Definition
Protein kinase B (PKB), also known as Akt (PKB/Akt), is a serine/threonine phosphoryl transferase and a downstream effector of the phosphoinositol–3 kinase (PI3K) signaling.
Discovery
The AKT protein kinase (also referred to as protein kinase B or Rac-protein kinase) was initially identified as an acute transforming component of the AKT8 virus isolated from a murine T cell lymphoma1, 2.
Classification
PKB/Akt belongs to the AGC subfamily of the protein kinase superfamily, which consists of 518 members in humans and is conserved from primitive metazoans to humans3.
Structural characteristics
The PKB subfamily comprises three mammalian isoforms, PKB , PKBß and PKB (Akt1, Akt2 and Akt3, respectively), which are products of distinct genes and share a conserved structure that includes three functional domains: an N-terminal pleckstrin homology (PH) domain, a central kinase domain, and a C-terminal regulatory domain containing the hydrophobic motif (HM) phosphorylation site [FxxF(S/T)Y]4.
Mechanism of action
As PKB is a downstream component of (PI3K) signaling, that is activated upon (1) autophosphorylation of receptor tyrosine kinases induced by ligands (such as insulin or other growth factors), (2) stimulation of G-protein-coupled receptors, or (3) activation of integrin signaling5, 6.
Functions
PKB/Akt plays an important role in all the cellular processes such as cell migration, survival, differentiation, as well as apoptosis7. Moreover, upregulation of Akt activity is recognized in variety of neoplasms, as well as chemoresistance8. To understand the role of PKB, tremendous efforts have been made to identify its physiological substrates. Most of the PKB substrates contain the minimal consensus sequence RxRxx(S/T), where x is any amino acid and S/T is the phosphorylation site. A genome–wide screen using this sequence motif will list more than 1,000 putative Akt phosphorylation targets in humans. Degenerate peptide library approach has also been used for screening various substrates for PKB/Akt9.
Reference:
1. Staal SP (1987). Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci, 84(14):5034-5037.
2. Staal SP, Hartley JW (1988). Thymic lymphoma induction by the AKT8 murine retrovirus. J Exp Med, 167(3):1259-64.
3. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC (2002). Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell, 10(1):151-62.
4. Hanada M, Feng J, Hemmings BA (2004). Structure, regulation and function of PKB/AKT--a major therapeutic target. Biochim Biophys Acta, 1697(1-2):3-16.
5. Foster, F. M., Traer, C. J., Abraham, S. M. and Fry, M. J. (2003). The phosphoinositide (PI) 3-kinase family. J. Cell Sci., 116, 3037-3040.
6. Wymann, M. P., Zvelebil, M. and Laffargue, M.(2003). Phosphoinositide 3-kinase signalling–which way to target? Trends Pharmacol. Sci., 24, 366-376.
7. Song G, Ouyang G, Bao S (2005). The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med, 9(1):59-71
8. Kim D, Dan HC, Park S, Yang L, Liu Q, Kaneko S, Ning J, He L, Yang H, Sun M, Nicosia SV, Cheng JQ (2005). AKT/PKB signaling mechanisms in cancer and chemoresistance. Front Biosci., 10:975-87.
9. Obata T, Yaffe MB, Leparc GG, Piro ET, Maegawa H, Kashiwagi A, Kikkawa R, Cantley LC (2000). Peptide and protein library screening defines optimal substrate motifs for AKT/PKB. J Biol Chem, 275(46):36108-36115.
Saturday, May 30, 2009
Alloferons
Definition
Alloferons also known as immunomodulating peptides are slightly cationic and non-toxic antiviral peptides that are isolated from the blood of an insect. Alloferons have no teratogenic, embryotoxic or mutagenic properties.
Discovery
Alloferons were first isolated from bacteria-challenged larvae of an experimentally infected blow fly, Calliphora vicina (Diptera) 1. This species, along with other surgical maggots, has a long history of medical use in wound and ulcer healing
Classification
Alloferons are members of cytokine-like peptide family of the insect immune system. They are naturally occurring peptides, usually consisting of 12-13 amino acids. Twenty types of alloferons are found in nature and are classified as as alloferon 1 to alloferon 20. Alloferons 1 and 2 are natural peptides, alloferons 3 and 4 are truncated forms of alloferon 1. Alloferons 5-20 are modifications of variable fragments of the basic structure of alloferon2.
Structural characteristics
Alloferons are linear, nonglycosylated oligopeptide having a unique amino acid sequence of molecular mass of about 1265 Da. Amino acid sequences of alloferons are homologous to influenza B virus precursor protein.
Mechanism of action
Alloferons mediate signalling by NF-?B pathway to boost recognition of viral and tumor antigens3. They are known to induce the production of endogenic interferons that promote a cascade of defense responses and also enhance CD25 receptor expression. Cytotoxic lymphocytes are stimulated by alloferons upon recognition of nonself or aberrant cells that are subsequently lysed.
Function
Alloferons are useful in the treatment or prophylaxis of various infectious or oncological diseases where improvement of innate immunity, including interferon system and natural cell mediated cytotoxicity can have therapeutic significance4. Alloferons is used as antiviral agent in the treatment of infections caused by influenza virus, herpes virus, papillomatosis, viral hepatitis, AIDS and AIDS relevant secondary infections. They are known also known to have antitumour property, used in the treatment of oncological conditions like acute and chronic leukemia.
References
1. Chernysh S, Kim SI, Bekker G, Pleskach VA, Filatova NA, Anikin VB, Platonov VG, Bulet P (2002). Antiviral and antitumor peptides from insects. Proceedings of the National Academy of Sciences, 99(20):12628-12632.
2. Kim SI, Chernysh S, Bekker G, Makhaldiani NB, Hoffman J, Bulet P (2008). Alloferons—immunomodulatory peptides. Free patents online, 7462360.
3. Ryu MJ, Anikin V, Hong SH, Jeon H, Yu YG, Yu MH, Chernysh S, Lee C (2008). Activation of NF-kappaB by alloferon through down-regulation of antioxidant proteins and IkappaBalpha. Mol Cell Biochem, vol 313(1-2):91-102.
4. Chernysh S (2006). Antitumoral and antiviral peptides. European patent publication, EP 1 705 182 A1.
Alloferons also known as immunomodulating peptides are slightly cationic and non-toxic antiviral peptides that are isolated from the blood of an insect. Alloferons have no teratogenic, embryotoxic or mutagenic properties.
Discovery
Alloferons were first isolated from bacteria-challenged larvae of an experimentally infected blow fly, Calliphora vicina (Diptera) 1. This species, along with other surgical maggots, has a long history of medical use in wound and ulcer healing
Classification
Alloferons are members of cytokine-like peptide family of the insect immune system. They are naturally occurring peptides, usually consisting of 12-13 amino acids. Twenty types of alloferons are found in nature and are classified as as alloferon 1 to alloferon 20. Alloferons 1 and 2 are natural peptides, alloferons 3 and 4 are truncated forms of alloferon 1. Alloferons 5-20 are modifications of variable fragments of the basic structure of alloferon2.
Structural characteristics
Alloferons are linear, nonglycosylated oligopeptide having a unique amino acid sequence of molecular mass of about 1265 Da. Amino acid sequences of alloferons are homologous to influenza B virus precursor protein.
Mechanism of action
Alloferons mediate signalling by NF-?B pathway to boost recognition of viral and tumor antigens3. They are known to induce the production of endogenic interferons that promote a cascade of defense responses and also enhance CD25 receptor expression. Cytotoxic lymphocytes are stimulated by alloferons upon recognition of nonself or aberrant cells that are subsequently lysed.
Function
Alloferons are useful in the treatment or prophylaxis of various infectious or oncological diseases where improvement of innate immunity, including interferon system and natural cell mediated cytotoxicity can have therapeutic significance4. Alloferons is used as antiviral agent in the treatment of infections caused by influenza virus, herpes virus, papillomatosis, viral hepatitis, AIDS and AIDS relevant secondary infections. They are known also known to have antitumour property, used in the treatment of oncological conditions like acute and chronic leukemia.
References
1. Chernysh S, Kim SI, Bekker G, Pleskach VA, Filatova NA, Anikin VB, Platonov VG, Bulet P (2002). Antiviral and antitumor peptides from insects. Proceedings of the National Academy of Sciences, 99(20):12628-12632.
2. Kim SI, Chernysh S, Bekker G, Makhaldiani NB, Hoffman J, Bulet P (2008). Alloferons—immunomodulatory peptides. Free patents online, 7462360.
3. Ryu MJ, Anikin V, Hong SH, Jeon H, Yu YG, Yu MH, Chernysh S, Lee C (2008). Activation of NF-kappaB by alloferon through down-regulation of antioxidant proteins and IkappaBalpha. Mol Cell Biochem, vol 313(1-2):91-102.
4. Chernysh S (2006). Antitumoral and antiviral peptides. European patent publication, EP 1 705 182 A1.
Amyloid b/A4 Protein Precursor (APP) Fragments
Definition
Amyloid precursor protein (APP) is a single transmembrane protein that undergoes sequential proteolysis to generate multiple peptides, including the amyloid beta peptide the major component of the senile plaques that are diagnostic hallmarks of Alzheimer disease (AD).
Discovery
In 1984, Glenner and Wong purified APP derived from the twisted beta-pleated sheet fibrils present in cerebrovascular amyloidoses and in the amyloid plaques associated with Alzheimer disease1.
Structural characteristics
APP is a 110-130 kDa, transmembrane cell surface glycoprotein, which contains N and O, linked sugars. The largest region of the molecule is the extracellular domain. This domain contains a cysteine-rich region of about 200 amino acids and is at the N-terminus of the protein. It has a single membrane-spanning domain towards the carboxyl terminus and a short cytoplasmic tail. APP contains a domain very similar to the Kunitz family of serine protease inhibitors and the APP protein is homologous to protein protease nexin-II2.
Mode of action
APP plays an essential role in the reduction of copper II to copper I. This electron transfer reaction is involved in the formation of reactive oxygen species (e.g., superoxide radical and hydroxyl radical)3 which are extremely reactive with many different cellular components. These reactions can produce large amounts of damage and ultimately results in cell death.
Function
APP plays major roles in the regulation of several important cellular functions, especially in the nervous system, where it is involved in synaptogenesis and synaptic plasticity. The secreted extracellular domain of APP, sAPPa, acts as a growth factor for many types of cells and promotes neuritogenesis in post-mitotic neurons4.
Reference:
1. Furuya H, Sasaki H, Goto I, Wong CW, Glenner GG, Sakaki Y. (1988). Amyloid beta-protein gene duplication is not common in Alzheimer's disease: analysis by polymorphic restriction fragments. Biochem Biophys Res Commun., 150 (1):75-81.
2. Ponte P, Gonzalez-DeWhitt P, Schilling J, Miller J, Hsu D, Greenberg B, Davis K, Wallace W, Lieberburg I, Fuller F (1988). A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature, 331 (6156):525-527.
3. Camakaris J, Voskoboinik I, Mercer JF (1999). Molecular mechanisms of copper homeostasis. Biochem Biophys Res Commun, 261:225-232.
4. Gralle M, Ferreira ST (2007). Structure and functions of the human amyloid precursor protein: the whole is more than the sum of its parts. Prog Neurobiol, 82 (1):11-32.
Amyloid precursor protein (APP) is a single transmembrane protein that undergoes sequential proteolysis to generate multiple peptides, including the amyloid beta peptide the major component of the senile plaques that are diagnostic hallmarks of Alzheimer disease (AD).
Discovery
In 1984, Glenner and Wong purified APP derived from the twisted beta-pleated sheet fibrils present in cerebrovascular amyloidoses and in the amyloid plaques associated with Alzheimer disease1.
Structural characteristics
APP is a 110-130 kDa, transmembrane cell surface glycoprotein, which contains N and O, linked sugars. The largest region of the molecule is the extracellular domain. This domain contains a cysteine-rich region of about 200 amino acids and is at the N-terminus of the protein. It has a single membrane-spanning domain towards the carboxyl terminus and a short cytoplasmic tail. APP contains a domain very similar to the Kunitz family of serine protease inhibitors and the APP protein is homologous to protein protease nexin-II2.
Mode of action
APP plays an essential role in the reduction of copper II to copper I. This electron transfer reaction is involved in the formation of reactive oxygen species (e.g., superoxide radical and hydroxyl radical)3 which are extremely reactive with many different cellular components. These reactions can produce large amounts of damage and ultimately results in cell death.
Function
APP plays major roles in the regulation of several important cellular functions, especially in the nervous system, where it is involved in synaptogenesis and synaptic plasticity. The secreted extracellular domain of APP, sAPPa, acts as a growth factor for many types of cells and promotes neuritogenesis in post-mitotic neurons4.
Reference:
1. Furuya H, Sasaki H, Goto I, Wong CW, Glenner GG, Sakaki Y. (1988). Amyloid beta-protein gene duplication is not common in Alzheimer's disease: analysis by polymorphic restriction fragments. Biochem Biophys Res Commun., 150 (1):75-81.
2. Ponte P, Gonzalez-DeWhitt P, Schilling J, Miller J, Hsu D, Greenberg B, Davis K, Wallace W, Lieberburg I, Fuller F (1988). A new A4 amyloid mRNA contains a domain homologous to serine proteinase inhibitors. Nature, 331 (6156):525-527.
3. Camakaris J, Voskoboinik I, Mercer JF (1999). Molecular mechanisms of copper homeostasis. Biochem Biophys Res Commun, 261:225-232.
4. Gralle M, Ferreira ST (2007). Structure and functions of the human amyloid precursor protein: the whole is more than the sum of its parts. Prog Neurobiol, 82 (1):11-32.
Amylin Peptides and Fragments
Definition
Amylin or Islet amyloid polypeptide (IAPP), a 37-amino acid peptide is secreted by beta-islet cells of the pancreas and a major component of the amyloid deposits in persons with type 2 diabetes mellitus. Amylin may be referred to as insulin’s “fraternal twin” as it is constitutively expressed with insulin in response to elevations of plasma glucose.
Discovery
The knowledge of occurrence of amyloid deposits in islets of Langerhans, major pathologic feature of diabetics has been known for a century. But, the discovery of amylin as a major component of amyloid deposits was by two independent groups in 19871, 2.
Structural characteristics
The human amylin has an amino acid sequence KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY, with a disulfide bridge between cysteine residues 2 and 7. The features, amidated C-terminus and the disulfide bridge are necessary for the full biological activity of amylin3. Amylin amino acid sequence is 46% and 43% identical to those of the calcitonin gene-related neuropeptides CGRP-2 and CGRP-1. The (20-29) fragment of amylin is critical to the pathogenesis of islet amyloid4.
Mechanism of action
Amylin is synthesized, packaged within the golgi apparatus and secreted within the secretory granule by the islet beta cell. They have binding sites within the renal cortex in the area of the juxtaglomerular apparatus and it activates the rennin angiotensin aldosterone system. It also acts upon the circulatory system by inhibiting the secretion of the atrial natriuretic peptide (ANP)5.
Function
Amylin inhibits gastric emptying and is important in controlling and delaying the rate of meal derived glucose. It inhibits hepatic release and production of glucose in the postprandial period. They also have been shown to inhibit glucagon secretion and somatostatin. Amylin causes vasodilatation by dilating the non-striated muscles of the blood vessels. It is also known to increase thirst level which indicates it has an action within the central nervous system6.
References
1. Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB, Reid KB (1987). Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci., 84(23):8628-32.
2. Westermark P, Wernstedt C, O'Brien TD, Hayden DW, Johnson KH (1987). Islet amyloid in type 2 human diabetes mellitus and adult diabetic cats contains a novel putative polypeptide hormone. Am J Pathol, 127(3):414-417.
3. Roberts AN, Leighton B, Todd JA, Cockburn D, Schofield PN, Sutton R, Holt S, Boyd Y, Day AJ, Foot EA, et al,(1989). Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus. Proc Natl Acad Sci, 86(24):9662-9666.
4. Guidobono F, Pagani F, Ticozzi C, Sibilia V, Pecile A, Netti C (1997). Protection by amylin of gastric erosions induced by indomethacin or ethanol in rats. Br J Pharmacol, 120(4):581-586.
5. Piao FL, Cao C, Han JH, Kim SZ, Cho KW, Kim SH (2004). Amylin-induced suppression of ANP secretion through receptors for CGRP1 and salmon calcitonin. Regul Pept, 117: 59-166.
6. Hayden MR, Tyagi SC (2002). Islet redox stress: the manifold toxicities of insulin resistance, metabolic syndrome and amylin derived islet amyloid in type 2 diabetes mellitus. Journal of the Pancrease, 3(4): 86-108.
Amylin or Islet amyloid polypeptide (IAPP), a 37-amino acid peptide is secreted by beta-islet cells of the pancreas and a major component of the amyloid deposits in persons with type 2 diabetes mellitus. Amylin may be referred to as insulin’s “fraternal twin” as it is constitutively expressed with insulin in response to elevations of plasma glucose.
Discovery
The knowledge of occurrence of amyloid deposits in islets of Langerhans, major pathologic feature of diabetics has been known for a century. But, the discovery of amylin as a major component of amyloid deposits was by two independent groups in 19871, 2.
Structural characteristics
The human amylin has an amino acid sequence KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY, with a disulfide bridge between cysteine residues 2 and 7. The features, amidated C-terminus and the disulfide bridge are necessary for the full biological activity of amylin3. Amylin amino acid sequence is 46% and 43% identical to those of the calcitonin gene-related neuropeptides CGRP-2 and CGRP-1. The (20-29) fragment of amylin is critical to the pathogenesis of islet amyloid4.
Mechanism of action
Amylin is synthesized, packaged within the golgi apparatus and secreted within the secretory granule by the islet beta cell. They have binding sites within the renal cortex in the area of the juxtaglomerular apparatus and it activates the rennin angiotensin aldosterone system. It also acts upon the circulatory system by inhibiting the secretion of the atrial natriuretic peptide (ANP)5.
Function
Amylin inhibits gastric emptying and is important in controlling and delaying the rate of meal derived glucose. It inhibits hepatic release and production of glucose in the postprandial period. They also have been shown to inhibit glucagon secretion and somatostatin. Amylin causes vasodilatation by dilating the non-striated muscles of the blood vessels. It is also known to increase thirst level which indicates it has an action within the central nervous system6.
References
1. Cooper GJ, Willis AC, Clark A, Turner RC, Sim RB, Reid KB (1987). Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci., 84(23):8628-32.
2. Westermark P, Wernstedt C, O'Brien TD, Hayden DW, Johnson KH (1987). Islet amyloid in type 2 human diabetes mellitus and adult diabetic cats contains a novel putative polypeptide hormone. Am J Pathol, 127(3):414-417.
3. Roberts AN, Leighton B, Todd JA, Cockburn D, Schofield PN, Sutton R, Holt S, Boyd Y, Day AJ, Foot EA, et al,(1989). Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus. Proc Natl Acad Sci, 86(24):9662-9666.
4. Guidobono F, Pagani F, Ticozzi C, Sibilia V, Pecile A, Netti C (1997). Protection by amylin of gastric erosions induced by indomethacin or ethanol in rats. Br J Pharmacol, 120(4):581-586.
5. Piao FL, Cao C, Han JH, Kim SZ, Cho KW, Kim SH (2004). Amylin-induced suppression of ANP secretion through receptors for CGRP1 and salmon calcitonin. Regul Pept, 117: 59-166.
6. Hayden MR, Tyagi SC (2002). Islet redox stress: the manifold toxicities of insulin resistance, metabolic syndrome and amylin derived islet amyloid in type 2 diabetes mellitus. Journal of the Pancrease, 3(4): 86-108.
ADP-Ribosylation Factors (ARF)
Definition
Adenosine diphosphate-ribosylation factor (ARF) proteins are members of the GTP-binding proteins of the Ras superfamily1. They are major regulators of vesicle biogenesis in intracellular traffic, lipid metabolism, microtubule dynamics, development and other cellular processes2.
Discovery
ARF was originally identified as a cofactor for cholera toxin A catalyzed ADP-ribosylation of the stimulatory GTP-binding component of adenylate cyclase3.
Classification
The mammalian ARFs can be grouped into three classes on the basis of their size and sequence identity. ARF1, ARF2 and ARF3 are grouped under class I, ARF4 and ARF5 under class II and ARF6 under class III4.
Structural Characteristics
ARFs contain consensus amino acid sequences involved in GTP binding and hydrolysis which determine their catalytic activity3. They contain two switch regions, which change relative positions between cycles of GDP/GTP-binding. They are similar to heterotrimeric G protein subunits, these peptides are frequently myristoylated in their N-terminal region, which contributes to their membrane association.
Mode of action
The controlled binding and hydrolysis of GTP is critical to ARF function. ARF proteins cycle between GDP-bound, inactive and GTP-bound, active forms, and the cycling is regulated by specific guanine nucleotide releasing factors (GEPs) and GTPase-activating protein (GAPs). GTPase activating proteins (GAPs) hydrolyze bound GTP to GDP, and guanine nucleotide exchange factors adopt a new GTP molecule in place of a bound GDP. The GTP hydrolysis is required in many secretory pathways like formation and docking of vesicles at various membranes. It affects membrane traffic by recruiting coat proteins, including COPI and clathrin adaptor complexes to membranes.
Functions
ARFs function both constitutively within the secretory pathway and as targets of signal transduction in the cell periphery1. ARF proteins function in the regulation of membrane traffic and the organization of the cytoskeleton that are crucial to fundamental cellular processes, such as intracellular sorting/trafficking of newly synthesized proteins and endocytosis/exocytosis. They act at membrane surfaces to modify lipid composition and to recruit coat proteins for the generation of transport vesicles5. ARF proteins play a key regulatory role in the remodeling of actin cytoskeleton necessary for the formation of membrane ruffles and protrusions in association with phospholipase D and members of the Rho GTPase family. These activities of ARF proteins influence the formation, stability and functional integrity of epithelial junctions6.
References
1. Randazzo PA, Nie Z, Miura K, and Hsu VW, (2000). Molecular Aspects of the Cellular Activities of ADP-Ribosylation Factors. Sci. STKE, 2000 (59)
2. Pasqualato S, Renault L, Cherfils J (2002). Arf, Arl, Arp and Sar proteins: a family of GTP-binding proteins with a structural device for 'front-back' communication. EMBO Rep, 3(11):1035-41.
3. Kahn RA and Gilman AG (1984). Purification of a protein cofactor required for ADP-ribosylation of the stimulatory regulatory component of adenylate cyclase by cholera toxin. J. Biol. Chem, 259, 6228-6234.
4. Moss J and Vaughan M (1995). Structure and Function of ARF Proteins: Activators of Cholera Toxin and Critical Components of Intracellular Vesicular Transport Processes. The American Society for Biochemistry and Molecular Biology, 270(21): 12327-12330.
5. Donaldson JG (2008). Arfs and membrane lipids: sensing, generating and responding to membrane curvature. Biochem J, 414(2):189-94.
6. Hiroi T (2009). Regulation of epithelial junctions by proteins of the ADP-ribosylation factor family. Front Biosci., 14:717-730.
Adenosine diphosphate-ribosylation factor (ARF) proteins are members of the GTP-binding proteins of the Ras superfamily1. They are major regulators of vesicle biogenesis in intracellular traffic, lipid metabolism, microtubule dynamics, development and other cellular processes2.
Discovery
ARF was originally identified as a cofactor for cholera toxin A catalyzed ADP-ribosylation of the stimulatory GTP-binding component of adenylate cyclase3.
Classification
The mammalian ARFs can be grouped into three classes on the basis of their size and sequence identity. ARF1, ARF2 and ARF3 are grouped under class I, ARF4 and ARF5 under class II and ARF6 under class III4.
Structural Characteristics
ARFs contain consensus amino acid sequences involved in GTP binding and hydrolysis which determine their catalytic activity3. They contain two switch regions, which change relative positions between cycles of GDP/GTP-binding. They are similar to heterotrimeric G protein subunits, these peptides are frequently myristoylated in their N-terminal region, which contributes to their membrane association.
Mode of action
The controlled binding and hydrolysis of GTP is critical to ARF function. ARF proteins cycle between GDP-bound, inactive and GTP-bound, active forms, and the cycling is regulated by specific guanine nucleotide releasing factors (GEPs) and GTPase-activating protein (GAPs). GTPase activating proteins (GAPs) hydrolyze bound GTP to GDP, and guanine nucleotide exchange factors adopt a new GTP molecule in place of a bound GDP. The GTP hydrolysis is required in many secretory pathways like formation and docking of vesicles at various membranes. It affects membrane traffic by recruiting coat proteins, including COPI and clathrin adaptor complexes to membranes.
Functions
ARFs function both constitutively within the secretory pathway and as targets of signal transduction in the cell periphery1. ARF proteins function in the regulation of membrane traffic and the organization of the cytoskeleton that are crucial to fundamental cellular processes, such as intracellular sorting/trafficking of newly synthesized proteins and endocytosis/exocytosis. They act at membrane surfaces to modify lipid composition and to recruit coat proteins for the generation of transport vesicles5. ARF proteins play a key regulatory role in the remodeling of actin cytoskeleton necessary for the formation of membrane ruffles and protrusions in association with phospholipase D and members of the Rho GTPase family. These activities of ARF proteins influence the formation, stability and functional integrity of epithelial junctions6.
References
1. Randazzo PA, Nie Z, Miura K, and Hsu VW, (2000). Molecular Aspects of the Cellular Activities of ADP-Ribosylation Factors. Sci. STKE, 2000 (59)
2. Pasqualato S, Renault L, Cherfils J (2002). Arf, Arl, Arp and Sar proteins: a family of GTP-binding proteins with a structural device for 'front-back' communication. EMBO Rep, 3(11):1035-41.
3. Kahn RA and Gilman AG (1984). Purification of a protein cofactor required for ADP-ribosylation of the stimulatory regulatory component of adenylate cyclase by cholera toxin. J. Biol. Chem, 259, 6228-6234.
4. Moss J and Vaughan M (1995). Structure and Function of ARF Proteins: Activators of Cholera Toxin and Critical Components of Intracellular Vesicular Transport Processes. The American Society for Biochemistry and Molecular Biology, 270(21): 12327-12330.
5. Donaldson JG (2008). Arfs and membrane lipids: sensing, generating and responding to membrane curvature. Biochem J, 414(2):189-94.
6. Hiroi T (2009). Regulation of epithelial junctions by proteins of the ADP-ribosylation factor family. Front Biosci., 14:717-730.
Adrenomedullin Peptides
Definition
Adrenomedullin (AM) is a pluripotent peptide and a hypotensive substance extracted from human adrenal tumour. Due to its origin of discovery, i.e. the medulla of the adrenal gland, the peptide is named adrenomedullin.
Discovery
AM was initially isolated from phaechromcytoma cells in 1993 by Kitmura K and his associates1.
Classification
AM is a member of the calcitonin family of peptides. In teleost fish, AM forms an independent subfamily consisting of five members viz. (AM1–AM5). This teleost AM family comprises three groups, AM1/AM4, AM2/AM3, and AM5 2,3.
Structural Characteristics
The peptide consists of 52 amino acids with a 6-member ring structure linked by a disulfide bond between amino acid 16 and 21 and amidated-COOH terminal4. It has 27 % homology with the calcitonin gene-related peptide (CGRP).
Mechanism of action
AM peptides act through specific receptors in the plasma membrane to activate adenylate cyclase activity and modulate Ca2+ flux in the target cells. The intracellular free Ca2+ increases on the activation of phospholipase C and formation of inositol 1, 4, 5-trisphosphate in the endothelial cells. The intracellular increase of Ca2+ activates endothelial nitric oxide synthase which leads to vascular relaxation5.
Function
AM is the most potent endogenous vasodilatory peptide found in the body6. They increase the tolerance of cells to oxidative stress, hypoxic injury and angiogenesis. It plays an important role in neurotransmission and ovarian function and in kidney, it acts as a diuretic and natriuretic7. AM is considered to play an important endocrine role in various tissues in maintaining electrolyte and fluid homeostasis8. It is used in the diagnosis and treatment of preeclampsia, type II diabetic patients and to promote fetal growth. They also play an important role in the regulation of insulin secretion and blood glucose metabolism.
References
1. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T (1993). Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun., 192 (2):553-560.
2. Ogoshi M, Nobata S, and Takei Y (2008). Potent osmoregulatory actions of homologous adrenomedullins administered peripherally and centrally in eels. Am J Physiol Regul Integr Comp Physiol, 295: 2075-2083.
3. Ogoshi M, Inoue K, Naruse K, Takei Y (2006). Evolutionary history of the calcitonin gene-related peptide family in vertebrates revealed by comparative genomic analyses. Peptides, 27 (12):3154-3164.
4. Cockcroft JR, Noon JP, Gardner-Medwin J, Bennett T (1997). Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels. Br J Clin Pharmacol, 44(1):57-60.
5. Shimekake Y, Nagata K, Ohta S, Kambayashi Y, Teraoka H, Kitamura K, Eto T, Kangawa K, Matsuo H (1995). Adrenomedullin stimulates two signal transduction pathways, cAMP accumulation and Ca2+ mobilization, in bovine aortic endothelial cells. J Biol Chem, 270: 4412-4417.
6. Yanagawa B, Nagaya N (2007). Adrenomedullin: molecular mechanisms and its role in cardiac disease. Amino Acids, 32 (1):157-164.
7. Vesely DL (2003). Natriuretic peptides and acute renal failure. Am J Physiol Renal Physiol, 285 (2):167-177.
8. Ruzicska E, Toth M, Tulassay Z, Somogyi A (2001). Adrenomedullin and diabetes mellitus. Diabetes Metab Res Rev, 17 (5):321-329.
Adrenomedullin (AM) is a pluripotent peptide and a hypotensive substance extracted from human adrenal tumour. Due to its origin of discovery, i.e. the medulla of the adrenal gland, the peptide is named adrenomedullin.
Discovery
AM was initially isolated from phaechromcytoma cells in 1993 by Kitmura K and his associates1.
Classification
AM is a member of the calcitonin family of peptides. In teleost fish, AM forms an independent subfamily consisting of five members viz. (AM1–AM5). This teleost AM family comprises three groups, AM1/AM4, AM2/AM3, and AM5 2,3.
Structural Characteristics
The peptide consists of 52 amino acids with a 6-member ring structure linked by a disulfide bond between amino acid 16 and 21 and amidated-COOH terminal4. It has 27 % homology with the calcitonin gene-related peptide (CGRP).
Mechanism of action
AM peptides act through specific receptors in the plasma membrane to activate adenylate cyclase activity and modulate Ca2+ flux in the target cells. The intracellular free Ca2+ increases on the activation of phospholipase C and formation of inositol 1, 4, 5-trisphosphate in the endothelial cells. The intracellular increase of Ca2+ activates endothelial nitric oxide synthase which leads to vascular relaxation5.
Function
AM is the most potent endogenous vasodilatory peptide found in the body6. They increase the tolerance of cells to oxidative stress, hypoxic injury and angiogenesis. It plays an important role in neurotransmission and ovarian function and in kidney, it acts as a diuretic and natriuretic7. AM is considered to play an important endocrine role in various tissues in maintaining electrolyte and fluid homeostasis8. It is used in the diagnosis and treatment of preeclampsia, type II diabetic patients and to promote fetal growth. They also play an important role in the regulation of insulin secretion and blood glucose metabolism.
References
1. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T (1993). Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun., 192 (2):553-560.
2. Ogoshi M, Nobata S, and Takei Y (2008). Potent osmoregulatory actions of homologous adrenomedullins administered peripherally and centrally in eels. Am J Physiol Regul Integr Comp Physiol, 295: 2075-2083.
3. Ogoshi M, Inoue K, Naruse K, Takei Y (2006). Evolutionary history of the calcitonin gene-related peptide family in vertebrates revealed by comparative genomic analyses. Peptides, 27 (12):3154-3164.
4. Cockcroft JR, Noon JP, Gardner-Medwin J, Bennett T (1997). Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels. Br J Clin Pharmacol, 44(1):57-60.
5. Shimekake Y, Nagata K, Ohta S, Kambayashi Y, Teraoka H, Kitamura K, Eto T, Kangawa K, Matsuo H (1995). Adrenomedullin stimulates two signal transduction pathways, cAMP accumulation and Ca2+ mobilization, in bovine aortic endothelial cells. J Biol Chem, 270: 4412-4417.
6. Yanagawa B, Nagaya N (2007). Adrenomedullin: molecular mechanisms and its role in cardiac disease. Amino Acids, 32 (1):157-164.
7. Vesely DL (2003). Natriuretic peptides and acute renal failure. Am J Physiol Renal Physiol, 285 (2):167-177.
8. Ruzicska E, Toth M, Tulassay Z, Somogyi A (2001). Adrenomedullin and diabetes mellitus. Diabetes Metab Res Rev, 17 (5):321-329.
Adipokinetic Hormones
Definition
Adipokinetic hormones (AKH) are a family of structurally related peptides that occur widely in insects, it belongs to member of a large arthropod neuropeptide family. It exerts a wide range of functions, many of which are analogous to those of vertebrate glucagons.
Discovery
It was discovered in the desert locust Schistocerca gregaria and it was first purified in 1976 by stone and team. It was isolated from corpora cardiaca of the painted lady butterfly, Vanessa cardui1.
Classification
There are 3 isoforms of AKH viz. AKH-1, AKH-II and AKH-III. AKH-I is a decapeptide, AKH –II and AKH-III are octapeptide the molecular proportion of these 3 peptides vary (14:2:1) respectively. All these hormones are derived from 63- and 61-amino-acid peptide precursors.
Structural Characteristics
The molecular weight of adipokinetic hormone is 1008.1 KDa. The amino acid sequence of the peptide is pGlu -leu-Asn-Phe-Thr-Pro-Asn-Trp-Gly-Thr-NH2. Insect AKHs are post-translationally modified at the N-terminus by pyroglutamic acid and at the C-terminus by carboxyamide2. They contain aromatic amino acids at position 4 (mostly phenylalanine, in a few cases tyrosine) and at position 8 (tryptophan). Position 9 is always glycine which is used in the octapeptides for the amidation, and the majority of the peptides do not have net charge.
Mode of action
AKH family regulate mobilisation of substrates from stores in the fat body of insects during episodes of flight. During the period of flight, AKHs bind to a G (q)-protein-coupled receptor, activates phospholipase C resulting in formation of inositol trisphosphate that releases Ca(2+) from internal stores. In addition, influx of extracellular Ca2+ is increased and via a kinase cascade glycogen phosphorylase is activated, glucose-1-phosphate produced, and transformed to trehalose which is released into the haemolymph3.
Functions
AKHs are multifunctional; they exert various physiological functions like cardio acceleration in cockroaches and migration of tegumentary and retinal distal pigments in crustaceans. It induces transcription of the cytochrome P450 gene in the fat body of cockroaches and expression of a gene encoding fatty acid binding protein in the flight muscle of locusts. These peptides have excitatory effects on motor neurons in moths4. There is enough evidence to show that AKH regulates the balance of carbohydrate and lipid oxidation in flight muscles.
References
1. Köllisch GV, Lorenz MW, Kellner R, Verhaert PD and Hoffmann KH (2004). Structure elucidation and biological activity of an unusual adipokinetic hormone from corpora cardiaca of the butterfly, Vanessa cardui. European Journal of Biochemistry, 267(17)5502 – 5508.
2. Gäde G, Simek P, Clark KD, Auerswald L (2006). Unique translational modification of an invertebrate neuropeptide: a phosphorylated member of the adipokinetic hormone peptide family. Biochem. J, 393: 705–713.
3. Gäde G, Auerswald L (2003).Mode of action of neuropeptides from the adipokinetic hormone family. Gen Comp Endocrinol, 132 (1): 10-20.
4. Van der Horst DJ, Van Marrewijk WJ, Diederen JH (2001). Adipokinetic hormones of insect release, signal transduction, and responses. Int Rev Cytol, 211: 179-240.
Adipokinetic hormones (AKH) are a family of structurally related peptides that occur widely in insects, it belongs to member of a large arthropod neuropeptide family. It exerts a wide range of functions, many of which are analogous to those of vertebrate glucagons.
Discovery
It was discovered in the desert locust Schistocerca gregaria and it was first purified in 1976 by stone and team. It was isolated from corpora cardiaca of the painted lady butterfly, Vanessa cardui1.
Classification
There are 3 isoforms of AKH viz. AKH-1, AKH-II and AKH-III. AKH-I is a decapeptide, AKH –II and AKH-III are octapeptide the molecular proportion of these 3 peptides vary (14:2:1) respectively. All these hormones are derived from 63- and 61-amino-acid peptide precursors.
Structural Characteristics
The molecular weight of adipokinetic hormone is 1008.1 KDa. The amino acid sequence of the peptide is pGlu -leu-Asn-Phe-Thr-Pro-Asn-Trp-Gly-Thr-NH2. Insect AKHs are post-translationally modified at the N-terminus by pyroglutamic acid and at the C-terminus by carboxyamide2. They contain aromatic amino acids at position 4 (mostly phenylalanine, in a few cases tyrosine) and at position 8 (tryptophan). Position 9 is always glycine which is used in the octapeptides for the amidation, and the majority of the peptides do not have net charge.
Mode of action
AKH family regulate mobilisation of substrates from stores in the fat body of insects during episodes of flight. During the period of flight, AKHs bind to a G (q)-protein-coupled receptor, activates phospholipase C resulting in formation of inositol trisphosphate that releases Ca(2+) from internal stores. In addition, influx of extracellular Ca2+ is increased and via a kinase cascade glycogen phosphorylase is activated, glucose-1-phosphate produced, and transformed to trehalose which is released into the haemolymph3.
Functions
AKHs are multifunctional; they exert various physiological functions like cardio acceleration in cockroaches and migration of tegumentary and retinal distal pigments in crustaceans. It induces transcription of the cytochrome P450 gene in the fat body of cockroaches and expression of a gene encoding fatty acid binding protein in the flight muscle of locusts. These peptides have excitatory effects on motor neurons in moths4. There is enough evidence to show that AKH regulates the balance of carbohydrate and lipid oxidation in flight muscles.
References
1. Köllisch GV, Lorenz MW, Kellner R, Verhaert PD and Hoffmann KH (2004). Structure elucidation and biological activity of an unusual adipokinetic hormone from corpora cardiaca of the butterfly, Vanessa cardui. European Journal of Biochemistry, 267(17)5502 – 5508.
2. Gäde G, Simek P, Clark KD, Auerswald L (2006). Unique translational modification of an invertebrate neuropeptide: a phosphorylated member of the adipokinetic hormone peptide family. Biochem. J, 393: 705–713.
3. Gäde G, Auerswald L (2003).Mode of action of neuropeptides from the adipokinetic hormone family. Gen Comp Endocrinol, 132 (1): 10-20.
4. Van der Horst DJ, Van Marrewijk WJ, Diederen JH (2001). Adipokinetic hormones of insect release, signal transduction, and responses. Int Rev Cytol, 211: 179-240.
Adenylate Cyclase
Definition
Adenylate cyclase (AC) or adenylyl cyclase or 3¢, 5¢ -cyclic AMP synthetase is a lyase enzyme. It initiates the conversion of adenosine triphosphate to cyclic adenosine monophosphate, a mediator of many physiologic activities. It is activated by the attachment of a hormone or neurotransmitter to a specific membrane-bound receptor.
Discovery
Reik and team were the first to report the histochemical localization of AC using a modification of the lead capture procedure popularized by Wachstein and Meisel, in this procedure ATP was used as a substrate and lead ions as the capture agent1.
Classification
Ten isoforms of mammalian AC are known, numbered from AC1-AC9 and soluble adenylyl cyclase (SAC). SAC are found in the nucleus, mitochondria and microtubules2.
Structural Characteristics
AC is an integral membrane protein that consists of two bundles of six transmembrane segments. Hormone-sensitive AC systems are composed of hormone-recognition units (R), a nucleotide-regulatory unit (N) for reaction with GTP and divalent cations, and the catalytic unit (C)3. The catalytic cytosolic regions of mammalian ACs also share significant sequence similarity to the corresponding regions of guanylyl cyclase (GCs)4. Two catalytic domains, the palm domain and the adenylyl cyclase catalytic core (ACYc) domain extend as loops into the cytoplasm.
Mode of action
Adenylate cyclase is stimulated by G proteins, forskolin as well as other class-specific substrates; G proteins are coupled to membrane receptors and responds to hormonal stimulus. Following activation of adenylate cyclase, the resulting cAMP acts as a second messenger by interacting with and regulating other proteins such as protein kinase A and cyclic nucleotide-gated ion channels. . Epinephrine, dopamine, prostaglandin PGE2, adenosine, and glucagon are a few examples of the many hormones that activate AC through membrane-bound receptors. Glucagon-bound receptors communicate with an intracellular, membrane-associated heterotrimeric G protein composed of a guanosine diphosphate (GDP)–bound α-subunit and an obligate βγ heterodimer. Hormone-dependent activation of receptors leads to the exchange of GDP for guanosine triphosphate (GTP). Conformational changes due to GTP binding result in the dissociation of the heterotrimeric G protein into a and By subunits, which then interact with their respective effectors4.
Functions
AC through the production of cyclic AMP (cAMP) can transduce dual signals, positive and negative, on cell growth and differentiation. Such dual signals are transmitted by RI and RII cAMP-binding receptor proteins respectively, the regulatory subunits of cAMP dependent protein kinases. The growth stimulatory RI and inhibitory RII are in a strict balance to maintain normal cells, and departure from such balance can cause a great variety of human diseases, including cancer. Experimental approaches using site-selective cAMP analogues, antisense oligodeoxynucleotides, and gene transfer have shown that restoration of the normal balance of RI/RII provides a biological means to the suppression of malignancy5.
References
1. Cutler LS, Christian CP (1980). Cytochemical Localization of Adenylate Cyclase. The Journal of Histochemistry and Cytochemistry, 28(1):62-65.
2. Feng Q, Zhang Y, Li Y, Liu Z, Zuo J, Fang F (2006). Two domains are critical for the nuclear localization of soluble adenylyl cyclase. Biochimie, 88 (3-4):319-28.
3. Rodbell M (1982). Structure-function relationships in adenylate cyclase systems. Ciba Found Symp, 90:3-21.
4. Roger K. Sunahara and Ron Taussig (2002). Isoforms of Mammalian Adenylyl Cyclase. Molecular interventions, 2 (3):168-184
5. Cho-Chung YS (1992). Modulation of adenylate cyclase signalling. Semin Cancer Biol., 3 (6):361-367.
Adenylate cyclase (AC) or adenylyl cyclase or 3¢, 5¢ -cyclic AMP synthetase is a lyase enzyme. It initiates the conversion of adenosine triphosphate to cyclic adenosine monophosphate, a mediator of many physiologic activities. It is activated by the attachment of a hormone or neurotransmitter to a specific membrane-bound receptor.
Discovery
Reik and team were the first to report the histochemical localization of AC using a modification of the lead capture procedure popularized by Wachstein and Meisel, in this procedure ATP was used as a substrate and lead ions as the capture agent1.
Classification
Ten isoforms of mammalian AC are known, numbered from AC1-AC9 and soluble adenylyl cyclase (SAC). SAC are found in the nucleus, mitochondria and microtubules2.
Structural Characteristics
AC is an integral membrane protein that consists of two bundles of six transmembrane segments. Hormone-sensitive AC systems are composed of hormone-recognition units (R), a nucleotide-regulatory unit (N) for reaction with GTP and divalent cations, and the catalytic unit (C)3. The catalytic cytosolic regions of mammalian ACs also share significant sequence similarity to the corresponding regions of guanylyl cyclase (GCs)4. Two catalytic domains, the palm domain and the adenylyl cyclase catalytic core (ACYc) domain extend as loops into the cytoplasm.
Mode of action
Adenylate cyclase is stimulated by G proteins, forskolin as well as other class-specific substrates; G proteins are coupled to membrane receptors and responds to hormonal stimulus. Following activation of adenylate cyclase, the resulting cAMP acts as a second messenger by interacting with and regulating other proteins such as protein kinase A and cyclic nucleotide-gated ion channels. . Epinephrine, dopamine, prostaglandin PGE2, adenosine, and glucagon are a few examples of the many hormones that activate AC through membrane-bound receptors. Glucagon-bound receptors communicate with an intracellular, membrane-associated heterotrimeric G protein composed of a guanosine diphosphate (GDP)–bound α-subunit and an obligate βγ heterodimer. Hormone-dependent activation of receptors leads to the exchange of GDP for guanosine triphosphate (GTP). Conformational changes due to GTP binding result in the dissociation of the heterotrimeric G protein into a and By subunits, which then interact with their respective effectors4.
Functions
AC through the production of cyclic AMP (cAMP) can transduce dual signals, positive and negative, on cell growth and differentiation. Such dual signals are transmitted by RI and RII cAMP-binding receptor proteins respectively, the regulatory subunits of cAMP dependent protein kinases. The growth stimulatory RI and inhibitory RII are in a strict balance to maintain normal cells, and departure from such balance can cause a great variety of human diseases, including cancer. Experimental approaches using site-selective cAMP analogues, antisense oligodeoxynucleotides, and gene transfer have shown that restoration of the normal balance of RI/RII provides a biological means to the suppression of malignancy5.
References
1. Cutler LS, Christian CP (1980). Cytochemical Localization of Adenylate Cyclase. The Journal of Histochemistry and Cytochemistry, 28(1):62-65.
2. Feng Q, Zhang Y, Li Y, Liu Z, Zuo J, Fang F (2006). Two domains are critical for the nuclear localization of soluble adenylyl cyclase. Biochimie, 88 (3-4):319-28.
3. Rodbell M (1982). Structure-function relationships in adenylate cyclase systems. Ciba Found Symp, 90:3-21.
4. Roger K. Sunahara and Ron Taussig (2002). Isoforms of Mammalian Adenylyl Cyclase. Molecular interventions, 2 (3):168-184
5. Cho-Chung YS (1992). Modulation of adenylate cyclase signalling. Semin Cancer Biol., 3 (6):361-367.
Thursday, May 14, 2009
RNA Interference
RNA interference (RNAi) or double-stranded RNA (dsRNA) is a system within living cells that helps to control which genes are active and how active they are. siRNAs were first discovered by David Baulcombe's group in Norwich, England, as part of post-transcriptional gene silencing (PTGS) in plants1 and later independently identified in wide variety of eukaryotic organisms. These dsRNAs are rapidly processed into short RNA duplexes of 21 to 28 nucleotides in length, which then guide the recognition and ultimately the cleavage of complementary single-stranded RNAs, such as messenger RNAs or viral genomic/antigenomic RNA (Fig. 1). According to their origin or function, naturally occurring small RNA have been described: short interfering RNAs (siRNA), repeat-associated short interfering RNA (rasiRNA or shRNA) and microRNA (miRNA). RNA interference has many biological functions – it is a vital part of the immune response against viruses and also downregulates gene expression by transcriptional silencing of genes or upregulates promoting by RNA activation. Finally, artificial introduction of long dsRNA or siRNA has been adopted as a tool to inactivate gene expression, both in cultured cells and in living organisms.
A biochemical understanding of the RNAi pathway was crucial to realizing that dsRNAs shorter than 30 base pairs (bp) could be used to trigger an RNAi response in mammals. Tuschl and colleagues showed that transfection of mammalian cells with short RNAs could induce the sequence-specific RNAi pathway, and so overcame the barrier to the use of RNAi as a genetic tool in mammals2. The impetus to use siRNAs and other small RNAs in mammalian cells also came from the long-standing view that protein kinase receptor (PKR) activation3 and similar responses were not effectively triggered by short dsRNAs. Following the initial reports, it took a remarkably short period of time for siRNAs triggers to be adopted as a standard component of the molecular biology toolkit. siRNAs can be introduced into mammalian cells using a variety of standard transfection methods. The strength and duration of the silencing response is determined by several factors: on a population basis, the silencing response is affected mainly by the overall efficiency of transfection, which can be addressed by optimizing conditions. In each cell, silencing depends on the amount of siRNA that is delivered and on the potential of each siRNA to suppress its target, or its potency. Even a relatively impotent siRNA can silence its target provided that sufficient quantities of the siRNA are delivered. However, essentially ‘forcing’ the system by delivering large amounts of reagent is likely to lead to numerous undesired effects.
Wednesday, May 6, 2009
What we need to know about the Swine Flu?
The origin. It is well known that most higher organisms carry the genomes of certain viruses that normally lie dormant in a quiescent state until they become activated by different factors and causing a number of problems. However in most cases, after infecting their hosts, viruses are cleared by an immunological response mounted by the host or eventually they kill their host this way putting an end to their replication cycle. Yet in either case, the newly produced virus can infect other hosts and start the reproductive cycle once more. Although most viruses have a restricted number of host species that they can infect, some viruses can infect other animal species. The infection of man by viruses from another animal species is known as zoonosis. Influenza virus is one of the best examples known of virus capable of causing a zoonosis, as the infectious virus can also originate from ducks or pigs. Moreover, influenza viruses from humans, swine and different birds can recombine to create new strains with new properties as well as more infectious, virulent and deathly.
About Mexico City. This is a city with over 22 million people, the largest in the western hemisphere and the second largest in the world. It sits at 7,349 feet above sea level in a high plateau. Due to its geographic location, there is no good air movement across it, and high levels of smog hangs over it; thus its inhabitants suffer from a number of respiratory ailments. So perhaps it is no surprising that swine flu started its spread form this city.
How the across species jump may occur? Fluid to fluid contact is what most scientist suspect; animal handlers that are in daily contact slaughtering animals, get the animals blood splashed on them and if an open cut is present on them, then the animal blood can infect them. Over the years, this kind of interaction may be responsible for the virus jumping to a new host, where it can mutate and become pathogenic to the new host.
Transmission. At this point, the infected human can get sick and transmit the virus via aerosolized micro drops of saliva produced during coughing, and he is also capable of passing the virus by direct contact with non-infected people
About vaccines against it. Currently there are not vaccines against the new swine flu virus strain and producing a vaccine can take 6-9 months. Vaccines against the influenza virus are strain specific, however because the virus has a high rate of mutations in those regions responsible for initiating the infection process there is a need to develop new vaccines every year.
Virulence. The ability for a virus to be more potently infectious; swine flu is intriguing, because it seems that its virulence is of greater power, as compared to other flu’s
About Tamiflu. ; This drug manufactured by Roche appears to be effective against the swine flu; influenza virus initiates the infection process by latching to sialoglycoproteins present of the cell surface via their neuraminidase. Inhibition of the viral neuraminidase interferes with the infection process contributing to reduce symptoms and complications. About the Centers for Disease Control. This is a government backed research outfit slocated in Atlanta, Georgia, whose principal mission is to evaluate , research and advise on any and all infectious agents that afflict not only the continental US but the rest of the world also; as the most serious diseases can become pandemic in nature and affect the entire world.. Their website is: www.cdc.gov
Recommendations. What can one do to lower the odds of contacting swine flu?
A viral peptide responsible for the susceptibility of infected cells to CTLs has been identified. Yet all of the epitopes in the virus responsible for susceptibility to T cell immunity are buried inside the particle and for that reason not available to the action of T cell immunity mediators.
About Mexico City. This is a city with over 22 million people, the largest in the western hemisphere and the second largest in the world. It sits at 7,349 feet above sea level in a high plateau. Due to its geographic location, there is no good air movement across it, and high levels of smog hangs over it; thus its inhabitants suffer from a number of respiratory ailments. So perhaps it is no surprising that swine flu started its spread form this city.
How the across species jump may occur? Fluid to fluid contact is what most scientist suspect; animal handlers that are in daily contact slaughtering animals, get the animals blood splashed on them and if an open cut is present on them, then the animal blood can infect them. Over the years, this kind of interaction may be responsible for the virus jumping to a new host, where it can mutate and become pathogenic to the new host.
Transmission. At this point, the infected human can get sick and transmit the virus via aerosolized micro drops of saliva produced during coughing, and he is also capable of passing the virus by direct contact with non-infected people
About vaccines against it. Currently there are not vaccines against the new swine flu virus strain and producing a vaccine can take 6-9 months. Vaccines against the influenza virus are strain specific, however because the virus has a high rate of mutations in those regions responsible for initiating the infection process there is a need to develop new vaccines every year.
Virulence. The ability for a virus to be more potently infectious; swine flu is intriguing, because it seems that its virulence is of greater power, as compared to other flu’s
About Tamiflu. ; This drug manufactured by Roche appears to be effective against the swine flu; influenza virus initiates the infection process by latching to sialoglycoproteins present of the cell surface via their neuraminidase. Inhibition of the viral neuraminidase interferes with the infection process contributing to reduce symptoms and complications. About the Centers for Disease Control. This is a government backed research outfit slocated in Atlanta, Georgia, whose principal mission is to evaluate , research and advise on any and all infectious agents that afflict not only the continental US but the rest of the world also; as the most serious diseases can become pandemic in nature and affect the entire world.. Their website is: www.cdc.gov
Recommendations. What can one do to lower the odds of contacting swine flu?
- Avoid crowded areas
- Avoid contact with infected peopl
- Wash hands as often as possible
- Avoid captive areas if at all possible, such as planes trains and the like.
A viral peptide responsible for the susceptibility of infected cells to CTLs has been identified. Yet all of the epitopes in the virus responsible for susceptibility to T cell immunity are buried inside the particle and for that reason not available to the action of T cell immunity mediators.
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