Monday, 26 June 2017

C-peptide kháng KATOIII

Evidence for an interaction between proinsulin C-peptide and GPR146

C-peptide kháng KATOIII

From Wikipedia, the free encyclopedia
Not to be confused with C-reactive protein or Protein C.
C-peptide[1]
C-Peptide.svg
Identifiers
3D model (JSmol)
ChemSpider
MeSHC-Peptide
PubChem CID
Properties
C129H211N35O48
Molar mass3020.29 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
The connecting peptide, or C-peptide, is a short 31-amino-acid polypeptide that connects insulin's A-chain to its B-chain in the proinsulin molecule. In diabetes and other diseases a measurement of C-peptide blood serum levels can be used to distinguish between certain diseases with similar clinical features.
In the insulin synthesis pathway, first preproinsulin is translocated into the endoplasmic reticulum of beta cells of the pancreas with an A-chain, a C-peptide, a B-chain, and a signal sequence. The signal sequence is cleaved from the N-terminus of the peptide by a signal peptidase, leaving proinsulin. After proinsulin is packaged into vesicles in the Golgi apparatus (beta-granules), the C-peptide is removed, leaving the A-chain B-chain, bound together by disulfide bonds, that constitute the insulin molecule.

History[edit]

Proinsulin C-peptide was first described in 1967 in connection with the discovery of the insulin biosynthesis pathway.[2] It serves as a linker between the A- and the B- chains of insulin and facilitates the efficient assembly, folding, and processing of insulin in the endoplasmic reticulum. Equimolar amounts of C-peptide and insulin are then stored in secretory granules of the pancreatic beta cells and both are eventually released to the portal circulation. Initially, the sole interest in C-peptide was as a marker of insulin secretion and has, as such, been of great value in furthering the understanding of the pathophysiology of type 1 and type 2 diabetes. The first documented use of the C-peptide test was in 1972. During the past decade, however, C-peptide has been found to be a bioactive peptide in its own right, with effects on microvascular blood flow and tissue health.

Function[edit]

Cellular effects of C-peptide[edit]

C-peptide has been shown to bind to the surface of a number of cell types such as neuronal, endothelial, fibroblast and renal tubular, at nanomolar concentrations to a receptor that is likely G-protein-coupled. The signal activates Ca2+-dependent intracellular signaling pathways such as MAPK, PLCγ, and PKC, leading to upregulation of a range of transcription factors as well as eNOS and Na+K+ATPase activities.[3] The latter two enzymes are known to have reduced activities in patients with type I diabetes and have been implicated in the development of long-term complications of type I diabetes such as peripheral and autonomic neuropathy.
In vivo studies in animal models of type 1 diabetes have established that C-peptide administration results in significant improvements in nerve and kidney function. Thus, in animals with early signs of diabetes-induced neuropathy, C peptide treatment in replacement dosage results in improved peripheral nerve function, as evidenced by increased nerve conduction velocity, increased nerve Na+,K+ ATPase activity, and significant amelioration of nerve structural changes.[4] Likewise, C-peptide administration in animals that had C-peptide deficiency (type 1 model) with nephropathy improves renal function and structure; it decreases urinary albumin excretion and prevents or decreases diabetes-induced glomerular changes secondary to mesangial matrix expansion.[5][6][7][8] C-peptide also has been reported to have anti-inflammatory effects as well as aid repair of smooth muscle cells.[9][10] ii

Clinical uses of C-peptide testing[edit]

  • Patients with diabetes may have their C-peptide levels measured as a means of distinguishing type 1 diabetes from type 2 diabetes or Maturity onset diabetes of the young (MODY).[11] Measuring C-peptide can help to determine how much of their own natural insulin a person is producing as C-peptide is secreted in equimolar amounts to insulin. C-peptide levels are measured instead of insulin levels because C-peptide can assess a person's own insulin secretion even if they receive insulin injections, and because the liver metabolizes a large and variable amount of insulin secreted into the portal vein but does not metabolise C-peptide, meaning blood C-peptide may be a better measure of portal insulin secretion than insulin itself.[12][13] A very low C-peptide confirms Type 1 diabetes and insulin dependence and is associated with high glucose variability, hyperglycaemia and increased complications. The test may be less helpful close to diagnosis, particularly where a patient is overweight and insulin resistant, as levels close to diagnosis in Type 1 diabetes may be high and overlap with those seen in type 2 diabetes.[14]
  • Differential diagnosis of hypoglycemia. The test may be used to help determine the cause of hypoglycaemia (low glucose), values will be low if a person has taken an overdose of insulin but not suppressed if hypoglycaemia is due to an insulinoma or sulphonylureas.
  • Factitious (or factitial) hypoglycemia may occur secondary to the surreptitious use of insulin. Measuring C-peptide levels will help differentiate a healthy patient from a diabetic one.
  • C-peptide may be used for determining the possibility of gastrinomas associated with Multiple Endocrine Neoplasm syndromes (MEN 1). Since a significant number of gastrinomas are associated with MEN involving other hormone producing organs (pancreas, parathyroids, and pituitary), higher levels of C-peptide together with the presence of a gastrinoma suggest that organs besides the stomach may harbor neoplasms.
  • C-peptide levels may be checked in women with Polycystic Ovarian Syndrome (PCOS) to help determine degree of insulin resistance.

Therapeutics[edit]

Therapeutic use of C-peptide has been explored in small clinical trials in diabetic kidney disease.[15][16] Creative Peptides,[17] Eli Lilly,[18] and Cebix[19] all had drug development programs for a C-peptide product. Cebix had the only ongoing program until it completed a Phase IIb trial in December 2014 that showed no difference between C-peptide and placebo, and it terminated its program and went out of business.[20][21]
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Cyanidin-3-O-glucoside 2-O-glucuronosyltransferase kháng KATOIII

Cyanidin 3-O-Glucoside Reduces Helicobacter pylori VacA-Induced .

Cyanidin-3-O-glucoside 2-O-glucuronosyltransferase kháng KATOIII

From Wikipedia, the free encyclopedia
Cyanidin-3-O-glucoside 2-O-glucuronosyltransferase
Identifiers
EC number2.4.1.254
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDBstructuresRCSB PDB PDBe PDBsum
Cyanidin-3-O-glucoside 2-O-glucuronosyltransferase (EC 2.4.1.254, BpUGT94B1, UDP-glucuronic acid:anthocyanin glucuronosyltransferase, UDP-glucuronic acid:anthocyanidin 3-glucoside 2'-O-beta-glucuronosyltransferase, BpUGAT, UDP-D-glucuronate:cyanidin-3-O-beta-glucoside 2-O-beta-glucuronosyltransferase) is an enzyme with systematic name UDP-D-glucuronate:cyanidin-3-O-beta-D-glucoside 2-O-beta-D-glucuronosyltransferase.[1][2] This enzyme catalyses the following chemical reaction
UDP-D-glucuronate + cyanidin 3-O-beta-D-glucoside  UDP + cyanidin 3-O-(2-O-beta-D-glucuronosyl)-beta-D-glucoside
The enzyme is highly specific for cyanidin 3-O-glucosides and UDP-D-glucuronate.
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Astaxanthin kháng KATOIII

Astaxanthin Inhibits Proliferation of Human Gastric Cancer Cell Lines ...

Astaxanthin kháng KATOIII

From Wikipedia, the free encyclopedia
Not to be confused with Anthoxanthin, a subclass of flavonoids.
Astaxanthin
Skeletal formula of astaxanthin
Space-filling model of the astaxanthin molecule
Names
IUPAC name
(6S)-6-Hydroxy-3-[(1E,3E,5E,7E,9E,11E,13E,15E,17E)-18-[(4S)-4-hydroxy-2,6,6-trimethyl-3-oxo-1-cyclohexenyl]-3,7,12,16-tetramethyloctadeca-1,3,5,7,9,11,13,15,17-nonaenyl]-2,4,4-trimethyl-1-cyclohex-2-enone
Other names
3,3'-dihydroxy-ß-carotene-4,4'-dione; Astaxanthin (6CI); β-Carotene-4,4'-dione, 3,3'-dihydroxy-, all-trans- (8CI); (3S,3'S)-Astaxanthin; (3S,3'S)-Astaxanthin; (3S,3'S)-all-trans-Astaxanthin; (S,S)-Astaxanthin; Aquasta; AstaREAL; AstaXin; Astared; Astaxanthin, all-trans-; Astots 10O; Astots 5O; BioAstin; BioAstin oleoresin; Carophyll Pink; Lucantin Pink; NatuRose; Natupink; Ovoester; all-trans-Astaxanthin; trans-Astaxanthin [1]
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard100.006.776
E numberE161j (colours)
PubChem CID
UNII
Properties
C40H52O4
Molar mass596.84 g/mol
Appearancered solid powder
Density1.071 g/mL [2]
Melting point216 °C (421 °F; 489 K)[2]
Boiling point774 °C (1,425 °F; 1,047 K)[2]
Solubility30 g/L in DCM; 10 g/L in CHCl3; 0.5 g/L in DMSO; 0.2 g/L in acetone [3]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references
Astaxanthin /æstəˈzænθᵻn/ is a keto-carotenoid.[4][5] It belongs to a larger class of chemical compounds known as terpenes (in Asthaxanthin's case, a tetraterpenoid); terpenes are built from five carbon precursors; isopentenyl diphosphate (or IPP) and dimethylallyl diphosphate (or DMAPP). Astaxanthin is classified as a xanthophyll(originally derived from a word meaning "yellow leaves" since yellow plant leaf pigments were the first recognized of the xanthophyll family of carotenoids), but currently employed to describe carotenoid compounds that have oxygen-containing moities, hydroxyl (-OH) or ketone (C=O), such as zeaxanthin and canthaxanthin. Indeed, astaxanthin is a metabolite of zeaxanthin and/or canthaxanthin, containing both hydroxyl and ketone functional groups.
Like many carotenoids, astaxanthin is a colorful, lipid-soluble pigment. This colour is due to the extended chain of conjugated (alternating double and single) double bonds at the centre of the compound. This chain of conjugated double bonds is also responsible for the antioxidant function of astaxanthin (as well as other carotenoids) as it results in a region of decentralized electrons that can be donated to reduce a reactive oxidizing molecule.
Astaxanthin is found in microalgae, yeast, salmon, trout, krill, shrimp, crayfish, crustaceans, and the feathers of some birds. It provides the red color of salmon meat and the red color of cooked shellfish. Professor Basil Weedon's group was the first to prove the structure of astaxanthin by synthesis, in 1975.[6]
Astaxanthin, unlike several carotenes and one other known carotenoid, is not converted to vitamin A (retinol) in the human body. Like other carotenoids, astaxanthin has self-limited absorption orally and such low toxicity by mouth that no toxic syndrome is known. It is an antioxidant with a slightly lower antioxidant activity in some model systems than other carotenoids. However, in living organisms the free-radical terminating effectiveness of each carotenoid is heavily modified by its lipid solubility, and thus varies with the type of system being protected.[7]
While astaxanthin is a natural dietary component, it can also be used as a food supplement. The supplement is intended for human, animal, and aquaculture consumption. The industrial production of astaxanthin comes from both natural and synthetic sources.
The U.S. Food and Drug Administration (FDA) has approved astaxanthin as a food coloring (or color additive) for specific uses in animal and fish foods.[8] The European Commission considers it food dye and it is given the E number E161j.[9] Natural astaxanthin is generally recognized as safe (GRAS) by the FDA, meaning it can be sold as a dietary supplement,[10][11] but as a food coloring in the United States it is restricted to use in animal food.[12]

Natural sources[edit]

The shell and smaller parts of the bodily tissue of Pandalus borealis(Arctic shrimp) is colored by astaxanthin, and is used commercially as an astaxanthin source.
File:Three-Dimensional-Ultrastructural-Study-of-Oil-and-Astaxanthin-Accumulation-during-Encystment-in-pone.0053618.s002.ogv
A Haematococcus pluvialis cyst filled with astaxanthin (red).
Krill is also used as an astaxanthin source
Astaxanthin is present in most red-coloured aquatic organisms. The content varies from species to species, but also from individual to individual as it is highly dependent on diet and living conditions. Astaxanthin, and other chemically related asta-carotenoids, has also been found in a number of lichen species of the arctic zone.
The primary natural sources for commercial production of astaxanthin comprise the following:
Astaxanthin concentrations in natural sources as found in nature are approximately:
SourceAstaxanthin concentration (ppm)
Salmonids~ 5
Plankton~ 60
Krill~ 120
Arctic shrimp (P borealis)~ 1,200
Phaffia yeast~ 10,000
Haematococcus pluvialis~ 40,000
Algae are the primary natural source of astaxanthin in the aquatic food chain. Currently, the primary industrial source for natural astaxanthin is the microalgae Haematococcus pluvialis. Haematococcus pluvialis seems to accumulate the highest levels of astaxanthin in nature. Commercially, more than 40 g of astaxanthin can be obtained from one kg of dry biomass.[13]Haematococcus pluvialis has the advantage of the population doubling every week, which means scaling up is not an issue. However, it does require some expertise to grow the algae with a high astaxanthin content. Specifically, the microalgae are grown in two phases. First, in the green phase, the cells are given an abundance of nutrients to promote proliferation of the cells. In the subsequent red phase, the cells are deprived of nutrients and subjected to intense sunlight to induce encystment (carotogenesis), during which the cells produce high levels of astaxanthin as a protective mechanism against the environmental stress. The cells, with their high concentrations of astaxanthin, are then harvested.[14]
Phaffia yeast Xanthophyllomyces dendrorhous exhibits 100% free, non-esterified astaxanthin, which is considered advantageous because it is readily absorbable and need not be hydrolysed in the digestive tract of the fish. In contrast to synthetic and bacteria sources of astaxanthin, yeast sources of astaxanthin consist mainly of the (3R, 3’R)-form, an important astaxanthin source in nature. Finally, the geometrical isomer, all-E, is higher in yeast sources of astaxanthin, as compared to synthetic sources. This contributes to greater efficacy because the all-E (trans) isomer has greater bio-availability than the cisisomer.[15]
In shellfish, astaxanthin is almost exclusively concentrated in the shells, with only low amounts in the flesh itself, and most of it only becomes visible during cooking, as the pigment separates from the denatured proteins that otherwise binds it. Astaxanthin is extracted from Euphausia superba (Antarctic krill)[16] and from shrimp processing waste. 12,000 pounds of wet shrimp shells can yield a 6–8 gallon astaxanthin/triglyceride oil mixture.[17]

Synthetic sources[edit]

Nearly all commercial astaxanthin for aquaculture is produced synthetically, with an annual turnover of over $200 million and a selling price of roughly $5000–6000 per kilo as of July 2012.[13] However, synthetic production of astaxanthin is not preferred in some cases because synthetic astaxanthin contains a mixture of stereoisomers. Astaxanthin is fairly abundant and obtainable from natural sources, and some consumers prefer natural products over synthetic ones.[14]
An efficient synthesis from isophorone, cis-3-methyl-2-penten-4-yn-1-ol and a symmetrical C10-dialdehyde has been discovered and is used commercially. It combines these chemicals together with an ethynylation and then a Wittig reaction.[18] Two equivalents of the proper ylide combined with the proper dialdehyde in a solvent of methanol, ethanol, or a mixture of the two, yields astaxanthin in up to 88% yields.[19]
Synthesis of astaxanthin by Wittig reaction

Metabolic engineering[edit]

The cost of astaxanthin production, high commercial price and lack of a leading fermentation production systems, combined with the shortfalls of chemical synthesis mean that research into alternative fermentation production methods has been carried out. Metabolic engineering offers the opportunity to create biological systems for the production of a specific target compound. The metabolic engineering of bacteria (Escherichia coli) recently allowed production of astaxanthin at >90% of the total carotenoids, providing the first engineered production system capable of efficient astaxanthin production.[20] Astaxanthin biosynthesis proceeds from beta-carotene via either zeaxanthin or canthaxanthin. Historically, it has been assumed that astaxanthin biosynthesis proceeds along both routes. However, recent work has suggested that efficient biosynthesis may, in fact, proceed from beta-carotene to astaxanthin via zeaxanthin.[21][22] The production of astaxanthin by metabolic engineering, in isolation, will not provide a suitable alternative to current commercial methods. Rather, a bioprocess approach should be adopted. Such an approach would consider fermentation conditions and economics, as well as downstream processing (extraction). Carotenoid extraction has been studied extensively, for example, the extraction of canthaxanthin (a precursor to astaxanthin) was studied within an E. coli production process demonstrating that extraction efficiency was increased substantially when two solvents, acetone and methanol, were used sequentially rather than as a combined solution.[23]

Difference between natural and synthetic forms[edit]

Astaxanthin has two chiral centers, at the 3- and 3′-positions. Therefore, there are three stereoisomers; (3R,3′R), (3R,3′S) (meso), and (3S,3′S). Synthetic astaxanthin contains a mixture of the three, in approximately 1:2:1 proportions. Naturally occurring astaxanthin varies considerably from one organism to another. The astaxanthin in fish is of whatever stereoisomer the fish ingested.[24] The astaxanthin produced by Haematococcus pluvialis, which is commonly used in the feed of animals that are in turn consumed by humans, is the (3S,3′S) stereoisomer.[14]

Uses[edit]

Astaxanthin is used as a feed supplement for salmon, crabs, shrimp, chickens and egg production.[25]

For seafood and animals[edit]

The primary use of synthetic astaxanthin today is as an animal feed additive to impart coloration, including farm-raised salmon and egg yolks.[13] Synthetic carotenoid pigments colored yellow, red or orange represent about 15–25% of the cost of production of commercial salmon feed.[26] Today, almost all commercial astaxanthin for aquaculture is produced synthetically from petrochemical sources.[27]
Class action lawsuits were filed against some major grocery store chains for not clearly labeling the salmon "color added".[28] The chains followed up quickly by labeling all such salmon as "color added". Law firm Smith & Lowney persisted with the suit for damages, but a Seattle judge dismissed the case, ruling that enforcement of the applicable food laws was up to government and not individuals.[29]

For humans[edit]

The primary use for humans is as a dietary supplement. Research suggests that, due to astaxanthin's antioxidant activity, it may be beneficial in vision and skin health, and in cardiovascular, immune, inflammatory and neurodegenerative diseases.[30][31] Some research supports the assumption that it may protect body tissues from oxidative and ultraviolet damage through its suppression of NF-κB activation.[32][33]
A 2015 meta-analysis of data from ten randomized, controlled trial groups in seven published clinical trials, doses ranging 4 to 20 mg/day, did not indicate a significant effect of supplementation with astaxanthin on plasma lipids profile or fasting glucose.[34]

Role in the food chain[edit]

It has been speculated that gulls are "flushed" pink when molting, especially in areas with farm-raised salmon.[35]
Lobsters, shrimp, and some crabs turn red when cooked because the astaxanthin, which was bound to the protein in the shell, becomes free as the protein denatures and unwinds. The freed pigment is thus available to absorb light and produce the red color.[36]

Regulations[edit]

In April 2009, the United States Food and Drug Administration approved astaxanthin as an additive for fish feed only as a component of a stabilized color additive mixture. Color additive mixtures for fish feed made with astaxanthin may contain only those diluents that are suitable.[8] The color additives astaxanthin, ultramarine blue, canthaxanthin, synthetic iron oxide, dried algae meal, Tagetes meal and extract, and corn endosperm oil are approved for specific uses in animal foods.[37]Haematococcus algae meal (21 CFR 73.185) and Phaffia yeast (21 CFR 73.355) for use in fish feed to color salmonoids were added in 2000.[38][39][40] In the European Union, astaxanthin-containing food supplements derived from sources that have no history of use as a source of food in Europe, fall under the remit of the Novel Food legislation, EC (No.) 258/97. Since 1997, there have been five novel food applications concerning products that contain astaxanthin extracted from these novel sources. In each case, these applications have been simplified or substantial equivalence applications, because astaxanthin is recognised as a food component in the EU diet.[41][42][43][44]
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