[go: up one dir, main page]

WO2003065979A2 - Procedes de diagnostic, de controle et de traitement de la sterilite - Google Patents

Procedes de diagnostic, de controle et de traitement de la sterilite Download PDF

Info

Publication number
WO2003065979A2
WO2003065979A2 PCT/US2002/038629 US0238629W WO03065979A2 WO 2003065979 A2 WO2003065979 A2 WO 2003065979A2 US 0238629 W US0238629 W US 0238629W WO 03065979 A2 WO03065979 A2 WO 03065979A2
Authority
WO
WIPO (PCT)
Prior art keywords
mtf
dopachrome
mif
fertility
seminal fluid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2002/038629
Other languages
English (en)
Other versions
WO2003065979A3 (fr
Inventor
Yousef Ai-Abed
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Feinstein Institutes for Medical Research
Original Assignee
North Shore Long Island Jewish Research Institute
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by North Shore Long Island Jewish Research Institute filed Critical North Shore Long Island Jewish Research Institute
Priority to AU2002365941A priority Critical patent/AU2002365941A1/en
Publication of WO2003065979A2 publication Critical patent/WO2003065979A2/fr
Publication of WO2003065979A3 publication Critical patent/WO2003065979A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/533—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving isomerase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors

Definitions

  • the present invention (1) generally relates to methods of using dopachrome tautomerase activity of macrophage migration inhibitory factor (MIF) and related or other proteins present in the seminal fluid (ejaculate) to evaluate fertility and other related diseases; (2) relates to the diagnosis and treatment of fertility; and (3) new methods of contraceptive.
  • MIF macrophage migration inhibitory factor
  • MTF macrophage migration inhibitory factor
  • MIF pro-inflammatory counter-regulator of the anti-inflammatory activities of the glucocorticoids.
  • rMIF purified, recombinant MTF
  • neutralizing anti-MTF antibodies were found to fully protect mice from an otherwise lethal LPS challenge, demonstrating that MTF, like TNF ⁇ , EL-l, and IFN ⁇ , plays a critical role in the inflammatory network leading to endotoxic shock and death (4).
  • MTF also is released from the same pituitary cell-type that releases adrenocorticotropic hormone (ACTH), a mediator that stimulates the adrenal secretion of glucocorticoids, potent anti-inflammatory hormones (5).
  • ACTH adrenocorticotropic hormone
  • MIF thus became the first mediator to be described that is actively released from cells upon glucocorticoid stimulation (6).
  • MIF expression abrogates the anti- inflammatory and immunosuppressive effect of glucocorticoids production on pro- inflammatory cytokines (TNF ⁇ , E -l, IL-2, IL-6, and TL-8).
  • mice In mice, the administration of rMIF together with dexamethasone completely blocks the protective effects of dexamethasone on LPS lethality (6).
  • the various pro-inflammatory effects of MIF appear to originate with the unique activity of MIF to override or counter-regulate the normal physiological inhibition of immune cell activation and pro-inflammatory cytokine cascades by glucocorticoids.
  • MTF has recently been implicated as a tumor angiogenic factor in cancer (10-11).
  • the recombinant human and mouse MIF proteins (rhuM F and rmuMIF, respectively) are 90% identical throughout their respective 115 amino acid sequences and have been compared biochemically to native muMIF prepared from liver, a rich source of MTF (12).
  • X- ray analysis of crystals formed from human or rat MIF indicates that the protein has a trimeric structure (13-18).
  • the MIF monomer comprises an / ⁇ structure that forms a homotrimer with dimensions of approximately 35A x 5 ⁇ A x 5 ⁇ A.
  • six -helices surround three ⁇ -sheets that completely wrap around to form a barrel containing a solvent- accessible channel (15).
  • MTF three-dimensional structure has defined a new protein fold and structural superfamily that so far has been found to be shared only with two small isomerases of bacterial origin, namely, 4-oxalocrotonate tautomerase (4-OT) and carboxymethyl hydroxymuconate isomerase (CHMI) (19).
  • MIF tautomerizes D-dopachrome or L-dopachrome methyl ester to their corresponding indole derivatives.
  • phenylpyruvic acid, p-hydroxyphenylpyruvic acid, 3,4-dihydroxyphenyliminochrome and norepinephrinechrome also have been found be recognized by MTF as substrates.
  • MTF displays weak primary sequence homology (27%) with the enzyme D-dopachrome tautomerase.
  • MTF catalyzes the tautomerization of D-dopachrome less efficiently than D-dopachrome tautomerase (20). MTF also catalyzes the enolization of phenylpyruvate and the ketonization of p-hydroxyphenylpyruvate (21,22).
  • MTF has been shown to exhibit significant structural (but no primary amino acid sequence) homology with bacterial enzymes 4-OT and CHMI (19). These bacterial proteins catalyze the tautomerization of low-molecular weight, unsaturated ketones.
  • 4-OT catalyzes the ketonization of 2-oxo-4-hexene-l,6-dioate, via 2-hydroxymuconate, to yield the ⁇ , ⁇ - unsaturated ketone, 2-oxo-3-hexene-l,6-dioate
  • CHMI catalyzes the tautomerization of 5-(carboxymethyl)-2-hydroxymuconate to 5-(carboxymethyl)-2-oxo-3-hexene-l,6-dioate (19).
  • MIF has much broader roles beyond its function as a classical cytokine. This is supported by the fact that the Leydig cells of the testis were found to secrete MTF, where it modulated inhibin production of Sertoli cells. Furthermore, MTF shows a unique compensatory production in rat testis. Depletion of the original MTF source, the Leydig cells, by the specific toxin, ethan dimethan sulfonate (EDS), caused a compensatory MTF expression by the Sertoli cells, which were negative in normal rat testis (10).
  • EDS ethan dimethan sulfonate
  • MTF was identified as a new component of the outer dense fibers (ODF), a cytoskeletal element of the mid- and principal piece of the sperm tail.
  • Infertility is diagnosed as the failure to become pregnant after one year of regular unprotected intercourse. About 10% of couples are infertile and it ahs been estimated that the male factor is the sole contributing cause in about forty percent of these cases. Semen analysis forms the basis of the initial evaluation for assessing male-factor infertility. In general, two to three semen analyses are performed because semen quality normally fluctuates for a given individual. Subjects are normally encouraged to refrain from intercourse for 2 to 3 days prior to evaluation. Traditional semen analysis evaluates a number of parameters, including, ejaculate volume, sperm count, sperm motility, forward progression, sperm morphology, pH, agglutination, leukospermia and viscosity.
  • the present invention provides methods of evaluating fertility using the dopachrome tautomerase activity present in the seminal fluid (ejaculate).
  • the present invention established the presence of MTF protein or related forms in the seminal fluid and the level of MIF protein or related forms provide a method of evaluating the fertility profile.
  • the present invention provides that the rate of decolorization (dopachrome tautomerization) can be utilized to evaluate fertility potential by converting an L- or D-dopachrome methyl ester to indol-carboxylic acid methyl ester.
  • the present invention also provides that inhibitors of the MTF tautomerase activity are useful in novel contraceptive strategies and methods.
  • the present invention further provide that MIF or MTF agonists can improve the sperm motility and also can be used to improve in vitro fertilization.
  • the present invention also provide that MIF or MTF antibodies, antagonists or agonist thereof, can be used to improve in vitro fertilization and implantation.
  • Figure 1 shows structures of dopachrome methyl ester, a chromogenic substrate used in enzymatic assays of MIF, and its tautomerized colorless product.
  • Figure 2 shows the presence of immunoreactive MTF by Western blot analysis of seminal fluid. 5 ul of seminal fluid was prepared and treated with 5 uL of Laemli sample buffer and then was electrophoresed, transferred by blotting and detected using anti-MIF antibody as described previously (12).
  • FIG. 3 shows the presence of immunoreactive MTF in Western blot analysis of purified MTF fractions obtained from seminal fluid . Purification was carried out using ion exchange chromatography and gel filtration as described previously (12, 28). Fractions 6, 7 and 8 were active in the dopachrome assay and also rich with MTF as evident by Western blot.
  • assay buffer 50 mM potassium phosphate, pH 6.0, 1 mM EDTA
  • Figure 5 shows an analysis of the dopachrome tautomerase activity in samples of seminal fluid obtained from control and infertile individuals, showing that infertile subjects have dopachrome tautomerase levels that are (i) above, or (ii) below the levels typical of normal controls.
  • MTF is present in the seminal fluid (SF) as shown in Figure 2 by Western blot analysis using specific anti-MTF antibody.
  • Other molecules with higher molecular weight also can be detected. These molecules may represent novel precursors of MIF molecule that may exert critical bioactivity.
  • MIF was purified by diluting the SF by equal volume of Tris-buffered saline and then filtered through a 45 ⁇ m membrane filter and subjected to MONO Q anion exchange chromatography using a fast protein liquid chromatography system (FPLC) (Pharmacia, Piscataway, NJ). The Mono Q column was equilibrated with Tris-buffered saline.
  • FPLC fast protein liquid chromatography system
  • MTF material was eluted with the same buffer in the first flow-through fractions. All collected fractions were analyzed for MTF presence using the rate of decolorization of the reddish dopachrome solution followed by Western blot analysis of active fractions (e.g. fraction 6,7 and 8) as shown in Figure 3.
  • the present invention further provides a method of monitoring fertility by measuring the rate of decolorization of a dopachrome solution as shown in Figure 4.
  • a 25 ⁇ l of seminal fluid obtained from fertile male individual decolorizes 1 ml of 1 mM solution of a dopachrome in 2.5-3.5 minutes ( Figure 5).
  • These results were based on testing 10 control individuals (decolorization times (min): 2.5, 2.5, 3.5, 4, 2.5, 3, 3.5, 2.5, 3, 3).
  • analysis of samples obtained from infertile individuals can be classified in two subgroups.
  • Samples from the first subgroup required less time (0.5-1.0 minutes) to decolorize the dopachrome solution, and comprised 17 infertile individuals with very low sperm counts (less than one million; decolorization times (min): 0.5, 1, 1, 1.5, 1, 0.5, 0.5, 1, 0.5, 1.5, 1.5, 1, 1, 1, 0.5, 0.5, 1) ( Figure 5).
  • the second group of patients (18 infertile individuals with greater than one million sperm counts but with low motility; decolorization times (min): 4, 4.5, 5, 5, 5, 5.5, 6, 6, 7.5, 7, 7, 8, 9, >10, >10, >10, >10, >10) required more than four minutes (Figure 5).
  • the SF of number of azospermia patients required more than 10 minutes to decolorize dopachrome solution and therefore were excluded from Figure 5.
  • Western blot analysis of those azospermia patients revealed the absence of MIF from the SF. .
  • MIF antagonists or substrate-like molecule(s) such as p-hydroxyphenylpyruvate or phenylpyruvate can inhibit MTF dopachrome tautomerase activity in SF.
  • p-hydroxyphenylpyruvate (1- 50 ⁇ M) or phenylpyruvate (1-50 ⁇ M) resulted in the reduction of the sperm motility obtained from fertile male by 10-80% as evident by microscopic analysis of the treated samples versus control (untreated).
  • p-hydroxyphenylpyruvate and phenylpyruvate are considered as MTF substrate and also as dopachrome tautomerase inhibitors, since both compete for the same active site at the surface of MTF. Therefore, a small molecule inhibitor of MTF tautomerase activity or specific antibody can be used to reduce the motility and thereby or otherwise provide a new method for contraceptive treatment.
  • MIF or MTF agonists provides a method to improve sperm motility, which is particularly valuable in the areas of infertility therapy, artificial insemination, and in vitro fertilization.
  • MIF macrophage migration inhibitory factor
  • Onodera S Tanji H, Suzuki K, Kaneda K, Mizue Y, Sagawa A, Nishihira J. (1999) High expression of macrophage migration inhibitory factor in the synovial tissues of rheumatoid joints. Cytokine, 11: 163-167. 9. Donnelly SC, Haslett C, Reid PT, Grant IS, Wallace WA, Metz CN, Bruce LJ, Bucala R.
  • the macrophage migration inhibitory factor MTF is a phenylpyruvate tautomerase.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Zoology (AREA)
  • Urology & Nephrology (AREA)
  • Physics & Mathematics (AREA)
  • Veterinary Medicine (AREA)
  • Biotechnology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Wood Science & Technology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Cell Biology (AREA)
  • Genetics & Genomics (AREA)
  • General Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Food Science & Technology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention porte en général sur des procédés d'utilisation de l'activité de la tautomérase dopachrome du facteur inhibiteur de la migration des macrophages et sur des protéines apparentées ou autres protéines présentes dans le liquide séminal (éjaculat) d'un mâle afin d'évaluer la stérilité et autres pathologies apparentées. L'invention porte également sur le diagnostic et le traitement de la stérilité, sur de nouvelles méthodes contraceptives et sur des procédés visant à améliorer l'insémination artificielle et la fécondation in vitro.
PCT/US2002/038629 2001-12-05 2002-12-05 Procedes de diagnostic, de controle et de traitement de la sterilite Ceased WO2003065979A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002365941A AU2002365941A1 (en) 2001-12-05 2002-12-05 Methods of diagnosis, monitoring and treatment of fertility

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US35575501P 2001-12-05 2001-12-05
US60/355,755 2001-12-05

Publications (2)

Publication Number Publication Date
WO2003065979A2 true WO2003065979A2 (fr) 2003-08-14
WO2003065979A3 WO2003065979A3 (fr) 2004-02-12

Family

ID=27734557

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/038629 Ceased WO2003065979A2 (fr) 2001-12-05 2002-12-05 Procedes de diagnostic, de controle et de traitement de la sterilite

Country Status (2)

Country Link
AU (1) AU2002365941A1 (fr)
WO (1) WO2003065979A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7084141B2 (en) 2001-05-24 2006-08-01 Avanir Pharmaceuticals Inhibitors of macrophase migration inhibitory factor and methods for identifying the same
US7235546B2 (en) 2003-02-14 2007-06-26 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7365200B2 (en) 2005-03-24 2008-04-29 Avanir Pharmaceuticals Thienopyridinone derivatives as macrophage migration inhibitory factor inhibitors
US20120197068A1 (en) * 2009-06-17 2012-08-02 Masayuki Shimada Sperm Diluent Solution and Method for Artificial Insemination Using Same
WO2014120643A1 (fr) * 2013-01-30 2014-08-07 Board Of Regents Of The Nevada System Of Higher Education, On Behalf Of The University Of Nevada, Reno Utilisation de 3-bromopyruvate comme contraceptif
US20180008705A1 (en) * 2005-10-07 2018-01-11 Yale University Use of mif and mif pathway agonists

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6420188B1 (en) * 1996-02-16 2002-07-16 The Picower Institute For Medical Research Screening assay for the identification of inhibitors for macrophage migration inhibitory factor
US6492428B1 (en) * 2000-07-26 2002-12-10 The Picower Institute For Medical Research Compounds having MIF antagonist activity

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7238809B2 (en) 2001-05-24 2007-07-03 Avanir Pharmaceuticals Process for the preparation of inhibitors of macrophage migration inhibitory factor
US7235565B2 (en) 2001-05-24 2007-06-26 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7129236B2 (en) 2001-05-24 2006-10-31 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7157469B2 (en) 2001-05-24 2007-01-02 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7192961B2 (en) 2001-05-24 2007-03-20 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7192955B2 (en) 2001-05-24 2007-03-20 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7202248B2 (en) 2001-05-24 2007-04-10 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7732146B2 (en) 2001-05-24 2010-06-08 Avanir Pharmaceuticals Method for screening an agent that modulates activity of macrophage migration inhibitory factor
US7514225B2 (en) 2001-05-24 2009-04-07 Avanir Pharmaceuticals Method for screening an agent that modulates activity of macrophage migration inhibitory factor
US7435737B2 (en) 2001-05-24 2008-10-14 Avanir Pharmaceutials Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7105519B2 (en) 2001-05-24 2006-09-12 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7084141B2 (en) 2001-05-24 2006-08-01 Avanir Pharmaceuticals Inhibitors of macrophase migration inhibitory factor and methods for identifying the same
US7230106B2 (en) 2001-05-24 2007-06-12 Avanir Pharmaceuticals Process for the preparation of inhibitors of macrophage migration inhibitory factor
US7432374B2 (en) 2001-05-24 2008-10-07 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7235546B2 (en) 2003-02-14 2007-06-26 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7312220B2 (en) 2003-02-14 2007-12-25 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7312221B2 (en) 2003-02-14 2007-12-25 Avanir Pharmaceuticals Inhibitors of macrophage migration inhibitory factor and methods for identifying the same
US7365200B2 (en) 2005-03-24 2008-04-29 Avanir Pharmaceuticals Thienopyridinone derivatives as macrophage migration inhibitory factor inhibitors
US20180008705A1 (en) * 2005-10-07 2018-01-11 Yale University Use of mif and mif pathway agonists
US10765739B2 (en) * 2005-10-07 2020-09-08 Yale University Use of MIF and MIF pathway agonists
US20120197068A1 (en) * 2009-06-17 2012-08-02 Masayuki Shimada Sperm Diluent Solution and Method for Artificial Insemination Using Same
US9439414B2 (en) * 2009-06-17 2016-09-13 Hiroshima University Sperm diluent solution and method for artificial insemination using same
WO2014120643A1 (fr) * 2013-01-30 2014-08-07 Board Of Regents Of The Nevada System Of Higher Education, On Behalf Of The University Of Nevada, Reno Utilisation de 3-bromopyruvate comme contraceptif

Also Published As

Publication number Publication date
AU2002365941A1 (en) 2003-09-02
WO2003065979A3 (fr) 2004-02-12
AU2002365941A8 (en) 2003-09-02

Similar Documents

Publication Publication Date Title
Eickhoff et al. Purification and characterization of macrophage migration inhibitory factor as a secretory protein from rat epididymis: evidences for alternative release and transfer to spermatozoa
Petersen et al. Outer dense fibre proteins from human sperm tail: molecular cloning and expression analyses of two cDNA transcripts encoding proteins of~ 70 kDa
Luo et al. Leydig cell aging: steroidogenic acute regulatory protein (StAR) and cholesterol side‐chain cleavage enzyme
Kleemann et al. Specific reduction of insulin disulfides by macrophage migration inhibitory factor (MIF) with glutathione and dihydrolipoamide: potential role in cellular redox processes
Bunick et al. Developmental expression of testis messenger ribonucleic acids in the rat following propylthiouracil-induced neonatal hypothyroidism
Clarke et al. Regulation of 11 beta-hydroxysteroid dehydrogenase type 2 activity in ovine placenta by fetal cortisol
US20050090474A1 (en) Methods and compositions for enhancing and inhibiting fertilization
US6506587B2 (en) TRF 1 binding protein, methods of use thereof
Bhasin et al. Y-chromosome microdeletions and male infertility
Schlicker et al. Genetics: Disturbances of nuclear condensation in human spermatozoa: search for mutations in the genes for protamine 1, protamine 2 and transition protein 1
WO2011038110A2 (fr) Méthodes de traitement des maladies métaboliques
WO2003065979A2 (fr) Procedes de diagnostic, de controle et de traitement de la sterilite
Moss et al. Conservation and function of a bovine sperm A-kinase anchor protein homologous to mouse AKAP82
Mischke et al. Structure activity studies of the cytokine macrophage migration inhibitory factor (MIF) reveal a critical role for its car☐ y terminus
Mostyn et al. Differential effects of leptin on thermoregulation and uncoupling protein abundance in the neonatal lamb
Zhang et al. Inhibition and reversal of nickel-induced transformation by the histone deacetylase inhibitor trichostatin A
Wheat et al. LDH-X: The sperm-specific C 4 isozyme of lactate dehydrogenase
EP0972015B1 (fr) Enzyme ayant une activite de type s-adenosyl-l-homocysteine hydrolase (ahcy)
Segev et al. Expression patterns of histone deacetylases in bovine oocytes and early embryos, and the effect of their inhibition on embryo development
US20050272636A1 (en) Treatment and diagnosis of a reproductive disorder by measuring or inhibiting interferon-gamma
Bewley et al. Developmental and tissue‐specific control of catalase expression in Drosophila melanogaster: Correlations with rates of enzyme synthesis and degradation
JP2003113111A (ja) 糖尿病治療用医薬
Fox et al. CCl4 Poisoning II: Serum Enzymes, Free Fatty Acids and Liver Pathology; Effects of Phenoxybenzamine and Phenergan®.
Zhang et al. Genomic structure and genitourinary expression of mouse cytosolic prostaglandin E2 synthase gene
Schäfer et al. Cloning and characterization of boar epididymal secretory proteins by homology to the human

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP