{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:20:23Z","timestamp":1790734823393,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T00:00:00Z","timestamp":1757548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["21K07348"],"award-info":[{"award-number":["21K07348"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endothelial dysfunction is closely linked to inflammation and oxidative stress and ultimately contributes to the development of cardiovascular diseases. Lipopolysaccharide (LPS), a major component of Gram-negative bacteria, induces vascular inflammation and oxidative damage in experimental models. Curcumin (Cur), a polyphenol from Curcuma longa, is well known for its anti-inflammatory and antioxidant properties. In this study, we examined the protective effects of CUD003, a novel synthetic Cur derivative, on the LPS-induced impairment of endothelium-dependent relaxation in the thoracic aorta of mice. Male ICR mice were pretreated with CUD003 or Cur (3 or 10 mg\/kg, p.o.) 30 min prior to LPS injection (10 mg\/kg, i.p.). Twenty-four hours after LPS injection, vascular reactivity was assessed in isolated aortic rings by evaluating vasorelaxation and vasoconstriction responses. LPS markedly impaired acetylcholine-induced vasorelaxation in the phenylephrine (PE)-precontracted aortic rings, while PE-induced contraction and sodium nitroprusside-induced relaxation were preserved, indicating that LPS impaired endothelium-dependent relaxation without affecting smooth muscle function. Immunohistochemical analysis revealed a reduction in eNOS expression and elevated levels of TNF-\u03b1, COX-2, O2\u2212, and malondialdehyde, indicating enhanced inflammation and oxidative stress in the aorta. Pretreatment with CUD003 (10 mg\/kg) significantly ameliorated these changes and showed superior protective effects compared to the same dose of Cur. These findings suggest that CUD003 protects against LPS-induced vascular dysfunction and suppresses inflammation and oxidative stress, supporting its potential as a preventive candidate against vascular inflammation and dysfunction.<\/jats:p>","DOI":"10.3390\/ijms26188850","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T15:10:46Z","timestamp":1757603446000},"page":"8850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["CUD003, a Novel Curcumin Derivative, Ameliorates LPS-Induced Impairment of Endothelium-Dependent Relaxation and Vascular Inflammation in Mice"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-0592-5160","authenticated-orcid":false,"given":"Hirokazu","family":"Matsuzaki","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7471-761X","authenticated-orcid":false,"given":"Anna","family":"Arai","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiyan","family":"Xuan","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3406-258X","authenticated-orcid":false,"given":"Bo","family":"Yuan","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Takayama","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Laboratory of Organic and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.vph.2017.05.005","article-title":"Oxidative Stress and Reactive Oxygen Species in Endothelial Dysfunction Associated with Cardiovascular and Metabolic Diseases","volume":"100","author":"Incalza","year":"2018","journal-title":"Vascul. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ro\u015fian, \u015e.H., Boarescu, I., and Boarescu, P.-M. (2025). Antioxidant and Anti-Inflammatory Effects of Bioactive Compounds in Atherosclerosis. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26031379"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Gallo, G., Volpe, M., and Savoia, C. (2022). Endothelial Dysfunction in Hypertension: Current Concepts and Clinical Implications. Front. Med., 8.","DOI":"10.3389\/fmed.2021.798958"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"J\u00f3zkowiak, M., Niebora, J., Domaga\u0142a, D., Data, K., Party\u0144ska, A., Kulus, M., Kotrych, K., Podralska, M., G\u00f3rska, A., and Chwi\u0142kowska, A. (2025). New Insights into Endothelial Cell Physiology and Pathophysiology. Biomed. Pharmacother., 190.","DOI":"10.1016\/j.biopha.2025.118415"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1089\/ars.2012.5149","article-title":"Reactive Oxygen Species in Inflammation and Tissue Injury","volume":"20","author":"Mittal","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7092151","DOI":"10.1155\/2019\/7092151","article-title":"Vascular Inflammation and Oxidative Stress: Major Triggers for Cardiovascular Disease","volume":"2019","author":"Steven","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Grylls, A., Seidler, K., and Neil, J. (2021). Link between Microbiota and Hypertension: Focus on LPS\/TLR4 Pathway in Endothelial Dysfunction and Vascular Inflammation, and Therapeutic Implication of Probiotics. Biomed. Pharmacother., 137.","DOI":"10.1016\/j.biopha.2021.111334"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Fock, E.M., and Parnova, R.G. (2021). Protective Effect of Mitochondria-Targeted Antioxidants against Inflammatory Response to Lipopolysaccharide Challenge: A Review. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13020144"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Kalyan, M., Tousif, A.H., Sonali, S., Vichitra, C., Sunanda, T., Praveenraj, S.S., Ray, B., Gorantla, V.R., Rungratanawanich, W., and Mahalakshmi, A.M. (2022). Role of Endogenous Lipopolysaccharides in Neurological Disorders. Cells, 11.","DOI":"10.3390\/cells11244038"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5839","DOI":"10.1073\/pnas.1804932115","article-title":"Oxygen Radicals, Nitric Oxide, and Peroxynitrite: Redox Pathways in Molecular Medicine","volume":"115","author":"Radi","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1093\/eurheartj\/ehr304","article-title":"Nitric Oxide Synthases: Regulation and Function","volume":"33","author":"Sessa","year":"2012","journal-title":"Eur. Heart J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1016\/j.hlc.2021.09.006","article-title":"The Effects of Probiotics on Inflammation, Endothelial Dysfunction, and Atherosclerosis Progression: A Mechanistic Overview","volume":"31","author":"Salari","year":"2022","journal-title":"Heart Lung Circ."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8623","DOI":"10.1002\/fsn3.4469","article-title":"On the Health Effects of Curcumin and Its Derivatives","volume":"12","author":"Ayub","year":"2024","journal-title":"Food Sci. Nutr."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kaur, K., Al-Khazaleh, A.K., Bhuyan, D.J., Li, F., and Li, C.G. (2024). A Review of Recent Curcumin Analogues and Their Antioxidant, Anti-Inflammatory, and Anticancer Activities. Antioxidants, 13.","DOI":"10.20944\/preprints202403.1292.v1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1111\/jpn.14029","article-title":"Curcumin, a Plant Polyphenol with Multiple Physiological Functions of Improving Antioxidation, Anti-Inflammation, Immunomodulation and Its Application in Poultry Production","volume":"108","author":"Zhang","year":"2024","journal-title":"J. Anim. Physiol. Anim. Nutr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4503","DOI":"10.2147\/DDDT.S327378","article-title":"Anti-Inflammatory Effects of Curcumin in the Inflammatory Diseases: Status, Limitations and Countermeasures","volume":"15","author":"Peng","year":"2021","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"12237","DOI":"10.1002\/jcp.27965","article-title":"Curcumin as a Therapeutic Candidate for Multiple Sclerosis: Molecular Mechanisms and Targets","volume":"234","author":"Ghanaatian","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ahmadabady, S., Beheshti, F., Shahidpour, F., Khordad, E., and Hosseini, M. (2021). A Protective Effect of Curcumin on Cardiovascular Oxidative Stress Indicators in Systemic Inflammation Induced by Lipopolysaccharide in Rats. Biochem. Biophys. Rep., 25.","DOI":"10.1016\/j.bbrep.2021.100908"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1038\/aps.2013.24","article-title":"Curcumin Inhibits LPS-Induced Inflammation in Rat Vascular Smooth Muscle Cells in Vitro via ROS-Relative TLR4-MAPK\/NF-\u03baB Pathways","volume":"34","author":"Meng","year":"2013","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"377","DOI":"10.3892\/etm.2014.2105","article-title":"Curcumin Protects against Lipopolysaccharide-Induced Vasoconstriction Dysfunction via Inhibition of Thrombospondin-1 and Transforming Growth Factor-\u03921","volume":"9","author":"Lu","year":"2014","journal-title":"Exp. Ther. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Vanucci-Bacqu\u00e9, C., and Bedos-Belval, F. (2021). Anti-Inflammatory Activity of Naturally Occuring Diarylheptanoids\u2014A Review. Bioorg. Med. Chem., 31.","DOI":"10.1016\/j.bmc.2020.115971"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"104490","DOI":"10.1016\/j.fitote.2020.104490","article-title":"Diarylheptanoid: A Privileged Structure in Drug Discovery","volume":"142","author":"Sun","year":"2020","journal-title":"Fitoterapia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e202400380","DOI":"10.1002\/asia.202400380","article-title":"Recent Advances in the Synthesis of Diarylheptanoids","volume":"19","author":"Sudarshan","year":"2024","journal-title":"Chem.\u2014Asian J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"H3726","DOI":"10.1152\/ajpheart.01116.2007","article-title":"Role of Angiotensin II in Endothelial Dysfunction Induced by Lipopolysaccharide in Mice","volume":"293","author":"Lund","year":"2007","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1124\/jpet.117.245217","article-title":"Paeonol Attenuates LPS-Induced Endothelial Dysfunction and Apoptosis by Inhibiting BMP4 and TLR4 Signaling Simultaneously but Independently","volume":"364","author":"Choy","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"B\u00e1nyai, B., R\u00e9p\u00e1s, C., Mikl\u00f3s, Z., Johnsen, J., Horv\u00e1th, E.M., and Benk\u0151, R. (2023). Delta 9-Tetrahydrocannabinol Conserves Cardiovascular Functions in a Rat Model of Endotoxemia: Involvement of Endothelial Molecular Mechanisms and Oxidative-Nitrative Stress. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0287168"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"138","DOI":"10.5152\/balkanmedj.2016.16879","article-title":"Resveratrol Prevented Lipopolysaccharide-Induced Endothelial Dysfunction in Rat Thoracic Aorta Through Increased eNOS Expression","volume":"33","year":"2016","journal-title":"Balk. Med. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.1080\/15384101.2022.2100682","article-title":"Protective Effect of Berberine against LPS-Induced Injury in the Intestine: A Review","volume":"21","author":"Izadparast","year":"2022","journal-title":"Cell Cycle"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kim, J.-D., Jain, A., and Fang, L. (2024). Mitigating Vascular Inflammation by Mimicking AIBP Mechanisms: A New Therapeutic End for Atherosclerotic Cardiovascular Disease. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910314"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s13105-025-01106-6","article-title":"The Role of Cell Junctions in Atherosclerosis: Implications for Inflammation, Endothelial Dysfunction, and Plaque Stability","volume":"81","author":"Dabravolski","year":"2025","journal-title":"J. Physiol. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.intimp.2014.01.024","article-title":"Curcumin Attenuates Inflammatory Responses by Suppressing TLR4-Mediated NF-\u03baB Signaling Pathway in Lipopolysaccharide-Induced Mastitis in Mice","volume":"20","author":"Fu","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular Properties That Influence the Oral Bioavailability of Drug Candidates","volume":"45","author":"Veber","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8856135","DOI":"10.1155\/2020\/8856135","article-title":"Comparation of Anti-Inflammatory and Antioxidantactivities of Curcumin, Tetrahydrocurcuminand Octahydrocurcuminin LPS-Stimulated RAW264.7 Macrophages","volume":"2020","author":"Xie","year":"2020","journal-title":"Evid.-Based Complement. Altern. Med. ECAM"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6603","DOI":"10.1002\/jsfa.12027","article-title":"Curcumin Alleviated Lipopolysaccharide-Induced Lung Injury via Regulating the Nrf2-ARE and NF-\u03baB Signaling Pathways in Ducks","volume":"102","author":"Liu","year":"2022","journal-title":"J. Sci. Food Agric."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3729399","DOI":"10.1155\/2023\/3729399","article-title":"Assessment of Safety Profile of Activated Curcumin C3 Complex (AC3\u00ae), Enriched Extract of Bisdemethoxycurcumin from the Rhizomes of Curcuma longa","volume":"2023","author":"Majeed","year":"2023","journal-title":"J. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.toxrep.2021.06.008","article-title":"Safety Assessment of a Highly Bioavailable Curcumin-Galactomannoside Complex (CurQfen) in Healthy Volunteers, with a Special Reference to the Recent Hepatotoxic Reports of Curcumin Supplements: A 90-Days Prospective Study","volume":"8","author":"Pancholi","year":"2021","journal-title":"Toxicol. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/ptr.6054","article-title":"Turmeric (Curcuma longa) and Its Major Constituent (Curcumin) as Nontoxic and Safe Substances: Review","volume":"32","author":"Soleimani","year":"2018","journal-title":"Phytother. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1111\/bcp.14460","article-title":"Acute Liver Injury Following Turmeric Use in Tuscany: An Analysis of the Italian Phytovigilance Database and Systematic Review of Case Reports","volume":"87","author":"Lombardi","year":"2021","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Asano, T., Matsuzaki, H., Xuan, M., Yuan, B., Takayama, J., Sakamoto, T., and Okazaki, M. (2025). Chronic Administration with FAD012 (3,5-Dimethyl-4-Hydroxycinnamic Acid) Maintains Cerebral Blood Flow and Ameliorates Swallowing Dysfunction After Chronic Cerebral Hypoperfusion in Rats. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26073277"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1089\/ars.2024.0629","article-title":"4-Octyl Itaconate Attenuates Cell Proliferation by Cellular Senescence via Glutathione Metabolism Disorders and Mitochondrial Dysfunction in Melanoma","volume":"42","author":"Hayashi","year":"2025","journal-title":"Antioxid. Redox Signal."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Asano, T., Xuan, M., Iwata, N., Takayama, J., Hayashi, K., Kato, Y., Aoyama, T., Sugo, H., Matsuzaki, H., and Yuan, B. (2023). Involvement of the Restoration of Cerebral Blood Flow and Maintenance of eNOS Expression in the Prophylactic Protective Effect of the Novel Ferulic Acid Derivative FAD012 against Ischemia\/Reperfusion Injuries in Rats. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119663"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.9734\/ijtdh\/2021\/v42i1130492","article-title":"In Silico ADME\/T Properties of Quinine Derivatives Using SwissADME and pkCSM Webservers","volume":"42","author":"Mvondo","year":"2021","journal-title":"Int. J. Trop. Dis. Health"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/8850\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:43:56Z","timestamp":1760035436000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/8850"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,11]]},"references-count":43,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26188850"],"URL":"https:\/\/doi.org\/10.3390\/ijms26188850","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,11]]}}}