Natural resources, chemical synthesis, chemo-bio transformations, metabolism, pharmacology, toxicology, and the underlying mechanisms of curdione

Abstract

Curcuma is a traditional Chinese medicine that has been utilized for centuries in the treatment of various diseases. Terpenoids, particularly monoterpenes and sesquiterpenes, constitute the primary bioactive components of the essential oil derived from Curcuma species. Among these, curdione—one of the key active constituents—has been identified in 25 Curcuma species, with the highest concentration reported in the rhizome essential oil of Curcuma trichosantha Gagnep. Curdione can also be synthesized through chemical methods, and its regio- and stereo-selectivity can be further optimized via chemo-bio transformations. This compound demonstrates significant therapeutic potential, including anticancer, anti-thrombotic, anti-inflammatory, anti-viral, anti-fungal, anti-diabetic, and multi-organ protective properties. Despite these promising biological activities, its clinical application is hindered by poor water solubility and potential toxicity. This review summarizes current knowledge on the natural sources, chemical synthesis, chemo-bio transformations, metabolism, pharmacokinetics, pharmacological effects, potential toxicities, and molecular mechanisms of curdione. Furthermore, perspectives on future drug development are discussed with the aim of promoting the clinical translation of this promising natural compound.

Keywords

Curdione / Source / Metabolism / Bioactivity / Toxicity / Mechanism

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 82192913 and 82304851), the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences (Nos. CI2023E002, CI2021B016, and CI2021A04801), and the Fundamental Research Funds for the Central Public Welfare Research Institutes (Nos. ZZ13-YQ-055 and ZXKT22044).

Declaration of competing interest

These authors have no conflict of interest to declare.

References

[1] Chopra B, Dhingra AK. Natural products: a lead for drug discovery and development. Phytother Res. 2021; 35(9):4660-4702. https://doi.org/10.1002/ptr.7099.

[2] Wang XL. Clinical effect observation of microwave and confort pessaries combination to chronic cervicitis. Chin Contin Med Edu. 2015; 7(7):235-236. https://doi.org/10.3969/j.issn.1674-9308.2015.07.199.

[3] Wang ZQ. Curative effect observation on treatment of 180 cases of vaginitis patients Compound Zedoary Turmeric Oil Suppoaitories. World Latest Med Inf. 2015; 15(11):7-8. https://doi.org/10.3969/j.issn.1671-3141.2015.11.005.

[4] Yuan FL, Xu YY, Jiang CX. Meta analysis of comparison between zedoary turmeric oil injection and ribavirin injection in treatment of viral lower respiratory tract infections in children. Chin Tradit Herbal Drugs. 2024; 55(12):4132-4139. https://doi.org/10.7501/j.issn.0253-2670.2024.12.020.

[5] Wang L, Tang SW, Xu H, et al. Efficacy and safety of zedoray turmeric oil injection in the treatment of rotavirus enteritis: a meta-analysis. Chin Pharm. 2019; 28(7):65-68. https://doi.org/10.3969/j.issn.1006-4931.2019.07.021.

[6] Zhang XJ, Xu FX, Ding MX, et al. Clinical observation of zedoary turmeric oil injection in treating cases of influenza. J Gannan Med Univ. 2019; 39(12):1220-1222. https://doi.org/10.3969/j.issn.1001-5779.2019.12.008.doi:10.3969/j.issn.1001-5779.2019.12.008.

[7] Zhao WQ. Effect of CAP chemotherapy combined with zedoary oil injection on quality of life in patients with early high-risk endometrial carcinoma. Jilin Med J. 2019; 40(9):2020-2021.

[8] Liang D, Yang MC, Lin Z, et al. Effect observation on treating ovarian cancer with curcuma oil injection plus conventional chemotherapy. Clin J Chin Med. 2014; 6(4):7-8. https://doi.org/10.3969/j.issn.1674-7860.2014.04.003.

[9] Wang B, Liu F, Li Q, et al. Antifungal activity of zedoary turmeric oil against Phytophthora capsici through damaging cell membrane. Pestic Biochem Physiol. 2019; 159:59-67. https://doi.org/10.1016/j.pestbp.2019.05.014.

[10] Hu YC, Zhang JM, Kong WJ, et al. Mechanisms of antifungal and anti-aflatoxigenic properties of essential oil derived from turmeric (Curcuma longa L.) on Aspergillus flavus. Food Chem. 2017; 220:1-8. https://doi.org/10.1016/j.foodchem.2016.09.179.

[11] Zhang SH, Liu D, Zhou YK, et al. Analysis of Curcuma wenyujin oil components with different extration method by GC-Q/TOF-MS. Cent South Pharm. 2020; 18(11):1879-1887. https://doi.org/10.7539/j.issn.1672-2981.2020.11.021.

[12] Wang F, Sun Z, Zhang QY, et al. Curdione induces ferroptosis mediated by m6A methylation via METTL14 and YTHDF2 in colorectal cancer. Chin Med. 2023; 18(1):122. https://doi.org/10.1186/s13020-023-00820-x.

[13] Wei W, Rasul A, Sadiqa A, et al. Curcumol: from plant roots to cancer roots. Int J Biol Sci. 2019; 15(8):1600-1609. https://doi.org/10.7150/ijbs.34716.

[14] Li J, Sun YT, Li GH, et al. The extraction, determination, and bioactivity of curcumenol: a comprehensive review. Molecules. 2024; 29(3):656. https://doi.org/10.3390/molecules29030656.

[15] Luo YH, Wang ZC, Jiang JE, et al. Curzerene suppresses hepatocellular carcinoma progression through the PI3K/AKT/MTOR pathway. Rev Invest Clin. 2024; 76(4):173-184. https://doi.org/10.24875/RIC.24000018.

[16] Lou GH, Huang Y, Wang Y, et al. Germacrone, a novel and safe anticancer agent from genus Curcuma: a review of its mechanism. Anticancer Agents Med Chem. 2023; 23(13):1490-1498. https://doi.org/10.2174/1871520623666230420094628.

[17] Feng YW, An QW, Zhao ZQ, et al. β-Elemene: a phytochemical with promise as a drug candidate for tumor therapy and adjuvant tumor therapy. Biomed Pharmacother. 2024; 172:116266. https://doi.org/10.1016/j.biopha.2024.116266.

[18] Lv XY, Sun JC, Hu LF, et al.Curcumol inhibits malignant biological behaviors and TMZ-resistance in glioma cells by inhibiting long noncoding RNA FOXD2-As1-promoted EZH2 activation. Aging. 2021; 13(21):24101-24116. https://doi.org/10.18632/aging.203662.

[19] Pan J, Miao D, Chen L. Germacrone reverses adriamycin resistance in human chronic myelogenous leukemia K562/ADM cells by suppressing MDR1 gene/P-glycoprotein expression. Chem Biol Interact. 2018; 288:32-37. https://doi.org/10.1016/j.cbi.2018.04.012.

[20] Zhang RN, Zheng YT, Zhu QR, et al. β-Elemene reverses gefitinib resistance in NSCLC cells by inhibiting lncRNA H19-mediated autophagy. Pharmaceuticals. 2024; 17(5):626. https://doi.org/10.3390/ph17050626.

[21] Zhang QZ, Yang F, Zhu JJ, et al. Essential oil composition of three herbal medicines from Curcumal wenyujin by GC-MS. Chin J Chin Mater Med. 2010; 35(19):2590-2593.

[22] Zang YF, Xu LL, Liu HC, et al. Determination of 8 main active compounds in Curcumae Rhizoma by HPLC wavelength switching method. Chin J Mod Appl Pharm. 2021; 38(18):2227-2233. https://doi.org/10.13748/j.cnki.issn1007-7693.2021.18.006.

[23] Ravindran PN, Babu KN, Sivaraman K. Turmeric:the genus. Curcuma. 1^st Ed. Boca Raton, BR: CRC Press; 2007. https://doi.org/10.1201/9781420006322.

[24] Anggriani L, Yasmin A, Wulandari AR, et al. Extract of temu ireng (Curcuma aeruginosa Roxb.) rhizome reduces doxorubicin-induced immunosuppressive effects. AIP Conf Proc. 2019; 2099(1): 020001. https://doi.org/10.1063/1.5098406.

[25] Tabtipwon P, Temsiririrkkul R, Thongpraditchote S, et al. Anti-inflammatory activity of Curcuma cf. amada roxb. ‘Wan en Lueang’. Pharm Sci Asia. 2020; 47(2):121-129. https://doi.org/10.29090/psa.2020.02.018.0051.

[26] Kojima H, Yanai T, Toyota A. Essential oil constituents from Japanese and Indian Curcuma aromatica rhizomes. Planta Med. 1998; 64(4):380-381. https://doi.org/10.1055/s-2006-957458.

[27] Albaqami JJ, Hamdi H, Narayanankutty A, et al. Chemical composition and biological activities of the leaf essential oils of Curcuma longa, Curcuma aromatica and Curcuma angustifolia. Antibiotics. 2022; 11(11):1547. https://doi.org/10.3390/antibiotics11111547.

[28] Dung N, Truong P, Ky PT, et al. Chemical composition of the essential oils of Curcuma cochinchinensis Gagnep. from Vietnam. ACGC Chem Res Commun. 1996; 5:11-16.

[29] Dũng NX, Truong PX, Ky PT, et al. Volatile constituents of the leaf, stem, rhizome, roof and flower oils of Curcuma harmandii gagnep. from Vietnam. J Essent Oil Res. 1997; 9(6):677-681. https://doi.org/10.1080/10412905.1997.9700810.

[30] Zhang LY, Yang ZW, Wei JW, et al. Contrastive analysis of chemical composition of essential oil from twelve Curcuma species distributed in China. Ind Crops Prod. 2017; 108:17-25. https://doi.org/10.1016/j.indcrop.2017.06.005.

[31] Devi LR, Rana VS, Devi SI, et al. Chemical composition and antimicrobial activity of the essential oil of Curcuma leucorhiza Roxb. J Essent Oil Res. 2012; 24(6):533-538. https://doi.org/10.1080/10412905.2012.728089.

[32] Thánh KP, Leclercq PA, et al. Volatile constituents of the essential oil of Curcuma trichosantha gagnep. from Vietnam. J Essent Oil Res. 1994; 6(2):213-214. https://doi.org/10.1080/10412905.1994.9698361.

[33] Thu NT, Tran-Trung H, Duc DX, et al. Rhizome essential oil of Curcuma zedoaroides Chaveer. & Tanee: chemical composition, cytotoxic activities, and molecular docking approach. J Essent Oil Res. 2024; 27(1):188-197. https://doi.org/10.1080/0972060X.2024.2314554.

[34] Zhou L, Zhang KW, Li J, et al. Inhibition of vascular endothelial growth factor-mediated angiogenesis involved in reproductive toxicity induced by sesquiterpenoids of Curcuma zedoaria in rats. Reprod Toxicol. 2013; 37:62-69. https://doi.org/10.1016/j.reprotox.2013.02.001.

[35] Nuzula AF, Kristanti AN, Aminah NS, et al. Isolation and strucure elucidation of secondary metabolite compounds from Curcuma aeruginosa. J Kimia Riset. 2023; 8:81-91. https://doi.org/10.20473/jkr.v8i1.44073.

[36] Giang PM, Son PT, Matsunami K, et al. New sesquiterpenoids from Curcuma aff. aeruginosa Roxb. Heterocycles. 2007; 74:977-981. https://doi.org/10.3987/COM-07-S(W)42.

[37] Jirovetz L, Buchbauer G, Puschmann C, et al. Essential oil analysis of Curcuma aeruginosa roxb. leaves from South India. J Essent Oil Res. 2000; 12(1):47-49. https://doi.org/10.1080/10412905.2000.9712039.

[38] Herath H, Wijayasiriwardene T, Premakumara G. GC-MS identification of endemic herb Curcuma albiflora THW. (Sri Lanka). ‌Int J Pharmacogn‌. 2018; 5(7):419-425. https://doi.org/10.13040/ijpsr.0975-8232.ijp.5(7).419-425.

[39] Herath H, Wijayasiriwardene T, Premakumara G. Comparative GC-MS analysis of all Curcuma species grown in Sri Lanka by multivariate test. Ruhuna J Sci. 2017; 8(2):103. https://doi.org/10.4038/rjs.v8i2.29.

[40] Srivastava AK, Srivastava SK, Syamsundar KV. Volatile composition of Curcuma angustifolia roxb. rhizome from central and southern India. Flavour Frag J. 2006; 21(3):423-426. https://doi.org/10.1002/ffj.1680.

[41] Qu Y, Xu FM, Nakamura S, et al. Sesquiterpenes from Curcuma comosa. J Nat Med. 2009; 63(1):102-104. https://doi.org/10.1007/s11418-008-0282-8.

[42] Ratchanaporn C, Prapapan P, Pawinee P, et al. Cytotoxic sesquiterpenoids and diarylheptanoids from the rhizomes of Curcuma elata Roxb. Rec Nat Prod. 2014; 8(1):46-50.

[43] Raj G, Baby S, Dan M, et al. Volatile constituents from the rhizomes of Curcuma haritha Mangaly and Sabu from southern India. Flavour Frag J. 2008; 23(5):348-352. https://doi.org/10.1002/ffj.1891.

[44] Malek SN, Seng CK, Zakaria Z, et al. The essential oil of Curcuma inodora aff. Blatter from Malaysia. J Essent Oil Res. 2006; 18(3):281-283. https://doi.org/10.1080/10412905.2006.9699088.

[45] Keeratinijakal V, Kongkiatpaiboon S. Distribution of phytoestrogenic diarylheptanoids and sesquiterpenoids components in Curcuma comosa rhizomes and its related species. Rev Bras Farmacogn. 2017; 27(3):290-296. https://doi.org/10.1016/j.bjp.2016.12.003.

[46] Mohammad NHS, Aspollah SM, Safinar II, et al. In vitro cytotoxic, radical scavenging and antimicrobial activities of Curcuma mangga valeton and van zijp. Int J Med Toxico Legal Med. 2020; 23:251-256. https://doi.org/10.5958/0974-4614.2020.00036.4.

[47] Nguyen MC, Vu TH, Pham NK, et al. Chemical compositions and antimicrobial activity of essential oil from the rhizomes of Curcuma singularis growing in Vietnam. Am J Essent Oil Nat Prod. 2017; 5(4):20-25.

[48] Hikino H, Sakurai Y, Takahashi H, et al. Structure of curdione. Chem Pharm Bull. 1966; 14(11):1310-1311. https://doi.org/10.1248/cpb.14.1310.

[49] Zhao RB, Wu YL. Total synthesis of (-)-Curdione. Acta Chim Sin. 1988; 46:615-616.

[50] Zhou QM, Wang WH, Xia P, et al. Content determination of six chemical components in Curcuma Rhizoma under different storage conditions by HPLC. China Pharm. 2020; 23(8):1669-1673.

[51] Ji ZZ, Zeng ZJ. A quantitative conversion from curdione into curcumol. J Shenyang Pharm Univ. 1985; 2(1):56-60. https://doi.org/10.14066/j.cnki.cn21-1349/r.1985.01.011.

[52] Zhou Y, Chen P, Lei M, et al. The optimization on transformation from curdione to curcumol. J Wuhan Polytech Univ. 2017; 36(1):30-33. https://doi.org/10.3969/j.issn.2095-7386.2017.01.006.

[53] David CB, Luis C, lan C, et al. Organic synthesis provides opportunities to transform drug discovery. Nat Chem. 2018; 10(4):383-394. https://doi.org/10.1038/s41557-018-0021-z.

[54] Chen YN, Zhang L, Qin B, et al. An insight into the curdione biotransformation pathway by Aspergillus niger. Nat Prod Res. 2014; 28(7):454-460. https://doi.org/10.1080/14786419.2013.873434.

[55] Ma XC, Zheng J, Wu LJ, et al. Structural determination of three new germacrane-type sesquiterpene alcohols from curdione by microbial transformation. Magn Reson Chem. 2007; 45(1):90-92. https://doi.org/10.1002/mrc.1922.

[56] Qin B, Li YX, Meng LX, et al. "Mirror-image" manipulation of curdione stereoisomer scaffolds by chemical and biological approaches: development of a sesquiterpenoid library. J Nat Prod. 2015; 78(2):272-278. https://doi.org/10.1021/np500864e.

[57] Guo F, Xu F, Yu JH, et al. Metabolism and distribution of two major constituents of 'Xing-Nao-Jing Injection'-germacrone and curdione in rats. J Pharm Biomed Anal. 2024; 248:116288. https://doi.org/10.1016/j.jpba.2024.116288.

[58] You J, Li QP, Yu YW, et al. Absorption of zedoary oil in rat intestine using in situ single pass perfusion model. Acta Pharm Sin. 2004; 39(10):849-853. https://doi.org/10.16438/j.0513-4870.2004.10.018.

[59] Li WJ, Hong B, Li ZJ, et al. GC-MS method for determination and pharmacokinetic study of seven volatile constituents in rat plasma after oral administration of the essential oil of Rhizoma Curcumae. J Pharm Biomed Anal. 2018; 149:577-585. https://doi.org/10.1016/j.jpba.2017.11.058.

[60] Li JC, Mao CQ, Li L, et al. Pharmacokinetics and liver distribution study of unbound curdione and curcumol in rats by microdialysis coupled with rapid resolution liquid chromatography (RRLC) and tandem mass spectrometry. J Pharm Biomed Anal. 2014; 95:146-150. https://doi.org/10.1016/j.jpba.2014.02.025.

[61] Peng Y, Zhang M, Li WW, et al. A validated LC-MS/MS assay for the quantitative determination of curdione in rabbit plasma and its application to a pharmacokinetic study after administration of zedoary turmeric oil and bioavailability of the oil. Biomed chromatogr. 2014; 28(10):1360-1365. https://doi.org/10.1002/bmc.3175.

[62] Zhang KY, LV LL, Chen JX, et al. Effect of curdione on MDA-MB-231 cell cycle and apoptosis. Chin J Exp Tradit Med Form. 2021; 27(12):74-81. https://doi.org/10.13422/j.cnki.syfjx.20211298.

[63] Engeland K. Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Differ. 2018; 25(1):114-132. https://doi.org/10.1038/cdd.2017.172.

[64] Wei C, Li DH, Liu Y, et al. Curdione induces antiproliferation effect on human uterine leiomy osarcoma targeting IDO1. Front Oncol. 2021; 11:637024. https://doi.org/10.3389/fonc.2021.637024.

[65] Wang JL, Wang X, Xia Q, et al. Study on the inhibitory effect of three sesquiterpenoids in Zedoary turmeric oil on hepatocellular carcinoma HepG 2 cells. Chin Tradit Pat Med. 2014; 36(7):1535-1539. https://doi.org/10.3969/j.issn.1001-1528.2014.07.045.

[66] Mahmoud G, Esen E, Hugh JB, et al. Raman spectroscopy detects biochemical changes due to different cell culture environments in live cells in vitro. Anal Bioanal Chem. 2018; 410(28):7537-7550. https://doi.org/10.1007/s00216-018-1371-5.

[67] Teresa LS, Paulo JO, Vilma AS, et al. Different concentrations of berberine result in distinct cellular localization patterns and cell cycle effects in a melanoma cell line. Cancer Chemother Pharmacol. 2008; 61(6):1007-1018. https://doi.org/10.1007/s00280-007-0558-9.

[68] Li J, Bian WH, Wan J, et al. Curdione inhibits proliferation of MCF-7 cells by inducing apoptosis. Asian Pac J Cancer Prev. 2014; 15(22):9997-10001. https://doi.org/10.7314/APJCP.2014.15.22.9997.

[69] Zhai LJ, Spranger S, Binder DC, et al. Molecular pathways: targeting IDO1 and other tryptophan dioxygenases for cancer immunotherapy. Clin Cancer Res. 2015; 21(24):5427-5433. https://doi.org/10.1158/1078-0432.CCR-15-0420.

[70] Sun CT, Li MZ, Zhang L, et al.IDO1 plays a tumor-promoting role via MDM2-mediated suppression of the p53 pathway in diffuse large B-cell lymphoma. Cell Death Dis. 2022; 13(6):572. https://doi.org/10.1038/s41419-022-05021-2.

[71] Wang HM, Luo YY, Ran R, et al. IDO1 modulates the sensitivity of epithelial ovarian cancer cells to cisplatin through ROS/p53-dependent apoptosis. Int J Mol Sci. 2022; 23(19):12002. https://doi.org/10.3390/ijms231912002.

[72] Yang YR, Jin Y, Yin LZ, et al. Sertaconazole nitrate targets IDO1 and regulates the MAPK signaling pathway to induce autophagy and apoptosis in CRC cells. Eur J Pharmacol. 2023; 942:175515. https://doi.org/10.1016/j.ejphar.2023.175515.

[73] Jiang NN, Dai QJ, Su XR, et al. Role of PI3K/AKT pathway in cancer: the framework of malignant behavior. Mol Biol Rep. 2020; 47(6):4587-4629. https://doi.org/10.1007/s11033-020-05435-1.

[74] He Y, Sun MM, Zhang GG, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. 2021; 6(1):425. https://doi.org/10.1038/s41392-021-00828-5.

[75] Wang P, Zhao WB, Wang YD. Inhibition proliferation and induced apoptosis effects of curdione on carcinom renal ACHN cells through PI3K/Akt signaling pathway. Chin J Tradit Med Sci Tech. 2020; 27(2):196-199.

[76] Wang CC, Guo J, Wu ZA. Combinative treatment of curdione and docetaxel triggers reactive oxygen species (ROS)-mediated intrinsic apoptosis of triple-negative breast cancer cells. Bioengineered. 2021; 12(2):10037-10048. https://doi.org/10.1080/21655979.2021.1994737.

[77] Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010; 221(1):3-12. https://doi.org/10.1002/path.2697.

[78] Liu SZ, Yao SJ, Yang H, et al. Autophagy: regulator of cell death. Cell Death Dis. 2023; 14(10):648. https://doi.org/10.1038/s41419-023-06154-8.

[79] Onorati AV, Dyczynski M, Ojha R, et al.Targeting autophagy in cancer. Cancer. 2018; 124(16):3307-3318. https://doi.org/10.1002/cncr.31335.

[80] Bravo-Cordero JJ, Hodgson L, Condeelis J. Directed cell invasion and migration during metastasis. Curr Opin Cell Biol. 2012; 24(2):277-283. https://doi.org/10.1016/j.ceb.2011.12.004.

[81] Webb AH, Gao BT, Goldsmith ZK, et al. Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma. BMC Cancer. 2017; 17(1):434. https://doi.org/10.1186/s12885-017-3418-y.

[82] Li XY, Huang GH, Liu QK, et al. Porf-2 inhibits tumor cell migration through the MMP-2/9 signaling pathway in neuroblastoma and glioma. Front Oncol. 2020; 10:975. https://doi.org/10.3389/fonc.2020.00975.

[83] Eidizade F, Soukhtanloo M, Zhiani R, et al. Inhibition of glioblastoma proliferation, invasion, and migration by Urolithin B through inducing G₀/G₁ arrest and targeting MMP-2/-9 expression and activity. Biofactors. 2023; 49(2):379-389. https://doi.org/10.1002/biof.1915.

[84] Sun XR, Yang K, Lv LL, et al. Effect and mechanism of curdione on migration and invasion of breast cancer HCC 1937 cells. Chin J Exp Tradit Med Form. 2019; 25(3):66-73. https://doi.org/10.13422/j.cnki.syfjx.20190326.

[85] Jiang E, Wang Z. Study of curdione on proliferation, apoptosis and invasion of human cervical carcinoma HeLa cells. Jilin Med J. 2021; 42(5):1032-1034. https://doi.org/10.3969/j.issn.1004-0412.2021.05.002.

[86] Tachibana H, Gi M, Kato M, et al. Carbonic anhydrase 2 is a novel invasion-associated factor in urinary bladder cancers. Cancer Sci. 2017; 108(3):331-337. https://doi.org/10.1111/cas.13143.

[87] Chi BJ, Duan ZL, Hasan A, et al. Effect and mechanism of curdione combined with gemcitabine on migration and invasion of bladder cancer. Biochem Genet. 2024; 62(4):2933-2945. https://doi.org/10.1007/s10528-023-10584-6.

[88] Jiang XJ, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021; 22(4):266-282. https://doi.org/10.1038/s41580-020-00324-8.

[89] Mou YH, Wang J, Wu JC, et al. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. 2019; 12(1):34. https://doi.org/10.1186/s13045-019-0720-y.

[90] Zhang C, Liu XY, Jin SD, et al. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Mol Cancer. 2022; 21(1):47. https://doi.org/10.1186/s12943-022-01530-y.

[91] Liu Y, Wan YC, Jiang Y, et al. GPX4: the hub of lipid oxidation, ferroptosis, disease and treatment. Biochim Biophys Acta Rev Cancer. 2023; 1878(3): 188890. https://doi.org/10.1016/j.bbcan.2023.188890.

[92] Zhang WZQ, Liu Y, Liao Y, et al. GPX4, ferroptosis, and diseases. Biomed Pharmacother. 2024; 174:116512. https://doi.org/10.1016/j.biopha.2024.116512.

[93] Fan ZY, Yang GW, Zhang W, et al. Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL 14 triggered YTHDF2-dependent silencing of SLC7A11. J Cell Mol Med. 2021; 25(21):10197-10212. https://doi.org/10.1111/jcmm.16957.

[94] Melincovici CS, Boşca AB, Şuşman S, et al. Vascular endothelial growth factor (VEGF)-key factor in normal and pathological angiogenesis. Rom J Morphol Embryol. 2018; 59(2):455-467.

[95] Yao DF, Wu XH, Zhu Y, et al. Quantitative analysis of vascular endothelial growth factor, microvascular density and their clinicopathologic features in human hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2005; 4(2):220-226.

[96] Fernández M, Semela D, Bruix J, et al.Angiogenesis in liver disease. J Hepatol. 2009; 50(3):604-620. https://doi.org/10.1016/j.jhep.2008.12.011.

[97] Zou Y, Guo CG, Yang ZG, et al. A small interfering RNA targeting vascular endothelial growth factor efficiently inhibits growth of VX2 cells and VX2 tumor model of hepatocellular carcinoma in rabbit by transarterial embolization-mediated siRNA delivery. Drug Des Devel Ther. 2016; 10:1243-1255. https://doi.org/10.2147/dddt.s94122.

[98] Cao RR, Zhou J, Wang QM, et al. The effect of the curdione on the proliferation of HHSEC under the microenvironment of HepG 2 cells via VEGF/VEGFR2 signaling pathway. J Hunan Univ Chin Med. 2021; 41(12):1835-1839. https://doi.org/10.3969/j.issn.1674-070X.2021.12.004.doi:10.3969/j.issn.1674-070X.2021.12.004

[99] Merten M, Thiagarajan P. P-selectin expression on platelets determines size and stability of platelet aggregates. Circulation. 2000; 102(16):1931-1936. https://doi.org/10.1161/01.CIR.102.16.1931.

[100] Tan TF, Cheng ZW, Han GW, et al. Study on intracellular uptake of curdione in platelets. J Pharm Anal. 2023; 43(2):253-261. https://doi.org/10.16155/j.0254-1793.2023.02.09.

[101] Tong HJ, Yu MT, Fei CH, et al. Bioactive constituents and the molecular mechanism of Curcumae Rhizoma in the treatment of primary dysmenorrhea based on network pharmacology and molecular docking. Phytomedicine. 2021; 86:153558. https://doi.org/10.1016/j.phymed.2021.153558.

[102] Xia Q, Dong TX, Zhan HQ, et al. Inhibition effect of curdione on platelet aggregation induced by ADP in rabbits. Chin Pharmacol Bull. 2006; 22(9):1151-1152.

[103] Wang X, Xia Q, Xu DJ, et al. Study on anticoagulant and antithrombotic effects of curdione in Curcuma. Chin Tradit Pat Med. 2012; 34(3):550-553.

[104] Xia Q, Wang X, Xu DJ, et al. Inhibition of platelet aggregation by curdione from Curcuma wenyujin essential Oil. Thromb Res. 2012; 130(3):409-414. https://doi.org/10.1016/j.thromres.2012.04.005.

[105] Bennett JS. Regulation of integrins in platelets. Biopolymers. 2015; 104(4):323-333. https://doi.org/10.1002/bip.22679.

[106] Huang JS, Li X, Shi XF, et al. Platelet integrin αIIbβ3: signal transduction, regulation, and its therapeutic targeting. J Hematol Oncol. 2019; 12(1):26. https://doi.org/10.1186/s13045-019-0709-6.

[107] Janus-Bell E, Mangin PH. The relative importance of platelet integrins in hemostasis, thrombosis and beyond. Haematologica. 2023; 108(7):1734-1747. https://doi.org/10.3324/haematol.2022.282136.

[108] Nieswandt B, Moser M, Pleines I, et al. Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo. J Exp Med. 2007; 204(13):3113-3118. https://doi.org/10.1084/jem.20071827.

[109] Petrich BG, Marchese P, Ruggeri ZM, et al. Talin is required for integrin-mediated platelet function in hemostasis and thrombosis. J Exp Med. 2007; 204(13):3103-3111. https://doi.org/10.1084/jem.20071800.

[110] Nanda SY, Hoang T, Patel P, et al. Vinculin regulates assembly of talin: β3 integrin complexes. J Cell Biochem. 2014; 115(6):1206-1216. https://doi.org/10.1002/jcb.24772.

[111] Kimmerlin Q, Moog S, Yakusheva A, et al. Loss of α4A- and β1-tubulins leads to severe platelet spherocytosis and strongly impairs hemostasis in mice. Blood. 2022; 140(21):2290-2299. https://doi.org/10.1182/blood.2022016729.

[112] Cuenca-Zamora EJ, Ferrer-Marín F, Rivera J, et al. Tubulin in platelets: when the shape matters. Int J Mol Sci. 2019; 20(14):3484. https://doi.org/10.3390/ijms20143484.

[113] Zhang DL, Qiao WH, Zhao YL, et al. Curdione attenuates thrombin-induced human platelet activation: β1-tubulin as a potential therapeutic target. Fitoterapia. 2017; 116:106-115. https://doi.org/10.1016/j.fitote.2016.11.016.

[114] Cheng ZW, Shi HB, Liu QH, et al. Inhibitory effect of curdione on thrombine-induced activation of human platelet integrin αⅡbβ3. Chin Tradit Pat Med. 2024; 46(6):2038-2041. https://doi.org/10.3969/j.issn.1001-1528.2024.06.044.

[115] Fang H, Gao BB, Zhao YL, et al. Curdione inhibits thrombin-induced platelet aggregation via regulating the AMP-activated protein kinase-vinculin/talin-integrin αIIbβ3 sign pathway. Phytomedicine. 2019; 61:152859. https://doi.org/10.1016/j.phymed.2019.152859.

[116] Kaplangoray M, Toprak K, Cekici Y, et al. Relationship between blood viscosity and thrombus burden in ST-segment elevation myocardial infarction. Clin Hemorheol Microcirc. 2023; 85(1):31-40. https://doi.org/10.3233/CH-231756.

[117] Çınar T, Şaylık F, Akbulut T, et al. The association between whole blood viscosity and high thrombus burden in patients with non-ST elevation myocardial infarction. Kardiol Pol. 2022; 80(4):429-435. https://doi.org/10.33963/KP.a2022.0043.

[118] Receveur N, Nechipurenko D, Knapp Y, et al. Shear rate gradients promote a bi-phasic thrombus formation on weak adhesive proteins, such as fibrinogen in a VWF-dependent manner. Haematologica. 2020; 105(10):2471-2483. https://doi.org/10.3324/haematol.2019.235754.

[119] Casa LDC, Ku DN. Thrombus formation at high shear rates. Annu Rev Biomed Eng. 2017; 19:415-433. https://doi.org/10.1146/annurev-bioeng-071516-044539.

[120] Si L, Wang X, Chen XH, et al. Effect of curdione on hemorheological indexs in rats with blood stasis syndrome. Anhui Med and Pharm J. 2012; 16(09):1229-1231.

[121] Tan C, Jin Y, Xia Q. Experimental study of the anti-inflammatory and analgesic of curdione. Chin J Bone Tumor Bone Dis. 2009; 8(3):168-170. https://doi.org/10.3969/j.issn.1671-1971.2009.06.011.

[122] Shi H, Shi L, Li JX. Effects of curdione on cognitive function and expression of inflammatory factors in the hippocampus after partial hepatectomy in aged mice. J Xi'an Jiaotong Univ Med Sci. 2017; 38(5):749-752. https://doi.org/10.7652/jdyxb201705026.

[123] Echizen K, Hirose O, Maeda Y, et al. Inflammation in gastric cancer: Interplay of the COX-2/prostaglandin E2 and Toll-like receptor/MyD 88 pathways. Cancer Sci. 2016; 107(4):391-397. https://doi.org/10.1111/cas.12901.

[124] Nasry W, Rodriguez-Lecompte J, Martin C. Role of COX-2/PGE2 mediated inflammation in oral squamous cell carcinoma. Cancers. 2018; 10(10):348. https://doi.org/10.3390/cancers10100348.

[125] Oh OJ, Min HY, Lee SK. Inhibition of inducible prostaglandin E2 production and cyclooxygenase-2 expression by curdione from Curcuma zedoaria. Arch Pharm Res. 2007; 30(10):1236-1239. https://doi.org/10.1007/BF02980264.

[126] Shi YY, Luo P, Wang WK, et al. M1 but not M0 extracellular vesicles induce polarization of RAW264.7 macrophages via the TLR4-NF-κB pathway in vitro. Inflammation. 2020; 43(5):1611-1619. https://doi.org/10.1007/s10753-020-01236-7.

[127] Cai YJ, Qiu L, Tao XY. Study on the effect of curdione in alleviating colitis in mice. In: The 6^th International Scientific Conference on Probiotics and Prebiotics. IPC. 2024;87. 2024; 87. https://doi.org/10.26914/c.cnkihy.2024.079038.

[128] Wu ZM, Zai WJ, Chen W, et al. Curdione ameliorated doxorubicin-induced cardiotoxicity through suppressing oxidative stress and activating Nrf2/HO-1 pathway. J Cardiovasc Pharmacol. 2019; 74(2):118-127. https://doi.org/10.1097/FJC.0000000000000692.

[129] Ma YL, Wang PH, Wu ZM, et al. Curdione relieved isoproterenol-induced myocardial damage through inhibiting oxidative stress and apoptosis. Am J Chin Med. 2023; 51(1):73-89. https://doi.org/10.1142/S0192415X23500052.

[130] Ho HY, Cheng ML, Chen CM, et al. Oxidative damage markers and antioxidants in patients with acute myocardial infarction and their clinical significance. BioFactors. 2008; 34(2):135-145. https://doi.org/10.1002/biof.5520340205.

[131] Lillo-Moya J, Rojas-Solé C, Muñoz-Salamanca D, et al. Targeting ferroptosis against ischemia/reperfusion cardiac injury. Antioxidants. 2021; 10(5):667. https://doi.org/10.3390/antiox10050667.

[132] Wang HH, Xie B, Shi ST, et al. Curdione inhibits ferroptosis in isoprenaline-induced myocardial infarction via regulating Keap1/Trx1/GPX4 signaling pathway. Phytother Res. 2023; 37(11):5328-5340. https://doi.org/10.1002/ptr.7964.

[133] Rathore P, Dohare P, Varma S, et al. Curcuma oil: reduces early accumulation of oxidative product and is anti-apoptogenic in transient focal ischemia in rat brain. Neurochem Res. 2008; 33(9):1672-1682. https://doi.org/10.1007/s11064-007-9515-6.

[134] Prakash P, Misra A, Surin W, et al. Anti-platelet effects of Curcuma oil in experimental models of myocardial ischemia-reperfusion and thrombosis. Thromb Res. 2011; 127(2):111-118. https://doi.org/10.1016/j.thromres.2010.11.007.

[135] Manhas A, Khanna V, Prakash P, et al. Curcuma oil reduces endothelial cell-mediated inflammation in postmyocardial ischemia/reperfusion in rats. J Cardiovasc Pharmacol. 2014; 64(3):228-236. https://doi.org/10.1097/FJC.0000000000000110.

[136] Li XJ, Liang L, Shi HX, et al. Neuroprotective effects of curdione against focal cerebral ischemia reperfusion injury in rats. Neuropsychiatr Dis Treat. 2017; 13:1733-1740. https://doi.org/10.2147/NDT.S139362.

[137] Gauldie J, Bonniaud P, Sime P, et al. TGF-β Smad3 and the process of progressive fibrosis. Biochem Soc Trans. 2007; 35:661-664. https://doi.org/10.1042/BST0350661.

[138] Gauldie J, Kolb M, Ask K, et al. Smad3 signaling involved in pulmonary fibrosis and emphysema. Biochem Soc Trans. 2006; 3(8):696-702. https://doi.org/10.1513/pats.200605-125SF.

[139] Bonniaud P, Margetts P, Ask K, et al. TGF-β and Smad3 signaling link inflammation to chronic fibrogenesis. J Immunol. 2005; 175(8):5390-5395. https://doi.org/10.4049/jimmunol.175.8.5390.

[140] Liu P, Miao K, Zhang L, et al. Curdione ameliorates bleomycin-induced pulmonary fibrosis by repressing TGF-β-induced fibroblast to myofibroblast differentiation. Respir Res. 2020; 21(1):58. https://doi.org/10.1186/s12931-020-1300-y.

[141] Zou SJ, Jie HY, Han XA, et al. The role of neutrophil extracellular traps in sepsis and sepsis-related acute lung injury. Int Immunopharmacol. 2023;124(Pt A):110436. https://doi.org/10.1016/j.intimp.2023.110436.

[142] Zhang H, Liu JL, Zhou YL, et al. Neutrophil extracellular traps mediate m(6)A modification and regulates sepsis-associated acute lung injury by activating ferroptosis in alveolar epithelial cells. Int J Biol Sci. 2022; 18(8):3337-3357. https://doi.org/10.7150/ijbs.69141.

[143] Qu MD, Chen ZY, Qiu ZY, et al. Neutrophil extracellular traps-triggered impaired autophagic flux via METTL3 underlies sepsis-associated acute lung injury. Cell Death Discov. 2022; 8(1):375. https://doi.org/10.1038/s41420-022-01166-3.

[144] Yang K, Wu B, Wei W, et al. Curdione ameliorates sepsis-induced lung injury by inhibiting platelet-mediated neutrophil extracellular trap formation. Int Immunopharmacol. 2023; 118:110082. https://doi.org/10.1016/j.intimp.2023.110082.

[145] Liu YN, Liu ZT, Wang KW. The Ca²⁺-activated chloride channel ANO1/TMEM16A: an emerging therapeutic target for epithelium-originated diseases? Acta Pharm Sin B. 2021; 11(6):1412-1433. https://doi.org/10.1016/j.apsb.2020.12.003.

[146] Grigoriev VV. Calcium-activated chloride channels: structure, properties, role in physiological and pathological processes. Biomed Khim. 2021; 67(1):17-33. https://doi.org/10.18097/pbmc20216701017.

[147] Yang YD, Cho HW, Koo JY, et al. TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature. 2008; 455(7217):1210-1215. https://doi.org/10.1038/nature07313.

[148] Terashima H, Picollo A, Accardi A. Purified TMEM16A is sufficient to form Ca²⁺-activated Cl- channels. Proc Natl Acad Sci USA. 2013; 110(48):19354-19359. https://doi.org/10.1073/pnas.1312014110.

[149] Huang F, Zhang HK, Wu M, et al. Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction. Proc Natl Acad Sci USA. 2012; 109(40):16354-16359. https://doi.org/10.1073/pnas.1214596109.

[150] Cabrita I, Benedetto R, Wanitchakool P, et al. TMEM16A mediates mucus production in human airway epithelial cells. Proc Natl Acad Sci USA. 2021; 64(1):50-58. https://doi.org/10.1165/rcmb.2019-0442OC.

[151] Benedetto R, Cabrita I, Schreiber R, et al. TMEM16A is indispensable for basal mucus secretion in airways and intestine. FASEB J. 2019; 33(3):4502-4512. https://doi.org/10.1096/fj.201801333RRR.

[152] Zhu XJ, Zhang WT, Jin LL, et al. Inhibitory activities of curzerenone, curdione, furanodienone, curcumol and germacrone on Ca-activated chloride channels. Fitoterapia. 2020; 147:104736. https://doi.org/10.1016/j.fitote.2020.104736.

[153] Matsuda H, Ninomiya K, Morikawa T, et al. Inhibitory effect and action mechanism of sesquiterpenes from Zedoariae Rhizoma on D-galactosamine/lipopolysaccharide-induced liver injury. Bioorg Med Chem Lett. 1998; 8(4):339-344. https://doi.org/10.1016/S0960-894X(98)00021-3.

[154] Morikawa T, Matsuda H, Ninomiya K, et al. Medicinal foodstuffs. XXIX. Potent protective effects of sesquiterpenes and curcumin from Zedoariae Rhizoma on liver injury induced by D-galactosamine/lipopolysaccharide or tumor necrosis factor-alpha. Bioorg Med Chem Lett. 2002; 25(5):627-631. https://doi.org/10.1248/bpb.25.627.

[155] Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017; 14(7):397-411. https://doi.org/10.1038/nrgastro.2017.38.

[156] Thoen L, Guimarães E, Dollé L, et al. A role for autophagy during hepatic stellate cell activation. J Hepatol. 2011; 55(6):1353-1360. https://doi.org/10.1016/j.jhep.2011.07.010.

[157] Zhou YN, Long D, Zhao Y, et al. Oxidative stress-mediated mitochondrial fission promotes hepatic stellate cell activation via stimulating oxidative phosphorylation. Cell Death Dis. 2022; 13(8):689. https://doi.org/10.1038/s41419-022-05088-x.

[158] Bates J, Vijayakumar A, Ghoshal S, et al. Acetyl-CoA carboxylase inhibition disrupts metabolic reprogramming during hepatic stellate cell activation. J Hepatol. 2020; 73(4):896-905. https://doi.org/10.1016/j.jhep.2020.04.037.

[159] Hao M, Yao ZH, Zhao MT, et al. Active ingredients screening and pharmacological mechanism research of curcumae rhizoma-sparganii rhizoma herb pair ameliorates liver fibrosis based on network pharmacology. J Ethnopharmacol. 2023; 305:116111. https://doi.org/10.1016/j.jep.2022.116111.

[160] Dai WZ, Qin Q, Li ZY, et al. Curdione and schisandrin C synergistically reverse Hepatic fibrosis via modulating the TGF-β pathway and inhibiting oxidative stress. Front Cell Dev Biol. 2021; 9:763864. https://doi.org/10.3389/fcell.2021.763864.

[161] Ling L, Qing X, Gang B, et al. Anti-H1N1 viral activity of three main active ingredients from zedoary oil. Fitoterapia. 2020; 142:104489. https://doi.org/10.1016/j.fitote.2020.104489.

[162] Quesada-Ocampo L, Parada-Rojas C, Hansen Z, et al. Phytophthora capsici: recent progress on fundamental biology and disease management 100 years after Its description. Annu Rev Phytopathol. 2023; 61:185-208. https://doi.org/10.1146/annurev-phyto-021622-103801.

[163] Niu G, Yang Q, Liao Y, et al. Advances in understanding Fusarium graminearum: genes involved in the regulation of sexual development, pathogenesis, and deoxynivalenol biosynthesis. Genes. 2024; 15(4):475. https://doi.org/10.3390/genes15040475.

[164] Khan M, Pandey A, Athar T, et al.Fusarium head blight in wheat: contemporary status and molecular approaches. 3 Biotech. 2020; 10(4):172. https://doi.org/10.1007/s13205-020-2158-x.

[165] Chen CQ, Long LI, Zhang FS, et al. Antifungal activity, main active components and mechanism of Curcuma longa extract against Fusarium graminearum. PLoS One. 2018; 13(3):e0194284. https://doi.org/10.1371/journal.pone.0194284.

[166] Mushtaq A, Azam U, Mehreen S, et al. Synthetic α-glucosidase inhibitors as promising anti-diabetic agents: recent developments and future challenges. Eur J Med Chem. 2023; 249:115119. https://doi.org/10.1016/j.ejmech.2023.115119.

[167] Cai Y, Xie H, Zhang J, et al. An updated overview of synthetic α-glucosidase inhibitors: chemistry and bioactivities. Curr Top Med Chem. 2023; 23(26):2488-2526. https://doi.org/10.2174/0115680266260682230921054652.

[168] Hossain U, Das AK, Ghosh S, et al. An overview on the role of bioactive α-glucosidase inhibitors in ameliorating diabetic complications. Food Chem Toxicol. 2020; 145:111738. https://doi.org/10.1016/j.fct.2020.111738.

[169] Joshi SR, Standl E, Tong NW, et al. Therapeutic potential of α-glucosidase inhibitors in type 2 diabetes mellitus: an evidence-based review. Expert Opin Pharmacother. 2015; 16(13):1959-1981. https://doi.org/10.1517/14656566.2015.1070827.

[170] Zhou CX, Zhang LS, Chen FF, et al. Terpenoids from Curcuma wenyujin increased glucose consumption on HepG2 cells. Fitoterapia. 2017; 121:141-145. https://doi.org/10.1016/j.fitote.2017.06.011.

[171] Ain Ibrahim N, Kamal N, Mediani A, et al. ¹H NMR-based metabolomics approach revealing metabolite variation of black turmeric (Curcuma caesia) extracts and correlation with its antioxidant and α-glucosidase inhibitory activities. Food Technol Biotechnol. 2023; 61(1):107-117. https://doi.org/10.17113/ftb.61.01.23.7711.

[172] Shaw R, Cantley L. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature. 2006; 441(7092):424-430. https://doi.org/10.1038/nature04869.

[173] Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004; 18(16):1926-1945. https://doi.org/10.1101/gad.1212704.

[174] Bai XZ, He T, Liu JQ, et al. Loureirin B inhibits fibroblast proliferation and extracellular matrix deposition in hypertrophic scar via TGF-β/Smad pathway. Exp Dermatol. 2015; 24(5):355-360. https://doi.org/10.1111/exd.12665.

[175] Song BY, Zhu YH, Zhao Y, et al. Machine learning and single-cell transcriptome profiling reveal regulation of fibroblast activation through THBS2/TGFβ1/P-Smad2/3 signalling pathway in hypertrophic scar. Int Wound J. 2024; 21(3):e14481. https://doi.org/10.1111/iwj.14481.

[176] Zhang H, Lin C, Zhou JM, et al. Pharmacological analysis of curdione on hypertrophic scar fibroblast. Chin Tradit Herbal Drugs. 2018; 49(8):1854-1859. https://doi.org/10.7501/j.issn.0253-2670.2018.08.018.

[177] Meng X, Zhang T, Li Y, et al. The toxicokinetic profile of curdione in pregnant SD rats and its transference in a placental barrier system detected by LC-MS/MS. Regul Toxicol Pharmacol. 2015; 71(2):158-163. https://doi.org/10.1016/j.yrtph.2014.12.005.

[178] Wu QB, Chen MT, Lin YF, et al. Multiomics profiling uncovers curdione-induced reproductive toxicity in HTR-8/SVneo cells. Heliyon. 2024; 10(21):e38650. https://doi.org/10.1016/j.heliyon.2024.e38650.

[179] Fonseca W, Monteiro C, Taborda-Barata L. Inhaled drug therapy-associated adverse reactions in obstructive respiratory diseases: a review of a decade of reporting to the portuguese pharmacovigilance system. Int J Environ Res Public Health. 2021; 18(23):12411. https://doi.org/10.3390/ijerph182312411.

[180] Kalyanasundaram A, Lincoff A. Managing adverse effects and drug-drug interactions of antiplatelet agents. Nat Rev Cardiol. 2011; 8(10):592-600. https://doi.org/10.1038/nrcardio.2011.128.

[181] Long K, Suresh K. Pulmonary toxicity of systemic lung cancer therapy. Respirology. 2020; 25(2):72-79. https://doi.org/10.1111/resp.13915.

[182] Chang H, Wu SF, Li YJ, et al. Analysis of 737 reports of adverse drug reactions induced by Zedoray Turmeric Oil Injection and literature review. Chin J Pharmacovigilance. 2017; 14(6):359-363.

[183] Yang ZR, Wang ZZ, Li JL, et al. Network pharmacology-based dissection of the underlying mechanisms of dyspnoea induced by zedoary turmeric oil. Basic Clin Pharmacol Toxicol. 2022; 130(5):606-617. https://doi.org/10.1111/bcpt.13722.

[184] Niu J, Straubinger RM, Mager DE.Pharmacodynamic drug-drug interactions. Clin Pharmacol Ther. 2019; 105(6):1395-1406. https://doi.org/10.1002/cpt.1434.

[185] Mar P, Horbal P, Chung M, et al. Drug interactions affecting antiarrhythmic drug use. Circ Arrhythm Electrophysiol. 2022; 15(5):e007955. https://doi.org/10.1161/CIRCEP.121.007955.

[186] Wang M, Zeraatkar D, Obeda M, et al. Drug-drug interactions with warfarin: a systematic review and meta-analysis. Br J Clin Pharmacol. 2021; 87(11):4051-4100. https://doi.org/10.1111/bcp.14833.

[187] Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007; 76(3):391-396. https://doi.org/10.1365/s10337-004-0469-4.

[188] Hakkola J, Hukkanen J, Turpeinen M, et al. Inhibition and induction of CYP enzymes in humans: an update. Arch Toxicol. 2020; 94(11):3671-3722. https://doi.org/10.1007/s00204-020-02936-7.

[189] Tian DD, Hu ZY. CYP3A4-mediated pharmacokinetic interactions in cancer therapy. Curr Drug Metab. 2014; 15(8):808-817. https://doi.org/10.2174/1389200216666150223152627.

[190] Hou XL, Hayashi-Nakamura E, Takatani-Nakase T, et al. Curdione plays an important role in the inhibitory effect of Curcuma aromatica on CYP3A 4 in Caco-2 cells. Evid Based Compl Alt. 2011; 2011:913898. https://doi.org/10.1093/ecam/nep229.

[191] Wei WL, Li ZW, Li Hj, et al. The inhibitory effect of 225 frequently-used traditional Chinese medicines for CYP3A4 metabolic enzyme by isoform-specific probe. Fitoterapia. 2021; 152:104858. https://doi.org/10.1016/j.fitote.2021.104858.

[192] Liu SY, Zhao Y, Tang X, et al. In vitro inhibition of six active sesquiterpenoids in zedoary turmeric oil on human liver cytochrome P 450 enzymes. J Ethnopharmacol. 2024; 322:117588. https://doi.org/10.1016/j.jep.2023.117588.