Chem Biol Drug Des. 2018;91:933–941. wileyonlinelibrary.com/journal/cbdd
© 2017 John Wiley & Sons A/S
Received: 13 May 2017
Revised: 19 October 2017
Accepted: 7 December 2017
Cucurbitacin- B attenuates CCl
- induced hepatic fibrosis in mice
through inhibition of STAT- 3
Alaliaa M. Sallam
Ashraf B. Abdel-Naim
Department of Biochemistry, Faculty of
Pharmacy, Ain Shams University, Abbasia,
Department of Pharmacology and
Toxicology, Faculty of Pharmacy, Ain
Shams University, Abbasia, Cairo, Egypt
Department of Pharmacology and
Toxicology, Faculty of Pharmacy, King
Abdulaziz University, Jeddah, Saudi Arabia
Ashraf B. Abdel-Naim, Professor of
Pharmacology and Toxicology, Faculty
of Pharmacy, King Abdulaziz University,
Jeddah, Saudi Arabia.
Liver fibrosis is a major health concern worldwide. Inhibitors of Signal Transducer
and Activator of Transcription 3 (STAT3) have been reported to attenuate experi-
mental liver fibrosis. Therefore, the aim of this study was to investigate the potential
ameliorative effect of cucurbitacin- B (Cucu- B) against CCl
- induced liver fibrosis in
mice. Treatment with Cucu- B (5 mg/kg) preserved hepatocellular membrane integ-
rity and amended the metabolic function as indicated by preventing the rise of serum
liver function markers. This was confirmed histologically. CCl
- induced oxidative
stress was improved by Cucu- B treatment (1 and 5 mg/kg). Furthermore, Cucu- B
treatment ameliorated the fibrotic state as evidenced by inhibiting the rise of
hydroxyproline liver content and mitigating the overexpressions of collagen- 1α,
α- smooth muscle actin (α- SMA) and transforming growth factor beta (TGF- β) as
well as the downexpression of matrix metalloproteinase- 2 (MMP- 2) mRNA.
Importantly, STAT3 activity was inhibited by Cucu- B as confirmed by decreased
phosphorylation of STAT3 without changing total STAT3 expression. This was sub-
stantiated by the reduced Bcl- 2 together with increased Bax mRNA expressions with
subsequent elevation of Bax/Bcl- 2 ratio. In conclusion, Cucu- B hampers CCl
induced liver fibrosis in mice. This can be attributed—at least partly—to inhibition
of oxidative stress, inflammation and STAT3 signalling.
cucurbitacin-B, fibrosis, liver, mice, STAT-3
Liver fibrosis is a serious health concern affecting millions of
people worldwide estimated to be ~2.8% in the general pop-
ulation older than 40 years.
. It is a chronic disease that may
progress to cirrhosis, hepatocellular carcinoma or even com-
plete liver failure.
Notably, the pathogenesis of liver fibrosis
involves the activation of hepatic stellate and Kupffer cells.
These two cells are responsible for propagation of oxidative
and inflammatory responses, with subsequent continuous
activation of various fibrogenic mediators.
there is no satisfactory drug for the treatment of fibrosis.
This necessitates the chronic use of drugs to protect against
the development of fibrotic complications associated with
the various hepatic injuries. On this point, natural products
have gained high recognition among the public and scientific
Cucurbitacins are a group of chemicals that belong
to tetracyclic triterpenoids.
Cucurbitacin- B (Cucu- B)
is one of the most active members of cucurbitacins. It has
demonstrated strong antioxidant and anti- inflammatory ac-
Furthermore, it has been shown to inhibit prolif-
eration and migration of different cancer cell lines as well as
induction of apoptosis and cell cycle arrest against various
cancer cell lines.
Experimentally, it exhibited potential
protection against lung injury and liver toxicity in rats.
It is worth mentioning that cucurbitacins are considered
selective inhibitors of Signal Transducer and Activator of