PMID- 25153320
OWN - NLM
STAT- MEDLINE
DCOM- 20150624
LR  - 20141006
IS  - 1543-8392 (Electronic)
IS  - 1543-8384 (Linking)
VI  - 11
IP  - 10
DP  - 2014 Oct 6
TI  - Mechanistic studies of a novel mycophenolic acid-glucosamine conjugate that 
      attenuates renal ischemia/reperfusion injury in rat.
PG  - 3503-14
LID - 10.1021/mp500282g [doi]
AB  - Renal ischemia/reperfusion (I/R) injury causes high mortality and morbidity 
      during renal procedures, yet current drugs should be used at high doses or for 
      long periods due to lack of tissue specificity. In previous work we described a 
      novel mycophenolic acid-glucosamine conjugate (MGC) that targets the proximal 
      tubule epithelium, where it efficiently reduces renal I/R injury in rats and 
      promotes recovery from reperfusion. Here we perform mechanistic studies of MGC in 
      rats that suggest that the conjugate works by repressing the activation of renal 
      inosine-5'-monophosphate dehydrogenase 2 (IMPDH2), thereby inhibiting the 
      proliferation and accumulation of lympholeukocytes in the proximal tubules. In 
      addition, MGC appears to inhibit inflammation through various pathways, including 
      inhibition of free oxygen radical production, upregulation of bone morphogenetic 
      protein-7, and downregulation of complement protein 3, TLR 4, intracellular 
      adhesion molecules in the endothelium, proinflammatory cytokines (e.g., TNF-alpha, 
      IL-6, IL-1, TGF-beta), and chemotactic cytokines [e.g., monocyte chemoattractant 
      protein-1 (MCP-1) and IL-8]. These findings suggest that MGC specifically targets 
      the proximal tubules and acts through numerous mechanisms to substantially 
      mitigate I/R injury in rats; this conjugate may provide a more effective 
      alternative to current combination therapy.
FAU - Wang, Xiaohong
AU  - Wang X
AD  - Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of 
      Education, West China School of Pharmacy, Sichuan University , Southern Renmin 
      Road, No. 17, Section 3, Chengdu 610041, P. R. China.
FAU - Xiong, Menghua
AU  - Xiong M
FAU - Zeng, Yingchun
AU  - Zeng Y
FAU - Sun, Xun
AU  - Sun X
FAU - Gong, Tao
AU  - Gong T
FAU - Zhang, Zhirong
AU  - Zhang Z
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140825
PL  - United States
TA  - Mol Pharm
JT  - Molecular pharmaceutics
JID - 101197791
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Interleukin-6)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 1.1.1.205 (IMP Dehydrogenase)
RN  - HU9DX48N0T (Mycophenolic Acid)
RN  - N08U5BOQ1K (Glucosamine)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/chemistry/*therapeutic use
MH  - Glucosamine/*chemistry/*therapeutic use
MH  - IMP Dehydrogenase/metabolism
MH  - Interleukin-6/metabolism
MH  - Kidney/drug effects/metabolism
MH  - Male
MH  - Mycophenolic Acid/*chemistry/*therapeutic use
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Reperfusion Injury/*drug therapy/*metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
OTO - NOTNLM
OT  - inflammation
OT  - ischemia/reperfusion
OT  - mycophenolic acid-glucosamine conjugate
OT  - renal targeting
EDAT- 2014/08/26 06:00
MHDA- 2015/06/25 06:00
CRDT- 2014/08/26 06:00
PHST- 2014/08/26 06:00 [entrez]
PHST- 2014/08/26 06:00 [pubmed]
PHST- 2015/06/25 06:00 [medline]
AID - 10.1021/mp500282g [doi]
PST - ppublish
SO  - Mol Pharm. 2014 Oct 6;11(10):3503-14. doi: 10.1021/mp500282g. Epub 2014 Aug 25.