{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:31:25Z","timestamp":1791919885487,"version":"4.3.4"},"reference-count":55,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2017,5,15]],"date-time":"2017-05-15T00:00:00Z","timestamp":1494806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>There is growing evidence that chronic hyperglycemia leads to the formation of advanced glycation end products (AGEs) which exerts its effect via interaction with the receptor for advanced glycation end products (RAGE). AGE-RAGE activation results in oxidative stress and inflammation. It is well known that this mechanism is involved in the pathogenesis of cardiovascular disease in diabetes. Kaempferol, a dietary flavonoid, is known to possess antioxidant, anti-apoptotic, and anti-inflammatory activities. However, little is known about the effect of kaempferol on myocardial ischemia-reperfusion (IR) injury in diabetic rats. Diabetes was induced in male albino Wistar rats using streptozotocin (70 mg\/kg; i.p.), and rats with glucose level &gt;250 mg\/dL were considered as diabetic. Diabetic rats were treated with vehicle (2 mL\/kg; i.p.) and kaempferol (20 mg\/kg; i.p.) daily for a period of 28 days and on the 28th day, ischemia was produced by one-stage ligation of the left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After completion of surgery, rats were sacrificed and the heart tissue was processed for biochemical, morphological, and molecular studies. Kaempferol pretreatment significantly reduced hyperglycemia, maintained hemodynamic function, suppressed AGE-RAGE axis activation, normalized oxidative stress, and preserved morphological alterations. In addition, there was decreased level of inflammatory markers (tumor necrosis factor-\u03b1 (TNF-\u03b1), interleukin-6 (IL-6), and NF-\u03baB), inhibition of active c-Jun N-terminal kinase (JNK) and p38 proteins, and activation of Extracellular signal regulated kinase 1\/2 (ERK1\/2) a prosurvival kinase. Furthermore, it also attenuated apoptosis by reducing the expression of pro-apoptotic proteins (Bax and Caspase-3), Terminal deoxynucleotidyl  transferase dUTP nick end labeling (TUNEL) positive cells, and increasing the level of anti-apoptotic protein (Bcl-2). In conclusion, kaempferol attenuated myocardial ischemia-reperfusion injury in diabetic rats by reducing AGE-RAGE\/ mitogen activated protein kinase (MAPK) induced oxidative stress and inflammation.<\/jats:p>","DOI":"10.3390\/ijms18051001","type":"journal-article","created":{"date-parts":[[2017,5,15]],"date-time":"2017-05-15T12:16:12Z","timestamp":1494850572000},"page":"1001","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":95,"title":["Molecular Pathways Involved in the Amelioration of Myocardial Injury in Diabetic Rats by Kaempferol"],"prefix":"10.3390","volume":"18","author":[{"given":"Kapil","family":"Suchal","sequence":"first","affiliation":[{"name":"Cardiovascular Research Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma","family":"Malik","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sana","family":"Khan","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameer","family":"Goyal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, R.C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra 425405, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagriti","family":"Bhatia","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7801-2966","authenticated-orcid":false,"given":"Shreesh","family":"Ojha","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi 17666, UAE"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dharamvir","family":"Arya","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1056\/NEJM199807233390404","article-title":"Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction","volume":"339","author":"Haffner","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.ahj.2007.06.020","article-title":"Infarct size, ejection fraction, and mortality in diabetic patients with acute myocardial infarction treated with thrombolytic therapy","volume":"154","author":"Alegria","year":"2007","journal-title":"Am. Heart J."},{"key":"ref_3","first-page":"1","article-title":"Making sense of advanced glycation end products and their relevance to diabetic complications","volume":"17","author":"Fraser","year":"2005","journal-title":"Inter. Diabetes Monit."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/414813a","article-title":"Biochemistry and molecular cell biology of diabetic complications","volume":"414","author":"Brownlee","year":"2001","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1161\/01.RES.0000069362.52165.C9","article-title":"Getting better without AGE: New insights into the diabetic heart","volume":"92","author":"Kass","year":"2003","journal-title":"Circ. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1161\/01.RES.0000065620.39919.20","article-title":"A breaker of advanced glycation end products attenuates diabetes-induced myocardial structural changes","volume":"92","author":"Candido","year":"2003","journal-title":"Circ. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1161\/CIRCRESAHA.109.212217","article-title":"The RAGE axis: A fundamental mechanism signaling danger to the vulnerable vasculature","volume":"106","author":"Yan","year":"2010","journal-title":"Circ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.2337\/db07-0326","article-title":"RAGE and modulation of ischemic injury in the diabetic myocardium","volume":"57","author":"Bucciarelli","year":"2008","journal-title":"Diabetes"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2461","DOI":"10.2337\/db07-1808","article-title":"Receptor for advanced glycation end products (RAGE) deficiency attenuates the development of atherosclerosis in diabetes","volume":"57","author":"Watson","year":"2008","journal-title":"Diabetes"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"E323","DOI":"10.1152\/ajpendo.00024.2008","article-title":"Cardiac inflammation associated with a Western diet is mediated via activation of RAGE by AGEs","volume":"295","author":"Tikellis","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/S1357-4310(99)01544-0","article-title":"P38 MAPK signalling cascades in inflammatory disease","volume":"5","author":"Herlaar","year":"1999","journal-title":"Mol. Med. Today"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"716","DOI":"10.2337\/db11-0477","article-title":"Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy","volume":"61","author":"Rajesh","year":"2012","journal-title":"Diabetes"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1016\/j.foodchem.2007.04.038","article-title":"Antioxidant activity and phenolic compounds in 32 selected herbs","volume":"105","author":"Wojdyo","year":"2007","journal-title":"Food Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1080\/01635580802143836","article-title":"Dietary flavonoid sources in Australian adults","volume":"60","author":"Somerset","year":"2008","journal-title":"Nutr. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"298","DOI":"10.2174\/138955711795305335","article-title":"A review on the dietary flavonoid kaempferol","volume":"11","year":"2011","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.3109\/13880209.2014.982301","article-title":"Influence of kaempferol, a flavonoid compound, on membrane-bound ATPases in streptozotocin-induced diabetic rats","volume":"53","author":"Veeramani","year":"2015","journal-title":"Pharm. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"971","DOI":"10.3892\/ijmm.2013.1468","article-title":"Kaempferol inhibits IL-1\u03b2-induced proliferation of rheumatoid arthritis synovial fibroblasts and the production of COX-2, PGE2 and MMPs","volume":"32","author":"Yoon","year":"2013","journal-title":"Int. J. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.tox.2011.11.018","article-title":"Kaempferol protects against doxorubicin-induced cardiotoxicity in vivo and in vitro","volume":"292","author":"Xiao","year":"2012","journal-title":"Toxicology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"532984","DOI":"10.1155\/2015\/532984","article-title":"Small molecule kaempferol promotes insulin sensitivity and preserved pancreatic \u03b2-cell mass in middle-aged obese diabetic mice","volume":"2015","author":"Alkhalidy","year":"2015","journal-title":"J. Diabetes Res."},{"key":"ref_20","unstructured":"Centers for Disease Control and Prevention (2017, April 10). National diabetes fact sheet, 2011, Available online: http:\/\/www.diabetesincontrol.com\/wp-content\/uploads\/PDF\/ndep_diabetes_facts_2011.pdf."},{"key":"ref_21","unstructured":"Centers for Disease Control and Prevention (2017, April 10). National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014, Available online: https:\/\/www.cdc.gov\/diabetes\/pubs\/statsreport14\/national-diabetes-report-web.pdf."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.numecd.2010.01.008","article-title":"Cardiovascular risk in women with diabetes","volume":"20","author":"Rivellese","year":"2010","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1039\/c4fo00068d","article-title":"Kaempferol attenuates the glutamate-induced oxidative stress in mouse-derived hippocampal neuronal HT22 cells","volume":"5","author":"Yang","year":"2014","journal-title":"Food Funct."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1111\/j.1582-4934.2008.00547.x","article-title":"Advanced glycation endproduct (AGE) accumulation and AGE receptor (RAGE) up-regulation contribute to the onset of diabetic cardiomyopathy","volume":"13","author":"Ma","year":"2009","journal-title":"J. Cell. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1007\/s00125-010-1900-z","article-title":"Hyperglycaemia-induced pro-inflammatory responses by retinal M\u00fcller glia are regulated by the receptor for advanced glycation end-products (RAGE)","volume":"53","author":"Zong","year":"2010","journal-title":"Diabetologia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.2310\/JIM.0b013e318231db64","article-title":"Levels of soluble advanced glycation end product-receptors and other soluble serum markers as indicators of diabetic neuropathy in the foot","volume":"59","author":"Hamdy","year":"2011","journal-title":"J. Investig. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.ajpath.2012.09.016","article-title":"Glucagon-like peptide-1 receptor agonist inhibits asymmetric dimethylarginine generation in the kidney of streptozotocin-induced diabetic rats by blocking advanced glycation end product-induced protein arginine methyltranferase-1 expression","volume":"182","author":"Ojima","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.ejphar.2011.08.011","article-title":"Flavonol kaempferol improves chronic hyperglycemia-impaired pancreatic \u03b2-cell viability and insulin secretory function","volume":"670","author":"Zhang","year":"2011","journal-title":"Eur. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.intimp.2015.07.018","article-title":"Kaempferol alleviates insulin resistance via hepatic IKK\/NF-\u03baB signal in type 2 diabetic rats","volume":"28","author":"Luo","year":"2015","journal-title":"Int. Immunopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9889","DOI":"10.1016\/S0021-9258(17)36966-1","article-title":"Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors\/binding proteins","volume":"269","author":"Yan","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1681\/ASN.2008050514","article-title":"RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes","volume":"20","author":"Coughlan","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1016\/j.bbamcr.2010.12.008","article-title":"Mitochondrial oxidative stress triggers cell death in simulated ischemia-reperfusion","volume":"1813","author":"Loor","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.fct.2014.07.038","article-title":"The berry constituents quercetin, kaempferol, and pterostilbene synergistically attenuate reactive oxygen species: Involvement of the Nrf2-ARE signaling pathway","volume":"72","author":"Saw","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"481405","DOI":"10.1155\/2015\/481405","article-title":"Protective effects of kaempferol against myocardial ischemia\/reperfusion injury in isolated rat heart via antioxidant activity and inhibition of glycogen synthase kinase-3\u03b2","volume":"2015","author":"Zhou","year":"2015","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1002\/hep.20045","article-title":"Blockade of receptor for advanced glycation end product (RAGE) attenuates ischemia and reperfusion injury to the liver in mice","volume":"39","author":"Zeng","year":"2004","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3220","DOI":"10.18632\/oncotarget.1908","article-title":"RAGE mediates S100A4-induced cell motility via MAPK\/ERK and hypoxia signaling and is a prognostic biomarker for human colorectal cancer metastasis","volume":"5","author":"Dahlmann","year":"2014","journal-title":"Oncotarget"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/S0952-7915(96)80131-2","article-title":"Mitogen-activated protein kinase cascades and regulation of gene expression","volume":"8","author":"Su","year":"1996","journal-title":"Curr. Opin. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/0092-8674(91)90098-J","article-title":"ERKs: A family of protein-serine\/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF","volume":"65","author":"Boulton","year":"1991","journal-title":"Cell"},{"key":"ref_39","first-page":"325","article-title":"Pioglitazone attenuates myocardial ischemia-reperfusion injury via up-regulation of ERK and COX-2","volume":"6","author":"Wang","year":"2012","journal-title":"Biosci. Trends"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s11010-014-2213-1","article-title":"Urocortin-2 suppression of p38-MAPK signaling as an additional mechanism for ischemic cardioprotection","volume":"398","author":"Gao","year":"2015","journal-title":"Mol. Cell. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"24313","DOI":"10.1074\/jbc.271.40.24313","article-title":"Sounding the alarm: Protein kinase cascades activated by stress and inflammation","volume":"271","author":"Kyriakis","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"16657","DOI":"10.1074\/jbc.272.26.16657","article-title":"A novel mechanism of JNK1 activation. Nuclear translocation and activation of JNK1 during ischemia and reperfusion","volume":"272","author":"Mizukami","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.lfs.2014.11.014","article-title":"Luteolin inhibits ROS-activated MAPK pathway in myocardial ischemia\/reperfusion injury","volume":"122","author":"Yu","year":"2015","journal-title":"Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s12012-013-9238-7","article-title":"Preventive effect of total flavones of Choerospondias axillaries on ischemia\/reperfusion-induced myocardial infarction-related MAPK signaling pathway","volume":"14","author":"Li","year":"2014","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Shi, L., Yu, X., Yang, H., and Wu, X. (2013). Advanced glycation end products induce human corneal epithelial cells apoptosis through generation of reactive oxygen species and activation of JNK and p38 MAPK pathways. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066781"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ma, C., Zhang, Y., Li, Y.Q., Chen, C., Cai, W., and Zeng, Y.L. (2015). The role of PPAR\u03b3 in advanced glycation end products-induced inflammatory response in human chondrocytes. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0125776"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s11010-015-2396-0","article-title":"HMGB1 binding to receptor for advanced glycation end products enhances inflammatory responses of human bronchial epithelial cells by activating p38 MAPK and ERK1\/2","volume":"405","author":"Liang","year":"2015","journal-title":"Mol. Cell. Biochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1111\/j.1440-1797.2007.00796.x","article-title":"Rodent models of streptozotocin-induced diabetic nephropathy","volume":"12","author":"Tesch","year":"2007","journal-title":"Nephrology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/j.phymed.2016.07.015","article-title":"Kampeferol protects against oxidative stress and apoptotic damage in experimental model of isoproterenol-induced cardiac toxicity in rats","volume":"23","author":"Suchal","year":"2016","journal-title":"Phytomedicine"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7580731","DOI":"10.1155\/2016\/7580731","article-title":"Kaempferol attenuates myocardial ischemic injury via Inhibition of MAPK signaling pathway in experimental model of myocardial ischemia-reperfusion injury","volume":"2016","author":"Suchal","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0003-2697(79)90738-3","article-title":"Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction","volume":"95","author":"Ohkawa","year":"1979","journal-title":"Anal. Biochem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/0304-4165(79)90289-7","article-title":"Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver","volume":"582","author":"Moron","year":"1979","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/j.1432-1033.1974.tb03714.x","article-title":"Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase","volume":"47","author":"Marklund","year":"1974","journal-title":"Eur. J. Biochem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0076-6879(84)05016-3","article-title":"Catalase in vitro","volume":"105","author":"Aebi","year":"1984","journal-title":"Methods Enzymol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/5\/1001\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:35:51Z","timestamp":1760207751000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/5\/1001"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,15]]},"references-count":55,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2017,5]]}},"alternative-id":["ijms18051001"],"URL":"https:\/\/doi.org\/10.3390\/ijms18051001","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,15]]}}}