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105-474: AKG may refer to: alpha -Ketoglutaric acid , also known as 2-Ketoglutaric acid, 2-Oxopentanedioic acid, 2-Oxoglutamate, 2-Oxoglutaric acid & Oxoglutaric acid Asian Kung-Fu Generation , a Japanese rock band Alternatív Közgazdasági Gimnázium , a high school in Budapest, Hungary A. K. Gopalan (1904–1977), Indian communist leader A. K. G. (film) ,

210-517: A methyl group (- CH 3 ) to a cystine adjacent to a guanine (termed a CpG island ) in an increasing number of CpG islands close to certain genes. These methylations often suppress the expression of the genes to which they are close. Assays (termed epigenetic clock tests) that determine the presence of methylations of cystines in CpG islands for key genes have been used to define an individual's biological age. The Rejuvant® study reported that

315-483: A 2007 Indian Malayalam documentary film The ICAO Code for No. 84 Squadron RAF , United Kingdom AKG (company) , an acoustics engineering and manufacturing company Buffalo AKG Art Museum , an art museum in Buffalo, New York Topics referred to by the same term [REDACTED] This disambiguation page lists articles associated with the title AKG . If an internal link led you here, you may wish to change

420-465: A 2014 study from McGill University in Montreal, Canada which suggests that mice handled by men rather than women showed higher stress levels. Another study in 2016 suggested that gut microbiomes in mice may have an impact upon scientific research. Ethical concerns, as well as the cost, maintenance and relative inefficiency of animal research has encouraged development of alternative methods for

525-678: A Jumonji C (JmjC) protein domain . They function as dioxygenases or hydroxylases to remove methyl groups from the lysine residues on the histones enveloping DNA and thereby alter the expression of diverse genes. These altered gene expressions lead to a wide range of changes in the functions of various cell types and thereby caused the development and/or progression of various cancers, pathological inflammations, and other disorders (see α-Ketoglutarate-dependent demethylase biological functions ). The TET enzymes (i.e., ten-eleven translocation (TET) methylcytosine dioxygenase family of enzymes) consists of three members, TET-1, TET-2, and TET-3. Like

630-639: A high fat or normal diet and given the resistance exercise of repeatedly climbing up a 1 meter ladder for 40 minutes had higher levels of α-ketoglutarate in their blood and 7 different muscles than non-exercising mice feeding respectively on the high fat or normal diet; b) mice conducting ladder climbing for several weeks and eating a high fat diet developed lower fat tissue masses and higher lean tissue masses than non-exercising mice on this diet; c) mice not in exercise training fed α-ketoglutarate likewise developed lower fat tissue and higher lean tissue masses than α-ketoglutarate-unfed, non-exercising mice; d) OXGR1

735-591: A local review board called the Institutional Animal Care and Use Committee (IACUC). All laboratory experiments involving living animals are reviewed and approved by this committee. In addition to proving the potential for benefit to human health, minimization of pain and distress, and timely and humane euthanasia, experimenters must justify their protocols based on the principles of Replacement, Reduction and Refinement. "Replacement" refers to efforts to engage alternatives to animal use. This includes

840-406: A lower total neutrophil fraction in the blood , a lower neutrophil enzymatic capacity, lower activity of the complement system , and a different set of pentraxins involved in the inflammatory process ; and lack genes for important components of the immune system, such as IL-8 , IL-37 , TLR10 , ICAM-3 , etc. Laboratory mice reared in specific-pathogen-free (SPF) conditions usually have

945-547: A model for neuronal development by Sydney Brenner in 1963, and has been extensively used in many different contexts since then. C. elegans was the first multicellular organism whose genome was completely sequenced, and as of 2012, the only organism to have its connectome (neuronal "wiring diagram") completed. Arabidopsis thaliana is currently the most popular model plant. Its small stature and short generation time facilitates rapid genetic studies, and many phenotypic and biochemical mutants have been mapped. A. thaliana

1050-666: A nearly transparent body during early development, which provides unique visual access to the animal's internal anatomy during this time period. Zebrafish are used to study development, toxicology and toxicopathology, specific gene function and roles of signaling pathways. Other important model organisms and some of their uses include: T4 phage (viral infection), Tetrahymena thermophila (intracellular processes), maize ( transposons ), hydras ( regeneration and morphogenesis ), cats (neurophysiology), chickens (development), dogs (respiratory and cardiovascular systems), Nothobranchius furzeri (aging), non-human primates such as

1155-460: A physiologically normal acid-base balance; and e) α-ketoglutarate stimulates OXGR1-bearing CDS cells to raise their levels of cytosolic Ca ) and in diabetic mice (and presumably other conditions involving high levels of blood and/or urine glucose) to increase these cells uptake of Na . Resistance exercise is exercising a muscle or muscle group against external resistance (see strength training ). Studies have found that: a) mice feeding on

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1260-551: A portal from which to download sequences (DNA, RNA, or protein) or to access functional information on specific genes, for example the sub-cellular localization of the gene product or its physiological role. Many animal models serving as test subjects in biomedical research, such as rats and mice, may be selectively sedentary , obese and glucose intolerant . This may confound their use to model human metabolic processes and diseases as these can be affected by dietary energy intake and exercise . Similarly, there are differences between

1365-588: A rather immature immune system with a deficit of memory T cells . These mice may have limited diversity of the microbiota , which directly affects the immune system and the development of pathological conditions. Moreover, persistent virus infections (for example, herpesviruses ) are activated in humans, but not in SPF mice, with septic complications and may change the resistance to bacterial coinfections . “Dirty” mice are possibly better suitable for mimicking human pathologies. In addition, inbred mouse strains are used in

1470-532: A small amount of the ionic sodium ( Na ) that they drank or received by intravenous injections; Montelukast reversed this defect in the streptozotocin-pretreated mice. These results indicate that in mice: a) α-ketoglutarate stimulates kidney OXGR1 to activate pendrin-mediated reabsorption of sodium and chloride by type B and non-A–non-B intercalated cells; b) high alkaline (i.e., sodium bicarbonate) intake produces significant increases in urine pH and α-ketoglutarate levels and impairs secretion of bicarbonate into

1575-468: A unicellular green alga with well-studied genetics, is used to study photosynthesis and motility . C. reinhardtii has many known and mapped mutants and expressed sequence tags, and there are advanced methods for genetic transformation and selection of genes. Dictyostelium discoideum is used in molecular biology and genetics , and is studied as an example of cell communication , differentiation , and programmed cell death . Among invertebrates,

1680-506: A wide variety of experimental techniques and goals from many different levels of biology—from ecology , behavior and biomechanics , down to the tiny functional scale of individual tissues , organelles and proteins . Inquiries about the DNA of organisms are classed as genetic models (with short generation times, such as the fruitfly and nematode worm), experimental models, and genomic parsimony models, investigating pivotal position in

1785-548: A wider assortment of lineages on the tree of life . The primary reason for the use of model organisms in research is the evolutionary principle that all organisms share some degree of relatedness and genetic similarity due to common ancestry . The study of taxonomic human relatives, then, can provide a great deal of information about mechanism and disease within the human body that can be useful in medicine. Various phylogenetic trees for vertebrates have been constructed using comparative proteomics , genetics, genomics as well as

1890-412: Is Escherichia coli ( E. coli ), which has been intensively investigated for over 60 years. It is a common, gram-negative gut bacterium which can be grown and cultured easily and inexpensively in a laboratory setting. It is the most widely used organism in molecular genetics , and is an important species in the fields of biotechnology and microbiology , where it has served as the host organism for

1995-441: Is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workings of other organisms. Model organisms are widely used to research human disease when human experimentation would be unfeasible or unethical . This strategy is made possible by the common descent of all living organisms, and

2100-708: Is a cofactor that is needed for certain enzymes in the histone-lysine demethylase protein superfamily to become activated. This superfamily consists of two groups, the FAD-dependent amine oxidases which do not require α-ketoglutarate for activation and the Fe2+/α-ketoglutarate-dependent dioxygenases (Fe2+ is the ferrous form of iron, i.e., Fe ). The latter group of more than 30 enzymes is classified into 7 subfamilies termed histone lysine demethylases, i.e., HDM2 to HDM7, with each subfamily having multiple members. These HDMs are characterized by containing

2205-453: Is a component of the citric acid cycle , a cyclical metabolic pathway located in the mitochondria . This cycle supplies the energy that cells need by sequentially metabolizing (indicated by → ) citrate through seven intermediate metabolites and then converting the eighth intermediate metabolite, oxaloacetate, back to citrate: In this cycle, the enzyme isocitrate dehydrogenase 3 converts isocitrate (isocitrate has 4 isomers of which only

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2310-400: Is also prevented form accumulating in tissues. In this metabolic pathway the −NH 2 group on an amino acid is transferred to α-ketoglutarate; this forms the α-keto acid of the original amino acid and the amine-containing product of α-ketoglutarate, glutamate. The celllular glutamate passes into the circulation and is taken up by the liver where it delivers its acquired −NH 2 group to

2415-474: Is assumed that Montelukast similarly blocks α-ketoglutarate's binding to, and thereby inhibits its activation of OXGR1. The pendrin protein promotes the electroneutral exchange of tissue chloride (Cl ) for urinary bicarbonate (HCO 3 ) in the apical surfaces (i.e., surfaces facing the urine) of the kidney's renal β-intercalated cells (also termed type B intercalated cells) and non-α non-β intercalated cells (also termed non-A non-B intercalated cells) in

2520-491: Is converted to α-Ketoglutarate by "donating" its −NH 2 to other compounds (see transamination ). Acting in these pathways, α-ketoglutarate contributes to the production of amino acids such as glutamine , proline , arginine , and lysine as well as the reduction of cellular carbon and nitrogen (i.e., N) levels; this prevents excessive levels of these two potentially toxic elements from accumulating in cells and tissues. The neurotoxin , ammonia (i.e., NH 3 ),

2625-439: Is difficult to build an animal model that perfectly reproduces the symptoms of depression in patients. Depression, as other mental disorders , consists of endophenotypes that can be reproduced independently and evaluated in animals. An ideal animal model offers an opportunity to understand molecular , genetic and epigenetic factors that may lead to depression. By using animal models, the underlying molecular alterations and

2730-645: Is no substitute for a living organism when studying complex interactions in disease pathology or treatments. Debate about the ethical use of animals in research dates at least as far back as 1822 when the British Parliament under pressure from British and Indian intellectuals enacted the first law for animal protection preventing cruelty to cattle. This was followed by the Cruelty to Animals Act of 1835 and 1849, which criminalized ill-treating, over-driving, and torturing animals. In 1876, under pressure from

2835-431: Is no useful in vitro model system available. Model organisms are drawn from all three domains of life, as well as viruses . One of the first model systems for molecular biology was the bacterium Escherichia coli ( E. coli ), a common constituent of the human digestive system. The mouse ( Mus musculus ) has been used extensively as a model organism and is associated with many important biological discoveries of

2940-420: Is particularly useful as a toxicology model, and as a neurological model and source of primary cell cultures, owing to the larger size of organs and suborganellar structures relative to the mouse, while eggs and embryos from Xenopus tropicalis and Xenopus laevis (African clawed frog) are used in developmental biology, cell biology, toxicology, and neuroscience. Likewise, the zebrafish ( Danio rerio ) has

3045-479: Is similar to a human condition. These test conditions are often termed as animal models of disease . The use of animal models allows researchers to investigate disease states in ways which would be inaccessible in a human patient, performing procedures on the non-human animal that imply a level of harm that would not be considered ethical to inflict on a human. The best models of disease are similar in etiology (mechanism of cause) and phenotype (signs and symptoms) to

3150-496: Is studied, again, because it is easy to grow for an animal, has various visible congenital traits and has a polytene (giant) chromosome in its salivary glands that can be examined under a light microscope. The roundworm Caenorhabditis elegans is studied because it has very defined development patterns involving fixed numbers of cells, and it can be rapidly assayed for abnormalities. Animal models serving in research may have an existing, inbred or induced disease or injury that

3255-528: Is thereby stimulated to activate G proteins that elicit pre-programmed responses in their parent cells. OXRG1 was identified as a receptor for: a) α-ketoglutarate in 2004; b) three leukotrienes viz., leukotrienes E4 , C4 , and D4 in 2013. and c) itaconate in 2023. These ligands have the following relative potencies in stimulating responses in OXGR1-bearing cells (Note that LTE4 can stimulate OXGR1 at concentrations far lower than those of

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3360-477: Is used with the aim of solving medical problems such as Alzheimer's disease, AIDS, multiple sclerosis, spinal cord injury, many headaches, and other conditions in which there is no useful in vitro model system available. Models are those organisms with a wealth of biological data that make them attractive to study as examples for other species and/or natural phenomena that are more difficult to study directly. Continual research on these organisms focuses on

3465-515: The National Anti-Vivisection Society , the Cruelty to Animals Act was amended to include regulations governing the use of animals in research. This new act stipulated that 1) experiments must be proven absolutely necessary for instruction, or to save or prolong human life; 2) animals must be properly anesthetized; and 3) animals must be killed as soon as the experiment is over. Today, these three principles are central to

3570-419: The citric acid cycle ; this cycle supplies the energy used by cells. It is also an intermediate in or product of several other metabolic pathways . These include its being a component of metabolic pathways that: make key amino acids and in the process regulate the cellular levels of carbon, nitrogen , and ammonia ; reduce the cellular levels of potentially toxic reactive oxygen species ; and synthesize

3675-410: The fruit fly Drosophila melanogaster is famous as the subject of genetics experiments by Thomas Hunt Morgan and others. They are easily raised in the lab, with rapid generations, high fecundity , few chromosomes , and easily induced observable mutations. The nematode Caenorhabditis elegans is used for understanding the genetic control of development and physiology. It was first proposed as

3780-481: The inhibitory neurotransmitter gamma-aminobutyric acid . These metabolic reactions occur at the ends of the inhibitory axons of the GABAergic neurons and result in the release of gamma-aminobutyric acid which then inhibits the activation of nearby neurons. OXGR1 (also known as GPR99) is a G protein-coupled receptor , i.e., a receptor located on the surface membrane of cells that binds certain ligands and

3885-616: The life span and/or delay the development of old age-related diseases in a species of roundworms and in mice. It nearly doubled the life span and delayed age-related deteriorations (e.g., decline in rapid, coordinated body movements) of Caenorhabditis elegans roundworms when added to their cell cultures . Similarly, mice fed a diet high in calcium-bound α-ketoglutarate had a longer life span and shorter length of time in which they suffered old age-related morbidities (e.g., increased frailty, hair loss, and changes in body weight). Cell cultures of splenocytes (i.e., primarily T cells ) from

3990-420: The neurotransmitter gamma-aminobutyric acid . It also acts as a direct stimulator of, or cofactor (i.e., required for but does not itself stimulate) for various cellular functions as defined in studies that are primarily preclinical (i.e., conducted in animal models of disease or on animal or human tissues). These studies have provided evidence that α-ketoglutarate contributes to regulating: kidney function;

4095-1168: The oral cavity . The study showed that β-ketoglutaric acid bound to the cancer-promoting protein TET-2 thereby inhibiting α-ketoglutarate's binding to this protein. Since α-ketoglutarate's binding of TET-2 is thought to be required for it to activate TET-2, the study suggested that β-ketoglutaric acid may not fulfill the requirements for TET-2 to be activatable and therefore may prove able to block α-ketoglutarate's cancer-promoting as well as inflammation-promoting and other actions that involve its activation of TET-2. Under glutamine-deprived conditions, α-ketoglutarate promotes naïve CD4+ T cells differentiation into inflammation-promoting T h 1 cells while inhibiting their differentiation into inflammation-inhibiting Treg cells thereby promoting certain inflammation responses. Click on genes, proteins and metabolites below to link to respective articles. Acetyl-CoA Oxaloacetate Malate Fumarate Succinate Succinyl-CoA Citrate cis- Aconitate Isocitrate Oxalosuccinate 2-oxoglutarate Model organism A model organism

4200-622: The rhesus macaque and chimpanzee ( hepatitis , HIV , Parkinson's disease , cognition , and vaccines ), and ferrets ( SARS-CoV-2 ) The organisms below have become model organisms because they facilitate the study of certain characters or because of their genetic accessibility. For example, E. coli was one of the first organisms for which genetic techniques such as transformation or genetic manipulation has been developed. The genomes of all model species have been sequenced , including their mitochondrial / chloroplast genomes. Model organism databases exist to provide researchers with

4305-762: The urea cycle . In effect, the latter pathway removes excess ammonia from the body in the form of urinary urea . Many conditions can cause the excessive accumulation of reactive oxygen species such as the hydroxyl radical (i.e., HO), hydrogen peroxide (i.e., H 2 O 2 ), and superoxide anion (i.e., O 2 ). These tissue-injuring oxygen species may lead to excessive inflammation, atherosclerosis , cardiovascular diseases , neurological disorders , aging-associated diseases , and various cancers. Antioxidant enzymes (i.e., superoxide dismutase , catalase , and glutathione peroxidase ) and non-enzymatic antioxidant agents (e.g., glutathione , vitamin C, and vitamin E) act to reduce

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4410-457: The (−)-d-threo-isomer is the naturally occurring isomer in the citric acid cycle. ) to α-ketoglutarate which in the next step is converted to succinyl-CoA by the oxoglutarate dehydrogenase complex of enzymes. Outside of the citric acid cycle, α-ketoglutarate is made by a) the enzymes isocitrate dehydrogenase 1 or 2 which remove a carboxy group from isocitrate by oxidative decarboxylation to form α-ketoglutarate; b) glutaminolysis in which

4515-561: The 20th and 21st centuries. Other examples include baker's yeast ( Saccharomyces cerevisiae ), the T4 phage virus, the fruit fly Drosophila melanogaster , the flowering plant Arabidopsis thaliana , and guinea pigs ( Cavia porcellus ). Several of the bacterial viruses ( bacteriophage ) that infect E. coli also have been very useful for the study of gene structure and gene regulation (e.g. phages Lambda and T4 ). Disease models are divided into three categories: homologous animals have

4620-498: The CDS tubules' lumens; c) the acid–base balance (i.e., levels of acids relative to their bases) in the face of high alkali intake depends on the activation of OXGR1 by α-ketoglutarate; d) alkaline loading directly or indirectly stimulates α-ketoglutarate secretion into the kidney's proximal tubules where further down these tubules it activates OXGR1 and thereby the absorption and secretion of various agents that contribute to restoring

4725-549: The DBA ("dilute, brown and non-agouti") inbred mouse strain and the systematic generation of other inbred strains. The mouse has since been used extensively as a model organism and is associated with many important biological discoveries of the 20th and 21st centuries. In the late 19th century, Emil von Behring isolated the diphtheria toxin and demonstrated its effects in guinea pigs. He went on to develop an antitoxin against diphtheria in animals and then in humans, which resulted in

4830-416: The Fe2+/α-ketoglutarate-dependent dioxygenases, all three TET enzymes require Fe and α-ketoglutarate as cofactors to become activated. Unlike the dioxygenases, however, they remove methyl groups from the 5-methylcytosines of DNA sites that regulate the expression of nearby genes. These demethylations have a variety of effects including, similar to the Fe2+/α-ketoglutarate-dependent dioxygenases, alteration of

4935-457: The OXGR1 on adrenal gland chromaffin cells to release epinephrine. Another study reported that middle‐aged, i.e., 10‐month‐old, mice had lower serum levels of α-ketoglutarate than 2‐month‐old mice. Middle aged mice fed a high fat diet gained body weight and fat mass in the lower parts of their bodies and had impaired glucose tolerance as defined in glucose tolerance tests. Adding α-ketoglutarate to

5040-433: The OXGR1 protein, or when their actions are inhibited by an OXGR1 receptor antagonists . OXGR1 is inhibited by Montelukast , a well-known inhibitor of the cysteinyl leukotriene receptor 1 , i.e., the receptor for LTD4, LTC4, and LTE4. Montelukast also blocks the binding of these leukotrienes to, and thereby inhibits their activation of, OXGR1. One study presented evidence suggesting that α-ketoglutarate binds to OXGR1. It

5145-622: The United States by 1965. It has been estimated that developing and producing the vaccines required the use of 100,000 rhesus monkeys, with 65 doses of vaccine produced from each monkey. Sabin wrote in 1992, "Without the use of animals and human beings, it would have been impossible to acquire the important knowledge needed to prevent much suffering and premature death not only among humans, but also among animals." Other 20th-century medical advances and treatments that relied on research performed in animals include organ transplant techniques,

5250-430: The United States. Subsequent research in model organisms led to further medical advances, such as Frederick Banting 's research in dogs, which determined that the isolates of pancreatic secretion could be used to treat dogs with diabetes . This led to the 1922 discovery of insulin (with John Macleod ) and its use in treating diabetes, which had previously meant death. John Cade 's research in guinea pigs discovered

5355-502: The activity of superoxide dismutase which converts the highly toxic ( O 2 ) radical to molecular oxygen (i.e., O 2 ) and H 2 O 2 . A study conducted on the GABAergic neurons (i.e., nerve cells) in the neocortex of rat brains reported that the cytosolic form of the aspartate transaminase enzyme metabolizes α-ketoglutarate to glutamate which in turn is metabolized by glutamic acid decarboxylase to

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5460-438: The anticonvulsant properties of lithium salts, which revolutionized the treatment of bipolar disorder , replacing the previous treatments of lobotomy or electroconvulsive therapy. Modern general anaesthetics, such as halothane and related compounds, were also developed through studies on model organisms, and are necessary for modern, complex surgical operations. In the 1940s, Jonas Salk used rhesus monkey studies to isolate

5565-457: The basic knowledge in fields such as human physiology and biochemistry , and has played significant roles in fields such as neuroscience and infectious disease . For example, the results have included the near- eradication of polio and the development of organ transplantation , and have benefited both humans and animals. From 1910 to 1927, Thomas Hunt Morgan 's work with the fruit fly Drosophila melanogaster identified chromosomes as

5670-468: The benefits that resistance exercise has in reducing obesity, strengthening muscles, and preventing muscle atrophy; glucose tolerance as defined in glucose tolerance tests ; aging and the development of changes that are associated with aging including old age-related disorders and diseases; the development and/or progression of certain types of cancer and inflammations ; and the differentiation of immature T cells into mature T cells. α-Ketoglutarate

5775-417: The biological actions that α-ketoglutarate has; it is even suggested to inhibit at least one action of α-ketoglutarate (see the following section titled, "β-Ketoglutaric acid and TET-2"). β-Ketoglutaric acid is used to synthesize other compounds (see applications of β-ketoglutaric acid ) such as cyclohexenone which is itself widely used to synthesize other compounds. α-Ketoglutarate is an intermediate in

5880-607: The blood serum levels of epinephrine in mice expressing OXGR1 but not in Oxgr1 gene knockout mice (i.e., mice lacking the OXGR1 gene and protein); g) mice on the high fat diet challenged with α-ketoglutarate increased their blood serum levels of epinephrine and developed lower fat tissue masses and higher lean tissue masses but neither OXGR1 gene knockout mice nor mice that had only their adrenal glands' OXGR1 gene knocked out showed these responses; and h) OXGR1 gene knockout mice fed

5985-420: The causal relationship between genetic or environmental alterations and depression can be examined, which would afford a better insight into pathology of depression. In addition, animal models of depression are indispensable for identifying novel therapies for depression. Model organisms are drawn from all three domains of life, as well as viruses . The most widely studied prokaryotic model organism

6090-443: The collecting ducts, loops of Henle, vasa recta , and interstitium of mouse kidneys raised their cytosolic ionic calcium, i.e., Ca levels in response to α-ketoglutarate but this response (which is an indicator of cell activation) was blocked by pretreating the cells with Montelukast; and c) compared to mice not treated with streptozotocin , streptozotocin-induced diabetic mice (an animal disease model of diabetes ) urinated only

6195-439: The conservation of metabolic and developmental pathways and genetic material over the course of evolution . Research using animal models has been central to most of the achievements of modern medicine. It has contributed most of the basic knowledge in fields such as human physiology and biochemistry , and has played significant roles in fields such as neuroscience and infectious disease . The results have included

6300-424: The development and/or progression of various cancers, immune responses, and other disorders (see functions of TET enzymes ). A recent study found that β-ketoglutaric acid was detected in the saliva of individuals chewing betel quid , a complex mixture derived from betel nuts mixed with various other materials. Chronic chewing betel quid is associated with the development of certain cancers, particularly those in

6405-462: The drinking water of these mice inhibited the development of these changes. These results suggest that drinking the α-ketoglutarate-rich water replenished the otherwise diminished supplies of α-ketoglutarate in middle aged mice; the replenished supply of α-ketoglutarate thereby became available to suppress obesity and improve glucose tolerance. Finally, a study in rats feed a low fat or high fat diet for 27 weeks and drinking α-ketoglutarate-rich water for

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6510-449: The enzyme glutaminase removes the amino group (i.e., −NH 2 ) from glutamine to form glutamate which is converted to α-ketoglutarate by any one of three different enzymes, glutamate dehydrogenase , alanine transaminase , or aspartate transaminase (see The glutaminolytic pathways ); and c) various pyridoxal phosphate -dependent transamination reactions mediated by, e.g., the alanine transaminase enzyme, in which glutamate

6615-533: The evolutionary tree. Historically, model organisms include a handful of species with extensive genomic research data, such as the NIH model organisms. Often, model organisms are chosen on the basis that they are amenable to experimental manipulation. This usually will include characteristics such as short life-cycle , techniques for genetic manipulation ( inbred strains, stem cell lines, and methods of transformation ) and non-specialist living requirements. Sometimes,

6720-455: The first to perform experiments on living animals. Discoveries in the 18th and 19th centuries included Antoine Lavoisier 's use of a guinea pig in a calorimeter to prove that respiration was a form of combustion, and Louis Pasteur 's demonstration of the germ theory of disease in the 1880s using anthrax in sheep. Research using animal models has been central to most of the achievements of modern medicine. It has contributed most of

6825-550: The genome arrangement facilitates the sequencing of the model organism's genome, for example, by being very compact or having a low proportion of junk DNA (e.g. yeast , arabidopsis , or pufferfish ). When researchers look for an organism to use in their studies, they look for several traits. Among these are size, generation time , accessibility, manipulation, genetics, conservation of mechanisms, and potential economic benefit. As comparative molecular biology has become more common, some researchers have sought model organisms from

6930-430: The geochemical and fossil record. These estimations tell us that humans and chimpanzees last shared a common ancestor about 6 million years ago (mya). As our closest relatives, chimpanzees have a lot of potential to tell us about mechanisms of disease (and what genes may be responsible for human intelligence). However, chimpanzees are rarely used in research and are protected from highly invasive procedures. Rodents are

7035-563: The guidance of animal models. Treatments for animal diseases have also been developed, including for rabies , anthrax , glanders , feline immunodeficiency virus (FIV), tuberculosis , Texas cattle fever, classical swine fever (hog cholera), heartworm , and other parasitic infections . Animal experimentation continues to be required for biomedical research, and is used with the aim of solving medical problems such as Alzheimer's disease, AIDS, multiple sclerosis, spinal cord injury, many headaches, and other conditions in which there

7140-540: The heart-lung machine, antibiotics , and the whooping cough vaccine. In researching human disease , model organisms allow for better understanding the disease process without the added risk of harming an actual human. The species of the model organism is usually chosen so that it reacts to disease or its treatment in a way that resembles human physiology , even though care must be taken when generalizing from one organism to another. However, many drugs, treatments and cures for human diseases are developed in part with

7245-428: The heart-lung machine, antibiotics , and the whooping cough vaccine. Treatments for animal diseases have also been developed, including for rabies , anthrax , glanders , feline immunodeficiency virus (FIV), tuberculosis , Texas cattle fever, classical swine fever (hog cholera), heartworm , and other parasitic infections . Animal experimentation continues to be required for biomedical research, and

7350-433: The high fat diet developed muscle protein degradation, muscle atrophy (i.e., wasting), and falls in body weight whereas control mice did not show these fat diet-induced changes. These findings indicate that in mice resistance exercise increases muscle production as well as serum levels of α-ketoglutarate which in turn suppresses diet-induced obesity (i.e., low body fat and high lean body masses) at least in part by stimulating

7455-412: The host cells for propagation. In eukaryotes , several yeasts, particularly Saccharomyces cerevisiae ("baker's" or "budding" yeast), have been widely used in genetics and cell biology , largely because they are quick and easy to grow. The cell cycle in a simple yeast is very similar to the cell cycle in humans and is regulated by homologous proteins. The fruit fly Drosophila melanogaster

7560-904: The human equivalent. However complex human diseases can often be better understood in a simplified system in which individual parts of the disease process are isolated and examined. For instance, behavioral analogues of anxiety or pain in laboratory animals can be used to screen and test new drugs for the treatment of these conditions in humans. A 2000 study found that animal models concorded (coincided on true positives and false negatives) with human toxicity in 71% of cases, with 63% for nonrodents alone and 43% for rodents alone. In 1987, Davidson et al. suggested that selection of an animal model for research be based on nine considerations. These include 1) appropriateness as an analog, 2) transferability of information, 3) genetic uniformity of organisms, where applicable, 4) background knowledge of biological properties, 5) cost and availability, 6) generalizability of

7665-621: The immune systems of model organisms and humans that lead to significantly altered responses to stimuli, although the underlying principles of genome function may be the same. The impoverished environments inside standard laboratory cages deny research animals of the mental and physical challenges are necessary for healthy emotional development. Without day-to-day variety, risks and rewards, and complex environments, some have argued that animal models are irrelevant models of human experience. Mice differ from humans in several immune properties: mice are more resistant to some toxins than humans; have

7770-492: The kidney's collecting duct system (i.e., CDS). A study in mice found that OXGR1 colocalizes with pendrin in the β-intercalated cells and non-α non-β intercalated cells lining the tubules of their kidney's CDS. The intercalated cells in the CDS tubules isolated from mice used pendrin in cooperation with the electroneutral sodium bicarbonate exchanger 1 protein to mediate the Cl for HCO 3 exchange. α-Ketoglutarate stimulated

7875-408: The laboratory. Some examples include: Spontaneous models refer to diseases that are analogous to human conditions that occur naturally in the animal being studied. These models are rare, but informative. Negative models essentially refer to control animals, which are useful for validating an experimental result. Orphan models refer to diseases for which there is no human analog and occur exclusively in

7980-696: The last 12 weeks of this 27 week period decreased their fat issue masses and increased their whole-body insulin sensitivity as defined in glucose tolerance tests. Rats fed either of these diets but not given α-ketoglutarate-rich water did not show these changes. This study indicates that α-ketoglutarate regulates body fat mass and insulin sensitivity in rats as well as mice. The following actions of α-ketoglutarate have not been evaluated for their dependency on activating OXGR1 and are here assumed to be OXGR1-independent. Futures studies are needed to determine if OXGR1 contributes in whole or part to these actions of α-ketoglutarate. α-Ketoglutarate has been reported to increase

8085-598: The laws and guidelines governing the use of animals and research. In the U.S., the Animal Welfare Act of 1970 (see also Laboratory Animal Welfare Act ) set standards for animal use and care in research. This law is enforced by APHIS's Animal Care program. In academic settings in which NIH funding is used for animal research, institutions are governed by the NIH Office of Laboratory Animal Welfare (OLAW). At each site, OLAW guidelines and standards are upheld by

8190-569: The levels of these disease-causing agents. α-Ketoglutarate is one of the non-enzymatic antioxidant agents. It reacts with hydrogen peroxide (H 2 O 2 ) to form succinate , carbon dioxide (i.e., CO 2 ), and water (i.e., ( H 2 O ) thereby reducing the levels of H 2 O 2 . The protective action of α-ketoglutarate in reducing the toxic effects of H 2 O 2 have been observed in Drosophila melanogaster (i.e., fruit flies), other animals, and humans. In addition, α-ketoglutarate increases

8295-547: The link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=AKG&oldid=1175716512 " Category : Disambiguation pages Hidden categories: Short description is different from Wikidata All article disambiguation pages All disambiguation pages Alpha-Ketoglutaric acid β-Ketoglutaric acid (also termed 3-oxoglutaric acid and acetonedicarboxlic acid) and its conjugate base, β-Ketoglutarate, differ from α-ketoglutaric acid and α-ketoglutarate by

8400-412: The majority of work with recombinant DNA . Simple model eukaryotes include baker's yeast ( Saccharomyces cerevisiae ) and fission yeast ( Schizosaccharomyces pombe ), both of which share many characters with higher cells, including those of humans. For instance, many cell division genes that are critical for the development of cancer have been discovered in yeast. Chlamydomonas reinhardtii ,

8505-469: The median and range of the biological age of females before treatment was 62.15 (range, 46.4 to 73) years and fell to 55.55 (range 33.4 to 63.7) years after an average of 7 months treatment. These values for men were 61.85 (range 41.9 to 79.7) years before and 53.3 (33 to 74.9) years after treatment. Overall, the combined group of males and females showed an average fall in biological age of 8 years compared to before treatment. The p -value for this difference

8610-401: The methylation of their CpG island. The study recommended that studies need to include control groups taking a placebo or the appropriate dosages of retinyl palmitate, vitamin A, and calcium. Also, TruMe Labs, who were the maker and marketer of the biological age assay used in this study, sponsored part of the study and contributed three of its employees as authors to the study. α-Ketoglutarate

8715-479: The modern methods of immunization and largely ended diphtheria as a threatening disease. The diphtheria antitoxin is famously commemorated in the Iditarod race, which is modeled after the delivery of antitoxin in the 1925 serum run to Nome . The success of animal studies in producing the diphtheria antitoxin has also been attributed as a cause for the decline of the early 20th-century opposition to animal research in

8820-550: The most common animal models. Phylogenetic trees estimate that humans and rodents last shared a common ancestor ~80-100mya. Despite this distant split, humans and rodents have far more similarities than they do differences. This is due to the relative stability of large portions of the genome, making the use of vertebrate animals particularly productive. Genomic data is used to make close comparisons between species and determine relatedness. Humans share about 99% of their genome with chimpanzees (98.7% with bonobos) and over 90% with

8925-497: The most virulent forms of the polio virus, which led to his creation of a polio vaccine . The vaccine, which was made publicly available in 1955, reduced the incidence of polio 15-fold in the United States over the following five years. Albert Sabin improved the vaccine by passing the polio virus through animal hosts, including monkeys; the Sabin vaccine was produced for mass consumption in 1963, and had virtually eradicated polio in

9030-436: The mouse. With so much of the genome conserved across species, it is relatively impressive that the differences between humans and mice can be accounted for in approximately six thousand genes (of ~30,000 total). Scientists have been able to take advantage of these similarities in generating experimental and predictive models of human disease. There are many model organisms. One of the first model systems for molecular biology

9135-463: The near- eradication of polio and the development of organ transplantation , and have benefited both humans and animals. From 1910 to 1927, Thomas Hunt Morgan 's work with the fruit fly Drosophila melanogaster identified chromosomes as the vector of inheritance for genes, and Eric Kandel wrote that Morgan's discoveries "helped transform biology into an experimental science". Research in model organisms led to further medical advances, such as

9240-463: The other four ligands): It may be difficult to determine if an OXGR1-stimulating agent elicits a functional response by activating OXGR1 as opposed to some other mechanism. To make this distinction, studies have shown that the action of an OXGR1-activating agent on cultured cells, cultured tissues, or animals does not occur or is reduced when these cells, tissues, or animals have been altered so that they do not express or express greatly reduced levels of

9345-454: The overwhelming majority of studies, while the human population is heterogeneous, pointing to the importance of studies in interstrain hybrid, outbred , and nonlinear mice. Some studies suggests that inadequate published data in animal testing may result in irreproducible research, with missing details about how experiments are done omitted from published papers or differences in testing that may introduce bias. Examples of hidden bias include

9450-438: The position of their ketone, i.e., carbon–oxygen double bond (C=O). β-Ketoglutaric acid's and β-ketoglutarate's C=O is on the second carbon from a CO 2 H whereas α-ketoglutaric acid's and α-ketoglutarate's C=O is on a carbon adjacent to a CO 2 H . "Ketoglutaric acid" and "ketoglutarate", when not qualified as α or β, almost always refers respectively to α-ketoglutaric acid or α-ketoglutarate. β-Ketoglutarate does not have

9555-451: The production of the diphtheria antitoxin and the 1922 discovery of insulin and its use in treating diabetes, which had previously meant death. Modern general anaesthetics such as halothane were also developed through studies on model organisms, and are necessary for modern, complex surgical operations. Other 20th-century medical advances and treatments that relied on research performed in animals include organ transplant techniques,

9660-410: The rate of this exchange in CDS tubules isolated from control mice (i.e., mice that had the Oxgr1 gene and protein) but not in CDS tubules isolated from Oxgr1 gene knockout mice (i.e., mice that lacked the Oxgr1 gene and protein). This study also showed that the α-ketoglutarate in the blood of mice filtered through their kidney's glomeruli into the proximal tubules and loops of Henle where it

9765-505: The results, 7) ease of and adaptability to experimental manipulation, 8) ecological consequences, and 9) ethical implications. Animal models can be classified as homologous, isomorphic or predictive. Animal models can also be more broadly classified into four categories: 1) experimental, 2) spontaneous, 3) negative, 4) orphan. Experimental models are most common. These refer to models of disease that resemble human conditions in phenotype or response to treatment but are induced artificially in

9870-476: The same causes, symptoms and treatment options as would humans who have the same disease, isomorphic animals share the same symptoms and treatments, and predictive models are similar to a particular human disease in only a couple of aspects, but are useful in isolating and making predictions about mechanisms of a set of disease features. The use of animals in research dates back to ancient Greece , with Aristotle (384–322 BCE) and Erasistratus (304–258 BCE) among

9975-469: The species studied. The increase in knowledge of the genomes of non-human primates and other mammals that are genetically close to humans is allowing the production of genetically engineered animal tissues, organs and even animal species which express human diseases, providing a more robust model of human diseases in an animal model. Animal models observed in the sciences of psychology and sociology are often termed animal models of behavior . It

10080-581: The study of disease. Cell culture, or in vitro studies, provide an alternative that preserves the physiology of the living cell, but does not require the sacrifice of an animal for mechanistic studies. Human, inducible pluripotent stem cells can also elucidate new mechanisms for understanding cancer and cell regeneration. Imaging studies (such as MRI or PET scans) enable non-invasive study of human subjects. Recent advances in genetics and genomics can identify disease-associated genes, which can be targeted for therapies. Many biomedical researchers argue that there

10185-491: The use of computer models, non-living tissues and cells, and replacement of “higher-order” animals (primates and mammals) with “lower” order animals (e.g. cold-blooded animals, invertebrates) wherever possible. "Reduction" refers to efforts to minimize number of animals used during the course of an experiment, as well as prevention of unnecessary replication of previous experiments. To satisfy this requirement, mathematical calculations of statistical power are employed to determine

10290-483: The vector of inheritance for genes. Drosophila became one of the first, and for some time the most widely used, model organisms, and Eric Kandel wrote that Morgan's discoveries "helped transform biology into an experimental science". D. melanogaster remains one of the most widely used eukaryotic model organisms. During the same time period, studies on mouse genetics in the laboratory of William Ernest Castle in collaboration with Abbie Lathrop led to generation of

10395-1012: The α-ketoglutarate-fed mice produced higher levels of the anti-inflammatory cytokine , interleukin-10 , than splenocytes from mice not fed α-ketoglutarate. (Chronic low-grade inflammation which might be inhibited by interleukin-10, is associated with the development of old age-related disorders and diseases. ) A small and very preliminary study suggested that α-ketoglutarate may also promote longevity in humans. Fourteen females (age 64.09, range 43.49 to 72.46 years) and 28 males (age 62.78, range 41.31 to 79.57 years) volunteered to take Rejuvant® for an average period of 7 months. The Rejuvant® commercial preparations they used contained 1,000 mg of calcium α-ketoglutarate monohydrate plus either 900 mg of retinyl palmitate (a form of vitamin A containing 190 mg of calcium) for males (i.e., Rejuvant® for males) or 25 mg of vitamin D containing 190 mg of calcium for females (i.e., Rejuvant® for females). As individuals age, their DNA develops additions of

10500-632: Was associated with blood bicarbonate levels significantly higher and blood chloride levels significantly lower than those in control mice drinking the sodium bicarbonate-rich water. Several other studies confirmed these findings and reported that cells in the proximal tubules of mice synthesize α-ketoglutarate and either broke it down thereby reducing its urine levels or secreted it into the tubules' lumens thereby increasing its urine levels. Another study showed that a) In silico computer simulations strongly suggested that α-ketoglutarate bound to mouse OXGPR1; b) suspensions of canal duct cells isolated from

10605-460: Was extraordinarily significant, i.e., 6.538x10-12, in showing that that this treatment decreased the participants' biological ages. However, the study did not: a) include a control group (i.e., concurrent study of individuals taking a placebo instead of Rejuvant®); b) determine if the retinyl palmitate, vitamin A, and/or calcium given with α-ketoglutarate contributed to the changes in biological ages; and c) disclose which genes were tracked for

10710-525: Was reabsorbed. Mice drinking water with a basic pH (i.e., >7) due to the addition of sodium bicarbonate and mice lacking the Oxgr1 gene and protein who drink water without sodium bicarbonate had urines that were more basic (i.e., pH about 7.8) and contained higher levels of urinary α-ketoglutarate than control mice drinking water without this additive. Furthermore, Oxgr1 gene knockout mice drinking sodium bicarbonate-rich water developed metabolic alkalosis (body tissue pH levels higher than normal) that

10815-449: Was strongly expressed in the mouse adrenal gland inner medullas and either resistance training or oral α-ketoglutarate increased this tissue's levels of the mRNA that is responsible for the synthesis of OXGR1; e) α-ketoglutarate stimulated chromaffin cells isolated from mouse adrenal glands to release epinephrine but reduction of these cells' OXGR1 levels by small interfering RNA reduced this response; f) α-ketoglutarate increased

10920-417: Was the bacterium Escherichia coli , a common constituent of the human digestive system. Several of the bacterial viruses ( bacteriophage ) that infect E. coli also have been very useful for the study of gene structure and gene regulation (e.g. phages Lambda and T4 ). However, it is debated whether bacteriophages should be classified as organisms, because they lack metabolism and depend on functions of

11025-569: Was the first plant to have its genome sequenced . Among vertebrates , guinea pigs ( Cavia porcellus ) were used by Robert Koch and other early bacteriologists as a host for bacterial infections, becoming a byword for "laboratory animal", but are less commonly used today. The classic model vertebrate is currently the mouse ( Mus musculus ). Many inbred strains exist, as well as lines selected for particular traits, often of medical interest, e.g. body size, obesity, muscularity, and voluntary wheel-running behavior. The rat ( Rattus norvegicus )

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