Author(s): Sumartini Dewi, Enny Rohmawaty, Aziiz Mardanarian Rosdianto, Hermin Aminah Usman, Ade Zuhrotun, Rini Hendriani, Yoga Windhu Wardhana, Savira Ekawardhani, Hesti Lina Wiraswati, Iceu Dimas Kulsum, Andri Reza Rahmadi, Emmy H. Pranggono

Email(s): e.rohmawaty@unpad.ac.id

DOI: 10.52711/0974-360X.2024.00275   

Address: Sumartini Dewi1, Enny Rohmawaty2*, Aziiz Mardanarian Rosdianto3, Hermin Aminah Usman4, Ade Zuhrotun5, Rini Hendriani6, Yoga Windhu Wardhana7, Savira Ekawardhani8, Hesti Lina Wiraswati8, Iceu Dimas Kulsum9, Andri Reza Rahmadi10, Emmy H. Pranggono9
1Immunology Study Center, Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
2Division of Pharmacology and Therapy, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
3Veterinary Medicine Program, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
4Department of Anatomical Pathology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
5Department of Biological Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, Indonesia.
6Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, Bandung, Indonesi

Published In:   Volume - 17,      Issue - 4,     Year - 2024


ABSTRACT:
Pulmonary fibrosis is a fatal lung disease with unknown pathogenesis and limited treatment options. Herbal medicine began to be developed as an antifibrosis drug for this disease. Ciplukan plant (Physalis angulata Linn.), is a wild plant that has been widely used for generations as traditional Indonesian medicine for various diseases; but has never been studied as an antifibrosis. This study aimed to determine Ciplukan herb ethanol extract (CPL) bioactivity as antifibrosis in pulmonary fibrosis disorders in experimental mice model induced by bleomycin. A total of 35 male mice and 35 female mice of the ddy strain was divided into 7 groups respectively with 1 normal control group and 6 experimental animal models of pulmonary fibrosis induced by bleomycin groups. For the pulmonary fibrosis model, bleomycin (BLM) was injected subcutaneously 8 times with a frequency of twice a week for 4 weeks. Furthermore, the mice were given CPL orally starting at week 6 of treatment with 2 different doses, 1.95mg (CPL-1) and 3.9mg (CPL) every day for 4 weeks. Pulmonary fibrosis histopathology was analyzed using HE and MT staining methods. Serum IL-6, KL-6, and TGF-ß1 levels determination was carried out using the ELISA method. The administration of CPL significantly reduced the fibrosis score from 2.80±1.095 to 1.67±0.577µm (p=0.026). The CPL also showed anti-inflammatory activity by reducing IL-6 levels from 1916.20±594.27 to 16.81±17.07pg/mL (p=0.003); TGF-ß1 levels from 51.25±2.25 to 22.48±0.93ng/mL (p=0.021); and KL-6 levels from 28.09±2.25 to 13.99±0.93ng/mL (p=0.000). CPL was proven to have pulmonary antifibrotic activity in experimental mice model. The pulmonary antifibrotic effect was evidenced by a decrease in pulmonary fibrosis scores also a decrease in KL-6 levels, IL-6 levels, and TGF-ß1. The administration of CPL-1 and CPL-2 can provide recovery of pulmonary fibrosis induced by bleomycin.


Cite this article:
Sumartini Dewi, Enny Rohmawaty, Aziiz Mardanarian Rosdianto, Hermin Aminah Usman, Ade Zuhrotun, Rini Hendriani, Yoga Windhu Wardhana, Savira Ekawardhani, Hesti Lina Wiraswati, Iceu Dimas Kulsum, Andri Reza Rahmadi, Emmy H. Pranggono. Ciplukan (Physalis angulata Linn) Bioactivity against Bleomycin-Induced Pulmonary Fibrosis in Mice by reducing Subpleural Fibrosis, KL-6 Level and Anti-Inflammatory properties. Research Journal of Pharmacy and Technology.2024; 17(4):1731-0. doi: 10.52711/0974-360X.2024.00275

Cite(Electronic):
Sumartini Dewi, Enny Rohmawaty, Aziiz Mardanarian Rosdianto, Hermin Aminah Usman, Ade Zuhrotun, Rini Hendriani, Yoga Windhu Wardhana, Savira Ekawardhani, Hesti Lina Wiraswati, Iceu Dimas Kulsum, Andri Reza Rahmadi, Emmy H. Pranggono. Ciplukan (Physalis angulata Linn) Bioactivity against Bleomycin-Induced Pulmonary Fibrosis in Mice by reducing Subpleural Fibrosis, KL-6 Level and Anti-Inflammatory properties. Research Journal of Pharmacy and Technology.2024; 17(4):1731-0. doi: 10.52711/0974-360X.2024.00275   Available on: https://rjptonline.org/AbstractView.aspx?PID=2024-17-4-49


REFERENCES:
1.    Sun L, Mao M, Yan Z, Zuo C, Zhang X. A Chinese traditional therapy for bleomycin-induced pulmonary fibrosis in mice. Canadian Respiratory Journal. 2018; 2018. doi.org/10.1155/2018/8491487
2.    Maher TM. Bendstrup E. Dron L. Langley J. Smith G. Khalid JM. Patel H. Kreuter M. Global incidence and prevalence of idiopathic pulmonary fibrosis. Respiratory Research. 2021; 22(1): 1-10. doi.org/10.1186/s12931-021-01791-z
3.    Glass DS, Grossfeld D, Renna HA, Agarwala P, Spiegler P, DeLeon J, Reiss AB. Idiopathic pulmonary fibrosis: Current and future treatment. The Clinical Respiratory Journal. 2022; 16(2): 84-96. doi.org/10.1111/crj.13466
4.    Choi WI. Pharmacological treatment of idiopathic pulmonary fibrosis and fibrosing interstitial lung diseases: current trends and future directions. Precision and Future Medicine. 2021; 5(1):31-40. doi.org/10.23838/pfm.2020.00205
5.    Jiang D, Xiao H, Dong R, Geng J, Xie B, Ren Y, Dai H. Krebs von den Lungen‐6 levels in untreated idiopathic pulmonary fibrosis. The Clinical Respiratory Journal. 2022; 16(3): 234-43. doi.org/10.1111/crj.13475
6.    She YX, Yu QY, Tang XX. Role of interleukins in the pathogenesis of pulmonary fibrosis. Cell Death Discovery. 2022; 7(1):52.
7.    Shen YH, Cheng MH, Liu XY, Zhu DW, Gao J. Sodium houttuyfonate inhibits bleomycin induced pulmonary fibrosis in mice. Frontiers in Pharmacology. 2021:204. doi.org/10.3389/fphar. 2021.596492
8.    Moor CC, Mostard RL, Grutters JC, Bresser P, Aerts JG, Dirksen CD, Kimman ML, Wijsenbeek MS. Patient expectations, experiences and satisfaction with nintedanib and pirfenidone in idiopathic pulmonary fibrosis: a quantitative study. Respiratory Research. 2020; 21(1):1-7. doi.org/10.1186/s12931-020-01458-1
9.    Hidayat T, Priyandoko D, Perdana FS, Insan AM. Cytotoxicity effects of leaf extracts of Ciplukan (Physalis angulata; Solanaceae) on human blood and ovary cancer cell lines. InJournal of Physics: Conference Series 2019; 1280(2): 022009. IOP Publishing. doi.org/10.1088/1742-6596/1280/2/022009
10.    Sylviningrum T, Wasita B, Purwanto B, Kariosentono H, Soetrisno S. Indonesian ciplukan extract inhibited TGF-β1/NF-κB pathway in experimental psoriasis mouse models. Open Access Macedonian Journal of Medical Sciences. 2022; 10(A): 938-46. doi.org/10.3889/oamjms.2022.9913
11.    Hasyim UH, Sari F, Kurniaty I, Ramadhani A. Effect of ultrasonication extraction time on determination of flavonoid levels in ciplukan plants. jurnal bahan alam terbarukan. 2022; 11(1): 33-6. doi.org/10.15294/jbat.v11i1.35254
12.    Fan JJ, Liu X, Zheng XL, Zhao HY, Xia H, Sun Y. A novel cytotoxic physalin from Physalis angulata. Natural Product Communications. 2017; 12(10): 1934578X1701201016.
13.    Rohmawaty E, Rosdianto AM, Usman HA, Saragih WA, Zuhrotun A, Hendriani R, Wardhana YW, Ekawardhani S, Wiraswati HL, Agustanti N, Bestari MB. Antifibrotic effect of the ethyl acetate fraction of ciplukan (Physalis angulata Linn.) in rat liver fibrosis induced by CCI4. Journal of Applied Pharmaceutical Science. 2021; 11(12): 175-82. doi.org/10.7324/JAPS.2021.1101217
14.    Dewi S, Isbagio H, Purwaningsih EH, Kertia N, Setiabudy R, Setiati S. A double-blind, randomized controlled trial of ciplukan (Physalis angulata Linn) extract on skin fibrosis, inflammatory, immunology, and fibrosis biomarkers in scleroderma patients. Acta Medica Indonesia. 2019; 51(4): 303-10.
15.    Braun RK, Ferrick DA, Sterner-Kock A, Kilshaw PJ, Hyde DM, Giri SN. Comparison of two models of bleomycin-induced lung fibrosis in mouse on the level of leucocytes and T cell subpopulations in bronchoalveolar lavage. Comparative Haematology International. 1996; 6: 141-8. doi.org/10.1007/BF00368457
16.    Morganroth PA, Kreider ME, Okawa J, Taylor L, Werth VP. Interstitial lung disease in classic and skin-predominant dermatomyositis: a retrospective study with screening recommendations. Archives of Dermatology. 2010; 146(7): 729-38. doi.org/ 10.1001/archdermatol.2010.134
17.    Yamane KE, Ihn HI, Kubo MA, Yazawa NO, Kikuchi KA, Soma YO, Tamaki KU. Serum levels of KL-6 as a useful marker for evaluating pulmonary fibrosis in patients with systemic sclerosis. The Journal of Rheumatology. 2000; 27(4): 930-4.
18.    Liu Y, Lu F, Kang L, Wang Z, Wang Y. Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium. BMC pulmonary medicine. 2017; 17:1-1. doi.org/10.1186/s12890-017-0405-7
19.    Kuchekar S, Jadhav R. Review on Idiopathic Pulmonary Fibrosis. Asian Journal of Research in Pharmaceutical Sciences. 2022; 12(1): 42-8. doi: 10.52711/2231-5659.2022.00008
20.    Gad ES, Salama AA, El-Shafie MF, Arafa HM, Abdelsalam RM, Khattab M. The anti-fibrotic and anti-inflammatory potential of bone marrow–derived mesenchymal stem cells and nintedanib in bleomycin-induced lung fibrosis in rats. Inflammation. 2020; 43: 123-34. doi.org/10.1007/s10753-019-01101-2
21.    Kseibati MO, Sharawy MH, Salem HA. Chrysin mitigates bleomycin-induced pulmonary fibrosis in rats through regulating inflammation, oxidative stress, and hypoxia. International immunopharmacology. 2020; 89: 107011. doi.org/10.1016/j.intimp.2020.107011
22.    Mehrzadi S, Hosseini P, Mehrabani M, Siahpoosh A, Goudarzi M, Khalili H, Malayeri A. Attenuation of bleomycin-induced pulmonary fibrosis in Wistar rats by combination treatment of two natural phenolic compounds: quercetin and gallic acid. Nutrition and Cancer. 2021; 73(10): 2039-49. doi.org/10.1080/01635581.2020.1820053
23.    Hosseini S, Imenshahidi M, Hosseinzadeh H, Karimi G. Effects of plant extracts and bioactive compounds on attenuation of bleomycin-induced pulmonary fibrosis. Biomedicine & Pharmacotherapy. 2018; 107: 1454-65. doi.org/10.1016/j.biopha.2018.08.111
24.    Fekri MS, Mandegary A, Sharififar F, Poursalehi HR, Nematollahi MH, Izadi A, Mehdipour M, Asadi A, Fekri MS. Protective effect of standardized extract of Myrtus communis L.(myrtle) on experimentally bleomycin-induced pulmonary fibrosis: biochemical and histopathological study. Drug and Chemical Toxicology. 2018; 41(4): 408-14. doi.org/10.1080/01480545.2018.1459670
25.    Zhao Y, Yan Z, Liu Y, Zhang Y, Shi J, Li J, Ji F. Effectivity of mesenchymal stem cells for bleomycin-induced pulmonary fibrosis: a systematic review and implication for clinical application. Stem Cell Research & Therapy. 2021; 12(1): 470. doi.org/10.1186/s13287-021-02551-y
26.    Timotius KH. Tjajaindra A. Sudradjat SE. Potential anti-inflammation of Physalis angulata L. International Journal of Herb Medicine, 2021; 9(5): 50-58.
27.    Merlin NJ, V Parthasarathy, R Manavalan. Role of Flavanoids in Free Radical Induced Hepatic Fibrosis. Research Journal of Pharmacy and Technology.  2022; 2(1): 52-57.
28.    Fekri MS, Poursalehi HR, Sharififar F, Mandegary A, Rostamzadeh F, Mahmoodi R. The effects of methanolic extract of Glycyrrhiza glabra on the prevention and treatment of bleomycin-induced pulmonary fibrosis in rat: experimental study. Drug and Chemical Toxicology. 2021; 44(4): 365-71. oi.org/10.1080/01480545.2019.1606232
29.    Parida GR, Pattnaik G, Behera A. Cellular and molecular mechanism of liver fibrosis: A critical insight. Research Journal of Pharmacy and Technology. 2021; 14(11): 6147-54. doi: 10.52711/0974-360X.2021.01066
30.    Le TT, Karmouty-Quintana H, Melicoff E, Le TT, Weng T, Chen NY, Pedroza M, Zhou Y, Davies J, Philip K, Molina J. Blockade of IL-6 Trans signaling attenuates pulmonary fibrosis. The Journal of Immunology. 2014; 193(7): 3755-68. doi.org/10.4049/jimmunol.1302470
31.    Shieh JM, Tseng HY, Jung F, Yang SH, Lin JC. Elevation of IL-6 and IL-33 levels in serum associated with lung fibrosis and skeletal muscle wasting in a bleomycin-induced lung injury mouse model. Mediators of Inflammation. 2019; 2019. oi.org/10.1155/2019/7947596
32.    Papiris SA, Tomos IP, Karakatsani A, Spathis A, Korbila I, Analitis A, Kolilekas L, Kagouridis K, Loukides S, Karakitsos P, Manali ED. High levels of IL-6 and IL-8 characterize early-on idiopathic pulmonary fibrosis acute exacerbations. Cytokine. 2018; 102:168-72. doi.org/10.1016/j.cyto.2017.08.019
33.    Xu L, Yang D, Zhu S, Gu J, Ding F, Bian W, Rong Z, Shen C. Bleomycin-induced pulmonary fibrosis is attenuated by an antibody against KL-6. Experimental Lung Research. 2013; 39(6): 241-8. doi.org/10.3109/01902148.2013.798056
34.    Aloisio E, Braga F, Puricelli C, Panteghini M. Prognostic role of Krebs von den Lungen-6 (KL-6) measurement in idiopathic pulmonary fibrosis: A systematic review and meta-analysis. Clinical Chemistry and Laboratory Medicine (CCLM). 2021; 59(8): 1400-8. doi.org/10.1515/cclm-2021-0199
35.    Gui X, Qiu X, Xie M, Tian Y, Min C, Huang M, Hongyan W, Chen T, Zhang X, Chen J, Cao M. Prognostic value of serum osteopontin in acute exacerbation of idiopathic pulmonary fibrosis. BioMed Research International. 2020; 2020. doi.org/10.1155/2020/3424208
36.    Luzina IG, Lillehoj EP, Lockatell V, Hyun SW, Lugkey KN, Imamura A, Ishida H, Cairo CW, Atamas SP, Goldblum SE. Therapeutic effect of neuraminidase-1–selective inhibition in mouse models of bleomycin-induced pulmonary inflammation and fibrosis. Journal of Pharmacology and Experimental Therapeutics. 2021; 376(1): 136-46. doi.org/10.1124/jpet.120.000223
37.    Wei P, Xie Y, Abel PW, Huang Y, Ma Q, Li L, Hao J, Wolff DW, Wei T, Tu Y. Transforming growth factor (TGF)-β1-induced miR-133a inhibits myofibroblast differentiation and pulmonary fibrosis. Cell Death & Disease. 2019; 10(9): 670. doi.org/10.1038/s41419-019-1873-x
38.    Guo J, Fang Y, Jiang F, Li L, Zhou H, Xu X, Ning W. Neohesperidin inhibits TGF-β1/Smad3 signaling and alleviates bleomycin-induced pulmonary fibrosis in mice. European Journal of Pharmacology. 2019; 864: 172712. doi.org/10.1016/j.ejphar.2019.172712
39.    Mohamed MZ, El Baky MF, Ali ME, Hafez HM. Aprepitant exerts anti-fibrotic effect via inhibition of TGF-β/Smad3 pathway in bleomycin-induced pulmonary fibrosis in rats. Environmental Toxicology and Pharmacology. 2022; 95: 103940. doi.org/10.1016/j.etap.2022.103940
40.    Zuo Y, Liu J, Xu H, Li Y, Tao R, Zhang Z. Pirfenidone inhibits cell fibrosis in connective tissue disease-associated interstitial lung disease by targeting the TNF-α/STAT3/KL6 pathway. Journal of Thoracic Disease. 2022; 14(6): 2089. doi.org/ 10.21037/jtd-22-41
41.    Zhao YL, Pu SB, Qi Y, Wu BF, Shang JH, Liu YP, Hu D, Luo XD. Pharmacological effects of indole alkaloids from Alstonia scholaris (L.) R. Br. on pulmonary fibrosis in vivo. Journal of Ethnopharmacology. 2021; 267: 113506. doi.org/10.1016/j.jep.2020.113506
42.    Li J, Deng SH, Li J, Li L, Zhang F, Zou Y, Wu DM, Xu Y. Obacunone alleviates ferroptosis during lipopolysaccharide-induced acute lung injury by upregulating Nrf2-dependent antioxidant responses. Cellular & Molecular Biology Letters. 2022; 27(1): 1-20. doi.org/10.1186/s11658-022-00318-8
43.    Guo P, Li B, Liu MM, Li YX, Weng GY, Gao Y. Protective effects of lotus plumule ethanol extracts on bleomycin-induced pulmonary fibrosis in mice. Drug and Chemical Toxicology. 2022;  45(3): 1432-41. doi.org/10.1080/01480545.2021.1993670
44.    Du Q, Wu X, An L, Zhou R, Xiao X, Wu C, Wang F, Yang H. Therapeutic effect of astragali radix extract injection combined with bone marrow mesenchymal stem cells in bleomycin-induced pulmonary fibrotic rats. Evidence-Based Complementary and Alternative Medicine. 2022; 2022. doi.org/10.1155/2022/4933255

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