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Stepwise inhibition of T cell recruitment at post-capillary venules by orally active desulfated heparins in inflammatory arthritis.

Abstract Identification of the structure-function relationship of heparin, particularly between 2-O-, 6-O-, and N-sulfation and its anticoagulant or anti-inflammatory activities, is critical in order to evaluate the biological effects of heparin, especially in conjunction with modifications for oral formulation. In this study, we demonstrated that removal of 2-O, 6-O, or N-desulfation and their hydrophobic modifications have differential effects on the blocking of interactions between sLeX and P-and L-selectins, with highest inhibition by 6-O desulfation, which was consistent with their in vivo therapeutic efficacies on CIA mice. The 6-O desulfation of lower molecular weight heparin (LMWH) retained the ability of LMWH to interfere with T cell adhesion via selectin-sLeX interactions. Furthermore, 6DSHbD coated on the apical surface of inflamed endothelium directly blocked the adhesive interactions of circulating T cells, which was confirmed in vivo by suppressing T cell adhesion at post-capillary venular endothelium. Thus, in series with our previous study demonstrating inhibition of transendothelial migration, oral delivery of low anticoagulant LMWH to venular endothelium of inflamed joint tissues ameliorated arthritis by the stepwise inhibition of T cell recruitment and provides a rationale for the development of modified oral heparins as innovative agents for the treatment of chronic inflammatory arthritis.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos one
Publication Year Start




PMID- 28419144
OWN - NLM
STAT- In-Process
DA  - 20170418
LR  - 20170418
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 4
DP  - 2017
TI  - Stepwise inhibition of T cell recruitment at post-capillary venules by orally
      active desulfated heparins in inflammatory arthritis.
PG  - e0176110
LID - 10.1371/journal.pone.0176110 [doi]
AB  - Identification of the structure-function relationship of heparin, particularly
      between 2-O-, 6-O-, and N-sulfation and its anticoagulant or anti-inflammatory
      activities, is critical in order to evaluate the biological effects of heparin,
      especially in conjunction with modifications for oral formulation. In this study,
      we demonstrated that removal of 2-O, 6-O, or N-desulfation and their hydrophobic 
      modifications have differential effects on the blocking of interactions between
      sLeX and P-and L-selectins, with highest inhibition by 6-O desulfation, which was
      consistent with their in vivo therapeutic efficacies on CIA mice. The 6-O
      desulfation of lower molecular weight heparin (LMWH) retained the ability of LMWH
      to interfere with T cell adhesion via selectin-sLeX interactions. Furthermore,
      6DSHbD coated on the apical surface of inflamed endothelium directly blocked the 
      adhesive interactions of circulating T cells, which was confirmed in vivo by
      suppressing T cell adhesion at post-capillary venular endothelium. Thus, in
      series with our previous study demonstrating inhibition of transendothelial
      migration, oral delivery of low anticoagulant LMWH to venular endothelium of
      inflamed joint tissues ameliorated arthritis by the stepwise inhibition of T cell
      recruitment and provides a rationale for the development of modified oral
      heparins as innovative agents for the treatment of chronic inflammatory
      arthritis.
FAU - Al Faruque, Hasan
AU  - Al Faruque H
AD  - Division of Rheumatology, Department of Internal Medicine, Kyungpook National
      University School of Medicine, Daegu, South Korea.
AD  - Department of Biochemistry and Cellular Biology, Kyungpook National University
      School of Medicine, Daegu, South Korea.
FAU - Kang, Jin Hee
AU  - Kang JH
AD  - Division of Rheumatology, Department of Internal Medicine, Kyungpook National
      University School of Medicine, Daegu, South Korea.
AD  - Department of Biochemistry and Cellular Biology, Kyungpook National University
      School of Medicine, Daegu, South Korea.
FAU - Hwang, Seung Rim
AU  - Hwang SR
AD  - College of Pharmacy, Chosun University, Gwangju, South Korea.
FAU - Sung, Shijin
AU  - Sung S
AD  - Division of Rheumatology, Department of Internal Medicine, Kyungpook National
      University School of Medicine, Daegu, South Korea.
AD  - Department of Biochemistry and Cellular Biology, Kyungpook National University
      School of Medicine, Daegu, South Korea.
FAU - Alam, Md Mahmudul
AU  - Alam MM
AD  - Division of Rheumatology, Department of Internal Medicine, Kyungpook National
      University School of Medicine, Daegu, South Korea.
AD  - Department of Biochemistry and Cellular Biology, Kyungpook National University
      School of Medicine, Daegu, South Korea.
FAU - Sa, Keum Hee
AU  - Sa KH
AD  - Division of Rheumatology, Department of Internal Medicine, Kyungpook National
      University School of Medicine, Daegu, South Korea.
AD  - Department of Biochemistry and Cellular Biology, Kyungpook National University
      School of Medicine, Daegu, South Korea.
FAU - Nam, Eon Jeong
AU  - Nam EJ
AD  - Division of Rheumatology, Department of Internal Medicine, Kyungpook National
      University School of Medicine, Daegu, South Korea.
FAU - Byun, Young Ro
AU  - Byun YR
AD  - Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul
      National University, Seoul, South Korea.
FAU - Kang, Young Mo
AU  - Kang YM
AD  - Division of Rheumatology, Department of Internal Medicine, Kyungpook National
      University School of Medicine, Daegu, South Korea.
AD  - Department of Biochemistry and Cellular Biology, Kyungpook National University
      School of Medicine, Daegu, South Korea.
LA  - eng
PT  - Journal Article
DEP - 20170418
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
EDAT- 2017/04/19 06:00
MHDA- 2017/04/19 06:00
CRDT- 2017/04/19 06:00
PHST- 2016/11/11 [received]
PHST- 2017/04/05 [accepted]
AID - 10.1371/journal.pone.0176110 [doi]
AID - PONE-D-16-44219 [pii]
PST - epublish
SO  - PLoS One. 2017 Apr 18;12(4):e0176110. doi: 10.1371/journal.pone.0176110.
      eCollection 2017.

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