{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:54:56Z","timestamp":1790823296006,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T00:00:00Z","timestamp":1727136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Guangdong General Colleges and Universities Key Area Project: Biomedicine and Health (Food) Key Area Project","award":["2024ZDZX2075"],"award-info":[{"award-number":["2024ZDZX2075"]}]},{"name":"Guangdong General Colleges and Universities Key Area Project: Biomedicine and Health (Food) Key Area Project","award":["20231208"],"award-info":[{"award-number":["20231208"]}]},{"name":"Guangdong General Colleges and Universities Key Area Project: Biomedicine and Health (Food) Key Area Project","award":["B2021324"],"award-info":[{"award-number":["B2021324"]}]},{"name":"Scientific research project of Guangdong Provincial Administration of Traditional Chinese Medicine","award":["2024ZDZX2075"],"award-info":[{"award-number":["2024ZDZX2075"]}]},{"name":"Scientific research project of Guangdong Provincial Administration of Traditional Chinese Medicine","award":["20231208"],"award-info":[{"award-number":["20231208"]}]},{"name":"Scientific research project of Guangdong Provincial Administration of Traditional Chinese Medicine","award":["B2021324"],"award-info":[{"award-number":["B2021324"]}]},{"name":"Guangdong Medical Research Fund","award":["2024ZDZX2075"],"award-info":[{"award-number":["2024ZDZX2075"]}]},{"name":"Guangdong Medical Research Fund","award":["20231208"],"award-info":[{"award-number":["20231208"]}]},{"name":"Guangdong Medical Research Fund","award":["B2021324"],"award-info":[{"award-number":["B2021324"]}]},{"name":"Guangdong Rural Science and Technology Specialist Team Program (2021)","award":["2024ZDZX2075"],"award-info":[{"award-number":["2024ZDZX2075"]}]},{"name":"Guangdong Rural Science and Technology Specialist Team Program (2021)","award":["20231208"],"award-info":[{"award-number":["20231208"]}]},{"name":"Guangdong Rural Science and Technology Specialist Team Program (2021)","award":["B2021324"],"award-info":[{"award-number":["B2021324"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Irritable bowel syndrome (IBS) is a common chronic functional bowel disorder and is strongly associated with an increased risk of depression and anxiety. The brain\u2013gut axis plays an important role in the pathophysiologic changes in IBS, yet effective treatments for IBS are still lacking. Sinisan, originating from the Treatise on Typhoid Fever by the medical sage Zhang Zhongjing, is a classic formula in the Eight Methods of Traditional Chinese Medicine (TCM) that focuses on dispersing the liver and regulating the spleen, relieving depression and transmitting evils, and has been widely used in the treatment of liver-depression and spleen-deficiency, diarrhea, and related liver and stomach disorders. However, the therapeutic effect of sinisan in IBS has not been clarified. The aim of this study was to investigate the effects of sinisan on stress-induced intestinal dysfunction and depressive behavior in IBS mice. We established a diarrhea-predominant irritable bowel syndrome (IBS-D) mouse model using a 4% acetic acid enema combined with restraint stress, and analyzed the results using behavioral tests, relevant test kits, hematoxylin-eosin (HE) staining, immunofluorescence (IF), Western blot (WB), and quantitative fluorescence polymerase chain reaction (qRT-PCR). The results showed that sinisan administration significantly alleviated intestinal dysfunction and depressive-like behaviors in IBS-D mice, improved mild colonic inflammation and intestinal mucosal permeability, up-regulated the expression of tight junction proteins ZO-1 and occludin. Sinisan significantly alleviated intestinal dysfunction and depressive-like behaviors in IBS-D mice by decreasing the expression of TNF-\u03b1, promoting the expression of tight junction proteins (occludin, ZO-1) expression, and inhibiting the Tlr4\/Myd88 signaling pathway, thereby attenuating the inflammatory response, protecting the intestinal barrier, and alleviating symptoms in the IBS-D mouse model. Taken together, sinisan may ameliorate intestinal inflammation and the intestinal barrier by regulating 5-HT expression and the Tlr4\/Myd88 pathway, thereby alleviating stress-induced intestinal dysfunction and depressive behaviors in IBS-D mice.<\/jats:p>","DOI":"10.3390\/ijms251910262","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T08:54:13Z","timestamp":1727168053000},"page":"10262","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Sinisan Alleviates Stress-Induced Intestinal Dysfunction and Depressive-like Behaviors in Mice with Irritable Bowel Syndrome by Enhancing the Intestinal Barrier and Modulating Central 5-Hydroxytryptamine"],"prefix":"10.3390","volume":"25","author":[{"given":"Haizhou","family":"Zeng","sequence":"first","affiliation":[{"name":"School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yupeng","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuxiong","family":"Yin","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinran","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Xiong","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyi","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimei","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3036-1512","authenticated-orcid":false,"given":"Guoqiang","family":"Qian","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1016\/j.mayocp.2018.04.032","article-title":"Management Options for Irritable Bowel Syndrome","volume":"93","author":"Camilleri","year":"2018","journal-title":"Mayo Clin. Proc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1038\/s41380-023-01972-w","article-title":"The neurobiology of irritable bowel syndrome","volume":"28","author":"Mayer","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1001\/jama.2015.0954","article-title":"Irritable bowel syndrome: A clinical review","volume":"313","author":"Chey","year":"2015","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1007\/s00109-022-02244-w","article-title":"The serotonin receptor 3E variant is a risk factor for female IBS-D","volume":"100","author":"Fritz","year":"2022","journal-title":"J. Mol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1001\/jama.2020.22532","article-title":"Diagnosis and Treatment of Irritable Bowel Syndrome: A Review","volume":"325","author":"Camilleri","year":"2021","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/S2468-1253(20)30217-X","article-title":"Global prevalence of irritable bowel syndrome according to Rome III or IV criteria: A systematic review and meta-analysis","volume":"5","author":"Oka","year":"2020","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Colomier, E., Algera, J., and Melchior, C. (2020). Pharmacological Therapies and Their Clinical Targets in Irritable Bowel Syndrome with Diarrhea. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.629026"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17","DOI":"10.14309\/ajg.0000000000001036","article-title":"ACG Clinical Guideline: Management of Irritable Bowel Syndrome","volume":"116","author":"Lacy","year":"2021","journal-title":"Am. J. Gastroenterol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s13020-023-00795-9","article-title":"Altered gut microbiota-host bile acid metabolism in IBS-D patients with liver depression and spleen deficiency pattern","volume":"18","author":"Du","year":"2023","journal-title":"Chin. Med."},{"key":"ref_10","first-page":"5163","article-title":"The Efficacy and Potential Mechanisms of Chinese Herbal Medicine on Irritable Bowel Syndrome","volume":"23","author":"Bi","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1016\/j.cgh.2015.06.022","article-title":"Efficacy of a Chinese Herbal Medicine in Providing Adequate Relief of Constipation-predominant Irritable Bowel Syndrome: A Randomized Controlled Trial","volume":"13","author":"Bensoussan","year":"2015","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"154350","DOI":"10.1016\/j.phymed.2022.154350","article-title":"Tong-Xie-Yao-Fang alleviates diarrhea-predominant irritable bowel syndrome in rats via the GCN2\/PERK-eIF2\u03b1-ATF4 signaling pathway","volume":"107","author":"Zhang","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"155163","DOI":"10.1016\/j.phymed.2023.155163","article-title":"Baizhu shaoyao decoction restores the intestinal barrier and brain-gut axis balance to alleviate diarrhea-predominant irritable bowel syndrome via FoxO1\/FoxO3a","volume":"122","author":"Wei","year":"2024","journal-title":"Phytomedicine"},{"key":"ref_14","first-page":"897","article-title":"Efficacy of Shenlingbaizhu formula on irritable bowel syndrome: A systematic review","volume":"40","author":"Wang","year":"2020","journal-title":"J. Tradit. Chin. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"154395","DOI":"10.1016\/j.phymed.2022.154395","article-title":"Sinisan alleviates depression-like behaviors by regulating mitochondrial function and synaptic plasticity in maternal separation rats","volume":"106","author":"Deng","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Shen, C., Cao, K., Cui, S., Cui, Y., Mo, H., Wen, W., Dong, Z., Lin, H., Bai, S., and Yang, L. (2020). SiNiSan ameliorates depression-like behavior in rats by enhancing synaptic plasticity via the CaSR-PKC-ERK signaling pathway. Biomed. Pharmacother., 124.","DOI":"10.1016\/j.biopha.2019.109787"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Cao, K., Shen, C., Yuan, Y., Bai, S., Yang, L., Guo, L., Zhang, R., and Shi, Y. (2019). SiNiSan Ameliorates the Depression-Like Behavior of Rats That Experienced Maternal Separation Through 5-HT1A Receptor\/CREB\/BDNF Pathway. Front. Psychiatry, 10.","DOI":"10.3389\/fpsyt.2019.00160"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"116067","DOI":"10.1016\/j.jep.2022.116067","article-title":"Si-Ni-San improves experimental colitis by favoring Akkermensia colonization","volume":"305","author":"Cai","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1080\/13880209.2023.2191643","article-title":"Sinisan ameliorates colonic injury induced by water immersion restraint stress by enhancing intestinal barrier function and the gut microbiota structure","volume":"61","author":"Xu","year":"2023","journal-title":"Pharm. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e34802","DOI":"10.1097\/MD.0000000000034802","article-title":"Causal association between psycho-psychological factors, such as stress, anxiety, depression, and irritable bowel syndrome: Mendelian randomization","volume":"102","author":"Diao","year":"2023","journal-title":"Medicine"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1631\/jzus.B1500181","article-title":"Nerve growth factor and diarrhea-predominant irritable bowel syndrome (IBS-D): A potential therapeutic target?","volume":"17","author":"Xu","year":"2016","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Wang, B., Lu, S., Zhang, C., Zhu, L., Li, Y., Bai, M., and Xu, E. (2020). Quantitative proteomic analysis of the liver reveals antidepressant potential protein targets of Sinisan in a mouse CUMS model of depression. Biomed. Pharmacother., 130.","DOI":"10.1016\/j.biopha.2020.110565"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/BF02835744","article-title":"Effect of modified Sinisan on anorectal manometry of the constipation predominant type of irritable bowel syndrome","volume":"11","author":"Yu","year":"2005","journal-title":"Chin. J. Integr. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s10020-022-00599-x","article-title":"Evaluation of two laboratory model methods for diarrheal irritable bowel syndrome","volume":"29","author":"Chen","year":"2023","journal-title":"Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/nyas.14798","article-title":"Tight junction proteins occludin and ZO-1 as regulators of epithelial proliferation and survival","volume":"1514","author":"Kuo","year":"2022","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1111\/j.1365-2982.2012.01921.x","article-title":"Intestinal barrier function in health and gastrointestinal disease","volume":"24","author":"Camilleri","year":"2012","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1136\/gutjnl-2018-316906","article-title":"Tight junction proteins in gastrointestinal and liver disease","volume":"68","author":"Zeisel","year":"2019","journal-title":"Gut"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Liu, N., Sun, S., Wang, P., Sun, Y., Hu, Q., and Wang, X. (2021). The Mechanism of Secretion and Metabolism of Gut-Derived 5-Hydroxytryptamine. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22157931"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Daut, R.A., and Fonken, L.K. (2019). Circadian regulation of depression: A role for serotonin. Front. Neuroendocrinol., 54.","DOI":"10.1016\/j.yfrne.2019.04.003"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S0301-0082(96)00021-4","article-title":"Activation of c-fos in the brain","volume":"50","author":"Herrera","year":"1996","journal-title":"Prog. Neurobiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e14365","DOI":"10.1111\/nmo.14365","article-title":"Role of inflammation in pediatric irritable bowel syndrome","volume":"35","author":"Cremon","year":"2023","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Cojocariu, R.O., Balmus, I.M., Lefter, R., Ababei, D.C., Ciobica, A., Hritcu, L., Kamal, F., and Doroftei, B. (2020). Behavioral and Oxidative Stress Changes in Mice Subjected to Combinations of Multiple Stressors Relevant to Irritable Bowel Syndrome. Brain Sci., 10.","DOI":"10.3390\/brainsci10110865"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1111\/nmo.12315","article-title":"Tight junctions and IBS\u2014The link between epithelial permeability, low-grade inflammation, and symptom generation?","volume":"26","author":"Piche","year":"2014","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"345","DOI":"10.2147\/JIR.S174982","article-title":"The role of inflammation in irritable bowel syndrome (IBS)","volume":"11","author":"Ng","year":"2018","journal-title":"J. Inflamm. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2263209","DOI":"10.1080\/19490976.2023.2263209","article-title":"Low-level inflammation, immunity, and brain-gut axis in IBS: Unraveling the complex relationships","volume":"15","author":"Yuan","year":"2023","journal-title":"Gut Microbes"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"107090","DOI":"10.1016\/j.phrs.2024.107090","article-title":"The therapeutic effects of saikosaponins on depression through the modulation of neuroplasticity: From molecular mechanisms to potential clinical applications","volume":"201","author":"Chen","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3898","DOI":"10.1039\/D0FO02736G","article-title":"Hesperetin ameliorates hepatic oxidative stress and inflammation via the PI3K\/AKT-Nrf2-ARE pathway in oleic acid-induced HepG2 cells and a rat model of high-fat diet-induced NAFLD","volume":"12","author":"Li","year":"2021","journal-title":"Food Funct."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ma, X., Zhang, W., Jiang, Y., Wen, J., Wei, S., and Zhao, Y. (2020). Paeoniflorin, a Natural Product With Multiple Targets in Liver Diseases-A Mini Review. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.00531"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"116716","DOI":"10.1016\/j.jep.2023.116716","article-title":"Paeonia lactiflora Pall. Polysaccharide alleviates depression in CUMS mice by inhibiting the NLRP3\/ASC\/Caspase-1 signaling pathway and affecting the composition of their intestinal flora","volume":"316","author":"Zhou","year":"2023","journal-title":"J. Ethnopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.intimp.2019.02.046","article-title":"Glycyrrhizin administration ameliorates Streptococcus aureus-induced acute lung injury","volume":"70","author":"Yao","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1007\/s12272-018-1068-5","article-title":"Recent advances in pharmacological research on the management of irritable bowel syndrome","volume":"41","author":"Nam","year":"2018","journal-title":"Arch. Pharm. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"173","DOI":"10.5056\/jnm21002","article-title":"Pathophysiological Commonality Between Irritable Bowel Syndrome and Metabolic Syndrome: Role of Corticotropin-releasing Factor-Toll-like Receptor 4-Proinflammatory Cytokine Signaling","volume":"28","author":"Nozu","year":"2022","journal-title":"J. Neurogastroenterol. Motil."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1007\/s00018-020-03656-y","article-title":"TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling","volume":"78","author":"Ciesielska","year":"2021","journal-title":"Cell Mol. Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.smim.2003.10.003","article-title":"TLR signaling pathways","volume":"16","author":"Takeda","year":"2004","journal-title":"Semin. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.gendis.2020.06.005","article-title":"The Nuclear Factor Kappa B (NF-kB) signaling in cancer development and immune diseases","volume":"8","author":"Zinatizadeh","year":"2021","journal-title":"Genes. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Laurindo, L.F., Santos, A., Carvalho, A.C.A., Bechara, M.D., Guiguer, E.L., Goulart, R.A., Vargas Sinatora, R., Ara\u00fajo, A.C., and Barbalho, S.M. (2023). Phytochemicals and Regulation of NF-kB in Inflammatory Bowel Diseases: An Overview of In Vitro and In Vivo Effects. Metabolites, 13.","DOI":"10.3390\/metabo13010096"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e14534","DOI":"10.1111\/cns.14534","article-title":"Paraventricular thalamus-insular cortex circuit mediates colorectal visceral pain induced by neonatal colonic inflammation in mice","volume":"30","author":"Zhang","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.neubiorev.2005.03.009","article-title":"The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice","volume":"29","author":"Cryan","year":"2005","journal-title":"Neurosci. Biobehav. Rev."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10262\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:01:36Z","timestamp":1760112096000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/19\/10262"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,24]]},"references-count":48,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms251910262"],"URL":"https:\/\/doi.org\/10.3390\/ijms251910262","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,24]]}}}