Hepatic regenerative response to long-term consumption of cinnamon-rich diet in aged rats

Document Type : Original Research Article

Authors

1 Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran

2 Medical Toxicology and Drug Abuse Research Center, Birjand University of Medical Sciences, Birjand, Iran

3 Department of Surgery, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran

4 Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences, Birjand, Iran

Abstract

Objective: The present study aimed to investigate the impact of cinnamon on liver regeneration in a rat model of partial hepatectomy (PH).
Materials and Methods: Thirty-two old male Sprague-Dawley rats (12 weeks old) were randomly divided into two equal groups (n=16). One group was fed with a standard diet (control) while the other group was fed with the same diet containing 1% cinnamon for 41 weeks. Then, all animals were subjected to the PH procedure and their livers were studied on postoperative days 2, 10 and 28. The liver contents of hepatic growth factor (HGF), insulin, malondialdehyde (MDA), nitric oxide metabolites (NOx), superoxide dismutase (SOD) and tumor necrosis factor-alpha (TNF-α) were evaluated. Also, the serum levels of liver function markers (alanine aminotransferase (ALT) and aspartate aminotransferase (AST), MDA, NOx and SOD activity were measured.
Results: The regenerated liver weight was significantly higher in cinnamon-treated animals than the controls on both day 10 and 28 post hepatectomy. The hepatic MDA levels in the cinnamon-treated animals were significantly lower than the control rats. Cinnamon led to a significant increase of SOD on day 2 after hepatectomy in serum and liver content. The basal level of HGF in the liver of cinnamon-consuming rats was significantly higher than in the control rats. Hepatic insulin level was significantly increased relative to baseline and control on day 2 in the cinnamon-consuming rats. Hepatic TNF-α levels dramatically decreased on postoperative days (POD) 2 relative to baseline in the control and cinnamon-treated rats.
Conclusion: Long-term cinnamon consumption enhanced liver regeneration outcomes in old rats.

Keywords


Alexandris IH, Assimakopoulos SF, Vagianos
CE, Patsoukis N, Georgiou C,
Nikolopoulou V, Scopa CD. 2004.
Oxidative state in intestine and liver after
partial hepatectomy in rats. Effect of
bombesin and neurotensin. Clin Biochem,
37: 350-356.
Andiran F, Kilinç K, Renda N, Ayhan A,
Tanyel FC. 2003. Lipid peroxidation and
extracellular matrix in normal and cirrhotic
rat livers following 70% hepatectomy.
Hepatogastroenterology, 50: 805-808.
Araújo TG, Oliveira AG, Carvalho BM,
Guadagnini D, Protzek AOP, Carvalheira
JBC, Boschero AC, Saad MJA. 2012.
Hepatocyte growth factor plays a key role
in insulin resistance-associated
compensatory mechanisms. Endocrinology,
153: 5760-5769.
Ataie Z, Mehrani H, Ghasemi A, Farrokhfall
K. 2019. Cinnamaldehyde has beneficial
effects against oxidative stress and nitric
oxide metabolites in the brain of aged rats
fed with long-term, high-fat diet. J Funct
Foods, 52: 545-551.
Beyer HS, Sherman R, Zieve L. 1991. Aging
is associated with reduced liver
regeneration and diminished thymidine
kinase mRNA content and enzyme activity
in the rat. J Lab Clin Med, 117: 101-108.
Biondo-Simões Mde L, Matias JE, Montibeller
GR, Siqueira LC, Nunes Eda S, Grassi CA.
2006. Effect of aging on liver regeneration
in rats. Acta Cir Bras, 21: 197-202.
Carnovale CE, Ronco MT. 2012. Role of nitric
oxide in liver regeneration. Ann Hepatol,
11: 636-647.
Carnovale CE, Scapini C, Alvarez ML, Favre
C, Monti J, Carrillo MC. 2000. Nitric oxide
release and enhancement of lipid
peroxidation in regenerating rat liver. J
Hepatol, 32: 798-804.
Cheeseman KH, Collins M, Maddix S, Milia
A, Proudfoot K, Slater TF, Burton GW,
Webb A, Ingold KU. 1986. Lipid
Zardast et al.
AJP, Vol. 13, No. 3, May-Jun 2023 314
peroxidation in regenerating rat liver. FEBS
letters, 209:191-196.
Choi D-Y, Baek Y-H, Huh J-E, Ko J-M, Woo
H, Lee J-D, Park D-S. 2009. Stimulatory
effect of Cinnamomum cassia and cinnamic
acid on angiogenesis through up-regulation
of VEGF and Flk-1/KDR expression. Int
Immunopharmacol, 9: 959-967.
Daemi A, Lotfi M, Farahpour MR, Oryan A,
Ghayour SJ, Sonboli A. 2019. Topical
application of Cinnamomum
hydroethanolic extract improves wound
healing by enhancing re-epithelialization
and keratin biosynthesis in streptozotocininduced diabetic mice. Pharm Biol, 57:
799-806.
Dastjerdi M, Nakhaee S, Askri M, Bayat F,
Farrokhfall K. 2020. Long-term cinnamon
consumption improves postoperative
recovery of liver resection surgery in aged
rats. J Surg Trauma, 8: 58-65.
Eidi A, Mortazavi P, Bazargan M,
Zaringhalam J. 2012. Hepatoprotective
activity of cinnamon ethanolic extract
against CCI4-induced liver injury in rats.
EXCLI J, 11: 495-507.
Enkhbold C, Morine Y, Utsunomiya T, Imura
S, Ikemoto T, Arakawa Y, Saito Y,
Yamada S, Ishikawa D, Shimada M. 2015.
Dysfunction of liver regeneration in aged
liver after partial hepatectomy. J
Gastroenterol Hepatol, 30: 1217-1224.
Farrokhfall K, Hashtroudi MS, Ghasemi A,
Mehrani H. 2015. Comparison of inducible
nitric oxide synthase activity in pancreatic
islets of young and aged rats. Iran J Basic
Med Sci, 18: 115-121.
Frith J, Jones D, Newton JL. 2009. Chronic
liver disease in an ageing population. Age
Ageing, 38: 11-18.
Gorla GR, Malhi H, Gupta S. 2001.
Polyploidy associated with oxidative injury
attenuates proliferative potential of cells. J
Cell Sci, 114: 2943-2951.
Haidari F, Mohammadshahi M, Abiri B, Zarei
M, Fathi M. 2020. Cinnamon extract
supplementation improves inflammation
and oxidative stress induced by acrylamide:
An experimental animal study. Avicenna J
Phytomed, 10: 243-252.
Helling TS. 2006. Liver failure following
partial hepatectomy. HPB, 8: 165-174.
Higgins GM. 1931. Experimental pathology of
the liver; I. Restoration of the liver of the
white rat following partial surgical
removal. Arch pathol, 12: 186-202.
Hortelano S, Dewez B, Genaro AM, DíazGuerra MJ, Boscá L. 1995. Nitric oxide is
released in regenerating liver after partial
hepatectomy. Hepatology, 21: 776-786.
Huh C-G, Factor VM, Sánchez A, Uchida K,
Conner EA, Thorgeirsson SS. 2004.
Hepatocyte growth factor/c-met signaling
pathway is required for efficient liver
regeneration and repair. Proc Natl Acad
Sci, 101: 4477-4482.
Khan A, Safdar M, Khan MMA, Khattak KN,
Anderson RA. 2003. Cinnamon improves
glucose and lipids of people with type 2
diabetes. Diabetes Care, 26: 3215-3218.
Khoshtabiat L, Mahdavi M. 2015. The role of
oxidative stress in proliferation and cell
death. J Mazand Univ Med Sci, 25: 130-
145.
Kim IH, Kisseleva T, Brenner DA. 2015.
Aging and liver disease. Curr Opin
Gastroenterol, 31: 184-191.
Kwon AH, Uetsuji S, Yamamura M, Hioki K,
Yamamoto M. 1990. Effect of
administration of fibronectin or aprotinin
on liver regeneration after experimental
hepatectomy. Ann Surg, 211: 295-300.
Lu J, Zhang K, Nam S, Anderson RA, Jove R,
Wen W. 2009. Novel angiogenesis
inhibitory activity in cinnamon extract
blocks VEGFR2 kinase and downstream
signaling. Carcinog, 31: 481-488.
Martins PN, Theruvath TP, Neuhaus P. 2008.
Rodent models of partial hepatectomies.
Liver Int, 28: 3-11.
Michalopoulos GK. 2010. Liver regeneration
after partial hepatectomy: critical analysis
of mechanistic dilemmas. Am J Pathol,
176: 2-13.
Mona AM. 2010. Impact of L-carnitine and
Cinnamon on insulin-like growth factor-1
and inducible nitric oxide synthase gene
expression in heart and brain of insulin
resistant rats. Am J Biochem Biotechnol, 6:
204-212.
Moselhy SS, Ali HK. 2009. Hepatoprotective
effect of cinnamon extracts against carbon
tetrachloride induced oxidative stress and
liver injury in rats. Biol Res, 42: 93-98.
Nakamura T, Mizuno S. 2010. The discovery
of hepatocyte growth factor (HGF) and its
significance for cell biology, life sciences
and clinical medicine. Proc Jpn Acad Ser B
Phys Biol Sci, 86: 588-610.
Cinnamon consumption and liver regeneration
AJP, Vol. 13, No. 3, May-Jun 2023 315
Nakhaee S, Dastjerdi M, Roumi H, Mehrpour
O, Farrokhfall K. 2021. N-acetylcysteine
dose-dependently improves the analgesic
effect of acetaminophen on the rat hot plate
test. BMC Pharmacol Toxicol, 22: 4.
Nejak-Bowen K, Orr A, Bowen WC, Jr.,
Michalopoulos GK. 2013. Conditional
genetic elimination of hepatocyte growth
factor in mice compromises liver
regeneration after partial hepatectomy.
PloS One, 8: e59836.
Pibiri M. 2018. Liver regeneration in aged
mice: new insights. Aging,10: 1801-1824.
Reagan-Shaw S, Nihal M, Ahmad N. 2008.
Dose translation from animal to human
studies revisited. FASEB J, 22: 659-661.
Sánchez-Hidalgo JM, Naranjo A, Ciria R,
Ranchal I, Aguilar-Melero P, Ferrín G,
Valverde A, Rufián S, López-Cillero P,
Muntané J, Briceno J. 2012. Impact of age
on liver regeneration response to injury
after partial hepatectomy in a rat model. J
Surg Res, 175: e1-9.
Suryanti V, Wibowo FR, Khotijah S,
Andalucki N. 2018. Antioxidant activities
of cinnamaldehyde derivatives. IOP Conf
Ser Mater Sci Eng, 333: 012077.
Tao Y, Wang M, Chen E, Tang H. 2017. Liver
regeneration: Analysis of the main relevant
signaling molecules. Mediators Inflamm,
2017: 4256352.
Toydemir T, Kanter M, Erboga M, Oguz S,
Erenoglu C. 2013. Antioxidative,
antiapoptotic, and proliferative effect of
curcumin on liver regeneration after partial
hepatectomy in rats. Toxicol Ind Health,
31: 162-172.
Yagi S, Hirata M, Miyachi Y, Uemoto S.
2020. Liver regeneration after hepatectomy
and partial liver transplantation. Int J Mol
Sci, 21: 8414.
Yang S, Tan TM, Wee A, Leow CK. 2004.
Mitochondrial respiratory function and
antioxidant capacity in normal and cirrhotic
livers following partial hepatectomy. Cell
Mol Life Sci, 61: 220-229.
Yuan X, Han L, Fu P, Zeng H, Lv C, Chang
W, Runyon RS, Ishii M, Han L, Liu K, Fan
T, Zhang W, Liu R. 2018. Cinnamaldehyde
accelerates wound healing by promoting
angiogenesis via up-regulation of PI3K and
MAPK signaling pathways. Lab Invest, 98:
783-798.
Zhang K, Han ES, Dellinger TH, Lu J, Nam S,
Anderson RA, Yim JH, Wen W. 2017.
Cinnamon extract reduces VEGF
expression via suppressing HIF‐ 1α gene
expression and inhibits tumor growth in
mice. Mol Carcinog, 56: 436-446.
Zhu C, Ikemoto T, Utsunomiya T, Yamada S,
Morine Y, Imura S, Arakawa Y, Takasu C,
Ishikawa D, Shimada M. 2014.
Senescence-related genes possibly
responsible for poor liver regeneration after
hepatectomy in elderly patients. J
Gastroenterol Hepatol, 29: 1102-1108.