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Håkan Melhus - One of the best experts on this subject based on the ideXlab platform.
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bones in humAn cyp26b1 deficiency And rAts with HypervitAminosis A phenocopy vegfA overexpression
Bone reports, 2018Co-Authors: Thomas Lind, Roberta Lugano, Annmarie Gustafson, Anna Dimberg, Arie Van Haeringen, Maria Norgård, Håkan Melhus, Stephen P Robertson, Goran AnderssonAbstract:AbstrAct AngulAted femurs Are present prenAtAlly both in CYP26B1 deficient humAns with A reduced cApAcity to degrAde retinoic Acid (RA, the Active metAbolite of vitAmin A), And mice overexpressing vAsculAr endotheliAl growth fActor A (VegfA). Since excessive ingestion of vitAmin A is known to induce spontAneous frActures And As the VegfA-induced femur AngulAtion in mice AppeArs to be cAused by intrAuterine frActures, we AnAlyzed bones from A CYP26B1 deficient humAn And rAts with HypervitAminosis A to further explore VegfA As A mechAnistic link for the effect of vitAmin A on bone. We show thAt bone from A humAn with CYP26B1 mutAtions displAyed periosteAl osteoclAsts in piles within deep resorption pits, A pAthognomonic sign of HypervitAminosis A. AnAlysis of the humAn AngulAted fetAl femur reveAled excessive bone formAtion in the mArrow cAvity And AbundAnt blood vessels. NormAl humAn endotheliAl cells showed disturbed cell-cell junctions And increAsed CYP26B1 And VEGFA expression upon RA exposure. Studies in rAts showed increAsed plAsmA And tissue VegfA concentrAtions And signs of bone mArrow microhemorrhAge on the first dAy of excess dietAry vitAmin A intAke. Subsequently HypervitAminosis A rAts displAyed excess bone formAtion, fibrosis And An increAsed number of megAkAryocytes in the bone mArrow, which Are known chArActeristics of VegfA overexpression. This study supports the notion thAt the skeletAl phenotype in CYP26B1 deficient humAn bone is cAused by excess RA. Our findings suggest thAt An initiAl pArt of the vitAmin A mechAnism cAusing bone AlterAtions is mediAted by excess VegfA And disturbed bone mArrow microvessel integrity.
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studies of indirect And direct effects of HypervitAminosis A on rAt bone by compAring free Access to food And pAir feeding
Upsala Journal of Medical Sciences, 2018Co-Authors: Thomas Lind, Monica P Lind, Lijuan Hu, Håkan MelhusAbstract:BACKGROUND: The most prominent feAtures of HypervitAminosis A in rAts Are spontAneous frActures And AnorexiA. Since cAloric restriction induces AlterAtions in bone, some effects could be secondAry to loss of Appetite. To clArify the mechAnisms behind vitAmin A-induced bone frAgility it is necessAry to distinguish between direct And indirect effects. MATERIALS AND METHODS: In this study we compAred rAts fed high doses of vitAmin A both with pAir-fed controls, which were fed the sAme Amount of chow As thAt consumed by the vitAmin A group to keep food intAke the sAme, And to controls with free Access to food. RESULTS: In contrAst to the pAir-fed AnimAls, rAts in the free Access group fed high doses of vitAmin A for 7 dAys hAd 13% lower food intAke, 15% lower body weight, And 2.7% shorter femurs compAred with controls. In Addition, serum biomArkers of bone turnover were reduced. PeripherAl quAntitAtive computed tomogrAphy of the femurs showed thAt the bone minerAl content, cross sectionAl AreA, And periosteAl circumference were similArly reduced in the pAir-fed And free Access groups. However, bone minerAl density (BMD) And corticAl pArAmeters were only significAntly decreAsed in the free Access group. CONCLUSIONS: Our dAtA indicAte thAt the mAjor direct short-term effect of high doses of vitAmin A on rAt bone is A reduced bone diAmeter, whereAs the effects on bone length, serum biomArkers of bone turnover, BMD, And bone cortex AppeAr to be mAinly indirect, cAused by A systemic toxicity with loss of Appetite, reduced food intAke, And generAl effects on growth.
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studies of indirect And direct effects of HypervitAminosis A on rAt bone by compAring free Access to food And pAir feeding
Upsala Journal of Medical Sciences, 2018Co-Authors: Thomas Lind, Monica P Lind, Håkan MelhusAbstract:BAckground: The most prominent feAtures of HypervitAminosis A in rAts Are spontAneous frActures And AnorexiA. Since cAloric restriction induces AlterAtions in bone, some effects could be secondAry ...
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Bones in humAn CYP26B1 deficiency And rAts with HypervitAminosis A phenocopy VegfA overexpression
'Elsevier BV', 2018Co-Authors: Thomas Lind, Roberta Lugano, Annmarie Gustafson, Anna Dimberg, Maria Norgård, Håkan Melhus, Stephen P Robertson, Arie Van Haeringen, Goran AnderssonAbstract:AngulAted femurs Are present prenAtAlly both in CYP26B1 deficient humAns with A reduced cApAcity to degrAde retinoic Acid (RA, the Active metAbolite of vitAmin A), And mice overexpressing vAsculAr endotheliAl growth fActor A (VegfA). Since excessive ingestion of vitAmin A is known to induce spontAneous frActures And As the VegfA-induced femur AngulAtion in mice AppeArs to be cAused by intrAuterine frActures, we AnAlyzed bones from A CYP26B1 deficient humAn And rAts with HypervitAminosis A to further explore VegfA As A mechAnistic link for the effect of vitAmin A on bone. We show thAt bone from A humAn with CYP26B1 mutAtions displAyed periosteAl osteoclAsts in piles within deep resorption pits, A pAthognomonic sign of HypervitAminosis A. AnAlysis of the humAn AngulAted fetAl femur reveAled excessive bone formAtion in the mArrow cAvity And AbundAnt blood vessels. NormAl humAn endotheliAl cells showed disturbed cell-cell junctions And increAsed CYP26B1 And VEGFA expression upon RA exposure. Studies in rAts showed increAsed plAsmA And tissue VegfA concentrAtions And signs of bone mArrow microhemorrhAge on the first dAy of excess dietAry vitAmin A intAke. Subsequently HypervitAminosis A rAts displAyed excess bone formAtion, fibrosis And An increAsed number of megAkAryocytes in the bone mArrow, which Are known chArActeristics of VegfA overexpression. This study supports the notion thAt the skeletAl phenotype in CYP26B1 deficient humAn bone is cAused by excess RA. Our findings suggest thAt An initiAl pArt of the vitAmin A mechAnism cAusing bone AlterAtions is mediAted by excess VegfA And disturbed bone mArrow microvessel integrity. Keywords: CYP26B1, VitAmin A, VEGFA, MicrohemorrhAge, HumAn, RAt, Bon
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Osteocyte mArkers in RA And RAR AntAgonist treAted MC3T3-E1 cells And periosteAl And serum phenotype in vitAmin A treAted rAts.
2013Co-Authors: Thomas Lind, Goran Andersson, Anders Sundqvist, Gunnar Pejler, Annica Jacobson, Håkan MelhusAbstract:QRT-PCR AnAlysis of Tnfsf11 (RANKL) And Dmp1, (A) Phex, Sost And Fgf23 (B) expression At dAy 14 And 21 during A minerAlizAtion experiment of MC3T3-E1 cells treAted with 400 nM RA or 1 µM AGN. (C) RepresentAtive Western blot AnAlysis of Phex, Dmp1 And full length RANKL At dAy 14 And 21 of MC3T3-E1 cells treAted As in (A) And quAntificAtion of Western bAnds relAtive to Actb (relAtive rAtio). (D) Dmp1 And CAthepsin K (CAtK) immunohistochemicAl stAining At the diAphyseAl periosteAl site in rAts suffering from HypervitAminosis A And in control rAts. Upper pAnel: Arrow heAds indicAte Dmp1 negAtive osteocytes close to the periosteum (Ps) in control rAt bone And Arrows indicAte Dmp1 positive osteocytes close to the periosteum in HypervitAminosis A rAt bone. Lower pAnel: only VitAmin A AnimAls show cleAr CAtK stAining At the Ps site. (E) Serum Fgf23 And phosphAte levels in rAts from (D). MeAns +/– SD, * p
Thomas Lind - One of the best experts on this subject based on the ideXlab platform.
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bones in humAn cyp26b1 deficiency And rAts with HypervitAminosis A phenocopy vegfA overexpression
Bone reports, 2018Co-Authors: Thomas Lind, Roberta Lugano, Annmarie Gustafson, Anna Dimberg, Arie Van Haeringen, Maria Norgård, Håkan Melhus, Stephen P Robertson, Goran AnderssonAbstract:AbstrAct AngulAted femurs Are present prenAtAlly both in CYP26B1 deficient humAns with A reduced cApAcity to degrAde retinoic Acid (RA, the Active metAbolite of vitAmin A), And mice overexpressing vAsculAr endotheliAl growth fActor A (VegfA). Since excessive ingestion of vitAmin A is known to induce spontAneous frActures And As the VegfA-induced femur AngulAtion in mice AppeArs to be cAused by intrAuterine frActures, we AnAlyzed bones from A CYP26B1 deficient humAn And rAts with HypervitAminosis A to further explore VegfA As A mechAnistic link for the effect of vitAmin A on bone. We show thAt bone from A humAn with CYP26B1 mutAtions displAyed periosteAl osteoclAsts in piles within deep resorption pits, A pAthognomonic sign of HypervitAminosis A. AnAlysis of the humAn AngulAted fetAl femur reveAled excessive bone formAtion in the mArrow cAvity And AbundAnt blood vessels. NormAl humAn endotheliAl cells showed disturbed cell-cell junctions And increAsed CYP26B1 And VEGFA expression upon RA exposure. Studies in rAts showed increAsed plAsmA And tissue VegfA concentrAtions And signs of bone mArrow microhemorrhAge on the first dAy of excess dietAry vitAmin A intAke. Subsequently HypervitAminosis A rAts displAyed excess bone formAtion, fibrosis And An increAsed number of megAkAryocytes in the bone mArrow, which Are known chArActeristics of VegfA overexpression. This study supports the notion thAt the skeletAl phenotype in CYP26B1 deficient humAn bone is cAused by excess RA. Our findings suggest thAt An initiAl pArt of the vitAmin A mechAnism cAusing bone AlterAtions is mediAted by excess VegfA And disturbed bone mArrow microvessel integrity.
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studies of indirect And direct effects of HypervitAminosis A on rAt bone by compAring free Access to food And pAir feeding
Upsala Journal of Medical Sciences, 2018Co-Authors: Thomas Lind, Monica P Lind, Lijuan Hu, Håkan MelhusAbstract:BACKGROUND: The most prominent feAtures of HypervitAminosis A in rAts Are spontAneous frActures And AnorexiA. Since cAloric restriction induces AlterAtions in bone, some effects could be secondAry to loss of Appetite. To clArify the mechAnisms behind vitAmin A-induced bone frAgility it is necessAry to distinguish between direct And indirect effects. MATERIALS AND METHODS: In this study we compAred rAts fed high doses of vitAmin A both with pAir-fed controls, which were fed the sAme Amount of chow As thAt consumed by the vitAmin A group to keep food intAke the sAme, And to controls with free Access to food. RESULTS: In contrAst to the pAir-fed AnimAls, rAts in the free Access group fed high doses of vitAmin A for 7 dAys hAd 13% lower food intAke, 15% lower body weight, And 2.7% shorter femurs compAred with controls. In Addition, serum biomArkers of bone turnover were reduced. PeripherAl quAntitAtive computed tomogrAphy of the femurs showed thAt the bone minerAl content, cross sectionAl AreA, And periosteAl circumference were similArly reduced in the pAir-fed And free Access groups. However, bone minerAl density (BMD) And corticAl pArAmeters were only significAntly decreAsed in the free Access group. CONCLUSIONS: Our dAtA indicAte thAt the mAjor direct short-term effect of high doses of vitAmin A on rAt bone is A reduced bone diAmeter, whereAs the effects on bone length, serum biomArkers of bone turnover, BMD, And bone cortex AppeAr to be mAinly indirect, cAused by A systemic toxicity with loss of Appetite, reduced food intAke, And generAl effects on growth.
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studies of indirect And direct effects of HypervitAminosis A on rAt bone by compAring free Access to food And pAir feeding
Upsala Journal of Medical Sciences, 2018Co-Authors: Thomas Lind, Monica P Lind, Håkan MelhusAbstract:BAckground: The most prominent feAtures of HypervitAminosis A in rAts Are spontAneous frActures And AnorexiA. Since cAloric restriction induces AlterAtions in bone, some effects could be secondAry ...
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Bones in humAn CYP26B1 deficiency And rAts with HypervitAminosis A phenocopy VegfA overexpression
'Elsevier BV', 2018Co-Authors: Thomas Lind, Roberta Lugano, Annmarie Gustafson, Anna Dimberg, Maria Norgård, Håkan Melhus, Stephen P Robertson, Arie Van Haeringen, Goran AnderssonAbstract:AngulAted femurs Are present prenAtAlly both in CYP26B1 deficient humAns with A reduced cApAcity to degrAde retinoic Acid (RA, the Active metAbolite of vitAmin A), And mice overexpressing vAsculAr endotheliAl growth fActor A (VegfA). Since excessive ingestion of vitAmin A is known to induce spontAneous frActures And As the VegfA-induced femur AngulAtion in mice AppeArs to be cAused by intrAuterine frActures, we AnAlyzed bones from A CYP26B1 deficient humAn And rAts with HypervitAminosis A to further explore VegfA As A mechAnistic link for the effect of vitAmin A on bone. We show thAt bone from A humAn with CYP26B1 mutAtions displAyed periosteAl osteoclAsts in piles within deep resorption pits, A pAthognomonic sign of HypervitAminosis A. AnAlysis of the humAn AngulAted fetAl femur reveAled excessive bone formAtion in the mArrow cAvity And AbundAnt blood vessels. NormAl humAn endotheliAl cells showed disturbed cell-cell junctions And increAsed CYP26B1 And VEGFA expression upon RA exposure. Studies in rAts showed increAsed plAsmA And tissue VegfA concentrAtions And signs of bone mArrow microhemorrhAge on the first dAy of excess dietAry vitAmin A intAke. Subsequently HypervitAminosis A rAts displAyed excess bone formAtion, fibrosis And An increAsed number of megAkAryocytes in the bone mArrow, which Are known chArActeristics of VegfA overexpression. This study supports the notion thAt the skeletAl phenotype in CYP26B1 deficient humAn bone is cAused by excess RA. Our findings suggest thAt An initiAl pArt of the vitAmin A mechAnism cAusing bone AlterAtions is mediAted by excess VegfA And disturbed bone mArrow microvessel integrity. Keywords: CYP26B1, VitAmin A, VEGFA, MicrohemorrhAge, HumAn, RAt, Bon
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Mcpt4-/- mice in ovAriectomy- And vitAmin A-induced osteoporosis models.
2016Co-Authors: Thomas Lind, Annmarie Gustafson, Goran Andersson, Gabriela Calounova, Annica Rasmusson, Kenneth B. Jonsson, Sara Wernersson, Magnus Åbrink, Sune LarssonAbstract:A) Body weight 6 weeks After shAm (n = 5) or ovAriectomy (OVX) in wt (shAm, OVX) (n = 7) And Mcpt4-/- (OVX) (n = 4). B) Femur trAbeculAr density And corticAl thickness in AnimAls As described in (A). C) Body weight After 1 week of HypervitAminosis A At the Age of 7 months. Number of AnimAls in eAch group Are wt controls (Cont, wt; n = 6), Mcpt4-/- controls (Cont, Mcpt4-/-; n = 5), controls vitAmin A (VitAmin A, wt; n = 5) And vitAmin A Mcpt4-/- (VitAmin A, Mcpt4-/-; n = 5). D) Femur diAphyseAl totAl cross sectionAl AreA (TotAl AreA) After 1 week of HypervitAminosis A. Results Are given As meAns ± SD. p < 0.05 *, p < 0.01 ** And p < 0.001 *** vs. wt/shAm/Cont., p < 0.05 # And p < 0.001 ### vs. Cont Mcpt4-/-, p < 0.001 ¤¤¤ vs. Cont wt.
P M Lind - One of the best experts on this subject based on the ideXlab platform.
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subclinicAl HypervitAminosis A in rAt meAsurements of bone minerAl density bmd do not reveAl Adverse skeletAl chAnges
Chemico-Biological Interactions, 2006Co-Authors: P M Lind, Monika Ronn, S Johansson, Håkan MelhusAbstract:We hAve previously shown thAt subclinicAl HypervitAminosis A in rAts cAuses frAgile bones. To begin to investigAte possible mechAnisms for VitAmin A Action we extended our previous study. Forty-fiv ...
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subclinicAl HypervitAminosis A in rAt meAsurements of bone minerAl density bmd do not reveAl Adverse skeletAl chAnges
Chemico-Biological Interactions, 2006Co-Authors: P M Lind, Monika Ronn, S Johansson, Håkan MelhusAbstract:We hAve previously shown thAt subclinicAl HypervitAminosis A in rAts cAuses frAgile bones. To begin to investigAte possible mechAnisms for VitAmin A Action we extended our previous study. Forty-five mAture femAle SprAgue-DAwley rAts were divided into three groups, eAch with 15 AnimAls. They were fed A stAndArd diet contAining 12IU VitAmin A per g pellet (control, C), or A stAndArd diet supplemented with 120 IU ("10xC") or 600 IU ("50xC") VitAmin A/g pellet for 12 weeks. At the end of the study, serum retinyl esters were elevAted 4- And 20-fold. Although neither AverAge food intAke nor finAl body weights were significAntly different between groups, A dose-dependent reduction in serum levels of VitAmin D And E, but not VitAmin K, wAs found. In the 50xC-group the length of the humerus wAs the sAme As in controls, but the diAmeter wAs reduced (-4.1%, p<0.05). PeripherAl quAntitAtive computed tomogrAphy (pQCT) At the diAphysis showed thAt bone minerAl density (BMD) wAs unchAnged And thAt periosteAl circumference hAd decreAsed significAntly (-3.7%, p<0.05). Ash weight of the humerus wAs not Affected, but since bone volume decreAsed, volumetric BMD, As meAsured by the bone Ash method, even increAsed (+2.5%, p<0.05). In conclusion, interference with other fAt-soluble VitAmins is A possible indirect mechAnism of VitAmin A Action. Moreover, BMD meAsurements do not reveAl eArly Adverse skeletAl chAnges induced by moderAte excesses of VitAmin A in rAts. Since the WHO criterium for osteoporosis is bAsed on BMD, further studies Are wArrAnted to exAmine whether this is Also true in humAns.
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subclinicAl HypervitAminosis A cAuses frAgile bones in rAts
Bone, 2002Co-Authors: S Johansson, P M Lind, Helen Hakansson, J Rberg, Hans Oxlund, Håkan MelhusAbstract:Excessive intAke of vitAmin A hAs been AssociAted with An increAsed risk of hip frActure in humAns. This finding hAs rAised the question of whether long-term intAke of relAtively moderAte doses (“subclinicAl” HypervitAminosis A) contributes to frActure risk. Although it hAs been known for more thAn hAlf A century thAt toxic doses of vitAmin A leAd to spontAneous frActures in rAts, the lowest intAke thAt induces Adverse effects is not known, And the result of exposure to excessive doses thAt do not cAuse generAl toxicity hAs been rArely investigAted. In this study, mAture femAle rAts were fed A stAndArd diet with 12 IU vitAmin A/g pellet (control, C), or stAndArd diet supplemented with either 120 IU (“10 × C”) or 600 IU (“50 × C”) vitAmin A/g pellet for 12 weeks. Fifteen AnimAls were included in eAch group. The supplemented diets correspond to A vitAmin A intAke of ApproximAtely 1800 IU/dAy And 9000 IU/dAy, respectively. The lAtter dose is About one third of thAt previously reported to cAuse skeletAl lesions. At the end of the study, serum retinyl esters were elevAted 4- (p < 0.01) And 20-fold (p < 0.001) And the totAl Amount of liver retinoid hAd increAsed 3- (p < 0.001) And 7-fold (p < 0.001) in the 10 × C And 50 × C group, respectively. The AnimAls showed no clinicAl signs of generAl toxicity, And there were no significAnt bone chAnges in the 10 × C group. However, in the 50 × C group, A chArActeristic thinning of the cortex (corticAl AreA −6.5% [p < 0.001]) And reduction of the diAmeter of the long bones were evident (bone cross-sectionAl AreA −7.2% [p < 0.01] At the midshAft And −11.0% [p < 0.01] At the metAphysis), As meAsured by peripherAl quAntitAtive computed tomogrAphy. In Agreement with these dAtA And A decreAsed polAr strength strAin index (−14.0%, p < 0.01), the three-point bending breAking force of the femur wAs reduced by 10.3% (p < 0.01) in the 50 × C group. These dAtA indicAte thAt the negAtive skeletAl effects AppeAr At A subchronic vitAmin A intAke of somewhere between 10 And 50 times the stAndArd diet. This level is considerAbly lower thAn previously reported. Our results suggest thAt long-term ingestion of modest excesses of vitAmin A mAy contribute to frActure risk.
S Johansson - One of the best experts on this subject based on the ideXlab platform.
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subclinicAl HypervitAminosis A in rAt meAsurements of bone minerAl density bmd do not reveAl Adverse skeletAl chAnges
Chemico-Biological Interactions, 2006Co-Authors: P M Lind, Monika Ronn, S Johansson, Håkan MelhusAbstract:We hAve previously shown thAt subclinicAl HypervitAminosis A in rAts cAuses frAgile bones. To begin to investigAte possible mechAnisms for VitAmin A Action we extended our previous study. Forty-fiv ...
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subclinicAl HypervitAminosis A in rAt meAsurements of bone minerAl density bmd do not reveAl Adverse skeletAl chAnges
Chemico-Biological Interactions, 2006Co-Authors: P M Lind, Monika Ronn, S Johansson, Håkan MelhusAbstract:We hAve previously shown thAt subclinicAl HypervitAminosis A in rAts cAuses frAgile bones. To begin to investigAte possible mechAnisms for VitAmin A Action we extended our previous study. Forty-five mAture femAle SprAgue-DAwley rAts were divided into three groups, eAch with 15 AnimAls. They were fed A stAndArd diet contAining 12IU VitAmin A per g pellet (control, C), or A stAndArd diet supplemented with 120 IU ("10xC") or 600 IU ("50xC") VitAmin A/g pellet for 12 weeks. At the end of the study, serum retinyl esters were elevAted 4- And 20-fold. Although neither AverAge food intAke nor finAl body weights were significAntly different between groups, A dose-dependent reduction in serum levels of VitAmin D And E, but not VitAmin K, wAs found. In the 50xC-group the length of the humerus wAs the sAme As in controls, but the diAmeter wAs reduced (-4.1%, p<0.05). PeripherAl quAntitAtive computed tomogrAphy (pQCT) At the diAphysis showed thAt bone minerAl density (BMD) wAs unchAnged And thAt periosteAl circumference hAd decreAsed significAntly (-3.7%, p<0.05). Ash weight of the humerus wAs not Affected, but since bone volume decreAsed, volumetric BMD, As meAsured by the bone Ash method, even increAsed (+2.5%, p<0.05). In conclusion, interference with other fAt-soluble VitAmins is A possible indirect mechAnism of VitAmin A Action. Moreover, BMD meAsurements do not reveAl eArly Adverse skeletAl chAnges induced by moderAte excesses of VitAmin A in rAts. Since the WHO criterium for osteoporosis is bAsed on BMD, further studies Are wArrAnted to exAmine whether this is Also true in humAns.
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subclinicAl HypervitAminosis A cAuses frAgile bones in rAts
Bone, 2002Co-Authors: S Johansson, P M Lind, Helen Hakansson, J Rberg, Hans Oxlund, Håkan MelhusAbstract:Excessive intAke of vitAmin A hAs been AssociAted with An increAsed risk of hip frActure in humAns. This finding hAs rAised the question of whether long-term intAke of relAtively moderAte doses (“subclinicAl” HypervitAminosis A) contributes to frActure risk. Although it hAs been known for more thAn hAlf A century thAt toxic doses of vitAmin A leAd to spontAneous frActures in rAts, the lowest intAke thAt induces Adverse effects is not known, And the result of exposure to excessive doses thAt do not cAuse generAl toxicity hAs been rArely investigAted. In this study, mAture femAle rAts were fed A stAndArd diet with 12 IU vitAmin A/g pellet (control, C), or stAndArd diet supplemented with either 120 IU (“10 × C”) or 600 IU (“50 × C”) vitAmin A/g pellet for 12 weeks. Fifteen AnimAls were included in eAch group. The supplemented diets correspond to A vitAmin A intAke of ApproximAtely 1800 IU/dAy And 9000 IU/dAy, respectively. The lAtter dose is About one third of thAt previously reported to cAuse skeletAl lesions. At the end of the study, serum retinyl esters were elevAted 4- (p < 0.01) And 20-fold (p < 0.001) And the totAl Amount of liver retinoid hAd increAsed 3- (p < 0.001) And 7-fold (p < 0.001) in the 10 × C And 50 × C group, respectively. The AnimAls showed no clinicAl signs of generAl toxicity, And there were no significAnt bone chAnges in the 10 × C group. However, in the 50 × C group, A chArActeristic thinning of the cortex (corticAl AreA −6.5% [p < 0.001]) And reduction of the diAmeter of the long bones were evident (bone cross-sectionAl AreA −7.2% [p < 0.01] At the midshAft And −11.0% [p < 0.01] At the metAphysis), As meAsured by peripherAl quAntitAtive computed tomogrAphy. In Agreement with these dAtA And A decreAsed polAr strength strAin index (−14.0%, p < 0.01), the three-point bending breAking force of the femur wAs reduced by 10.3% (p < 0.01) in the 50 × C group. These dAtA indicAte thAt the negAtive skeletAl effects AppeAr At A subchronic vitAmin A intAke of somewhere between 10 And 50 times the stAndArd diet. This level is considerAbly lower thAn previously reported. Our results suggest thAt long-term ingestion of modest excesses of vitAmin A mAy contribute to frActure risk.
Robert Y Peng - One of the best experts on this subject based on the ideXlab platform.
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VAlproic Acid DownregulAtes RBP4 And Elicits HypervitAminosis A-TerAtogenesis—A Kinetic AnAlysis on Retinol/Retinoic Acid HomeostAtic System
2016Co-Authors: Lan Hsieh, Robert Y PengAbstract:BAckground: VAlproic Acid (VPA) is An Antiepileptic And Anti-migrAine prophylActic drug. VPA exhibits two severe side effects, nAmely Acute liver toxicity And terAtogenicity. These side effects Are usuAlly seen At the genetic And somAtic levels. The cited Action mechAnisms involve inhibition of histone deAcetylAse, hypofolAtenemiA, hyperhomocysteinemiA, And reActive oxidAtive stress. The proteomic informAtion AssociAted with VPA terAtogenicity is still unAvAilAble. We hypothesized thAt proteomic AnAlysis might help us identify functionAl proteins thAt could be relevAntly Affected by VPA, And this phenomenon could be very sensitive in eArly embryonic stAge, resulting in VPA terAtogenicity. Methodology/PrincipAl Findings: Proteomic AnAlysis on the chicken embryos At HAmburger And HAmilton (HH) stAge 28 showed thAt there were significAnt downregulAtions of ovotrAnsferrins, cArbonic AnhydrAse-2, retinol binding protein-4 (RBP4), NADH cytochrome b5 reductAse 2 (CYB5R2), Apolipoprotein A1, And protein SET, together with upregulAtion of 60S ribosomAl protein L22. Among these, RBP4 wAs the most significAntly downregulAted (232%). Kinetic AnAlysis suggested thAt this situAtion could trigger HypervitAminosis A (+39.3%), A condition thAt hAs been well known to induce terAtogenesis.. Conclusions/SignificAnce: This is the first report showing thAt VPA dowregulAtes RBP4. Our finding not only hAs led to
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vAlproic Acid downregulAtes rbp4 And elicits HypervitAminosis A terAtogenesis A kinetic AnAlysis on retinol retinoic Acid homeostAtic system
PLOS ONE, 2012Co-Authors: Chao Ming Chuang, Chiung Chi Peng, Chiu Lan Hsieh, Chi-huang Chang, Hui Er Wang, Kuan Chou Chen, Robert Y PengAbstract:BAckground VAlproic Acid (VPA) is An Antiepileptic And Anti-migrAine prophylActic drug. VPA exhibits two severe side effects, nAmely Acute liver toxicity And terAtogenicity. These side effects Are usuAlly seen At the genetic And somAtic levels. The cited Action mechAnisms involve inhibition of histone deAcetylAse, hypofolAtenemiA, hyperhomocysteinemiA, And reActive oxidAtive stress. The proteomic informAtion AssociAted with VPA terAtogenicity is still unAvAilAble. We hypothesized thAt proteomic AnAlysis might help us identify functionAl proteins thAt could be relevAntly Affected by VPA, And this phenomenon could be very sensitive in eArly embryonic stAge, resulting in VPA terAtogenicity. Methodology/PrincipAl Findings Proteomic AnAlysis on the chicken embryos At HAmburger And HAmilton (HH) stAge 28 showed thAt there were significAnt downregulAtions of ovotrAnsferrins, cArbonic AnhydrAse-2, retinol binding protein-4 (RBP4), NADH cytochrome b5 reductAse 2 (CYB5R2), Apolipoprotein A1, And protein SET, together with upregulAtion of 60S ribosomAl protein L22. Among these, RBP4 wAs the most significAntly downregulAted (−32%). Kinetic AnAlysis suggested thAt this situAtion could trigger HypervitAminosis A (+39.3%), A condition thAt hAs been well known to induce terAtogenesis.. Conclusions/SignificAnce This is the first report showing thAt VPA dowregulAtes RBP4. Our finding not only hAs led to A possible mechAnism of VPA terAtogenesis, but Also hAs initiAted new preventive strAtegies for Avoiding VPA terAtogeneis.