Curcumin in Redox and Inflammatory Signaling: Mechanistic Insights into NF-κB and Nrf2 Pathway Regulation
Sorourozaman Shakeri Torshizi
1
(
Department of Food Science and Technology, Faculty of Agriculture, Ferdowsi University of Mashhad. Mashhad, Iran
)
Raed Fanoukh Aboqader
2
(
Al-Aouadi College of Medicine, Al-Ayen Iraqi University, AUIQ, An Nasiriyah, Iraq
)
Nuriddin Muhammadov
3
(
Department of Neurosurgery, Samarkand State Medical University, Samarkand, Uzbekistan
)
Oygul Khujaniyozova
4
(
Department of pedagogy and psychology, Urgench state university, Urgench, Uzbekistan
)
Zilolakhon Ruzmetova
5
(
Senior Lecturer of the Department of "Roman-Germanic Philology" Mamun University
)
Mehrigul Hayitova
6
(
Department of Medicine, Termez University of Economics and Service, Termez, Uzbekistan
)
Mohammadhossein Sakhaei Shahreza
7
(
Doctor Veterinary Medicine, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
)
Girish M S
8
(
Dental College and Hospital, JSS Academy of Higher Education and Research, SS NAGARA, Bannimantapa, Mysuru State:Karnataka , India
)
Farhad Safarpoor Dehkordi
9
(
Department of Food Hygiene, University of Tehran, Tehran, Iran
)
Shohreh Vahed
10
(
Department of Engineering, Shah. C., Islamic Azad University, Shahreza, Iran
)
Keywords: Curcumin, NF-κB, ROS, SOD, TNF-alpha, COX-2,
Abstract :
Curcumin demonstrates its anti-inflammatory properties via a multitude of molecular pathways. It effectively prevents the activation of nuclear factor-kappa B (NF-κB), a vital transcription factor responsible for the production of modifiable pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Additionally, curcumin downregulates the expression of cyclooxygenase-2 (COX-2) and lipoxygenase (LOX), thereby reducing the production of pro-inflammatory eicosanoids. Furthermore, it suppresses the activity of inducible nitric oxide synthase (iNOS), resulting in reduced nitric oxide synthesis and disrupting the expression of chemokines and adhesion molecules. Moreover, curcumin modulates immune responses by influencing the functionality of various immune cell types ultimately leading to a reduction in inflammation. These diverse actions render curcumin a promising candidate for the therapeutic management of chronic inflammatory disorders. Beyond its anti-inflammatory effects, curcumin possesses significant antioxidant capabilities. It directly scavenges reactive oxygen species (ROS), counting the superoxide anion, hydroxyl radical, and nitrogen dioxide. Indirectly, curcumin augments endogenous antioxidant defenses. Additionally, curcumin inhibits lipid peroxidation, thereby preserving the integrity of cellular membranes and mitigating oxidative damage. To surmount these challenges, various methodologies have been devised, including the application of nanoparticles, liposomes, phospholipid complexes, and co-administration with bioavailability accompaniments. Due to its capacity to concurrently target inflammatory and oxidative stress pathways, curcumin exhibits significant potential as an adjunctive therapeutic agent in a range of diseases considered by these pathological mechanisms. Ongoing clinical trials are actively assessing its efficacy and safety within human populations.
1. Olia B., Kabir F., Mashhadi Rafiei S., 2024. Impacts of curcumin on the healing procedure of eye cataracts in a rabbit model. Caspian Journal of Environmental Sciences. 1–8.
2. Lestari M.L.A.D., Indrayanto G., 2014. Curcumin. Profiles of Drug Substances, Excipients and Related Methodology. 39, 113–204.
3. Urošević M., Nikolić L., Gajić I., Nikolić V., Dinić A., Miljković V., 2022. Curcumin: Biological activities and modern pharmaceutical forms. Antibiotics.11(2), 135-145.
4. Geyer C.E., Mes L., Newling M., den Dunnen J., Hoepel W., 2021. Physiological and Pathological Inflammation Induced by Antibodies and Pentraxins. Cells. 10(5), 1175-1197.
5. Hamilton J.A., Cook A.D., Tak P.P., 2016. Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases. Nature Reviews. Drug Discovery. 16(1), 53–70.
6. Aggarwal D., Chaudhary M., Bajaj N., Sharma D., Upadhyay S.K., Garg V.K., Abdulabbas H.S., Tuli H.S., Rani I., 2024. Anti-inflammatory potential of curcumin: From chemistry and mechanistic insight to nanoformulations. Current Bioactive Compounds. 20(1), 10–20.
7. Sharifi-Rad J., Rayess Y. El, Rizk A.A., Sadaka C., Zgheib R., Zam W., Sestito S., Rapposelli S., Neffe-Skocińska K., Zielińska D., Salehi B., Setzer W. N., Dosoky N. S., Taheri Y., El Beyrouthy M., Martorell M., Ostrander E. A., Suleria H. A. R., Cho W. C., Martins N., 2020. Turmeric and Its Major Compound Curcumin on Health: Bioactive Effects and Safety Profiles for Food, Pharmaceutical, Biotechnological and Medicinal Applications. Frontiers in Pharmacology. 11, 1021-1044.
8. Peng Y., Ao M., Dong B., Jiang Y., Yu L., Chen Z., Hu C., Xu R., 2021. Anti-inflammatory effects of curcumin in the inflammatory diseases: status, limitations and countermeasures. Drug Design, Development and Therapy. 4503–4525.
9. Menon V.P., Sudheer A.R., 2007. Antioxidant and anti-inflammatory properties of curcumin. The Molecular Targets and Therapeutic Uses of Curcumin in Health and Disease. 105–125.
10. Rapti E., Adamantidi T., Efthymiopoulos P., Kyzas G.Z., Tsoupras A., 2024. Potential Applications of the Anti-Inflammatory, Antithrombotic and Antioxidant Health-Promoting Properties of Curcumin: A Critical Review. Nutraceuticals. 4(4), 562–595.
11. Jain S.K., Rains J., Croad J., Larson B., Jones K., 2009. Curcumin supplementation lowers TNF-alpha, IL-6, IL-8, and MCP-1 secretion in high glucose-treated cultured monocytes and blood levels of TNF-alpha, IL-6, MCP-1, glucose, and glycosylated hemoglobin in diabetic rats. Antioxidants & Redox Signaling. 11(2), 241–249.
12. Buhrmann C., Mobasheri A., Busch F., Aldinger C., Stahlmann R., Montaseri A., Shakibaei M., 2011. Curcumin modulates nuclear factor kappaB (NF-kappaB)-mediated inflammation in human tenocytes in vitro: role of the phosphatidylinositol 3-kinase/Akt pathway. The Journal of Biological Chemistry. 286(32), 28556–28566.
13. Rudrapal M., Eltayeb W.A., Rakshit G., El-Arabey A.A., Khan J., Aldosari S.M., Alshehri B., Abdalla M., 2023. Dual synergistic inhibition of COX and LOX by potential chemicals from Indian daily spices investigated through detailed computational studies. Scientific Reports. 13(1), 8656-8683.
14. Alam M.S., Anwar M.J., Maity M.K., Azam F., Jaremko M., Emwas A.H., 2024. The Dynamic Role of Curcumin in Mitigating Human Illnesses: Recent Advances in Therapeutic Applications. Pharmaceuticals (Basel, Switzerland). 17(12).
15. Islam M.R., Rauf A., Akash S., Trisha S.I., Nasim A.H., Akter M., Dhar P.S., Ogaly H.A., Hemeg H.A., Wilairatana P., Thiruvengadam M., 2024. Targeted therapies of curcumin focus on its therapeutic benefits in cancers and human health: Molecular signaling pathway-based approaches and future perspectives. Biomedicine & Pharmacotherapy. 170, 116034.
16. Hong J., Bose M., Ju J., Ryu J.H., Chen X., Sang S., Lee M.J., Yang C.S., 2004. Modulation of arachidonic acid metabolism by curcumin and related beta-diketone derivatives: effects on cytosolic phospholipase A(2), cyclooxygenases and 5-lipoxygenase. Carcinogenesis. 25(9), 1671–1679.
17. Liu T., Zhang L., Joo D., Sun S.C., 2017. NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy. 2, 17023-1745.
18. Natarajan K., Abraham P., Kota R., Isaac B., 2018. NF-κB-iNOS-COX2-TNF α inflammatory signaling pathway plays an important role in methotrexate induced small intestinal injury in rats. Food and Chemical Toxicology : An International Journal Published for the British Industrial Biological Research Association. 118, 766–783.
19. Aggarwal B.B., Harikumar K.B., 2009. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. The International Journal of Biochemistry & Cell Biology. 41(1), 40–59.
20. Lirk P., Hoffmann G., Rieder J., 2002. Inducible nitric oxide synthase--time for reappraisal. Current Drug Targets. Inflammation and Allergy. 1(1), 89–108.
21. Kim M.E., Lee J.S., 2025. Advances in the Regulation of Inflammatory Mediators in Nitric Oxide Synthase: Implications for Disease Modulation and Therapeutic Approaches. International Journal of Molecular Sciences. 26(3), 1204 -1223.
22. Fadus M.C., Lau C., Bikhchandani J., Lynch H.T., 2017. Curcumin: An age-old anti-inflammatory and anti-neoplastic agent. Journal of Traditional and Complementary Medicine. 7(3), 339–346.
23. Moon D.O., 2024. Curcumin in cancer and inflammation: An in-depth exploration of molecular interactions, therapeutic potentials, and the role in disease management. International Journal of Molecular Sciences. 25(5), 2911-2923.
24. Aggarwal B.B., Gupta S.C., Sung B., 2013. Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers. British Journal of Pharmacology. 169(8), 1672–1692.
25. Abd El-Hack M.E., El-Saadony M.T., Swelum A.A., Arif M., Abo Ghanima M.M., Shukry M., Noreldin A., Taha A.E., El-Tarabily K.A., 2021. Curcumin, the active substance of turmeric: its effects on health and ways to improve its bioavailability. Journal of the Science of Food and Agriculture. 101(14), 5747–5762.
26. Popko K., Gorska E., Stelmaszczyk-Emmel A., Plywaczewski R., Stoklosa A., Gorecka D., Pyrzak B., Demkow U., 2010. Proinflammatory cytokines Il-6 and TNF-α and the development of inflammation in obese subjects. European Journal of Medical Research. 15 Suppl 2(Suppl 2), 120–122.
27. Shakour N., Cabezas R., Santos J.G., Barreto G.E., Jamialahmadi T., Hadizadeh F., Sahebkar A., 2021. Curcumin can bind and interact with CRP: an in silico study. Pharmacological Properties of Plant-Derived Natural Products and Implications for Human Health. 91–100.
28. Guo Q., Jin Y., Chen X., Ye X., Shen X., Lin M., Zeng C., Zhou T., Zhang J., 2024. NF-κB in biology and targeted therapy: new insights and translational implications. Signal Transduction and Targeted Therapy. 9(1), 53.
29. Kim G.Y., Kim K.H., Lee S.H., Yoon M.S., Lee H.J., Moon D.O., Lee C.M., Ahn S.C., Park Y.C., Park Y.M., 2005. Curcumin inhibits immunostimulatory function of dendritic cells: MAPKs and translocation of NF-kappa B as potential targets. Journal of Immunology (Baltimore, Md.: 1950). 174(12), 8116–8124.
30. Pulido-Moran M., Moreno-Fernandez J., Ramirez-Tortosa C., Ramirez-Tortosa Mc., 2016. Curcumin and Health. Molecules. 21(3), 264-286.
31. Ferrer M.D., Busquets-Cortés C., Capó X., Tejada S., Tur J.A., Pons A., Sureda A., 2019. Cyclooxygenase-2 inhibitors as a therapeutic target in inflammatory diseases. Current Medicinal Chemistry. 26(18), 3225–3241.
32. Borra S.K., Mahendra J., Gurumurthy P., Iqbal S.S., Mahendra L., 2014. Effect of curcumin against oxidation of biomolecules by hydroxyl radicals. Journal of Clinical and Diagnostic Research: JCDR. 8(10), CC01-28.
33. Emami A.M., Homaee H.M., Azarbayjani M.A., 2016. Effects of high intensity interval training and curcumin supplement on glutathione peroxidase (GPX) activity and malondialdehyde (MDA) concentration of the liver in STZ induced diabetic rats. Iranian Journal of Diabetes and Obesity. 8(3), 129–134.
34. Suryanarayana P., Satyanarayana A., Balakrishna N., Kumar P.U., Reddy G.B., 2007., Effect of turmeric and curcumin on oxidative stress and antioxidant enzymes in streptozotocin-induced diabetic rat. Med Sci Monit. 13(12), 286-292.
35. Ming J., Ye J., Zhang Y., Xu Q., Yang X., Shao X., Qiang J., Xu P., 2020. Optimal dietary curcumin improved growth performance, and modulated innate immunity, antioxidant capacity and related genes expression of NF-κB and Nrf2 signaling pathways in grass carp (Ctenopharyngodon idella) after infection with Aeromonas hydrophila. Fish & Shellfish Immunology. 97, 540–553.
36. Sun Y.M., Wang R.X., Yuan S.L., Lin X.J., Liu C.B., 2010. Theoretical study on the antioxidant activity of curcumin. Chinese Journal of Chemistry. 22, 827–830.
37. Litwinienko G., Ingold K.U., 2004. Abnormal solvent effects on hydrogen atom abstraction. 2. Resolution of the curcumin antioxidant controversy. The role of sequential proton loss electron transfer. The Journal of Organic Chemistry. 69(18), 5888–5896.
38. Farhan M., Rizvi A., Aatif M., Ahmad A., 2023. Current understanding of flavonoids in cancer therapy and prevention. Metabolites. 13(4), 481-500.
39. Alhasawi M.A.I., Aatif M., Muteeb G., Alam M.W., Oirdi M. El, Farhan M., 2022. Curcumin and its derivatives induce apoptosis in human cancer cells by mobilizing and redox cycling genomic copper ions. Molecules. 27(21), 7410-7427.
40. Wolnicka-Glubisz A., Wisniewska-Becker A., 2023. Dual action of curcumin as an anti-and pro-oxidant from a biophysical perspective. Antioxidants. 12(9), 1725-1743.
41. Marton L.T., Barbalho S.M., Sloan K.P., Sloan L.A., Goulart R.A., Araújo A.C., Bechara M.D., 2022. Curcumin, autoimmune and inflammatory diseases: going beyond conventional therapy–a systematic review. Critical Reviews in Food Science and Nutrition. 62(8), 2140–2157.
42. Kandezi N., Mohammadi M., Ghaffari M., Gholami M., Motaghinejad M., Safari S., 2020. Novel Insight to Neuroprotective Potential of Curcumin: A Mechanistic Review of Possible Involvement of Mitochondrial Biogenesis and PI3/Akt/ GSK3 or PI3/Akt/CREB/BDNF Signaling Pathways TT. International Journal of Molecular and Cellular Medicine. 9(1), 1–32.
43. Miri Z.S., Bagheri H., Amani A., Karami H., 2025. Anti-tumor Effects of Curcumin and ABT-737 in Combination Therapy for Glioblastoma in Vivo. International Journal of Molecular and Cellular Medicine. 14(1), 552-566
44. Dcodhar S.D., Sethi R., Srimal R.C., 1980. Preliminary study on antirheumatic activity of curcumin (diferuloyl methane). Indian Journal of Medical Research. 71, 632-634.
45. Tazeoglu A., Ozdenkaya Y., Kamali G.H., Tazeoglu D., 2023., Anti-inflammatory activity of curcumin in a model of L-arginine-induced acute pancreatitis in rats. Annali Italiani Di Chirurgia. 12, 1–7.
46. Holt P.R., Katz S., Kirshoff R., 2005. Curcumin therapy in inflammatory bowel disease: a pilot study. Digestive Diseases and Sciences. 50, 2191–2193.
47. Lal B., Kapoor A.K., Agrawal P., Asthana O., Srimal R., 2000. Role of curcumin in idiopathic inflammatory orbital pseudotumours. Phytotherapy Research : PTR. 14, 443–447.
48. Guo J., Li Z., Yao Y., Fang L., Yu M., Wang Z., 2024. Curcumin in the treatment of inflammation and oxidative stress responses in traumatic brain injury: a systematic review and meta-analysis. Frontiers in Neurology. 15, 1380353-1380371.
49. Fuloria S., Mehta J., Chandel A., Sekar M., Rani N.N.I.M., Begum M.Y., Subramaniyan V., Chidambaram K., Thangavelu L., Nordin, R., Wu Y.S., Sathasivam K.V, Lum P.T., Meenakshi D.U., Kumarasamy V., Azad A.K., Fuloria N.K., 2022. A Comprehensive Review on the Therapeutic Potential of Curcuma longa Linn. in Relation to its Major Active Constituent Curcumin. Frontiers in Pharmacology. 13, 820806-820836.
50. Alizadeh M., Kheirouri S., 2019. Curcumin reduces malondialdehyde and improves antioxidants in humans with diseased conditions: a comprehensive meta-analysis of randomized controlled trials. BioMedicine. 9(4), 23-42.
51. Bagherniya M., Darand M., Askari G., Guest P.C., Sathyapalan T., Sahebkar A., 2021. The Clinical Use of Curcumin for the Treatment of Rheumatoid Arthritis: A Systematic Review of Clinical Trials. Advances in Experimental Medicine and Biology. 1291, 251–263.
52. Haftcheshmeh S., Khosrojerdi A., Aliabadi A., Lotfi S., Mohammadi A., Momtazi A.A., 2020. Immunomodulatory Effects of Curcumin in Rheumatoid Arthritis: Evidence from Molecular Mechanisms to Clinical Outcomes. In Reviews of Physiology, Biochemistry and Pharmacology .179,1-29.
53. Kou H., Huang L., Jin M., He Q., Zhang R., Ma J., 2023. Effect of curcumin on rheumatoid arthritis: a systematic review and meta-analysis. Frontiers in Immunology. 14, 1121655-1121678.
54. Xiao J., Cai X., Zhou W., Wang R., Ye Z., 2022. Curcumin relieved the rheumatoid arthritis progression via modulating the linc00052/miR-126-5p/PIAS2 axis. Bioengineered. 13(4), 10973–10983.
55. He Y., Yue Y., Zheng X., Zhang K., Chen S., Du Z., 2015. Curcumin, inflammation, and chronic diseases: how are they linked? Molecules (Basel, Switzerland). 20(5), 9183–9213.
56. Hamed A.M.R., Abdel-Shafi I.R., Elsayed M.D.A., Mahfoz A.M., Tawfeek S.E., Abdeltawab M.S.A., 2022. Investigation of the effect of curcumin on oxidative stress, local inflammatory response, COX-2 expression, and microvessel density in Trichinella spiralis induced enteritis, myositis and myocarditis in mice. Helminthologia. 59(1), 18-36.
57. Akyuz S., Turan F., Gurbuzler L., Arici A., Sogut E., Ozkan O., 2016. The Anti-Inflammatory and Antioxidant Effects of Curcumin in Middle Ear Infection. The Journal of Craniofacial Surgery. 27(5), e494-7.
58. Sanuelly A., De M., Orlando R., Oliveira F., Oliveira M., Moura F., 2023. Curcumin in inflammatory bowel diseases: Cellular targets and molecular mechanisms. Biocell. 47(11), 2547-2565.
59. Singla V., Pratap Mouli V., Garg S. K., Rai T., Choudhury B.N., Verma P., Deb R., Tiwari V., Rohatgi S., Dhingra R., 2014. Induction with NCB-02 (curcumin) enema for mild-to-moderate distal ulcerative colitis—A randomized, placebo-controlled, pilot study. Journal of Crohn’s and Colitis. 8(3), 208–214.
60. Hanai H., Iida T., Takeuchi K., Watanabe F., Maruyama Y., Andoh A., Tsujikawa T., Fujiyama Y., Mitsuyama K., Sata M., Yamada M., Iwaoka Y., Kanke K., Hiraishi H., Hirayama K., Arai H., Yoshii S., Uchijima M., Nagata T., Koide Y., 2006. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clinical Gastroenterology and Hepatology : The Official Clinical Practice Journal of the American Gastroenterological Association. 4(12), 1502–1506.
61. Banerjee R., Pal P., Penmetsa A., Kathi P., Girish G., Goren I., Reddy D.N., 2021. Novel Bioenhanced Curcumin With Mesalamine for Induction of Clinical and Endoscopic Remission in Mild-to-Moderate Ulcerative Colitis: A Randomized Double-Blind Placebo-controlled Pilot Study. Journal of Clinical Gastroenterology. 55(8), 702–708.
62. Ali B.H., Al-Salam S., Al Suleimani Y., Al Kalbani J., Al Bahlani S., Ashique M., Manoj P., Al Dhahli B., Al Abri N., Naser H.T., Yasin J., Nemmar A., Al Za’abi M., Hartmann C., Schupp N., 2018. Curcumin Ameliorates Kidney Function and Oxidative Stress in Experimental Chronic Kidney Disease. Basic & Clinical Pharmacology & Toxicology. 122(1), 65–73.
63. Bayrak O., Uz E., Bayrak R., Turgut F., Atmaca A. F., Sahin S., Yildirim M. E., Kaya A., Cimentepe E., Akcay A. 2008., Curcumin protects against ischemia/reperfusion injury in rat kidneys. World Journal of Urology. 26(3), 285–291.
64. Gibson P.G., Qin L., Puah S.H., 2020. COVID‐19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre‐COVID‐19 ARDS. The Medical Journal of Australia. 213(2), 54-71.
65. Rattis B.A.C., Ramos S.G., Celes M., 2021. Curcumin as a potential treatment for COVID-19. Frontiers in Pharmacology. 12, 675287-675298.