{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T01:30:12Z","timestamp":1792546212235,"version":"4.5.0"},"reference-count":229,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T00:00:00Z","timestamp":1668729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish MCIN through the Agencia Estatal de Investigaci\u00f3n (AEI)","award":["PID2019-107009RB-100"],"award-info":[{"award-number":["PID2019-107009RB-100"]}]},{"name":"Spanish MCIN through the Agencia Estatal de Investigaci\u00f3n (AEI)","award":["COOPB20586"],"award-info":[{"award-number":["COOPB20586"]}]},{"DOI":"10.13039\/501100003339","name":"CSIC i-COOP program","doi-asserted-by":"publisher","award":["PID2019-107009RB-100"],"award-info":[{"award-number":["PID2019-107009RB-100"]}],"id":[{"id":"10.13039\/501100003339","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003339","name":"CSIC i-COOP program","doi-asserted-by":"publisher","award":["COOPB20586"],"award-info":[{"award-number":["COOPB20586"]}],"id":[{"id":"10.13039\/501100003339","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Despite the health benefits associated with the ingestion of the bioactive compounds in cocoa, the high concentrations of polyphenols and methylxanthines in the raw cocoa beans negatively influence the taste, confer the astringency and bitterness, and affect the stability and digestibility of the cocoa products. It is, therefore, necessary to process cocoa beans to develop the characteristic color, taste, and flavor, and reduce the astringency and bitterness, which are desirable in cocoa products. Processing, however, affects the composition and quantities of the bioactive compounds, resulting in the modification of the health-promoting properties of cocoa beans and chocolate. In this advanced review, we sought to better understand the effect of cocoa\u2019s transformational process into chocolate on polyphenols and methylxanthine and the mechanism of action of the original flavanols and methylxanthines. More data on the cocoa processing effect on cocoa bioactives are still needed for better understanding the effect of each processing step on the final polyphenolic and methylxanthine composition of chocolate and other cocoa products. Regarding the mechanisms of action, theobromine acts through the modulation of the fatty acid metabolism, mitochondrial function, and energy metabolism pathways, while flavanols mainly act though the protein kinases and antioxidant pathways. Both flavanols and theobromine seem to be involved in the nitric oxide and neurotrophin regulation.<\/jats:p>","DOI":"10.3390\/ijms232214365","type":"journal-article","created":{"date-parts":[[2022,11,21]],"date-time":"2022-11-21T02:52:21Z","timestamp":1668999141000},"page":"14365","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":96,"title":["From Cocoa to Chocolate: Effect of Processing on Flavanols and Methylxanthines and Their Mechanisms of Action"],"prefix":"10.3390","volume":"23","author":[{"given":"Luis","family":"Goya","sequence":"first","affiliation":[{"name":"Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), Jose Antonio Novais 10, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6575-5362","authenticated-orcid":false,"given":"John Edem","family":"Kongor","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), Jose Antonio Novais 10, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8546-8507","authenticated-orcid":false,"given":"Sonia","family":"de Pascual-Teresa","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), Jose Antonio Novais 10, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1080\/10408398.2020.1819769","article-title":"Traceability, authenticity and sustainability of cocoa and chocolate products: A challenge for the chocolate industry","volume":"62","author":"Perez","year":"2022","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"111629","DOI":"10.1016\/j.lwt.2021.111629","article-title":"Colour, fatty acids, bioactive compounds, and total antioxidant capacity in commercial cocoa beans (Theobroma cacao L.)","volume":"147","year":"2021","journal-title":"LWT Food Sci. Technol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1007\/s13197-020-04706-w","article-title":"Evaluation of the content of bioactive compounds in cocoa beans during the fermentation process","volume":"58","author":"Melo","year":"2021","journal-title":"J. Food Sci. Technol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1016\/j.crfs.2022.10.017","article-title":"Dark chocolate: An overview of its biological activity, processing, and fortification approaches","volume":"5","author":"Samanta","year":"2022","journal-title":"Curr. Res. Food Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12263-010-0185-7","article-title":"Chocolate: (un)Healthy source of polyphenols?","volume":"6","author":"Rimbach","year":"2011","journal-title":"Genes Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.foodres.2016.01.012","article-title":"Factors influencing quality variation in cocoa (Theobroma cacao) bean flavour profile\u2014A review","volume":"82","author":"Kongor","year":"2016","journal-title":"Food Res. Int."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.njas.2012.06.009","article-title":"Incentives for cocoa bean production in Ghana: Does quality matter?","volume":"60\u201363","author":"Quarmine","year":"2012","journal-title":"NJAS Wagening J. Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1080\/10641955.2018.1446977","article-title":"Changes in endothelial function, arterial stiffness and blood pressure in pregnant women after consumption of high-flavanol and high-theobromine chocolate: A double blind randomized clinical trial","volume":"37","author":"Babar","year":"2018","journal-title":"Hypertens. Pregnancy"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.bbrc.2021.07.051","article-title":"Neuroprotective effects of theobromine in transient global cerebral ischemia-reperfusion rat model","volume":"571","author":"Gupta","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1787","DOI":"10.1007\/s11011-022-00995-6","article-title":"Neuroprotective effects of theobromine in permanent bilateral common carotid artery occlusion rat model of cerebral hypoperfusion","volume":"37","author":"Kumar","year":"2022","journal-title":"Metab. Brain Dis."},{"key":"ref_11","first-page":"449","article-title":"Association between dietary theobromine and cognitive function in a representative American population: A cross-sectional study","volume":"3","author":"Gao","year":"2022","journal-title":"J. Prev. Alzheimer Dis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Cichon, N., Saluk-Bijak, J., Gorniak, L., Przyslo, L., and Bijak, M. (2020). Flavonoids as a natural enhancer of neuroplasticity. An overview of the mechanism of neurorestorative action. Antioxidants, 9.","DOI":"10.3390\/antiox9111035"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.2174\/0929867328666211129123459","article-title":"Polyphenols\u2019 effect on cerebrovascular health","volume":"29","author":"Goya","year":"2021","journal-title":"Curr. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Gasmi, A., Mujawdiya, P.K., Noor, S., Lysiuk, R., Darmohray, R., Piscopo, S., Lenchyk, L., Antonyak, H., Dehtiarova, K., and Shanaida, M. (2022). Polyphenols in Metabolic Diseases. Molecules, 27.","DOI":"10.3390\/molecules27196280"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Afoakwa, E.O. (2016). Chocolate Science and Technology, Wiley-Blackwell. [2nd ed.].","DOI":"10.1002\/9781118913758"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.3389\/fimmu.2017.01207","article-title":"From cocoa to chocolate: The impact of processing on in vitro antioxidant activity and the effects of chocolate on antioxidant markers in vivo","volume":"8","author":"Sacchetti","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.foodres.2018.07.017","article-title":"The effect on bioactive components and characteristics of chocolate by functionalization with raw cocoa beans","volume":"113","author":"Budryn","year":"2018","journal-title":"Food Res. Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1080\/10408398.2019.1581726","article-title":"An overview of the physical and biochemical transformation of cocoa seeds to beans and to chocolate: Flavor formation","volume":"60","author":"Cortina","year":"2020","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"108550","DOI":"10.1016\/j.foodres.2019.108550","article-title":"Tuning the aroma profiles of FORASTERO cocoa liquors by varying pod storage and bean roasting temperature","volume":"125","author":"Hinneh","year":"2019","journal-title":"Food Res. Int."},{"key":"ref_20","unstructured":"Hii, C.L., and Bor\u00e9m, F.M. (2020). Flavor development during cocoa roasting. Drying and Roasting of Cocoa and Coffee, CRC Press\u2014Taylor & Francis Group. [1st ed.]."},{"key":"ref_21","first-page":"1","article-title":"Chemical and biological properties of cocoa beans affected by processing: A review","volume":"62","author":"Febrianto","year":"2021","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8658","DOI":"10.1021\/acs.jafc.0c02909","article-title":"Changes in the composition of methylxanthines, polyphenols, and volatiles and sensory profiles of cocoa beans from the Sul 1 genotype affected by fermentation","volume":"68","author":"Febrianto","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"106887","DOI":"10.1016\/j.foodcont.2019.106887","article-title":"Determination of theobromine and caffeine in fermented and unfermented Amazonian cocoa (Theobroma cacao L.) beans using square wave voltammetry after chromatographic separation","volume":"108","author":"Lopes","year":"2020","journal-title":"Food Control"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1021\/jf0728754","article-title":"Flavanol and flavonol contents of cocoa powder products: Influence of the manufacturing process","volume":"56","author":"Monagas","year":"2008","journal-title":"J. Agric. Food Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Eker, M.E., Aaby, K., Budic-Leto, I., Rimac Brn\u010di\u0107, S., El, S.N., Karakaya, S., Simsek, S., Manach, C., Wiczkowski, W., and de Pascual-Teresa, S. (2020). A review of factors affecting anthocyanin bioavailability: Possible implications for the inter-individual variability. Foods, 9.","DOI":"10.3390\/foods9010002"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Afoakwa, E. (2014). Cocoa Production and Processing Technology, CRC Press. [1st ed.].","DOI":"10.1201\/b16546"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.foodchem.2015.02.084","article-title":"Fast and neat\u2014Determination of biochemical quality parameters in cocoa using near-infrared spectroscopy","volume":"181","author":"Engel","year":"2015","journal-title":"Food Chem."},{"key":"ref_28","unstructured":"Dand, R. (2010). The International Cocoa Trade, Woodhead Publishing. [3rd ed.]."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Schwan, R.F., and Fleet, G.H. (2015). Methods of cocoa fermentation and drying. Cocoa and Coffee Fermentations, CRC Press\u2014Taylor & Francis Group. [1st ed.].","DOI":"10.1201\/b17536"},{"key":"ref_30","first-page":"427","article-title":"Profiles of phenolic compounds and purine alkaloids during the development of seeds of Theobroma cacao cv. Trinitario","volume":"61","author":"Borges","year":"2012","journal-title":"J. Agric. Food Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9501","DOI":"10.1021\/acs.jafc.9b03448","article-title":"Diversity in composition of bioactive compounds among 26 cocoa genotypes","volume":"67","author":"Febrianto","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1007\/s11130-018-0700-3","article-title":"Effects of maturity at harvest and fermentation conditions on bioactive compounds of cocoa beans","volume":"74","author":"Dang","year":"2019","journal-title":"Plant Foods Hum. Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1078\/0176-1617-01253","article-title":"Biosynthesis, accumulation and degradation of theobromine in developing Theobroma cacao fruits","volume":"161","author":"Zheng","year":"2004","journal-title":"J. Plant Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.indcrop.2006.03.013","article-title":"Effect of pulp pre-conditioning on the content of polyphenols in cocoa beans (Theobroma cacao) during fermentation","volume":"24","author":"Nazaruddin","year":"2006","journal-title":"Ind. Crops Prod."},{"key":"ref_35","first-page":"1843","article-title":"Changes in nib acidification and biochemical composition during fermentation of pulp pre-conditioned cocoa (Theobroma cacao) beans","volume":"20","author":"Afoakwa","year":"2013","journal-title":"Int. Food Res. J."},{"key":"ref_36","first-page":"455","article-title":"Colour and antioxidant properties of cocoa beans from pods storage and fermentation using shallow box","volume":"3","author":"Sulaiman","year":"2017","journal-title":"Int. J. Sci. Technol."},{"key":"ref_37","first-page":"66","article-title":"Effects of fermentation intensity on polyphenols and antioxidant capacity of cocoa beans","volume":"5","author":"Aikpokpodion","year":"2010","journal-title":"Int. J. Sustain. Crop Prod."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1111\/jfq.12070","article-title":"Effect of fermentation and roasting on the phenolic concentration and antioxidant activity of cocoa from Nicaragua","volume":"37","author":"Suazo","year":"2014","journal-title":"J. Food Qual."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9948","DOI":"10.1021\/acs.jafc.5b01062","article-title":"Effect of fermentation and drying on cocoa polyphenols","volume":"63","author":"Albertini","year":"2015","journal-title":"J. Agric. Food Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1080\/10408398.2012.686934","article-title":"The content of polyphenolic compounds in cocoa beans (Theobroma cacao L.), depending on variety, growing region, and processing operations: A review","volume":"55","author":"Oracz","year":"2015","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.foodchem.2017.08.018","article-title":"Bioactive compounds in Mexican genotypes of cocoa cotyledon and husk","volume":"240","year":"2018","journal-title":"Food Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.1007\/s00217-019-03333-w","article-title":"Changes in the composition and content of polyphenols in chocolate resulting from pre-treatment method of cocoa beans and technological process","volume":"245","author":"Derewiaka","year":"2019","journal-title":"Eur. Food Res. Technol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1002\/jsfa.3349","article-title":"Fermentation of cocoa beans: Influence of microbial activities and polyphenol concentrations on the flavour of chocolate","volume":"88","author":"Camu","year":"2008","journal-title":"J. Sci. Food Agric."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"355","DOI":"10.17268\/sci.agropecu.2016.04.01","article-title":"Methylxanthine and catechin content of fresh and fermented cocoa beans, dried cocoa beans, and cocoa liquor","volume":"7","author":"Camasca","year":"2016","journal-title":"Sci. Agropecu."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e07738","DOI":"10.1016\/j.heliyon.2021.e07738","article-title":"Traceability of polyphenols in cocoa during the postharvest and industrialization processes and their biological antioxidant potential","volume":"7","author":"Gil","year":"2021","journal-title":"Heliyon"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/1752-153X-5-53","article-title":"Impact of fermentation, drying, roasting and Dutch processing on flavan-3-ol stereochemistry in cacao beans and cocoa ingredients","volume":"5","author":"Hurst","year":"2011","journal-title":"Chem. Cent. J."},{"key":"ref_47","unstructured":"Preedy, V. (2015). Cocoa processing and impact on composition. Processing and Impact on Active Components in Food, Academic Press."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/1541-4337.12180","article-title":"Flavor chemistry of cocoa and cocoa products\u2014An overview","volume":"15","author":"Aprotosoaie","year":"2016","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.foodres.2016.03.026","article-title":"The influence of the roasting process conditions on the polyphenol content in cocoa beans, nibs and chocolates","volume":"89","author":"Krysiak","year":"2016","journal-title":"Food Res. Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.foodchem.2018.02.036","article-title":"Impact of roasting on the flavan-3-ol composition, sensory-related chemistry, and in vitro pancreatic lipase inhibitory activity of cocoa beans","volume":"255","author":"Stanley","year":"2018","journal-title":"Food Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00217-018-3144-y","article-title":"Effect of roasting parameters on the physicochemical characteristics of high-molecular-weight Maillard reaction products isolated from cocoa beans of different Theobroma cacao L. groups","volume":"245","author":"Oracz","year":"2019","journal-title":"Eur. Food Res. Technol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Bari\u0161i\u0107, V., Kopjar, M., Jozinovi\u0107, A., Flanjak, I., A\u010dkar, \u0110., Mili\u010devi\u0107, B., \u0160ubari\u0107, D., Joki\u0107, S., and Babi\u0107, J. (2019). The chemistry behind chocolate production. Molecules, 24.","DOI":"10.3390\/molecules24173163"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jfca.2011.04.010","article-title":"The effect of alkalization on the bioactive and flavor related components in commercial cocoa powder","volume":"25","author":"Li","year":"2012","journal-title":"J. Food Compos. Anal."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1111\/1541-4337.12581","article-title":"Changes in cocoa properties induced by the alkalization process: A review","volume":"19","year":"2020","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_55","first-page":"297","article-title":"Effects of alkali concentration and conching temperature on antioxidant activity and physical properties of chocolate","volume":"15","author":"Sulistyowati","year":"2008","journal-title":"Int. Food Res. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1080\/10408390701719272","article-title":"Flavor formation and character in cocoa and chocolate: A critical review","volume":"48","author":"Afoakwa","year":"2008","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.foodres.2014.04.009","article-title":"Effect of different conching processes on procyanidins content and antioxidant properties of chocolate","volume":"63","author":"Martuscelli","year":"2014","journal-title":"Food Res. Int."},{"key":"ref_58","first-page":"606","article-title":"Development and evaluation of a laboratory-scale conch for chocolate production","volume":"44","author":"Brandelli","year":"2009","journal-title":"Int. J. Food Sci. Technol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1007\/s13197-015-2036-4","article-title":"Variation of total aroma and polyphenol content of dark chocolate during three phase of conching","volume":"53","author":"Albak","year":"2016","journal-title":"J. Food Sci. Technol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.lwt.2015.10.047","article-title":"Influence of processing conditions on procyanidin profiles and antioxidant capacity of chocolates: Optimization of dark chocolate manufacturing by response surface methodology","volume":"66","author":"Berktas","year":"2016","journal-title":"LWT Food Sci. Technol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/jam.13045","article-title":"The cocoa bean fermentation process: From ecosystem analysis to starter culture development","volume":"121","author":"Weckx","year":"2016","journal-title":"J. Appl. Microbiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S0963-9969(00)00068-5","article-title":"Review on polyphenols in Theobroma cacao: Changes in composition during the manufacture of chocolate and methodology for identification and quantification","volume":"33","author":"Wollgast","year":"2000","journal-title":"Food Res. Int."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Afoakwa, E.O. (2010). Chocolate Science and Technology, Wiley-Blackwell Publishers. [1st ed.].","DOI":"10.1002\/9781444319880"},{"key":"ref_64","unstructured":"Doyle, M.P., and Beuchat, R.L. (2013). Cocoa and coffee. Food Microbiology: Fundamentals and Frontiers, ASM Press. [4th ed.]."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Prabhakaran Nair, K.P. (2010). Cocoa (Theobroma cacao L.). The Agronomy and Economy of Important Tree Crops of the Developing World, Elsevier. Chapter 5.","DOI":"10.1016\/B978-0-12-384677-8.00005-9"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"8830127","DOI":"10.1155\/2020\/8830127","article-title":"A review of cocoa drying technologies and the effect on bean quality parameters","volume":"2020","author":"Dzelagha","year":"2020","journal-title":"Int. J. Food Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1186\/s42269-021-00634-7","article-title":"Effects of fermentation and drying durations on the quality of cocoa (Theobroma cacao L.) beans during the rainy season in the Juaboso District of the Western-North Region, Ghana","volume":"45","author":"Ackah","year":"2021","journal-title":"Bull. Natl. Res. Cent."},{"key":"ref_68","first-page":"184","article-title":"Effect of drying methods on the chemical quality traits of cocoa raw material","volume":"2","author":"Zahouli","year":"2010","journal-title":"Adv. J. Food Sci. Technol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.foodcont.2012.05.054","article-title":"Optimizing chocolate production through traceability: A review of the influence of farming practices on cocoa bean quality","volume":"29","author":"Saltini","year":"2013","journal-title":"Food Control"},{"key":"ref_70","unstructured":"Bharath, S., and Bowen-O\u2019Connor, C. (2008). Assessing Drying Rates of Cacao Beans Using Small Samples, Cocoa Research Unit. Available online: https:\/\/www.worldcocoafoundation.org\/wp-content\/uploads\/files_mf\/bharath2008.pdf."},{"key":"ref_71","unstructured":"Beckett, S.T. (2009). Production and quality standards of cocoa mass, cocoa butter and cocoa powder. Industrial Chocolate Manufacture and Use, John Wiley & Sons. [4th ed.]."},{"key":"ref_72","first-page":"31","article-title":"Alkalizing cocoa and chocolate","volume":"95","author":"Moser","year":"2015","journal-title":"Manuf. Confect."},{"key":"ref_73","first-page":"99","article-title":"Developments in cocoa bean processing","volume":"89","author":"Sommer","year":"2009","journal-title":"Manuf. Confect."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"132082","DOI":"10.1016\/j.foodchem.2022.132082","article-title":"The effect of cocoa alkalization on the non-volatile and volatile mood-enhancing compounds","volume":"381","author":"Sioriki","year":"2022","journal-title":"Food Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"108598","DOI":"10.1016\/j.lwt.2019.108598","article-title":"Changes in methylxanthines and flavanols during cocoa powder processing and their quantification by near-infrared spectroscopy","volume":"117","author":"Barat","year":"2020","journal-title":"LWT Food Sci. Technol."},{"key":"ref_76","unstructured":"Dyer, B. (2003, January 28\u201330). Alkalized cocoa powders. Proceedings of the 57th PMCA Production Conference, Hershey, PA, USA."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Beckett, S.T., Fowler, M.S., and Ziegler, G.R. (2017). Flavour development in cocoa and chocolate. Industrial Chocolate Manufacture and Use, Wiley-Blackwell. [5th ed.].","DOI":"10.1002\/9781118923597"},{"key":"ref_78","unstructured":"Hii, C.L., and Bor\u00e9m, F.M. (2020). Roasting equipment for cocoa processing. Drying and Roasting of Cocoa and Coffee, CRC Press\u2014Taylor & Francis Group."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1111\/jfq.12009","article-title":"Factors affecting the colour of roasted cocoa bean","volume":"36","author":"Krysiak","year":"2013","journal-title":"J. Food Qual."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Beckett, S.T., Fowler, M.S., and Ziegler, G.R. (2017). Traditional chocolate making. Industrial Chocolate Manufacture and Use, Wiley-Blackwell. [5th ed.].","DOI":"10.1002\/9781118923597"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3656","DOI":"10.1016\/j.foodchem.2013.06.049","article-title":"Temperature influences epimerization and composition of flavanol monomers, dimers and trimers during cocoa bean roasting","volume":"141","author":"Kothe","year":"2013","journal-title":"Food Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.foodchem.2014.11.019","article-title":"Flavanols, proanthocyanidins and antioxidant activity changes during cocoa (Theobroma cacao L.) roasting as affected by temperature and time of processing","volume":"174","author":"Ioannone","year":"2015","journal-title":"Food Chem."},{"key":"ref_83","first-page":"371","article-title":"Safety of food and beverages: Coffee, tea and herbals, cocoa and derived products","volume":"Volume 3","author":"Motarjemi","year":"2014","journal-title":"Encyclopedia of Food Safety"},{"key":"ref_84","unstructured":"Caballero, B. (2003). Cocoa | Production, products, and use. Encyclopedia of Food Sciences and Nutrition, Academic Press. [2nd ed.]."},{"key":"ref_85","first-page":"95","article-title":"The nib-grinding process","volume":"89","author":"Velthuis","year":"2009","journal-title":"Manuf. Confect."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"012050","DOI":"10.1088\/1755-1315\/355\/1\/012050","article-title":"Effect of extraction time and pressing temperature on characteristic of cocoa powder quality","volume":"355","author":"Anoraga","year":"2019","journal-title":"IOP Conf. Ser. Earth Environ. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1111\/1541-4337.12301","article-title":"State-of-the-art chocolate manufacture: A review","volume":"16","year":"2017","journal-title":"Compr. Rev. Food Sci. Food Saf."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1111\/j.1745-4549.2011.00602.x","article-title":"Effect of fermentation method roasting and conching conditions on the aroma volatiles of dark chocolate","volume":"36","author":"Owusu","year":"2012","journal-title":"J. Food Process. Preserv."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.tifs.2019.07.047","article-title":"Chocolate quality and conching","volume":"91","author":"Toker","year":"2019","journal-title":"Trends Food Sci. Technol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Urba\u0144ska, B., Kowalska, H., Szulc, K., Ziarno, M., Pochitskaya, I., and Kowalska, J. (2021). Comparison of the effects of conching parameters on the contents of three dominant flavan3-ols, rheological properties and sensory quality in chocolate milk mass based on liquor from unroasted cocoa beans. Molecules, 26.","DOI":"10.3390\/molecules26092502"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/s00217-012-1873-x","article-title":"Influence of conching temperature and some bulk sweeteners on physical and rheological properties of prebiotic milk chocolate including containing inulin","volume":"23","author":"Konar","year":"2013","journal-title":"Eur. Food Res. Technol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1007\/s13197-011-0420-2","article-title":"Relationship of sensory and instrumental aroma measurements of dark chocolate as influenced by fermentation method, roasting and conching conditions","volume":"50","author":"Owusu","year":"2013","journal-title":"J. Food Sci. Technol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.cofs.2018.07.002","article-title":"Current context on chocolate flavor development\u2014A review","volume":"21","author":"Engeseth","year":"2018","journal-title":"Curr. Opin. Food Sci."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Tiefenbacher, K.F. (2017). Adjuncts\u2014Filling creams, inclusions, cacao and chocolate. Wafer and Waffle, Academic Press. Chapter 5.","DOI":"10.1016\/B978-0-12-809438-9.00005-3"},{"key":"ref_95","first-page":"185","article-title":"Cocoa: Production, chemistry, and use","volume":"Volume 5","author":"Caballero","year":"2016","journal-title":"The Encyclopedia of Food and Health"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1002\/mnfr.201500961","article-title":"Anti-diabetic actions of cocoa flavonoids","volume":"60","author":"Goya","year":"2016","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2020","DOI":"10.1021\/jf062556x","article-title":"Molecular mechanisms of (\u2212)-epicatechin and chlorogenic acid on the regulation of the apoptotic and survival\/proliferation pathways in a human hepatoma cell line (HepG2)","volume":"55","author":"Goya","year":"2007","journal-title":"J. Agric. Food Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.jnutbio.2007.12.006","article-title":"Time-course regulation of survival pathways by epicathechin on HepG2","volume":"20","author":"Goya","year":"2009","journal-title":"J. Nutr. Biochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.jnutbio.2008.10.009","article-title":"Cocoa flavonoids up-regulate antioxidant enzymes activity via ERK1\/2 pathway to protect against oxidative stress-induced apoptosis in HepG2 cells","volume":"21","author":"Ramos","year":"2010","journal-title":"J. Nutr. Biochem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1017\/S0007114509991747","article-title":"Epicatechin induces NF-\u03baB, activator protein-1 (AP-1) and nuclear transcription factor erythroid 2p45-related (Nrf2) via phosphatidylinositol-3-kiinase\/protein kinase B (PI3K\/AKT) and extracellular regulated kinase (ERK) signalling in HepG2 cells","volume":"103","author":"Haegeman","year":"2010","journal-title":"Brit. J. Nutr."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1016\/j.jnutbio.2010.10.005","article-title":"Procyanidin B2 and a cocoa polyphenolic extract inhibit acrylamide-induced apoptosis in human Caco-2 cells by preventing oxidative stress and activation of JNK pathway","volume":"22","author":"Ramos","year":"2011","journal-title":"J. Nutr. Biochem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1007\/s00394-011-0269-1","article-title":"Procyanidin B2 induces Nrf2 translocation and glutathione-S-transferase P1 expression and via ERKs and p38-MAPK pathways and protect human colonic cells against oxidative stress","volume":"51","author":"Ramos","year":"2012","journal-title":"Eur. J. Nutr."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1002\/mnfr.201200500","article-title":"Cocoa flavonoids improve insulin signalling and repress glucose production via AKT and AMPK in HepG2 cells","volume":"57","author":"Bravo","year":"2013","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1002\/mnfr.201400492","article-title":"Cocoa flavonoids protect hepatic cells against high glucose-induced oxidative stress: Relevance of MAPKs","volume":"59","author":"Goya","year":"2015","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.fct.2014.01.044","article-title":"Microbial phenolic metabolites improve glucose-stimulated insulin secretion and protect pancreatic beta cells against oxidative stress via ERKs and PKC pathways","volume":"66","author":"Ramos","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jff.2018.04.051","article-title":"(\u2212)-Epicatechin and the colonic metabolite 3,4-dihydroxyphenylacetic acid protect renal proximal tubular cell against high glucose-induced oxidative stress by modulating NOX-4\/SIRT-1 signalling","volume":"46","author":"Goya","year":"2018","journal-title":"J. Funct. Foods"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1080\/10408398.2020.1723057","article-title":"Advances in physiological functions and mechanisms of (\u2212)-epicatechin","volume":"61","author":"Zhihao","year":"2021","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"851","DOI":"10.2147\/JIR.S349981","article-title":"Anti-Inflammatory Effects of Camellia fascicularis Polyphenols via Attenuation of NF-\u03baB and MAPK Pathways in LPS-Induced THP-1 Macrophages","volume":"15","author":"Gao","year":"2022","journal-title":"J. Inflamm. Res."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Kim, J.K., Yang, H.J., and Go, Y. (2022). Quercus acuta Thunb. Suppresses LPS-Induced Neuroinflammation in BV2 Microglial Cells via Regulating MAPK\/NF-\u03baB and Nrf2\/HO-1 Pathway. Antioxidants, 11.","DOI":"10.3390\/antiox11101851"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"114897","DOI":"10.1016\/j.jep.2021.114897","article-title":"Polyphenols extracted from Enteromorpha clathrata alleviates inflammation in lipopolysaccharide-induced RAW 264.7 cells by inhibiting the MAPKs\/NF-\u03baB signaling pathways","volume":"286","author":"Huang","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Khan, A., Khan, S.U., Khan, A., Shal, B., Rehman, S.U., Rehman, S.U., Htar, T.T., Khan, S., Anwar, S., and Alafnan, A. (2022). Anti-inflammatory and anti-rheumatic potential of selective plant compounds by targeting TLR-4\/AP-1 signaling: A comprehensive molecular docking and simulation approaches. Molecules, 27.","DOI":"10.3390\/molecules27134319"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1762","DOI":"10.1080\/13880209.2022.2101672","article-title":"Small ubiquitin-related modifier (SUMO)ylation of SIRT1 mediates (\u2212)-epicatechin inhibited- differentiation of cardiac fibroblasts into myofibroblasts","volume":"60","author":"Luo","year":"2022","journal-title":"Pharm. Biol."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Behl, T., Upadhyay, T., Singh, S., Chigurupati, S., Alsubayiel, A.M., Mani, V., Vargas-De-La-Cruz, C., Uivarosan, D., Bustea, C., and Sava, C. (2021). Polyphenols targeting MAPK mediated oxidative stress and inflammation in rheumatoid arthritis. Molecules, 26.","DOI":"10.3390\/molecules26216570"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"710304","DOI":"10.3389\/fphar.2021.710304","article-title":"Polyphenols as antitumor agents targeting key players in cancer-driving signaling pathways","volume":"12","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"106398","DOI":"10.1016\/j.phrs.2022.106398","article-title":"A renewed concept on the MAPK signaling pathway in cancers: Polyphenols as a choice of therapeutics","volume":"184","author":"Anjum","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"5372","DOI":"10.1080\/10408398.2021.1924613","article-title":"Exploring the role of polyphenols in rheumatoid arthritis","volume":"62","author":"Behl","year":"2022","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1007\/s12094-021-02709-3","article-title":"Inhibitory effect of polyphenols (phenolic acids, lignans and stilbenes) on cancer by regulating signal transduction pathways: A review","volume":"24","author":"Hazafa","year":"2022","journal-title":"Clin. Transl. Oncol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"9208","DOI":"10.1039\/D2FO01663J","article-title":"Potential roles and molecular mechanisms of phytochemicals against cancer","volume":"13","author":"Zheng","year":"2022","journal-title":"Food Funct."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Bernatoniene, J., and Kopustinskiene, D.M. (2018). The role of catechins in cellular responses to oxidative stress. Molecules, 23.","DOI":"10.3390\/molecules23040965"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Ruiz-Iglesias, P., Massot-Cladera, M., Rodr\u00edguez-Lagunas, M.J., Franch, A., Camps-Bossacoma, M., P\u00e9rez-Cano, F.J., and Castell, M. (2022). Protective effect of a cocoa-enriched diet on oxidative stress induced by intensive acute exercise in rats. Antioxidants, 11.","DOI":"10.3390\/antiox11040753"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.2174\/0929867326666190517113533","article-title":"The effects of dietary supplements that overactivate the Nrf2\/ARE system","volume":"27","author":"Smith","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.1111\/j.1471-4159.2008.05542.x","article-title":"Dietary flavonoid (\u2212) epicatechin stimulates phosphatidylinositol 3-kinase-dependent anti-oxidant response element activity and up-regulates glutathione in cortical astrocytes","volume":"106","author":"Bahia","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.jnutbio.2012.01.010","article-title":"Catechin protects against ketoprofen-induced oxidative damage of the gastric mucosa by up-regulating Nrf2 in vitro and in vivo","volume":"24","author":"Cheng","year":"2013","journal-title":"J. Nutr. Biochem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.neuroscience.2015.09.012","article-title":"Synergistic neuroprotection by epicatechin and quercetin: Activation of convergent mitochondrial signaling pathways","volume":"308","author":"Nichols","year":"2015","journal-title":"Neuroscience"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1177\/1479164115620982","article-title":"(\u2212)-Epicatechin-induced recovery of mitochondria from simulated diabetes: Potential role of endothelial nitric oxide synthase","volume":"13","author":"Ulloa","year":"2016","journal-title":"Diabetes Vasc. Dis. Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jnutbio.2017.07.015","article-title":"Monomeric cocoa catechins enhance \u03b2-cell function by increasing mitochondrial respiration","volume":"49","author":"Rowley","year":"2017","journal-title":"J. Nutr. Biochem."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Sapian, S., Taib, I.S., Latip, J., Katas, H., Chin, K.Y., Nor, N.A.M., Jubaidi, F.F., and Budin, S.B. (2021). Therapeutic Approach of Flavonoid in Ameliorating Diabetic Cardiomyopathy by Targeting Mitochondrial-Induced Oxidative Stress. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111616"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s10787-021-00895-8","article-title":"Therapeutic benefits of flavonoids against neuroinflammation: A systematic review","volume":"30","author":"Hamsalakshmi","year":"2022","journal-title":"Inflammopharmacology"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1007\/s11033-020-06041-x","article-title":"The effect of dietary phytochemicals on nuclear factor erythroid 2-related factor 2 (Nrf2) activation: A systematic review of human intervention trials","volume":"48","author":"Clifford","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1089\/jmf.2021.0158","article-title":"Epicatechin ameliorates cardiac fibrosis in a female rat model of pre-heart failure with preserved ejection fraction","volume":"25","author":"Haro","year":"2022","journal-title":"J. Med. Food"},{"key":"ref_131","doi-asserted-by":"crossref","unstructured":"Daussin, F.N., Cuillerier, A., Touron, J., Bensaid, S., Melo, B., Rewashdy, A.A., Vasam, G., Menzies, K.J., Harper, M.E., and Heyman, E. (2021). Dietary cocoa flavanols enhance mitochondrial function in skeletal muscle and modify whole-body metabolism in healthy mice. Nutrients, 13.","DOI":"10.3390\/nu13103466"},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-D\u00edez, E., L\u00f3pez-Oliva, M.E., Caro-Vadillo, A., P\u00e9rez-Vizca\u00edno, F., P\u00e9rez-Jim\u00e9nez, J., Ramos, S., and Mart\u00edn, M.A. (2022). Supplementation with a cocoa\u2013carob blend, alone or in combination with metformin, attenuates diabetic cardiomyopathy, cardiac oxidative stress and inflammation in zucker diabetic rats. Antioxidants, 11.","DOI":"10.3390\/antiox11020432"},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Merino, J.A., de Lucas, B., Herrera-Rocha, K., Moreno-P\u00e9rez, D., Montalvo-Lominchar, M.G., Fern\u00e1ndez-Romero, A., Santiago, C., P\u00e9rez-Ruiz, M., and Larrosa, M. (2022). Flavanol-rich cocoa supplementation inhibits mitochondrial biogenesis triggered by exercise. Antioxidants, 11.","DOI":"10.3390\/antiox11081522"},{"key":"ref_134","unstructured":"Watson, R.R., and Preedy, V.R. (2015). Dietary Supplements as Cognitive Enhancers: The Role of Flavonoid-Rich Foods and their Relevance in Age-Related Neurodegeneration. Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain Disease, Academic Press."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.arr.2016.09.010","article-title":"Nutrition for the ageing brain: Towards evidence for an optimal diet","volume":"35","author":"Vauzour","year":"2017","journal-title":"Ageing Res. Rev."},{"key":"ref_136","first-page":"276","article-title":"Nutritional prevention of cognitive decline and dementia","volume":"89","author":"Dominguez","year":"2018","journal-title":"Acta Biomed."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3389\/fnut.2017.00019","article-title":"Enhancing human cognition with cocoa flavonoids","volume":"4","author":"Socci","year":"2017","journal-title":"Front. Nutr."},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Haskell-Ramsay, C.F., Schmitt, J., and Actis-Goretta, L. (2018). The impact of epicatechin on human cognition: The role of cerebral blood flow. Nutrients, 10.","DOI":"10.3390\/nu10080986"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1016\/S0891-5849(02)01137-1","article-title":"Uptake and metabolism of epicatechin and its access to the brain after oral ingestion","volume":"33","author":"Kuhnle","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"S215","DOI":"10.1097\/00005344-200606001-00018","article-title":"The effect of flavanol-rich cocoa on the fMRI response to a cognitive task in healthy young people","volume":"47","author":"Francis","year":"2006","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/S0092-8674(04)00115-1","article-title":"Translational control by MAPK signaling in long-term synaptic plasticity and memory","volume":"116","author":"Kelleher","year":"2004","journal-title":"Cell"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1111\/j.1471-4159.2006.04434.x","article-title":"(\u2212)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and upregulates GluR2 in cortical neurons","volume":"101","author":"Schroeter","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1161\/HYPERTENSIONAHA.112.193060","article-title":"Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: The Cocoa, Cognition, and Aging (CoCoA) study","volume":"60","author":"Desideri","year":"2012","journal-title":"Hypertension"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1177\/0269881112473791","article-title":"Cocoa polyphenols enhance positive mood states but not cognitive performance: A randomized, placebo-controlled trial","volume":"27","author":"Pase","year":"2013","journal-title":"J. Psychopharmacol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"3227","DOI":"10.1007\/s00213-015-3972-4","article-title":"The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: A placebo controlled, crossover, acute trial","volume":"232","author":"Lamport","year":"2015","journal-title":"J. Psychopharmacol."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Ammar, A., Trabelsi, K., M\u00fcller, P., Bouaziz, B., Boukhris, O., Glenn, J.M., Bott, N.T., Driss, T., Chtourou, H., and M\u00fcller, N. (2020). The effect of (poly)phenol-rich interventions on cognitive functions and neuroprotective measures in healthy aging adults: A systematic review and meta-analysis. J. Clin. Med., 9.","DOI":"10.3390\/jcm9030835"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11130-019-00779-x","article-title":"Effects of cocoa-derived polyphenols on cognitive function in humans. Systematic review and analysis of methodological aspects","volume":"75","author":"Tejero","year":"2020","journal-title":"Plant Foods Hum. Nutr."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Di Meo, F., Valentino, A., Petillo, O., Peluso, G., Filosa, S., and Crispi, S. (2020). Bioactive polyphenols and neuromodulation: Molecular mechanisms in neurodegeneration. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072564"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"101079","DOI":"10.1016\/j.arr.2020.101079","article-title":"Nutrition and the ageing brain: Moving towards clinical applications","volume":"62","author":"Flanagan","year":"2020","journal-title":"Ageing Res. Rev."},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Mart\u00edn, M.A., Goya, L., and de Pascual-Teresa, S. (2020). Effect of cocoa and cocoa products on cognitive performance in young adults. Nutrients, 12.","DOI":"10.3390\/nu12123691"},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Vinciguerra, F., Graziano, M., Hagn\u00e4s, M., Frittitta, L., and Tumminia, A. (2020). Influence of the Mediterranean and ketogenic diets on cognitive status and decline: A narrative review. Nutrients, 12.","DOI":"10.3390\/nu12041019"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"5065","DOI":"10.1039\/D0FO00486C","article-title":"(\u2212)-Epicatechin mitigates high fat diet-induced neuroinflammation and altered behavior in mice","volume":"11","author":"Kang","year":"2020","journal-title":"Food Funct."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"19409","DOI":"10.1038\/s41598-020-76160-9","article-title":"Dietary flavanols improve cerebral cortical oxygenation and cognition in healthy adults","volume":"10","author":"Gratton","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Baynham, R., Veldhuijzen van Zanten, J.J.C.S., Johns, P.W., Pham, Q.S., and Rendeiro, C. (2021). Cocoa flavanols improve vascular responses to acute mental stress in young healthy adults. Nutrients, 13.","DOI":"10.3390\/nu13041103"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"3504","DOI":"10.1039\/D0FO03084H","article-title":"Stimulatory effects of (\u2212)-epicatechin and its enantiomer (+)-epicatechin on mouse frontal cortex neurogenesis markers and short-term memory: Proof of concept","volume":"12","author":"Ayala","year":"2021","journal-title":"Food Funct."},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Cordero, J., Pino, A., Cuevas, C., Puertas-Mart\u00edn, V., San Rom\u00e1n, R., and de Pascual-Teresa, S. (2022). Neurocognitive effects of cocoa and red-berries consumption in healthy adults. Nutrients, 14.","DOI":"10.3390\/nu14010001"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"108013","DOI":"10.1016\/j.pharmthera.2021.108013","article-title":"Polyphenols and neuroprotection: Therapeutic implications for cognitive decline","volume":"232","author":"Caruso","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"ref_158","doi-asserted-by":"crossref","unstructured":"Lalonde, R., and Strazielle, C. (2022). Cocoa flavanols and the aging brain. Curr. Aging Sci., 15.","DOI":"10.2174\/1874609815666220819145845"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"110933","DOI":"10.1016\/j.exger.2020.110933","article-title":"The short-term effect of dark chocolate flavanols on cognition in older adults: A randomized controlled trial (FlaSeCo)","volume":"136","author":"Suominen","year":"2020","journal-title":"Exp. Gerontol."},{"key":"ref_160","doi-asserted-by":"crossref","unstructured":"Baker, L.D., Manson, J.E., Rapp, S.R., Sesso, H.D., Gaussoin, S.A., Shumaker, S.A., and Espeland, M.A. (2022). Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial. Alzheimer Dement., 1\u201312.","DOI":"10.1002\/alz.12767"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1017\/S136898001900394X","article-title":"Long-term dietary flavonoid intake and change in cognitive function in the Framingham Offspring Cohort","volume":"23","author":"Shishtar","year":"2020","journal-title":"Public Health Nutr."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"640381","DOI":"10.3389\/fnagi.2021.640381","article-title":"Intake of products containing anthocyanins, flavanols, and flavanones, and cognitive function: A narrative review","volume":"13","author":"Gardener","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"139","DOI":"10.3233\/BPL-200111","article-title":"Polyphenols and cognition in humans: An overview of current evidence from recent systematic reviews and meta-analyses","volume":"6","author":"Lamport","year":"2021","journal-title":"Brain Plast."},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Rodrigo-Gonzalo, M.J., Gonz\u00e1lez-Manzano, S., Mendez-S\u00e1nchez, R., Santos-Buelga, C., and Recio-Rodr\u00edguez, J.I. (2022). Effect of polyphenolic complements on cognitive function in the elderly: A systematic review. Antioxidants, 11.","DOI":"10.3390\/antiox11081549"},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Zeli, C., Lombardo, M., Storz, M.A., Ottaviani, M., and Rizzo, G. (2022). Chocolate and cocoa-derived biomolecules for brain cognition during ageing. Antioxidants, 11.","DOI":"10.3390\/antiox11071353"},{"key":"ref_166","doi-asserted-by":"crossref","unstructured":"European Food Safety Authority (2010). Scientific Opinion on the substantiation of health claims related to cocoa flavanols and protection of lipids from oxidative damage and maintenance of normal blood pressure. EFSA J., 8, 1792.","DOI":"10.2903\/j.efsa.2010.1792"},{"key":"ref_167","doi-asserted-by":"crossref","unstructured":"European Food Safety Authority (2012). Scientific opinion on the substantiation of a health claim related to cocoa flavanols and maintenance of normal endothelium-dependent vasodilation. EFSA J., 10, 2809.","DOI":"10.2903\/j.efsa.2012.2809"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"6322","DOI":"10.1039\/C9FO01747J","article-title":"Dose-response relationship between cocoa flavanols and human endothelial function: A systematic review and meta-analysis of randomized trials","volume":"10","author":"Sun","year":"2019","journal-title":"Food Funct."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1097\/00041433-200202000-00007","article-title":"Evidence that the antioxidant flavonoids in tea and cocoa are beneficial for cardiovascular health","volume":"13","author":"Keen","year":"2002","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1001\/jama.290.8.1030","article-title":"Vascular effects of cocoa rich in flavan-3-ols","volume":"290","author":"Heiss","year":"2003","journal-title":"J. Am. Med. Assoc."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1097\/00004872-200312000-00016","article-title":"Flavanol rich cocoa induces nitric oxide-dependent vasodilation in healthy humans","volume":"1","author":"Fisher","year":"2003","journal-title":"J. Hypertens."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"S99","DOI":"10.1097\/00005344-200606001-00002","article-title":"Vascular action of cocoa flavanols in humans: The roots of the story","volume":"47","author":"Hollenberg","year":"2006","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1073\/pnas.0510168103","article-title":"(\u2212)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans","volume":"3","author":"Schroeter","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1016\/j.bbrc.2007.05.200","article-title":"(\u2212)-Epicatechin elevates nitric oxide in endothelial cells via inhibition of NADPH oxidase","volume":"359","author":"Steffen","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1001\/jama.298.1.49","article-title":"Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide","volume":"298","author":"Taubert","year":"2007","journal-title":"J. Am. Med. Assoc."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"2141","DOI":"10.1016\/j.jacc.2008.01.059","article-title":"Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients. a double-masked, randomized, controlled trial","volume":"51","author":"Balzer","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1093\/ajcn\/88.1.58","article-title":"Acute dark chocolate and cocoa ingestion and endothelial function: A randomized controlled crossover trial","volume":"8","author":"Faridi","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1093\/jn\/138.9.1671","article-title":"Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high polyphenol dark chocolate","volume":"38","author":"Grassi","year":"2008","journal-title":"J. Nutr."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1093\/ajcn\/88.1.38","article-title":"Flavonoids, flavonoid-rich foods, and cardiovascular risk: A meta-analysis of randomized controlled trials","volume":"88","author":"Hooper","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_180","doi-asserted-by":"crossref","unstructured":"Ried, K., Sullivan, T.R., Fakler, P., Frank, O., and Stocks, N. (2010). Does chocolate reduce blood pressure? A meta-analysis. BMC Med., 8.","DOI":"10.1186\/1741-7015-8-39"},{"key":"ref_181","first-page":"CD008893","article-title":"Effect of cocoa on blood pressure","volume":"15","author":"Ried","year":"2012","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"8093","DOI":"10.1021\/acs.jafc.7b04055","article-title":"Advances in polyphenol research: A journal of agricultural and food chemistry virtual issue","volume":"65","author":"Clifford","year":"2017","journal-title":"J. Agric. Food Chem."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"36","DOI":"10.3389\/fnut.2017.00036","article-title":"Cocoa, blood pressure, and vascular function","volume":"4","author":"Ludovici","year":"2017","journal-title":"Front. Nutr."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"4903","DOI":"10.2174\/0929867323666160919094339","article-title":"Cocoa polyphenols: Chemistry, bioavailability and effects on cardiovascular performance","volume":"25","author":"Dugo","year":"2018","journal-title":"Curr. Med. Chem."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1161\/CIRCRESAHA.117.309008","article-title":"Flavonoids, dairy foods, and cardiovascular and metabolic health. A review of emerging biologic pathways","volume":"122","author":"Mozaffarian","year":"2018","journal-title":"Circ Res."},{"key":"ref_186","doi-asserted-by":"crossref","unstructured":"Ciumarnean, L., Milaciu, M.V., Runcan, O., Vesa, S.C., Rachis, A.L., Negrean, V., Pern\u00e9, M.-G., Donca, V.I., Alexescu, T.-G., and Para, I. (2020). The effects of flavonoids in cardiovascular diseases. Molecules, 25.","DOI":"10.3390\/molecules25184320"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.clnesp.2019.10.017","article-title":"Effect of dark chocolate on flow-mediated dilatation: Systematic review, meta-analysis, and dose\u2013response analysis of randomized controlled trials","volume":"36","author":"Ebaditabar","year":"2020","journal-title":"Clin. Nutr. ESPEN"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"112121","DOI":"10.1016\/j.fct.2021.112121","article-title":"Impact of cocoa flavanols on human health","volume":"151","author":"Martin","year":"2021","journal-title":"Food Chem. Toxicol."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1080\/10408398.2020.1733484","article-title":"Chronic and acute effects of cocoa products intake on arterial stiffness and platelet count and function: A systematic review and dose-response Meta-analysis of randomized clinical trials","volume":"61","author":"Azad","year":"2021","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_190","doi-asserted-by":"crossref","unstructured":"Tanghe, A., Heyman, E., Lespagnol, E., Stautemas, J., Celie, B., Op \u2018t Roodt, J., Rietzschel, E., Dias Soares, D., Hermans, N., and Tuenter, E. (2022). Acute effects of cocoa flavanols on blood pressure and peripheral vascular reactivity in type 2 diabetes mellitus and essential hypertension. Nutrients, 14.","DOI":"10.3390\/nu14132692"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.clnu.2019.03.041","article-title":"Acute study of dose-dependent effects of (\u2212)-epicatechin on vascular function in healthy male volunteers: A randomized controlled trial","volume":"39","author":"Castle","year":"2020","journal-title":"Clin. Nutr."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1021\/acs.jafc.9b02251","article-title":"Cocoa flavanols improve endothelial functional integrity in healthy young and elderly subjects","volume":"68","author":"Sansone","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"17964","DOI":"10.1038\/s41598-020-74863-7","article-title":"Biomarker-estimated flavan-3-ol intake is associated with lower blood pressure in cross-sectional analysis in EPIC Norfolk","volume":"10","author":"Ottaviani","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"2100991","DOI":"10.1002\/mnfr.202100991","article-title":"Flavanol consumption in healthy men preserves integrity of immunological-endothelial barrier cell functions: Nutri(epi)genomic analysis","volume":"66","author":"Milenkovic","year":"2022","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1093\/ajcn\/nqac055","article-title":"Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial","volume":"115","author":"Sesso","year":"2022","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11906-019-1005-0","article-title":"Cocoa consumption and blood pressure in middle-aged and elderly subjects: A meta-analysis","volume":"22","author":"Jafarnejad","year":"2020","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"5587","DOI":"10.1016\/j.clnu.2021.09.038","article-title":"The effect of monomeric and oligomeric FLAVAnols in patients with type 2 diabetes and microalbuminuria (FLAVA-trial): A double blind randomized controlled trial","volume":"40","author":"Rashid","year":"2021","journal-title":"Clin. Nutr."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"7222","DOI":"10.1080\/10408398.2021.1913091","article-title":"Natural products targeting into cancer hallmarks: An update on caffeine, theobromine, and (+) catechin","volume":"62","year":"2022","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"2597","DOI":"10.1080\/10408398.2018.1461607","article-title":"Pharmacological potential of methylxanthines: Retrospective analysis and future expectations","volume":"59","author":"Monteiro","year":"2019","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"3605","DOI":"10.1021\/acs.jafc.8b07248","article-title":"Role of theobromine in cocoa\u2019s metabolic properties in healthy rats","volume":"67","author":"Cambras","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"292","DOI":"10.34067\/KID.0001252019","article-title":"Targeting inflammation in diabetic kidney disease: Is there a role for pentoxifylline?","volume":"1","author":"Leehey","year":"2020","journal-title":"Kidney 360"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.ejphar.2014.10.051","article-title":"Modulation of high affinity ATP-dependent cyclic nucleotide transporters by specific and non-specific cyclic nucleotide phosphodiesterase inhibitors","volume":"745","author":"Aronsen","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_203","first-page":"63","article-title":"Effect of purinergic receptor antagonists suramin and theobromine on tumor-induced angiogenesis in BALB\/c mice","volume":"39","author":"Gil","year":"1993","journal-title":"Folia Biol."},{"key":"ref_204","first-page":"517","article-title":"The influence of theobromine on angiogenic activity and proangiogenic cytokines production of human ovarian cancer cells","volume":"5","author":"Barcz","year":"1998","journal-title":"Oncol. Rep."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1080\/01635581.2013.877497","article-title":"Theobromine, the primary methylxanthine found in theobroma cacao, prevents malignant glioblastoma proliferation by negatively regulating phosphodiesterase-4, extracellular signal-regulated kinase, Akt\/mammalian target of rapamycin kinase, and nuclear factor-\u03baB","volume":"66","author":"Sugimoto","year":"2014","journal-title":"Nutr. Cancer"},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.1039\/C5FO00397K","article-title":"Theobromine inhibits differentiation of 3T3-L1 cells during the early stage of adipogenesis via AMPK and MAPK signaling pathways","volume":"6","author":"Jang","year":"2015","journal-title":"Food Funct."},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"F209","DOI":"10.1152\/ajprenal.00252.2014","article-title":"Theobromine increases NAD+\/Sirt-1 activity and protects the kidney under diabetic conditions","volume":"308","author":"Papadimitriou","year":"2015","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.2174\/1871520616666151217121138","article-title":"Guarana a caffeine-rich food increases oxaliplatin sensitivity of colorectal HT-29 cells by apoptosis pathway modulation","volume":"16","author":"Cadonna","year":"2016","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jnutbio.2016.10.002","article-title":"Theobromine up-regulates cerebral brain-derived neurotrophic factor and facilitates motor learning in mice","volume":"39","author":"Yoneda","year":"2017","journal-title":"J. Nutr. Biochem."},{"key":"ref_210","first-page":"2438","article-title":"Theobromine suppresses adipogenesis through enhancement of CCAAT enhancer-binding protein \u03b2 degradation by adenosine receptor A1","volume":"1864","author":"Mitani","year":"2017","journal-title":"BBA Mol. Cell Res."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"111140","DOI":"10.1016\/j.biopha.2020.111140","article-title":"Oncopreventive effects of theanine and theobromine on dimethylhydrazine-induced colon cancer model","volume":"134","author":"Khosroushahi","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"108898","DOI":"10.1016\/j.jnutbio.2021.108898","article-title":"Theobromine enhances the conversion of white adipocytes into beige adipocytes in a PPAR \u03b3activation-dependent manner","volume":"100","author":"Tanaka","year":"2022","journal-title":"J. Nutr. Biochem."},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1139\/cjpp-2020-0259","article-title":"Theobromine ameliorates nonalcoholic fatty liver disease by regulating hepatic lipid metabolism via mTOR signaling pathway in vivo and in vitro","volume":"99","author":"Wei","year":"2021","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_214","doi-asserted-by":"crossref","unstructured":"Janitschke, D., Lauer, A.A., Bachmann, C.M., Winkler, J., Griebsch, L.V., Pilz, S.M., Theiss, E.L., Grimm, H.S., Hartmann, T., and Grimm, M.O.W. (2022). Methylxanthines induce a change in the AD\/neurodegeneration- linked lipid profile in neuroblastoma cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23042295"},{"key":"ref_215","doi-asserted-by":"crossref","unstructured":"Rebollo-Hernanz, M., Aguilera, Y., Martin-Cabrejas, M.A., and Gonzalez de Mejia, E. (2022). Phytochemicals from the cocoa shell modulate mitochondrial function, lipid and glucose metabolism in hepatocytes via activation of FGF21\/ERK, AKT, and mTOR pathways. Antioxidants, 11.","DOI":"10.3390\/antiox11010136"},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1039\/C5FO00052A","article-title":"Catecholaminergic and cholinergic systems of mouse brain are modulated by LMN diet, rich in theobromine polyphenols and polyunsaturated fatty acids","volume":"6","author":"Esteban","year":"2015","journal-title":"Food Funct."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"106226","DOI":"10.1016\/j.intimp.2020.106226","article-title":"Theobromine mitigates IL-1\u03b2-induced oxidative stress, inflammatory response, and degradation of type II collagen in human chondrocytes","volume":"82","author":"Gu","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"e9953","DOI":"10.7717\/peerj.9953","article-title":"Cocoa colonic phenolic metabolites are related to HDL-cholesterol raising effects and methylxanthine metabolites and insoluble dietary fibre to anti-inflammatory and hypoglycemic effects in humans","volume":"8","author":"Bravo","year":"2020","journal-title":"PeerJ"},{"key":"ref_219","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Rodr\u00edguez, P., Ragusky, K., Phuthong, S., Ruvira, S., Ramiro-Cortijo, D., Ca\u00f1as, S., Rebollo-Hernanz, M., Morales, M.D., L\u00f3pez de Pablo, A.L., and Mart\u00edn-Cabrejas, M.A. (2022). Vasoactive properties of a cocoa shell extract: Mechanism of action and effect on endothelial dysfunction in aged rats. Antioxidants, 11.","DOI":"10.3390\/antiox11020429"},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"e1800027","DOI":"10.1002\/mnfr.201800027","article-title":"Theobromine does not affect fasting and postprandial HDL cholesterol efflux capacity, while it decreases fasting miR-92a levels in humans","volume":"62","author":"Talbot","year":"2018","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1007\/s00394-018-1612-6","article-title":"Theobromine consumption does not improve fasting and postprandial vascular function in overweight and obese subjects","volume":"58","author":"Smolders","year":"2019","journal-title":"Eur. J. Nutr."},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s00213-019-5172-0","article-title":"Exploring cocoa properties: Is theobromine a cognitive modulator?","volume":"236","author":"Cova","year":"2019","journal-title":"Psychopharmacology"},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1023\/A:1006901005925","article-title":"Chronic effects of xanthines on levels of central receptors in mice","volume":"19","author":"Shi","year":"1999","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1271\/bbb.80815","article-title":"Effect of cocoa tea (Camellia ptilophylla) co-administrated with green tea on ambulatory behaviors","volume":"73","author":"He","year":"2009","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.physbeh.2011.07.027","article-title":"Differential contributions of theobromine and caffeine on mood, psychomotor performance and blood pressure","volume":"104","author":"Mitchell","year":"2011","journal-title":"Physiol. Behav."},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.3233\/JAD-150374","article-title":"Does caffeine consumption modify cerebrospinal fluid amyloid-\u03b2 levels in patients with Alzheimer\u2019s disease?","volume":"47","author":"Travassos","year":"2015","journal-title":"J. Alzheimer Dis."},{"key":"ref_227","first-page":"1273","article-title":"Theobromine-induced changes in A1 purinergic receptor gene expression and distribution in a rat brain Alzheimer\u2019s disease model","volume":"55","author":"Padilla","year":"2017","journal-title":"J. Alzheimer Dis."},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"1700238","DOI":"10.1002\/mnfr.201700238","article-title":"Effect of cocoa\u2019s theobromine on intestinal microbiota of rats","volume":"61","author":"Franch","year":"2017","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s40495-021-00276-3","article-title":"Methylxanthines as potential inhibitor of SARS-CoV-2: An In Silico Approach","volume":"8","author":"Rolta","year":"2022","journal-title":"Curr. Pharmacol. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14365\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:21:42Z","timestamp":1760145702000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/22\/14365"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,18]]},"references-count":229,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232214365"],"URL":"https:\/\/doi.org\/10.3390\/ijms232214365","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,18]]}}}