An Aza resveratrol–chalcone derivative 6b protects mice against
diabetic cardiomyopathy by alleviating inﬂammation and
a, b, #
, Jianchang Qian
a, c, #
, Chuchu Sun
a, c, #
, Hailing Zhang
, Shiju Ye
, Zheng Xu
, Jingying Wang
, Weijian Huang
*, Guang Liang
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang,
Department of Cardiology, the First Afﬁliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
Translational Medicine Center in Afﬁliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
Department of Endocrinology, the First Afﬁliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
Received: August 21, 2017; Accepted: October 4, 2017
Inﬂammation and oxidative stress play a crucial role in the development of diabetic cardiomyopathy (DCM). We previously had synthesized an
Aza resveratrol–chalcone derivative 6b, of which effectively suppressing lipopolysaccharide (LPS)-induced inﬂammatory response in macro-
phages. This study aimed to investigate the potential protective effect of 6b on DCM and underlying mechanism. In H9c2 myocardial cells, 6b
potently decreased high glucose (HG)-induced cell ﬁbrosis, hypertrophy and apoptosis, alleviating inﬂammatory response and oxidant stress.
In STZ-induced type 1 diabetic mice (STZ-DM1), orally administration with 6b for 16 weeks signiﬁcantly attenuated cardiac hypertrophy, apop-
tosis and ﬁbrosis. The expression of inﬂammatory cytokines and oxidative stress biomarkers was also suppressed by 6b distinctly, without
affecting blood glucose and body weight. The anti-inﬂammatory and antioxidative activities of 6b were mechanistic associated with nuclear fac-
tor-kappa B (NF-jB) nucleus entry blockage and Nrf2 activation both in vitro and in vivo. The results indicated that 6b can be a promising car-
dioprotective agent in treatment of DCM via inhibiting inﬂammation and alleviating oxidative stress. This study also validated the important role
of NF-jB and Nrf2 taken in the pathogenesis of DCM, which could be therapeutic targets for diabetic comorbidities.
Cardiovascular disease is considered to be a leading cause of morbid-
ity and mortality in diabetic patients . DCM is characterized by
structural and functional abnormalities in the myocardium such as
cardiac ﬁbrosis, ventricular hypertrophy and heart failure . Several
mechanisms have been implicated to be associated with the patho-
genesis of DCM, including myocardial insulin resistance, cardiac
inﬂammation, oxidative stress, interstitial ﬁbrosis, cardiac cell death
and apoptosis [3–6].
It is well known that hyperglycaemia, the major clinical presenta-
tion of diabetes, is associated with chronic inﬂammation and oxida-
tive stress . Hyperglycaemia can increase the expression and
release of pro-inﬂammatory cytokines such as interleukin 6 (IL-6), IL-
1b and tumour necrosis factor a (TNF-a), by activating the NF-jB
pathway [8, 9]. For another, hyperglycaemia can also increase reac-
tive oxygen species (ROS) and/or reactive nitrogen species (RNS)
production from both non-mitochondrial and mitochondrial sources
. The crosstalk between inﬂammation and oxidative stress sig-
nalling can further inﬂuence on each other. Thus, inhibition of inﬂam-
mation and oxidative stress could be promising strategy for treatment
The discovery of natural products may help the identiﬁcation of
bioactive lead compounds with anti-inﬂammatory and antioxidative
These authors contribute equally to this work.
*Correspondence to: Guang LIANG, Ph.D.
Prof. Weijian HUANG
ª 2018 The Authors.
Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
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J. Cell. Mol. Med. Vol 22, No 3, 2018 pp. 1931-1943