{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T17:24:02Z","timestamp":1781198642537,"version":"3.54.1"},"reference-count":52,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sichuan Science and Technology Program","award":["2021YFYZ0012"],"award-info":[{"award-number":["2021YFYZ0012"]}]},{"name":"National Modern Agricultural Industry Technology System Sichuan Innovation Team","award":["SCCXTD-2024-19"],"award-info":[{"award-number":["SCCXTD-2024-19"]}]},{"name":"Sichuan Agricultural University Discipline Construction Support Program Project"},{"name":"Featured Medicinal Plants Sharing and Service Platform of Sichuan Province"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cryptotanshinone (CPT), the main active compound of Salvia miltiorrhiza, is known for its anti-inflammatory, antioxidative, and antifibrotic effects. In this study, the hepatoprotective effect and mechanisms of CPT were explored using transcriptome and network pharmacology. A carbon tetrachloride-induced acute liver injury (ALI) mouse model was established. The anti-ALI effects of different doses of CPT were evaluated by analysis of biochemical indicators, histopathological staining, and immunohistochemical analysis. Combining network pharmacology with transcriptomic analysis revealed therapeutic targets, which were subsequently validated through polymerase chain reaction and Western blotting. CPT (40 mg\/kg) treatment significantly reduced the levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, tumor necrosis factor-\u03b1, interleukin-6, and interleukin-1\u03b2 in model mice and regulated oxidative stress indicators, including malonaldehyde, superoxide dismutase, glutathione, and catalase. MCP-1 protein expression in the liver was inhibited by treatment with CPT. Network pharmacology revealed 72 core targets involved in the treatment of ALI by CPT. By combining transcriptomic data from liver tissue, three key targets\u2014TNF-\u03b1, TLR9, and ADORA2B\u2014were identified, along with the TLR, IL-17, and TNF signaling pathways. Furthermore, PCR and Western blot assays revealed that CPT significantly decreased TNF-\u03b1, TLR9, and ADORA2B expression levels in the livers of ALI mice. In conclusion, the hepatoprotective effects of CPT may be related to the suppression of TNF-\u03b1-, TLR9-, and ADORA2B-mediated inflammation, oxidative stress, and apoptosis. These results provide a foundation for the development of CPT as a potential therapeutic agent for ALI.<\/jats:p>","DOI":"10.3390\/biom15101449","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T10:37:14Z","timestamp":1760438234000},"page":"1449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Mechanistic Insights into the Protective Effects of Cryptotanshinone Against CCl4-Induced Acute Liver Injury in Mice via Network Pharmacology and Transcriptomics"],"prefix":"10.3390","volume":"15","author":[{"given":"Xin","family":"Zhang","sequence":"first","affiliation":[{"name":"College of Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiulin","family":"Luo","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Food, Southwest Minzu University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanting","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Food, Southwest Minzu University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puyang","family":"Gong","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Food, Southwest Minzu University, Chengdu 610041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunsong","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Science, Sichuan Agricultural University, Ya\u2019an 625014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/s41419-022-04708-w","article-title":"Mesenchymal stem cells protect against ferroptosis via exosome-mediated stabilization of SLC7A11 in acute liver injury","volume":"13","author":"Lin","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_2","first-page":"110","article-title":"Portulaca oleracea alleviates CCl(4)-induced acute liver injury by regulating hepatic S100A8 and S100A9","volume":"15","author":"Qian","year":"2023","journal-title":"Chin. Herb. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"120415","DOI":"10.1016\/j.jep.2025.120415","article-title":"Fufang epimedium formula alleviates acute liver injury through dual modulation of PI3K\/AKT\/Bcl-2 anti-apoptotic signaling pathway and cGAS-STING-IRF3 anti-inflammatory signaling pathway","volume":"353","author":"Feng","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2808","DOI":"10.1097\/CM9.0000000000003332","article-title":"Cell therapy for end-stage liver disease: Current state and clinical challenge","volume":"137","author":"Zhang","year":"2024","journal-title":"Chin. Med. J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9361","DOI":"10.3892\/mmr.2017.7824","article-title":"Cryptotanshinone exhibits therapeutical effects on cerebral stroke through the PI3K\/AKT\u2014eNOS signaling pathway","volume":"16","author":"Zhu","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"105384","DOI":"10.1016\/j.phrs.2020.105384","article-title":"Cryptotanshinone specifically suppresses NLRP3 inflammasome activation and protects against inflammasome-mediated diseases","volume":"164","author":"Liu","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2742","DOI":"10.1016\/j.fct.2009.08.007","article-title":"Preventive effects of a purified extract isolated from Salvia miltiorrhiza enriched with tanshinone I, tanshinone IIA and cryptotanshinone on hepatocyte injury in vitro and in vivo","volume":"47","author":"Park","year":"2009","journal-title":"Food Chem. Toxicol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2616","DOI":"10.3748\/wjg.v29.i17.2616","article-title":"Cryptotanshinone induces apoptosis of activated hepatic stellate cells via modulating endoplasmic reticulum stress","volume":"29","author":"Hou","year":"2023","journal-title":"World J. Gastroenterol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Baiz\u00e1n, N., Ribas, L., and Piferrer, F. (2022). Improved biomarker discovery through a plot twist in transcriptomic data analysis. BMC Biol., 20.","DOI":"10.1186\/s12915-022-01398-w"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"114699","DOI":"10.1016\/j.jep.2021.114699","article-title":"Integrated lipidomics, transcriptomics and network pharmacology analysis to reveal the mechanisms of Danggui Buxue Decoction in the treatment of diabetic nephropathy in type 2 diabetes mellitus","volume":"283","author":"Sun","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Noor, F., Asif, M., Ashfaq, U.A., Qasim, M., and Tahir Ul Qamar, M. (2023). Machine learning for synergistic network pharmacology: A comprehensive overview. Brief. Bioinform., 24.","DOI":"10.1093\/bib\/bbad120"},{"key":"ref_12","first-page":"323","article-title":"Network pharmacology approaches for research of traditional Chinese medicines","volume":"21","author":"Li","year":"2023","journal-title":"Chin. J. Nat. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zhang, X., Yi, Y., Jiang, Y., Liao, J., Yang, R., Deng, X., and Zhang, L. (2023). Targeted therapy of acute liver injury via cryptotanshinone-loaded biomimetic nanoparticles derived from mesenchymal stromal cells driven by homing. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15122764"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Gao, Y., Li, X., Gao, Q., Fan, L., Jin, H., and Guo, Y. (2019). Differential effects of olive oil, soybean oil, corn oil and lard oil on carbon tetrachloride-induced liver fibrosis in mice. Biosci. Rep., 39.","DOI":"10.1042\/BSR20191913"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhang, L., Liu, C., Yin, L., Huang, C., and Fan, S. (2023). Mangiferin relieves CCl4-induced liver fibrosis in mice. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-30582-3"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/978-1-0716-1099-2_2","article-title":"The illumina sequencing protocol and the NovaSeq 6000 system","volume":"2242","author":"Modi","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"107598","DOI":"10.1016\/j.intimp.2021.107598","article-title":"MCP-1: Function, regulation, and involvement in disease","volume":"101","author":"Singh","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1038\/s41419-018-1136-2","article-title":"Chloroquine ameliorates carbon tetrachloride-induced acute liver injury in mice via the concomitant inhibition of inflammation and induction of apoptosis","volume":"9","author":"Dai","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.2174\/0115665240257603230919103539","article-title":"Deciphering molecular mechanisms of carbon tetrachloride-induced hepatotoxicity: A brief systematic review","volume":"24","author":"Fareed","year":"2024","journal-title":"Curr. Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1080\/713611034","article-title":"Hepatotoxicity and mechanism of action of haloalkanes: Carbon tetrachloride as a toxicological model","volume":"33","author":"Weber","year":"2003","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_21","first-page":"755","article-title":"Breviscapine ameliorates CCl4\u2014Induced liver injury in mice through inhibiting inflammatory apoptotic response and ROS generation","volume":"42","author":"Liu","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhu, L., Lv, B., Gao, Y., and Qin, D. (2025). Lactucin alleviates liver fibrosis by regulating the TLR4-MyD88-MAPK\/NF-\u03baB signaling pathway through intestinal flora. Arch. Biochem. Biophys., 766.","DOI":"10.1016\/j.abb.2025.110341"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"116343","DOI":"10.1016\/j.ecoenv.2024.116343","article-title":"Curcumin alleviates zearalenone-induced liver injury in mice by scavenging reactive oxygen species and inhibiting mitochondrial apoptosis pathway","volume":"277","author":"Yang","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.fsi.2022.05.015","article-title":"Yinchenhao Decoction ameliorates the high-carbohydrate diet induced suppression of immune response in largemouth bass (Micropterus salmoides)","volume":"125","author":"Zhao","year":"2022","journal-title":"Fish Shellfish Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"R453","DOI":"10.1016\/j.cub.2014.03.034","article-title":"ROS function in redox signaling and oxidative stress","volume":"24","author":"Schieber","year":"2014","journal-title":"Curr. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"437","DOI":"10.3390\/oxygen2040030","article-title":"RONS and oxidative stress: An overview of basic concepts","volume":"2","year":"2022","journal-title":"Oxygen"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sun, L., Zhang, Y., Wen, S., Li, Q., Chen, R., Lai, X., Zhang, Z., Zhou, Z., Xie, Y., and Zheng, X. (2022). Extract of Jasminum grandiflorum L. alleviates CCl(4)-induced liver injury by decreasing inflammation, oxidative stress and hepatic CYP2E1 expression in mice. Biomed. Pharmacother., 152.","DOI":"10.1016\/j.biopha.2022.113255"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"156323","DOI":"10.1016\/j.phymed.2024.156323","article-title":"Unveiling the hepatoprotective mechanisms of Desmodium heterocarpon (L.) DC: Novel flavonoid identification and Keap1\/Nrf2 pathway activation","volume":"136","author":"Pu","year":"2025","journal-title":"Phytomedicine"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.jconrel.2022.02.033","article-title":"Nanoreactor for cascade reaction between SOD and CAT and its tissue regeneration effect","volume":"344","author":"Kwon","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"118042","DOI":"10.1016\/j.ecoenv.2025.118042","article-title":"Edgeworthia gardneri (Wall.) Meisn Mitigates CCL4-induced liver injury in mice by modulating gut microbiota, boosting antioxidant defense, and reducing inflammation","volume":"293","author":"Hu","year":"2025","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"113513","DOI":"10.1016\/j.celrep.2023.113513","article-title":"Liver receptor homolog-1 (NR5A2) orchestrates hepatic inflammation and TNF-induced cell death","volume":"42","author":"Lambrecht","year":"2023","journal-title":"Cell Rep."},{"key":"ref_32","first-page":"4","article-title":"Potential roles of vitamin D binding protein in attenuating liver injury in sepsis","volume":"9","author":"Xiao","year":"2022","journal-title":"Mil. Med. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.jhep.2015.04.010","article-title":"Heatstroke induces liver injury via IL-1\u03b2 and HMGB1-induced pyroptosis","volume":"63","author":"Geng","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Flores Molina, M., Abdelnabi, M.N., Mazouz, S., Villafranca-Baughman, D., Trinh, V.Q.-H., Muhammad, S., Bedard, N., Osorio Laverde, D., Hassan, G.S., and Di Polo, A. (2022). Distinct spatial distribution and roles of kupffer cells and monocyte-derived macrophages in mouse acute liver injury. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.994480"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1002\/eji.201948351","article-title":"Sphingosine 1-phosphate\/microRNA-1249-5p\/MCP-1 axis is involved in macrophage\u2014Associated inflammation in fatty liver injury in mice","volume":"50","author":"Ji","year":"2020","journal-title":"Eur. J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Xie, J., Yang, L., Tian, L., Li, W., Yang, L., and Li, L. (2016). Macrophage migration inhibitor factor upregulates MCP-1 expression in an autocrine manner in hepatocytes during acute mouse liver injury. Sci. Rep., 6.","DOI":"10.1038\/srep27665"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Monaco, G., van Dam, S., Casal Novo Ribeiro, J.L., Larbi, A., and de Magalh\u00e3es, J.P. (2015). A comparison of human and mouse gene co-expression networks reveals conservation and divergence at the tissue, pathway and disease levels. BMC Evol. Biol., 15.","DOI":"10.1186\/s12862-015-0534-7"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"114654","DOI":"10.1016\/j.intimp.2025.114654","article-title":"Unravelling the role of interleukin-12 in neuroinflammatory mechanisms: Pathogenic pathways linking neuroinflammation to neuropsychiatric disorders","volume":"156","author":"Chauhan","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s13020-020-00303-3","article-title":"Cryptotanshinone from Salvia miltiorrhiza Bunge (Danshen) inhibited inflammatory responses via TLR4\/MyD88 signaling pathway","volume":"15","author":"Li","year":"2020","journal-title":"Chin. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/s41419-025-07473-8","article-title":"Circulating mitochondrial DNA promotes M2 polarization of tumor associated macrophages and HCC resistance to sorafenib","volume":"16","author":"Yang","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.7150\/ijms.43500","article-title":"Tumor-derived circulating exosomal miR-342-5p and miR-574-5p as promising diagnostic biomarkers for early-stage Lung Adenocarcinoma","volume":"17","author":"Han","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"424","DOI":"10.3892\/mmr.2021.12063","article-title":"Cryptotanshinone interferes with chondrocyte apoptosis in osteoarthritis by inhibiting the expression of miR-574-5p","volume":"23","author":"Yue","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"155550","DOI":"10.1016\/j.phymed.2024.155550","article-title":"Multi-omics reveals that 5-O-methylvisammioside prevention acute liver injury in mice by regulating the TNF\/MAPK\/NF-\u03baB\/arachidonic acid pathway","volume":"128","author":"Zhang","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Gao, Z., Dai, H., Zhang, Q., Yang, F., Bu, C., and Chen, S. (2024). Hydroxytyrosol alleviates acute liver injury by inhibiting the TNF-\u03b1\/PI3K\/AKT signaling pathway via targeting TNF-\u03b1 signaling. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312844"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.jgg.2021.09.009","article-title":"Tumor necrosis factor-\u03b1 signaling in nonalcoholic steatohepatitis and targeted therapies","volume":"49","author":"Lu","year":"2022","journal-title":"J. Genet. Genom."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Song, H., Jiang, L., Yang, W., Dai, Y., Wang, Y., Li, Z., Liu, P., and Chen, J. (2023). Cryptotanshinone alleviates lipopolysaccharide and cigarette smoke-induced chronic obstructive pulmonary disease in mice via the Keap1\/Nrf2 axis. Biomed. Pharmacother., 165.","DOI":"10.1016\/j.biopha.2023.115105"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Li, P., Pang, K.L., Chen, S.J., Yang, D., Nai, A.T., He, G.C., Fang, Z., Yang, Q., Cai, M.B., and He, J.Y. (2025). ADORA2B promotes proliferation and migration in head and neck squamous cell carcinoma and is associated with immune infiltration. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-14102-2"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Li, X., Berg, N.K., Mills, T., Zhang, K., Eltzschig, H.K., and Yuan, X. (2020). Adenosine at the interphase of hypoxia and inflammation in lung injury. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.604944"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Ngamsri, K.C., Putri, R.A., Jans, C., Schindler, K., Fuhr, A., Zhang, Y., Gamper-Tsigaras, J., Ehnert, S., and Konrad, F.M. (2021). CXCR4 and CXCR7 inhibition ameliorates the formation of platelet-neutrophil complexes and neutrophil extracellular traps through Adora2b signaling. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413576"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1097\/ALN.0000000000001234","article-title":"Adenosine receptor Adora2b plays a mechanistic role in the protective effect of the volatile anesthetic sevoflurane during liver ischemia\/reperfusion","volume":"125","author":"Granja","year":"2016","journal-title":"Anesthesiology"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Gan, X., Dai, Z., Ge, C., Yin, H., Wang, Y., Tan, J., Sun, S., Zhou, W., Yuan, S., and Yang, F. (2022). FTO promotes liver inflammation by suppressing m6A mRNA methylation of IL-17RA. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.989353"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"108894","DOI":"10.1016\/j.intimp.2022.108894","article-title":"Cryptotanshinone ameliorates dextran sulfate sodium-induced murine acute and chronic ulcerative colitis via suppressing STAT3 activation and Th17 cell differentiation","volume":"108","author":"Fan","year":"2022","journal-title":"Int. Immunopharmacol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/10\/1449\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T11:44:29Z","timestamp":1760442269000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/10\/1449"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,14]]},"references-count":52,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["biom15101449"],"URL":"https:\/\/doi.org\/10.3390\/biom15101449","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,14]]}}}