{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T20:54:14Z","timestamp":1788900854264,"version":"build-2803163510"},"reference-count":31,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,25]],"date-time":"2025-12-25T00:00:00Z","timestamp":1766620800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100023674","name":"Deanship of Scientific Research at King Khalid University","doi-asserted-by":"crossref","award":["RGP 2\/411\/46"],"award-info":[{"award-number":["RGP 2\/411\/46"]}],"id":[{"id":"10.13039\/501100023674","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background:\u00a0d-Limonene (LIM) is a food-derived monoterpenoid phytocompound predominantly found in citrus peels, endowed with potent antioxidant and anti-inflammatory properties, and has been reported to inhibit xanthine oxidase (XO) activity in vitro. This study investigated the dose-sparing efficacy of this dietary bioactive compound in combination with low-dose allopurinol (ALP) using a dual rat model combining potassium oxonate (PO)-induced hyperuricemia and monosodium urate (MSU)-triggered gouty arthritis, thereby capturing both metabolic and inflammatory dimensions of gout. Methods: Female Wistar rats were PO-primed and MSU-challenged, then treated with LIM (50 mg\/kg), ALP (5 or 10 mg\/kg), or LIM + ALP. Outcomes included paw thickness, dysfunction and inflammation indices, serum uric acid, urea, creatinine, AST\/ALT, cytokines (IL-1\u03b2, TNF-\u03b1, IL-6), oxidative stress markers (MDA, SOD, catalase, GSH), and NLRP3 immunoreactivity, supported by radiographic and histopathological analyses. Data were analyzed by one-way ANOVA with Tukey\u2019s post hoc test. Results: LIM improved clinical and biochemical outcomes versus monotherapies. However, LIM + low-dose ALP exhibited the greatest overall efficacy. On Day 30, paw thickness was significantly lower with LIM + ALP than with LIM alone (3.25 \u00b1 0.31 vs. 3.98 \u00b1 0.72 mm; p &lt; 0.001). Serum uric acid and hepatic transaminases declined most with the combination (p &lt; 0.0001 vs. LIM), accompanied by improved renal indices (p &lt; 0.001). Pro-inflammatory cytokines were markedly reduced, NLRP3 immunostaining was minimal, and oxidative balance shifted toward homeostasis (\u2193 MDA; \u2191 SOD, catalase, GSH). Radiographic and histological evaluations corroborated attenuation of joint inflammation and tissue damage. Conclusions: In the PO + MSU gout model, co-administration of the food-derived compound LIM with low-dose ALP achieved additive, dose-sparing benefits across metabolic, inflammatory, and histological endpoints. While in vivo XO activity was not directly assessed, the findings are consistent with XO-pathway modulation, NLRP3\u2013IL-1\u03b2 suppression, and redox restoration. These results highlight the potential of dietary bioactives such as d-Limonene to complement standard urate-lowering therapy, warranting further pharmacokinetic and safety validation.<\/jats:p>","DOI":"10.3390\/nu18010072","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T02:07:58Z","timestamp":1766714878000},"page":"72","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Dose-Sparing Efficacy of d-Limonene with Low-Dose Allopurinol in a Dual Model of Hyperuricemia and Gouty Arthritis in Rats"],"prefix":"10.3390","volume":"18","author":[{"given":"Krishnaraju","family":"Venkatesan","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pooja","family":"Muralidharan","sequence":"additional","affiliation":[{"name":"Undergraduate Program, PSG College of Pharmacy, Peelamedu, Coimbatore 641004, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Durgaramani","family":"Sivadasan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, College of Pharmacy, Jazan University, Jizan 45142, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manimekalai","family":"Pichaivel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Swamy Vivekanadha College of Pharmacy, Elayampalayam, Nammakkal 637205, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8466-8694","authenticated-orcid":false,"given":"Yahya I.","family":"Asiri","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid A.","family":"Asseri","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5453-6332","authenticated-orcid":false,"given":"Nizar","family":"Sirag","sequence":"additional","affiliation":[{"name":"Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7964-1294","authenticated-orcid":false,"given":"Hassabelrasoul","family":"Elfadil","sequence":"additional","affiliation":[{"name":"Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5744-7773","authenticated-orcid":false,"given":"Mahmoud","family":"Elodemi","sequence":"additional","affiliation":[{"name":"Pharmacology Department, Faculty of Medicine, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kousalya","family":"Prabahar","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5117-480X","authenticated-orcid":false,"given":"Premalatha","family":"Paulsamy","sequence":"additional","affiliation":[{"name":"College of Nursing, Mahalah Branch for Girls King Khalid University, Khamis Mushayt 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7981-4562","authenticated-orcid":false,"given":"Kumarappan","family":"Chidambaram","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41572-019-0115-y","article-title":"Gout (primer)","volume":"5","author":"Dalbeth","year":"2019","journal-title":"Nat. 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