{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T01:04:52Z","timestamp":1768007092166,"version":"3.49.0"},"reference-count":54,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,22]],"date-time":"2022-01-22T00:00:00Z","timestamp":1642809600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["20120601005"],"award-info":[{"award-number":["20120601005"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A diet-induced non-alcoholic fatty liver disease (NAFLD) model causing obesity in rodents was used to examine whether sitagliptin and gliclazide therapies have similar protective effects on pathological liver change. Methods: Male mice were fed a high-fat diet (HFD) or standard chow (Chow) ad libitum for 25 weeks and randomly allocated to oral sitagliptin or gliclazide treatment for the final 10 weeks. Fasting blood glucose and circulating insulin were measured. Inflammatory and fibrotic liver markers were assessed by qPCR. The second messenger ERK and autophagy markers were examined by Western immunoblot. F4\/80, collagens and CCN2 were assessed by immunohistochemistry (IHC). Results: At termination, HFD mice were obese, hyperinsulinemic and insulin-resistant but non-diabetic. The DPP4 inhibitor sitagliptin prevented intrahepatic induction of pro-fibrotic markers collagen-IV, collagen-VI, CCN2 and TGF-\u03b21 and pro-inflammatory markers TNF-\u03b1 and IL-1\u03b2 more effectively than sulfonylurea gliclazide. By IHC, liver collagen-VI and CCN2 induction by HFD were inhibited only by sitagliptin. Sitagliptin had a greater ability than gliclazide to normalise ERK-protein liver dysregulation. Conclusion: These data indicate that sitagliptin, compared with gliclazide, exhibits greater inhibition of pro-fibrotic and pro-inflammatory changes in an HFD-induced NAFLD model. Sitagliptin therapy, even in the absence of diabetes, may have specific benefits in diet-induced NAFLD.<\/jats:p>","DOI":"10.3390\/molecules27030727","type":"journal-article","created":{"date-parts":[[2022,1,23]],"date-time":"2022-01-23T20:34:40Z","timestamp":1642970080000},"page":"727","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Sitagliptin Is More Effective Than Gliclazide in Preventing \u00a0Pro-Fibrotic and Pro-Inflammatory Changes in a Rodent Model of Diet-Induced Non-Alcoholic Fatty Liver Disease"],"prefix":"10.3390","volume":"27","author":[{"given":"Jing","family":"Ren","sequence":"first","affiliation":[{"name":"Greg Brown Diabetes and Endocrinology Research Laboratories, Sydney Medical School (Central), Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Greg Brown Diabetes and Endocrinology Research Laboratories, Sydney Medical School (Central), Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Yee","sequence":"additional","affiliation":[{"name":"Greg Brown Diabetes and Endocrinology Research Laboratories, Sydney Medical School (Central), Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0528-2604","authenticated-orcid":false,"given":"Mark D.","family":"Gorrell","sequence":"additional","affiliation":[{"name":"Liver Enzymes in Metabolism and Inflammation Program, Centenary Institute, The University of Sydney, Newtown, NSW 2042, Australia"},{"name":"A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan V.","family":"McLennan","sequence":"additional","affiliation":[{"name":"Greg Brown Diabetes and Endocrinology Research Laboratories, Sydney Medical School (Central), Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia"},{"name":"Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia"},{"name":"New South Wales Health Pathology (Eastern), Camperdown, NSW 2050, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen M.","family":"Twigg","sequence":"additional","affiliation":[{"name":"Greg Brown Diabetes and Endocrinology Research Laboratories, Sydney Medical School (Central), Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia"},{"name":"Department of Endocrinology, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.jhep.2018.10.033","article-title":"Non-alcoholic fatty liver disease-A global public health perspective","volume":"70","author":"Younossi","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/liv.13299","article-title":"The epidemiology of non-alcoholic fatty liver disease","volume":"37","author":"Bellentani","year":"2017","journal-title":"Liver. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.1038\/516S8a","article-title":"Fatty liver disease: The liver labyrinth","volume":"516","author":"Morgan","year":"2014","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1210\/er.2012-1009","article-title":"Diabetes and nonalcoholic Fatty liver disease: A pathogenic duo","volume":"34","author":"Williams","year":"2013","journal-title":"Endocr. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1097\/TP.0000000000002355","article-title":"Waiting List Mortality and Transplant Rates for NASH Cirrhosis When Compared With Cryptogenic, Alcoholic, or AIH Cirrhosis","volume":"103","author":"Thuluvath","year":"2019","journal-title":"Transplantation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9330","DOI":"10.3748\/wjg.v20.i28.9330","article-title":"Non-alcoholic fatty liver disease and obesity: Biochemical, metabolic and clinical presentations","volume":"20","author":"Milic","year":"2014","journal-title":"World J. Gastroenterol. WJG"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/j.1872-034X.2007.00008.x","article-title":"Longitudinal analysis of murine steatohepatitis model induced by chronic exposure to high-fat diet","volume":"37","author":"Ito","year":"2007","journal-title":"Hepatol. Res. Off. J. Jpn. Soc. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1161\/ATVBAHA.107.147538","article-title":"Fatty liver: A novel component of the metabolic syndrome","volume":"28","author":"Kotronen","year":"2008","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_9","first-page":"60","article-title":"Incretins: A new treatment option for type 2 diabetes?","volume":"65","year":"2007","journal-title":"Neth. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1210\/jc.2003-031907","article-title":"Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes","volume":"89","author":"Ahren","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1177\/44.5.8627002","article-title":"Organ distribution of aminopeptidase A and dipeptidyl peptidase IV in normal mice","volume":"44","author":"Mentzel","year":"1996","journal-title":"J. Histochem. Cytochem. Off. J. Histochem. Soc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/S1665-2681(19)31905-2","article-title":"Dipeptidyl peptidase IV (DDP IV) in NASH patients","volume":"6","author":"Balaban","year":"2007","journal-title":"Ann. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1007\/s40618-020-01392-5","article-title":"Circulating dipeptidyl peptidase-4 is independently associated with the presence and severity of NAFLD\/NASH in individuals with and without obesity and metabolic disease","volume":"44","author":"Barchetta","year":"2021","journal-title":"J. Endocrinol. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1089\/met.2012.0128","article-title":"Effects of sitagliptin on nonalcoholic fatty liver disease in diet-induced obese rats","volume":"11","author":"Akaslan","year":"2013","journal-title":"Metab. Syndr. Relat. Disord."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"23","DOI":"10.2147\/HMER.S158053","article-title":"Effect of sitagliptin on hepatic histological activity and fibrosis of nonalcoholic steatohepatitis patients: A 1-year randomized control trial","volume":"10","author":"Alam","year":"2018","journal-title":"Hepat Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6895","DOI":"10.3892\/mmr.2015.4329","article-title":"Therapeutic effects of the dipeptidyl peptidase-IV inhibitor, sitagliptin, on non-alcoholic steatohepatitis in FLS-ob\/ob male mice","volume":"12","author":"Onoyama","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"385","DOI":"10.2165\/00003495-200565030-00005","article-title":"Oral antidiabetic agents: Current role in type 2 diabetes mellitus","volume":"65","author":"Krentz","year":"2005","journal-title":"Drugs"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1002\/eji.201141715","article-title":"F4\/80 and the related adhesion-GPCRs","volume":"41","author":"Gordon","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.livres.2018.09.004","article-title":"Autophagy in non-alcoholic fatty liver disease and alcoholic liver disease","volume":"2","author":"Khambu","year":"2018","journal-title":"Liver. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1042\/CS20030285","article-title":"Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients","volume":"106","author":"Videla","year":"2004","journal-title":"Clin. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1210\/en.2011-1502","article-title":"PPARgamma agonist improves neuronal insulin receptor function in hippocampus and brain mitochondria function in rats with insulin resistance induced by long term high-fat diets","volume":"153","author":"Pipatpiboon","year":"2012","journal-title":"Endocrinology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.2337\/dc07-0233","article-title":"Dipeptidyl peptidase-4 inhibitors: Clinical data and clinical implications","volume":"30","author":"Ahren","year":"2007","journal-title":"Diabetes Care"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/j.1463-1326.2011.01508.x","article-title":"Treating diabetes today with gliclazide MR: A matter of numbers","volume":"14","author":"Avogaro","year":"2012","journal-title":"Diabetes Obes. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1111\/j.1463-1326.2012.01568.x","article-title":"Sitagliptin promotes macrophage-to-faeces reverse cholesterol transport through reduced intestinal cholesterol absorption in obese insulin resistant CETP-apoB100 transgenic mice","volume":"14","author":"Briand","year":"2012","journal-title":"Diabetes Obes. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4888","DOI":"10.1210\/jc.2004-2460","article-title":"Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes","volume":"90","author":"Mari","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1042\/CS20100372","article-title":"Sitagliptin prevents the development of metabolic and hormonal disturbances, increased beta-cell apoptosis and liver steatosis induced by a fructose-rich diet in normal rats","volume":"120","author":"Maiztegui","year":"2011","journal-title":"Clin. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1016\/j.jhep.2006.02.011","article-title":"Systemic inflammation in nonalcoholic fatty liver disease is characterized by elevated levels of CCL2","volume":"44","author":"Haukeland","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8591","DOI":"10.3390\/ijms15058591","article-title":"Evolving concepts in the pathogenesis of NASH: Beyond steatosis and inflammation","volume":"15","author":"Peverill","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.gendis.2014.07.007","article-title":"The molecular pathogenic role of inflammatory stress in dysregulation of lipid homeostasis and hepatic steatosis","volume":"1","author":"Chen","year":"2014","journal-title":"Genes Dis."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Allam, M.M., Ibrahim, R.M., El Gazzar, W.B., and Said, M.A. (2021). Dipeptedyl peptidase-4 (DPP-4) inhibitor downregulates HMGB1\/TLR4\/NF-kappaB signaling pathway in a diabetic rat model of non-alcoholic fatty liver disease. Arch. Physiol. Biochem., 1\u20139.","DOI":"10.1080\/13813455.2021.1975758"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e14191","DOI":"10.14814\/phy2.14191","article-title":"Dipeptidyl peptidase-4 inhibitors and aerobic exercise synergistically protect against liver injury in ovariectomized rats","volume":"7","author":"Younan","year":"2019","journal-title":"Physiol. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.jhep.2010.09.032","article-title":"Glucagon-like peptide-1 reduces hepatic lipogenesis via activation of AMP-activated protein kinase","volume":"54","author":"Zvibel","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1002\/hep.23521","article-title":"Long-term mortality in nonalcoholic fatty liver disease: Is liver histology of any prognostic significance?","volume":"51","author":"Angulo","year":"2010","journal-title":"Hepatology"},{"key":"ref_34","first-page":"661","article-title":"Noninvasive Diagnosis of NASH and Liver Fibrosis Within the Spectrum of NAFLD","volume":"8","author":"Alkhouri","year":"2012","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1046\/j.1365-2362.2000.00698.x","article-title":"Elevated serum dipeptidyl peptidase IV (CD26, EC 3.4.14.5) activity in experimental liver cirrhosis","volume":"30","author":"Lakatos","year":"2000","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/S0168-8278(99)80211-6","article-title":"Elevated serum dipeptidyl peptidase IV (CD26, EC 3.4.14.5) activity in patients with primary biliary cirrhosis","volume":"30","author":"Lakatos","year":"1999","journal-title":"J. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/icb.2016.116","article-title":"The pro-fibrotic role of dipeptidyl peptidase 4 in carbon tetrachloride-induced experimental liver injury","volume":"95","author":"Wang","year":"2017","journal-title":"Immunol. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1042\/bj2620327","article-title":"Evidence for a role of dipeptidyl peptidase IV in fibronectin-mediated interactions of hepatocytes with extracellular matrix","volume":"262","author":"Piazza","year":"1989","journal-title":"Biochem. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"24600","DOI":"10.1074\/jbc.M303424200","article-title":"A novel consensus motif in fibronectin mediates dipeptidyl peptidase IV adhesion and metastasis","volume":"278","author":"Cheng","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"G759","DOI":"10.1152\/ajpgi.00078.2012","article-title":"When GLP-1 hits the liver: A novel approach for insulin resistance and NASH","volume":"302","author":"Kim","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1002\/hep.23569","article-title":"Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway","volume":"51","author":"Gupta","year":"2010","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1038\/sj.jid.5701104","article-title":"Inhibitors of dipeptidyl peptidase IV-like activity mediate antifibrotic effects in normal and keloid-derived skin fibroblasts","volume":"128","author":"Thielitz","year":"2008","journal-title":"J. Investig. Dermatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.atherosclerosis.2010.08.064","article-title":"DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes","volume":"213","author":"Ta","year":"2010","journal-title":"Atherosclerosis"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1016\/j.yexcr.2006.03.008","article-title":"Involvement of H- and N-Ras isoforms in transforming growth factor-beta1-induced proliferation and in collagen and fibronectin synthesis","volume":"312","author":"Santos","year":"2006","journal-title":"Exp. Cell Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e1179","DOI":"10.1038\/cddis.2014.162","article-title":"Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD","volume":"5","author":"Mayoral","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"14050","DOI":"10.1074\/jbc.M117.799304","article-title":"Function of inhibitor of Bruton\u2019s tyrosine kinase isoform alpha (IBTKalpha) in nonalcoholic steatohepatitis links autophagy and the unfolded protein response","volume":"292","author":"Willy","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1053\/j.gastro.2011.12.044","article-title":"Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues","volume":"142","author":"Rozenfeld","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.jhep.2010.10.039","article-title":"Diabetes is a progression factor for hepatic fibrosis in a high fat fed mouse obesity model of non-alcoholic steatohepatitis","volume":"55","author":"Lo","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"E410","DOI":"10.1152\/ajpendo.00463.2010","article-title":"Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice","volume":"300","author":"Dobrian","year":"2011","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"E475","DOI":"10.1152\/ajpendo.00025.2013","article-title":"One year of sitagliptin treatment protects against islet amyloid-associated beta-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice","volume":"305","author":"Subramanian","year":"2013","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_51","first-page":"98","article-title":"Hypoglycemic effects of a sesquiterpene glycoside isolated from leaves of loquat (Eriobotrya japonica (Thunb.) Lindl.)","volume":"15","author":"Chen","year":"2008","journal-title":"Phytomedicine Int. J. Phytother. Phytopharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1248\/bpb.29.455","article-title":"Anti-diabetic and hypolipidemic effects of aqueous-extract from the flower of Inula japonica in alloxan-induced diabetic mice","volume":"29","author":"Shan","year":"2006","journal-title":"Biol. Pharm. Bull."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/BF00280883","article-title":"Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man","volume":"28","author":"Matthews","year":"1985","journal-title":"Diabetologia"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s13353-013-0173-x","article-title":"Reference genes in real-time PCR","volume":"54","author":"Kozera","year":"2013","journal-title":"J. Appl. Genet."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/3\/727\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:06:01Z","timestamp":1760133961000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/3\/727"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,22]]},"references-count":54,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["molecules27030727"],"URL":"https:\/\/doi.org\/10.3390\/molecules27030727","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,22]]}}}