PMID- 32579365
OWN - NLM
STAT- MEDLINE
DCOM- 20211011
LR  - 20211011
IS  - 1543-8392 (Electronic)
IS  - 1543-8384 (Linking)
VI  - 18
IP  - 2
DP  - 2021 Feb 1
TI  - Silencing of Gasdermin D by siRNA-Loaded PEI-Chol Lipopolymers Potently Relieves 
      Acute Gouty Arthritis through Inhibiting Pyroptosis.
PG  - 667-678
LID - 10.1021/acs.molpharmaceut.0c00229 [doi]
AB  - Gasdermin D (GSDMD) plays a causal role in NOD-like receptor protein 3 (NLRP3) 
      inflammasome-mediated pyroptosis eruption, which has been regarded as a potential 
      therapeutic target for pyroptosis-related diseases including acute gouty 
      arthritis. In the present study, the synthesized PEI-Chol (cholesterol grafted 
      polyethylenimine) was assembled with GSDMD small interfering RNA (siRNA) to form 
      PEI-Chol/siGSDMD polyplexes, which provided high transfection efficiency for 
      siRNA-mediated GSDMD knockdown. Then we evaluated the effect of GSDMD 
      siRNA-loaded PEI-Chol on inflammatory cascades in bone-marrow-derived macrophages 
      (BMDMs) and acute gouty arthritis animal models under MSU exposure. When 
      accompanied by pyroptosis blockade and decreased release of interleukin-1 beta 
      (IL-1beta), NLRP3 inflammasome activation was also suppressed by GSDMD knockdown in 
      vivo and in vitro. Moreover, in MSU-induced acute gouty arthritis mice, blocking 
      GSDMD with siRNA significantly improved ankle swelling and inflammatory 
      infiltration observed in histopathological analysis. Furthermore, investigation 
      using a mouse air pouch model verified the effect of siGSDMD-loaded PEI-Chol on 
      pyroptosis of recruited macrophages and related signaling pathways in response to 
      MSU. These novel findings exhibited that GSDMD knockdown relieved acute gouty 
      arthritis through inhibiting pyroptosis, providing a possible therapeutic 
      approach for MSU-induced acute gouty arthritis molecular therapy using PEI-Chol 
      as a nucleic acid delivery carrier.
FAU - Ye, Shu-Min
AU  - Ye SM
AD  - State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and 
      Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
AD  - School of Pharmacy, China Pharmaceutical University, Nanjing 211198, PRChina.
FAU - Zhou, Meng-Ze
AU  - Zhou MZ
AD  - State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and 
      Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
FAU - Jiang, Wen-Jiao
AU  - Jiang WJ
AD  - State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and 
      Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
FAU - Liu, Chun-Xiao
AU  - Liu CX
AD  - State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and 
      Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
AD  - School of Pharmacy, China Pharmaceutical University, Nanjing 211198, PRChina.
FAU - Zhou, Zhan-Wei
AU  - Zhou ZW
AD  - School of Pharmacy, China Pharmaceutical University, Nanjing 211198, PRChina.
FAU - Sun, Min-Jie
AU  - Sun MJ
AD  - School of Pharmacy, China Pharmaceutical University, Nanjing 211198, PRChina.
FAU - Hu, Qing-Hua
AU  - Hu QH
AUID- ORCID: 0000-0003-1045-5466
AD  - State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and 
      Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
AD  - School of Pharmacy, China Pharmaceutical University, Nanjing 211198, PRChina.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200706
PL  - United States
TA  - Mol Pharm
JT  - Molecular pharmaceutics
JID - 101197791
RN  - 0 (Drug Carriers)
RN  - 0 (Gsdmd protein, mouse)
RN  - 0 (IL1B protein, mouse)
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Nlrp3 protein, mouse)
RN  - 0 (Phosphate-Binding Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - 268B43MJ25 (Uric Acid)
RN  - 9002-98-6 (Polyethyleneimine)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Animals
MH  - Arthritis, Experimental/chemically induced/drug therapy/immunology/pathology
MH  - Arthritis, Gouty/chemically induced/*drug therapy/immunology/pathology
MH  - Cells, Cultured
MH  - Cholesterol
MH  - Drug Carriers/*chemistry
MH  - Gene Knockdown Techniques/methods
MH  - Humans
MH  - Inflammasomes/drug effects/immunology/metabolism
MH  - Interleukin-1beta/metabolism
MH  - Intracellular Signaling Peptides and Proteins/*antagonists & 
      inhibitors/genetics/metabolism
MH  - Macrophages/drug effects/immunology/metabolism
MH  - Male
MH  - Mice
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - Phosphate-Binding Proteins/*antagonists & inhibitors/genetics/metabolism
MH  - Polyethyleneimine/chemistry
MH  - Primary Cell Culture
MH  - Pyroptosis/*drug effects
MH  - RNA, Small Interfering/*administration & dosage
MH  - Signal Transduction/drug effects/immunology
MH  - Uric Acid/administration & dosage/toxicity
OTO - NOTNLM
OT  - BMDMs
OT  - GSDMD siRNA
OT  - PEI-Chol
OT  - acute gouty arthritis
OT  - pyroptosis
EDAT- 2020/06/25 06:00
MHDA- 2021/10/12 06:00
CRDT- 2020/06/25 06:00
PHST- 2020/06/25 06:00 [pubmed]
PHST- 2021/10/12 06:00 [medline]
PHST- 2020/06/25 06:00 [entrez]
AID - 10.1021/acs.molpharmaceut.0c00229 [doi]
PST - ppublish
SO  - Mol Pharm. 2021 Feb 1;18(2):667-678. doi: 10.1021/acs.molpharmaceut.0c00229. Epub 
      2020 Jul 6.