Ciplukan (Physalis Angulata Linn.) Extract Compounds Potential on High-Fat Diet Induced Nonalcoholic Fatty Liver Disease (NAFLD) for Liver Anti-Fibrotic Drug Development
Keywords:
Ciplukan, Physalis angulata, liver fibrosis, NAFLD, ALT, Cholesterol, IL-6
Abstract
An increasing percentage of people have or are at risk to develop the non-alcoholic fatty liver disease (NAFLD) worldwide. Fibrosis has also been identified as the most important predictor of prognosis in patients with NAFLD. Ciplukan (Physalis angulata Linn.) was reported to have antifibrotic potency in CCl4-induced liver fibrotic rats. This study was conducted to evaluate the antifibrotic effect of ciplukan extract through repairing the liver function, anti-inflammatory, and lowering cholesterol. The liver fibrosis model using 20% margarine was injected subcutaneously 8 times with a frequency of twice a week for 4 weeks in 35 male and 35 female Wistar strains which were divided into 7 groups. Furthermore, the rats were given Ciplukan extract (CPL) orally starting the 6th week of treatment with 2 different doses, namely 13.5 mg (CPL-1) and 27 mg (CPL-2) every day for 4 weeks. The histopathological changes of liver fibrosis was analyzed using Haematoxylin Eosin (HE) staining. Determination of serum IL-6 and TGF-β1 levels was carried out by the ELISA method. ALT and cholesterol levels were tested using a diagnostic kit. Single and multiple doses of ciplukan extract with or without standard therapy (Vitamin E) can reduce fibrotic scores up to 1.30±0.95 (p=0.001), TGF-β1 levels up to 24.20±2.02 ng/mL (p = 0.000), IL-6 levels up to 1.68±0.52 pg/mL (p=0.156), ALT levels up to 104.57±2.02 U/mL (p=0.001), and cholesterol levels up to 81, 07±2.02 mg/dL (p=0.000). Ciplukan herb ethanol extract was proven to have liver antifibrotic activity, which means it has potential as a liver fibrotic drug. The liver antifibrotic effect of Ciplukan herb was shown by a histopathological decrease in liver fibrosis scores accompanied by a decrease in TGF-β1, IL-6, ALT, and cholesterol levels.
Keywords: Physalis angulata Linn (Ciplukan), liver fibrosis, NAFLD, ALT, Cholesterol, IL-6
References
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Ramadan, M. F. (2012). Physalis peruviana pomace suppresses highcholesterol diet-induced hypercholesterolemia in rats. Grasasyaceites, 63, 4.
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Xia, H. M., Wang, J., Xie, X. J., Xu, L. J., & Tang, S. Q. (2019). Green tea polyphenols attenuate hepatic steatosis, and reduce insulin resistance and inflammation in high-fat diet-induced rats. International journal of molecular medicine, 44(4), 1523-1530.
Xiang, D., Zou, J., Zhu, X., Chen, X., Luo, J., Kong, L., & Zhang, H. (2020). Physalin D attenuates hepatic stellate cell activation and liver fibrosis by blocking TGF-β/Smad and YAP signaling. Phytomedicine, 78, 153294.
Yamaguchi, K., Nishimura, T., Ishiba, H., Seko, Y., Okajima, A., Fujii, H., ... & Itoh, Y. (2015). Blockade of interleukin 6 signalling ameliorates systemic insulin resistance through upregulation of glucose uptake in skeletal muscle and improves hepatic steatosis in high‐fat diet fed mice. Liver International, 35(2), 550-561.
Younossi, Z. M., Blissett, D., Blissett, R., Henry, L., Stepanova, M., Younossi, Y., ... & Beckerman, R. (2016). The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology, 64(5), 1577-1586.
Yustisia, I., Tandiari, D., Cangara, M. H., Hamid, F., & Nu'man, A. S. (2022). A high-fat, high-fructose diet induced hepatic steatosis, renal lesions, dyslipidemia, and hyperuricemia in non-obese rats. Heliyon, 8(10), e10896.
Zhang, M. H., Li, J., Zhu, X. Y., Zhang, Y. Q., Ye, S. T., Leng, Y. R., ... & Kong, L. Y. (2021). Physalin B ameliorates nonalcoholic steatohepatitis by stimulating autophagy and NRF2 activation mediated improvement in oxidative stress. Free Radical Biology and Medicine, 164, 1-12.
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Ahmed, H., Umar, M. I., Imran, S., Javed, F., Syed, S. K., Riaz, R., & Hassan, W. (2021). TGF-β1 signaling can worsen NAFLD with liver fibrosis backdrop. Experimental and Molecular Pathology, 104733.
Biernacka, A., Dobaczewski, M., & Frangogiannis, N. G. (2011). TGF-β signaling in fibrosis. Growth factors, 29(5), 196-202.
Brancaccio, M., D’Argenio, G., Lembo, V., Palumbo, A., & Castellano, I. (2018). Antifibrotic effect of marine ovothiol in an in vivo model of liver fibrosis. Oxidative Medicine and Cellular Longevity, 2018.
Chalasani, N., Younossi, Z., Lavine, J. E., Charlton, M., Cusi, K., Rinella, M., ... & Sanyal, A. J. (2018). The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology, 67(1), 328-357.
Chen, Z., & O’Shea, J. J. (2008). Th17 cells: a new fate for differentiating helper T cells. Immunologic research, 41(2), 87-102.
Del Campo, J. A., Gallego, P., & Grande, L. (2018). Role of inflammatory response in liver diseases: Therapeutic strategies. World journal of hepatology, 10(1), 1.
Dewi, S., Isbagio, H., Purwaningsih, E. H., Kertia, N., Setiabudy, R., & Setiati, S. (2019). A double-blind, randomized controlled trial of ciplukan (physalis angulata Linn) extract on skin fibrosis, inflammatory, immunology, and fibrosis biomarkers in scleroderma patients. Acta Med Indones, 51(4), 303-310.
Dewidar, B., Meyer, C., Dooley, S., & Meindl-Beinker, N. (2019). TGF-β in hepatic stellate cell activation and liver fibrogenesis. Cells, 8(11), 1419.
Ding, N., Lu, Y., Cui, H., Ma, Q., Qiu, D., Wei, X., ... & Cao, N. (2020). Physalin D inhibits RANKL-induced osteoclastogenesis and bone loss via regulating calcium signaling. BMB reports, 53(3), 154.
Dropmann, A., Dediulia, T., Breitkopf-Heinlein, K., Korhonen, H., Janicot, M., Weber, S. N., ... & Meindl-Beinker, N. M. (2016). TGF-β1 and TGF-β2 abundance in liver diseases of mice and men. Oncotarget, 7(15), 19499.
El-Shawi, O. E., El-Nashar, H. A., Abd El-Rahman, S. S., Eldahshan, O. A., & Singab, A. N. B. (2022). Protective effect of Acrocarpus fraxinifolius extract against hepatic fibrosis induced by gamma irradiation and carbon tetrachloride in albino rats. International Journal of Radiation Biology, 1-11.
European Association for the Study of The Liver and European Association for the Study of Diabetes (EASD, 2016. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Obesity facts, 9(2), 65-90.
Fan, J. J., Liu, X., Zheng, X. L., Zhao, H. Y., Xia, H., & Sun, Y. (2017). A novel cytotoxic physalin from Physalis angulata. Natural Product Communications, 12(10), 1934578X1701201016.
Hasyim, U. H., Sari, F., Kurniaty, I., & Ramadhani, A. (2022). Effect of Ultrasonication Extraction Time on Determination of Flavonoid Levels in Ciplukan Plants. Jurnal Bahan Alam Terbarukan, 11(1), 33-36.
Ioannou, G. N., Van Rooyen, D. M., Savard, C., Haigh, W. G., Yeh, M. M., Teoh, N. C., & Farrell, G. C. (2015). Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH. Journal of lipid research, 56(2), 277-285.
Jeznach-Steinhagen, A., Ostrowska, J., Czerwonogrodzka-Senczyna, A., Boniecka, I., Shahnazaryan, U., & Kuryłowicz, A. (2019). Dietary and pharmacological treatment of nonalcoholic fatty liver disease. Medicina, 55(5), 166.
Lonardo, A., Arab, J. P., & Arrese, M. (2021). Perspectives on precision medicine approaches to NAFLD diagnosis and management. Advances in Therapy, 38(5), 2130-2158.
Longhi, R. (2019). Trans fatty acid in the liver and central nervous system. In Dietary Interventions in Liver Disease (pp. 275-286). Academic Press.
Ma, X., Liu, S., Zhang, J., Dong, M., Wang, Y., Wang, M., & Xin, Y. (2020). Proportion of NAFLD patients with normal ALT value in overall NAFLD patients: a systematic review and meta-analysis. BMC gastroenterology, 20(1), 1-8.
Ouyang, W., Kolls, J. K., & Zheng, Y. (2008). The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity, 28(4), 454-467.
Ramadan, M. F. (2012). Physalis peruviana pomace suppresses highcholesterol diet-induced hypercholesterolemia in rats. Grasasyaceites, 63, 4.
Ren, S. M., Zhang, Q. Z., Chen, M. L., Jiang, M., Zhou, Y., Xu, X. J., ... & Liu, X. Q. (2021). Anti-NAFLD effect of defatted walnut powder extract in high fat diet-induced C57BL/6 mice by modulating the gut microbiota. Journal of Ethnopharmacology, 270, 113814.
Rohmawaty, E., Rosdianto, A. M., Usman, H. A., Saragih, W. A., Zuhrotun, A., Hendriani, R., ... & Dewi, S. (2021). Antifibrotic effect of the ethyl acetate fraction of ciplukan (Physalis angulata Linn.) in rat liver fibrosis induced by CCI4. Journal of Applied Pharmaceutical Science, 11(12), 175-182.
Rosada, M., Wasityastuti, W., Pratama, Y. Y., Siwi, K., Widasari, D. I., & Wahyuni, T. S. (2022). The Effects of High-Fat Diet and CCl₄ Administration on Liver Function and Lipid Profile in Non-Alcoholic Fatty Liver Disease Rat Model. In 7th International Conference on Biological Science (ICBS 2021) (pp. 533-539). Atlantis Press.
Saber, A.P.R., & Noshahry, F. (2021). Study On Association Of Non-Alcoholic Fatty Liver Disease And Serum Vitamin A, E, And Selenium Levels In High-Fat Fed Diet Rats. International Journal of Diabetes in Developing Countries, 1-7.
Sales, R. C., Medeiros, P. C., Spreafico, F., De Velasco, P. C., Gonçalves, F. K., Martín-Hernández, R., ... & Tavares do Carmo, M. G. (2018). Olive oil, palm oil, and hybrid palm oil distinctly modulate liver transcriptome and induce NAFLD in mice fed a high-fat diet. International journal of molecular sciences, 20(1), 8.
Xia, H. M., Wang, J., Xie, X. J., Xu, L. J., & Tang, S. Q. (2019). Green tea polyphenols attenuate hepatic steatosis, and reduce insulin resistance and inflammation in high-fat diet-induced rats. International journal of molecular medicine, 44(4), 1523-1530.
Xiang, D., Zou, J., Zhu, X., Chen, X., Luo, J., Kong, L., & Zhang, H. (2020). Physalin D attenuates hepatic stellate cell activation and liver fibrosis by blocking TGF-β/Smad and YAP signaling. Phytomedicine, 78, 153294.
Yamaguchi, K., Nishimura, T., Ishiba, H., Seko, Y., Okajima, A., Fujii, H., ... & Itoh, Y. (2015). Blockade of interleukin 6 signalling ameliorates systemic insulin resistance through upregulation of glucose uptake in skeletal muscle and improves hepatic steatosis in high‐fat diet fed mice. Liver International, 35(2), 550-561.
Younossi, Z. M., Blissett, D., Blissett, R., Henry, L., Stepanova, M., Younossi, Y., ... & Beckerman, R. (2016). The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology, 64(5), 1577-1586.
Yustisia, I., Tandiari, D., Cangara, M. H., Hamid, F., & Nu'man, A. S. (2022). A high-fat, high-fructose diet induced hepatic steatosis, renal lesions, dyslipidemia, and hyperuricemia in non-obese rats. Heliyon, 8(10), e10896.
Zhang, M. H., Li, J., Zhu, X. Y., Zhang, Y. Q., Ye, S. T., Leng, Y. R., ... & Kong, L. Y. (2021). Physalin B ameliorates nonalcoholic steatohepatitis by stimulating autophagy and NRF2 activation mediated improvement in oxidative stress. Free Radical Biology and Medicine, 164, 1-12.
Veteläinen, R. L., Bennink, R. J., de Bruin, K., van Vliet, A., & van Gulik, T. M. (2006). Hepatobiliary function assessed by 99mTc-mebrofenin cholescintigraphy in the evaluation of severity of steatosis in a rat model. European journal of nuclear medicine and molecular imaging, 33(10), 1107-1114.
Published
2023-12-15
How to Cite
Rohmawaty, E., Dewi, S., Rosdianto, A. M., Usman, H. A., Zuhrotun, A., Hendriani, R., Wardhana, Y. W., Ekawardhani, S., Wiraswati, H. L., Rahmadi, A. R., Agustanti, N., & Bestari, M. B. (2023). Ciplukan (Physalis Angulata Linn.) Extract Compounds Potential on High-Fat Diet Induced Nonalcoholic Fatty Liver Disease (NAFLD) for Liver Anti-Fibrotic Drug Development. Indonesian Journal of Pharmacy, 34(4), 584-592. https://doi.org/10.22146/ijp.6259
Issue
Section
Research Article
