{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T04:11:29Z","timestamp":1789186289651,"version":"build-2803163510"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The RA Ministry of Education, Science, Culture and Sports Higher Education and Science Committee: Organization","award":["23LCG-1F010"],"award-info":[{"award-number":["23LCG-1F010"]}]},{"name":"The RA Ministry of Education, Science, Culture and Sports Higher Education and Science Committee: Organization","award":["21AG-1F068"],"award-info":[{"award-number":["21AG-1F068"]}]},{"name":"The RA Ministry of Education, Science, Culture and Sports Higher Education and Science Committee: Organization","award":["24WS-1F036"],"award-info":[{"award-number":["24WS-1F036"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Plants of the Hypericaceae family have been traditionally used for their medicinal properties, including antibacterial, antiviral, and antioxidant activities. Among these, <jats:italic>Hypericum alpestre<\/jats:italic> (HA) extracts have shown notable cytotoxicity against various cancer cell lines, drawing attention to their phenolic compounds as potential anticancer agents. Similarly, N(G)-Nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS) activity, has emerged as a promising candidate in cancer therapy. However, the precise molecular mechanisms underlying the anticancer effects of both HA and L-NAME remain unclear. This study aimed to clarify the impact of HA and L-NAME on the phosphoinositide 3-kinase (PI3K)\/protein kinase B (Akt)\/ mammalian target of rapamycin (mTOR) signaling pathway in A549 human lung adenocarcinoma and MDA-MB-231 breast cancer triple-negative cells, with particular emphasis on the tumor necrosis factor-alpha (TNF\u03b1)\/cyclooxygenase-2 (COX-2) and vascular endothelial growth factor A (VEGF\u03b1)\/matrix metalloproteinase-2 (MMP-2) pathways. <jats:italic>In silico<\/jats:italic> analyses identified compounds within HA extracts with the highest affinity for PI3K\/Akt, a finding subsequently confirmed by <jats:italic>in vitro<\/jats:italic> experiments. Notably, the combination of HA and L-NAME demonstrated greater efficacy than the combination of HA and 5-fluorouracil (5-FU), as evidenced by enhanced apoptotic activity. Both HA alone and in combination with L-NAME inhibited the TNF\u03b1\/COX-2 and VEGF\u03b1\/MMP-2 pathways. These results suggest that the therapeutic effects of HA, especially in combination with L-NAME, may be mediated through the PI3K\/Akt signaling pathway. A better understanding of the interaction between HA polyphenols and PI3K\/Akt signaling could pave the way for novel therapeutic strategies against cancer, including drug-resistant tumors.<\/jats:p>","DOI":"10.1371\/journal.pone.0303736","type":"journal-article","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T19:23:10Z","timestamp":1743708190000},"page":"e0303736","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Elucidating the impact of Hypericum alpestre extract and L-NAME on the PI3K\/Akt signaling pathway in A549 lung adenocarcinoma and MDA-MB-231 triple-negative breast cancer cells"],"prefix":"10.1371","volume":"20","author":[{"given":"Hayarpi","family":"Javrushyan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikayel","family":"Ginovyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1613-1019","authenticated-orcid":true,"given":"Tigran","family":"Harutyunyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smbat","family":"Gevorgyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaruhi","family":"Karabekian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Maloyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7033-4546","authenticated-orcid":true,"given":"Nikolay","family":"Avtandilyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"issue":"1 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