds designed to release controlled amounts of carbon monoxide (CO). CORMs are being developed as potential therapeutic agents to locally deliver CO to cells and tissues, thus overcomin ...
References
External links
*
{{DEFAULTSORT:Nfe2l2
Transcription factors