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Impairment of SERCA associated with activity\/expression decrease has been implicated in multiple chronic conditions, including cardiovascular diseases, diabetes, cancer, neurodegenerative diseases, and skeletal muscle pathologies. Natural polyphenols have been recognized to interact with several target proteins involving SERCA. To date, only a limited number of polyphenolic compounds or their derivatives have been described either to increase SERCA activity\/expression directly or to affect Ca2+ signaling pathways. In this study, we tested polyphenols for their ability to activate SERCA1a in the absence or presence of methylglyoxal or palmitate and to impact insulin release in pancreatic beta cells. The protective effects of these compounds against methylglyoxal- or palmitate-induced injury were evaluated. Results indicate that 6-gingerol, resveratrol, and ellagic acid activate SERCA1a and protect against activity decrease induced by methylglyoxal and palmitate. Molecular docking analysis revealed the binding of these polyphenols to Glu439 in the SERCA1a P-domain, suggesting a critical role in the stimulation of enzyme activity. Ellagic acid was found to directly stimulate the activity of SERCA1a, marking the first instance of such an observation.<\/jats:p>","DOI":"10.3390\/cells13221860","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T08:01:27Z","timestamp":1731312087000},"page":"1860","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Polyphenolic Compounds Activate SERCA1a and Attenuate Methylglyoxal- and Palmitate-Induced Impairment in Pancreatic INS-1E Beta Cells"],"prefix":"10.3390","volume":"13","author":[{"given":"Vladimir","family":"Heger","sequence":"first","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine of the Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbora","family":"Benesova","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine of the Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"},{"name":"Faculty of Natural Sciences, Comenius University, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8633-3276","authenticated-orcid":false,"given":"Magdalena","family":"Majekova","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine of the Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petronela","family":"Rezbarikova","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine of the Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0074-3472","authenticated-orcid":false,"given":"Attila","family":"Hunyadi","sequence":"additional","affiliation":[{"name":"Institute of Pharmacognosy, University of Szeged, H-6720 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0229-5888","authenticated-orcid":false,"given":"Lubica","family":"Horakova","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine of the Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4856-883X","authenticated-orcid":false,"given":"Jana","family":"Viskupicova","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, Centre of Experimental Medicine of the Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1002\/mus.20745","article-title":"SERCA Pump Isoforms: Their Role in Calcium Transport and Disease","volume":"35","author":"Periasamy","year":"2007","journal-title":"Muscle Nerve"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1016\/j.bbamcr.2014.08.002","article-title":"Expression of Sarco (Endo) Plasmic Reticulum Calcium ATPase (SERCA) System in Normal Mouse Cardiovascular Tissues, Heart Failure and Atherosclerosis","volume":"1843","author":"Lipskaia","year":"2014","journal-title":"Biochim. 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