PMID- 30814273
OWN - NLM
STAT- MEDLINE
DCOM- 20191217
LR  - 20191217
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Linking)
VI  - 476
IP  - 5
DP  - 2019 Mar 15
TI  - Azadirachtin inhibits amyloid formation, disaggregates pre-formed fibrils and 
      protects pancreatic beta-cells from human islet amyloid polypeptide/amylin-induced 
      cytotoxicity.
PG  - 889-907
LID - 10.1042/BCJ20180820 [doi]
AB  - The human islet amyloid polypeptide (hIAPP) or amylin is the major constituent of 
      amyloidogenic aggregates found in pancreatic islets of type 2 diabetic patients 
      that have been associated with beta-cell dysfunction and/or death associated with 
      type 2 diabetes mellitus (T2DM). Therefore, developing and/or identifying 
      inhibitors of hIAPP aggregation pathway and/or compound that can mediate 
      disaggregation of preformed aggregates holds promise as a medical intervention 
      for T2DM management. In the current study, the anti-amyloidogenic potential of 
      Azadirachtin (AZD)-a secondary metabolite isolated from traditional medicinal 
      plant Neem (Azadirachta indica)-was investigated by using a combination of 
      biophysical and cellular assays. Our results indicate that AZD supplementation 
      not only inhibits hIAPP aggregation but also disaggregates pre-existing hIAPP 
      fibrils by forming amorphous aggregates that are non-toxic to pancreatic beta-cells. 
      Furthermore, AZD supplementation in pancreatic beta-cells (INS-1E) resulted in 
      inhibition of oxidative stress; along with restoration of the DNA damage, lipid 
      peroxidation and the associated membrane damage, endoplasmic reticulum stress and 
      mitochondrial membrane potential. AZD treatment also restored glucose-stimulated 
      insulin secretion from pancreatic islets exposed to hIAPP. All-atom molecular 
      dynamics simulation studies on full-length hIAPP pentamer with AZD suggested that 
      AZD interacted with four possible binding sites in the amyloidogenic region of 
      hIAPP. In summary, our results suggest AZD to be a promising candidate for 
      combating T2DM and related amyloidogenic disorders.
CI  - (c) 2019 The Author(s). Published by Portland Press Limited on behalf of the 
      Biochemical Society.
FAU - Dubey, Richa
AU  - Dubey R
AD  - Department of Biosciences and Bioengineering, Indian Institute of Technology 
      Bombay, Powai, Mumbai, Maharashtra 400076, India.
FAU - Patil, Ketaki
AU  - Patil K
AD  - Department of Biotechnology, Savitribai Phule Pune University (Formerly 
      University of Pune), Ganeshkhind, Pune, Maharashtra 411007, India.
FAU - Dantu, Sarath C
AU  - Dantu SC
AD  - Department of Biosciences and Bioengineering, Indian Institute of Technology 
      Bombay, Powai, Mumbai, Maharashtra 400076, India.
AD  - Department of Computer Science-Synthetic Biology Theme, Brunel University London, 
      Uxbridge UB83PH, U.K.
FAU - Sardesai, Devika M
AU  - Sardesai DM
AD  - Department of Biotechnology, Savitribai Phule Pune University (Formerly 
      University of Pune), Ganeshkhind, Pune, Maharashtra 411007, India.
FAU - Bhatia, Parnika
AU  - Bhatia P
AD  - Department of Biotechnology, Savitribai Phule Pune University (Formerly 
      University of Pune), Ganeshkhind, Pune, Maharashtra 411007, India.
FAU - Malik, Nikita
AU  - Malik N
AD  - Department of Biosciences and Bioengineering, Indian Institute of Technology 
      Bombay, Powai, Mumbai, Maharashtra 400076, India.
FAU - Acharya, Jhankar D
AU  - Acharya JD
AD  - Department of Zoology, Savitribai Phule Pune University (Formerly University of 
      Pune), Ganeshkhind, Pune, Maharashtra 411007, India.
FAU - Sarkar, Soham
AU  - Sarkar S
AD  - Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 
      Maharashtra 400076, India.
FAU - Ghosh, Soumadwip
AU  - Ghosh S
AD  - Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 
      Maharashtra 400076, India.
FAU - Chakrabarti, Rajarshi
AU  - Chakrabarti R
AUID- ORCID: 0000-0002-0785-1508
AD  - Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai, 
      Maharashtra 400076, India.
FAU - Sharma, Shilpy
AU  - Sharma S
AD  - Department of Biotechnology, Savitribai Phule Pune University (Formerly 
      University of Pune), Ganeshkhind, Pune, Maharashtra 411007, India 
      ashutoshk@iitb.ac.in ssharma@unipune.ac.in.
FAU - Kumar, Ashutosh
AU  - Kumar A
AUID- ORCID: 0000-0002-5061-8162
AD  - Department of Biosciences and Bioengineering, Indian Institute of Technology 
      Bombay, Powai, Mumbai, Maharashtra 400076, India ashutoshk@iitb.ac.in 
      ssharma@unipune.ac.in.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190315
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Amyloid)
RN  - 0 (Islet Amyloid Polypeptide)
RN  - 0 (Limonins)
RN  - O4U1SAF85H (azadirachtin)
SB  - IM
MH  - *Amyloid/chemistry/metabolism
MH  - Amyloidosis/drug therapy/metabolism/pathology
MH  - Diabetes Mellitus, Type 2/drug therapy/metabolism/pathology
MH  - Humans
MH  - *Islet Amyloid Polypeptide/chemistry/metabolism
MH  - Limonins/*pharmacology
MH  - *Molecular Dynamics Simulation
MH  - Oxidative Stress/*drug effects
OTO - NOTNLM
OT  - Azadirachtin
OT  - amyloid
OT  - apoptosis
OT  - hIAPP
OT  - molecular dynamics
OT  - pancreatic beta-cell
EDAT- 2019/03/01 06:00
MHDA- 2019/12/18 06:00
CRDT- 2019/03/01 06:00
PHST- 2018/10/18 00:00 [received]
PHST- 2019/02/18 00:00 [revised]
PHST- 2019/02/27 00:00 [accepted]
PHST- 2019/03/01 06:00 [pubmed]
PHST- 2019/12/18 06:00 [medline]
PHST- 2019/03/01 06:00 [entrez]
AID - BCJ20180820 [pii]
AID - 10.1042/BCJ20180820 [doi]
PST - epublish
SO  - Biochem J. 2019 Mar 15;476(5):889-907. doi: 10.1042/BCJ20180820.