{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T06:36:20Z","timestamp":1776753380137,"version":"3.51.2"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Tenofovir, a nucleotide reverse transcriptase inhibitor (NRTI), is a first-line therapy for HBV and HIV and is administered as tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). However, long-term use of TDF is linked to renal and other organ toxicities, which is largely attributed to oxidative stress mediated by xanthine oxidase (XO), a key enzyme in purine metabolism. To address this, plants with documented nephroprotective and XO-inhibitory properties were investigated through computational,\n                      <jats:italic>in vitro<\/jats:italic>\n                      , and\n                      <jats:italic>in vivo<\/jats:italic>\n                      approaches.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Bioactive compounds from nine medicinal plants were subjected to computational screening for XO inhibition, leading to the selection of\n                      <jats:italic>Allium cepa<\/jats:italic>\n                      and\n                      <jats:italic>Vitex negundo<\/jats:italic>\n                      as promising candidates. Fifteen extracts from different plant parts were prepared and assessed\n                      <jats:italic>in vitro<\/jats:italic>\n                      for XO inhibitory activity. The methanolic extract of\n                      <jats:italic>A. cepa<\/jats:italic>\n                      bulb (AC) and the hydroalcoholic extract of\n                      <jats:italic>V. negundo<\/jats:italic>\n                      root (VN) demonstrated the highest potency. These extracts were further evaluated for their antioxidant potential and tested against TDF-induced renal and hepatic toxicities in a 35-day rat model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Both AC and VN significantly mitigated TDF-induced elevations in serum biomarker levels, including creatinine, BUN, AST, ALT, GGT, bilirubin, and alkaline phosphatase, while enhancing albumin levels. They also restored the levels of oxidative stress markers such as MDA, GSH, catalase, and SOD. Histopathological examination confirmed substantial structural recovery of liver and kidney tissues.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Overall, this preclinical study demonstrates that\n                      <jats:italic>A. cepa<\/jats:italic>\n                      and\n                      <jats:italic>V. negundo<\/jats:italic>\n                      extracts effectively alleviate TDF-induced organ toxicities and oxidative damage, supporting their potential as adjunct therapies to enhance the safety of TDF treatment in HBV and HIV management.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1775162","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T05:36:16Z","timestamp":1776749776000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Xanthine oxidase inhibition by medicinal plants mitigates tenofovir-induced nephrotoxicity: a comprehensive computational and experimental study"],"prefix":"10.3389","volume":"17","author":[{"given":"Chaitanya","family":"Sankannavar","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Indian Council of Medical Research-National Institute of Traditional Medicine","place":["Belagavi, Karnataka, India"]},{"name":"Department of Pharmacology, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research (KAHER)","place":["Belagavi, Karnataka, India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harish R.","family":"Darasaguppe","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Indian Council of Medical Research-National Institute of Traditional Medicine","place":["Belagavi, Karnataka, India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vishal S.","family":"Patil","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Indian Council of Medical Research-National Institute of Traditional Medicine","place":["Belagavi, Karnataka, India"]},{"name":"Department of Pharmacology, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research (KAHER)","place":["Belagavi, Karnataka, India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faizan A.","family":"Beerwala","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Indian Council of Medical Research-National Institute of Traditional Medicine","place":["Belagavi, Karnataka, India"]},{"name":"Department of Pharmacology, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research (KAHER)","place":["Belagavi, Karnataka, India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swarup S.","family":"Gujarathi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Indian Council of Medical Research-National Institute of Traditional Medicine","place":["Belagavi, Karnataka, India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajitha","family":"Charla","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Indian Council of Medical Research-National Institute of Traditional Medicine","place":["Belagavi, Karnataka, India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priyanka P.","family":"Patil","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research (KAHER)","place":["Belagavi, Karnataka, India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vishwambhar V.","family":"Bhandare","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Indian Council of Medical Research-National Institute of Traditional Medicine","place":["Belagavi, Karnataka, India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nayeem A.","family":"Khatib","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, KLE College of Pharmacy, Belagavi, KLE Academy of Higher Education and Research (KAHER)","place":["Belagavi, Karnataka, India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Subarna","family":"Roy","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Indian Council of Medical Research-National Institute of Traditional Medicine","place":["Belagavi, Karnataka, India"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4855","DOI":"10.1002\/JCB.26696","article-title":"Suppressive effects of tenofovir disoproxil fumarate, an antiretroviral prodrug, on mineralization and type II and type III sodium-dependent phosphate transporters expression in primary human osteoblasts","volume":"119","author":"Barbieri","year":"2018","journal-title":"J. Cellular Biochemistry"},{"key":"B2","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/J.SAJB.2023.12.014","article-title":"Decoding the alpha-amylase inhibitory activity of Garcinia indica Choisy by computational and experimental studies","volume":"165","author":"Beerwala","year":"2024","journal-title":"South Afr. J. Bot."},{"key":"B3","doi-asserted-by":"publisher","first-page":"100010","DOI":"10.1016\/J.INSI.2025.100010","article-title":"Harnessing the therapeutic potential of Garcinia indica choisy constituents against olanzapine-induced cardiac and metabolic disorders","volume":"1","author":"Beerwala","year":"2025","journal-title":"Silico Res. Biomed."},{"key":"B4","first-page":"52","article-title":"Effects of Trachyspermum ammi L. (apiaceae) on serum, urine and hepatic uric acid levels in oxonate-induced rats and in vitro xanthine oxidase inhibition assay","volume":"18","author":"Bilal","year":"2019","journal-title":"Indian J. Traditional Knowl."},{"key":"B5","doi-asserted-by":"publisher","first-page":"195","DOI":"10.2174\/0929867023371229","article-title":"Progress towards the discovery of Xanthine oxidase inhibitors","volume":"9","author":"Borges","year":"2012","journal-title":"Curr. Med. Chem."},{"key":"B6","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1159\/000512178","article-title":"Clinical effects of Xanthine oxidase inhibitors in hyperuricemic patients","volume":"30","author":"Cicero","year":"2021","journal-title":"Med. Princ. Pract."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1074342","DOI":"10.3389\/FPHAR.2022.1074342\/BIBTEX","article-title":"Elucidating type 2 diabetes mellitus risk factor by promoting lipid metabolism with gymnemagenin: an in vitro and in silico approach","volume":"13","author":"DasNandy","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.3390\/V2061279","article-title":"Antiviral treatment of chronic hepatitis B virus (HBV) infections","volume":"2","author":"de Clercq","year":"2010","journal-title":"Viruses"},{"key":"B9","doi-asserted-by":"publisher","first-page":"763150","DOI":"10.3389\/FMOLB.2021.763150\/BIBTEX","article-title":"Potential molecular targets of Tenofovir disoproxil fumarate for alleviating chronic liver diseases via a non-antiviral effect in a normal mouse model","volume":"8","author":"Duan","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/j.apjtm.2017.06.002","article-title":"Xanthine oxidase inhibitors from Archidendron clypearia (Jack.) I.C. Nielsen: results from systematic screening of Vietnamese medicinal plants","volume":"10","author":"Duong","year":"2017","journal-title":"Asian Pac. J. Trop. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/S2468-1253(24)00089-X","article-title":"WHO 2024 hepatitis B guidelines: an opportunity to transform care","volume":"9","author":"Easterbrook","year":"2024","journal-title":"Lancet Gastroenterology Hepatology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1080\/07315724.2019.1649218","article-title":"Nephroprotective effect of Moringa Oleifera seed oil on gentamicin-induced nephrotoxicity in rats: biochemical evaluation of antioxidant, anti-inflammatory, and antiapoptotic pathways","volume":"39","author":"Edeogu","year":"2020","journal-title":"J. Am. Coll. Nutr."},{"key":"B13","doi-asserted-by":"publisher","first-page":"3450","DOI":"10.1016\/j.bmc.2007.03.010","article-title":"The screening and characterization of 6-aminopurine-based xanthine oxidase inhibitors","volume":"15","author":"Hsieh","year":"2007","journal-title":"Bioorg. Med. Chem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S12906-023-03923-Y\/FIGURES\/6","article-title":"In vitro antioxidant and free-radical scavenging activities of polar leaf extracts of Vernonia amygdalina","volume":"23","author":"Hussen","year":"2023","journal-title":"BMC Complementary Med. Ther."},{"key":"B15","first-page":"280","article-title":"Protective potential of Trachyspermum ammi seeds in gentamicin-induced nephrotoxicity in rabbit model","volume":"14","author":"Ishaq","year":"2015","journal-title":"Lat. Am. Caribb. Bull. Med. Aromatic Plants"},{"key":"B16","first-page":"706","article-title":"Nephroprotective effect of Vitex negundo linn. on cisplatin induced nephrotoxicity in male albino rats","volume":"3","author":"Janakiraman","year":"2015","journal-title":"World J. Pharm. Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e7133","DOI":"10.1097\/MD.0000000000007133","article-title":"Fatal lactic acidosis in hepatitis B virus-associated decompensated cirrhosis treated with tenofovir: a case report","volume":"96","author":"Jung","year":"2017","journal-title":"Medicine"},{"key":"B18","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1038\/labinvest.2009.14","article-title":"Tenofovir renal toxicity targets mitochondria of renal proximal tubules","volume":"89","author":"Kohler","year":"2009","journal-title":"Lab. Investig."},{"key":"B19","doi-asserted-by":"publisher","first-page":"687","DOI":"10.5937\/jomb0-56238","article-title":"Serum TNF-a and biomarkers levels after tenofovir therapy in patients with serum HBeAg-positive chronic hepatitis B","volume":"44","author":"Lai","year":"2025","journal-title":"J. Med. Biochem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2543","DOI":"10.1097\/00002030-200311210-00021","article-title":"Acute tubular necrosis in a patient receiving tenofovir [1]","volume":"17","author":"Lee","year":"2003","journal-title":"AIDS"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e0261067","DOI":"10.1371\/JOURNAL.PONE.0261067","article-title":"Tenofovir disoproxil fumarate directly ameliorates liver fibrosis by inducing hepatic stellate cell apoptosis via downregulation of PI3K\/Akt\/mTOR signaling pathway","volume":"16","author":"Lee","year":"2021","journal-title":"PLoS ONE"},{"key":"B22","doi-asserted-by":"publisher","first-page":"e105322","DOI":"10.1590\/fst.105322","article-title":"Optimization of total polyphenol extraction and flavonoid screening by mass spectrometry in mango (Mangifera indica L.) waste from Peru","volume":"43","author":"Le\u00f3n-Roque","year":"2023","journal-title":"Food Sci. Technol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1038\/KI.2008.252","article-title":"Rosiglitazone reverses tenofovir-induced nephrotoxicity","volume":"74","author":"Lib\u00f3rio","year":"2008","journal-title":"Kidney Int."},{"key":"B24","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1006\/BBRC.1994.1764","article-title":"The nitric oxide-scavenging properties of Ginkgo Biloba extract EGb 761","volume":"201","author":"Marcocci","year":"1994","journal-title":"Biochem. Biophysical Res. Commun."},{"key":"B25","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1007\/S11418-009-0331-Y","article-title":"Hydroxychavicol: a potent xanthine oxidase inhibitor obtained from the leaves of betel, Piper betle","volume":"63","author":"Murata","year":"2009","journal-title":"J. Nat. Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1097\/QAD.0B013E3280B07B33","article-title":"The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years","volume":"21","author":"Nelson","year":"2007","journal-title":"AIDS"},{"key":"B27","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1080\/21553769.2014.901926","article-title":"Total phenolics, antioxidant and xanthine oxidase inhibitory activity of three colored onions (Allium cepa L.)","volume":"7","author":"Nile","year":"2013","journal-title":"Front. Life Sci."},{"key":"B28","first-page":"531","article-title":"HPTLC analysis, antioxidant and antigout activity of Indian plants","volume":"13","author":"Nile","year":"2014","journal-title":"Iran. J. Pharm. Res. IJPR"},{"key":"B29","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/S00775-014-1210-X","article-title":"Mechanistic insights into xanthine oxidoreductase from development studies of candidate drugs to treat hyperuricemia and gout","volume":"20","author":"Nishino","year":"2015","journal-title":"J. Biol. Inorg. Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1016\/J.SJBS.2017.08.005","article-title":"Antioxidant and xanthine oxidase inhibitory activities of total polyphenols from onion","volume":"25","author":"Ouyang","year":"2017","journal-title":"Saudi J. Biol. Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1124\/PR.58.1.6","article-title":"Therapeutic effects of xanthine oxidase inhibitors: Renaissance half a century after the discovery of allopurinol","volume":"58","author":"Pacher","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1174867","DOI":"10.3389\/fphar.2023.1174867","article-title":"Computational and experimental pharmacology to decode the efficacy of Theobroma cacao L. against doxorubicin-induced organ toxicity in EAC-mediated solid tumor-induced mice","volume":"14","author":"Patil","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1080\/07391102.2024.2333991","article-title":"Sesamin regulates breast cancer through reprogramming of lipid metabolism","volume":"44","author":"Patil","year":"2025","journal-title":"J. Biomol. Struct. Dyn."},{"key":"B35","doi-asserted-by":"publisher","first-page":"109147","DOI":"10.1016\/J.JNUTBIO.2022.109147","article-title":"Crosstalk between xanthine oxidase (XO) inhibiting and cancer chemotherapeutic properties of comestible flavonoids-a comprehensive update","volume":"110","author":"Rahaman","year":"2022","journal-title":"J. Nutr. Biochem."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2610","DOI":"10.1016\/j.matpr.2022.07.276","article-title":"Investigation of geranium oil extraction performance by using soxhlet extraction","volume":"72","author":"Rajesh","year":"2023","journal-title":"Mater. Today Proc."},{"key":"B37","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1177\/0960327118802619","article-title":"Mitochondrial pathway of apoptosis and necrosis contribute to tenofovir disoproxil fumarate\u2013induced renal damage in rats","volume":"38","author":"Ramamoorthy","year":"2019","journal-title":"Hum. and Exp. Toxicol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1177\/0960327120968860","article-title":"Melatonin protects against tenofovir-induced nephrotoxicity in rats by targeting multiple cellular pathways","volume":"40","author":"Ramamoorthy","year":"2021","journal-title":"Hum. and Exp. Toxicol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"132","DOI":"10.7324\/JAPS.2021.110616","article-title":"Nephroprotectivity of Coccinia indica leaves against gentamycin-induced nephrotoxicity using in vitro and in vivo models","volume":"11","author":"Satrasala","year":"2021","journal-title":"J. Appl. Pharm. Sci."},{"key":"B30","first-page":"1","article-title":"Xanthine oxidase inhibitory activity of medicinal plants","volume":"6","author":"Taejarernwiriyakul","year":"2011","journal-title":"Thai Pharm. Health. Sci. J."},{"key":"B40","doi-asserted-by":"publisher","first-page":"12","DOI":"10.53388\/TA202305012","article-title":"Assessment of different formalin concentrations on the histochemical staining of liver, kidneys and lungs of Wistar rats","volume":"5","author":"Taiwo Oluwaloye","year":"2023","journal-title":"Toxicol. Adv."},{"key":"B41","doi-asserted-by":"publisher","first-page":"6262","DOI":"10.3748\/WJG.V20.I20.6262","article-title":"Management of chronic hepatitis B infection: current treatment guidelines, challenges, and new developments","volume":"20","author":"Tang","year":"2014","journal-title":"World J. Gastroenterology WJG"},{"key":"B42","doi-asserted-by":"publisher","first-page":"154","DOI":"10.5146\/TJPATH.2020.01478","article-title":"Long-term effects of Tenofovir on liver histopathology in patients with chronic viral hepatitis B infection","volume":"36","author":"Tatar","year":"2020","journal-title":"Turkish J. Pathology"},{"key":"B43","doi-asserted-by":"publisher","first-page":"113808","DOI":"10.1016\/j.jep.2021.113808","article-title":"Xanthine oxidase inhibitory activity and antihyperuricemic effect of Moringa oleifera Lam. leaf hydrolysate rich in phenolics and peptides","volume":"270","author":"Tian","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"477","DOI":"10.3742\/OPEM.2008.7.5.477","article-title":"Hypouricemic and xanthine oxidase inhibitory activities of the fractions of Coccinia grandis L. Voigt","volume":"7","author":"Umamaheswari","year":"2008","journal-title":"Orient. Pharm. Exp. Med."},{"key":"B45","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1016\/j.jep.2006.08.020","article-title":"Xanthine oxidase inhibitory activity of some Indian medical plants","volume":"109","author":"Umamaheswari","year":"2007","journal-title":"J. Ethnopharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/J.DIT.2013.09.001","article-title":"Nephroprotector activity of hydro alcoholic extract of Tinospora cordifolia roots on cisplatin induced nephrotoxicity in rats","volume":"5","author":"Uppuluri","year":"2013","journal-title":"Drug Invent. Today"},{"key":"B47","doi-asserted-by":"publisher","first-page":"100114","DOI":"10.1016\/J.HSR.2023.100114","article-title":"Inflammatory properties of tenofovir in human liver cells","volume":"8","author":"Vazi","year":"2023","journal-title":"Health Sci. Rev."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2325958220919231","DOI":"10.1177\/2325958220919231","article-title":"A review and clinical understanding of Tenofovir: tenofovir disoproxil fumarate versus Tenofovir Alafenamide","volume":"19","author":"Wassner","year":"2020","journal-title":"J. Int. Assoc. Providers AIDS Care"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1775162\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T05:36:21Z","timestamp":1776749781000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1775162\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,21]]},"references-count":48,"alternative-id":["10.3389\/fphar.2026.1775162"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1775162","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,21]]},"article-number":"1775162"}}