Synergistic Efficacy and Mechanistic Pathways of Curcumin-Based Combinations in the Management of Inflammation: A Comprehensive Review

Abstract

As inflammation plays a significant part in the pathophysiology of many diseases, it has emerged as a therapeutic target for the creation of novel pharmaceutical treatments. Non-steroidal anti-inflammatory medications and the steroid class of medications are known to have certain adverse effects when used to treat inflammation. Therefore, reducing inflammation is essential to reducing the disease's severity. Combining more than one drug to prevent inflammation in a synergistic way is one way to solve this issue. Over the past few decades, a lot of study has been done on the anti-inflammatory properties of curcumin, a bioactive component, particularly in the Zingiberaceae family, which offers a number of health benefits. Combinations of curcumin have been observed to improve anti-inflammatory properties. A review of the literature on curcumin combination studies has been conducted using several electronic sources, such as PubMed and Google Scholar. In this review, we provide an overview of curcumin's pharmacological action when combined with additional substances, with a focus on the synergistic anti-inflammatory effects. We offer enhanced bioavailability, which boosts antioxidants' ability to block inflammatory mediators, receptors, and important signaling pathways, in order to figure out how combinations produce a synergistic effect. This review offers information and promotes further investigation into the combination of pharmaceuticals to reduce inflammation.

Keywords

Introduction

There are around 200 various types of inflammatory diseases. Inflammation is indicated by the names of diseases that end in "itis." Although inflammation from chronic illnesses like cholangitis can induce colon cancer, acute inflammation is thought of as a defensive mechanism since it promotes recovery. Since inflammation contributes to the development of many chronic illnesses, including autoimmune, endocrine, neurological, and cardiovascular disorders, it will worsen these conditions if left untreated (1). Numerous enzymes, cytokines, chemokines, and polypeptide hormones that might mediate inflammation have been identified as a result of research into the molecular mechanisms behind inflammation. TNF, IL-1α, interleukin-1β (IL-1β), IL-6, interleukin-8 (IL-8), IL-18, chemokine, matrix metallopeptidase 9 (MMP-9), vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and 5-lipoxygenase (5-LOX) are among them. If the numbers of monocytes, neutrophils, eosinophils, and mast cells are not managed, additional immune cells will be drawn in to produce more proinflammatory chemicals. Because the process creates nitric oxide (NO) and reactive oxygen species (ROS), which harm the structure, function, and integrity of lipids, proteins, and nucleic acids, the result will be a variety of chronic disorders(2)The transcription factor of nucleus-κβ (NF-κβ) significantly controls the expression of this gene (3). Because it causes the release of several kinds of cytokines, chemokines, adhesion molecules, and leukocyte recruitment, the NF-κβ pathway weakens the NF-κβ pathway as a therapeutic approach for chronic inflammation(4). Non-steroidal anti-inflammatory drugs, for example, can raise the risk of adverse gastrointestinal, renal, and cardiovascular effects. Anti-inflammatory drugs temporarily reduce inflammation symptoms, but the disease progresses over time(5). Although anti-inflammatory corticosteroid medications have a potent therapeutic benefit for a number of conditions, prolonged use also has negative side effects(6).

Many rhizomes of the Curcuma longa and Zingiberaceae family contain curcumin, a secondary metabolite used as a medicinal plant with anti-inflammatory and antioxidant qualities (7). Up until today, curcumin has been used widely in traditional medicine. Numerous studies have been conducted to understand the medicinal uses of curcumin, 1, 7-bis (4-hydroxy-3-methoxyphenyl)-1,6-heptadien-3,5-dione, and the yellow pigment in turmeric rhizome, particularly in the Asian region(8). Because curcumin interacts with numerous inflammatory routes and processes, it has pharmacological effects on decreasing inflammation. Curcumin has been shown to have a number of health advantages, including anti-inflammatory, antioxidant, chemopreventive, and chemotherapeutic properties(9). Human clinical trials, animal models, and cultured cells have all shown the pharmacological action(10). Opportunities for treating drug resistance and toxicity are presented by compound combination studies(11). Severe and chronic illnesses are treated with a combination of medications. Achieving a synergistic therapeutic impact, lowering the dosage to minimize toxicity, and limiting or postponing the establishment of drug resistance are just a few of the many therapy benefits that this combination offers(12).  The purpose of this review is to examine how curcumin can work in concert with two or more other medications to have an anti-inflammatory effect as opposed to just one application. The anti-inflammatory benefits that emerge from combining different components with curcumin are summarized in this paper, with a focus on the outcomes of the synergistic anti-inflammatory impact. The advantages of this review include scientific data about the combined effects of curcumin with other ingredients to reduce inflammation. It is anticipated that the review's findings would bring clarity on methods for managing inflammation that work in concert with one another to deliver a successful treatment with minimal side effects.

METHOD

To identify all papers on the topic up until March 2026, a thorough search of the PubMed and Google Scholar databases was carried out. The keywords "curcumin, combination, and anti-inflammatory" were used to locate relevant papers. Articles utilizing a combination of curcumin components (drugs or phytochemicals) that can have anti-inflammatory effects, comparing the effects of curcumin alone with a combination, and producing anti-inflammatory effects that are synergistic or superior to using curcumin alone were all included in this review. A few English-language publications were chosen on the basis that they offer comparison information between curcumin's single usage and its combination. Conference, review, and thesis articles were not considered primary articles. found 67 main articles of components combined with curcumin (Table 1). These chosen articles were based on research on curcumin and its combination conducted both in vitro and in vivo. During the selection of these articles, we reviewed them primarily by evaluating the kinds of test animals, cells, induction agent employed, and the results of these combinations.

Determination of the effects of a combination

In medicine, it is common practice to combine several kinds of drug components. Combinations of two or more elements can provide additive, synergistic, or antagonistic effects; a single method does not necessarily improve its particular pharmacological impact. Worldwide, the Chou-Talalay approach has been utilized in conjunction with drug research and effect assessments. According to(13), the combination index (CI) shows additive impact when CI = 1, synergism when CI < 1, and antagonism when CI > 1. Our investigation revealed that this approach is frequently employed for medication combination research. The following formula was used to calculate the combination of indexes.:

CI =D1Dm1+D2Dm2

 

 (D)1 and (D)2 are the concentrations of components X and Y which are combined to produce a value of IC50. (Dm)1 and (Dm)2 are the concentrations of components X and Y given singly and obtained the value of IC50. The same method used in CI was used to determine the cumulative effect in test animals. Combination studies, however, show that medications have limitations, including higher costs, longer processing times, and population and group restrictions. In this review, we were able to quantify the combined in vitro effect by comparing the drug's combined and uncombined effects. A straightforward formula of X + Y > X or X + Y > Y produced the effect. It can be determined that a medication combination has a synergistic impact in clinical trial research if it produces a better pharmacological effect than monotherapy(12). It is known from this review that a number of in vitro investigations have employed the CI method. Only the curcumin combination with a synergistic anti-inflammatory effect was explored in studies that used test animals to determine the synergy effect based on a comparison between combination and single use.

Effect of curcumin on anti-inflammation

Several pharmacological effects of curcumin, particularly its anti-inflammatory qualities, have been documented. It is well known that curcumin can reduce both acute and chronic inflammation(8). Curcumin can act alone or in combination through a number of different methods. Curcumin inhibits the COX and LOX pathways, arachidonic acid metabolic activities, and prostaglandin formation as part of its anti-inflammatory mechanism. COX-2 expression is selectively inhibited by curcumin(14, 15). Compared to the COX-1 enzyme, curcumin is more active against the COX-2 enzyme(16). By decreasing COX-2 and preventing prostaglandin E2 synthesis (PGE2), curcumin can stop anti-inflammatory reactions in synovial fibroblasts(17). Cyclooxygenase activity on human platelets and 5-LOX inhibition on rat peritoneal neutrophils both demonstrate curcumin's anti-inflammatory properties(18). Because curcumin can lower the production of proinflammatory cytokines like IL-8, inflammatory protein monocyte-1, chemotactic protein monocyte-1 (MCP-1), IL-1β, and tumor necrosis factor-α (TNF-α), its ability to suppress inflammation has been demonstrated in both in vitro and in vivo studies(19, 20).  Curcumin inhibits the effects of high hyperglycemia and the release of TNF-α, MCP-1, IL-6, and IL-8 in cultured monocytes(21). Curcumin has demonstrated its effectiveness as a potent asthma reliever in another trial. This action is caused by a mechanism that lowers immunoglobulin E2 and inhibits the production of IL-2, IL-4, and IL-5(22). By controlling the production of NF-κβ, activator protein 1, inducible nitric oxide synthase (iNOS), TNF-α, and IL-6, curcumin also exhibits anti-inflammatory effects in pancreatitis rats(23). The in vitro test demonstrated curcumin's capacity to inhibit the NF-κβ and mitogen-activated protein kinase (MAPK) pathways; it also reduces TNF-α and IL-6 in BV2 microglia cells challenged with lipopolysaccharide(24).

By lowering ROS production and boosting enzymatic activity, such as the expression of methionine sulfoxide reductase A, curcumin activity might lessen inflammation. Additionally, it raises enzymes including glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD)(25). Curcumin at a dose of 200 mg/kg can help boost SOD activity, CAT, and total liver antioxidant capacity in rats given thallium acetate(26).  Because of its antioxidant properties, curcumin can function as an oxidative DNA cleaver and a NO scavenger(27). Curcumin also inhibits the expression of the iNOS gene in BALB/c mice recovered from peritoneal macrophages and livers of mice treated with lipopolysaccharide (LPS)(28). In RAW 264.7 cells treated with lipopolysaccharide or interferon-γ, curcumin can reduce NO generation, iNOS, and messenger ribonucleic acid (mRNA) protein expression(29). Lipid peroxidation, a process seen in rat liver microsomes, has been demonstrated to be inhibited by curcumin(30). Curcuminoids also exhibit antioxidant action in rat brain homogenates(31).

Chronic inflammation caused by oxidative stress has a significant impact on the production of TNF-α and nucleus-κβ (NF-κβ) factor pathways, which increase the inflammatory response. Curcumin inhibits IκB kinase (IKK) and constitutive NF-κβ. NF-κβ controls the reduction of proliferation, cell cycle arrest, and apoptosis induction brought on by the blockage of several gene product expression pathways(95).

Enhancing the bioavailability of curcumin

Several studies have been carried out to determine the oral curcumin's bioavailability in experimental rats, which corresponds to about 1% (96). By controlling absorption, distribution, metabolism, and excretion, medication combinations can have strong or reductive pharmacokinetic effects that can either improve or decrease the therapeutic efficacy of one drug by the other(13). Curcumin has a low pharmacokinetic profile, weak water solubility, and chemical instability. Therefore, regardless of its effectiveness and safety, curcumin's comparatively low bioavailability in humans raises questions about its potential therapeutic function(97).In this review, we discovered that using piperine in combination reduces inflammation more effectively than using it alone. Piperine is a potent bioavailability enhancer that can increase curcumin's absorption(32). When combined with piperine, curcumin can boost its bioavailability in rats and humans, but it also causes half-time elimination and drastically reduces maximal time and clearance(36). Because piperine lowers the activity of the glucuronidase enzyme, curcumin absorption increases(98). By increasing intestinal perfusion and enterocyte permeability, piperine's additional mechanism improves curcumin's bioavailability(99). Male Wistar rats given 50 mg/kg of curcumin and 2.5 mg/kg of piperine orally for 21 days had lower levels of inflammatory mediator parameters, including NO, TNF-α, and NF-κβ. Piperine inhibits small intestine glucuronidation, which increases curcumin absorption. Additionally, piperine has the ability to slow down curcumin's transit through the digestive tract, prolonging its stay in the intestine and facilitating a higher absorption process(38).Intestinal bacteria, including Blautia sp. and Escherichia coli, metabolize curcumin. According to (100), these microorganisms are discovered to be active by a NADPH-dependent reductase in a two-step reduction pathway from curcumin to the intermediate product, dihydrocurcumin, and the final product, tetrahydrocurcumin. In the same way, piperine increases the conversion of curcumin into tetrahydrocurcumin through microbial metabolism in the digestive system. Consequently, the adipose tissue may be reached by this molecule(34). According to (101), the addition of curcumin to emu oil may increase the flux through the mouse skin by 1.84 and 4.25 times, which can lower the expression of proinflammatory mediators IL-1 β, IL-6, and TNF-α (46). This suggests that curcumin is a newly effective treatment for wound healing. Increasing curcumin's bioavailability can be done in conjunction with topical or oral use, according to this review.

Increasing antioxidant

Curcumin's structure contains numerous functional groups, including as carbon–carbon double bonds, β-diketone groups, and phenyl rings with hydroxyl and methoxy substituents. The action of curcumin is significantly influenced by the presence of phenolic OH in the curcumin structure(102). The synergistic impact of the components may boost its effectiveness at low doses to prevent or completely eradicate tissue damage brought on by the start of oxidative stress. By controlling important genes brought on by oxidative stress and preventing the production of cytokines that cause inflammatory pathways, the combination of antioxidants can protect against the development of oxidative stress and inflammation(60). LPS, viruses, proinflammatory cytokines, and oxidative stress can all stimulate NF-κβ, which ultimately controls IkBα phosphorylation and proteasomal breakdown. In order to produce proinflammatory mediators such cytokines, COX-2, and iNOS, this mechanism will lead to translocation that continues after NF-κβ binds to the gene promoter region in the nucleus(76).By boosting antioxidant defense through free radical scavenging, resveratrol and curcumin reduce tissue oxidative damage and work in concert to reverse it. By functioning as an antioxidant, resveratrol shields curcumin molecules from one another(40). Combining curcumin at a dose of 50 mg/kg with quercetin at a dose of 50 mg/kg can boost its anti-inflammatory and antioxidant properties in a synergistic way. For four weeks, 100 mg/kg of quercetin and 5 ml/kg of curcumin should be administered. By lowering excessive MDA generation, preserving tissue antioxidant capacity, and enhancing liver enzymatic activity, diazinon-induced rats exhibit a synergistic protective effect (26).The combination of 50 mg/kg of curcumin and 50 mg/kg of berberine has an increased anti-inflammatory impact that may reduce lipid metabolism, oxidative stress, and liver inflammation(61). Additionally, berberine combination treatment has a synergistic effect on lowering oxidative stress and inflammatory responses in rats' hippocampus and cortex(72).
The antioxidant capacity is increased by the addition of vitamin E. 1.5 mg/g of vitamin E and 1 mg/g of curcumin raise fatty acid β oxidation, CAT activity, and mitochondrial biogenesis. Hepatic steatosis and lobular inflammation are reduced by the combination(59). Because vitamin B2 stimulates antioxidant genes such heme oxygenase 1 (HO-1), nuclear transcription factor erythroid 2 (Nrf2), and peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, it reduces inflammation(60). Because curcumin is a potent antioxidant that raises SOD, GSH, HO-1, and CAT, it can be added to medications like metformin, acetylsalicylic acid, and Rhizoma Paridis saponins to prevent liver damage(79). Combining curcumin with polyunsaturated fatty acid, docosahexaenoic acid, or eicosapentaenoic acid can increase its anti-inflammatory and antioxidant properties in a synergistic manner(73). Curcumin is used in triple therapy regimens for patients with chronic gastritis. These regimens show antioxidant benefits, prevent oxidative damage to DNA cells, and ultimately lower the rate of chronic inflammation(103).
Numerous substances are said to possess antioxidant properties that can directly scavenge reactive oxygen species (ROS), temper the mitochondrial respiratory chain and metal chelating agents, and boost endogenous antioxidant enzymes including glutathione peroxidase, SOD, and CAT(104).
Certain mechanisms cause an increase in antioxidant activity, such as the self-protecting mechanism because the combined compound can simultaneously detect multiple antioxidant functions and scavenge certain physiological radical species, inhibit the prooxidant apoenzyme, and reduce and chelate iron ions(105). These elements shield one another from oxidative agents through a range of antioxidant pathways(106). Synergistic antioxidant interactions are made easier by variations in the orientation of the constituents at the water or lipid interface(107).
Inhibiting essential signaling pathways, receptors, and inflammatory mediatorsChemical components interact with inflammatory marker cells and signaling pathways, and these relationships are quite detailed. Reaching the threshold level of pathway activation is crucial for the combination delivery strategy, as the separate components are unable to do so. According to reports, proinflammatory molecules such TNF-α, IL-1β, IL-6, and NO are inhibited by resveratrol quercetin puerarin, luteolin, and thymoquinone. On RAW 264.7 cells, quercetin and resveratrol(108). decrease inflammatory-inducing enzymes such COX-2 and iNOS, which can also lower NO levels by controlling the NF-κβ pathway. The anti-inflammatory cytokine IL-10 is known to be stimulated by phytochemicals like resveratrol and a class of flavonoids like luteolin and quercetin(109). MDA, TNFα, nitrite levels, COX-1, and COX-2 are all significantly inhibited by flavocoxid(110). By lowering T-cell activation and proliferation, vitamin D and curcumin work together in response to inflammation and prevent altered lymphocyte activity in rheumatic rats(62). Curcumin exhibits cell-specific interactions, signaling pathways, and inflammatory indicators when combined with these constituents.
To provide a synergistic anti-inflammatory action, two or more components can target the same immune cell or distinct cells, controlling the generation of inflammatory markers along the same or alternative routes. Molecular events, such as the activation of immune cells and an increased level of inflammatory enzymes like cytokines, are involved in chronic inflammation that results in carcinogenesis. The pathophysiology of many diseases, including cancer, is initiated by dysregulation of the mammalian target of rapamycin complex 1 (mTORC1). Curcumin and piperine together have a greater ability to control mTORC1 activity than curcumin by itself. In this combination, piperine suppresses COX-2 production and the TNF-α signaling pathway through mTORC1(35). Curcumin and piperine's capacity to inhibit the NF-κβ signaling pathway can cause inflammation; this inhibition prevents TNF-α from being produced and lowers the expression of intercellular protein, adhesion molecule-1, and vascular cell adhesion molecule-1 (VCAM-1)(81).The primary inflammatory mediators, such TNF-α, produce intermediates for a number of chronic inflammatory diseases, autoimmune disorders, and more severe cancers when they are not properly controlled and secreted over time(111). By preventing NF-κβ from translocating into the nucleus, luteolin suppresses TNF-α-induced monocyte adhesion as well as the production of MCP-1 and VCAM-1(112). The combined synergistic impact of curcumin and resveratrol results in a CI value of CI < 1.0 on the prevention of colon cancer growth, which is linked to diminished NF-κβ activity, apoptosis stimulation, and proliferation inhibition(42). It has been demonstrated that curcumin and capsaicin reduce NF-κβ activation; Animals given carrageenan injections experience the inhibitory impact of inflammation of both components in the enzyme 5-lipoxygenase(80). By preventing NF-κβ from being activated, a combination of curcuminoid extract, hydrolyzed collagen, and green tea extract can lower inflammation as well as the production of inflammatory and catabolic mediators by chondrocytes(57). Because resveratrol can hold onto phosphorylated IκBα and prevent activated NF-κβ from moving to the nucleus, both curcumin and resveratrol have the ability to suppress the NF-κβ signal transduction pathway. Curcumin also has the effect of reducing the translocation of activated NF-κβ to the nucleus(41). The primary signaling proteins in response to inflammation, cytokines, are involved in the inflammatory process. Growth factor β and interferon γ are altered by the proinflammatory cytokines IL-1, IL-6, IL-15, IL-17, IL-23, and TNF-α and the anti-inflammatory cytokines IL-4, IL-10, and IL-13(113). One significant class of cytokines that is crucial for immunological regulation is interleukins. This modulation includes IL-1, which controls the transformation of phagocytes that infiltrate during cancer or inflammation, causing the production of inflammatory molecules like chemokines, integrins, and MMP as well as free radicals like ROS and reactive nitrogen species(114). At a dose of 1 grams per kilogram and piperine at a dose of 50 milligrams per kilogram can both considerably lower IL-1β and reduce the weight of mice caused by excessive fat(37). If unchecked production results in a variety of inflammatory disorders, the presence of IL-6 is crucial in acute inflammation(115). Curcumin and ursolic acid together have a big impact. on preventing IκBα and NF-κβ from being phosphorylated. The NF-κβ signaling pathway is inhibited by lower COX-2 protein levels and lower production of inflammatory marker genes such IL-1β, IL-6, and CXCL2(64). In LPS-induced Sprague Dawley rats, puerarin with curcumin boosts anti-inflammatory cytokines like IL-10 and lowers proinflammatory cytokines like IL-1β and MMP-9, making it more effective and nontoxic(53). Mice with LPS exhibit altered behavior and elevated cytokine levels, whereas mice given 5 mg/kg salidroside and 20 mg/kg curcumin exhibit antidepressant-like effects similar to those of fluoxetine, as well as possible synergistic reduction of TNF-α and IL-6 and anti-stress effects(66).By blocking the activity of the inhibitory I-kB kinase, the anti-inflammatory combination regulates several pathways, inhibits the MAPK pathway, and stimulates NF-κβ generated by cytokines and proinflammatory gene expression. Additionally, it prevents the production of prostaglandins by inhibiting iNOS expression, arachidonic acid pathways, and the proinflammatory cytokine synthesis pathway. This suppresses immune cell migration and proliferation, which in turn prevents inflammation.

CONCLUSION

Enhanced antioxidants, enhanced curcumin bioavailability, modulation of many pathways, and inflammatory markers all contribute to the curcumin combination's anti-inflammatory action. In order to reduce the consequences of oxidative stress, the combination with certain components can directly scavenge enhanced ROS and boost antioxidants. Further reduction of the NF-κβ signaling pathway is directly regulated by the decreased ROS. Proinflammatory indicators' transcription and translation processes are deregulated by attenuated NF-κβ, while antiinflammatory molecules are elevated. Combining curcumin with piperine can boost its bioavailability. This review offers suggestions for further investigation into the use of chemicals in combination to lower inflammation. The present analysis has given an outline of how inflammation's molecular mechanisms occur, their pharmaceutical remedies, and the manner in which the present review has offered An outline of how inflammation's molecular mechanisms occur, their pharmacological therapies, and the potential interactions between curcumin molecules in their pharmacological effects while preventing negative side effects. The evolution of Drug combination techniques is crucial for more effective treatment of a range of inflammatory diseases, both acute and chronic. In this review, we gathered and examined curcumin research data. combination and determined that there are multiple elements to
be used in addition with curcumin to provide anti-inflammatory activity, and clinical trials have included such experiments.

REFERENCES

1. Chen L, Deng H, Cui H, Fang J, Zuo Z, Deng J, et al. Inflammatory responses and inflammation-associated diseases in organs. 2017;9(6):7204.
2. Ben-Baruch A, editor Inflammation-associated immune suppression in cancer: the roles played by cytokines, chemokines and additional mediators. Seminars in cancer biology; 2006: Elsevier.
3. Aggarwal BB, Gupta SC, Sung BJBjop. Curcumin: an orally bioavailable blocker of TNF and other pro?inflammatory biomarkers. 2013;169(8):1672-92.
4. Lawrence TJCSHpib. The nuclear factor NF-κB pathway in inflammation. 2009;1(6):a001651.
5. Bacchi S, Palumbo P, Sponta A, Coppolino MFJA-I, Chemistry A-AAiM. Clinical pharmacology of non-steroidal anti-inflammatory drugs: a review. 2012;11(1):52-64.
6. Buchman ALJJocg. Side effects of corticosteroid therapy. 2001;33(4):289-94.
7. Lestari ML, Indrayanto GJPods, excipients, methodology r. Curcumin. 2014;39:113-204.
8. Noorafshan A, Ashkani-Esfahani SJCpd. A review of therapeutic effects of curcumin. 2013;19(11):2032-46.
9. Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, Ramirez-Tortosa MJM. Curcumin and health. 2016;21(3):264.
10. Hatcher H, Planalp R, Cho J, Torti FM, Torti SVJC, sciences ml. Curcumin: from ancient medicine to current clinical trials. 2008;65(11):1631-52.
11. Bulusu KC, Guha R, Mason DJ, Lewis RP, Muratov E, Motamedi YK, et al. Modelling of compound combination effects and applications to efficacy and toxicity: state-of-the-art, challenges and perspectives. 2016;21(2):225-38.
12. Chou T-CJCr. Drug combination studies and their synergy quantification using the Chou-Talalay method. 2010;70(2):440-6.
13. Chou T-CJPr. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. 2006;58(3):621-81.
14. Goel A, Boland CR, Chauhan DPJCl. Specific inhibition of cyclooxygenase-2 (COX-2) expression by dietary curcumin in HT-29 human colon cancer cells. 2001;172(2):111-8.
15. Kunnumakkara AB, Diagaradjane P, Anand P, Kuzhuvelil HB, Deorukhkar A, Gelovani J, et al. Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX?2, MMP?9, VEGF and CXCR4 expression in an orthotopic mouse model. 2009;125(9):2187-97.
16. Ramsewak R, DeWitt D, Nair MJP. Cytotoxicity, antioxidant and anti-inflammatory activities of curcumins I–III from Curcuma longa. 2000;7(4):303-8.
17. Moon D-O, Kim M-O, Choi YH, Park Y-M, Kim G-YJIi. Curcumin attenuates inflammatory response in IL-1β-induced human synovial fibroblasts and collagen-induced arthritis in mouse model. 2010;10(5):605-10.
18. Ammon H, Safayhi H, Mack T, Sabieraj JJJoe. Mechanism of antiinflammatory actions of curcumine and boswellic acids. 1993;38(2-3):105-12.
19. Anthwal A, Thakur BK, Rawat M, Rawat D, Tyagi AK, Aggarwal BBJBri. Synthesis, characterization and in vitro anticancer activity of C?5 curcumin analogues with potential to inhibit TNF?α?induced NF?κB activation. 2014;2014(1):524161.
20. Gupta SC, Tyagi AK, Deshmukh-Taskar P, Hinojosa M, Prasad S, Aggarwal BBJAob, et al. Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. 2014;559:91-9.
21. Jain SK, Rains J, Croad J, Larson B, Jones KJA, signaling r. Curcumin supplementation lowers TNF-α, IL-6, IL-8, and MCP-1 secretion in high glucose-treated cultured monocytes and blood levels of TNF-α, IL-6, MCP-1, glucose, and glycosylated hemoglobin in diabetic rats. 2009;11(2):241-9.
22. Chung S-H, Choi SH, Choi JA, Chuck RS, Joo C-KJMV. Curcumin suppresses ovalbumin-induced allergic conjunctivitis. 2012;18:1966.
23. Gulcubuk A, Haktanir D, Cakiris A, Ustek D, Guzel O, Erturk M, et al. Effects of curcumin on proinflammatory cytokines and tissue injury in the early and late phases of experimental acute pancreatitis. 2013;13(4):347-54.
24. Cho J-W, Lee K-S, Kim C-WJIjomm. Curcumin attenuates the expression of IL-1β, IL-6, and TNF-α as well as cyclin E in TNF-α-treated HaCaT cells; NF-κB and MAPKs as potential upstream targets. 2007;19(3):469-74.
25. Dai C, Tang S, Li D, Zhao K, Xiao XJTm, methods. Curcumin attenuates quinocetone-induced oxidative stress and genotoxicity in human hepatocyte L02 cells. 2015;25(4):340-6.
26. Abdel-Daim MM, Abdou RHJCJ. Protective effects of diallyl sulfide and curcumin separately against thallium-induced toxicity in rats. 2015;17(2):379.
27. Ahsan H, Parveen N, Khan NU, Hadi SJC-bi. Pro-oxidant, anti-oxidant and cleavage activities on DNA of curcumin and its derivatives demethoxycurcumin and bisdemethoxycurcumin. 1999;121(2):161-75.
28. Chan MM-Y, Huang H-I, Fenton MR, Fong DJBp. In vivo inhibition of nitric oxide synthase gene expression by curcumin, a cancer preventive natural product with anti-inflammatory properties. 1998;55(12):1955-62.
29. Fu X-y, Yang M-f, Cao M-z, Li D-w, Yang X-y, Sun J-y, et al. Strategy to suppress oxidative damage-induced neurotoxicity in PC12 cells by curcumin: the role of ROS-mediated DNA damage and the MAPK and AKT pathways. 2016;53(1):369-78.
30. Pulla Reddy AC, Lokesh BJM, biochemistry c. Studies on spice principles as antioxidants in the inhibition of lipid peroxidation of rat liver microsomes. 1992;111(1):117-24.
31. Sreejayan, Rao MJJoP, Pharmacology. Curcuminoids as potent inhibitors of lipid peroxidation. 1994;46(12):1013-6.
32. Jangra A, Kwatra M, Singh T, Pant R, Kushwah P, Sharma Y, et al. Piperine augments the protective effect of curcumin against lipopolysaccharide-induced neurobehavioral and neurochemical deficits in mice. 2016;39(3):1025-38.
33. Rinwa P, Kumar A, Garg SJPo. Suppression of neuroinflammatory and apoptotic signaling cascade by curcumin alone and in combination with piperine in rat model of olfactory bulbectomy induced depression. 2013;8(4):e61052.
34. Neyrinck AM, Alligier M, Memvanga PB, Névraumont E, Larondelle Y, Préat V, et al. Curcuma longa extract associated with white pepper lessens high fat diet-induced inflammation in subcutaneous adipose tissue. 2013;8(11):e81252.
35. Kaur H, He B, Zhang C, Rodriguez E, Hage DS, Moreau RJTJonb. Piperine potentiates curcumin-mediated repression of mTORC1 signaling in human intestinal epithelial cells: implications for the inhibition of protein synthesis and TNFα signaling. 2018;57:276-86.
36. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PJPm. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. 1998;64(04):353-6.
37. Miyazawa T, Nakagawa K, Kim SH, Thomas MJ, Paul L, Zingg J-M, et al. Curcumin and piperine supplementation of obese mice under caloric restriction modulates body fat and interleukin-1β. 2018;15(1):12.
38. Bishnoi M, Chopra K, Rongzhu L, Kulkarni SKJNr. Protective effect of curcumin and its combination with piperine (bioavailability enhancer) against haloperidol-associated neurotoxicity: cellular and neurochemical evidence. 2011;20(3):215-25.
39. Martins CA, Leyhausen G, Volk J, Geurtsen WJJoe. Curcumin in combination with piperine suppresses osteoclastogenesis in vitro. 2015;41(10):1638-45.
40. AlBasher G, Abdel-Daim MM, Almeer R, Ibrahim KA, Hamza RZ, Bungau S, et al. Synergistic antioxidant effects of resveratrol and curcumin against fipronil-triggered oxidative damage in male albino rats. 2020;27(6):6505-14.
41. Csaki C, Mobasheri A, Shakibaei MJAr, therapy. Synergistic chondroprotective effects of curcumin and resveratrol in human articular chondrocytes: inhibition of IL-1β-induced NF-κB-mediated inflammation and apoptosis. 2009;11(6):R165.
42. Majumdar AP, Banerjee S, Nautiyal J, Patel BB, Patel V, Du J, et al. Curcumin synergizes with resveratrol to inhibit colon cancer. 2009;61(4):544-53.
43. Coradini K, Lima F, Oliveira C, Chaves P, Athayde M, Carvalho L, et al. Co-encapsulation of resveratrol and curcumin in lipid-core nanocapsules improves their in vitro antioxidant effects. 2014;88(1):178-85.
44. Friedrich RB, Kann B, Coradini K, Offerhaus HL, Beck RC, Windbergs MJEjops. Skin penetration behavior of lipid-core nanocapsules for simultaneous delivery of resveratrol and curcumin. 2015;78:204-13.
45. Malhotra A, Nair P, Dhawan DKJEJoCP. Curcumin and resveratrol synergistically stimulate p21 and regulate cox-2 by maintaining adequate zinc levels during lung carcinogenesis. 2011;20(5):411-6.
46. Zhang L, Wang X, Si HJTJoNB. Synergistic anti-inflammatory effects and mechanisms of the combination of resveratrol and curcumin in human vascular endothelial cells and rodent aorta. 2022;108:109083.
47. Gan Z, Wei W, Li Y, Wu J, Zhao Y, Zhang L, et al. Curcumin and resveratrol regulate intestinal bacteria and alleviate intestinal inflammation in weaned piglets. 2019;24(7):1220.
48. Corrêa M, Pires P, Ribeiro F, Pimentel S, Casarin R, Cirano F, et al. Systemic treatment with resveratrol and/or curcumin reduces the progression of experimental periodontitis in rats. 2017;52(2):201-9.
49. Zaky A, Bassiouny A, Farghaly M, El-Sabaa BMJJoAsD. A combination of resveratrol and curcumin is effective against aluminum chloride-induced neuroinflammation in rats. 2017;60(s1):S221-S35.
50. Baptistella MM, Assunção RRS, Sales de Oliveira C, Siqueira AP, Gonçalves dos Santos E, de Freitas Silva M, et al. A synthetic resveratrol–curcumin hybrid derivative exhibits chemopreventive effects on colon pre-neoplastic lesions by targeting Wnt/β-catenin signaling, anti-inflammatory and antioxidant pathways. 2024;76(5):479-88.
51. Heeba GH, Mahmoud ME, Hanafy AAEJT, health i. Anti-inflammatory potential of curcumin and quercetin in rats: role of oxidative stress, heme oxygenase-1 and TNF-α. 2014;30(6):551-60.
52. Güran M, ?anl?türk G, Kerküklü NR, Altunda? EM, Yalç?n ASJEJoP. Combined effects of quercetin and curcumin on anti-inflammatory and antimicrobial parameters in vitro. 2019;859:172486.
53. Singh AK, Jiang Y, Gupta S, Younus M, Ramzan MJJomf. Anti-inflammatory potency of nano-formulated puerarin and curcumin in rats subjected to the lipopolysaccharide-induced inflammation. 2013;16(10):899-911.
54. Murakami A, Furukawa I, Miyamoto S, Tanaka T, Ohigashi HJB. Curcumin combined with turmerones, essential oil components of turmeric, abolishes inflammation?associated mouse colon carcinogenesis. 2013;39(2):221-32.
55. Jia Q, Ivanov I, Zlatev ZZ, Alaniz RC, Weeks BR, Callaway ES, et al. Dietary fish oil and curcumin combine to modulate colonic cytokinetics and gene expression in dextran sodium sulphate-treated mice. 2011;106(4):519-29.
56. Man S, Li J, Liu J, Chai H, Liu Z, Wang J, et al. Curcumin alleviated the toxic reaction of Rhizoma Paridis saponins in a 45?day subchronic toxicological assessment of rats. 2016;31(12):1935-43.
57. Comblain F, Sanchez C, Lesponne I, Balligand M, Serisier S, Henrotin YJPo. Curcuminoids extract, hydrolyzed collagen and green tea extract synergically inhibit inflammatory and catabolic mediator’s synthesis by normal bovine and osteoarthritic human chondrocytes in monolayer. 2015;10(3):e0121654.
58. Jeengar MK, Shrivastava S, Veeravalli SCM, Naidu V, Sistla RJN. Amelioration of FCA induced arthritis on topical application of curcumin in combination with emu oil. 2016;32(9):955-64.
59. Heritage M, Jaskowski L, Bridle K, Campbell C, Briskey D, Britton L, et al. Combination curcumin and vitamin E treatment attenuates diet-induced steatosis in Hfe-/-mice. 2017;8(2):67.
60. Vanella L, Li Volti G, Distefano A, Raffaele M, Zingales V, Avola R, et al. A new antioxidant formulation reduces the apoptotic and damaging effect of cigarette smoke extract on human bronchial epithelial cells. 2017;21(23):5478-84.
61. Feng W-w, Kuang S-y, Tu C, Ma Z-j, Pang J-y, Wang Y-h, et al. Natural products berberine and curcumin exhibited better ameliorative effects on rats with non-alcohol fatty liver disease than lovastatin. 2018;99:325-33.
62. da Silva JLG, Passos DF, Bernardes VM, Cabral FL, Schimites PG, Manzoni AG, et al. Co-nanoencapsulation of vitamin D3 and curcumin regulates inflammation and purine metabolism in a model of arthritis. 2019;42(5):1595-610.
63. Gheibi S, Ghaleh HEG, Motlagh BM, Azarbayjani AFJB, Pharmacotherapy. Therapeutic effects of curcumin and ursodexycholic acid on non-alcoholic fatty liver disease. 2019;115:108938.
64. Tremmel L, Rho O, Slaga TJ, DiGiovanni JJMC. Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin. 2019;58(2):185-95.
65. Khayyal MT, El-Hazek RM, El-Sabbagh WA, Frank J, Behnam D, Abdel-Tawab MJN. Micellar solubilisation enhances the antiinflammatory activities of curcumin and boswellic acids in rats with adjuvant-induced arthritis. 2018;54:189-96.
66. Vasileva LV, Saracheva KE, Ivanovska MV, Petrova AP, Marchev AS, Georgiev MI, et al. Antidepressant-like effect of salidroside and curcumin on the immunoreactivity of rats subjected to a chronic mild stress model. 2018;121:604-11.
67. Abdel-Magied N, Elkady AAJE, pathology m. Possible curative role of curcumin and silymarin against nephrotoxicity induced by gamma-rays in rats. 2019;111:104299.
68. Yan F, Li H, Zhong Z, Zhou M, Lin Y, Tang C, et al. Co-delivery of prednisolone and curcumin in human serum albumin nanoparticles for effective treatment of rheumatoid arthritis. 2019:9113-25.
69. Al Fayi M, Otifi H, Alshyarba M, Dera AA, Rajagopalan PJJoDT. Thymoquinone and curcumin combination protects cisplatin-induced kidney injury, nephrotoxicity by attenuating NFκB, KIM-1 and ameliorating Nrf2/HO-1 signalling. 2020;28(9):913-22.
70. D’Ascola A, Irrera N, Ettari R, Bitto A, Pallio G, Mannino F, et al. Exploiting Curcumin Synergy With Natural Products Using Quantitative Analysis of Dose–Effect Relationships in an Experimental In Vitro Model of Osteoarthritis. 2019;10:1347.
71. Zhou X, Afzal S, Wohlmuth H, Münch G, Leach D, Low M, et al. Synergistic anti-inflammatory activity of ginger and turmeric extracts in inhibiting lipopolysaccharide and interferon-γ-induced proinflammatory mediators. 2022;27(12):3877.
72. Lin L, Li C, Zhang D, Yuan M, Chen C-h, Li MJNr. Synergic effects of berberine and curcumin on improving cognitive function in an Alzheimer’s disease mouse model. 2020;45(5):1130-41.
73. Saw CLL, Huang Y, Kong A-NJBp. Synergistic anti-inflammatory effects of low doses of curcumin in combination with polyunsaturated fatty acids: docosahexaenoic acid or eicosapentaenoic acid. 2010;79(3):421-30.
74. Cheung KL, Khor TO, Kong A-NJPr. Synergistic effect of combination of phenethyl isothiocyanate and sulforaphane or curcumin and sulforaphane in the inhibition of inflammation. 2009;26(1):224-31.
75. Bansal S, Chhibber SJJomm. Curcumin alone and in combination with augmentin protects against pulmonaryinflammation and acute lung injury generated during Klebsiella pneumoniae B5055-induced lung infection in BALB/c mice. 2010;59(4):429-37.
76. Wu Y, Antony S, Meitzler JL, Doroshow JHJCl. Molecular mechanisms underlying chronic inflammation-associated cancers. 2014;345(2):164-73.
77. Toden S, Theiss AL, Wang X, Goel AJSr. Essential turmeric oils enhance anti-inflammatory efficacy of curcumin in dextran sulfate sodium-induced colitis. 2017;7(1):814.
78. Zhou Z, Pan C, Lu Y, Gao Y, Liu W, Yin P, et al. Combination of erythromycin and curcumin alleviates Staphylococcus aureus induced osteomyelitis in rats. 2017;7:379.
79. Cao L, Zhi D, Han J, Kumar Sah S, Xie YJJofb. Combinational effect of curcumin and metformin against gentamicin?induced nephrotoxicity: Involvement of antioxidative, anti?inflammatory and antiapoptotic pathway. 2019;43(7):e12836.
80. Manjunatha H, Srinivasan KJTFj. Protective effect of dietary curcumin and capsaicin on induced oxidation of low?density lipoprotein, iron?induced hepatotoxicity and carrageenan?induced inflammation in experimental rats. 2006;273(19):4528-37.
81. Kumar S, Singhal V, Roshan R, Sharma A, Rembhotkar GW, Ghosh BJEjop. Piperine inhibits TNF-α induced adhesion of neutrophils to endothelial monolayer through suppression of NF-κB and IκB kinase activation. 2007;575(1-3):177-86.
82. Al-Dossari MH, Fadda LM, Attia HA, Hasan IH, Mahmoud AMJBter. Curcumin and selenium prevent lipopolysaccharide/diclofenac-induced liver injury by suppressing inflammation and oxidative stress. 2020;196(1):173-83.
83. Mahfouz MKMJJoAS. Curcumin/irbesartan combination improves insulin sensitivity and ameliorates serum pro-inflammatory cytokines levels in diabetes rat model. 2010;11:6.
84. Mohapatra TK, Nayak RR, Subudhi BBJJPPR. Exploration of anti-inflammatory and hepatoprotective effect of curcumin on co-administration with acetylsalicylic acid. 2019;7(310.10):56499.
85. Boarescu I, Pop RM, Boarescu P-M, Boc?an IC, Gheban D, Râjnoveanu R-M, et al. Anti-inflammatory and analgesic effects of curcumin nanoparticles associated with diclofenac sodium in experimental acute inflammation. 2022;23(19):11737.
86. Bisht A, Dickens M, Rutherfurd-Markwick K, Thota R, Mutukumira AN, Singh HJN. Chlorogenic acid potentiates the anti-inflammatory activity of curcumin in LPS-stimulated THP-1 cells. 2020;12(9):2706.
87. Rinkunaite I, Simoliunas E, Alksne M, Dapkute D, Bukelskiene VJBcm, therapies. Anti-inflammatory effect of different curcumin preparations on adjuvant-induced arthritis in rats. 2021;21(1):39.
88. Zhai F, Wang J, Wan X, Liu Y, Mao XJB, Communications BR. Dual anti-inflammatory effects of curcumin and berberine on acetaminophen-induced liver injury in mice by inhibiting NF-κB activation via PI3K/AKT and PPARγ signaling pathways. 2024;734:150772.
89. Ibrahim SG, El-Emam SZ, Mohamed EA, Abd Ellah MFJIi. Dimethyl fumarate and curcumin attenuate hepatic ischemia/reperfusion injury via Nrf2/HO-1 activation and anti-inflammatory properties. 2020;80:106131.
90. Piotrowska M, Krajewska JB, Talar M, D?ugosz O, Banach M, Fichna JJJoDDS, et al. Anti-inflammatory properties of curcumin and silver (I) nanocomplexes in inflammatory bowel disease: in vitro and in vivo examination. 2023;86:104723.
91. Pan Q, Xie L, Zhu H, Zong Z, Wu D, Liu R, et al. Curcumin-incorporated EGCG-based nano-antioxidants alleviate colon and kidney inflammation via antioxidant and anti-inflammatory therapy. 2024;11:rbae122.
92. Asif HM, Zafar F, Ahmad K, Iqbal A, Shaheen G, Ansari KA, et al. Synthesis, characterization and evaluation of anti-arthritic and anti-inflammatory potential of curcumin loaded chitosan nanoparticles. 2023;13(1):10274.
93. Azimzadeh M, Shapoori S, Jafarinia MJI. Synergistic effects of melatonin and curcumin in ameliorating experimental autoimmune encephalomyelitis: insights into anti-inflammatory, antioxidant, and neuroprotective mechanisms. 2025:1-14.
94. Serini S, Trombino S, Cassano R, Marino M, Calviello GJN. Anti-inflammatory effects of curcumin-based nanoparticles containing α-linolenic acid in a model of psoriasis in vitro. 2025;17(4):692.
95. Jobin C, Bradham CA, Russo MP, Juma B, Narula AS, Brenner DA, et al. Curcumin blocks cytokine-mediated NF-κB activation and proinflammatory gene expression by inhibiting inhibitory factor I-κB kinase activity. 1999;163(6):3474-83.
96. Yang K-Y, Lin L-C, Tseng T-Y, Wang S-C, Tsai T-HJJocB. Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC–MS/MS. 2007;853(1-2):183-9.
97. Dei Cas M, Ghidoni RJN. Dietary curcumin: correlation between bioavailability and health potential. 2019;11(9):2147.
98. Panahi Y, Hosseini MS, Khalili N, Naimi E, Majeed M, Sahebkar AJCn. Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with metabolic syndrome: a randomized controlled trial and an updated meta-analysis. 2015;34(6):1101-8.
99. Atal C, Dubey RK, Singh JJTJop, therapeutics e. Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism. 1985;232(1):258-62.
100. Hassaninasab A, Hashimoto Y, Tomita-Yokotani K, Kobayashi MJPotNAoS. Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism. 2011;108(16):6615-20.
101. Mohanty C, Sahoo SKJDdt. Curcumin and its topical formulations for wound healing applications. 2017;22(10):1582-92.
102. Priyadarsini KI, Maity DK, Naik G, Kumar MS, Unnikrishnan M, Satav J, et al. Role of phenolic OH and methylene hydrogen on the free radical reactions and antioxidant activity of curcumin. 2003;35(5):475-84.
103. Judaki A, Rahmani A, Feizi J, Asadollahi K, Hafezi Ahmadi MRJAdg. Curcumin in combination with triple therapy regimes ameliorates oxidative stress and histopathologic changes in chronic gastritis-associated Helicobacter pylori infection. 2017;54:177-82.
104. Wolfe KL, Liu RHJJoa, chemistry f. Structure− activity relationships of flavonoids in the cellular antioxidant activity assay. 2008;56(18):8404-11.
105. Soccio M, Laus MN, Flagella Z, Pastore DJM. Assessment of antioxidant capacity and putative healthy effects of natural plant products using soybean lipoxygenase-based methods. An overview. 2018;23(12):3244.
106. Becker EM, Ntouma G, Skibsted LHJFC. Synergism and antagonism between quercetin and other chain-breaking antioxidants in lipid systems of increasing structural organisation. 2007;103(4):1288-96.
107. Liang R, Han R-M, Fu L-M, Ai X-C, Zhang J-P, Skibsted LHJJoa, et al. Baicalin in radical scavenging and its synergistic effect with β-carotene in antilipoxidation. 2009;57(15):7118-24.
108. Yu W, Tao M, Zhao Y, Hu X, Wang MJM. 4′-Methoxyresveratrol alleviated AGE-induced inflammation via RAGE-mediated NF-κB and NLRP3 inflammasome pathway. 2018;23(6):1447.
109. Comalada M, Ballester I, Bailón E, Sierra S, Xaus J, Gálvez J, et al. Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure–activity relationship. 2006;72(8):1010-21.
110. Altavilla D, Squadrito F, Bitto A, Polito F, Burnett B, Di Stefano V, et al. Flavocoxid, a dual inhibitor of cyclooxygenase and 5?lipoxygenase, blunts pro?inflammatory phenotype activation in endotoxin?stimulated macrophages. 2009;157(8):1410-8.
111. Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi GJBp. Inflammation and cancer: how hot is the link? 2006;72(11):1605-21.
112. Zhang L, Virgous C, Si HJTJonb. Synergistic anti-inflammatory effects and mechanisms of combined phytochemicals. 2019;69:19-30.
113. Berczi I, Szentivanyi A. Cytokines and chemokines.  Neuroimmune biology. 3: Elsevier; 2003. p. 191-220.
114. Apte RN, Krelin Y, Song X, Dotan S, Recih E, Elkabets M, et al. Effects of micro-environment-and malignant cell-derived interleukin-1 in carcinogenesis, tumour invasiveness and tumour–host interactions. 2006;42(6):751-9.
115. Balkwill F, Mantovani AJCP, Therapeutics. Cancer and inflammation: implications for pharmacology and therapeutics. 2010;87(4):401-6.