Effect of Diosmin on The Expression of Epithelial-Mesenchymal Transition Signaling Molecules in Ndea-Induced Hepato-Cellular Carcinoma in Experimental Rats

Download Article

DOI: 10.21522/TIJPH.2013.SE.23.01.Art008

Authors : Vishnu Priya Veeraraghavan, Gayathri R, Kavitha S, M B Sai Sreekar Reddy, Selvaraj Jayaraman

Abstract:

Hepatocellular carcinoma (HCC) is a primary liver cancer, distinct from other cancers originating in other organs. Previous study demonstrated that diosmin exhibits anticancer effects by influencing the expression of apoptotic signaling molecules in NDEA-induced hepatocellular carcinoma in rats. However, its impact on the epithelial-mesenchymal transition (EMT) signaling pathway, crucial in liver cancer progression, remains unknown. The research aimed to investigate diosmin’s effects on EMT signaling molecule expression in NDEA-induced hepatocellular carcinoma in rats. In this experiment, adult male albino rats were categorized into three groups: a control group, NDEA-induced hepatocellular carcinogenic rats and rats with HCC treated with diosmin orally for 28 days. Liver function markers (AST and ALT) were done by biochemical analysis while mNRA expression analysis of EMT-signaling molecules ( E-cadherin and vimentin) were analyzed by Real Time-RT-PCR analysis. One-Way-ANOVA was used for the statistical analysis and significance was considered at p<0.05. Diosmin treatment resulted in a significant decrease in liver function markers compared to the control group (p<0.05). Moreover, diosmin administration led to a notable reduction in mRNA levels of EMT signaling molecules, specifically E-cadherin and vimentin, indicating its potential chemopreventive role against liver cancer. Findings of the present study concludes that diosmin, an alkaloid, may merge as a promising candidate for hepatocellular carcinoma treatment based on its demonstrated efficacy in this experimental model.
Keywords: Novel method, Hepatocellular carcinoma, EMT signaling, diosmin, wistar rats, liver function, innovative technique.

References:

[1] Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., and Jemal, A. 2018. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. https://doi.org/10.3322/caac.21492.

[2] Mittal, S., and El-Serag, H. B. 2013. Epidemiology of hepatocellular carcinoma: consider the population. Journal of clinical gastroenterology, 47 Suppl(0): S26.

[3] Hanin, S. M. A., Dharman, S., and Girija, A. S. S. 2022. Association of salivary microbes with oral mucositis among patients undergoing chemoradiotherapy in head and neck cancer: A hospital-based prospective . Journal of International Oral Health. Retrieved from https://www.jioh.org/article.asp?issn=0976-7428;year=2022;volume=14;issue=1;spage=53;epage=60;aulast=Azima.

[4] Bhoori, S., and  Mazzaferro, V. 2014. Corrigendum to Current challenges in liver transplantation for hepatocellular carcinoma. Best Practice & Research Clinical Gastroenterology, 28 (2014): 867879. https://doi.org/10.1016/j.bpg.2014.10.007.

[5] Liberal, R., and Grant, C. R. 2016. Cirrhosis and autoimmune liver disease: Current understanding. World journal of hepatology, 8(28): 11571168.

[6] Blagotinsek, K., and Rozman, D. 2017. Targeting Signalling Pathways in Hepatocellular Carcinoma. Current pharmaceutical design, 23(1): 170175.

[7] Abijeth, B., and Ezhilarasan, D. 2020. Syringic acid induces apoptosis in human oral squamous carcinoma cells through mitochondrial pathway. Journal of oral and maxillofacial pathology: JOMFP, 24(1): 4045.

[8] Hu, T.H., Huang, C.C., Lin, P.R., Chang, H.W., Ger, L.P., Lin, Y.W.,Changchien, C.S., Lee, C.M., Tai, M.H. 2003. Expression and prognostic role of tumor suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma. Cancer, 97(8): 19291940.

[9] Sushma, B., Vishnu Priya, V., Karthik Ganesh, M., and Gayathri, R. 2020. Awareness on risk factors associated with oral cancer among school students in chennai. International journal of current research and review, 12(24): S87S94.

[10] Sun, E. J., Wankell, M., Palamuthusingam, P., McFarlane, C., and Hebbard, L. 2021. Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma. Biomedicines. https://doi.org/10.3390/biomedicines9111639.

[11] Sivakumar, N., Geetha, R. V., and Priya, V. 2021. Gayathri R, Dhanraj Ganapathy. Targeted Phytotherapy for Reactive Oxygen Species Linked Oral Cancer. Int J Dentistry Oral Sci, 8(1): 14251429.

[12] Knowledge about the effects of medicinal plants against COVID-19 among dental students-A questionnaire study. (n.d.). Retrieved from https://pesquisa.bvsalud.org/global-literature-on-novel-coronavirus-2019-ncov/resource/pt/covidwho-995148.

[13] Karthik, E. V. G., Priya, V.  V., Gayathri, R., Dhanraj, G.  2021. Health Benefits Of Annona Muricata-A Review. Int J Dentistry Oral Sci, 8(7): 29652967.

[14] Lakshmi, T. (n.d.). Medicinal value and oral health aspects of acacia catechu-an update. International journal of dentistry and oral science.

[15] Lewinska, A., Siwak, J., Rzeszutek, I., and Wnuk, M. 2015. Diosmin induces genotoxicity and apoptosis in DU145 prostate cancer cell line. Toxicology in vitro: an international journal published in association with BIBRA, 29(3): 417425.

[16] Perumal, S., and Langeswaran, K. 2020. Diosmin anti-tumour efficacious against Hepatocellular Carcinoma. Research Journal of Pharmacy and Technology. https://doi.org/10.5958/0974-360x.2020.00308.x.

[17] Srinivasan, S., and Pari, L. 2012. Ameliorative effect of diosmin, a citrus flavonoid against streptozotocin-nicotinamide generated oxidative stress induced diabetic rats. Chemico-biological interactions, 195(1): 4351.

[18] Queenthy, S. S., and John, B. 2013. Diosmin exhibits anti-hyperlipidemic effects in isoproterenol induced myocardial infarcted rats. European journal of pharmacology, 718(1-3): 213218.

[19] Jayaraman, S., Krishnamoorthy, K., Prasad, M., Veeraraghavan, V.P., Krishnamoorthy, R., Alshuniaber, M.A., Gatasheh, M.K., Elrobh, M., and Gunassekaran. 2023. Glyphosate potentiates insulin resistance in skeletal muscle through the modulation of IRS-1/PI3K/Akt mediated mechanisms: An in vivo and in silico analysis. International Journal Biological Macromolecules, 242(Pt 2):124917.

[20] Selvaraj, J., Muthusamy, T., Srinivasan, C., and Balasubramanian, K. 2009. Impact of excess aldosterone on glucose homeostasis in adult male rat. Clinic Chimica Acta. 407(1-2):51-7.

[21] Lafaro, K. J., Demirjian, A. N., and Pawlik, T. M. 2015. Epidemiology of hepatocellular carcinoma. Surgical oncology clinics of North America, 24(1): 117.

[22] Darvesh, A. S., and Bishayee, A. 2013. Chemopreventive and Therapeutic Potential of Tea Polyphenols in Hepatocellular Cancer. Nutrition and Cancer. https://doi.org/10.1080/01635581.2013.767367.

[23] Santos, N. P., Colaço, A., da Costa, R. M. G., Oliveira, M. M., Peixoto, F., and Oliveira, P. A. 2014. N-diethylnitrosamine mouse hepatotoxicity: Time-related effects on histology and oxidative stress. Experimental and Toxicologic Pathology. https://doi.org/10.1016/j.etp.2014.07.002.

[24] Sakthisekaran, D. 2011. Resveratrol interferes with N-nitrosodiethylamine-induced hepatocellular carcinoma at early and advanced stages in male
Wistar rats.
Molecular Medicine Reports. https://doi.org/10.3892/mmr.2011.555.

[25] Bishayee, A., Politis, T., and Darvesh, A. S. 2010. Resveratrol in the chemoprevention and treatment of hepatocellular carcinoma. Cancer Treatment Reviews. https://doi.org/10.1016/j.ctrv.2009.10.002.

[26] Silvestro, L., Tarcomnicu, I., Dulea, C., Attili, N. R. B., Ciuca, V., Peru, D., and Savu, S. R. 2013. Confirmation of diosmetin 3-O-glucuronide as major metabolite of diosmin in humans, using micro-liquid-chromatographymass spectrometry and ion mobility mass spectrometry. Analytical and Bioanalytical Chemistry. https://doi.org/10.1007/s00216-013-7237-y.

[27] Ali, T. M., Abo-Salem, O. M., El Esawy, B. H., and El Askary, A. 2020. The Potential Protective Effects of Diosmin on Streptozotocin-Induced Diabetic Cardiomyopathy in Rats. The American Journal of the Medical Sciences. https://doi.org/10.1016/j.amjms.2019.10.005.

[28] Tanrikulu, Y., Şahin, M., Kismet, K., Kilicoglu, S. S., Devrim, E., Tanrikulu, C. S., Erdemli, E., Erel, S., Bayraktar, K., Akkus, M. A. 2013. The protective effect of diosmin on hepatic ischemia reperfusion injury: an experimental study. Bosnian Journal of Basic Medical Sciences. https://doi.org/10.17305/bjbms.2013.2305.

[29] Tahir, M., Rehman, M. U., Lateef, A., Khan, R., Khan, A. Q., Qamar, W, Ali, F., O’Hamiza, O., Sultana, S. 2013. Diosmin protects against ethanol-induced hepatic injury via alleviation of inflammation and regulation of TNF-α and NF-κB activation. Alcohol. https://doi.org/10.1016/j.alcohol.2012.12.010.

[30] Carlson, B. A., Dubay, M. M., Sausville, E. A., Brizuela, L., and Worland, P. J. 1996. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer research, 56(13): 29732978.