US20030113733A1 - Gene regulator - Google Patents

Gene regulator Download PDF

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Publication number
US20030113733A1
US20030113733A1 US10/028,075 US2807501A US2003113733A1 US 20030113733 A1 US20030113733 A1 US 20030113733A1 US 2807501 A US2807501 A US 2807501A US 2003113733 A1 US2003113733 A1 US 2003113733A1
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Prior art keywords
cell
nmpf
gene
peptide
cells
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US10/028,075
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English (en)
Inventor
Nisar Khan
Robert Benner
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Biotempt BV
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Individual
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Priority to EP01203748A priority Critical patent/EP1300418A1/de
Application filed by Individual filed Critical Individual
Priority to US10/028,075 priority patent/US20030113733A1/en
Assigned to ERASMUS UNIVERSITEIT ROTTERDAM reassignment ERASMUS UNIVERSITEIT ROTTERDAM ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BENNER, ROBERT, KHAN, NISAR AHMED
Priority to EP02763111A priority patent/EP1432733B1/de
Priority to JP2003532537A priority patent/JP2005519867A/ja
Priority to AU2002328028A priority patent/AU2002328028B2/en
Priority to KR10-2004-7005020A priority patent/KR20040074975A/ko
Priority to EP08171373A priority patent/EP2036924B1/de
Priority to CNA028242947A priority patent/CN1599753A/zh
Priority to AT02763111T priority patent/ATE517915T1/de
Priority to HK04106110.8A priority patent/HK1063327B/en
Priority to NZ532173A priority patent/NZ532173A/en
Priority to CN200910163475A priority patent/CN101721676A/zh
Priority to IL16120102A priority patent/IL161201A0/xx
Priority to EP08171382A priority patent/EP2060585A3/de
Priority to AT08171373T priority patent/ATE535542T1/de
Priority to CA002462796A priority patent/CA2462796A1/en
Priority to PCT/NL2002/000639 priority patent/WO2003029292A2/en
Priority to US10/409,671 priority patent/US20030220261A1/en
Priority to US10/409,694 priority patent/US20030224995A1/en
Priority to US10/409,654 priority patent/US20030220259A1/en
Priority to US10/409,657 priority patent/US20040013661A1/en
Priority to US10/409,659 priority patent/US20030220260A1/en
Priority to US10/409,027 priority patent/US7501391B2/en
Priority to US10/409,630 priority patent/US7560433B2/en
Priority to US10/409,642 priority patent/US20030220258A1/en
Priority to US10/409,032 priority patent/US20030220257A1/en
Publication of US20030113733A1 publication Critical patent/US20030113733A1/en
Priority to US10/753,510 priority patent/US7358330B2/en
Priority to IL161201A priority patent/IL161201A/en
Priority to US10/817,756 priority patent/US20050214943A1/en
Priority to US10/821,240 priority patent/US20050037430A1/en
Priority to US11/346,761 priority patent/US7524820B1/en
Assigned to BIOTEMPT B.V. reassignment BIOTEMPT B.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ERASMUS UNIVERSITEIT ROTTERDAM
Priority to US11/593,329 priority patent/US8216998B2/en
Priority to US11/859,265 priority patent/US20080076719A1/en
Priority to US11/986,043 priority patent/US20080242837A1/en
Priority to US11/981,505 priority patent/US7786084B2/en
Priority to US11/981,491 priority patent/US20080194489A1/en
Priority to US11/982,293 priority patent/US20080242618A1/en
Priority to US11/982,292 priority patent/US20080318871A1/en
Priority to US12/001,035 priority patent/US20080176243A1/en
Priority to US12/069,401 priority patent/US20080306009A1/en
Priority to US12/074,020 priority patent/US20090042807A1/en
Priority to AU2008261169A priority patent/AU2008261169A1/en
Priority to US12/386,135 priority patent/US20110105415A1/en
Priority to US12/802,967 priority patent/US20100297258A1/en
Priority to US13/065,317 priority patent/USRE43309E1/en
Abandoned legal-status Critical Current

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Definitions

  • Gene control is generally thought to occur at four levels: 1) transcription (either initiation or termination), 2) processing of primary transcripts, 3) stabilization or destabilization of mRNAs, and 4) mRNA translation.
  • the primary function of gene control in cells is to adjust the enzymatic machinery of the cell to its nutritional, chemical and physical environment.
  • the membrane-impermeable signal molecules include acetylcholine, growth factors, extracellular matrix components, thrombin, lysophosphatidic acid, the yeast mating factors and, for the social amoeba Dictyostellium discoideum , folic acid and cyclic AMP. They are recognized by receptors, which are localized on the plasma membrane of the cell. The receptors are specific for one particular signal molecule or a family of closely related signal molecules. Upon binding of their ligands, these receptors transduce the signals by several mechanisms.
  • cyclopentenone prostaglandins may be endogenous anti-inflammatory mediators and promote the resolution of inflammation in vivo. Others have shown a temporal shift to the production of anti-inflammatory lipoxins during the resolution of inflammation. In recent years, apoptosis has been identified as an important mechanism for the resolution of inflammation in vivo. It has been postulated that defects in leukocyte apoptosis are important in the pathogenesis of inflammatory disease. In addition, the selective induction of apoptosis in leukocytes may offer a new therapeutic approach to inflammatory disease.
  • NF-kappaB is thought by many to be a primary effector of disease (A. S. Baldwin, J. Clin. Invest., 2001, 107:3-6), numerous efforts are underway to develop safe inhibitors of NF-kappaB to be used in treatment of both chronic and acute disease situations. Specific inhibitors of NF-kappaB should reduce side effects associated with drugs such as NSAIDS and glucocorticoids and would offer significant potential for the treatment of a variety of human and animal diseases.
  • peptides or analogues can be circularised (for example by providing them with (terminal) cysteines, dimerised or multimerised, for example by linkage to lysine or cystein or other compounds with side-chains that allow linkage or multimerisation, brought in tandem- or repeat-configuration, conjugated or otherwise linked to carriers known in the art, if only by a labile link that allows dissociation.
  • the invention also provides a signalling molecule for modulating expression of a gene in a cell comprising a small peptide or functional analogue or derivative thereof.
  • a small peptide acts as a signalling molecule that can modulatesignal transduction pathways and gene expression.
  • a functional analogue or derivative of a small peptide that acts as such a signalling molecule for modulating expression of one or more genes in a cell can be identified or obtained by at least one of various methods for finding such a signalling molecule as provided herein.
  • the I ⁇ B family is characterized by the presence of multiple copies of ankyrin repeats, which are protein-protein interaction motifs that interact with NF- ⁇ B via the RHD.
  • I ⁇ B phosphorylated by I ⁇ B kinases (IKKs), polyubiquitinated by a ubiquitin ligase complex, and degraded by the 26S proteosome. Consequently, NF- ⁇ B is released and translocates into the nucleus to initiate gene expression.
  • IKKs I ⁇ B kinases
  • NF- ⁇ B related transcription factors regulate the expression of a wide variety of genes that play critical roles in innate immune responses.
  • NF- ⁇ B target genes include those encoding cytokines (e.g., IL-1, IL-2, IL-6, IL-12, TNF- ⁇ , LT ⁇ , LT ⁇ , and GM-CSF), adhesion molecules (e.g., ICAM, VCAM, endothelial leukocyte adhesion molecule [ELAM]), acute phase proteins (e.g., SAA), and inducible enzymes (e.g., iNOS and COX-2).
  • cytokines e.g., IL-1, IL-2, IL-6, IL-12, TNF- ⁇ , LT ⁇ , LT ⁇ , and GM-CSF
  • adhesion molecules e.g., ICAM, VCAM, endothelial leukocyte adhesion molecule [ELAM]
  • SAA endothelial leukocyte adhesion molecule
  • NF-kappaB is rapidly activated upon microbial and viral invasion, and this activation usually correlates with resistance of the host to infection.
  • persistent activation of NF-kappaB may lead to the production of excessive amounts of pro-inflammatory mediators such as IL-12 and TNF-alpha, resulting in tissue damage, as in insulin dependent diabetes mellitus, atherosclerosis, Crohn's disease, organ failure, and even death of the host, as in bacterial infection-induced septic shock.
  • the invention surprisingly provides a signalling molecule capable of modulating expression of a gene in a cell, the molecule being a short peptide, preferably of at most 30 amino acids long or a functional analogue or derivative thereof.
  • the peptide is an oligopeptide of from about 3 to at about 15 amino acids long, preferably 4 to 12, more preferably 4 to 9, most preferably 4 to 6 amino acids long, or a functional analogue or derivative thereof.
  • signalling molecule can be longer, for example by extending it (N- and/or C-terminally, with more amino acids or other side groups, which can for example be (enzymatically) cleaved off when the molecule enters the place of final destination. Such extension may even be preferable to prevent the signalling molecule from becoming active in an untimely fashion, however, the core or active fragment of the molecule comprises the aforementioned oligopeptide or analogue or derivative thereof.
  • the invention provides a modulator of NF-kappaB/Rel protein activation comprising a signalling molecule according to the invention.
  • modulators are widely searched after these days.
  • the invention provides use of a signalling molecule according to the invention for the production of a pharmaceutical composition for the modulation of gene expression.
  • the treatment comprises administering to the subject a pharmaceutical composition comprising an oligopeptide or functional analogue thereof also capable of reducing production of NO by a ceel, for example wherein the composition comprises at least two oligopeptides or functional analogues thereof each capable of reducing production of NO and/or TNF-alpha by a cell, in particular wherein the at least two oligopeptides are selected from the group LQGV, AQGV and VLPALP.
  • a signal molecule is administered in an effective concentration to an animal or human systemically, e.g. by intravenous, intra-muscular or intraperitoneal administration.
  • Another way of administration comprises perfusion of organs or tissue, be it in vivo or ex vivo, with a perfusion fluid comprising a signal molecule according to the invention.
  • Topical administration e.g. in ointments or sprays, may also apply, e.g. in inflammations of the skin or mucosal surfaces of for example mouth, nose and/or genitals.
  • Suitable approach for single dose delivery of an active molecule in accordance with the present invention involves the use of viscous installates.
  • high molecular weight carriers are used in admixture with the active molecule, giving rise to a structure which produces a solution with high viscosity.
  • Suitable high molecular weight carriers include, but are not limited to, the following: dextrans and cyclodextrans; hydrogels; (cross-linked) viscous materials, including (cross-linked) viscoelastics; carboxymethylcellulose; hyaluronic acid; and chondroitin sulfate.
  • dextrans and cyclodextrans include, but are not limited to, the following: dextrans and cyclodextrans; hydrogels; (cross-linked) viscous materials, including (cross-linked) viscoelastics; carboxymethylcellulose; hyaluronic acid; and chondroitin sulfate.
  • the preparation and use of drug-loaded viscous instillates is well
  • NF-kappaB/Rel proteins are a group of structurally related and evolutionarily conserved proteins (Rel). Well known are c-Rel, RelA (p65), RelB, NF-kappaB 1 (p50 and its precursor p105), and NF-kappaB2 (p52 and its precursor p100). Most NF-kappaB dimers are activators of transcription, p50/p50 and p52/p52 homodimers repress the transcription of their target genes. All NF-kappaB/Rel proteins share a highly conserved NH2-terminal Rel homology domain (RHD). RHD is responsible for DNA binding, dimerization, association with inhibitory proteins known as IkappaBs.
  • RHD NH2-terminal Rel homology domain
  • IkappaB Upon appropriate stimulation, IkappaB is phosphorylated by IkappaB Kinase (IKKs), polyubiquitinated by ubiquitin ligase complex, and degraded by the 26S proteosome. NF-kappaB is released and translocates into nucleus to initiate gene expression.
  • IKKs IkappaB Kinase
  • NF-kappaB NF-kappaB is released and translocates into nucleus to initiate gene expression.
  • the invention also provides a method to mitigate or treat neonatal lung disease, also called chronic lung disease of prematurity, a condition often seen with premature children who develop a prolonged pulmonary inflammation or bronchopulmonary dysplasia. Treating such premature children with an NF-kappaB inhibitor, such as oligopeptide LQGV, or functional analogue or derivative thereof, as provided herein allows such lung conditions to be prevented or ameliorated as well.
  • neonatal lung disease also called chronic lung disease of prematurity
  • an NF-kappaB inhibitor such as oligopeptide LQGV, or functional analogue or derivative thereof, as provided herein allows such lung conditions to be prevented or ameliorated as well.
  • the invention thus also provides a method of treatment of a bone disease, such as osteoporosis (which is often, but not exclusively seen with post-meno-pausal women) Furthermore, NO and TNF-alpha modulators as provided herein inhibit the inflammatory response and bone loss in periodontitis. Furthermore, considering that there is a correlation between TNF-alpha activity, and severity of clinical manifestations in ankylosing spondylitis, the invention provides the treatment of spondylitis by use of a signalling molecule as provided herein.
  • PAMPS Pathogen associated molecular patterns
  • LPS lipopolysaccharides
  • BLP lipoproteins
  • PPN peptidoglycans
  • LAM lipoarabinomannan
  • LTA lipoteichoic acid
  • a signalling molecule according to the invention is found in the prevention or mitigation of ischemia-related tissue damage seen after infarcts, seen for example in vivo in brain or heart, or ex vivo in organs or tissue that is being prepared or stored in preparation of further use as a transplant. Ischemia related tissue damage can now be mitigated by perfusing the (pre)ischemic area with a signalling molecule according to the invention that inhibits NF-kappaB activation.
  • the invention provides a method for perfusing a transplant with a perfusing fluid comprising at least one signalling molecule according to the invention; ischemic or pre-implantation damage due to activation of NF-kappaB in the transplant can than greatly be diminished, allowing a wider use of the transplants.
  • the invention provides a method and a signalling molecule for the treatment of conditions that are associated with dysfunctional LDL receptors such as ApoE and other members of the apolipoprotein family.
  • a signalling molecule comprising GVLPALPQ and/or VLPALP or a functional analogue or derivative thereof is preferred.
  • the invention provides the use of a signalling molecule according to the invention for the preparation of a pharmaceutical composition or medicament for modulating angiogenesis or vascularisation, in particular during embryonal development, or after transplantation to stimulate vascularisation into the transplanted organ or inhibit it in a later phase.
  • Signalling molecules that effect angiogenesis are disclosed herein in the detailed description.
  • FIGS. 20 - 32 In vivo treatment of fertilised chicken eggs with NMPF and the effect of NMPF on angiogenesis. Fertile chicken eggs (day 0) were treated with either PBS, NMPF, VEGF or VEGF in combination with NMPF. Ten eggs were injected for every condition. On day 8 of incubation, the embryos were removed from the eggs and were placed in a 100-mm Petri dish. The embryo and the blood vessels were photographed in vivo with the use of a microscope. Of each egg one overview picture was taken and 4 detail pictures of the blood vessels were taken. Quantification of angiogenesis (vessels branches) was accomplished by counting the number of blood vessels branches. Quantification of this vasculogenesis was accomplished by measuring the blood vessel thickness.
  • FIG. 50 show the NO production of LPS (10 ⁇ g/ml) stimulated RAW 264.7 macrophages co-stimulated with different NMPF peptides (1 pg/ml).
  • FIG. 51 These figures show the NO production of LPS (10 ⁇ g/ml) stimulated RAW 264.7 macrophages co-stimulated with different NMPF peptides with three different concentrations.
  • NF-kappaB which can be activated within minutes by a variety of stimuli, including membrane receptors (for example pattern recognition receptors like Toll-like receptor binding to pathogen-associated molecular patterns), inflammatory cytokines such as TNF- ⁇ , IL-1, T-cell activation signals, growth factors and stress inducers.
  • Apolipoprotein E (apo E) deficiency is associated with a series of pathological conditions including dyslipidemia, atherosclerosis, Alzheimer's disease, increase body weight and shorter life span. Inheritance of different alleles of the POLYMORPHIC apoE gene is responsible for 10% of the variation in plasma cholesterol in most populations. Individuals HOMOZYGOUS for one variant. apoE2, can develop type III dysbetalipoproteinaemia if an additional genetic or environmental factor is present. Some much rarer alleles of apoE produce dominant expression of this disorder in heterozygous individuals.
  • ApoE is a ligand for the LDL receptor and its effects on plasma cholesterol are mediated by differences in the affinity of the LDL receptor for lipoproteins carrying variant apoE proteins.
  • the factors that regulate apoE gene transcription have been investigated extensively by the expression of gene constructs in transgenic mice and involve complex interactions between factors that bind elements in the 5′ promoter region, in the first intron and in 3′ regions many kilobases distant from the structural gene.
  • Deletion of the apo E gene is associated with changes in lipoprotein metabolism [plasma total cholesterol), HDL cholesterol, HDL/TC, and HDL/LDL ratios, esterification rate in apo B-depleted plasma, plasma triglyceride, hepatic HMG-CoA reductase activity, hepatic cholesterol content, decreased plasma homocyst(e)ine and glucose levels, and severe atherosclerosis and cutaneous xanthomatosis.
  • peptides that show the modulation of translocation of NF-kB are: (NMPF-1)VLPALPQVVC, (NMPF-2)LQGVLPALPQ, (NMPF-3)LQG, (NMPF-4)LQGV, (NMPF-5)GVLPALPQ, (NMPF-6)VLPALP, (NMPF-7)VLPALPQ, (NMPF-8)GVLPALP, (NMPF-9)VVC, (NMPF-11)MTRV, (NMPF-12)MTR.
  • FIG. 34 shows HPLC chromatograph (wave length 206) in which data profile obtained from the nuclear protein extracts of LPS and LPS in combination with NMPF-4 (LQGV) stimulated RAW264.7 cells are overlayed. This figure also show the presence or absence of number of molecule signals in the nuclear extracts of oligopeptide+LPS treated cells as compared to nuclear extracts of LPS treated cells. Since HPLC profile of LQGV showed that the peptide elutes at around 12 minutes (data not shown), fraction corresponding to region 10-15 minutes was collected and analysed for the presence of this peptide in MS.
  • FIG. 35 shows some other molecular weights. This is to be explained by the high concentration of the peptide which induces the formation of dimers and sodium-adducts (m/z 416-[M+H]+, 438-[M+Na]+, 831-[2M+H]+, 853-[2M+Na]+, 1245-[3M+H]+, 1257-[3M+Na]+).
  • FIG. 36 shows the MS results of 10-15 min. fraction of nuclear extract obtained from LPS stimulated cells. These results show the absence of 416 dalton mass, while FIG. 37 shows the presence of 416 dalton mass of which the MSn data (FIG. 37) and MS-sequence confirm the presence of LQGV peptide in the nuclear protein extract obtained from LQGV+LPS stimulated RAW264.7 cells.
  • mice were injected i.p. either with 10 mg/kg or with 11 mg/kg LPS ( E. coli 026:B6; Difco Lab., Detroit, Mich., USA). Subsequently mice were treated after 2 hours and 24 hours of LPS treatment with NMPF peptides.
  • LPS E. coli 026:B6; Difco Lab., Detroit, Mich., USA.
  • FIGS. 4 - 7 there is a significant decrease in cell yield in LPS treated BM cells as compared to PBS.
  • NMPF have immunoregulatory effects in chronic inflammatory as well as acute inflammatory mice models. Since certain cytokines like TGF-beta1, TNF-alpha, IL-1 and ROS (reactive oxygen species) have been implicated in irreversible myocardial damage produced by prolonged episodes of coronary artery occlusion and reperfusion in vivo that leads to ischaemia and myocardial infarct, we tested the cardio-protective properties of peptides in ad libitum fed male Wistar rats (300 g).
  • the coronary artery was re-occluded and was perfused with 10 ml Trypan Blue (0.4%, Sigma Chemical Co.) to stain the normally perfused myocardium dark blue and delineate the nonstained area at risk (AR).
  • the heart was then quickly excised and cut into slices of 1 mm from apex to base. From each slice, the right ventricle was removed and the left ventricle was divided into the AR and the remaining left ventricle, using micro-surgical scissors. The AR was then incubated for 10 min in 37° C. Nitro-Blue-Tetrazolium (Sigma Chemical Co.; 1 mg per 1 ml Sorensen buffer, pH 7.4), which stains vital tissue purple but leaves infarcted tissue unstained. After the infarcted area (IA) was isolated from the noninfarcted area, the different areas of the LV were dried and weighed separately. Infarct size was expressed as percentage of the AR. Control rats were treated with PBS.
  • FIGS. 20 - 30 show that NMPF 3, 4, 9 and 11 promoted angiogenesis (p ⁇ 0.05), while NMPF VEGF, 7, 43, 44, 45, 46, 51 and 56 inhibited angiogenesis (p ⁇ 0.05).
  • NMPF 6, 7, 12, 45, 46 and 66 were able to inhibit angiogenesis induced by VEGF.
  • NMPF 6 itself did not show any effect on angiogensis, but it inhibited (p ⁇ 0.05) NMPF 3 induced angiogenesis.
  • the RAW 264.7 murine macrophage cell line obtained from American Type Culture Collection (Manassas, Va., USA), were cultured at 37° C. in 5% CO 2 using DMEM containing 10% fetal calf serum (FCS), 50 U/ml penicillin, 50 ⁇ g/ml streptomycin, 0.2 M Na-pyruvate, 2 mM glutamine and 50 ⁇ M 2-mercaptoethanol (Bio Whittaker, Europe). The medium was changed every 2 days.
  • FCS fetal calf serum
  • penicillin 50 ⁇ g/ml streptomycin
  • 0.2 M Na-pyruvate 2 mM glutamine
  • 2-mercaptoethanol Bio Whittaker, Europe
  • the invention provides a method and a signalling molecule for the treatment of conditions that are associated with dysfunctional LDL receptors such as ApoE and other members of the apolipoprotein family.
  • a signalling molecule comprising GVLPALPQ (NMPF-5) and/or VLPALP (NMPF-6) or a functional analogue or derivative thereof is preferred.
  • AI188872 11.3 366 327 18 382 [ Homo sapiens ]qd27c01.x1 Soares_placenta — 8 to 9weeks — 2NbHP8 to 9W
  • AI126906 19.8 418 343 1 418 [ Homo sapiens ]qb95f01.x1 Soares_fetal_heart_NbHH19W
  • AI221581 29.1 456 341 23 510 [ Homo sapiens ]qg20a03.x1 Soares_placenta — 8 to 9 weeks 2 NbHP8 to 9W Homo sapiens cDNA clone IMAGE:1760044 3′ similar to gb:J00117 CHORIOGONADOTROPIN BETA CHAIN PRECURSOR (HUMAN);, mRNA sequence.; minus strand; translated
  • VLQAILPSAPQ LQA, LQAIL, PSAP, LPS
  • VLQAILPSAPQ LQA, LQAIL, PSAP, PSAPQ
  • Hs.303116.2 PROTSIM pir; T33097 stromal cell-derived factor 2-like1; translated
  • MMRVLQAVLPPLPQVVC MMR, MMRV, LQA, LQAV, VLPPLP, PPLP, QVVC, VVC, VLPPLPQ, AVLPPLP, AVLPPLPQ
  • MMRVLQAVLPPVPQVVC MMR, MMRV, LQA, LQAG, VLPPVP, VLPPVPQ, QVVC, VVC, AVLPPVP, AVLPPVPQ
  • NMPF a mixture 1:1:1 of LQGV, AQGV and VLPALP
  • NMPF a mixture 1:1:1 of LQGV, AQGV and VLPALP
  • Overwhelming inflammatory and immune responses are essential features of septic shock and play a central part in the pathogenesis of tissue damage, multiple organ failure, and death induced by sepsis.
  • Cytokines especially tumour necrosis factor (TNF)- ⁇ interleukin (IL)-1 ⁇ , and macrophage migration inhibitory factor (MIF) have been shown to be critical mediators of septic shock. Yet, traditional anti-TNF and anti-IL-1 therapies have not demonstrated much benefit for patients with severe sepsis.
  • the monkeys were kept anaesthetized throughout the observation period and sacrificed 7 hours after the start of the bacterium infusion for pathological examination.
  • the animals underwent a gross necropsy in which the abdominal and throrac cavities were opened and internal organs examined in situ.
  • the Escherichia coli strain was purchased from ATCC ( E - coli; 086a: K61 serotype, ATCC 33985). In a control experiment the strain proved equally susceptible to bactericidal factors in human and rhesus monkey serum.
  • E.coli dose was used to calculate the E.coli dose and E.coli stock was suspended in isotonic saline (N.P.B.I., Emmer-Compascuum, The Netherlands) at the concentration needed for infusion (total dose volume for infusion approximately 10 ml/kg.
  • the E.coli suspension was kept on ice until infusion.
  • the femoral or the cephalic vein was cannulated and used for infusing isotonic saline, live E.coli and antibiotic administration. Insensible fluid loss was compensated for by infusing isotonic saline containing 2.5% glucose (Fresenius, 's Hertogenbosch, The Netherlands) at a rate of 3.3 ml/kg/hr.
  • Baytril was administered intravenously immediately after completion of the 2 h. E.coli infusion (i.v.; dose 9 mg/kg).
  • NMPF NMPF oligopeptide
  • LQGV LQGV
  • AQGV AQGV
  • VLPALP VLPALP
  • Tissues of all organs were preserved in neutral aqueous phosphate buffered 4% solution of formaldehyde. Lymphoid organs were be cryopreserved. All tissues will be processed for histopathological examination.
  • the gene chip expression analysis revealed that due to LQGV treatment of PM1 (T-cell line) cells for 4 hours in the presence of PHA/IL-2 down-regulated at least 120 genes more than 2 fold as compared to control PM1 cells (stimulated with PHA/IL-2) only. Moreover, at least 6 genes were up-regulated more than 2 fold in peptide treated cells as compared to control cells.
  • HEF1 Homo sapiens enhancer of filamentation
  • H.sapiens NAP nucleosome assembly protein
  • complete cds /cds (75,1250)
  • Some diseases associated with dysregulation of NF-kB and related transcription factors are: Atherosclerosis, asthma, arthritis, anthrax, cachexia, cancer, diabetes, euthyroid sick syndrome, AIDS, inflammatory bowel disease, stroke, (sepsis) septic shock, inflammation, neuropathological diseases, autoimmunity, thrombosis, cardiovascular disease, psychological disease, post surgical depression, wound healing, burn-wounds healing and neurodegenerative disorders.
  • PKC plays an essential role in T cell activation via stimulation of for example AP-1 and NF-kB that selectively translocate to the T cell synapse via Vav/Rac pathway.
  • PKC is involved in a variety of immunological and non-immunological diseases as is clear from standard text books of internal medicine (examples are metabolic diseases, cancer, angiogenesis, immune mediated disorders, diabetes etc.)
  • LPS and ceramide induce differential multimeric receptor complexes, including CD14, CD11b, Fc-gRIII, CD36, TAPA, DAF and TLR4. This signal transduction pathway explains the altered function of monocytes in hypercholesterolemia and lipid disorders.
  • Oxidized low-density lipoproteins contribute to stages of the atherogenic process and certain concentrations of oxidized low-density lipoproteins induce apoptosis in macrophages through signal transduction pathways. These pathways are involved in various vascular diseases such as atherosclerosis, thrombosis etc.
  • TLR9 Toll like receptor 9
  • MyD88 Toll like receptor 9
  • TLR9 Toll like receptor 9
  • MyD88 Toll like receptor 9
  • Recognition of dsRNA during viral infection seems to be dependent on intracellular recognition by the dsRNA dependent protein kinase PKR.
  • TLRs play an essential role in the immune system and they are important in bridging and balancing innate immunity and adaptive immunity. Modulation of these receptors or their down-stream signalling pathways are important for the treatment of various immunological conditions such as infections, cancer, immune-mediated diseases, autoimmunity, certain metabolic diseases with immunological component, vascular diseases, inflammatory diseases etc.
  • PDGF-AA Effect of growth factor PDGF-AA on NF-kB and proinflammatory cytokine expression in rheumatoid synoviocytes; PDGF-AA augmented NF-kB activity and mRNA expression of IL-1b, IL-8 and MIP-1a. Therefore, PDGF-AA may play an important role in progression of inflammation as well as proliferation of synoviocytes in RA.
  • DC activation is a critical event for the induction of immune responses.
  • DC activation induced by LPS can be separated into two distinct processes: first, maturation, leading to upregulation of MHC and costimulatory molecules, and second, rescue from immediate apoptosis after withdrawal of growth factors (survival).
  • LPS induces NF-kB transcription factor. Inhibition of NF-kB activation blocked maturation of DCs in terms of upregulation of MHC and costimulatory molecules.
  • LPS activates the extracellular signal-regulated kinases (ERK), and specific inhibition of MEK1, the kinase which activates ERK, abrogate the ability of LPS to prevent apoptosis but do not inhibit DC maturation or NF-kB nuclear translocation.
  • ERK and NF-kB regulate different aspects of LPS induced DC activation.
  • Our DC data and NF-kB data also show the various effects of NMPF peptide on DC maturation and proliferation in the presence or absence of LPS.
  • NMPF peptides modulate these pathways and are novel tools for the regulation of DC function and immunoregulation. This opens new ways for the treatment of immune diseases, particularly those in which the immune system is in disbalance (DC1-DC2, Th1-Th2, regulatory cell etc.)
  • DC cells and other antigen presenting cells like macrophages, B-cells
  • DC cells and other antigen presenting cells play an essential role in the immune system and they are also important in bridging and balancing innate immunity and adaptive immunity. Modulation of these cells or their down-stream signalling pathways are important for the treatment of various immunological conditions such as infections, cancer, immune-mediated diseases, autoimmunity, certain metabolic diseases with immunological component, vascular diseases, inflammatory diseases etc.
  • mast cells play important roles in exerting the innate immunity by releasing inflammatory cytokines and recruitment of neutrophils after recognition of infectious agents through TLRs on mast cells.
  • STAT1 In murine macrophages infected with Mycobacterium tuberculosis through JAK pathway activate STAT1 and activation of STAT1 may be the main transcription factor involved in IFN-g-induced MHC class II inhibition.
  • MBL mannose-binding lectin
  • NFkappaB Nuclear factor-kappaB
  • PPARs Peroxisome proliferator-activated receptors
  • PPAR alpha is highly expressed in liver, muscle, kidney and heart, where it stimulates the beta-oxidative degradation of fatty acids.
  • PPAR gamma is predominantly expressed in intestine and adipose tissue, where it triggers adipocyte differentiation and promotes lipid storage. Recently, the expression of PPAR alpha and PPAR gamma was also reported in cells of the vascular wall, such as monocyte/macrophages, endothelial and smooth muscle cells.
  • hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPAR alpha and PPAR gamma, respectively.
  • fatty acid-derivatives and eicosanoids are natural PPAR ligands: PPAR alpha is activated by leukotriene B4, whereas prostaglandin J2 is a PPAR gamma ligand, as well as of some components of oxidized LDL, such as 9- and 13-HODE.
  • PPAR activators were shown to inhibit the activation of inflammatory response genes (such as IL-2, IL-6, IL-8, TNF alpha and metalloproteases) by negatively interfering with the NF-kappa B, STAT and AP-1 signalling pathways in cells of the vascular wall.
  • inflammatory response genes such as IL-2, IL-6, IL-8, TNF alpha and metalloproteases
  • PPARs may also control lipid metabolism in the cells of the atherosclerotic plaque.
  • PPARs are also involved in a variety of immunological and non-immunological diseases as is clear from standard text books of internal medicine (examples are metabolic diseases, cancer, angiogenesis, immune mediated disorders, diabetes etc.)
  • Proliferative diabetic retinopathy is one of the major causes of acquired blindness.
  • the hallmark of PDR is neovascularisation (NV), abnormal angiogenesis that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment.
  • NV neovascularisation
  • NMPF peptides have angiogenesis stimulatory as well as inhibitory effects and have the ability to modulate intracellular signaling involved in growth factors (like insulin)
  • pharmacologic therapy with certain NMPF peptides can improve metabolic control (like glucose) or blunt the biochemical consequences of hyperglycaemia (through mechanisms such as in which aldose reductase, protein kinase C (PKC), PPARs are involved).

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EP01203748A EP1300418A1 (de) 2001-10-04 2001-10-04 Genregulation durch Oligopeptide
US10/028,075 US20030113733A1 (en) 2001-10-04 2001-12-21 Gene regulator
EP02763111A EP1432733B1 (de) 2001-10-04 2002-10-04 Methode zur Identifikation gen-regulierender Peptide
JP2003532537A JP2005519867A (ja) 2001-10-04 2002-10-04 遺伝子制御ペプチド
AU2002328028A AU2002328028B2 (en) 2001-10-04 2002-10-04 Gene regulatory peptides
KR10-2004-7005020A KR20040074975A (ko) 2001-10-04 2002-10-04 유전자 조절 펩티드
EP08171373A EP2036924B1 (de) 2001-10-04 2002-10-04 Gen-regulierende Peptide
CNA028242947A CN1599753A (zh) 2001-10-04 2002-10-04 基因调节肽
AT02763111T ATE517915T1 (de) 2001-10-04 2002-10-04 Methode zur identifikation gen-regulierender peptide
HK04106110.8A HK1063327B (en) 2001-10-04 2002-10-04 Method for identifying gene regulatory peptides
NZ532173A NZ532173A (en) 2001-10-04 2002-10-04 Signalling molecules for modulating gene expression particularly transcription factors derived from hCG
CN200910163475A CN101721676A (zh) 2001-10-04 2002-10-04 基因调节肽
IL16120102A IL161201A0 (en) 2001-10-04 2002-10-04 Gene regulatory peptides
EP08171382A EP2060585A3 (de) 2001-10-04 2002-10-04 Gen-regulierende Peptide
AT08171373T ATE535542T1 (de) 2001-10-04 2002-10-04 Gen-regulierende peptide
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PCT/NL2002/000639 WO2003029292A2 (en) 2001-10-04 2002-10-04 Gene regulatory peptides
US10/409,671 US20030220261A1 (en) 2001-12-21 2003-04-08 Treatment of iatrogenic disease
US10/409,694 US20030224995A1 (en) 2001-12-21 2003-04-08 Treatment of burns
US10/409,654 US20030220259A1 (en) 2001-12-21 2003-04-08 Treatment of neurological disorders
US10/409,657 US20040013661A1 (en) 2001-12-21 2003-04-08 Stratification
US10/409,659 US20030220260A1 (en) 2001-12-21 2003-04-08 Peptide compositions
US10/409,027 US7501391B2 (en) 2001-12-21 2003-04-08 Treatment of transplant survival
US10/409,630 US7560433B2 (en) 2001-12-21 2003-04-08 Treatment of multiple sclerosis (MS)
US10/409,642 US20030220258A1 (en) 2001-12-21 2003-04-08 Treatment of ischemic events
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US10/753,510 US7358330B2 (en) 2001-03-29 2004-01-07 Immunoregulatory compositions
IL161201A IL161201A (en) 2001-10-04 2004-03-31 Signalling molecules derived from hcg for modulating gene expression
US10/817,756 US20050214943A1 (en) 2001-10-04 2004-04-02 Gene regulatory peptides
US10/821,240 US20050037430A1 (en) 2000-03-29 2004-04-08 Methods and uses for protein breakdown products
US11/346,761 US7524820B1 (en) 2001-10-04 2006-02-03 Compounds of therapeutic value in the treatment of multiple sclerosis and other diseases wherein foamy cells are involved in the disease etiology
US11/593,329 US8216998B2 (en) 2001-12-21 2006-11-06 Treatment of ischemic events
US11/859,265 US20080076719A1 (en) 2001-03-29 2007-09-21 Immunoregulatory compositions
US11/986,043 US20080242837A1 (en) 2001-12-21 2007-10-30 Peptide compositions
US11/981,505 US7786084B2 (en) 2001-12-21 2007-10-30 Treatment of burns
US11/981,491 US20080194489A1 (en) 2001-12-21 2007-10-30 Treatment of iatrogenic disease
US11/982,293 US20080242618A1 (en) 2001-12-21 2007-10-31 Stratification
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US12/001,035 US20080176243A1 (en) 2001-10-04 2007-12-06 Gene regulator
US12/069,401 US20080306009A1 (en) 2001-03-29 2008-02-08 Immunoregulatory compositions
US12/074,020 US20090042807A1 (en) 1998-05-20 2008-02-29 Oligopeptide treatment of ischemia reperfusion injury
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US12/386,135 US20110105415A1 (en) 2001-10-04 2009-04-14 Gene regulator
US12/802,967 US20100297258A1 (en) 2001-12-21 2010-06-16 Treatment of burns
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US10/409,630 Continuation-In-Part US7560433B2 (en) 2001-12-21 2003-04-08 Treatment of multiple sclerosis (MS)
US10/409,671 Continuation-In-Part US20030220261A1 (en) 2001-12-21 2003-04-08 Treatment of iatrogenic disease
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US20040138096A1 (en) * 1998-05-20 2004-07-15 Erasmus Universiteit Rotterdam Immunoregulator
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WO2005116051A3 (de) * 2004-05-25 2006-03-02 Immatics Biotechnologies Gmbh An mhc-moleküle bindende tumor-assoziierte peptide
US20060111292A1 (en) * 2003-04-08 2006-05-25 Biotempt, B.V. Compositions for mucosal and oral administration comprising HCG fragments
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