Effect of Diosmin on mTOR/Akt Signaling Molecules in NDEA-induced Hepatocellular Carcinoma in Experimental Rats

Download Article

DOI: 10.21522/TIJPH.2013.SE.24.01.Art008

Authors : Vishnu Priya Veeraraghavan, R. Gayathri, Kavitha. S, J. Selvaraj, Nithish Shankar


Background: Diosmin is a natural compound with a wide range of biological activity, e.g., it improves lymphatic drainage, supports microcirculation, and increases venous tone, and venous elasticity, hence, it is applied in the pharmacotherapy of chronic venous disorders (CVD). This work aims to analyze the effect of diosmin on mTOR and Akt-signaling molecules in NDEA-induced hepatocellular carcinoma (HCC) in experimental rats. Materials and Methods: Healthy adult rats were split into four groups randomly. Each group consisted of 6 animals. Group I: Control, Group II: NDEA-induced hepatocellular carcinogenic rats, Group III: Cancer-bearing animals treated with diosmin (200 mg) orally for 28 days. Group IV: Control animals treated with diosmin (200 mg) alone for 28 days. Liver function markers (ALP and AST) were measured by biochemical analysis while mTOR and Akt mRNA expression were analyzed by q-PCR analysis. Results:  ALP and AST concentration in the serum and mRNA expression of the transcription factor, mTOR  were found to be upregulated in HCC bearing rats but Akt mRNA expression was reduced. However, a 200 mg dose of diosmin controls the altered levels of liver function markers and signalling molecules. Conclusion: Results of this study suggest that diosmin may be one of the pharmacological and therapeutic natural compounds against hepatocellular carcinoma.


[1] Caillot, F., Derambure, C., Bioulac-Sage, P., Francois, A., Scotte, M., Goria, O., Hiron, M., Daveau, M.,  Salier, J. P., 2009, Transient and etiology-related transcription regulation in cirrhosis prior to hepatocellular carcinoma occurrence. World journal of gastroenterology, 15(3), 300–309, https://doi.org/10.3748/wjg.15.300.

[2] Silvestro, L., Tarcomnicu, I., Dulea, C., Attili, N. R., Ciuca, V., Peru, D., Rizea Savu, S., 2013, Confirmation of diosmetin 3-O-glucuronide as major metabolite of diosmin in humans, using micro-liquid-chromatography-mass spectrometry and ion mobility mass spectrometry. Analytical and bioanalytical chemistry, 405(25), 8295–8310, https://doi.org/10.1007/s00216-013-7237-y.

[3] Kang, M. H., Reynolds, C. P., 2009, Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clinical cancer research: an official journal of the American Association for Cancer Research, 15(4), 1126–1132. https://doi.org/10.1158/1078-0432.CCR-08-0144.

[4] Perumal, S., Langeshwaran, K., Selvaraj, J., Ponnulakshmi, R., Shyamaladevi, B., Balasubramanian, M.P., 2018, Effect of diosmin on apoptotic signaling molecules in N-nitrosodiethylamine-induced hepatocellular carcinoma in experimental rats. Molecular Cellular Biochemistry, 449(1-2):27-37. doi:10.1007/s11010-018-3339-3.

[5] Benavente-García, O., Castillo, J., Alcaraz, M., Vicente, V., Del Río, J.A., Ortuño, A., 2007, Beneficial action of Citrus flavonoids on multiple cancer-related biological pathways. Current Cancer Drug Targets, 7(8):795-809. doi:10.2174/156800907783220435.

[6] Sathivel, A., Raghavendran, H. R., Srinivasan, P., Devaki, T., 2008, Anti-peroxidative and anti-hyperlipidemic nature of Ulva lactuca crude polysaccharide on D-galactosamine induced hepatitis in rats. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 46(10), 3262–3267. https://doi.org/10.1016/j.fct.2008.07.016.

[7] Sekar, D., Lakshmanan, G., Mani, P., Biruntha, M., 2019, Methylation-dependent circulating microRNA 510 in preeclampsia patients. Hypertension research : official journal of the Japanese Society of Hypertension, 42(10), 1647–1648. https://doi.org/10.1038/s41440-019-0269-8.

[8] Rajeshkumar, S., Menon, S., Venkat Kumar, S., Tambuwala, M. M., Bakshi, H. A., Mehta, M., Satija, S., Gupta, G., Chellappan, D. K., Thangavelu, L., Dua, K., 2019, Antibacterial and antioxidant potential of biosynthesized copper nanoparticles mediated through Cissus arnotiana plant extract. Journal of photochemistry and photobiology B Biology, 197, 111531. https://doi.org/10.1016/j.jphotobiol.2019.111531.

[9] Felicita, A. S., Chandrasekar, S., Shanthasundari, K. K., 2012, Determination of craniofacial relation among the subethnic Indian population: a modified approach - (Sagittal relation). Indian journal of dental research : official publication of Indian Society for Dental Research, 23(3), 305–312. https://doi.org/10.4103/0970-9290.102210.

[10] Saravanan, A., Senthil Kumar, P., Jeevanantham, S., Karishma, S., Tajsabreen, B., Yaashikaa, P. R., Reshma, B., 2021, Effective water/wastewater treatment methodologies for toxic pollutants removal: Processes and applications towards sustainable development. Chemosphere, 280, 130595. https://doi.org/10.1016/j.chemosphere.2021.130595

[11] Sahu, D., Kannan, G. M., Vijayaraghavan, R., 2014, Size-dependent effect of zinc oxide on toxicity and inflammatory potential of human monocytes. Journal of toxicology and environmental health. Part A, 77(4), 177–191. https://doi.org/10.1080/15287394.2013.853224.

[12] Wang, Y., Zhang, Y., Guo, Y., Lu, J., Veeraraghavan, V. P., Mohan, S. K., Wang, C.,  Yu, X., 2019, Synthesis of Zinc oxide nanoparticles from Marsdenia tenacissima inhibits the cell proliferation and induces apoptosis in laryngeal cancer cells (Hep-2). Journal of photochemistry and photobiology. B Biology, 201, 111624. https://doi.org/10.1016/j.jphotobiol.2019.111624.

[13] Wadhwa, R., Paudel, K. R., Chin, L. H., Hon, C. M., Madheswaran, T., Gupta, G., Panneerselvam, J., Lakshmi, T., Singh, S. K., Gulati, M., Dureja, H., Hsu, A., Mehta, M., Anand, K., Devkota, H. P., Chellian, J., Chellappan, D. K., Hansbro, P. M., Dua, K., 2021, Anti-inflammatory and anticancer activities of Naringenin-loaded liquid crystalline nanoparticles in vitro. Journal of food biochemistry, 45(1), e13572. https://doi.org/10.1111/jfbc.13572.

[14] Lafaro, K. J., Demirjian, A. N., Pawlik, T. M. 2015, Epidemiology of hepatocellular carcinoma. Surgical oncology clinics of North America, 24(1), 1–17. https://doi.org/10.1016/j.soc.2014.09.001.

[15] Paula Santos, N., Colaço, A., Gil da Costa, R.M., Manuel Oliveira, M., Peixoto, F., Alexandra Oliveira, P., 2014, N-diethylnitrosamine mouse hepatotoxicity: time-related effects on histology and oxidative stress. Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie, 66(9-10), 429–436. https://doi.org/10.1016/j.etp.2014.07.002.

[16] Srinivasan, S., Pari, L., 2012, Ameliorative effect of diosmin, a citrus flavonoid against streptozotocin-nicotinamide generated oxidative stress induced diabetic rats. Chemico-biological interactions, 195(1), 43–51. https://doi.org/10.1016/j.cbi.2011.10.003.

[17] Lafaro, K. J., Demirjian, A. N., Pawlik, T. M., 2015, Epidemiology of hepatocellular carcinoma. Surgical oncology clinics of North America, 24(1), 1–17. https://doi.org/10.1016/j.soc.2014.09.001.

[18] Feldo, M., Wójciak-Kosior, M., Sowa, I., Kocki, J., Bogucki, J., Zubilewicz, T., Kęsik, J., Bogucka-Kocka, A., 2019, Effect of Diosmin Administration in Patients with Chronic Venous Disorders on Selected Factors Affecting Angiogenesis. Molecules (Basel, Switzerland), 24(18), 3316. https://doi.org/10.3390/molecules24183316.

[19] Huwait, E., Mobashir, M., 2022, Potential and Therapeutic Roles of Diosmin in Human Diseases. Biomedicines, 10(5), 1076. https://doi.org/10.3390/biomedicines10051076.

[20] Jayaraman, S., Krishnamoorthy, K., Prasad, M., Veeraraghavan, V.P., Krishnamoorthy, R., Alshuniaber, M.A., Gatasheh, M.K., Elrobh, M., 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 of Biological Macromolecules, 242(Pt 2), 124917. https://doi.org/10.1016/j.ijbiomac.2023.124917.

[21] Selvaraj, J., Muthusamy, T., Srinivasan, C., Balasubramanian, K., 2009, Impact of excess aldosterone on glucose homeostasis in adult male rat. Clinica Chimica Acta; International Journal of Clinical Chemistry, 407(1-2), 51–57. https://doi.org/10.1016/j.cca.2009.06.030.

[22] Jayaraman, S., Priya, V. V., Gayathri, R., 2023, Effect Of Antioxidant Vitamins On Protein Kinase-C And Phosphotyrosine Phosphatase 1b Expression In The Liver Of Glyphosate-Induced Experimental Diabetic Rats. Journal of Namibian Studies: History Politics Culture, 33, 5951-5962.

[23] Mohan, S.K., Priya, V.V., 2009, Lipid peroxidation, glutathione, ascorbic acid, vitamin E, antioxidant enzyme and serum homocysteine status in patients with polycystic ovary syndrome. Early Pregnancy, 1: 44–49.

[24] Karthik, E.V.G., Priya, V.V., & Gayathri. R (2021). Dhanraj Ganapathy. Health Benefits Of Annona Muricata-A Review. Int J Dentistry Oral Sci. 8(7), 29657.

[25] Chandran, D., Jayaraman, S., Sankaran, K., Veeraraghavan, V.P., Gayathri, R., 2023, Antioxidant Vitamins Attenuate Glyphosate-Induced Development of Type-2 Diabetes Through the Activation of Glycogen Synthase Kinase-3 β and Forkhead Box Protein O 1 in the Liver of Adult Male Rats. Cureus, 15(12), e51088. https://doi.org/10.7759/cureus.51088.

[26] Suresh, M., Vishnu Priya, V., Gayathri, R., 2018, Effect of e-learning on academic performance of undergraduate students. Drug Invention Today, 10(9), 1797-1800.

[27] Veeraraghavan, V. P., Periadurai, N. D., Karunakaran, T., Hussain, S., Surapaneni, K. M., Jiao, X., 2021, Green synthesis of silver nanoparticles from aqueous extract of Scutellaria barbata and coating on the cotton fabric for antimicrobial applications and wound healing activity in fibroblast cells (L929). Saudi journal of biological sciences, 28(7), 3633–3640. https://doi.org/10.1016/j.sjbs.2021.05.007.

[28] Shah, P.M., Priya, V.V., Gayathri, R., 2016, Quercetin-a flavonoid: a systematic review.  Research Journal of Pharmaceutical, Biological and Chemical Sciences, 8, 878.

[29] Jayaraman, S., Devarajan, N., Rajagopal, P., Babu, S., Ganesan, S. K., Veeraraghavan, V. P., Palanisamy, C. P., Cui, B., Periyasamy, V., Chandrasekar, K, 2021, β-Sitosterol Circumvents Obesity Induced Inflammation and Insulin Resistance by down-Regulating IKKβ/NF-κB and JNK Signaling Pathway in Adipocytes of Type 2 Diabetic Rats. Molecules (Basel, Switzerland), 26(7), 2101. https://doi.org/10.3390/molecules26072101.

[30] Manohar, J., Gayathri, R., Vishnupriya, V., 2016, Tenderisation of meat using bromelain from pineapple extract.  International Journal of Pharmaceutical Sciences Review and Research, 39: 81–85.

[31] Balaji, V., Priya, V.V., Gayathri, R., 2017, Awareness of risk factors for obesity among College students in Tamil Nadu: A Questionnaire based study. Research Journal of Pharmacy and Technology, 10, 1367–1369. https://www.i-scholar.in/index.php/rjpt/article/view/155904.

[32] Dave, P.H., Vishnupriya, V., Gayathri, R., 2016, Herbal remedies for anxiety and depression-a review. Research Journal of Pharmacy and Technology, 9, 1253–1256.