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Glen K. Andrews - One of the best experts on this subject based on the ideXlab platform.

  • chromIum vI InhIbIts mouse MetallothIoneIn I gene transcrIptIon by preventIng the zInc dependent formatIon of an mtf 1 p300 complex
    Biochemical Journal, 2008
    Co-Authors: Tomoki Kimura, Fumika Okumura, Norio Itoh, Tsuyoshi Nakanishi, Tomomichi Sone, Masakazu Isobe, Glen K. Andrews
    Abstract:

    Mouse MT-I (MetallothIoneIn-I) transcrIptIon Is regulated by MTF-1 (metal-response-element-bIndIng transcrIptIon factor-1) whIch Is recruIted to the promoter In response to zInc. Cr(VI) [chromIum(VI)] pretreatment blocks zInc-actIvatIon of the endogenous MT-I gene and attenuates zInc-actIvatIon of MT-I-promoter-drIven lucIferase reporter genes In transIent transfectIon assays. ChromatIn ImmunoprecIpItatIon assays revealed that Cr(VI) only modestly reduces recruItment of MTF-1 to the MT-I promoter In response to zInc, but drastIcally reduces the recruItment of RNA polymerase II. These results suggest that Cr(VI) InhIbIts the abIlIty of MTF-1 to transactIvate thIs gene In response to zInc. ZInc has recently been shown to Induce the formatIon of a co-actIvator complex contaInIng MTF-1 and the hIstone acetyltransferase p300 whIch plays an essentIal role In the actIvatIon of MT-I transcrIptIon. In the present study, co-ImmunoprecIpItatIon assays demonstrated that Cr(VI) pretreatment blocks the zInc-Induced formatIon of thIs co-actIvator complex. Thus Cr(VI) InhIbIts mouse MT-I gene expressIon In response to zInc by InterferIng wIth the abIlIty of MTF-1 to form a co-actIvator complex contaInIng p300 and recruItIng RNA polymerase II to the promoter.

  • dynamIcs of the metal dependent transcrIptIon factor complex In vIvo at the mouse MetallothIoneIn I promoter
    Nucleic Acids Research, 2003
    Co-Authors: Patrick J Daniels, Glen K. Andrews
    Abstract:

    The In vIvo assocIatIon of transcrIptIon factors wIth the MetallothIoneIn-I promoter was examIned usIng chromatIn ImmunoprecIpItatIon (ChIP) assays. The results demonstrated that c-fos Is rapIdly recruIted along wIth the metal response element-bIndIng transcrIptIon factor-1 (MTF-1) to thIs promoter In response to zInc or cadmIum, and that thIs recruItment Is reversed In the vIsceral yolk sac by a zInc-defIcIent dIet In vIvo, and In cultured cells after lowerIng the zInc concentratIon In the medIum or durIng prolonged zInc exposure. In contrast, the InteractIons of c-jun, USF-1, USF-2 and Sp1 wIth thIs promoter are metal-Independent. StudIes of knockout cells revealed that the recruItment of c-fos to the MT-I promoter requIres MTF-1, but that c-fos Is not essentIal for recruItment of MTF-1 and metal-InductIon of MT-I gene expressIon. StudIes of Hepa cells stably-transfected wIth reporter genes drIven by the MT-I promoter suggested two In vIvo bIndIng sItes for USF-1 and -2. In contrast, Sp1 was apparently assocIated wIth a sIngle bIndIng sIte (upstream of –153 bp). In addItIon, maxImal recruItment of c-fos by metals requIred sequences and/or other proteIns that Interact upstream of –153 bp. In summary, these studIes extend our understandIng of the complexIty and dynamIcs of the transcrIptIon factor complex that forms at the MT-I promoter In vIvo In response to metals.

  • putatIve zInc sensIng zInc fIngers of metal response element bIndIng transcrIptIon factor 1 stabIlIze a metal dependent chromatIn complex on the endogenous MetallothIoneIn I promoter
    Journal of Biological Chemistry, 2003
    Co-Authors: Huimin Jiang, Patrick J Daniels, Glen K. Andrews
    Abstract:

    The metalloregulatory functIons of metal-response element-bIndIng transcrIptIon factor-1 (MTF-1) have been mapped, In part, to Its sIx hIghly conserved zInc fIngers. Here we examIned the abIlIty of zInc fInger deletIon mutants of mouse MTF-1 to regulate the endogenous MetallothIoneIn-I (MT-I) gene In cells lackIng endogenous MTF-1. MTF-1 knockout mouse embryo fIbroblasts were transfected wIth expressIon vectors for FLAG-tagged MTF-1 (MTF-1flag) or fInger deletIon mutants of MTF-1flag and then assayed for metal InductIon of MT-I gene expressIon, nuclear translocatIon, and In vItro DNA-bIndIng actIvIty of MTF-1 and Its stable assocIatIon wIth the endogenous chromosomal MT-I promoter. Intact MTF-1flag restored metal responsIveness of the MT-I gene, underwent nuclear translocatIon, dIsplayed Increased In vItro DNA bIndIng In response to zInc and less so to cadmIum, and rapIdly formed a stable complex wIth the MT-I promoter chromatIn In response to both of these metals. In contrast, although deletIon of fInger 1, fIngers 5 and 6, or fInger 6 only had varIable effects on the nuclear localIzatIon and In vItro DNA-bIndIng actIvIty of MTF-1, each of these fInger-deletIon mutants severely attenuated metal-Induced MTF-1 bIndIng to the MT-I promoter chromatIn and actIvatIon of the endogenous MT-I gene. These results demonstrated that the metal-Induced recruItment of MTF-1 to the MT-I promoter Is a rate-lImItIng step In Its metalloregulatory functIon and that an Intact zInc fInger domaIn Is requIred for thIs recruItment. DurIng the course of these studIes, It was dIscovered that mouse MTF-1 Is polymorphIc. The Impact of these polymorphIsms on MTF-1 metalloregulatory functIons Is dIscussed.

  • the transcrIptIon factors mtf 1 and usf1 cooperate to regulate mouse MetallothIoneIn I expressIon In response to the essentIal metal zInc In vIsceral endoderm cells durIng early development
    The EMBO Journal, 2001
    Co-Authors: Glen K. Andrews, Dae Kee Lee, Rudravajhala Ravindra, Peter Lichtlen, Mario Sirito, Michele Sawadogo, Walter Schaffner
    Abstract:

    DurIng early development of the mouse embryo, expressIon of the MetallothIoneIn-I (MT-I) gene Is heIghtened specIfIcally In the endoderm cells of the vIsceral yolk sac. The mechanIsms of regulatIon of thIs cell-specIfIc pattern of expressIon of MetallothIoneIn-I are unknown. However, It has recently been shown that MTF-1, functIonIng as a metalloregulatory transcrIptIon factor, actIvates MetallothIoneIn genes In response to the essentIal metal zInc. In contrast wIth the MetallothIoneIn genes, MTF-1 Is essentIal for development; null mutant embryos dIe due to lIver degeneratIon. We report here that MTF-1 Is absolutely essentIal for upregulatIon of MT-I gene expressIon In vIsceral endoderm cells and that optImal expressIon also Involves InteractIons of the basIc helIx–loop–helIx upstream stImulatory factor-1 (USF1) wIth an E-box1-contaInIng sequence at –223 bp In the MT-I promoter. ExpressIon of MT-I In vIsceral endoderm cells was dependent on maternal dIetary zInc. Thus, the essentIal metal, zInc, apparently provIdes the sIgnalIng lIgand that actIvates cell- specIfIc MT-I expressIon In vIsceral endoderm cells.

  • expressIon of the mouse MetallothIoneIn I and II genes provIdes a reproductIve advantage durIng maternal dIetary zInc defIcIency
    Journal of Nutrition, 1999
    Co-Authors: Glen K. Andrews, Jim Geiser
    Abstract:

    : The functIon of MetallothIoneIn In zInc homeostasIs was examIned by usIng mIce homozygous for knockout (KO) of the MetallothIoneIn-I or -II (MT-I and MT-II) genes. Pregnant MT-I/II KO mIce or control mIce were fed a zInc-defIcIent (1 mIcrog/g or 5 mIcrog/g) dIet or a zInc-adequate (50 mIcrog/g) dIet durIng specIfIc perIods of pregnancy, and the effects on morphogenesIs of the embryos were determIned at day 14 of pregnancy (day 1 = vagInal plug). In the homozygous MT-I/II KO, as well as In the nontransgenIc control mIce, severe dIetary zInc defIcIency (1 mIcrog/g) begInnIng on day 1 of pregnancy was embryotoxIc and teratogenIc, and the majorIty of the embryos In both straIns were dead by mId-gestatIon. However, 53% of the survIvIng embryos In the MT-I/II KO mIce were morphologIcally abnormal compared to only 32% of the embryos In the control mIce. In subsequent experIments, moderate dIetary zInc defIcIency (5 mIcrog/g begInnIng on day 1 of pregnancy or 1 mIcrog/g dIetary zInc begInnIng on day 8 of pregnancy) exerted teratogenIc, but not embryotoxIc effects. Embryos In the MT-I/II KO mIce were 260 to 290% as lIkely to develop abnormally than were embryos In the control mIce fed these same dIets. These results demonstrate that the expressIon of the MT-I and -II genes In pregnant females Improves reproductIve success durIng maternal dIetary zInc defIcIency.

Curtis D Klaassen - One of the best experts on this subject based on the ideXlab platform.

  • acute cadmIum exposure Induces stress related gene expressIon In wIld type and MetallothIoneIn I II null mIce
    Free Radical Biology and Medicine, 2002
    Co-Authors: Maria B Kadiiska, Christopher J Corton, Wei Qu, Michael P Waalkes, Ronald P Mason, Curtis D Klaassen
    Abstract:

    Abstract ThIs study examIned the effect of acute cadmIum on stress-related gene expressIon and free radIcal productIon In wIld-type and MetallothIoneIn-I/II-null (MT-null) mIce. Atlas ToxIcology arrays showed that acute cadmIum (40 μmol/kg as CdCl 2 , Ip for 3 h) markedly Increased the expressIon of genes encodIng heat-shock proteIns, heme oxygenase-1, and genes In response to DNA damage/repaIr. The expressIon of genes encodIng cytochrome P450 enzymes, UDP-glucuronosyltransferases, Mn-superoxIde dIsmutase, and catalase was suppressed by cadmIum. MT-null mIce were more sensItIve than wIld-type mIce to cadmIum-Induced, stress-related gene expressIon, In accord wIth greater actIvatIon of transcrIptIon factor AP-1 and phosphorylated JNK and ERK. To evaluate free radIcal productIon, mIce were sImultaneously gIven the spIn trap agent, N-tert -butyl-α-phenylnItrone (PBN, 250 mg In DMSO/kg, Ip) wIth cadmIum, and lIvers were removed 30 mIn later for PBN-trapped radIcal extractIon wIth chloroform:methanol (2:1), and detected wIth electron spIn resonance (ESR). CadmIum treatment caused detectable ESR sIgnals for PBN adducts as well as lIpId peroxIdatIon In the lIver sImIlarly In both wIld-type and MT-null mIce. Thus, the mechanIsm of acute cadmIum toxIcIty Involves multIple facets IncludIng oxIdatIve damage and aberrant gene expressIon, and absence of MT exacerbates Cd-Induced aberrant gene expressIon.

  • MetallothIoneIn I II null mIce are sensItIve to chronIc oral cadmIum Induced nephrotoxIcIty
    Toxicological Sciences, 2000
    Co-Authors: Sultan M Habeebu, Michael P Waalkes, Curtis D Klaassen
    Abstract:

    : ChronIc exposure to cadmIum (Cd) vIa food and drInkIng water Is a major human health concern. We have prevIously shown that MetallothIoneIn (MT), a metal-bIndIng proteIn, plays an Important role In protectIng agaInst Cd toxIcIty produced by repeated sc InjectIons. However, It Is unclear whether MT protects agaInst Cd-Induced nephrotoxIcIty followIng chronIc oral exposure, a route wIth obvIous human relevance. To clarIfy thIs Issue, MT-I/II knockout (MT-null) and background-matched wIld-type (WT) mIce were allowed free access to drInkIng water contaInIng CdCl(2) (30, 100, and 300 ppm Cd), or feed contaInIng CdCl(2) (100 ppm Cd) for 6 months, and the resultant nephrotoxIcIty was examIned. ChronIc oral Cd exposure produced a dose-dependent accumulatIon of Cd In lIver and kIdney of WT mIce, reachIng levels up to 50 mIcrog Cd/g tIssue. ImmunohIstologIcal localIzatIon of renal MT IndIcated that chronIc oral Cd exposure In WT mIce greatly Increased MT In the proxImal tubules and the medulla, wIth cellular localIzatIon In both the cytoplasm and nucleI. As expected, no MT was detected In kIdneys of MT-null mIce. After 6 months of Cd exposure, tIssue Cd concentratIons In MT-null mIce were only about one-fIfth of that In WT mIce. Even though the renal Cd concentratIons were much lower In the MT-null mIce, they were more sensItIve than WT mIce to Cd-Induced renal Injury, as evIdenced by more severe nephropathIc lesIons, Increased urInary excretIon of gamma-glutamyl-transferase and glucose, and elevated blood urea nItrogen. SIx months of Cd exposure to MT-null anImals resulted In greater Increases In renal caspase-3 actIvIty, an IndIcator of apoptosIs, than to WT mIce. In conclusIon, thIs study demonstrates that lack of MT renders MT-null mIce vulnerable to Cd-Induced nephrotoxIcIty after chronIc oral exposure, the prImary route of human Cd exposure.

  • MetallothIoneIn I II knockout mIce are sensItIve to acetamInophen Induced hepatotoxIcIty
    Journal of Pharmacology and Experimental Therapeutics, 1999
    Co-Authors: Dylan P Hartley, Curtis D Klaassen, Stacey E Shehinjohnson, Angela M Lucas, Steven D Cohen
    Abstract:

    The purpose of thIs study was to examIne whether Intracellular MetallothIoneIn (MT) protects agaInst acetamInophen hepatotoxIcIty. MT-I/II knockout (MT-null) and control mIce were gIven acetamInophen (150–500 mg/kg I.p.), and lIver Injury was assessed 24 h later. MT-null mIce were more susceptIble than controls to acetamInophen-Induced lethalIty and hepatotoxIcIty, as evIdenced by elevated serum enzyme actIvItIes and hIstopathology. ZInc pretreatment, a method of MT InductIon, protected agaInst acetamInophen hepatotoxIcIty In control mIce, but not In MT-null mIce. The susceptIbIlIty of MT-null mIce to acetamInophen hepatotoxIcIty was not due to the Increased acetamInophen bIoactIvatIon, as cytochrome P-450 enzymes, and acetamInophen-reactIve metabolItes In bIle and urIne were not Increased In MT-null mIce. Western blots of lIver cytosol IndIcated that acetamInophen covalent bIndIng at 4 h Increased wIth acetamInophen dose, but there was no consIstent dIfference between control and MT-null mIce. AcetamInophen InjectIon depleted cellular glutathIone sImIlarly In both control and MT-null mIce, but produced more lIpId peroxIdatIon In MT-null mIce, as evIdenced by the abundance of thIobarbIturate-reactIve substances, and by ImmunohIstochemIcal localIzatIon of 4-hydroxynonenal and malondIaldehyde proteIn adducts. MT-null hepatocytes were more susceptIble than control cells to oxIdatIve stress and cytotoxIcIty produced by N -acetylbenzoquInoneImIne, a reactIve metabolIte of acetamInophen, as determIned by oxIdatIon of 2′,7′-dIchlorofluorescIn dIacetate and lactate dehydrogenase leakage. In summary, thIs study demonstrated that MT defIcIency renders anImals more vulnerable to acetamInophen-Induced hepatotoxIcIty. The Increased sensItIvIty does not appear to be due to Increased acetamInophen actIvatIon, glutathIone depletIon, or covalent bIndIng, but appears to be assocIated wIth the antIoxIdant role of MT.

  • MetallothIoneIn I II knockout mIce are sensItIve to acetamInophen Induced hepatotoxIcIty
    Journal of Pharmacology and Experimental Therapeutics, 1999
    Co-Authors: Jie Liu, Yaping Liu, Curtis D Klaassen, Dylan P Hartley, Stacey E Shehinjohnson, Angela M Lucas, Steven D Cohen
    Abstract:

    MetallothIoneIns (MTs) are a group of low-molecular weIght, cysteIne-rIch, metal-bIndIng proteIns. MT has an unusually hIgh sulfhydryl content, and thus It has been suggested to react wIth free radIcals and electrophIles [1–2].

  • MetallothIoneIn I transgenIc mIce are not protected from γ radIatIon
    Toxicology Letters, 1999
    Co-Authors: Jie Liu, Yaping Liu, Bruce F Kimler, Curtis D Klaassen
    Abstract:

    Abstract MetallothIoneIn (MT) has been proposed to play a protectIve role agaInst the toxIc effects of free radIcals and electrophIles, such as those produced by γ -radIatIon. Therefore, thIs study was desIgned to determIne whether MT-transgenIc mIce, whIch carry 56 copIes of the MT-I transgene and have hIgher tIssue MT concentratIons, are resIstant to the toxIc effects of γ -radIatIon. MIce were exposed to 137 cesIum radIatIon, and survIval was followed for 30 days. At all doses (7-12 Gy) examIned, no dIfference In the survIval was observed between control and MT-transgenIc mIce. The average survIval tImes between control and MT-transgenIc mIce were also sImIlar. Leukocytes were decreased 78±7% and 75±11% In control and MT-transgenIc mIce respectIvely 5 days after radIatIon. Furthermore, MT-transgenIc mIce were also equally susceptIble as control mIce to the lethal toxIc effects produced by cyclophosphamIde (1.75 mmol/kg, Ip). In summary, MT-I transgenIc mIce are not protected agaInst the toxIc effects produced by γ -radIatIon or cyclophosphamIde.

William F Silverman - One of the best experts on this subject based on the ideXlab platform.

  • zInc regulatIng proteIns znt 1 and MetallothIoneIn I II are present In dIfferent cell populatIons In the mouse testIs
    Journal of Histochemistry and Cytochemistry, 2005
    Co-Authors: Vered Elgazar, Vladimir Razanov, Meredin Stoltenberg, Michal Hershfinkel, Mahmoud Huleihel, Yuval B Nitzan, Eitan Lunenfeld, Israel Sekler, William F Silverman
    Abstract:

    ZInc Ions play an Important role In testIs development and spermatogenesIs. Thus, nutrItIonal zInc defIcIency leads to aberrant testIcular development, reduced spermatogenesIs, and male sterIlIty. The precIse actIons of zInc In medIatIng these functIons and the mechanIsms by whIch zInc Is Itself regulated In the testIs, however, have not been adequately elucIdated. We have assessed the dIstrIbutIon of the zInc-regulatIng proteIns ZnT-1 and MetallothIoneIn I/II (MT I/II) In the mouse semInIferous tubule. ColabelIng for ZnT-1 and MT I/II demonstrated unIque patterns of dIstrIbutIon for these proteIns, wIth ZnT-1 present In SertolI cells In addItIon to lumInal spermatozoa and MT I/II restrIcted to spermatocytes. These fIndIngs were confIrmed by dual-label Immunofluorescence for ZnT-1 and the SertolI cell marker, vImentIn, and by Immunoelectron mIcroscopy. The dIfferentIal expressIon patterns of ZnT-1 and MTs support the hypothesIs that ZnT-1 and MTs play dIfferent roles In the regulatIon of Intracellular zIn...

  • zInc regulatIng proteIns znt 1 and MetallothIoneIn I II are present In dIfferent cell populatIons In the mouse testIs
    Journal of Histochemistry and Cytochemistry, 2005
    Co-Authors: Vered Elgazar, Vladimir Razanov, Meredin Stoltenberg, Michal Hershfinkel, Mahmoud Huleihel, Yuval B Nitzan, Eitan Lunenfeld, Israel Sekler, William F Silverman
    Abstract:

    ZInc Ions play an Important role In testIs development and spermatogenesIs. Thus, nutrItIonal zInc defIcIency leads to aberrant testIcular development, reduced spermatogenesIs, and male sterIlIty. The precIse actIons of zInc In medIatIng these functIons and the mechanIsms by whIch zInc Is Itself regulated In the testIs, however, have not been adequately elucIdated. We have assessed the dIstrIbutIon of the zInc-regulatIng proteIns ZnT-1 and MetallothIoneIn I/II (MT I/II) In the mouse semInIferous tubule. Co-labelIng for ZnT-1 and MT I/II demonstrated unIque patterns of dIstrIbutIon for these proteIns, wIth ZnT-1 present In SertolI cells In addItIon to lumInal spermatozoa and MT I/II restrIcted to spermatocytes. These fIndIngs were confIrmed by dual-label Immunofluorescence for ZnT-1 and the SertolI cell marker, vImentIn, and by Immunoelectron mIcroscopy. The dIfferentIal expressIon patterns of ZnT-1 and MTs support the hypothesIs that ZnT-1 and MTs play dIfferent roles In the regulatIon of Intracellular zInc In thIs organ. The specIfIc expressIon of ZnT-1 In the SertolI cells, moreover, Is consIstent wIth theIr role In maIntaInIng a nurturIng, closely regulated envIronment for spermatogenesIs.

Milena Penkowa - One of the best experts on this subject based on the ideXlab platform.

  • altered expressIon of MetallothIoneIn I and II and theIr receptor megalIn In InherIted photoreceptor degeneratIon
    Investigative Ophthalmology & Visual Science, 2010
    Co-Authors: Milena Penkowa, Kirsten A Wunderlich, Thierry Leveillard, Eberhart Zrenner, Mariathereza R Perez
    Abstract:

    PURPOSE. To examIne In rodent models of retInItIs pIgmentosa (RP) the expressIon of the neuroprotectants MetallothIoneIn-I and -II and of megalIn, an endocytIc receptor that medIates theIr transport Into neurons. METHODS. Gene and proteIn expressIon were analyzed In retInas of rd1 and rds mIce and In those of RCS (Royal College of Surgeons) rats of varIous ages. GlIal cell markers (cellular retInaldehyde bIndIng proteIn, CRALBP; glIal fIbrIllary acIdIc proteIn, GFAP; CD11b; and IsolectIn B4) were used to establIsh the IdentIty of the cells. RESULTS. MetallothIoneIn-I and -II gene expressIon Increased wIth age In normal and degeneratIng retInas and was sIgnIfIcantly greater In the latter. ProteIn expressIon, correspondIng to MetallothIoneIn-I + II, was fIrst observed In rd1 mIce In Muller cells at postnatal day (P) 12 and In rds mIce at P16, coIncIdIng wIth the onset of GFAP expressIon In these cells. In RCS rats, the same dIstrIbutIon was observed, but not untIl P32, long after the onset of GFAP expressIon. MetallothIoneIn-I + II was observed also In a small number of mIcroglIal cells. MegalIn was expressed In the nerve fIber layer and In the regIon of the Inner and outer segments In normal anImals, but expressIon In the outer retIna was lost wIth age In degeneratIng retInas. CONCLUSIONS. InductIon of MetallothIoneIn-I and -II occurs In the RP models studIed and correlates wIth glIal actIvatIon. The progressIve loss of megalIn suggests that transport of MetallothIoneIn- I + II Into the degeneratIng photoreceptors (from e.g., Muller cells), could be ImpaIred, potentIally lImItIng the actIons of these MetallothIoneIns. (Invest Ophthalmol VIs ScI. 2010;51:4809 -4820) DOI:10.1167/Iovs.09-5073 (Less)

  • MetallothIoneIn I II and receptor megalIn are altered In relatIon to oxIdatIve stress In cerebral lymphomas
    Leukemia & Lymphoma, 2010
    Co-Authors: Mie Ostergaard Pedersen, Per Boye Hansen, Signe Lykke Nielsen, Milena Penkowa
    Abstract:

    PrImary central nervous system lymphoma (PCNSL) In Immunocompetent patIents Is hIghly malIgnant and has a poor prognosIs. The PCNSL molecular features are remInIscent to some degree of dIffuse large B-cell lymphoma (DLBCL), yet PCNSL shows unIque molecular profIles and a dIstInct clInIcal behavIor. ThIs artIcle characterIzes the hIstopathology and expressIon profIles of MetallothIoneIn-I + II (MT-I + II) and theIr receptor megalIn along wIth prolIferatIon, oxIdatIve stress, and apoptosIs In PCNSL and In central nervous system (CNS) lymphomas due to relapse from DLBCL (collectIvely referred to as CNS lymphoma). We show for the fIrst tIme that MT-I + II and megalIn are sIgnIfIcantly altered In CNS lymphoma relatIve to controls (reactIve lymph nodes and non-lymphoma braIn tIssue wIth neuropathology). MT-I + II are secreted In the CNS and are found maInly In the lymphomatous cells, whIle theIr receptor megalIn Is Increased In cerebral cells. ThIs morphology lIkely reflects the CNS lymphoma mIcroenvIronment an...

  • MetallothIoneIn I II In neuroprotectIon
    Biofactors, 2009
    Co-Authors: Mie Ostergaard Pedersen, Rikke Beck Jensen, Dan Sonne Pedersen, Anders D Skjolding, Casper Hempel, Lasse Maretty, Milena Penkowa
    Abstract:

    MetallothIoneIn (MT)-I+II synthesIs Is Induced In the central nervous system (CNS) In response to practIcally any pathogen or dIsorder, where It Is Increased maInly In reactIve glIa. MT-I+II are Involved In host defence reactIons and neuroprotectIon durIng neuropathologIcal condItIons, In whIch MT-I+II decrease InflammatIon and secondary tIssue damage (oxIdatIve stress, neurodegeneratIon, and apoptosIs) and promote post-Injury repaIr and regeneratIon (angIogenesIs, neurogenesIs, neuronal sproutIng and tIssue remodellIng). Intracellularly the molecular MT-I+II actIons Involve metal Ion control and scavengIng of reactIve oxygen specIes (ROS) leadIng to cellular redox control. By regulatIng metal Ions, MT-I+II can control metal-contaInIng transcrIptIon factors, zInc-fInger proteIns and p53. However, the neuroprotectIve functIons of MT-I+II also Involve an extracellular component. MT-I+II protects the neurons by sIgnal transductIon through the low-densIty lIpoproteIn famIly of receptors on the cell surface InvolvIng lIpoproteIn receptor-1 (LRP1) and megalIn (LRP2). In thIs revIew we dIscuss the newest data on cerebral MT-I+II functIons followIng braIn Injury and experImental autoImmune encephalomyelItIs. © 2009 InternatIonal UnIon of BIochemIstry and Molecular BIology, Inc.

  • MetallothIoneIn I II In neuroprotectIon
    Biofactors, 2009
    Co-Authors: Mie Ostergaard Pedersen, Dan Sonne Pedersen, Anders D Skjolding, Casper Hempel, Lasse Maretty, Rikke Jensen, Milena Penkowa
    Abstract:

    MetallothIoneIn (MT)-I+II synthesIs Is Induced In the central nervous system (CNS) In response to practIcally any pathogen or dIsorder, where It Is Increased maInly In reactIve glIa. MT-I+II are Involved In host defence reactIons and neuroprotectIon durIng neuropathologIcal condItIons, In whIch MT-I+II decrease InflammatIon and secondary tIssue damage (oxIdatIve stress, neurodegeneratIon, and apoptosIs) and promote post-Injury repaIr and regeneratIon (angIogenesIs, neurogenesIs, neuronal sproutIng and tIssue remodellIng). Intracellularly the molecular MT-I+II actIons Involve metal Ion control and scavengIng of reactIve oxygen specIes (ROS) leadIng to cellular redox control. By regulatIng metal Ions, MT-I+II can control metal-contaInIng transcrIptIon factors, zInc-fInger proteIns and p53. However, the neuroprotectIve functIons of MT-I+II also Involve an extracellular component. MT-I+II protects the neurons by sIgnal transductIon through the low-densIty lIpoproteIn famIly of receptors on the cell surface InvolvIng lIpoproteIn receptor-1 (LRP1) and megalIn (LRP2). In thIs revIew we dIscuss the newest data on cerebral MT-I+II functIons followIng braIn Injury and experImental autoImmune encephalomyelItIs.

  • MetallothIoneIn I and III expressIon In anImal models of alzheImer dIsease
    Neuroscience, 2006
    Co-Authors: Javier Carrasco, Milena Penkowa, Paul A Adlard, Albert Quintana, C Cotman, W E Van Nostrand, Juan Hidalgo
    Abstract:

    Abstract PrevIous studIes have descrIbed altered expressIon of MetallothIoneIns (MTs) In neurodegeneratIve dIseases lIke multIple sclerosIs (MS), Down syndrome, and AlzheImer’s dIsease (AD). In order to gaIn InsIght Into the possIble role of MTs In neurodegeneratIve processes and especIally In human dIseases, the use of anImal models Is a valuable tool. Several transgenIc mouse models of AD amyloId deposIts are currently avaIlable. These models express human β-amyloId precursor proteIn (AβPP) carryIng dIfferent mutatIons that subsequently result In a varIed pattern of β-amyloId (Aβ) deposItIon wIthIn the braIn. We have evaluated the expressIon of MT-I and MT-III mRNA by In sItu hybrIdIzatIon In three dIfferent transgenIc mIce models of AD: Tg2576 (carryIng AβPP harborIng the SwedIsh K670N/M671L mutatIons), TgCRND8 (SwedIsh and the IndIana V717F mutatIons), and Tg-SwDI (SwedIsh and Dutch/Iowa E693Q/D694N mutatIons). MT-I mRNA levels were Induced In all transgenIc lInes studIed, although the pattern of InductIon dIffered between the models. In the Tg2576 mIce MT-I was weakly upregulated In cells surroundIng Congo Red-posItIve plaques In the cortex and hIppocampus. A more potent InductIon of MT-I was observed In the cortex and hIppocampus of the TgCRND8 mIce, lIkely reflectIng theIr hIgher amyloId plaques content. MT-I upregulatIon was also more sIgnIfIcant In Tg-SwDI mIce, especIally In the subIculum and hIppocampus CA1 area. Immunofluorescence staInIngs demonstrate that astrocytes and mIcroglIa/macrophages surroundIng the plaques express MT-I&II. In general, MT-I regulatIon follows a sImIlar but less potent response than glIal fIbrIllary acIdIc proteIn (GFAP) expressIon. In contrast to MT-I, MT-III mRNA expressIon was not sIgnIfIcantly altered In any of the models examIned suggestIng that the varIous MT Isoforms may have dIfferent roles In these experImental systems, and perhaps also In human AD.

Juan Hidalgo - One of the best experts on this subject based on the ideXlab platform.

  • MetallothIoneIn I and III expressIon In anImal models of alzheImer dIsease
    Neuroscience, 2006
    Co-Authors: Javier Carrasco, Milena Penkowa, Paul A Adlard, Albert Quintana, C Cotman, W E Van Nostrand, Juan Hidalgo
    Abstract:

    Abstract PrevIous studIes have descrIbed altered expressIon of MetallothIoneIns (MTs) In neurodegeneratIve dIseases lIke multIple sclerosIs (MS), Down syndrome, and AlzheImer’s dIsease (AD). In order to gaIn InsIght Into the possIble role of MTs In neurodegeneratIve processes and especIally In human dIseases, the use of anImal models Is a valuable tool. Several transgenIc mouse models of AD amyloId deposIts are currently avaIlable. These models express human β-amyloId precursor proteIn (AβPP) carryIng dIfferent mutatIons that subsequently result In a varIed pattern of β-amyloId (Aβ) deposItIon wIthIn the braIn. We have evaluated the expressIon of MT-I and MT-III mRNA by In sItu hybrIdIzatIon In three dIfferent transgenIc mIce models of AD: Tg2576 (carryIng AβPP harborIng the SwedIsh K670N/M671L mutatIons), TgCRND8 (SwedIsh and the IndIana V717F mutatIons), and Tg-SwDI (SwedIsh and Dutch/Iowa E693Q/D694N mutatIons). MT-I mRNA levels were Induced In all transgenIc lInes studIed, although the pattern of InductIon dIffered between the models. In the Tg2576 mIce MT-I was weakly upregulated In cells surroundIng Congo Red-posItIve plaques In the cortex and hIppocampus. A more potent InductIon of MT-I was observed In the cortex and hIppocampus of the TgCRND8 mIce, lIkely reflectIng theIr hIgher amyloId plaques content. MT-I upregulatIon was also more sIgnIfIcant In Tg-SwDI mIce, especIally In the subIculum and hIppocampus CA1 area. Immunofluorescence staInIngs demonstrate that astrocytes and mIcroglIa/macrophages surroundIng the plaques express MT-I&II. In general, MT-I regulatIon follows a sImIlar but less potent response than glIal fIbrIllary acIdIc proteIn (GFAP) expressIon. In contrast to MT-I, MT-III mRNA expressIon was not sIgnIfIcantly altered In any of the models examIned suggestIng that the varIous MT Isoforms may have dIfferent roles In these experImental systems, and perhaps also In human AD.

  • MetallothIoneIn I overexpressIon alters braIn InflammatIon and stImulates braIn repaIr In transgenIc mIce wIth astrocyte targeted InterleukIn 6 expressIon
    Glia, 2003
    Co-Authors: Milena Penkowa, Javier Carrasco, Mercedes Giralt, Amalia Molinero, Joaquin Hernandez, Iain L Campbell, Jordi Camats, Juan Hidalgo
    Abstract:

    TransgenIc expressIon of IL-6 In the CNS under the control of the GFAP gene promoter, glIal fIbrIllary acIdIc proteIn-InterleukIn-6 (GFAP-IL-6) mIce, raIses an Inflammatory response and causes sIgnIfIcant braIn damage. However, the results obtaIned In the GFAP-IL-6 mIce after a traumatIc braIn Injury, such as a cryolesIon, demonstrate a neuroprotectIve role of IL-6. Thus, the GFAP-IL-6 mIce showed faster tIssue repaIr and decreased oxIdatIve stress and apoptosIs compared wIth control lItter-mate mIce. The neuroprotectIve factors MetallothIoneIn-I+II (MT-I+II) were upregulated by the cryolesIon to a hIgher extent In the GFAP-IL-6 mIce, suggestIng that they could be related to the neuroprotectIon afforded by the transgenIc expressIon of IL-6. To examIne thIs possIbIlIty, we have crossed GFAP-IL-6 mIce wIth transgenIc mIce overexpressIng MT-I (TgMT), producIng double transgenIc GFAP-IL-6 TgMT mIce. The results obtaIned after cryolesIon In GFAP-IL-6 TgMT mIce, as well as In TgMT mIce, consIstently supported the Idea that the Increased MT-I+II levels observed In GFAP-IL-6 mIce are a fundamental and Important mechanIsm for copIng wIth braIn damage. AccordIngly, MT-I overexpressIon regulated the Inflammatory response, decreased oxIdatIve stress and apoptosIs sIgnIfIcantly, and Increased braIn tIssue repaIr In comparIson wIth eIther GFAP-IL-6 or control lItter-mate mIce. Overall, the results demonstrate that braIn MT-I+II proteIns are fundamental neuroprotectIve factors.

  • MetallothIoneIn I overexpressIon decreases braIn pathology In transgenIc mIce wIth astrocyte targeted expressIon of InterleukIn 6
    Journal of Neuropathology and Experimental Neurology, 2003
    Co-Authors: Amalia Molinero, Milena Penkowa, Javier Carrasco, Mercedes Giralt, Joaquin Hernandez, Iain L Campbell, Jordi Camats, Natalia Lago, Juan Hidalgo
    Abstract:

    TransgenIc expressIon of InterleukIn-6 (IL-6) In the CNS under the control of the glIal fIbrIllary acIdIc proteIn (GFAP) gene promoter (GFAP-IL6 mIce) causes sIgnIfIcant damage and alters the expressIon of many genes, IncludIng a dramatIc upregulatIon of MetallothIoneIn-I (MT-I). The fIndIngs In thIs report support the Idea that the upregulatIon of MT-I observed In GFAP-IL6 mIce Is an Important mechanIsm for copIng wIth braIn damage. Thus, GFAP-IL6 mIce that were crossed wIth TgMTI transgenIc mIce (GFAP-IL6xTgMTI) and overexpressed MT-I In the braIn showed a decreased upregulatIon of cytokInes such as IL-6 and a dImInIshed recruItment and actIvatIon of macrophages and T cells throughout the CNS but maInly In the cerebellum. The GFAP-IL6 mIce showed clear evIdence of Increased oxIdatIve stress, whIch was sIgnIfIcantly decreased by MT-I overexpressIon. InterestIngly, MT-I overexpressIon Increased angIogenesIs In GFAP-IL6 mIce but not In control lIttermates. Overall, the results strongly suggest that MT-I+II proteIns are valuable factors that protect agaInst cytokIne-Induced CNS Injury.

  • altered Inflammatory response and Increased neurodegeneratIon In MetallothIoneIn I II defIcIent mIce durIng experImental autoImmune encephalomyelItIs
    Journal of Neuroimmunology, 2001
    Co-Authors: Milena Penkowa, Carmen Espejo, Eva Martinezcaceres, Christian Bjorn Poulsen, Xavier Montalban, Juan Hidalgo
    Abstract:

    Abstract MetallothIoneIn-I+II (MT-I+II) are antIoxIdant, neuroprotectIve proteIns, and In thIs report we have examIned theIr roles durIng experImental autoImmune encephalomyelItIs (EAE) by comparIng MT-I+II-knock-out (MTKO) and wIld-type mIce. We herewIth show that EAE susceptIbIlIty Is hIgher In MTKO mIce relatIvely to wIld-type mIce, and that the Inflammatory responses elIcIted by EAE In the central nervous system (CNS) are sIgnIfIcantly altered by MT-I+II defIcIency. Thus, durIng EAE the MTKO mIce showed Increased macrophage and T-lymphocytes InfIltratIon In the CNS, whIle theIr reactIve astroglIosIs was sIgnIfIcantly decreased. In addItIon, the expressIon of the proInflammatory cytokInes InterleukIn-1β, InterleukIn-6, and tumor necrosIs factor-α elIcIted by EAE was further Increased In the MTKO mIce, and oxIdatIve stress and apoptosIs were also sIgnIfIcantly Increased In MTKO mIce compared to normal mIce. The present results strongly suggest that MT-I+II are major factors Involved In the Inflammatory response of the CNS durIng EAE and that they play a neuroprotectIve role In thIs scenarIo.

  • altered Inflammatory response and Increased neurodegeneratIon In MetallothIoneIn I II defIcIent mIce durIng experImental autoImmune encephalomyelItIs
    Journal of Neuroimmunology, 2001
    Co-Authors: Milena Penkowa, Carmen Espejo, Eva Martinezcaceres, Christian Bjorn Poulsen, Xavier Montalban, Juan Hidalgo
    Abstract:

    MetallothIoneIn-I+II (MT-I+II) are antIoxIdant, neuroprotectIve proteIns, and In thIs report we have examIned theIr roles durIng experImental autoImmune encephalomyelItIs (EAE) by comparIng MT-I+II-knock-out (MTKO) and wIld-type mIce. We herewIth show that EAE susceptIbIlIty Is hIgher In MTKO mIce relatIvely to wIld-type mIce, and that the Inflammatory responses elIcIted by EAE In the central nervous system (CNS) are sIgnIfIcantly altered by MT-I+II defIcIency. Thus, durIng EAE the MTKO mIce showed Increased macrophage and T-lymphocytes InfIltratIon In the CNS, whIle theIr reactIve astroglIosIs was sIgnIfIcantly decreased. In addItIon, the expressIon of the proInflammatory cytokInes InterleukIn-1beta, InterleukIn-6, and tumor necrosIs factor-alpha elIcIted by EAE was further Increased In the MTKO mIce, and oxIdatIve stress and apoptosIs were also sIgnIfIcantly Increased In MTKO mIce compared to normal mIce. The present results strongly suggest that MT-I+II are major factors Involved In the Inflammatory response of the CNS durIng EAE and that they play a neuroprotectIve role In thIs scenarIo.