Effect of Diosmin on mTOR/Akt Signaling Molecules in NDEA-induced Hepatocellular Carcinoma in Experimental Rats
Abstract:
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.
References:
[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.
[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.
