Multipotent Stromal Cells from Subcutaneous Adipose Tissue of Normal Weight and Obese Subjects: Modulation of Their Adipogenic Differentiation by Adenosine A<sub<1</sub< Receptor Ligands
Adenosine A<sub<1</sub< receptor (A<sub<1</sub<R) activation, stimulating lipogenesis and decreasing insulin resistance, could be useful for metabolic syndrome management in obese subjects. Since full A<sub<1</sub<R agonists induce harmful side-effects, while part...
Ausführliche Beschreibung
Autor*in: |
Mariachiara Zuccarini [verfasserIn] Catia Lambertucci [verfasserIn] Marzia Carluccio [verfasserIn] Patricia Giuliani [verfasserIn] Maurizio Ronci [verfasserIn] Andrea Spinaci [verfasserIn] Rosaria Volpini [verfasserIn] Renata Ciccarelli [verfasserIn] Patrizia Di Iorio [verfasserIn] |
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Format: |
E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2021 |
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Übergeordnetes Werk: |
In: Cells - MDPI AG, 2012, 10(2021), 12, p 3560 |
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Übergeordnetes Werk: |
volume:10 ; year:2021 ; number:12, p 3560 |
Links: |
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DOI / URN: |
10.3390/cells10123560 |
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Katalog-ID: |
DOAJ014198509 |
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10.3390/cells10123560 doi (DE-627)DOAJ014198509 (DE-599)DOAJeadce9d5aa25496ea2a74c68af0bc765 DE-627 ger DE-627 rakwb eng QH573-671 Mariachiara Zuccarini verfasserin aut Multipotent Stromal Cells from Subcutaneous Adipose Tissue of Normal Weight and Obese Subjects: Modulation of Their Adipogenic Differentiation by Adenosine A<sub<1</sub< Receptor Ligands 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Adenosine A<sub<1</sub< receptor (A<sub<1</sub<R) activation, stimulating lipogenesis and decreasing insulin resistance, could be useful for metabolic syndrome management in obese subjects. Since full A<sub<1</sub<R agonists induce harmful side-effects, while partial agonists show a better pharmacological profile, we investigated the influence of two derivatives of the full A<sub<1</sub<R agonist 2-chloro-<i<N</i<<sup<6</sup<-cyclopentyladenosine (CCPA), C1 and C2 behaving as A<sub<1</sub<R partial agonists in animal models, on the adipogenic differentiation of stromal/stem cells (ASCs) from human subcutaneous adipose tissue, which mainly contribute to increase fat mass in obesity. The ASCs from normal-weight subjects showed increased proliferation and A<sub<1</sub<R expression but reduced adipogenic differentiation compared to obese individual-derived ASCs. Cell exposure to CCPA, C1, C2 or DPCPX, an A<sub<1</sub<R antagonist, did not affect ASC proliferation, while mainly C2 and DPCPX significantly decreased adipogenic differentiation of both ASC types, reducing the activity of glycerol-3-phosphate dehydrogenase and the expression of PPARγ and FABP-4, all adipogenic markers, and phosphorylation of Akt in the phosphatidylinositol-3-kinase pathway, which plays a key-role in adipogenesis. While requiring confirmation in in vivo models, our results suggest that A<sub<1</sub<R partial agonists or antagonists, by limiting ASC differentiation into adipocytes and, thereby, fat mass expansion, could favor development/worsening of metabolic syndrome in obese subjects without a dietary control. adipose stromal cells (ASCs) subcutaneous adipose tissue adenosine A<sub<1</sub< receptors adipogenic differentiation adipogenic markers Cytology Catia Lambertucci verfasserin aut Marzia Carluccio verfasserin aut Patricia Giuliani verfasserin aut Maurizio Ronci verfasserin aut Andrea Spinaci verfasserin aut Rosaria Volpini verfasserin aut Renata Ciccarelli verfasserin aut Patrizia Di Iorio verfasserin aut In Cells MDPI AG, 2012 10(2021), 12, p 3560 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:10 year:2021 number:12, p 3560 https://doi.org/10.3390/cells10123560 kostenfrei https://doaj.org/article/eadce9d5aa25496ea2a74c68af0bc765 kostenfrei https://www.mdpi.com/2073-4409/10/12/3560 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 12, p 3560 |
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10.3390/cells10123560 doi (DE-627)DOAJ014198509 (DE-599)DOAJeadce9d5aa25496ea2a74c68af0bc765 DE-627 ger DE-627 rakwb eng QH573-671 Mariachiara Zuccarini verfasserin aut Multipotent Stromal Cells from Subcutaneous Adipose Tissue of Normal Weight and Obese Subjects: Modulation of Their Adipogenic Differentiation by Adenosine A<sub<1</sub< Receptor Ligands 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Adenosine A<sub<1</sub< receptor (A<sub<1</sub<R) activation, stimulating lipogenesis and decreasing insulin resistance, could be useful for metabolic syndrome management in obese subjects. Since full A<sub<1</sub<R agonists induce harmful side-effects, while partial agonists show a better pharmacological profile, we investigated the influence of two derivatives of the full A<sub<1</sub<R agonist 2-chloro-<i<N</i<<sup<6</sup<-cyclopentyladenosine (CCPA), C1 and C2 behaving as A<sub<1</sub<R partial agonists in animal models, on the adipogenic differentiation of stromal/stem cells (ASCs) from human subcutaneous adipose tissue, which mainly contribute to increase fat mass in obesity. The ASCs from normal-weight subjects showed increased proliferation and A<sub<1</sub<R expression but reduced adipogenic differentiation compared to obese individual-derived ASCs. Cell exposure to CCPA, C1, C2 or DPCPX, an A<sub<1</sub<R antagonist, did not affect ASC proliferation, while mainly C2 and DPCPX significantly decreased adipogenic differentiation of both ASC types, reducing the activity of glycerol-3-phosphate dehydrogenase and the expression of PPARγ and FABP-4, all adipogenic markers, and phosphorylation of Akt in the phosphatidylinositol-3-kinase pathway, which plays a key-role in adipogenesis. While requiring confirmation in in vivo models, our results suggest that A<sub<1</sub<R partial agonists or antagonists, by limiting ASC differentiation into adipocytes and, thereby, fat mass expansion, could favor development/worsening of metabolic syndrome in obese subjects without a dietary control. adipose stromal cells (ASCs) subcutaneous adipose tissue adenosine A<sub<1</sub< receptors adipogenic differentiation adipogenic markers Cytology Catia Lambertucci verfasserin aut Marzia Carluccio verfasserin aut Patricia Giuliani verfasserin aut Maurizio Ronci verfasserin aut Andrea Spinaci verfasserin aut Rosaria Volpini verfasserin aut Renata Ciccarelli verfasserin aut Patrizia Di Iorio verfasserin aut In Cells MDPI AG, 2012 10(2021), 12, p 3560 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:10 year:2021 number:12, p 3560 https://doi.org/10.3390/cells10123560 kostenfrei https://doaj.org/article/eadce9d5aa25496ea2a74c68af0bc765 kostenfrei https://www.mdpi.com/2073-4409/10/12/3560 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 12, p 3560 |
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10.3390/cells10123560 doi (DE-627)DOAJ014198509 (DE-599)DOAJeadce9d5aa25496ea2a74c68af0bc765 DE-627 ger DE-627 rakwb eng QH573-671 Mariachiara Zuccarini verfasserin aut Multipotent Stromal Cells from Subcutaneous Adipose Tissue of Normal Weight and Obese Subjects: Modulation of Their Adipogenic Differentiation by Adenosine A<sub<1</sub< Receptor Ligands 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Adenosine A<sub<1</sub< receptor (A<sub<1</sub<R) activation, stimulating lipogenesis and decreasing insulin resistance, could be useful for metabolic syndrome management in obese subjects. Since full A<sub<1</sub<R agonists induce harmful side-effects, while partial agonists show a better pharmacological profile, we investigated the influence of two derivatives of the full A<sub<1</sub<R agonist 2-chloro-<i<N</i<<sup<6</sup<-cyclopentyladenosine (CCPA), C1 and C2 behaving as A<sub<1</sub<R partial agonists in animal models, on the adipogenic differentiation of stromal/stem cells (ASCs) from human subcutaneous adipose tissue, which mainly contribute to increase fat mass in obesity. The ASCs from normal-weight subjects showed increased proliferation and A<sub<1</sub<R expression but reduced adipogenic differentiation compared to obese individual-derived ASCs. Cell exposure to CCPA, C1, C2 or DPCPX, an A<sub<1</sub<R antagonist, did not affect ASC proliferation, while mainly C2 and DPCPX significantly decreased adipogenic differentiation of both ASC types, reducing the activity of glycerol-3-phosphate dehydrogenase and the expression of PPARγ and FABP-4, all adipogenic markers, and phosphorylation of Akt in the phosphatidylinositol-3-kinase pathway, which plays a key-role in adipogenesis. While requiring confirmation in in vivo models, our results suggest that A<sub<1</sub<R partial agonists or antagonists, by limiting ASC differentiation into adipocytes and, thereby, fat mass expansion, could favor development/worsening of metabolic syndrome in obese subjects without a dietary control. adipose stromal cells (ASCs) subcutaneous adipose tissue adenosine A<sub<1</sub< receptors adipogenic differentiation adipogenic markers Cytology Catia Lambertucci verfasserin aut Marzia Carluccio verfasserin aut Patricia Giuliani verfasserin aut Maurizio Ronci verfasserin aut Andrea Spinaci verfasserin aut Rosaria Volpini verfasserin aut Renata Ciccarelli verfasserin aut Patrizia Di Iorio verfasserin aut In Cells MDPI AG, 2012 10(2021), 12, p 3560 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:10 year:2021 number:12, p 3560 https://doi.org/10.3390/cells10123560 kostenfrei https://doaj.org/article/eadce9d5aa25496ea2a74c68af0bc765 kostenfrei https://www.mdpi.com/2073-4409/10/12/3560 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 12, p 3560 |
allfieldsGer |
10.3390/cells10123560 doi (DE-627)DOAJ014198509 (DE-599)DOAJeadce9d5aa25496ea2a74c68af0bc765 DE-627 ger DE-627 rakwb eng QH573-671 Mariachiara Zuccarini verfasserin aut Multipotent Stromal Cells from Subcutaneous Adipose Tissue of Normal Weight and Obese Subjects: Modulation of Their Adipogenic Differentiation by Adenosine A<sub<1</sub< Receptor Ligands 2021 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Adenosine A<sub<1</sub< receptor (A<sub<1</sub<R) activation, stimulating lipogenesis and decreasing insulin resistance, could be useful for metabolic syndrome management in obese subjects. Since full A<sub<1</sub<R agonists induce harmful side-effects, while partial agonists show a better pharmacological profile, we investigated the influence of two derivatives of the full A<sub<1</sub<R agonist 2-chloro-<i<N</i<<sup<6</sup<-cyclopentyladenosine (CCPA), C1 and C2 behaving as A<sub<1</sub<R partial agonists in animal models, on the adipogenic differentiation of stromal/stem cells (ASCs) from human subcutaneous adipose tissue, which mainly contribute to increase fat mass in obesity. The ASCs from normal-weight subjects showed increased proliferation and A<sub<1</sub<R expression but reduced adipogenic differentiation compared to obese individual-derived ASCs. Cell exposure to CCPA, C1, C2 or DPCPX, an A<sub<1</sub<R antagonist, did not affect ASC proliferation, while mainly C2 and DPCPX significantly decreased adipogenic differentiation of both ASC types, reducing the activity of glycerol-3-phosphate dehydrogenase and the expression of PPARγ and FABP-4, all adipogenic markers, and phosphorylation of Akt in the phosphatidylinositol-3-kinase pathway, which plays a key-role in adipogenesis. While requiring confirmation in in vivo models, our results suggest that A<sub<1</sub<R partial agonists or antagonists, by limiting ASC differentiation into adipocytes and, thereby, fat mass expansion, could favor development/worsening of metabolic syndrome in obese subjects without a dietary control. adipose stromal cells (ASCs) subcutaneous adipose tissue adenosine A<sub<1</sub< receptors adipogenic differentiation adipogenic markers Cytology Catia Lambertucci verfasserin aut Marzia Carluccio verfasserin aut Patricia Giuliani verfasserin aut Maurizio Ronci verfasserin aut Andrea Spinaci verfasserin aut Rosaria Volpini verfasserin aut Renata Ciccarelli verfasserin aut Patrizia Di Iorio verfasserin aut In Cells MDPI AG, 2012 10(2021), 12, p 3560 (DE-627)718622081 (DE-600)2661518-6 20734409 nnns volume:10 year:2021 number:12, p 3560 https://doi.org/10.3390/cells10123560 kostenfrei https://doaj.org/article/eadce9d5aa25496ea2a74c68af0bc765 kostenfrei https://www.mdpi.com/2073-4409/10/12/3560 kostenfrei https://doaj.org/toc/2073-4409 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2021 12, p 3560 |
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Multipotent Stromal Cells from Subcutaneous Adipose Tissue of Normal Weight and Obese Subjects: Modulation of Their Adipogenic Differentiation by Adenosine A<sub<1</sub< Receptor Ligands |
abstract |
Adenosine A<sub<1</sub< receptor (A<sub<1</sub<R) activation, stimulating lipogenesis and decreasing insulin resistance, could be useful for metabolic syndrome management in obese subjects. Since full A<sub<1</sub<R agonists induce harmful side-effects, while partial agonists show a better pharmacological profile, we investigated the influence of two derivatives of the full A<sub<1</sub<R agonist 2-chloro-<i<N</i<<sup<6</sup<-cyclopentyladenosine (CCPA), C1 and C2 behaving as A<sub<1</sub<R partial agonists in animal models, on the adipogenic differentiation of stromal/stem cells (ASCs) from human subcutaneous adipose tissue, which mainly contribute to increase fat mass in obesity. The ASCs from normal-weight subjects showed increased proliferation and A<sub<1</sub<R expression but reduced adipogenic differentiation compared to obese individual-derived ASCs. Cell exposure to CCPA, C1, C2 or DPCPX, an A<sub<1</sub<R antagonist, did not affect ASC proliferation, while mainly C2 and DPCPX significantly decreased adipogenic differentiation of both ASC types, reducing the activity of glycerol-3-phosphate dehydrogenase and the expression of PPARγ and FABP-4, all adipogenic markers, and phosphorylation of Akt in the phosphatidylinositol-3-kinase pathway, which plays a key-role in adipogenesis. While requiring confirmation in in vivo models, our results suggest that A<sub<1</sub<R partial agonists or antagonists, by limiting ASC differentiation into adipocytes and, thereby, fat mass expansion, could favor development/worsening of metabolic syndrome in obese subjects without a dietary control. |
abstractGer |
Adenosine A<sub<1</sub< receptor (A<sub<1</sub<R) activation, stimulating lipogenesis and decreasing insulin resistance, could be useful for metabolic syndrome management in obese subjects. Since full A<sub<1</sub<R agonists induce harmful side-effects, while partial agonists show a better pharmacological profile, we investigated the influence of two derivatives of the full A<sub<1</sub<R agonist 2-chloro-<i<N</i<<sup<6</sup<-cyclopentyladenosine (CCPA), C1 and C2 behaving as A<sub<1</sub<R partial agonists in animal models, on the adipogenic differentiation of stromal/stem cells (ASCs) from human subcutaneous adipose tissue, which mainly contribute to increase fat mass in obesity. The ASCs from normal-weight subjects showed increased proliferation and A<sub<1</sub<R expression but reduced adipogenic differentiation compared to obese individual-derived ASCs. Cell exposure to CCPA, C1, C2 or DPCPX, an A<sub<1</sub<R antagonist, did not affect ASC proliferation, while mainly C2 and DPCPX significantly decreased adipogenic differentiation of both ASC types, reducing the activity of glycerol-3-phosphate dehydrogenase and the expression of PPARγ and FABP-4, all adipogenic markers, and phosphorylation of Akt in the phosphatidylinositol-3-kinase pathway, which plays a key-role in adipogenesis. While requiring confirmation in in vivo models, our results suggest that A<sub<1</sub<R partial agonists or antagonists, by limiting ASC differentiation into adipocytes and, thereby, fat mass expansion, could favor development/worsening of metabolic syndrome in obese subjects without a dietary control. |
abstract_unstemmed |
Adenosine A<sub<1</sub< receptor (A<sub<1</sub<R) activation, stimulating lipogenesis and decreasing insulin resistance, could be useful for metabolic syndrome management in obese subjects. Since full A<sub<1</sub<R agonists induce harmful side-effects, while partial agonists show a better pharmacological profile, we investigated the influence of two derivatives of the full A<sub<1</sub<R agonist 2-chloro-<i<N</i<<sup<6</sup<-cyclopentyladenosine (CCPA), C1 and C2 behaving as A<sub<1</sub<R partial agonists in animal models, on the adipogenic differentiation of stromal/stem cells (ASCs) from human subcutaneous adipose tissue, which mainly contribute to increase fat mass in obesity. The ASCs from normal-weight subjects showed increased proliferation and A<sub<1</sub<R expression but reduced adipogenic differentiation compared to obese individual-derived ASCs. Cell exposure to CCPA, C1, C2 or DPCPX, an A<sub<1</sub<R antagonist, did not affect ASC proliferation, while mainly C2 and DPCPX significantly decreased adipogenic differentiation of both ASC types, reducing the activity of glycerol-3-phosphate dehydrogenase and the expression of PPARγ and FABP-4, all adipogenic markers, and phosphorylation of Akt in the phosphatidylinositol-3-kinase pathway, which plays a key-role in adipogenesis. While requiring confirmation in in vivo models, our results suggest that A<sub<1</sub<R partial agonists or antagonists, by limiting ASC differentiation into adipocytes and, thereby, fat mass expansion, could favor development/worsening of metabolic syndrome in obese subjects without a dietary control. |
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container_issue |
12, p 3560 |
title_short |
Multipotent Stromal Cells from Subcutaneous Adipose Tissue of Normal Weight and Obese Subjects: Modulation of Their Adipogenic Differentiation by Adenosine A<sub<1</sub< Receptor Ligands |
url |
https://doi.org/10.3390/cells10123560 https://doaj.org/article/eadce9d5aa25496ea2a74c68af0bc765 https://www.mdpi.com/2073-4409/10/12/3560 https://doaj.org/toc/2073-4409 |
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author2 |
Catia Lambertucci Marzia Carluccio Patricia Giuliani Maurizio Ronci Andrea Spinaci Rosaria Volpini Renata Ciccarelli Patrizia Di Iorio |
author2Str |
Catia Lambertucci Marzia Carluccio Patricia Giuliani Maurizio Ronci Andrea Spinaci Rosaria Volpini Renata Ciccarelli Patrizia Di Iorio |
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doi_str |
10.3390/cells10123560 |
callnumber-a |
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up_date |
2024-07-03T21:47:51.034Z |
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