{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T11:10:08Z","timestamp":1789125008534,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002301","name":"Estonian Research Council","doi-asserted-by":"publisher","award":["PRG1903"],"award-info":[{"award-number":["PRG1903"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]},{"award":["PRG1903"],"award-info":[{"award-number":["PRG1903"]}],"id":[{"id":"https:\/\/ror.org\/00jjeja18","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Symphytum officinale L. is a traditional medicinal plant widely used for wound healing and bone regeneration; however, comparative studies evaluating the biological activities of extracts prepared from different plant organs remain limited. The present study compared the antimicrobial and anti-inflammatory activities of organ-specific S. officinale extracts and investigated their potential molecular mechanisms of bioactivities using molecular docking. Antimicrobial activity was evaluated against six bacterial reference strains by broth serial dilution, whereas anti-inflammatory activity was assessed in a serotonin-induced paw oedema model in rats together with the determination of serum prostaglandin E2 (PGE2), tumour necrosis factor-\u03b1 (TNF-\u03b1), and nitrotyrosine levels. Molecular docking was performed against bacterial peptide deformylases, cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX). The 40% ethanolic leaf extract (S-7) and 70% ethanolic flower extract (S-13) exhibited the broadest antimicrobial spectrum, with pronounced activity against S. aureus, E. faecalis, E. coli, and L. monocytogenes. The 70% ethanolic leaf extract (S-8) demonstrated the strongest early anti-exudative activity (47.50%), whereas the 70% ethanolic flower extract (S-13) most effectively reduced PGE2, TNF-\u03b1, and nitrotyrosine levels. Molecular docking suggested that kaempferol-3-O-glucoside may be the principal contributor to antimicrobial activity through interactions with bacterial peptide deformylases, while hyperoside, isoquercitrin, and rosmarinic acid exhibited favourable interactions with COX-2 and 5-LOX, indicating their key role in exerting anti-inflammatory effects. These findings demonstrate pronounced organ-specific pharmacological differences among S. officinale extracts and identify hydroethanolic leaf, flower, and root extracts as promising candidates for further development as multitarget wound-healing phytopharmaceuticals.<\/jats:p>","DOI":"10.3390\/ijms27188060","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T10:27:21Z","timestamp":1789036041000},"page":"8060","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Anti-Inflammatory and Antimicrobial Activities of Extracts Developed from Symphytum officinale Leaves, Flowers, and Roots: Experimental Evaluation and Molecular Docking Study"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9545-8548","authenticated-orcid":false,"given":"Oleh","family":"Koshovyi","sequence":"first","affiliation":[{"name":"Institute of Pharmacy, Faculty of Medicine, University of Tartu, 50411 Tartu, Estonia"},{"name":"Zaporizhzhia State Medical and Pharmaceutical University, 69035 Zaporizhzhia, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3094-3737","authenticated-orcid":false,"given":"Getter","family":"Dolgo\u0161ev","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Faculty of Medicine, University of Tartu, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrii","family":"Kaplaushenko","sequence":"additional","affiliation":[{"name":"Zaporizhzhia State Medical and Pharmaceutical University, 69035 Zaporizhzhia, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6102-3455","authenticated-orcid":false,"given":"Oleksandr","family":"Panasenko","sequence":"additional","affiliation":[{"name":"Zaporizhzhia State Medical and Pharmaceutical University, 69035 Zaporizhzhia, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volodymyr","family":"Zazharskyi","sequence":"additional","affiliation":[{"name":"Dnipro State Agrarian and Economic University, 49009 Dnipro, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4390-9949","authenticated-orcid":false,"given":"Yuriy","family":"Karpenko","sequence":"additional","affiliation":[{"name":"Zaporizhzhia State Medical and Pharmaceutical University, 69035 Zaporizhzhia, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roman","family":"Shcherbyna","sequence":"additional","affiliation":[{"name":"Zaporizhzhia State Medical and Pharmaceutical University, 69035 Zaporizhzhia, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andriy","family":"Hotsulia","sequence":"additional","affiliation":[{"name":"Zaporizhzhia State Medical and Pharmaceutical University, 69035 Zaporizhzhia, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1070-6739","authenticated-orcid":false,"given":"Mariia","family":"Shanaida","sequence":"additional","affiliation":[{"name":"I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5559-5476","authenticated-orcid":false,"given":"Ivo","family":"Laidm\u00e4e","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Faculty of Medicine, University of Tartu, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5996-5144","authenticated-orcid":false,"given":"Jyrki","family":"Hein\u00e4m\u00e4ki","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Faculty of Medicine, University of Tartu, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8731-7366","authenticated-orcid":false,"given":"Ain","family":"Raal","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Faculty of Medicine, University of Tartu, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1002\/ptr.4612","article-title":"Comfrey: A Clinical Overview","volume":"26","author":"Staiger","year":"2012","journal-title":"Phytother. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2812191","DOI":"10.1155\/term\/2812191","article-title":"Plant-Origin Compounds and Materials for Advancing Bone Tissue Engineering and 3D Bioprinting: Traditional Medicine Aspects and Current Perspectives","volume":"2025","author":"Koshovyi","year":"2025","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1007\/s11101-024-09977-1","article-title":"Symphytum Genus\u2014From Traditional Medicine to Modern Uses: An Update on Phytochemistry, Pharmacological Activity, and Safety","volume":"24","author":"Trifan","year":"2025","journal-title":"Phytochem. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Salehi, B., Sharopov, F., Boyunegmez Tumer, T., Ozleyen, A., Rodr\u00edguez-P\u00e9rez, C., Ezzat, S.M., Azzini, E., Hosseinabadi, T., Butnariu, M., and Sarac, I. (2019). Symphytum Species: A Comprehensive Review on Chemical Composition, Food Applications and Phytopharmacology. Molecules, 24.","DOI":"10.3390\/molecules24122272"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Dolgo\u0161ev, G., Kolesnyk, Y.M., Hancheva, O., Panasenko, O., Kaplaushenko, A., Shcherbyna, R., Jak\u0161tas, V., \u017dvikas, V., Laidm\u00e4e, I., and Hein\u00e4m\u00e4ki, J. (2026). Organ-Specific Phytochemical Profiles, Wound-Healing and Hemostatic Activities of Symphytum officinale Aerial Parts and Roots with Differential Pyrrolizidine Alkaloid Content. Molecules, 31.","DOI":"10.20944\/preprints202605.1842.v1"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1002\/jat.3205","article-title":"The Comparative Toxicity of a Reduced, Crude Comfrey (Symphytum officinale) Alkaloid Extract and the Pure, Comfrey-derived Pyrrolizidine Alkaloids, Lycopsamine and Intermedine in Chicks (Gallus gallus domesticus)","volume":"36","author":"Brown","year":"2016","journal-title":"J. Appl. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Kimel, K., Godlewska, S., Gle\u0144sk, M., Gobis, K., O\u015bko, J., Grembecka, M., and Krauze-Baranowska, M. (2023). LC-MS\/MS Evaluation of Pyrrolizidine Alkaloids Profile in Relation to Safety of Comfrey Roots and Leaves from Polish Sources. Molecules, 28.","DOI":"10.3390\/molecules28166171"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"104784","DOI":"10.1016\/j.yrtph.2020.104784","article-title":"Safety of Medicinal Comfrey Cream Preparations (Symphytum officinale s.l.): The Pyrrolizidine Alkaloid Lycopsamine Is Poorly Absorbed through Human Skin","volume":"118","author":"Kuchta","year":"2020","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1055\/a-1505-8524","article-title":"Support for Regulatory Assessment of Percutaneous Absorption of Retronecine-Type Pyrrolizidine Alkaloids through Human Skin","volume":"88","author":"Plaza","year":"2022","journal-title":"Planta Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"EFSA Panel on Contaminants in the Food Chain (CONTAM), Knutsen, H.K., Alexander, J., Barreg\u00e5rd, L., Bignami, M., Br\u00fcschweiler, B., Ceccatelli, S., Cottrill, B., Dinovi, M., and Edler, L. (2017). Risks for Human Health Related to the Presence of Pyrrolizidine Alkaloids in Honey, Tea, Herbal Infusions and Food Supplements. EFSA J., 15, e04908.","DOI":"10.2903\/j.efsa.2017.4908"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1080\/14786419.2017.1326492","article-title":"Proliferative and Antioxidant Activity of Symphytum officinale Root Extract","volume":"32","author":"Sowa","year":"2018","journal-title":"Nat. Prod. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Liu, X., Huang, X., and Song, X. (2026). Ethnopharmacological Insights into Symphytum officinale L.: Traditional Uses, Phytochemical Composition, Therapeutic Potential, and Clinical-Toxicological Implications. Front. Pharmacol., 17.","DOI":"10.3389\/fphar.2026.1793084"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.homp.2010.08.002","article-title":"Homeopathic Symphytum officinale Increases Removal Torque and Radiographic Bone Density around Titanium Implants in Rats","volume":"99","author":"Belluci","year":"2010","journal-title":"Homeopathy"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"585","DOI":"10.3897\/pharmacia.68.e67774","article-title":"Experimental Study the Anti-Inflammatory and Osteo-Regenerative Qualities of the Paste Based on Symphytum officinale Tincture and Calcium Hydroxide","volume":"68","author":"Kostyiuk","year":"2021","journal-title":"Pharmacia"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"M\u00e2rza, S.M., D\u0103escu, A.M., Purdoiu, R.C., Dragomir, M., T\u0103taru, M., Melega, I., Nagy, A.-L., Gal, A., T\u0103b\u0103ran, F., and Bogdan, S. (2024). Healing of Skin Wounds in Rats Using Creams Based on Symphytum officinale Extract. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25063099"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"355","DOI":"10.31083\/ph.2012.1563","article-title":"In Vivo Wound Healing Effects of Symphytum officinale L. Leaves Extract in Different Topical Formulations","volume":"67","author":"Araujo","year":"2012","journal-title":"Pharmazie"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.phymed.2004.02.001","article-title":"Efficacy and Tolerance of a Comfrey Root Extract (Extr. Rad. Symphyti) in the Treatment of Ankle Distorsions: Results of a Multicenter, Randomized, Placebo-Controlled, Double-Blind Study","volume":"11","author":"Koll","year":"2004","journal-title":"Phytomedicine"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Neagu, E., Paun, G., Albu, C., Eremia, S.A.-M.V., and Radu, G.L. (2023). Artemisia Abrotanum and Symphytum officinale Polyphenolic Compounds-Rich Extracts with Potential Application in Diabetes Management. Metabolites, 13.","DOI":"10.3390\/metabo13030354"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"112828","DOI":"10.1016\/j.biopha.2022.112828","article-title":"Chemical Characterization of Extracts of Leaves of Kadsua Coccinea (Lem.) A.C. Sm. by UHPLC-Q-Exactive Orbitrap Mass Spectrometry and Assessment of Their Antioxidant and Anti-Inflammatory Activities","volume":"149","author":"Shi","year":"2022","journal-title":"Biomed. Pharmacother."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Deng, Y., Liang, L., Lin, H., Shen, X., Zheng, H., Deng, Y., Tian, X., Huang, J., Zhang, Y., and Li, B. (2026). Integrated LC-Orbitrap-MS and Network Pharmacology Decipher the Pharmacological Basis of Eucommiae Folium in Treating Rheumatoid Arthritis. Mol. Divers.","DOI":"10.1007\/s11030-026-11495-5"},{"key":"ref_21","first-page":"e01593","article-title":"Applications of Molecular Docking in Natural Products-Based Drug Discovery","volume":"20","author":"Asiamah","year":"2023","journal-title":"Sci. Afr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1016\/j.sajb.2021.11.010","article-title":"An Insight into the Molecular Docking Interactions of Plant Secondary Metabolites with Virulent Factors Causing Common Human Diseases","volume":"149","author":"Kumar","year":"2022","journal-title":"South Afr. J. Bot."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"153626","DOI":"10.1016\/j.phymed.2021.153626","article-title":"Antibacterial Plant Compounds, Extracts and Essential Oils: An Updated Review on Their Effects and Putative Mechanisms of Action","volume":"90","author":"Micol","year":"2021","journal-title":"Phytomedicine"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Oulahal, N., and Degraeve, P. (2022). Phenolic-Rich Plant Extracts with Antimicrobial Activity: An Alternative to Food Preservatives and Biocides?. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.753518"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.tifs.2021.01.068","article-title":"The Role of Phenolic Compounds against Listeria Monocytogenes in Food. A Review","volume":"110","author":"Zamuz","year":"2021","journal-title":"Trends Food Sci. Technol."},{"key":"ref_26","first-page":"92","article-title":"Antibacterial Activity of the Plant Extract of Symphytum officinale L. against Selected Pathogenic Bacteria","volume":"2","author":"Sumathi","year":"2011","journal-title":"Int. J. Res. Pharm. Sci."},{"key":"ref_27","first-page":"323","article-title":"Evaluation of Phytochemical Constituents and Antibacterial Activities of Symphytum officinale L.","volume":"5","author":"Sumathi","year":"2011","journal-title":"J. Pure Appl. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Ibrahim, S.M., Al-Mizraqchi, A.S., and Haider, J. (2023). Metronidazole Potentiation by Panax Ginseng and Symphytum officinale: A New Strategy for P. gingivalis Infection Control. Antibiotics, 12.","DOI":"10.20944\/preprints202307.0569.v1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/s41374-021-00593-7","article-title":"Serotonin-Induced Vascular Permeability Is Mediated by Transient Receptor Potential Vanilloid 4 in the Airways and Upper Gastrointestinal Tract of Mice","volume":"101","author":"Retamal","year":"2021","journal-title":"Lab. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"463145","DOI":"10.1155\/2013\/463145","article-title":"Suppressions of Serotonin-Induced Increased Vascular Permeability and Leukocyte Infiltration by Bixa Orellana Leaf Extract","volume":"2013","author":"Yong","year":"2013","journal-title":"BioMed Res. Int."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Negi, P., Agarwal, S., Garg, P., Ali, A., and Kulshrestha, S. (2023). In Vivo Models of Understanding Inflammation (in Vivo Methods for Inflammation). Recent Developments in Anti-Inflammatory Therapy, Elsevier.","DOI":"10.1016\/B978-0-323-99988-5.00017-6"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Boarescu, I., Pop, R., Boarescu, P.-M., Boc\u0219an, I., Gheban, D., R\u00e2jnoveanu, R.-M., R\u00e2jnoveanu, A., Bulboac\u0103, A., Buzoianu, A., and Bolboac\u0103, S. (2022). Anti-Inflammatory and Analgesic Effects of Curcumin Nanoparticles Associated with Diclofenac Sodium in Experimental Acute Inflammation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911737"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1161\/ATVBAHA.110.207449","article-title":"Prostaglandins and Inflammation","volume":"31","author":"Ricciotti","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/path.2287","article-title":"TNF-mediated Inflammatory Disease","volume":"214","author":"Bradley","year":"2008","journal-title":"J. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Momot, K., Krauz, K., Czarzasta, K., Zar\u0119bi\u0144ski, M., Puchalska, L., and Wojciechowska, M. (2023). Evaluation of Nitrosative\/Oxidative Stress and Inflammation in Heart Failure with Preserved and Reduced Ejection Fraction. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242115944"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3939","DOI":"10.1007\/s00018-014-1662-8","article-title":"Tyrosine Nitration as Mediator of Cell Death","volume":"71","author":"Franco","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Seigner, J., Junker-Samek, M., Plaza, A., D\u2018Urso, G., Masullo, M., Piacente, S., Holper-Schichl, Y.M., and De Martin, R. (2019). A Symphytum officinale Root Extract Exerts Anti-Inflammatory Properties by Affecting Two Distinct Steps of NF-\u03baB Signaling. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.00289"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"113169","DOI":"10.1016\/j.jep.2020.113169","article-title":"Symphytum officinale L.: Liquid-Liquid Chromatography Isolation of Caffeic Acid Oligomers and Evaluation of Their Influence on pro-Inflammatory Cytokine Release in LPS-Stimulated Neutrophils","volume":"262","author":"Trifan","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lou, K.-H., Tsai, M.-S., and Wu, J.-Y. (2023). Investigating the Microwave-Assisted Extraction Conditions and Antioxidative and Anti-Inflammatory Capacities of Symphytum officinale WL Leaves. Processes, 11.","DOI":"10.20944\/preprints202308.1541.v1"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Liu, Y.-Z., Wang, Y.-X., and Jiang, C.-L. (2017). Inflammation: The Common Pathway of Stress-Related Diseases. Front. Hum. Neurosci., 11.","DOI":"10.3389\/fnhum.2017.00316"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"504253","DOI":"10.1155\/2015\/504253","article-title":"Role of Polyphenols and Other Phytochemicals on Molecular Signaling","volume":"2015","author":"Upadhyay","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Koshovyi, O., Hrytsyk, Y., Perekhoda, L., Suleiman, M., Jak\u0161tas, V., \u017dvikas, V., Grytsyk, L., Yurchyshyn, O., Hein\u00e4m\u00e4ki, J., and Raal, A. (2025). Solidago Canadensis L. Herb Extract, Its Amino Acids Preparations and 3D-Printed Dosage Forms: Phytochemical, Technological, Molecular Docking and Pharmacological Research. Pharmaceutics, 17.","DOI":"10.20944\/preprints202502.2331.v1"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Koshovyi, O., Sepp, J., Jak\u0161tas, V., \u017dvikas, V., Kireyev, I., Karpun, Y., Odyntsova, V., Hein\u00e4m\u00e4ki, J., and Raal, A. (2024). German Chamomile (Matricaria chamomilla L.) Flower Extract, Its Amino Acid Preparations and 3D-Printed Dosage Forms: Phytochemical, Pharmacological, Technological, and Molecular Docking Study. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202406.1591.v1"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.jclinepi.2012.09.015","article-title":"Citation Bias Favoring Statistically Significant Studies Was Present in Medical Research","volume":"66","author":"Jannot","year":"2013","journal-title":"J. Clin. Epidemiol."},{"key":"ref_45","unstructured":"Lapach, S.N., Chubenko, A.V., and Babich, P.N. (2000). Statistical Methods in Biomedical Research Using Excel, MORION."},{"key":"ref_46","unstructured":"Stefanov, O.V. (2001). Preclinical Studies of Drugs, Avicenna."},{"key":"ref_47","unstructured":"Council of Europe (1999). European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes, European Union."},{"key":"ref_48","unstructured":"Verkhovna Rada of Ukraine (2006). Law of Ukraine No. 3447-IV of 21.02.2006 \u201cOn the Protection of Animals from Cruelty\u201d (as Amended and Supplemented)."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1159\/000377721","article-title":"Ethics in Animal-Based Research","volume":"55","author":"Gross","year":"2015","journal-title":"Eur. Surg. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8060\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T10:52:49Z","timestamp":1789123969000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/18\/8060"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":49,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27188060"],"URL":"https:\/\/doi.org\/10.3390\/ijms27188060","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]}}}