UTP. UDP, UMP purinergisessä signaloinnissakin? Laktoosin synteesissä , galaktoosin aineenvaihdunnassa ym

UTP, UDP  sokeriaineenvaihdunnan puolella: Laktoosisynteesistä kaava: 

 https://link.springer.com/article/10.1007/s10911-021-09490-7

 

 Eri nukleotidien aineenvaihdunnalliset aitiot.  

Yksi HAKU:    Purinergic signalling?  by UTP, UDP ,UMP

5 results

1

Ectonucleotidases in Inflammation, Immunity, and Cancer.

Haas CB, Lovászi M, Braganhol E, Pacher P, Haskó G. J Immunol. 2021 May 1;206(9):1983-1990. doi: 10.4049/jimmunol.2001342. PMID: 33879578 Free PMC article. Review.

Abstract

Nucleoside triphosphate diphosphohydrolases (NTPDases) are a family of enzymes that hydrolyze nucleotides such as ATP, UTP, ADP, and UDP to monophosphates derivates such as AMP and UMP. The NTPDase family consists of eight enzymes, of which NTPDases 1, 2, 3, and 8 are expressed on cell membranes thereby hydrolyzing extracellular nucleotides. 

Cell membrane NTPDases are expressed in all tissues, in which they regulate essential physiological tissue functions such as development, blood flow, hormone secretion, and neurotransmitter release. They do so by modulating nucleotide-mediated purinergic signaling through P2 purinergic receptors. NTPDases 1, 2, 3, and 8 also play a key role during infection, inflammation, injury, and cancer. Under these conditions, NTPDases can contribute and control the pathophysiology of infectious, inflammatory diseases and cancer. 

In this review, we discuss the role of NTPDases, focusing on the less understood NTPDases 2-8, in regulating inflammation and immunity during infectious, inflammatory diseases, and cancer.

Copyright © 2021 by The American Association of Immunologists, Inc.

2

Coupling of airway ciliary activity and mucin secretion to mechanical stresses by purinergic signaling.

Davis CW, Lazarowski E. Respir Physiol Neurobiol. 2008 Nov 30;163(1-3):208-13. doi: 10.1016/j.resp.2008.05.015. Epub 2008 May 28. PMID: 18635403 Free PMC article. Review.

At rest, ATP is released onto airway surfaces at approximately 370fmol/mincm2, but only approximately 3% of released ATP is recovered in ASL. Secreted UTP meets with a similar fate. A wide variety of hydrolytic and transphosphorylating ecto-enzymes convert the triphosphate … 

 

3

Human Keratinocytes Respond to Extracellular UTP by Induction of Hyaluronan Synthase 2 Expression and Increased Hyaluronan Synthesis.

Jokela T, Kärnä R, Rauhala L, Bart G, Pasonen-Seppänen S, Oikari S, Tammi MI, Tammi RH. J Biol Chem. 2017 Mar 24;292(12):4861-4872. doi: 10.1074/jbc.M116.760322. Epub 2017 Feb 10. PMID: 28188289 Free PMC article.

The release of nucleotides into extracellular space is triggered by insults like wounding and ultraviolet radiation, resulting in stimulatory or inhibitory signals via plasma membrane nucleotide receptors. As similar insults are known to activate hyaluronan synthesis we ex …

 

4

ATP- and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells.

Schafer R, Sedehizade F, Welte T, Reiser G. Am J Physiol Lung Cell Mol Physiol. 2003 Aug;285(2):L376-85. doi: 10.1152/ajplung.00447.2002. Epub 2003 Apr 4. PMID: 12691958 Free article.

The nucleotide efficacy profile [ATP = ADP > UDP >or= UTP > adenosine >or= 2-methylthioadenosine-5'-diphosphate, with alpha,beta-methylene adenosine 5'-triphosphate, 2',3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate, AMP, UMP, and ATPalphaS inac … 

 

5

Adenine nucleotides inhibit proliferation of the human lung adenocarcinoma cell line LXF-289 by activation of nuclear factor kappaB1 and mitogen-activated protein kinase pathways.

Schäfer R, Hartig R, Sedehizade F, Welte T, Reiser G. FEBS J. 2006 Aug;273(16):3756-67. doi: 10.1111/j.1742-4658.2006.05384.x. PMID: 16911524 Free article.

ATP and ADP strongly inhibited LXF-289 cell proliferation. The nucleotide potency profile was ATP = ADP = ATPgammaS > > UTP, UDP, whereas alpha,beta-methylene-ATP, beta,gamma-methylene-ATP, 2',3'-O-(4-benzoylbenzoyl)-ATP, AMP and UMP were inactive. ...I …

Toinen HAKU:  UTP  sokeriaineenvaihdunnan  aitiossa

31 results

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1

Liver-specific increase of UTP and UDP-sugar concentrations in rats induced by dietary vitamin B6-deficiency and its relation to complex N-glycan structures of liver membrane-proteins.

Renner AB, Rieger K, Grunow D, Zimmermann-Kordmann M, Gohlke M, Reutter W. Glycoconj J. 2007 Dec;24(9):531-41. doi: 10.1007/s10719-007-9048-x. Epub 2007 Jun 19. PMID: 17577663

In contrast to liver, the heart muscle uracil nucleotide concentrations were decreased by 40%. In kidney, the sum of UTP, UDP and UMP showed a decrease of 40%, whereas UDP-sugars were increased 1.4-fold. ...Despite the 4 to 6-fold increase of UTP …

Tools and drugs for uracil nucleotide-activated P2Y receptors.

Rafehi M, Müller CE. Pharmacol Ther. 2018 Oct;190:24-80. doi: 10.1016/j.pharmthera.2018.04.002. Epub 2018 Apr 13. PMID: 29660366 Review.

 P2Y receptors (P2YRs) are a family of G protein-coupled receptors activated by extracellular nucleotides. Physiological P2YR agonists include purine and pyrimidine nucleoside di- and triphosphates, such as ATP, ADP, UTP, UDP, nucleotide sugars, and dinucleotides. Eight subtypes exist, P2Y₁, P2Y₂, P2Y₄, P2Y₆, P2Y₁₁, P2Y₁₂, P2Y₁₃, and P2Y₁₄, which represent current or potential future drug targets.

 Here we provide a comprehensive overview of ligands for the subgroup of the P2YR family that is activated by uracil nucleotides: P2Y₂ (UTP, also ATP and dinucleotides), P2Y₄ (UTP), P2Y₆ (UDP), and P2Y₁₄ (UDP, UDP-glucose, UDP-galactose). The physiological agonists are metabolically unstable due to their fast hydrolysis by ectonucleotidases. A number of agonists with increased potency, subtype-selectivity and/or enzymatic stability have been developed in recent years. Useful P2Y₂R agonists include MRS2698 (6-01, highly selective) and PSB-1114 (6-05, increased metabolic stability). A potent and selective P2Y₂R antagonist is AR-C118925 (10-01). For studies of the P2Y₄R, MRS4062 (3-15) may be used as a selective agonist, while PSB-16133 (10-06) is a selective antagonist. Several potent P2Y₆R agonists have been developed including 5-methoxyuridine 5'-O-((R_p)α-boranodiphosphate) (6-12), PSB-0474 (3-11), and MRS2693 (3-26). The isocyanate MRS2578 (10-08) is used as a selective P2Y₆R antagonist, although its reactivity and low water-solubility are limiting. With MRS2905 (6-08), a potent and metabolically stable P2Y₁₄R agonist is available, while PPTN (10-14) represents a potent and selective P2Y₁₄R antagonist. The radioligand [³H]UDP can be used to label P2Y₁₄Rs. In addition, several fluorescent probes have been developed. Uracil nucleotide-activated P2YRs show great potential as drug targets, especially in inflammation, cancer, cardiovascular and neurodegenerative diseases.

4

Extracellular nucleotides and nucleosides as signalling molecules.

Giuliani AL, Sarti AC, Di Virgilio F. Immunol Lett. 2019 Jan;205:16-24. doi: 10.1016/j.imlet.2018.11.006. Epub 2018 Nov 12. PMID: 30439478 Review.

Extracellular nucleotides, mainly ATP, but also ADP, UTP, UDP and UDP-sugars, adenosine, and adenine base participate in the "purinergic signalling" pathway, an ubiquitous system of cell-to-cell communication. ...

5 (2022)

P2Y purinergic signaling in prostate cancer: Emerging insights into pathophysiology and therapy.

Khalafalla MG, Tran HN, Khalafalla FG. Biochim Biophys Acta Rev Cancer. 2022 May;1877(3):188732. doi: 10.1016/j.bbcan.2022.188732. Epub 2022 Apr 26. PMID: 35483490 Review.

Extracellular nucleotides play a central role in the growth and progression of a variety of cancer types - almost all tumor cells and immune cells express purinergic membrane receptors for extracellular nucleotides (ATP, ADP, UTP, UDP, UDP-sugar) and t …

6 (1997)

Potential signalling roles for UTP and UDP: sources, regulation and release of uracil nucleotides.

Anderson CM, Parkinson FE. Trends Pharmacol Sci. 1997 Oct;18(10):387-92. doi: 10.1016/s0165-6147(97)01106-1. PMID: 9357323 Review.

Cells can synthesize uracil nucleotides de novo or by salvage of uridine. UTP made from salvage might be preferentially used for RNA synthesis in the nucleus, while UTP synthesized de novo seems to be used for UDP-sugar and CDP-phospholipid production. …

7 (2017)

Extracellular purines, purinergic receptors and tumor growth.

Di Virgilio F, Adinolfi E. Oncogene. 2017 Jan 19;36(3):293-303. doi: 10.1038/onc.2016.206. Epub 2016 Jun 20. PMID: 27321181 Free PMC article. Review.

Virtually, all tumor cells as well as all immune cells express plasma membrane receptors for extracellular nucleosides (adenosine) and nucleotides (ATP, ADP, UTP, UDP and sugar UDP). The tumor microenvironment is characterized by an unusually high conc …

8(1990)

In vivo metabolism and UTP-depleting action of 2-deoxy-2-fluoro-D-galactose.

Grün BR, Berger U, Oberdorfer F, Hull WE, Ostertag H, Keppler D. Adv Enzyme Regul. 1990;30:231-42. doi: 10.1016/0065-2571(90)90020-3. PMID: 2403033

The noninvasive in vivo 19F-NMR technique is particularly advantageous, since it allows the simultaneous analysis of all dGalF metabolites. The diversion of uridylate, due to the accumulation of UDP-2-deoxy-2-fluoro-D-hexoses, was associated with a rapid depletion of hepat …

9(2006)

Preparation of UDP-galacturonic acid using UDP-sugar pyrophosphorylase.

Ohashi T, Cramer N, Ishimizu T, Hase S. Anal Biochem. 2006 May 15;352(2):182-7. doi: 10.1016/j.ab.2006.02.026. Epub 2006 Mar 15. PMID: 16581011

Here we show that UDP-sugar pyrophosphorylase from Pisum sativum with a broad specificity has UDP-GalUA pyrophosphorylase activity. ...The recombinant UDP-sugar pyrophosphorylase had optimal pH of 6.0, and the apparent K(m) values for GalUA 1-ph …

10(1987)

Hepatic UDP-glucose and UDP-glucuronic acid synthesis rates in rats during a reduced energy state.

Dills RL, Howell SR, Klaassen CD. Drug Metab Dispos. 1987 May-Jun;15(3):281-8. PMID: 2886300

Hepatic synthesis rates of UDP-glucose and UDP-glucuronic acid were determined in rats. Two high pressure liquid chromatographic methods were developed to quantitate and isolate UTP, UDP-glucose, and UDP-glucuronic acid from perchloric acid extr … 

 

 https://pubmed.ncbi.nlm.nih.gov/14190461/

 

 https://pubmed.ncbi.nlm.nih.gov/29660366/

 

Purinergisistä reseptoreista

https://journals.lww.com/nrronline/Fulltext/2023/08000/The_role_of_purinergic_receptors_in_neural_repair.9.aspx

Classification, Distribution, and Primary Roles of Purinergic Receptors in the Central Nervous System

Purinergic receptors are expressed on the cell surface and bind to and react with purines (Burnstock, 2018). Purinergic receptors fall into two major families: P1 and P2 receptors. These receptors can be activated by purines, which can also act as neurotransmitters when they bind to purinergic receptors to transmit information (Burnstock, 2008; Burnstock et al., 2012).

At present, there are several subtypes of P1 receptors: A1, A2a, A2b, and A3. These four subtypes are all G protein coupled receptors. Adenosine and AMP can activate P1 receptors (Sawynok, 2007; Ciruela, 2011). P2 receptors are divided into P2X and P2Y receptors. Seven subtypes of P2X receptors (P2X1–7) and nine subtypes of P2Y receptors (P2Y1, 2, 4, 6, 11, 12, 13, 14, and P2Y15) have been identified thus far (Abbracchio and Burnstock, 1994). ATP and ADP can both act on P2 receptors (Müller et al., 2020).

Many studies have focused on the regulatory roles of purinergic signalling in the CNS (Burnstock, 2017; Rodrigues et al., 2019). Purinergic receptor subtypes are widely distributed in the CNS and act by regulating the release of ATP and adenosine during synaptic transmission (Abbracchio et al., 2009). In the CNS, multiple purinergic receptors are expressed in glial cells, including astrocytes, microglia and oligodendrocytes. The A1 and A3 receptors inhibit promote the production of cAMP through G protein coupling while A2a and A2b receptors inhibit this process (Sciaraffia et al., 2014; Wang and Zhou, 2019).

A1 receptors can inhibit the release of glutamate, an excitatory neurotransmitter. Following CNS injury, excitatory amino acids activate N-methyl-D-aspartic acid receptors in the postsynaptic membrane, thus resulting in the release of a large amount of adenosine (Lu et al., 2003). This adenosine binds to A1 receptors in the presynaptic membrane to inhibit associated calcium channels, thus reducing the generation and release of glutamate and reducing the excitability of nerve cells to exert a protective effect (Lu and Rosenberg, 2007). In the macaque middle cerebral artery embolization model, AST-004 treatment was shown to significantly slow the growth of ischemic lesions and reduce infarct volumes; AST-004 is a novel agonist for adenosine A1 and A3 receptors. These findings suggested that the activation of adenosine A1 and A3 receptors can exert neuroprotective effects (Liston et al., 2022). A1 receptors can also reduce the accumulation of Ca²⁺ and mitochondrial Ca²⁺ overload after CNS injury to alleviate neural injury (Kashfi et al., 2017). As an important component of the P1 signalling pathway, A2 receptors are involved in regulating the pathological and physiological processes involved in CNS diseases and injuries, but with effects opposite to those of A1 receptors. The activation of A2 receptors aggravates Ca²⁺ accumulation after neural injury (Dai and Zhou, 2011).

Adenosine exerts multiple functions in the CNS, including regulating the functions of neurons and glial cells and glial signalling, and affecting neurodevelopment (McGaraughty et al., 2001). Abnormalities of adenosine and P1 receptors are involved in the changes associated with various neurodegenerative diseases such as Parkinson’s disease, Huntington’s disease and Alzheimer’s disease (Burnstock, 2008).

The P2X receptor is an ion channel receptor that binds ATP and then affects Na⁺, K⁺, and Ca²⁺ channels in the absence of a cell membrane and intracellular signal transduction (Burnstock, 2016). P2X1–7 receptors are widely expressed in astrocytes and neurons. Some of these are also expressed in oligodendrocytes, Schwann cells, and microglia. P2X receptors participate in different physiological processes in the CNS, including synaptic transmission and signal transduction between gliocytes and neurons (Lambrecht, 2000; Fu et al., 2009). Multiple subtypes of P2X receptors are expressed in CNS neurons. Of these, the P2X3 receptor is expressed in sensory neurons in the dorsal horn of the spinal cord and dorsal root ganglia (de Melo Aquino et al., 2019; Marucci et al., 2019). P2X2 and P2X4 receptors are widely expressed in the spinal cord, hippocampus, cerebral cortex and cerebellum (Khaira et al., 2009; Sivcev et al., 2020). P2X7 receptors are also expressed in axonal growth cones and presynaptic terminals. These receptors affect neuronal activity and mediate microglial and neuron-glial interactions in the pathophysiological processes involved in CNS diseases (Volonté et al., 2012; Kan et al., 2019; Miras-Portugal et al., 2021).

P2Y receptors are widely distributed in the nervous system. After being activated by extracellular purines and pyrimidine nucleotides, the P2Y receptors activate intracellular signalling pathways by coupling with G proteins (Rafehi and Müller, 2018; von Kügelgen, 2021). P2Y1, P2Y2 and P2Y12 receptors are expressed in the spinal cord, hippocampus and cerebral cortex (Puchałowicz et al., 2014; Grohmann et al., 2021). P2Y1, 2, 4, and P2Y6 receptors are expressed in the spinal cord, trigeminal ganglia and dorsal root ganglia (D’Ambrosi et al., 2006; Wen et al., 2020). P2Y2 and P2Y14 receptors are also expressed in astrocytes in the CNS (Martiáñez et al., 2012). P2Y receptors are involved in a wide range of regulatory functions, including neural signalling, glial proliferation and migration, cell differentiation, ion transport, nerve cell regeneration and nerve cell apoptosis. Extracellular ATP, released at high concentrations from intracellular stores after injury, acts on the P2Y receptors expressed in astrocytes to activate the P2Y signalling pathways which then stimulate the proliferation of astrocytes and aggravate tissue damage.

Moreover, ATP can also mediate programmed death of nerve cells through P2Y receptors. A previous study of brain injury observed an upregulation in the expression of P2Y receptors and that these high expression levels were related to the activation of glial cells in different ways. Cultured rat cortical astrocytes exhibited significant increases in the synthesis of glial fibrillary acidic protein after the administration of exogenous ATP; this might be related to the effect of ATP on P2Y receptors (Ceruti et al., 2009).

P2Y4 and P2Y12 receptors can inhibit K⁺ and Ca²⁺ channels to inhibit action potentials and affect neurotransmitter release. In the spinal cord, ATP can induce superoxide production through P2Y1 receptors (Xia and Zhu, 2014). Under pathological conditions, such as CNS injury, the expression of P2Y6 receptors on the microglia is upregulated, thus promoting the extension of microglial protrusions, enhancing phagocytosis, and inducing the production of chemokines that participate in the process of neural injury and repair (Quintas et al., 2014). The P2Y13 receptors expressed in the dorsal horn of the spinal cord and hippocampus are known to be involved in neurodevelopment and axonal growth (Guarracino et al., 2016), while P2Y1 and P2Y7 receptors act synergistically to promote the growth and extension of axons. In CNS injury, on one hand, the expression of the P2Y2 receptor increases; on the other hand, such injury leads to the massive release of extracellular ATP, which acts on P2Y2 receptors and increases intracellular Ca²⁺ concentration, thereby promoting the release of neurotransmitters and altering synaptic transmission efficiency. In addition, P2Y2 receptors may play a key role in both nerve and glial cells (Arthur et al., 2006).

Cited by

• The role of purinergic receptors in neural repair and regeneration after spinal cord injury.

  Cheng RD, Ren W, Luo BY, Ye XM. Neural Regen Res. 2023 Aug;18(8):1684-1690. doi: 10.4103/1673-5374.363186. PMID: 36751780 Free PMC article. Review.
• Therapeutic potential for P2Y₂ receptor antagonism.

  Jasmer KJ, Muñoz Forti K, Woods LT, Cha S, Weisman GA. Purinergic Signal. 2023 Jun;19(2):401-420. doi: 10.1007/s11302-022-09900-3. Epub 2022 Oct 11. PMID: 36219327 Free PMC article. Review.
• Characterisation of P2Y receptor subtypes mediating vasodilation and vasoconstriction of rat pulmonary artery using selective antagonists.

  Dales MO, Mitchell C, Gurney AM, Drummond RM, Kennedy C. Purinergic Signal. 2022 Dec;18(4):515-528. doi: 10.1007/s11302-022-09895-x. Epub 2022 Aug 26. PMID: 36018534 Free PMC article.
• Immunomodulation by foods and microbes: Unravelling the molecular tango.

  Forde B, Yao L, Shaha R, Murphy S, Lunjani N, O'Mahony L. Allergy. 2022 Dec;77(12):3513-3526. doi: 10.1111/all.15455. Epub 2022 Aug 3. PMID: 35892227 Free PMC article. Review.
• ATP, an attractive target for the treatment of refractory chronic cough.

  Zhang M, Sykes DL, Sadofsky LR, Morice AH. Purinergic Signal. 2022 Sep;18(3):289-305. doi: 10.1007/s11302-022-09877-z. Epub 2022 Jun 21. PMID: 35727480 Free PMC article. Review.

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Artikkeleita, jotka käsittelevt tästägeenistä vain "asprosiinin" osuutta glukoosiaineenvaihdunnan puolelta

 https://pubmed.ncbi.nlm.nih.gov/36686442/

ASPROSIINI (asprosin) glukoosihomeostaasiin vaikuttava tekijä ( FBN1 gene 15q21.1)

 https://w

Aliases for FBN1 Gene (15q21.1)

• GeneCards Symbol: FBN1 ²
• Fibrillin 1 ^{2 3 5}
• MASS ^{2 3 5}
• OCTD ^{2 3 5}
• SGS ^{2 3 5}
• FBN ^{3 4 5}
• Fibrillin-1 ^{3 4}
• Asprosin ^{2 3}
• MFS1 ^{3 5}
• WMS ^{3 5}
• Epididymis Secretory Sperm Binding Protein ³

• Fibrillin 1 (Marfan Syndrome) ²
• Fibrillin-1 Preproprotein ³
• Marfan Syndrome ²
• Fibrillin 15 ³
• GPHYSD2 ³
• ACMICD ³
• ECTOL1 ³
• MFLS ³
• SSKS ³
• WMS2 ³

External Ids for FBN1 Gene

ww.genecards.org/cgi-bin/carddisp.pl?gene=FBN1&keywords=fibrillin,1

Summaries for FBN1 Gene

NCBI Gene Summary for FBN1 Gene

• This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

GeneCards Summary for FBN1 Gene

FBN1 (Fibrillin 1) is a Protein Coding gene. Diseases associated with FBN1 include Marfan Syndrome and Stiff Skin Syndrome. Among its related pathways are Integrin Pathway and ERK Signaling. Gene Ontology (GO) annotations related to this gene include calcium ion binding and extracellular matrix structural constituent. An important paralog of this gene is FBN2.

UniProtKB/Swiss-Prot Summary for FBN1 Gene

[Fibrillin-1]: Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues (PubMed:1860873, 15062093). Fibrillin-1-containing microfibrils provide long-term force bearing structural support (PubMed:27026396). In tissues such as the lung, blood vessels and skin, microfibrils form the periphery of the elastic fiber, acting as a scaffold for the deposition of elastin (PubMed:27026396). In addition, microfibrils can occur as elastin-independent networks in tissues such as the ciliary zonule, tendon, cornea and glomerulus where they provide tensile strength and have anchoring roles (PubMed:27026396). Fibrillin-1 also plays a key role in tissue homeostasis through specific interactions with growth factors, such as the bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and latent transforming growth factor-beta-binding proteins (LTBPs), cell-surface integrins and other extracellular matrix protein and proteoglycan components (PubMed:27026396). Regulates osteoblast maturation by controlling TGF-beta bioavailability and calibrating TGF-beta and BMP levels, respectively (By similarity). Negatively regulates osteoclastogenesis by binding and sequestering an osteoclast differentiation and activation factor TNFSF11 (PubMed:24039232). This leads to disruption of TNFSF11-induced Ca(2+) signaling and impairment of TNFSF11-mediated nuclear translocation and activation of transcription factor NFATC1 which regulates genes important for osteoclast differentiation and function (PubMed:24039232). Mediates cell adhesion via its binding to cell surface receptors integrins ITGAV:ITGB3 and ITGA5:ITGB1 (PubMed:12807887, 17158881). Binds heparin and this interaction has an important role in the assembly of microfibrils (PubMed:11461921). ( FBN1_HUMAN,P35555 )

[Asprosin]: Adipokine secreted by white adipose tissue that plays an important regulatory role in the glucose metabolism of liver, muscle and pancreas (PubMed:27087445, 30853600). Hormone that targets the liver in response to fasting to increase plasma glucose levels (PubMed:27087445). Binds the olfactory receptor OR4M1 at the surface of hepatocytes and promotes hepatocyte glucose release by activating the protein kinase A activity in the liver, resulting in rapid glucose release into the circulation (PubMed:27087445, 31230984). May act as a regulator of adaptive thermogenesis by inhibiting browning and energy consumption, while increasing lipid deposition in white adipose tissue (By similarity). Also acts as an orexigenic hormone that increases appetite: crosses the blood brain barrier and exerts effects on the hypothalamus (By similarity). In the arcuate nucleus of the hypothalamus, asprosin directly activates orexigenic AgRP neurons and indirectly inhibits anorexigenic POMC neurons, resulting in appetite stimulation (By similarity). Activates orexigenic AgRP neurons via binding to the olfactory receptor OR4M1 (By similarity). May also play a role in sperm motility in testis via interaction with OR4M1 receptor (By similarity). ( FBN1_HUMAN,P35555 )

Gene Wiki entry for FBN1 Gen

Protein attributes for FBN1 Gene

Size:

2871 amino acids

Molecular mass:

312298 Da

Protein existence level:

PE1

Quaternary structure:

• [Fibrillin-1]: Interacts with COL16A1 (PubMed:15165854).
  Interacts with integrin alpha-V/beta-3 (PubMed:15062093).
  Interacts with ADAMTS10; this interaction promotes microfibril assembly (PubMed:21402694).
  Interacts with THSD4; this interaction promotes fibril formation (By similarity).
  Interacts (via N-terminal domain) with FBLN2 and FBLN5 (PubMed:15790312, 17255108).
  Interacts with ELN (PubMed:15790312).
  Forms a ternary complex with ELN and FBLN2 or FBLN5 and a significant interaction with ELN seen only in the presence of FBLN2 or FBLN5 (PubMed:17255108).
  Interacts (via N-terminal domain) with LTBP2 (via C-terminal domain) in a Ca(+2)-dependent manner (PubMed:17293099).
  Interacts (via N-terminal domain) with LTBP1 (via C-terminal domain) (PubMed:17293099).
  Interacts with integrins ITGA5:ITGB1, ITGAV:ITGB3 and ITGAV:ITGB6 (PubMed:17158881, 12807887).
  Interacts (via N-terminal domain) with BMP2, BMP4, BMP7, BMP10 and GDF5 (PubMed:18339631).
  Interacts (via N-terminal domain) with MFAP2 and MFAP5 (PubMed:15131124).
  Interacts with ADAMTSL5 (PubMed:23010571).
  Interacts with MFAP4 (PubMed:26601954).
  Interacts (via N-terminal domain) with TNFSF11 in a Ca(+2)-dependent manner (PubMed:24039232).
  Interacts (via N-terminal domain) with EFEMP2; this interaction inhibits EFEMP2 binding to LOX and ELN (PubMed:17255108, 19349279, 19570982).

Sequence caution:

• The sequence CAA45118.1 differs from that shown. Reason: Erroneous initiation Extended N-terminus. {ECO:0000305}

Miscellaneous:

• [Asprosin]: Was named after the Greek word for white, because of the reduction in subcutaneous white adipose tissue that is displayed by asprosin-deficient patients.

 ASPROSIININ LIIKAERITYKSESTÄ on artikkeleita:

https://en.wikipedia.org/wiki/Asprosin

 

(ASPROSIININ  funktiomekanismi  kekushermoston puolella on kuvattu myös: kosotaan huolimatta  sitä menee harvinaisen paljon veriaivoesteen läpi aivojen puolelle ja se säätelee  ravinnonottoaja täten  ravintoaineiden saantia ja sokeritasapainoa. mainitaan tie, mitä kautta se vaikuttaa: Se sitoutuu proteiinityrosiinifosfataasireseptori deltaan PTPRD.  Jos tuota reseptoria puuttuu seuraa  äärimmäminen rakenteellsiten kudosten vaje  (laihuus) ja ruokahalun kato, siis proteiinernergiavaje, malnutritio ja anorektinen tila. Tätä on tutkittu koe-eläimissä . Luulisi että tämäkin puoli asprosiinin metaboliasa olisi lääkekellisesti autettavissa. Varsinainen asprosiinin geneettinen  vaje tai  vähäisyys  antaa vaikutuksesna  riippuen myös tuosta PTPRD- reseptorin  tilasta. 

STRING kartta. osoittaa asian laajuuden. https://string-db.org/cgi/network?taskId=b7pCY90Jm51Z&sessionId=bMvOhMepV0Lw

 

Asprosin can also exit the bloodstream and cross the blood–brain barrier to function in the brain. The first indication that asprosin was in fact a cerebrospinal fluid (CSF) protein, in addition to being a plasma protein, was the observation of asprosin in the CSF of rats at concentrations 5- to 10-fold lower than in the plasma. Additionally, intravenously introduced asprosin showed a dramatic ability to cross the blood–brain barrier and enter the CSF.^[2]

A central mechanism of appetite regulation is via orexigenic AgRP neurons and anorexigenic POMC neurons in the arcuate nucleus of the hypothalamus. Asprosin directly activates orexigenic AgRP neurons and, using the neurotransmitter GABA, indirectly inhibits anorexigenic POMC neurons.^[2]

Asprosin’s orexigenic effects are mediated through binding to protein tyrosine phosphatase receptor delta (PTPRD).^[16] Genetic ablation of PTPRD results in extreme leanness and loss of appetite. More specifically, resistance to diet-induced obesity can occur through the loss of PTPRD in AgRP neurons.  When asprosin binds to PTPRD, this leads to the de-phosphorylation and de-activation of Stat3. PTPRD is highly expressed throughout the entire brain, especially in the cerebellum and cerebellar hemisphere. PTPRD is also highly expressed in the coronary arteries, the aorta, and the ovaries.

who neuvoo välttämään keinotekoisia makeuttajia 1.5. 2023

 

WHO advises not to use non-sugar sweeteners for weight control in newly released guideline

15 May 2023

Departmental news

Reading time: 1 min (390 words)

The World Health Organization (WHO) has released a new guideline on non-sugar sweeteners (NSS), which recommends against the use of NSS to control body weight or reduce the risk of noncommunicable diseases (NCDs).

The recommendation is based on the findings of a systematic review of the available evidence which suggests that use of NSS does not confer any long-term benefit in reducing body fat in adults or children. Results of the review also suggest that there may be potential undesirable effects from long-term use of NSS, such as an increased risk of type 2 diabetes, cardiovascular diseases, and mortality in adults.

"Replacing free sugars with NSS does not help with weight control in the long term. People need to consider other ways to reduce free sugars intake, such as consuming food with naturally occurring sugars, like fruit, or unsweetened food and beverages,” says Francesco Branca, WHO Director for Nutrition and Food Safety. "NSS are not essential dietary factors and have no nutritional value. People should reduce the sweetness of the diet altogether, starting early in life, to improve their health."

The recommendation applies to all people except individuals with pre-existing diabetes and includes all synthetic and naturally occurring or modified non-nutritive sweeteners that are not classified as sugars found in manufactured foods and beverages, or sold on their own to be added to foods and beverages by consumers. Common NSS include acesulfame K, aspartame, advantame, cyclamates, neotame, saccharin, sucralose, stevia and stevia derivatives.

The recommendation does not apply to personal care and hygiene products containing NSS, such as toothpaste, skin cream, and medications, or to low-calorie sugars and sugar alcohols (polyols), which are sugars or sugar derivatives containing calories and are therefore not considered NSS.

Because the link observed in the evidence between NSS and disease outcomes might be confounded by baseline characteristics of study participants and complicated patterns of NSS use, the recommendation has been assessed as conditional, following WHO processes for developing guidelines. This signals that policy decisions based on this recommendation may require substantive discussion in specific country contexts, linked for example to the extent of consumption in different age groups.

The WHO guideline on NSS is part of a suite of existing and forthcoming guidelines on healthy diets that aim to establish lifelong healthy eating habits, improve dietary quality and decrease the risk of NCDs worldwide.

Beetasolu käyttää Eph/efriini-signalointia glukoosihomeostaasin ja insuliinierityksen hienosäädössä

 

Eph/ EFRIINI signalointi ja Haiman Beetasolu

9.3. 2023

EphA Forward signaling säätyy alas vasteena glukoosille ja viittaa siihen, että* basaaliolosuhteissa käyttävät beeta-solut EphA forward- signalointia vaimentaessaan insuliinin eritystä ja *stimulatorisessa olosuhteessa beetasolut tekevät vaihteen reversoivaan suuntaan efriini-A- signaloinnilla lisätäkseen insuliinin erittymistä.

EphA forward signaling is downregulated in response to glucose, which indicates that, under basal conditions, beta cells use EphA forward signaling to suppress insulin secretion

ja toistaalta and that, under stimulatory conditions, they shift to ephrin-A reverse signaling to enhance insulin secretion.20. Apr. 2007

Cell 2007 Apr 20;129(2):359-70.

doi: 10.1016/j.cell.2007.02.044. EphA-Ephrin-A-mediated beta cell communication regulates insulin secretion from pancreatic islets Irena Konstantinova  1 , Ganka Nikolova, Mica Ohara-Imaizumi, Paolo Meda, Tomás Kucera, Konstantinos Zarbalis, Wolfgang Wurst, Shinya Nagamatsu, Eckhard Lammert

• PMID: 17448994

• DOI: 10.1016/j.cell.2007.02.044 Abstract

Selkärankaisilla beetasolut ovat aggrekoituneet haimasaarekkeiksi. Niiden saarekkeiden sisällä beetasolujen välinen kommunikaatio pystyy estämään basaali-insuliinin erittymistä ( siis turhan runsaan insuliinin tuoton) ja toisaalta lisäämään glukoosin stimuloiman insuliinin erittymistä ja täten antamaan osansa sokerin tasapainoon eli homeostaasin sekä paaston että ravinnonoton aikana. Etsittäessä taustalla olevaa mekanismia on löydetty beetasolujen kommunikoiva kyky, missä se käyttää efriiniA ligandien ja EphA-reseptoreiden välillä tapahtuvaa kommunikaatiota.

In vertebrates, beta cells are aggregated in the form of pancreatic islets. Within these islets, communication between beta cells inhibits basal insulin secretion and enhances glucose-stimulated insulin secretion, thus contributing to glucose homeostasis during fasting and feeding. In the search for the underlying molecular mechanism, we have discovered that beta cells communicate via ephrin-As and EphAs.

Tutkijat ovat osoittaneet, että efriini-5A niminen proteiini vaaditaan glukoosin stimuloimaan insuliinineritykseen. (Tutkijat osoittavat erään reseptori tyrosiinikinaaseille (RTK) aivan ainutlaatuisen ominaisuuden: ne voivat signaloida kolmeen suntaan: eteenpäin, käänteissuuntaan sekä bidirektionaalisesti kahteen suuntaan. (Niin eivät tee muut reseptorityrosiinikinaasit, joihin ainutlaatuiset Eph reseptorit myös kuuluva. Edellä on mainittu eteenpäin suntautunut Eph forward signalointi, sekä reversoiva signalointi).

Nyt tutkijat löysivät bidirektionaalisesta signaloinnista näytön.

Eph reseptorin eteenpäin suuntautuva signalointi estää insuliinin erityksen, kun taas efriini-A ligandilla käänteinen signaloini stimuloi insuliinin sekreetion.

EphA reseptorin eteenpäin suuntautuva signaloini säätyy alas vasteena glukoosille, mikä viittaa siihen, että basaaliolosuhteissa beetasolut käyttävät EphA-reseptorin eteenpäin signalointia insuliinin erityksen vaimentamiseen ja että glukoosilla stimuloituneessa tilanteessa beetasolut tekevät vaihteen efriiniA:lla tapahtuvaan päinvastaiseen signalointiin lisätäkseen insuliinin eritykstä. Täten selittyy, miten betasolukommunikaatio pankreassaarekkeessa näillä päinvastaisuuksilla vaikuttaa basaaliin ja glukoosin stimuloimaan insuliinieritykseen kohentaen glukoosin homeostaasia.

We provide evidence that ephrin-A5 is required for glucose-stimulated insulin secretion. We further show that EphA-ephrin-A-mediated beta cell communication is bidirectional: EphA forward signaling inhibits insulin secretion, whereas ephrin-A reverse signaling stimulates insulin secretion. EphA forward signaling is downregulated in response to glucose, which indicates that, under basal conditions, beta cells use EphA forward signaling to suppress insulin secretion and that, under stimulatory conditions, they shift to ephrin-A reverse signaling to enhance insulin secretion. Thus, we explain how beta cell communication in pancreatic islets conversely affects basal and glucose-stimulated insulin secretion to improve glucose homeostasis.

Artikkeli, jossa lötyyy kuva:

Preview| Volume 129, ISSUE 2, P241-243, April 20, 2007

PDF [409 KB]

Figures

Ephs and Ephrins Keep Pancreatic β Cells Connected (2007)

• Rohit N. Kulkarni

• C. Ronald Kahn

Open ArchiveDOI:https://doi.org/10.1016/j.cell.2007.04.006

Glucose-stimulated insulin release typically occurs in two phases—a rapid first phase (2–3 min in the mouse and 10 min in humans) after glucose stimulation and a prolonged second phase that lasts up to 30 min. In contrast to many factors—such as the insulin receptor tyrosine kinase (RTK) —that regulates the first phase glucose-induced insulin release (

Kulkarni et al., 1999), Eph-ephrin signaling predominantly affects the second phase of insulin release. Another avenue to pursue is whether there might be interaction between these two RTK systems that both regulate β cell function and insulin secretion.

Although a part of the mystery underlying β cell-to-β cell communication has been unraveled, the relevance of these observations to disease needs clarification. Could abnormalities in the expression of Ephs and ephrins contribute to defects in altered insulin secretion or maintenance of β cell mass that are characteristic of type 2 diabetes or other insulin-resistant states? Are there polymorphisms in the genes that code for Ephs and ephrins that are associated with altered glucose homeostasis in humans? Further integrative studies should help define the functions of Ephs and ephrins and their role in diabetes and metabolic diseases.

Eph/Ephrin signaling disorders https://pubmed.ncbi.nlm.nih.gov/18394988/