EXAMINING THE HEPATOPROTECTIVE EFFECTS OF GRAPE SEED EXTRACT AND THE ANTI-ESTROGENIC POTENTIAL OF LETROZOLE: EXPRESSING AROMATASE GENE PATTERN IN N-ETHYL-NITROSAMINE-INDUCED HEPATOCELLULAR CARCINOMA USING AN ANIMAL MODEL.
Main Article Content
Keywords
Mitogen-Activated Protein Kinases, Grape Seed Extract, Hepatocellular Carcinoma, carcinoma, Aromatase
Abstract
The study investigates the inhibitory effects of grape seed extract on HepG2 cell proliferation, focusing on processes like autophagy and the upregulation of proteins linked to the mitogen-activated protein kinase (MAPK) pathway. Extending previous research, it examines the effects of grape seed extract alone and in combination with letrozole on N-ethylnitrosamine-induced hepatocellular carcinoma in male albino Wistar rats. Employing a quasi-experimental design with purposive sampling, fifty rats were divided into five groups. Significant variations (p < 0.001) in serum albumin and liver enzyme levels were observed among groups through one-way ANOVA analysis. Additionally, a notable disparity (p < 0.05) was found in the relative gene expression of the aromatase gene. The results indicate significant impacts of both letrozole and grape seed extract on liver enzyme levels and highlight Group C as showing restored gene expression (p < 0.05). This study underscores the potential therapeutic effects of grape seed extract and letrozole in mitigating hepatocellular carcinoma progression, emphasizing the importance of further investigation into their mechanisms and clinical applications.
References
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18. Shiraishi K, Oka S, Matsuyama H. Testicular testosterone and estradiol concentrations and aromatase expression in men with nonobstructive azoospermia. The Journal of Clinical Endocrinology & Metabolism. 2021 Apr 1;106(4):1803-15.
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24. Green MR, Sambrook J. Synthesis of cDNA probes from mRNA using random oligonucleotide primers. Cold Spring Harbor Protocols. 2019 Jul 1;2019(7):pdb-rot100636.
25. Mukherjee AG, Wanjari UR, Nagarajan D, Vibhaa KK, Anagha V, Chakraborty R, Renu K, Dey A, Vellingiri B, Gopalakrishnan AV. Letrozole: Pharmacology, toxicity and potential therapeutic effects. Life Sciences. 2022 Oct 13:121074.
26. Zhao H, Zhou L, Shangguan AJ, Bulun SE. Aromatase expression and regulation in breast and endometrial cancer. Journal of molecular endocrinology. 2016 Jul 1;57(1):R19-33.
27. Ghufran H, Azam M, Mehmood A, Butt H, Riazuddin S. Standardization of diethylnitrosamine-induced hepatocellular carcinoma rat model with time based molecular assessment. Experimental and Molecular Pathology. 2021 Dec 1;123: 104715.
28. Khan F, Khan TJ, Kalamegam G, Pushparaj PN, Chaudhary A, Abuzenadah A, Kumosani T, Barbour E, Al-Qahtani M. Anti-cancer effects of Ajwa dates (Phoenix dactylifera L.) in diethylnitrosamine induced hepatocellular carcinoma in Wistar rats. BMC complementary and alternative medicine. 2017 Dec;17(1):1-0.
29. Abd Eldaim MA, Tousson E, Soliman MM, El Sayed IE, Abdel Aleem AA, Elsharkawy HN. Grape seed extract ameliorated Ehrlich solid tumor-induced hepatic tissue and DNA damage with reduction of PCNA and P53 protein expression in mice. Environmental Science and Pollution Research. 2021 Aug;28:44226-38.
30. Yousef MI, Mahdy MA, Abdou HM. The potential protective role of grape seed proanthocyanidin extract against the mixture of carboplatin and thalidomideinduced hepatotoxicity and cardiotoxicity in male rats. Preventive Medicine. 2019; 2:1-7
31. Aldubayan MA. Grape seed proanthocyanidin alleviates oxidative stress and apoptosis involved in liver of hyperthyroid mice. Annual Research & Review in Biology. 2019 Dec 3:1-1.
32. Chen J, Wang Y, Meng W, Zhao R, Lin W, Xiao H, Liao Y. Stearoyl-CoA Desaturases1 Accelerates Non-Small Cell Lung Cancer Metastasis by Promoting Aromatase Expression to Improve Estrogen Synthesis. International Journal of Molecular Sciences. 2023 Apr 6;24(7):6826.
33. Wang Y, Li S, Zhu L, Zou J, Jiang X, Chen M, Chen B. Letrozole improves the sensitivity of breast cancer cells overexpressing aromatase to cisplatin via down-regulation of FEN1. Clinical and Translational Oncology. 2019 Aug 12; 21:1026-33.
34. Mukherjee AG, Wanjari UR, Nagarajan D, Vibhaa KK, Anagha V, Chakraborty R, Renu K, Dey A, Vellingiri B, Gopalakrishnan AV. Letrozole: Pharmacology, toxicity and potential therapeutic effects. Life Sciences. 2022 Oct 13:121074.
2. Ranasinghe KN, Premarathna AD, Mahakapuge TA, Wijesundera KK, Ambagaspitiya AT, Jayasooriya AP, Kularatne SA, Rajapakse RP. In vivo anticancer effects of Momordica charantia seed fat on hepatocellular carcinoma in a rat model. Journal of Ayurveda and Integrative Medicine. 2021 Jul 1;12(3):435-42.
3. Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, Roberts LR, Heimbach JK. Diagnosis, S taging, and M anagement of H epatocellular C arcinoma: 2018 P ractice G uidance by the A merican A ssociation for the S tudy of L iver D iseases. Hepatology. 2018 Aug;68(2):723-50.
4. Alam L. A year of hepatocellular carcinoma at a glance. Demographics, 3 biochemical and radiological characteristics and treatment 4 modalities from a specialized facility of Pakistan 5.
5. Alneanaey RH, Taha NM, Lebda MA, Hashem AE, Sultan AS. Oligomeric proanthocyanidin grape seed extracts inhibited oncogenic signaling crosstalk of ERK1/2, β-catenin, and STAT3 through apoptosis induction in human liver and breast cancer cell lines. Biochemistry Letters. 2023 Dec 1;19(1):78-102.
6. Ikeda M, Morizane C, Ueno M, Okusaka T, Ishii H, Furuse J. Chemotherapy for hepatocellular carcinoma: current status and future perspectives. Japanese journal of clinical oncology. 2018 Feb 1;48(2):103-14.
7. Yu Y, Feng M. Radiotherapy for hepatocellular carcinoma. InSeminars in Radiation Oncology 2018 Oct 1 (Vol. 28, No. 4, pp. 277-287). WB Saunders.
8. Wang Y, Li J, Xia L. Plant-derived natural products and combination therapy in liver cancer. Frontiers in Oncology. 2023 Feb 14; 13:1116532.
9. Anwanwan D, Singh SK, Singh S, Saikam V, Singh R. Challenges in liver cancer and possible treatment approaches. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2020 Jan 1;1873(1):188314.
10. Gupta M, Dey S, Marbaniang D, Pal P, Ray S, Mazumder B. Grape seed extract: Having a potential health benefits. Journal of food science and technology. 2020 Apr;57: 1205-15.
11. Lei C, Tang X, Li H, Chen H, Yu S. Molecular hybridization of grape seed extract: Synthesis, structural characterization and anti-proliferative activity in vitro. Food Research International. 2020 May 1;131: 109005.
12. Augimeri G, Montalto FI, Giordano C, Barone I, Lanzino M, Catalano S, Andò S, De Amicis F, Bonofiglio D. Nutraceuticals in the mediterranean diet: Potential avenues for breast cancer treatment. Nutrients. 2021 Jul 26;13(8):2557.
13. Wang L, Zhan J, Huang W. Grape seed proanthocyanidins induce apoptosis and cell cycle arrest of HepG2 cells accompanied by induction of the MAPK pathway and NAG-1. Antioxidants. 2020 Nov 28;9(12):1200.
14. Bao X, Li J, Ren C, Wei J, Lu X, Wang X, Du W, Jin X, Ma B, Zhang Q, Ma B. Aucubin ameliorates liver fibrosis and hepatic stellate cells activation in diabetic mice via inhibiting ER stress-mediated IRE1α/TXNIP/NLRP3 inflammasome through NOX4/ROS pathway. Chemico-Biological Interactions. 2022 Sep 25; 365: 110074.
15. Castro-Piedras I, Sharma M, den Bakker M, Molehin D, Martinez EG, Vartak D, Pruitt WM, Deitrick J, Almodovar S, Pruitt K. DVL1 and DVL3 differentially localize to CYP19A1 promoters and regulate aromatase mRNA in breast cancer cells. Oncotarget. 2018 Nov 11;9(86):35639.
16. Hong Y, Chen S. Aromatase inhibitors: structural features and biochemical characterization. Annals of the New York Academy of Sciences. 2006 Nov;1089(1):237-51.
17. Boutas I, Pergialiotis V, Salakos N, Agrogiannis G, Konstantopoulos P, Korou LM, Kalampokas T, Gregoriou O, Creatsas G, Perrea D. The impact of Anastrazole and Letrozole on the metabolic profile in an experimental animal model. Scientific reports. 2015 Dec 1;5(1):17493.
18. Shiraishi K, Oka S, Matsuyama H. Testicular testosterone and estradiol concentrations and aromatase expression in men with nonobstructive azoospermia. The Journal of Clinical Endocrinology & Metabolism. 2021 Apr 1;106(4):1803-15.
19. Ghufran H, Azam M, Mehmood A, Butt H, Riazuddin S. Standardization of diethylnitrosamine-induced hepatocellular carcinoma rat model with time based molecular assessment. Experimental and Molecular Pathology. 2021 Dec 1;123: 104715.
20. Hamza AA, Heeba GH, Elwy HM, Murali C, El-Awady R, Amin A. Molecular characterization of the grape seeds extract’s effect against chemically induced liver cancer: In vivo and in vitro analyses. Scientific reports. 2018 Jan 19;8(1):1270.
21. Mukherjee AG, Wanjari UR, Nagarajan D, Vibhaa KK, Anagha V, Chakraborty R, Renu K, Dey A, Vellingiri B, Gopalakrishnan AV. Letrozole: Pharmacology, toxicity and potential therapeutic effects. Life Sciences. 2022 Oct 13:121074.
22. Green MR, Sambrook J. Purification of total RNA from mammalian cells and tissues. Cold Spring Harb. Protoc. 2020 Jan 2;2020.
23. Simanavicius M, Juskaite K, Verbickaite A, Jasiulionis M, Tamosiunas PL, Petraityte-Burneikiene R, Zvirbliene A, Ulrich RG, Kucinskaite-Kodze I. Detection of rat hepatitis E virus, but not human pathogenic hepatitis E virus genotype 1–4 infections in wild rats from Lithuania. Veterinary microbiology. 2018 Jul 1; 221 :129-33.
24. Green MR, Sambrook J. Synthesis of cDNA probes from mRNA using random oligonucleotide primers. Cold Spring Harbor Protocols. 2019 Jul 1;2019(7):pdb-rot100636.
25. Mukherjee AG, Wanjari UR, Nagarajan D, Vibhaa KK, Anagha V, Chakraborty R, Renu K, Dey A, Vellingiri B, Gopalakrishnan AV. Letrozole: Pharmacology, toxicity and potential therapeutic effects. Life Sciences. 2022 Oct 13:121074.
26. Zhao H, Zhou L, Shangguan AJ, Bulun SE. Aromatase expression and regulation in breast and endometrial cancer. Journal of molecular endocrinology. 2016 Jul 1;57(1):R19-33.
27. Ghufran H, Azam M, Mehmood A, Butt H, Riazuddin S. Standardization of diethylnitrosamine-induced hepatocellular carcinoma rat model with time based molecular assessment. Experimental and Molecular Pathology. 2021 Dec 1;123: 104715.
28. Khan F, Khan TJ, Kalamegam G, Pushparaj PN, Chaudhary A, Abuzenadah A, Kumosani T, Barbour E, Al-Qahtani M. Anti-cancer effects of Ajwa dates (Phoenix dactylifera L.) in diethylnitrosamine induced hepatocellular carcinoma in Wistar rats. BMC complementary and alternative medicine. 2017 Dec;17(1):1-0.
29. Abd Eldaim MA, Tousson E, Soliman MM, El Sayed IE, Abdel Aleem AA, Elsharkawy HN. Grape seed extract ameliorated Ehrlich solid tumor-induced hepatic tissue and DNA damage with reduction of PCNA and P53 protein expression in mice. Environmental Science and Pollution Research. 2021 Aug;28:44226-38.
30. Yousef MI, Mahdy MA, Abdou HM. The potential protective role of grape seed proanthocyanidin extract against the mixture of carboplatin and thalidomideinduced hepatotoxicity and cardiotoxicity in male rats. Preventive Medicine. 2019; 2:1-7
31. Aldubayan MA. Grape seed proanthocyanidin alleviates oxidative stress and apoptosis involved in liver of hyperthyroid mice. Annual Research & Review in Biology. 2019 Dec 3:1-1.
32. Chen J, Wang Y, Meng W, Zhao R, Lin W, Xiao H, Liao Y. Stearoyl-CoA Desaturases1 Accelerates Non-Small Cell Lung Cancer Metastasis by Promoting Aromatase Expression to Improve Estrogen Synthesis. International Journal of Molecular Sciences. 2023 Apr 6;24(7):6826.
33. Wang Y, Li S, Zhu L, Zou J, Jiang X, Chen M, Chen B. Letrozole improves the sensitivity of breast cancer cells overexpressing aromatase to cisplatin via down-regulation of FEN1. Clinical and Translational Oncology. 2019 Aug 12; 21:1026-33.
34. Mukherjee AG, Wanjari UR, Nagarajan D, Vibhaa KK, Anagha V, Chakraborty R, Renu K, Dey A, Vellingiri B, Gopalakrishnan AV. Letrozole: Pharmacology, toxicity and potential therapeutic effects. Life Sciences. 2022 Oct 13:121074.
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Published
Mar 25, 2024
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How to Cite
Sadia Kazi, Nasreen Qazi, Kumayl Abbas Meghji, Ali Abbas Thalho, Naila Noor, & Mozna Talpur. (2024). EXAMINING THE HEPATOPROTECTIVE EFFECTS OF GRAPE SEED EXTRACT AND THE ANTI-ESTROGENIC POTENTIAL OF LETROZOLE: EXPRESSING AROMATASE GENE PATTERN IN N-ETHYL-NITROSAMINE-INDUCED HEPATOCELLULAR CARCINOMA USING AN ANIMAL MODEL. Journal of Population Therapeutics and Clinical Pharmacology, 31(3), 2271-2280. https://doi.org/10.53555/jptcp.v31i3.5108
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Author Biographies
Sadia Kazi
Department of Pharmacology, Isra University, Hyderabad.
Nasreen Qazi
Department of Pharmacology, Bilawal Medical College, Jamshoro.
Kumayl Abbas Meghji
Department of Physiology, Isra University, Hyderabad.
Ali Abbas Thalho
Department of Pharmacology, Isra University, Hyderabad.
Naila Noor
Department of Physiology, Muhammad Medical College, Mirpurkhas.
Mozna Talpur
Department of Pharmacology, Isra University, Hyderabad.
How to Cite
Sadia Kazi, Nasreen Qazi, Kumayl Abbas Meghji, Ali Abbas Thalho, Naila Noor, & Mozna Talpur. (2024). EXAMINING THE HEPATOPROTECTIVE EFFECTS OF GRAPE SEED EXTRACT AND THE ANTI-ESTROGENIC POTENTIAL OF LETROZOLE: EXPRESSING AROMATASE GENE PATTERN IN N-ETHYL-NITROSAMINE-INDUCED HEPATOCELLULAR CARCINOMA USING AN ANIMAL MODEL. Journal of Population Therapeutics and Clinical Pharmacology, 31(3), 2271-2280. https://doi.org/10.53555/jptcp.v31i3.5108