The Dynamic Role of Curcumin in Mitigating Human Illnesses: Recent Advances in Therapeutic Applications.

1. Introduction

The utilization of plants as medicinal remedies has been a cornerstone of human health across diverse societies and civilizations throughout history [ 1 , 2 ]. Curcuma longa ( C. longa ), commonly known as turmeric, belongs to the Zingiberaceae family and is widely recognized for its diverse applications worldwide. Native to tropical South Asia, turmeric has been traditionally used as a dye, a cleansing agent (e.g., before marriage), a food additive (spice), and a medicine [ 3 ].

The structure of curcumin, supported by its synthesis, was published as early as 1910 by Miłobędzka and coworkers [ 4 ]. Later, Lampe [ 5 ] introduced another synthetic method in 1918. This multi-step process began with ethyl acetoacetate and carbomethoxyferuloyl as the primary reagents. Later, Pabon [ 6 ] developed a more efficient and straightforward synthesis with improved yields ( Scheme 1 ). His method involved reacting acetyl acetone with boron trioxide (B 2 O 3 ), substituted aromatic aldehydes, primary amine, and alkyl borate. With minor modifications, Pabon’s synthetic approach has been widely adopted by researchers worldwide, forming the basis for most curcumin syntheses [ 7 , 8 , 9 , 10 ].

Modern studies have confirmed that turmeric is very rich in antioxidants, which is in line with its historically known anti-inflammatory properties. Curcumin, the primary active compound in turmeric, along with other curcuminoids, such as dihydrocurcumin, tetrahydrocurcumin, bis-demethoxycurcumin, and demethoxycurcumin ( Figure 1 ), has attracted considerable attention for its therapeutic potential [ 11 , 12 , 13 , 14 ]. These compounds have been extensively studied for their efficacy in preventing and treating a wide array of illnesses, including inflammatory diseases, cancer, diabetes, bacterial and fungal infections, ulcers, and liver and circulatory disorders, and as an anticoagulant agent ( Figure 2 ) [ 11 , 12 , 13 , 14 ]. In addition, curcumin has been tested in clinical studies both alone and in conjunction with several other medications, including sulfasalazine, quercetin, piperine, lactoferrin, docetaxel, prednisone, gemcitabine, and pantoprazole [ 15 ].

Despite the promising therapeutic benefits demonstrated in both preclinical and clinical studies, the exact molecular mechanisms through which curcumin exerts its effects remain only partially understood. Curcumin’s ability to modulate multiple cellular signaling pathways suggests a multifaceted mechanism of action, which may contribute to its effectiveness as both an adjuvant and alternative therapy [ 14 , 16 ]. For instance, clinical trials have shown that curcumin can decrease inflammatory markers and enhance antioxidant capacities in healthy individuals [ 17 ], improve circulation [ 18 ], chelate metals [ 19 , 20 ], and support neurogenesis [ 21 ], among other benefits.

This review hypothesizes that the diverse pharmacological characteristics of curcumin, especially its antioxidant and anti-inflammatory properties, are critical in influencing the fundamental disease mechanisms involved in a variety of human illnesses. By targeting multiple cellular pathways, curcumin has the potential to improve therapeutic outcomes when used alone or in combination with other therapies.

To explore this hypothesis, the following sections will provide an in-depth analysis of recent studies on curcumin, focusing on its molecular mechanisms of action and therapeutic applications in various human diseases, including cancer, inflammatory bowel disease, osteoarthritis, atherosclerosis, peptic ulcers, COVID-19, psoriasis, vitiligo, and depression. Additionally, the review will examine synergistic responses and the implications of curcumin in diverse pathogenesis by modulating a variety of biomolecules and mediators.

2. Preclinical and Clinical Evidence for Therapeutic Applications of Curcumin

2.1. Cancer

Curcumin demonstrates significant anticancer properties by modulating key molecular signaling pathways, leading to apoptosis and inhibiting tumor growth and metastasis [ 22 ]. It effectively suppresses NF-κB by inhibiting IkBs, thereby reducing the expression of pro-inflammatory genes, like TNF-α ( Figure 3 ) [ 23 , 24 ]. Additionally, curcumin downregulates AP-1, which is associated with anti-apoptotic proteins, promoting cancer cell death [ 25 ]. By targeting the IL-6/STAT3 pathway, curcumin disrupts oncogenic signaling, further inhibiting tumorigenesis [ 26 , 27 ]. These mechanisms underscore curcumin’s dual role as an anti-inflammatory and pro-apoptotic agent, enhancing its potential as both a standalone and adjunctive therapy across various cancer types, including pancreatic, prostate, breast, oral, lung, colorectal cancers, and multiple myeloma [ 28 , 29 , 30 ].

In colorectal cancer, curcumin addresses the complex etiology involving genetic, environmental, and inflammatory factors [ 31 , 32 ]. Clinical trials have shown that standardized curcuma extracts achieve pharmacologically active levels in colorectal tissues, reducing polyp size and number in familial adenomatous polyposis patients and preventing precancerous lesions in smokers without significant toxicity [ 15 , 33 , 34 , 35 ]. For instance, a dose-escalation study administering up to 3.6 g/day of curcumin demonstrated effective tissue concentrations and safety, while combinations with quercetin further enhanced therapeutic outcomes [ 19 , 33 , 35 ]. These findings highlight curcumin’s efficacy and safety, emphasizing the need for larger, randomized clinical trials to optimize its bioavailability and fully validate its therapeutic benefits in colorectal cancer treatment.

2.2. Inflammatory Bowel Disease

Curcumin demonstrates substantial anti-inflammatory effects by interacting with toll-like receptors and regulating mediators, such as MAPK and NF-κB, making it a promising therapeutic agent for inflammatory bowel disease (IBD) [ 36 , 37 ]. Clinical trials have shown that curcumin effectively induces and maintains remission in IBD patients. For example, studies report significant reductions in the inflammatory markers ESR and CRP in patients with ulcerative proctitis and Crohn’s disease following curcumin administration [ 38 ]. Additionally, maintenance therapy combining curcumin with sulfasalazine or mesalamine results in lower recurrence rates compared to a placebo [ 39 ], and case reports indicate that curcumin alongside prednisone can achieve clinical and endoscopic remission [ 40 ]. Another clinical trial demonstrated that curcumin supplementation at 1500 mg per day for eight weeks significantly improves clinical conditions and reduces inflammatory markers in individuals with mild-to-moderate ulcerative colitis [ 41 ]. Dose-dependent studies reveal that curcumin lowers levels of MAPK, NF-κB, and MMP3 while increasing IL-10 and reducing IL-1beta [ 42 ], and in vivo research supports its role in inhibiting the NLRP3 inflammasome [ 43 ]. However, curcumin’s inhibition of hepcidin may exacerbate anemia in IBD patients, necessitating careful monitoring [ 44 , 45 ]. These findings underscore curcumin’s potential as a complementary therapy for IBD, warranting further large-scale randomized trials to confirm its efficacy and safety.

2.3. Osteoarthritis

Osteoarthritis (OA) is a chronic inflammatory condition marked by joint degradation and cartilage damage, driven by dysregulated pro-inflammatory markers and cytokines, such as IL-1 and TNF-alpha. Curcumin emerges as a promising candidate due to its ability to modulate key inflammatory and catabolic pathways involved in OA pathogenesis. Preclinical studies demonstrate that curcumin reduces the expression of pro-inflammatory cytokines and matrix metalloproteinases, thereby protecting cartilage integrity and inhibiting disease progression [ 46 , 47 , 48 , 49 , 50 ]. Formulations, such as Advanced Ultrasol Curcumin and curcumin-loaded nanoparticles, have improved its bioavailability and therapeutic efficacy in animal models [ 51 ]. In addition, nanoparticles loaded with curcumin alleviated type II collagen loss, resulting in the reversal of elevated malondialdehyde levels in monosodium iodoacetate-induced knee OA in rodents [ 52 ]. Clinically, proprietary formulations, like Meriva™, have shown significant improvements in pain, joint function, and inflammatory markers in OA patients, while reducing the need for NSAIDs and minimizing adverse effects [ 53 , 54 , 55 , 56 ]. These outcomes suggest that curcumin not only addresses symptomatic relief but may also influence the underlying disease mechanisms. Integrating curcumin into OA management could offer a multifaceted approach by targeting inflammation, protecting cartilage, and enhancing patient quality of life [ 57 ]. Further large-scale randomized trials are warranted to fully establish its efficacy, optimize dosing regimens, and confirm its role as a viable adjunct therapy in osteoarthritis treatment protocols.

2.4. Atherosclerosis

Atherosclerosis is a chronic inflammatory condition of the vascular tissues and a major risk factor for cardiovascular diseases, primarily driven by oxidative stress that damages the vascular endothelium, triggering disease development [ 58 ]. Curcumin has emerged as a promising therapeutic agent due to its potent anti-inflammatory and antioxidant properties, which influence inflammatory cells and enzymes involved in atherosclerosis [ 59 , 60 ]. By scavenging reactive oxygen species (ROS) and enhancing the activity of endogenous antioxidant enzymes, such as glutathione peroxidase and superoxide dismutase, curcumin mitigates oxidative stress and protects vascular integrity [ 61 , 62 , 63 , 64 , 65 ]. Furthermore, curcumin modulates the TLR4/MAPK/NF-κB pathway, reducing the activity of pro-inflammatory M1 macrophages and lowering overall inflammation, thereby inhibiting the progression of atherosclerosis [ 66 , 67 , 68 , 69 ]. Clinical studies reinforce curcumin’s cardiovascular benefits. Randomized controlled trials have shown that curcumin supplementation improves lipid profiles by increasing high-density lipoprotein cholesterol (HDL-C) and decreasing plasma triglycerides (TGs) [ 70 ]. Additionally, curcumin (Theracurmin ® ) significantly decreased LDL-C levels in patients with chronic obstructive pulmonary disease (COPD), highlighting its role in reducing atherosclerotic risk factors [ 71 ]. However, some meta-analyses report no significant changes in total cholesterol or low-density lipoprotein cholesterol (LDL-C), indicating the need for more comprehensive research [ 72 ]. These findings underscore curcumin’s potential as a multifaceted adjunct therapy for atherosclerosis by targeting oxidative stress, inflammation, and lipid metabolism. Nonetheless, further large-scale randomized trials are essential to validate its efficacy and optimize dosing strategies for cardiovascular disease management.

2.5. Peptic Ulcer

Peptic ulcer disease arises from the disruption of the gastrointestinal (GI) tract protective barrier, primarily due to increased gastric acid secretion or decreased duodenal bicarbonate production. This disruption leads to mucosal injury and inflammation. Curcumin offers a promising therapeutic approach by reinforcing the mucosal barrier through its anti-apoptotic and antioxidant properties. Inhibition of caspase-3 by curcumin reduces gastric acid secretion and mitigates oxidative stress, thereby protecting the gastric mucosa [ 73 ]. Curcumin also exhibits antisecretory activity against nonsteroidal anti-inflammatory drugs (NSAIDs), enhancing gastroprotective effects [ 74 ]. Studies demonstrate that curcumin and bisdemethoxycurcumin decrease inducible nitric oxide synthase (iNOS) expression without affecting tumor necrosis factor-alpha (TNF-α), thereby reducing inflammation and acid secretion [ 75 ]. In rodent models, curcumin administration increases gastric juice pH, reduces neutrophil activity, and lowers oxidative stress markers, showcasing anti-ulcer efficacy [ 76 ]. Several formulations, such as chitosan–curcumin mixtures and omeprazole–curcumin-loaded hydrogel beads, further improve curcumin’s therapeutic outcomes by enhancing its antioxidant and anti-inflammatory activities [ 77 , 78 , 79 ]. Additionally, curcumin has demonstrated anti-Helicobacter pylori effects in mouse models, evidenced by significant reductions in serum IL-4, IFN-γ, somatostatin, gastrin, lipid peroxide, myeloperoxidase, and bacterial counts, alongside increased anti-H. pylori antibodies [ 80 ]. Clinically, turmeric supplementation has shown significant ulcer remission and symptom improvement, although antacids remain more effective in some cases [ 81 , 82 ]. The potential of curcumin as a complementary therapy for peptic ulcer disease is emphasized by these findings, which demonstrate that it can protect and repair the gastric mucosa through multifaceted mechanisms. However, larger randomized trials are necessary to fully validate its efficacy and optimize dosing regimens for clinical application.

2.6. COVID-19

COVID-19 is characterized by a hyperinflammatory state marked by elevated levels of colony-stimulating factors (G-CSF and GM-CSF), inflammatory markers (IL-1β, IL-6, IL-8, and TNF-α), and activated cytokine-tracing agents [ 83 ]. Central to its pathogenesis is the activation of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, which contributes to the catastrophic cytokine storm leading to acute respiratory distress syndrome (ARDS) and increased mortality, especially in patients with comorbidities, like diabetes and obesity [ 84 , 85 , 86 , 87 ]. Curcumin presents a multifaceted therapeutic potential by modulating these inflammatory pathways. It inhibits the NLRP3 inflammasome, thereby reducing the excessive inflammatory response [ 88 ]. Additionally, curcumin regulates Treg and Th17 cell populations, lowering inflammatory markers and mitigating immune dysregulation in COVID-19 patients [ 89 ].

Preclinical studies demonstrate curcumin’s ability to inhibit SARS-CoV-2 entry into cells, impede viral replication, and reduce inflammatory mediator production, which collectively diminish disease severity [ 90 ]. Clinical trials further support these findings, showing that curcumin supplementation improves oxygen levels, reduces hospital stays, and accelerates recovery in COVID-19 patients [ 91 , 92 ]. Moreover, combination therapies involving curcumin and other agents, such as piperine, have been shown to enhance clinical outcomes and reduce mortality rates [ 92 ]. Recent research also highlights specific curcuminoids, like Me08 and Me23, for their antiviral and anti-inflammatory effects, suggesting their potential in targeting both the virus and the host’s inflammatory response [ 93 ].

These integrated actions of curcumin underscore its potential as an effective adjuvant therapy for COVID-19, addressing both viral replication and the detrimental hyperinflammatory response. However, further large-scale randomized clinical trials are essential to validate curcumin’s efficacy, optimize dosing regimens, and fully integrate it into COVID-19 treatment protocols.

2.7. Psoriasis

Psoriasis is a chronic inflammatory skin condition characterized by scaly, red, and thick plaques that can affect any part of the body. Current treatments, such as UVB therapy and systemic medications, like methotrexate and cyclosporine, are often time-consuming and may pose risks to vital organs. Curcumin, renowned for its anti-inflammatory, antioxidant, and antimicrobial properties, emerges as an ideal herbal compound for managing psoriasis [ 94 ]. Curcumin exerts its therapeutic effects by modulating key inflammatory pathways, including the inhibition of NF-κB and the reduction of pro-inflammatory cytokines, like TNF-alpha, IL-17, and IL-22, thereby alleviating the inflammatory environment associated with psoriasis [ 95 , 96 , 97 , 98 ]. Additionally, curcumin inhibits the Kv1.3 potassium channel, which is crucial for T cell activation and proliferation, further mitigating psoriatic inflammation [ 99 , 100 , 101 ]. Moreover, the Lineweaver–Burk plot analysis demonstrated that curcumin is a non-competitive inhibitor of PhK with an inhibition constant (Ki) of 0.075 mM [ 102 ]. Advanced formulations, such as curcumin-loaded nanoparticles and SmartPearls, enhance skin penetration and therapeutic efficacy, resulting in improved anti-keratinization and a reduction in inflammatory markers [ 103 , 104 , 105 , 106 ]. Clinical studies demonstrate that curcumin supplementation significantly reduces psoriasis severity scores and inflammatory markers, though some trials indicate the necessity for larger, placebo-controlled studies to confirm these benefits [ 107 , 108 ]. These findings highlight curcumin’s potential as a multifaceted adjunct therapy for psoriasis, targeting both symptom relief and underlying inflammatory processes, warranting further comprehensive clinical research.

2.8. Vitiligo

Vitiligo is a chronic inflammatory skin condition characterized by the loss of melanocytes, resulting in white patches on the skin. Oxidative stress plays a significant role in melanocyte destruction, contributing to the disease’s etiology [ 109 , 110 ]. Curcumin, with its potent antioxidant and anti-inflammatory properties, emerges as a promising therapeutic agent for vitiligo. By reducing oxidative stress and modulating inflammatory pathways, curcumin helps protect melanocytes and promote skin repigmentation [ 111 , 112 ].

Preclinical research highlights curcumin’s ability to decrease advanced glycation end-products and activate the NRF2 antioxidant pathway, enhancing cellular protection against oxidative damage [ 111 , 112 ]. These findings underscore curcumin’s potential as a complementary therapy for vitiligo, addressing both oxidative stress and inflammation to restore skin pigmentation. Further large-scale randomized trials are essential to validate curcumin’s efficacy and optimize treatment protocols for vitiligo patients.

Clinical studies support curcumin’s efficacy in managing vitiligo. In a trial with ten patients, the combination of tetrahydrocurcuminoid cream and narrowband UVB (NB-UVB) therapy resulted in significant repigmentation compared to baseline, with enhanced outcomes observed in the combination group [ 109 ]. Additionally, turmeric cream applied twice daily for four months significantly reduced lesion size and improved vitiligo scores compared to placebo controls [ 113 ]. A case study further illustrated spontaneous repigmentation following the consumption of a curcumin-based herbal remedy [ 114 ].

2.9. Depression

Depression is increasingly recognized as being closely linked to inflammation, where dysregulated innate and adaptive immune responses contribute to its onset [ 115 , 116 ]. Curcumin, renowned for its anti-inflammatory and antioxidant properties, presents a promising therapeutic option for alleviating depressive symptoms. By inhibiting the NLRP3 inflammasome, curcumin reduces the expression of pro-inflammatory cytokines, thereby mitigating the inflammatory processes associated with depression [ 117 ]. Preclinical studies demonstrate that curcumin administration reverses depressive-like behaviors in stressed rodents by restoring neurotransmitter levels, including serotonin, norepinephrine, and dopamine, and modulating the serotonergic system through 5-HT receptors [ 118 , 119 , 120 , 121 , 122 ]. Additionally, curcumin enhances the brain-derived neurotrophic factor (BDNF) pathway, promoting neuronal survival and synaptic plasticity, which are critical for mood regulation [ 123 , 124 ].

Enhanced formulations, such as curcumin-coated nanoparticles, have further improved its bioavailability and therapeutic efficacy, resulting in significant behavioral and biochemical improvements in animal models of depression [ 125 , 126 , 127 ]. Clinical trials support these findings, with curcumin supplementation showing reductions in inflammatory markers and improvements in depressive symptoms [ 128 , 129 , 130 ]. However, some studies highlight the need for larger, randomized controlled trials to confirm curcumin’s antidepressant efficacy and optimize dosing strategies [ 129 , 130 ]. These integrated actions of curcumin underscore its potential as a multifaceted adjunct therapy for depression, targeting both inflammatory pathways and neurochemical imbalances to enhance mental health outcomes.

2.10. Diabetes Mellitus

Diabetes mellitus, particularly type 2 diabetes (T2DM), is a chronic metabolic disorder characterized by impaired glucose metabolism, insulin resistance, and associated complications, such as neuropathy, cardiovascular, and renal damage. Curcumin, with its multifaceted bioactive properties, has been extensively investigated for its potential to manage diabetes and its complications through mechanisms including improved lipid metabolism, reduced inflammation, antioxidant effects, and prevention of cell death [ 131 , 132 , 133 ].

Curcumin administration has demonstrated significant benefits in clinical trials. In a randomized, double-blind, placebo-controlled study, nano-curcumin (80 mg/day) for three months in T2DM patients resulted in notable reductions in glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), triglycerides (TG), and body mass index (BMI), along with improvements in low-density lipoprotein cholesterol (LDL-C) levels [ 134 ]. Additionally, curcumin administration at 300 mg/kg for three months in diabetic obese patients significantly reduced fasting blood sugar, insulin resistance, HbA1c, serum triglycerides, and free fatty acids (FFAs), while increasing lipoprotein lipase activity, highlighting its efficacy in lipid metabolism modulation [ 135 ]. Proprietary formulations, like Theracurmin ® , have shown efficacy in reducing α1-antitrypsin-LDL levels and increasing adiponectin in non-insulin-dependent diabetic patients [ 136 ]. Additionally, combining curcumin with piperine significantly improved glycemic control and hepatic parameters, although effects on high-sensitivity C-reactive protein (hs-CRP) were inconclusive due to study limitations [ 137 ].

Curcumin also plays a role in mitigating diabetic complications. Topical application of curcumin ointments significantly reduced the size of diabetic foot ulcers, enhancing wound healing through sustained local concentrations and anti-inflammatory effects [ 138 , 139 ]. These findings underscore curcumin’s potential as a comprehensive adjunct therapy for managing diabetes and its complications, although further large-scale, long-term randomized trials are necessary to fully establish its efficacy and optimize dosing strategies.

2.11. Malaria

Malaria, caused by Plasmodium species, remains a significant global health challenge, particularly due to the emergence of drug-resistant strains. Curcumin, a polyphenolic compound from turmeric, has shown promising antimalarial potential through multiple mechanisms. Preclinical studies indicate that curcumin inhibits the histone acetyl transferase (HAT) enzyme and generates reactive oxygen species (ROS) within the malaria parasite, leading to cellular damage and reduced parasitemia [ 140 , 141 ]. Notably, curcumin effectively targets chloroquine-resistant Plasmodium falciparum with an IC₅₀ of approximately 5 µM and significantly decreases parasitic loads and increases survival rates in Plasmodium berghei -infected mice [ 142 ]. Additionally, curcumin enhances the efficacy of traditional antimalarial drugs, like α,β-arteether, resulting in 100% survival and protection against recrudescence when combined [ 142 , 143 ].

Mechanistically, curcumin mitigates cerebral malaria by inhibiting pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ, thereby preventing blood–brain barrier disruption and neuronal injury [ 144 , 145 ]. Several curcumin formulations, including PLGA nanoparticles [ 146 ], nano-emulsions [ 147 ], hydrogel nanoparticles [ 148 ], solid–lipid dispersions [ 149 ], chitosan nanoparticles [ 150 ], polymeric capsules [ 151 ], and lipoidal drug delivery systems [ 152 ], have demonstrated improved bioavailability and greater efficacy in reducing inflammatory markers, preventing infected red blood cell sequestration in the brain, and exhibiting antimalarial activity in experimental animals. Furthermore, combinations of curcumin with bioavailability enhancers, like piperine, have shown enhanced antimalarial effects by increasing ROS production, which is cytotoxic to Plasmodium parasites [ 153 ].

Despite the promising preclinical outcomes, clinical studies are limited. Future research should focus on comprehensive clinical trials to validate curcumin’s antimalarial efficacy, optimize dosing regimens, and explore its potential to counteract drug resistance, thereby contributing to sustained malaria control and eradication efforts.

2.12. Antimicrobial Properties

Curcumin, the primary curcuminoid in turmeric, has long been recognized for its antimicrobial properties, complementing its well-documented anti-inflammatory and antioxidant effects [ 154 , 155 ]. Curcumin combats bacterial infections through multiple mechanisms, including the inhibition of FtsZ, a crucial enzyme for bacterial cell division, and the disruption of bacterial cell membranes due to its amphipathic nature [ 156 , 157 ]. These actions render curcumin effective against both Gram-positive and Gram-negative bacteria, such as Escherichia coli and Staphylococcus aureus [ 156 , 157 ]. Additionally, curcumin impedes biofilm formation in pathogens, like Pseudomonas aeruginosa , enhancing the efficacy of conventional antibiotics and offering a promising strategy against antibiotic-resistant strains [ 158 , 159 ].

Beyond antibacterial effects, curcumin exhibits antiviral activity, demonstrated by its ability to interfere with viral entry and replication processes in Herpes Simplex Virus type 1 (HSV-1), thereby reducing viral load and infection severity [ 160 ]. Curcumin also shows potential against Helicobacter pylori , effectively lowering bacterial counts and mitigating infection-related inflammation in preclinical models [ 161 ].

However, the clinical application of curcumin is limited by its poor bioavailability, rapid metabolism, and systemic elimination. Advances in nanotechnology have led to the development of nanocurcumin formulations, which significantly enhance curcumin’s stability, absorption, and therapeutic efficacy [ 162 ]. These innovative delivery systems not only improve antimicrobial activity but also enable synergistic interactions with existing antimicrobial agents, reducing the required dosages and minimizing side effects [ 163 , 164 ].

Despite the promising preclinical outcomes, comprehensive clinical studies are necessary to fully establish curcumin’s efficacy and safety as an antimicrobial agent. Future research should focus on optimizing curcumin formulations and exploring its potential as an adjunct therapy to overcome the growing challenge of antimicrobial resistance.

2.13. Neuroprotective Properties

Neurodegenerative disorders (NDs), such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by the progressive loss of neurons and impaired neural function, significantly impacting the aging population [ 165 ]. Current pharmacological treatments for NDs are limited by their inability to halt disease progression and their adverse side effects, prompting the exploration of alternative therapeutic strategies. Curcumin, a bioactive compound from turmeric, has emerged as a promising neuroprotective agent due to its multifaceted mechanisms of action.

Curcumin mitigates neuronal degeneration by suppressing oxidative stress, inflammation, cell death, and mitochondrial dysfunction [ 165 ]. It activates the NRF2 pathway by dissociating from Keap1, leading to the increased expression of antioxidant enzymes, such as heme oxygenase-1 (HO1) and NAD(P)H–quinone oxidoreductase 1 (NQO1), while inhibiting pro-inflammatory cytokines, like TNF-alpha, IL-6, and IL-1beta [ 166 ]. This dual action enhances neuronal survival and plasticity, critical for combating neurodegeneration.

In animal models, curcumin has demonstrated significant neuroprotective effects. For instance, chronic administration of curcumin in stressed rats reduced IL-1beta expression and neuronal death in the ventromedial prefrontal cortex, correlating with decreased depressive behavior [ 167 ]. Additionally, curcumin enhanced neurotransmitter levels and modulated the serotonergic system, contributing to its antidepressant effects [ 168 ]. Nanotechnology-based formulations, such as curcumin-coated nanoparticles, have further improved its bioavailability and efficacy, leading to enhanced behavioral and biochemical outcomes in rodent models of neurodegeneration [ 169 , 170 , 171 ].

In PD models induced by 6-hydroxydopamine, curcumin protected dopaminergic neurons, improved memory function, and increased dopamine and acetylcholine levels in the substantia nigra, while reducing oxidative stress and upregulating neurotrophic factors, like BDNF and TrkB [ 172 , 173 , 174 ]. Similarly, in AD models, curcumin reduced beta-amyloid plaque formation, oxidative stress, and neuronal damage, demonstrating its potential to slow disease progression [ 175 , 176 , 177 , 178 ]. Furthermore, the transcriptional modification of dysfunctional microglial miR-155 reduced retinal inflammation and related vasculopathy by decreasing the generation of Clec7a/Galectin-3+ microglia, which led to neurodegenerative outcomes [ 179 ]. Interestingly, curcumin at a lower dose stimulated microglial migration to and phagocytosis of amyloid plaques, decreased miR-155-mediated neurodegenerative phenotype, and reduced amyloid stress in mouse brains [ 180 ]. Clinical studies in humans have shown that bioavailable curcumin formulations, such as Theracurmin ® and CurQfen ® , improve cognitive function and reduce biomarkers of neuronal degeneration, although some studies report inconclusive results, highlighting the need for larger trials [ 181 , 182 , 183 ].

Overall, curcumin’s ability to enhance antioxidant defenses, suppress inflammatory pathways, and promote neuronal health underscores its potential as a neuroprotective agent. Continued research, particularly large-scale clinical trials, is essential to fully establish curcumin’s efficacy and optimize its therapeutic applications in neurodegenerative diseases.

3. Curcumin’s Bioavailability: Challenges and Innovative Formulations

Despite the numerous advantageous effects of curcumin, its oral bioavailability continues to be a significant constraint in curcumin therapy, necessitating further research to resolve this problem. Curcumin has been demonstrated to have an exceptionally poor bioavailability, as evidenced by numerous studies that have demonstrated either undetectable or extremely low concentrations in plasma and other tissues [ 184 ]. The primary factors contributing to low bioavailability are insufficient absorption, swift first-pass metabolism, limited tissue penetration, chemical instability, and rapid elimination [ 185 ].

To overcome these obstacles, various strategies have been employed to enhance curcumin’s bioavailability. These includes the formulations of curcumin as nanoparticles, lipid formulations, drug complexation, and the use of structural analogs, such as turmeric oil [ 186 , 187 ]. Combining curcumin with 20 mg of piperine significantly boosts its bioavailability, increasing absorption by 2000%, resulting in a raised plasma concentration within 1 h of co-administration in both rats and humans without producing adverse effects [ 188 ]. The stability of curcumin complexes with metals was improved, which contributed to the enhancement of biological activities, including antioxidant, anti-inflammatory, antimicrobial, antineoplastic, neuroprotective, and anti-ulcer activity, in comparison to unformulated curcumin [ 189 ].

Nanotechnology-based formulations have shown promise in increasing the bioavailability and therapeutic efficacy of curcumin. For example, N-carboxymethyl chitosan-coated solid lipid nanoparticles of curcumin exhibited a 6.3-fold increase in oral bioavailability and a 9.5-fold increase in lymphatic absorption when contrasted with curcumin solution [ 190 ]. These findings suggest that NCC-SLN could serve as an effective oral delivery system for curcumin, improving both absorption and distribution. Currently, a variety of formulations, including BioCurc, Cavacurcmin, CurcuWIN, Hydrocurc, Meriva, Nanocurcumin, Novasol, Theracurmin, and Turmipure Gold, are available in the global market with the potential to enhance bioavailability and solubility. Emulsifiers, such as polyethoxylated hydrogenated castor oil, carbohydrate complexes, lipoidal/phospholipid complexes, and polysorbates, are commonly used in these preparations to further improve bioavailability and solubility [ 191 ]. In addition, poloxamers offer an intriguing approach to enhance the steric stability and assimilation of conventional liposomes. Curcumin’s bioavailability was elevated to 43.3% in the pluronic-modified liposomal formulation, as compared to 26.9% with the standard liposomal formulation [ 192 ]. These formulations have been shown to significantly enhance the bioavailability of curcumin, making it more effective for therapeutic use in various chronic diseases.

4. Safety Profile of Curcumin

According to the results of safety investigations, curcumin is generally considered safe for human consumption. It has also been revealed by several studies that curcuminoids, including curcumin, and the extracts of Curcuma longa do not elevate the incidence of adverse events [ 193 , 194 ]. Curcumin is safe for human consumption, even at comparatively high doses, as support from studies conducted in humans indicate that healthy volunteers can tolerate doses of up to 8 g/d and even 12 g/d. Furthermore, a meta-analysis of 6 human studies including 172 participants found that curcuminoids substantially reduced circulating C-reactive protein levels when compared to placebo, with no adverse effects [ 195 ]. Studies on its potential toxicity indicated that it is generally safe, even at larger quantities (up to 12 g in human) [ 196 , 197 ]. According to toxicological studies, curcumin does not cause any discernible mutagenic, teratogenic, or subchronic toxicity damage [ 193 , 198 ]. Furthermore, research conducted by a study group stated that the administration of 8 g per day of curcumin plus gemcitabine to pancreatic cancer patients was found to be well-tolerated and safe [ 20 , 21 ]. However, curcumin and its derivative, bisdemethoxycurcumin, have been reported to prolong the aPTT and PT, and inhibited the activity of thrombin and factor Xa [ 199 ]. Therefore, curcumin should be used cautiously in patients with bleeding disorders and in pregnant and nursing women. Curcumin’s advantageous effects are evident; however, it is crucial to evaluate its antiplatelet properties, as it has the potential to enhance the efficacy of other antiplatelet medications, including ginkgo biloba, garlic, and other anticoagulants [ 200 ], which could result in a significant risk of hemorrhagic complications. Notably, the inappropriate bioavailability of the administered formulation could also be considered, as the various formulations achieved varying plasma concentrations, which may also affect these interactions. Despite its anti-inflammatory properties, it has been recognized as an allergen causing contact dermatitis in some individuals [ 201 ]. Consequently, it is imperative that patients and dermatologists remain vigilant regarding potential allergic reactions.

5. Probable Mechanisms of Action of Curcumin

Curcumin’s efficacy in preventing the development of disease is shown, e.g., by its ability to efficiently counteract the effects of reactive oxygen species (ROS) and nitrogen species [ 202 ]. Curcumin inhibits lipid peroxidation and peroxide-induced DNA damage via the inhibition of oxidative stress by reducing the production of ROS, including the generation of highly reactive free radicals, such as hydroxyl groups, univalent anion oxygen, and singlet oxygen, etc. [ 203 ]. Nevertheless, the inflammatory response can be induced by oxidative stress, which in turn generates a greater proportion of free radicals that can further exacerbate oxidative stress. Cardiovascular ailments, diabetes, and arthritic conditions are among the conditions that can result from this cycle, as chronic inflammation can be induced by oxidative stress [ 204 ]. Curcumin modulates many signaling molecules to exert powerful anti-inflammatory and anti-carcinogenic effects [ 205 ]. Numerous crucial elements in cellular signal transduction pathways connected to proliferation, differentiation, and malignant transformations have been demonstrated to be inhibited by curcumin ( Table 1 ) [ 206 ].

Furthermore, a multitude of studies have reported the implications of increased prostaglandin biosynthesis following upregulated cyclooxygenase-2 (COX-2) expression, which leads to activation of c-Jun/AP-1 and protein kinases in inflammatory conditions [ 207 ]. However, reports suggest that curcumin’s anti-inflammatory properties contribute to its inhibitory effect on enzymes, like 5-lipooxygenase and COX-2 [ 208 ]. In addition, curcumin has been reported to suppress lipopolysaccharide-induced increased expression of inflammatory genes, such as COX-2 and iNOS, in RAW 264.7 macrophages cells [ 209 ]. Furthermore, curcumin alleviated the carrageenan-induced increase in inflammatory cytokines, such as IFN-γ, IL-1β, IL-6, IL-13, and IL-17, through suppressing the NF-κB/COX-2 pathway and inhibiting iNOS expression [ 210 ].

Figure 3 , illustrates the action mechanisms of curcumin in diverse pathologic conditions. Nuclear factor-kappa B (NF-kB) is a transcription factor that regulates the expression of numerous genes, including pro-inflammatory genes. It is a critical mediator between inflammation and the development of a variety of human diseases. Its activity is strictly regulated by a variety of mechanisms ( Figure 3 ) and it functions in the regulation, activation, and maintenance of innate white blood cells, such as T- and B lymphocytes [ 86 ]. Tumor necrosis factor alpha (TNF-α) is a pleiotropic cytokine that is a significant regulator of inflammatory processes [ 252 ]. It is implicated in the pathogenesis of a wide range of pathologic conditions, including neurologic [ 253 ], autoimmune [ 254 ], and endocrine disorders [ 255 ], as well as obesity [ 256 ]. As shown in Figure 3 , curcumin inhibits the expression of inflammatory genes by direct inhibitory action on NF-κB [ 257 ] and also by inhibiting the TNFα signal transduction pathway [ 258 ]. In addition, curcumin inhibits TLR4 homodimerization required for activation of the MyD88 adaptor protein. This suppresses downstream signaling molecules, like IRAK1 and IRAK4 kinases, preventing TAK1-mediated activation of the IKK complex and activation of NF-κB [ 259 ]. The inhibition of NF-κB pathways exerts modulatory action on cellular oxidative stress by regulating the production of cytokines, adhesion molecules, COX-2, iNOS [ 260 ], HO-1, and NQO-1 [ 261 ], which is crucial for the adipocyte hyperplasia and hypertrophy leading to obesity. NAD(P)H–quinone oxidoreductase 1 (NQO1) is a key enzyme in the antioxidative system, catalyzing the reduction of two electrons, which takes place in different endogenous and exogenous quinones where flavin adenine nucleotides (FAD) acts as a cofactor. The promoter domain of the NQO1 gene encodes antioxidant response element (ARE) sequences, which have been shown to be regulated by nuclear factor (erythroid-derived 2)-like 2 (NRF2) [ 262 ]. Curcumin may activate the NRF2 pathway, which may reduce the expression of cytokines that promote inflammation, such as MCP-1, TNF-a, IL-6, and IL-1β, and induce antioxidant enzymes [ 263 , 264 ]. Furthermore, curcumin exerts direct inhibitory action on adipocyte hyperplasia and hypertrophy [ 265 ]. The vast majority of tumor therapies rely on the direct destruction of cancer cells or promoting the action of antitumor immune cells, such as natural killer (NK) cells and cytotoxic CD8+ T lymphocytes (CTLs) [ 266 ]. Interestingly, curcumin exerts direct antitumor and cytotoxic action by elevating NK cells [ 267 ], cytotoxic CD8+ T cells [ 268 ], and INFγ [ 269 ], and by reducing the activity of Tregs and MDSC in tumor cells [ 270 ]. Also, curcumin suppresses tumor progression by reducing Tregs and MDSC [ 271 ]. It directly suppresses the phosphorylation of AKT, leading to a reduction in cellular survival, differentiation, and angiogenesis through the inhibition of GSK3β-mediated stabilization of β-catenin. Further inhibition of AKT activation leads to the inhibition of transcription factors for inflammatory genes through TSC1/2 and mTORC1 inhibition, thus contributing to the immunomodulatory, anti-inflammatory, and neuroprotective actions of curcumin [ 272 ].

Furthermore, curcumin has been shown to inhibit the adherence of Streptococcus mutants to human dental surfaces and the extracellular matrix protein [ 273 ]. Curcumin suppresses the expression of Pseudomonas aeruginosa (PAO1) virulence factors, including biofilm formation, pyocyanin biosynthesis, elastase/protease activity, and acyl homoserine lactone (HSL) production [ 274 ]. The antimicrobial action of curcumin is multifactorial, including the disruption of cell membrane function, the inhibition of bacterial cell division by binding to FtsZ, the induction of bacterial apoptosis, and the induction of phototoxicity due to a photosensitizer under blue-light irradiation [ 275 ]. As shown in Figure 4 , curcumin reduces the bacterial virulence due to the instability of the biofilm structure, increased susceptibility to antibiotics, and the host immune system through the inhibition of a biofilm promotor gene [ 276 ]. In addition, it also prevents bacterial growth by disrupting the membrane structures and inhibits DNA gyrase, which in turn leads to bacterial lysis. Curcumin’s several antibacterial modes of action have made it a promising candidate for overcoming bacterial resistance and serving as an effective addition to antimicrobial therapy. However, the issues of its instability and low oral bioavailability from conventional dosage forms must be overcome in order to achieve the appropriate outcomes for therapeutic purposes.

6. Future Perspectives

While curcumin has demonstrated extensive therapeutic potential across various chronic diseases, several critical areas require further investigation to fully harness its benefits. Enhancing bioavailability remains a paramount challenge; innovative delivery systems, such as nanotechnology-based formulations, liposomal encapsulations, and curcumin–piperine combinations, show promise in overcoming curcumin’s poor absorption and rapid metabolism. Future studies should focus on optimizing these formulations to maximize bio-efficacy and ensure consistent therapeutic outcomes.

Large-scale clinical trials are essential to validate the promising preclinical findings and establish standardized dosing regimens. Most existing clinical studies on curcumin are limited by small sample sizes and short durations. Comprehensive, multi-center trials are necessary to assess curcumin’s long-term safety, efficacy, and role as an adjunct therapy in managing diseases, like cancer, diabetes, neurodegenerative disorders, and inflammatory conditions.

Combination therapies represent a promising avenue, where curcumin is used alongside conventional medications to enhance efficacy and reduce side effects. Investigating synergistic effects with existing drugs could lead to more effective treatment protocols, particularly in combating antibiotic resistance and enhancing antimalarial strategies.

Standardization and quality control of curcumin supplements are important to ensure consistency and reliability in clinical outcomes. Establishing standardized extraction methods and formulation protocols will enhance the reproducibility of research findings and facilitate regulatory approval.

Taken together, bridging the existing knowledge gaps through targeted research initiatives, innovative formulation strategies, and rigorous clinical evaluations will significantly advance curcumin’s role in modern medicine. These efforts will not only validate curcumin’s therapeutic efficacy but also pave the way for its integration into mainstream treatment protocols for a wide array of chronic diseases.

7. Conclusions

The health-promoting effects of curcumin are well recognized and have been in practice in traditional medicine since ancient times. Curcumin is used in traditional system-based medicinal products for diseases management because it is non-toxic and has only slight side effects. Numerous in vitro and in vivo laboratory based studies, as well as human clinical trials, have demonstrated the effectiveness of turmeric and its constituents as a favorable modulator of biological processes. Curcumin has shown a diverse range of effects in inflammatory disorders, perhaps by influencing multiple genes, signaling molecules, and enzymes. However, additional research is necessary to enlighten ourselves with the knowledge of curcumin’s wide-ranging benefits, efficiency, plausible uses, and working mechanisms, especially in terms of its usage in the prevention and treatment of human illnesses. The combination of curcumin with other potential therapeutic reagents should further be explored and tested in controlled clinical studies.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Conflicts of Interest

The authors declare no conflicts of interest.

References

1. El-Saadony M.T. Yang T. Korma S.A. Sitohy M. Abd El-Mageed T.A. Selim S. Al Jaouni S.K. Salem H.M. Mahmmod Y. Soliman S.M. Impacts of Turmeric and Its Principal Bioactive Curcumin on Human Health: Pharmaceutical, Medicinal, and Food Applications: A Comprehensive Review Front. Nutr. 2022 9 1040259 10.3389/fnut.2022.1040259 36712505 PMC9881416

2. Hewlings S.J. Kalman D.S. Curcumin: A Review of Its Effects on Human Health Foods 2017 6 92 10.3390/foods6100092 29065496 PMC5664031

3. Fuloria S. Mehta J. Chandel A. Sekar M. Rani N.N.I.M. Begum M.Y. Subramaniyan V. Chidambaram K. Thangavelu L. Nordin R. A Comprehensive Review on the Therapeutic Potential of Curcuma Longa Linn. in Relation to Its Major Active Constituent Curcumin Front. Pharmacol. 2022 13 820806 10.3389/fphar.2022.820806 35401176 PMC8990857

4. Miłobȩdzka J. Kostanecki S.V. Lampe V. Zur Kenntnis Des Curcumins Berichte Dtsch. Chem. Ges. 1910 43 2163 2170 10.1002/cber.191004302168

5. Lampe V. Milobedzka J. Studien Über Curcumin Berichte Dtsch. Chem. Ges. 1913 46 2235 2240 10.1002/cber.191304602149

6. Pabon H.J.J. A Synthesis of Curcumin and Related Compounds Recl. Trav. Chim. des Pays-Bas 1964 83 379 386 10.1002/recl.19640830407

7. Grynkiewicz G. Ślifirski P. Curcumin and Curcuminoids in Quest for Medicinal Status Acta Biochim. Pol. 2012 59 201 212 10.18388/abp.2012_2139 22590694

8. Esatbeyoglu T. Huebbe P. Ernst I.M.A. Chin D. Wagner A.E. Rimbach G. Curcumin—From Molecule to Biological Function Angew. Chem. Int. Ed. 2012 51 5308 5332 10.1002/anie.201107724 22566109

9. Venkateswarlu S. Ramachandra M.S. Subbaraju G.V. Synthesis and Biological Evaluation of Polyhydroxycurcuminoids Bioorg. Med. Chem. 2005 13 6374 6380 10.1016/j.bmc.2005.06.050 16112582

10. Priyadarsini K.I. The Chemistry of Curcumin: From Extraction to Therapeutic Agent Molecules 2014 19 20091 20112 10.3390/molecules191220091 25470276 PMC6270789

11. Chattopadhyay I. Biswas K. Bandyopadhyay U. Banerjee R.K. Turmeric and Curcumin: Biological Actions and Medicinal Applications Curr. Sci. 2004 87 44 53

12. Anand P. Thomas S.G. Kunnumakkara A.B. Sundaram C. Harikumar K.B. Sung B. Tharakan S.T. Misra K. Priyadarsini I.K. Rajasekharan K.N. Biological Activities of Curcumin and Its Analogues (Congeners) Made by Man and Mother Nature Biochem. Pharmacol. 2008 76 1590 1611 10.1016/j.bcp.2008.08.008 18775680

13. Aggarwal B.B. Harikumar K.B. Potential Therapeutic Effects of Curcumin, the Anti-Inflammatory Agent, against Neurodegenerative, Cardiovascular, Pulmonary, Metabolic, Autoimmune and Neoplastic Diseases Int. J. Biochem. Cell Biol. 2009 41 40 59 10.1016/j.biocel.2008.06.010 18662800 PMC2637808

14. Witkin J.M. Li X. Curcumin, an Active Constiuent of the Ancient Medicinal Herb Curcuma Longa L.: Some Uses and the Establishment and Biological Basis of Medical Efficacy CNS Neurol. Disord. Drug Targets 2013 12 487 497 10.2174/1871527311312040007 23574161

15. Sharma R.A. McLelland H.R. Hill K.A. Ireson C.R. Euden S.A. Manson M.M. Pirmohamed M. Marnett L.J. Gescher A.J. Steward W.P. Pharmacodynamic and Pharmacokinetic Study of Oral Curcuma Extract in Patients with Colorectal Cancer Clin. Cancer Res. 2001 7 1894 1900 11448902

16. Aggarwal B.B. Sung B. Pharmacological Basis for the Role of Curcumin in Chronic Diseases: An Age-Old Spice with Modern Targets Trends Pharmacol. Sci. 2009 30 85 94 10.1016/j.tips.2008.11.002 19110321

17. DiSilvestro R.A. Joseph E. Zhao S. Bomser J. Diverse Effects of a Low Dose Supplement of Lipidated Curcumin in Healthy Middle Aged People Nutr. J. 2012 11 79 10.1186/1475-2891-11-79 23013352 PMC3518252

18. Ide H. Tokiwa S. Sakamaki K. Nishio K. Isotani S. Muto S. Hama T. Masuda H. Horie S. Combined Inhibitory Effects of Soy Isoflavones and Curcumin on the Production of Prostate-specific Antigen Prostate 2010 70 1127 1133 10.1002/pros.21147 20503397

19. Sharma R.A. Euden S.A. Platton S.L. Cooke D.N. Shafayat A. Hewitt H.R. Marczylo T.H. Morgan B. Hemingway D. Plummer S.M. Phase I Clinical Trial of Oral Curcumin: Biomarkers of Systemic Activity and Compliance Clin. Cancer Res. 2004 10 6847 6854 10.1158/1078-0432.CCR-04-0744 15501961

20. Dhillon N. Aggarwal B.B. Newman R.A. Wolff R.A. Kunnumakkara A.B. Abbruzzese J.L. Ng C.S. Badmaev V. Kurzrock R. Phase II Trial of Curcumin in Patients with Advanced Pancreatic Cancer Clin. Cancer Res. 2008 14 4491 4499 10.1158/1078-0432.CCR-08-0024 18628464

21. Kanai M. Yoshimura K. Asada M. Imaizumi A. Suzuki C. Matsumoto S. Nishimura T. Mori Y. Masui T. Kawaguchi Y. A Phase I/II Study of Gemcitabine-Based Chemotherapy plus Curcumin for Patients with Gemcitabine-Resistant Pancreatic Cancer Cancer Chemother. Pharmacol. 2011 68 157 164 10.1007/s00280-010-1470-2 20859741

22. 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. Targeted Therapies of Curcumin Focus on Its Therapeutic Benefits in Cancers and Human Health: Molecular Signaling Pathway-Based Approaches and Future Perspectives Biomed. Pharmacother. 2024 170 116034 10.1016/j.biopha.2023.116034 38141282

23. He Z.-Y. Shi C.-B. Wen H. Li F.-L. Wang B.-L. Wang J. Upregulation of P53 Expression in Patients with Colorectal Cancer by Administration of Curcumin Cancer Invest. 2011 29 208 213 10.3109/07357907.2010.550592 21314329

24. Shanmugam M.K. Rane G. Kanchi M.M. Arfuso F. Chinnathambi A. Zayed M.E. Alharbi S.A. Tan B.K.H. Kumar A.P. Sethi G. The Multifaceted Role of Curcumin in Cancer Prevention and Treatment Molecules 2015 20 2728 2769 10.3390/molecules20022728 25665066 PMC6272781

25. Sivani B.M. Azzeh M. Patnaik R. Pantea Stoian A. Rizzo M. Banerjee Y. Reconnoitering the Therapeutic Role of Curcumin in Disease Prevention and Treatment: Lessons Learnt and Future Directions Metabolites 2022 12 639 10.3390/metabo12070639 35888763 PMC9320502

26. Moon D.-O. Curcumin in Cancer and Inflammation: An In-Depth Exploration of Molecular Interactions, Therapeutic Potentials, and the Role in Disease Management Int. J. Mol. Sci. 2024 25 2911 10.3390/ijms25052911 38474160 PMC10932100

27. Fetoni A.R. Paciello F. Mezzogori D. Rolesi R. Eramo S.L.M. Paludetti G. Troiani D. Molecular Targets for Anticancer Redox Chemotherapy and Cisplatin-Induced Ototoxicity: The Role of Curcumin on PSTAT3 and Nrf-2 Signalling Br. J. Cancer 2015 113 1434 1444 10.1038/bjc.2015.359 26469832 PMC4815880

28. Zoi V. Galani V. Lianos G.D. Voulgaris S. Kyritsis A.P. Alexiou G.A. The Role of Curcumin in Cancer Treatment Biomedicines 2021 9 1086 10.3390/biomedicines9091086 34572272 PMC8464730

29. Mansouri K. Rasoulpoor S. Daneshkhah A. Abolfathi S. Salari N. Mohammadi M. Rasoulpoor S. Shabani S. Clinical Effects of Curcumin in Enhancing Cancer Therapy: A Systematic Review BMC Cancer 2020 20 791 10.1186/s12885-020-07256-8 32838749 PMC7446227

30. Aggarwal B.B. Kumar A. Bharti A.C. Anticancer Potential of Curcumin: Preclinical and Clinical Studies Anticancer Res. 2003 23 363 398 12680238

31. Screening P.D.Q. Board P.E. Colorectal Cancer Screening (PDQ ® ) PDQ Cancer Information Summaries [Internet] National Cancer Institute (US) Bethesda, MD, USA 2023

32. Sharma N. Alam M.S. Sharma A. Garg S. Maity M.K. Colorectal Cancer in Young Adults: Epidemiology, Risk Factors, Development, Symptoms, Traditional Herbal Therapy And Prevention J. Pharm. Negat. Results 2022 14 1370 1382

33. Garcea G. Berry D.P. Jones D.J.L. Singh R. Dennison A.R. Farmer P.B. Sharma R.A. Steward W.P. Gescher A.J. Consumption of the Putative Chemopreventive Agent Curcumin by Cancer Patients: Assessment of Curcumin Levels in the Colorectum and Their Pharmacodynamic Consequences Cancer Epidemiol. Biomark. Prev. 2005 14 120 125 10.1158/1055-9965.120.14.1 15668484

34. Carroll R.E. Benya R.V. Turgeon D.K. Vareed S. Neuman M. Rodriguez L. Kakarala M. Carpenter P.M. McLaren C. Meyskens F.L. Jr. Phase IIa Clinical Trial of Curcumin for the Prevention of Colorectal Neoplasia Cancer Prev. Res. 2011 4 354 364 10.1158/1940-6207.CAPR-10-0098 21372035 PMC4136551

35. Cruz–Correa M. Shoskes D.A. Sanchez P. Zhao R. Hylind L.M. Wexner S.D. Giardiello F.M. Combination Treatment with Curcumin and Quercetin of Adenomas in Familial Adenomatous Polyposis Clin. Gastroenterol. Hepatol. 2006 4 1035 1038 10.1016/j.cgh.2006.03.020 16757216

36. Gao Y. Zhuang Z. Lu Y. Tao T. Zhou Y. Liu G. Wang H. Zhang D. Wu L. Dai H. Curcumin Mitigates Neuro-Inflammation by Modulating Microglia Polarization through Inhibiting TLR4 Axis Signaling Pathway Following Experimental Subarachnoid Hemorrhage Front. Neurosci. 2019 13 496029 10.3389/fnins.2019.01223 PMC6872970 31803007

37. Zhang J. Zheng Y. Luo Y. Du Y. Zhang X. Fu J. Curcumin Inhibits LPS-Induced Neuroinflammation by Promoting Microglial M2 Polarization via TREM2/TLR4/NF-ΚB Pathways in BV2 Cells Mol. Immunol. 2019 116 29 37 10.1016/j.molimm.2019.09.020 31590042

38. Holt P.R. Katz S. Kirshoff R. Curcumin Therapy in Inflammatory Bowel Disease: A Pilot Study Dig. Dis. Sci. 2005 50 2191 2193 10.1007/s10620-005-3032-8 16240238

39. Hanai H. Iida T. Takeuchi K. Watanabe F. Maruyama Y. Andoh A. Tsujikawa T. Fujiyama Y. Mitsuyama K. Sata M. Curcumin Maintenance Therapy for Ulcerative Colitis: Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial Clin. Gastroenterol. Hepatol. 2006 4 1502 1506 10.1016/j.cgh.2006.08.008 17101300

40. Lahiff C. Moss A.C. Curcumin for Clinical and Endoscopic Remission in Ulcerative Colitis Inflamm. Bowel Dis. 2011 17 E66 10.1002/ibd.21710 21484966

41. Sadeghi N. Mansoori A. Shayesteh A. Hashemi S.J. The Effect of Curcumin Supplementation on Clinical Outcomes and Inflammatory Markers in Patients with Ulcerative Colitis Phyther. Res. 2020 34 1123 1133 10.1002/ptr.6581 31802559

42. Epstein J. Docena G. MacDonald T.T. Sanderson I.R. Curcumin Suppresses P38 Mitogen-Activated Protein Kinase Activation, Reduces IL-1β and Matrix Metalloproteinase-3 and Enhances IL-10 in the Mucosa of Children and Adults with Inflammatory Bowel Disease Br. J. Nutr. 2010 103 824 832 10.1017/S0007114509992510 19878610

43. Karthikeyan A. Young K.N. Moniruzzaman M. Beyene A.M. Do K. Kalaiselvi S. Min T. Curcumin and Its Modified Formulations on Inflammatory Bowel Disease (IBD): The Story so Far and Future Outlook Pharmaceutics 2021 13 484 10.3390/pharmaceutics13040484 33918207 PMC8065662

44. Kaitha S. Bashir M. Ali T. Iron Deficiency Anemia in Inflammatory Bowel Disease World J. Gastrointest. Pathophysiol. 2015 6 62 72 10.4291/wjgp.v6.i3.62 26301120 PMC4540708

45. Jiao Y. Wilkinson J. IV Di X. Wang W. Hatcher H. Kock N.D. D’Agostino R. Jr. Knovich M.A. Torti F.M. Torti S.V. Curcumin, a Cancer Chemopreventive and Chemotherapeutic Agent, Is a Biologically Active Iron Chelator Blood J. Am. Soc. Hematol. 2009 113 462 469 10.1182/blood-2008-05-155952 18815282 PMC2615657

46. Nicoliche T. Maldonado D.C. Faber J. da Silva M.C.P. Evaluation of the Articular Cartilage in the Knees of Rats with Induced Arthritis Treated with Curcumin PLoS ONE 2020 15 e0230228 10.1371/journal.pone.0230228 32163510 PMC7067390

47. Yan D. He B. Guo J. Li S. Wang J. Involvement of TLR4 in the Protective Effect of Intra-Articular Administration of Curcumin on Rat Experimental Osteoarthritis Acta Cirúrgica Bras. 2019 34 e201900604 10.1590/s0102-865020190060000004 PMC6705335 31432995

48. Sun Y. Liu W. Zhang H. Li H. Liu J. Zhang F. Jiang T. Jiang S. Curcumin Prevents Osteoarthritis by Inhibiting the Activation of Inflammasome NLRP3 J. Interf. Cytokine Res. 2017 37 449 455 10.1089/jir.2017.0069 29028430

49. Guo C. Fu R. Wang S. Huang Y. Li X. Zhou M. Zhao J. Yang N. NLRP3 Inflammasome Activation Contributes to the Pathogenesis of Rheumatoid Arthritis Clin. Exp. Immunol. 2018 194 231 243 10.1111/cei.13167 30277570 PMC6194337

50. Martinon F. Pétrilli V. Mayor A. Tardivel A. Tschopp J. Gout-Associated Uric Acid Crystals Activate the NALP3 Inflammasome Nature 2006 440 237 241 10.1038/nature04516 16407889

51. Sahin K. Orhan C. Er B. Durmus A.S. Ozercan I.H. Sahin N. Padigaru M. Morde A. Rai D. Protective Effect of a Novel Highly Bioavailable Formulation of Curcumin in Experimentally Induced Osteoarthritis Rat Model Curr. Dev. Nutr. 2020 4 1765 10.1093/cdn/nzaa066_020

52. Hamdalla H.M. Ahmed R.R. Galaly S.R. Naguib I.A. Alghamdi B.S. Ahmed O.M. Farghali A. Abdul-Hamid M. Ameliorative Effect of Curcumin Nanoparticles against Monosodium Iodoacetate-Induced Knee Osteoarthritis in Rats Mediat. Inflamm. 2022 2022 8353472 10.1155/2022/8353472 36578323 PMC9792255

53. Paultre K. Cade W. Hernandez D. Reynolds J. Greif D. Best T.M. Therapeutic Effects of Turmeric or Curcumin Extract on Pain and Function for Individuals with Knee Osteoarthritis: A Systematic Review BMJ Open Sport Exerc. Med. 2021 7 e000935 10.1136/bmjsem-2020-000935 33500785 PMC7812094

54. Chandran B. Goel A. A Randomized, Pilot Study to Assess the Efficacy and Safety of Curcumin in Patients with Active Rheumatoid Arthritis Phyther. Res. 2012 26 1719 1725 10.1002/ptr.4639 22407780

55. Belcaro G. Cesarone M.R. Dugall M. Pellegrini L. Ledda A. Grossi M.G. Togni S. Appendino G. Efficacy and Safety of Meriva ® , a Curcumin-Phosphatidylcholine Complex, during Extended Administration in Osteoarthritis Patients Altern. Med. Rev. 2010 15 337 344 21194249

56. Belcaro G. Cesarone M.R. Dugall M. Pellegrini L. Ledda A. Grossi M.G. Togni S. Appendino G. Product-Evaluation Registry of Meriva ® , a Curcumin-Phosphatidylcholine Complex, for the Complementary Management of Osteoarthritis Panminerva Med. 2010 52 55 62 20657536

57. Saber M.M. Mahmoud M.M. Amin H.M. Essam R.M. Therapeutic Effects of Combining Curcumin and Swimming in Osteoarthritis Using a Rat Model Biomed. Pharmacother. 2023 166 115309 10.1016/j.biopha.2023.115309 37573656 PMC10538387

58. Singh L. Sharma S. Xu S. Tewari D. Fang J. Curcumin as a Natural Remedy for Atherosclerosis: A Pharmacological Review Molecules 2021 26 4036 10.3390/molecules26134036 34279384 PMC8272048

59. Chen Y. Chai Y. Xie K. Yu F. Wang C. Lin S. Yang Y. Xu F. Curcumin Promotes the Expression of IL-35 by Regulating Regulatory T Cell Differentiation and Restrains Uncontrolled Inflammation and Lung Injury in Mice Inflammation 2020 43 1913 1924 10.1007/s10753-020-01265-2 32535666

60. Cox F.F. Misiou A. Vierkant A. Ale-Agha N. Grandoch M. Haendeler J. Altschmied J. Protective Effects of Curcumin in Cardiovascular Diseases—Impact on Oxidative Stress and Mitochondria Cells 2022 11 342 10.3390/cells11030342 35159155 PMC8833931

61. Sun Y. Hu X. Hu G. Xu C. Jiang H. Curcumin Attenuates Hydrogen Peroxide-Induced Premature Senescence via the Activation of SIRT1 in Human Umbilical Vein Endothelial Cells Biol. Pharm. Bull. 2015 38 1134 1141 10.1248/bpb.b15-00012 26235577

62. Ak T. Gülçin I. Antioxidant and Radical Scavenging Properties of Curcumin Chem. Biol. Interact. 2008 174 27 37 10.1016/j.cbi.2008.05.003 18547552

63. Jovanovic S.V. Steenken S. Boone C.W. Simic M.G. H-Atom Transfer Is a Preferred Antioxidant Mechanism of Curcumin J. Am. Chem. Soc. 1999 121 9677 9681 10.1021/ja991446m

64. Menon V.P. Sudheer A.R. Antioxidant and Anti-Inflammatory Properties of Curcumin Adv. Exp. Med. Biol. 2007 595 105 125 17569207 10.1007/978-0-387-46401-5_3

65. Faten R.A. Ibrahim A.E. Khaled A.E. Protective and Modulatory Effects of Curcumin and L-Carnitine against Methotrexate-Induced Oxidative Stress in Albino Rats Res. J. Pharm. Biol. Chem. Sci. 2013 4 744 754

66. Gao S. Zhang W. Zhao Q. Zhou J. Wu Y. Liu Y. Yuan Z. Wang L. Curcumin Ameliorates Atherosclerosis in Apolipoprotein E Deficient Asthmatic Mice by Regulating the Balance of Th2/Treg Cells Phytomedicine 2019 52 129 135 10.1016/j.phymed.2018.09.194 30599892

67. Momtazi-Borojeni A.A. Abdollahi E. Nikfar B. Chaichian S. Ekhlasi-Hundrieser M. Curcumin as a Potential Modulator of M1 and M2 Macrophages: New Insights in Atherosclerosis Therapy Heart Fail. Rev. 2019 24 399 409 10.1007/s10741-018-09764-z 30673930

68. Zhang S. Zou J. Li P. Zheng X. Feng D. Curcumin Protects against Atherosclerosis in Apolipoprotein E-Knockout Mice by Inhibiting Toll-like Receptor 4 Expression J. Agric. Food Chem. 2018 66 449 456 10.1021/acs.jafc.7b04260 29224353

69. Han Y. Sun H.-J. Tong Y. Chen Y.-Z. Ye C. Qiu Y. Zhang F. Chen A.-D. Qi X.-H. Chen Q. Curcumin Attenuates Migration of Vascular Smooth Muscle Cells via Inhibiting NFκB-Mediated NLRP3 Expression in Spontaneously Hypertensive Rats J. Nutr. Biochem. 2019 72 108212 10.1016/j.jnutbio.2019.07.003 31473513

70. Simental-Mendía L.E. Pirro M. Gotto A.M. Jr. Banach M. Atkin S.L. Majeed M. Sahebkar A. Lipid-Modifying Activity of Curcuminoids: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Crit. Rev. Food Sci. Nutr. 2019 59 1178 1187 10.1080/10408398.2017.1396201 29185808

71. Funamoto M. Sunagawa Y. Katanasaka Y. Miyazaki Y. Imaizumi A. Kakeya H. Yamakage H. Satoh-Asahara N. Komiyama M. Wada H. Highly Absorptive Curcumin Reduces Serum Atherosclerotic Low-Density Lipoprotein Levels in Patients with Mild COPD Int. J. Chron. Obstruct. Pulmon. Dis. 2016 11 2029 2034 10.2147/COPD.S104490 27616885 PMC5008445

72. Sahebkar A. A Systematic Review and Meta-Analysis of Randomized Controlled Trials Investigating the Effects of Curcumin on Blood Lipid Levels Clin. Nutr. 2014 33 406 414 10.1016/j.clnu.2013.09.012 24139527

73. Czekaj R. Majka J. Magierowska K. Sliwowski Z. Magierowski M. Pajdo R. Ptak-Belowska A. Surmiak M. Kwiecien S. Brzozowski T. Mechanisms of Curcumin-Induced Gastroprotection against Ethanol-Induced Gastric Mucosal Lesions J. Gastroenterol. 2018 53 618 630 10.1007/s00535-017-1385-3 28856444 PMC5910495

74. Mei X. Xu D. Xu S. Zheng Y. Xu S. Novel Role of Zn (II)–Curcumin in Enhancing Cell Proliferation and Adjusting Proinflammatory Cytokine-Mediated Oxidative Damage of Ethanol-Induced Acute Gastric Ulcers Chem. Biol. Interact. 2012 197 31 39 10.1016/j.cbi.2012.03.006 22465177

75. Mahattanadul S. Nakamura T. Panichayupakaranant P. Phdoongsombut N. Tungsinmunkong K. Bouking P. Comparative Antiulcer Effect of Bisdemethoxycurcumin and Curcumin in a Gastric Ulcer Model System Phytomedicine 2009 16 342 351 10.1016/j.phymed.2008.12.005 19188055

76. Tuorkey M. Karolin K. Anti-Ulcer Activity of Curcumin on Experimental Gastric Ulcer in Rats and Its Effect on Oxidative Stress/Antioxidant, IL-6 and Enzyme Activities Biomed. Environ. Sci. 2009 22 488 495 10.1016/S0895-3988(10)60006-2 20337222

77. Mahattanadul S. Mustafa M.W. Kuadkaew S. Pattharachayakul S. Ungphaiboon S. Sawanyawisuth K. Oral Ulcer Healing and Anti-Candida Efficacy of an Alcohol-Free Chitosan-Curcumin Mouthwash Eur. Rev. Med. Pharmacol. Sci. 2018 22 7020 7023 30402869 10.26355/eurrev_201810_16173

78. Kuadkaew S. Ungphaiboon S. Phdoongsombut N. Kaewsuwan S. Mahattanadul S. Efficacy of a Chitosan-Curcumin Mixture in Treating Indomethacininduced Acute Gastric Ulcer in Rats Curr. Pharm. Biotechnol. 2021 22 1919 1931 10.2174/1389201022666210127115427 33504303

79. Heikal E.J. Kaoud R.M. Gad S. Mokhtar H.I. Aldahish A.A. Alzlaiq W.A. Zaitone S.A. Moustafa Y.M. Hammady T.M. Design and Optimization of Omeprazole-Curcumin-Loaded Hydrogel Beads Coated with Chitosan for Treating Peptic Ulcers Pharmaceuticals 2023 16 795 10.3390/ph16060795 37375745 PMC10305022

80. Vetvicka V. Vetvickova J. Fernandez-Botran R. Effects of Curcumin on Helicobacter Pylori Infection Ann. Transl. Med. 2016 4 479 10.21037/atm.2016.12.52 28149841 PMC5233496

81. Kositchaiwat C. Kositchaiwat S. Havanondha J. Curcuma Longa Linn. in the Treatment of Gastric Ulcer Comparison to Liquid Antacid: A Controlled Clinical Trial J. Med. Assoc. Thail. 1993 76 601 605 7964234

82. Prucksunand C. Indrasukhsri B. Leethochawalit M. Hungspreugs K. Phase II Clinical Trial on Effect of the Long Turmeric ( Curcuma Longa Linn.) on Healing of Peptic Ulcer Southeast Asian J. Trop. Med. Public Health 2001 32 208 215 11485087

83. Huang C. Wang Y. Li X. Ren L. Zhao J. Hu Y. Zhang L. Fan G. Xu J. Gu X. Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China Lancet 2020 395 497 506 10.1016/S0140-6736(20)30183-5 31986264 PMC7159299

84. Jiang H. He H. Chen Y. Huang W. Cheng J. Ye J. Wang A. Tao J. Wang C. Liu Q. Identification of a Selective and Direct NLRP3 Inhibitor to Treat Inflammatory Disorders J. Exp. Med. 2017 214 3219 10.1084/jem.20171419 29021150 PMC5679172

85. Sahoo M. Ceballos-Olvera I. del Barrio L. Re F. Role of the Inflammasome, IL-1beta, and IL-18 in Bacterial Infections Sci. World J. 2011 11 2037 2050 10.1100/2011/212680 PMC3217589 22125454

86. Liu T. Zhang L. Joo D. Sun S.-C. NF-ΚB Signaling in Inflammation Signal Transduct. Target. Ther. 2017 2 17023 10.1038/sigtrans.2017.23 29158945 PMC5661633

87. Marín-Palma D. Tabares-Guevara J.H. Zapata-Cardona M.I. Flórez-Álvarez L. Yepes L.M. Rugeles M.T. Zapata-Builes W. Hernandez J.C. Taborda N.A. Curcumin Inhibits in Vitro SARS-CoV-2 Infection in Vero E6 Cells through Multiple Antiviral Mechanisms Molecules 2021 26 6900 10.3390/molecules26226900 34833991 PMC8618354

88. Rattis B.A.C. Ramos S.G. Celes M. Curcumin as a Potential Treatment for COVID-19 Front. Pharmacol. 2021 12 675287 10.3389/fphar.2021.675287 34025433 PMC8138567

89. Tahmasebi S. Saeed B.Q. Temirgalieva E. Yumashev A.V. El-Esawi M.A. Navashenaq J.G. Valizadeh H. Sadeghi A. Aslani S. Yousefi M. Nanocurcumin Improves Treg Cell Responses in Patients with Mild and Severe SARS-CoV2 Life Sci. 2021 276 119437 10.1016/j.lfs.2021.119437 33789145 PMC8005319

90. Golpour-Hamedani S. Pourmasoumi M. Askari G. Bagherniya M. Majeed M. Guest P.C. Sahebkar A. Antiviral Mechanisms of Curcumin and Its Derivatives in Prevention and Treatment of COVID-19: A Review Adv. Exp. Med. Biol. 2023 1412 397 411 10.1007/978-3-031-28012-2_21 37378779

91. Saber-Moghaddam N. Salari S. Hejazi S. Amini M. Taherzadeh Z. Eslami S. Rezayat S.M. Jaafari M.R. Elyasi S. Oral Nano-curcumin Formulation Efficacy in Management of Mild to Moderate Hospitalized Coronavirus Disease-19 Patients: An Open Label Nonrandomized Clinical Trial Phyther. Res. 2021 35 2616 2623 10.1002/ptr.7004 33389761

92. Kahkhaie K.R. Mirhosseini A. Aliabadi A. Mohammadi A. Mousavi M.J. Haftcheshmeh S.M. Sathyapalan T. Sahebkar A. Curcumin: A Modulator of Inflammatory Signaling Pathways in the Immune System Inflammopharmacology 2019 27 885 900 10.1007/s10787-019-00607-3 31140036

93. Nicoliche T. Bartolomeo C.S. Lemes R.M.R. Pereira G.C. Nunes T.A. Oliveira R.B. Nicastro A.L.M. Soares É.N. da Cunha Lima B.F. Rodrigues B.M. Antiviral, Anti-Inflammatory and Antioxidant Effects of Curcumin and Curcuminoids in SH-SY5Y Cells Infected by SARS-CoV-2 Sci. Rep. 2024 14 10696 10.1038/s41598-024-61662-7 38730068 PMC11087556

94. Kasprzak-Drozd K. Niziński P. Hawrył A. Gancarz M. Hawrył D. Oliwa W. Pałka M. Markowska J. Oniszczuk A. Potential of Curcumin in the Management of Skin Diseases Int. J. Mol. Sci. 2024 25 3617 10.3390/ijms25073617 38612433 PMC11012053

95. Bahraini P. Rajabi M. Mansouri P. Sarafian G. Chalangari R. Azizian Z. Turmeric Tonic as a Treatment in Scalp Psoriasis: A Randomized Placebo-Control Clinical Trial J. Cosmet. Dermatol. 2018 17 461 466 10.1111/jocd.12513 29607625

96. Zhang S. Wang J. Liu L. Sun X. Zhou Y. Chen S. Lu Y. Cai X. Hu M. Yan G. Efficacy and Safety of Curcumin in Psoriasis: Preclinical and Clinical Evidence and Possible Mechanisms Front. Pharmacol. 2022 13 903160 10.3389/fphar.2022.903160 36120325 PMC9477188

97. Jain A. Doppalapudi S. Domb A.J. Khan W. Tacrolimus and Curcumin Co-Loaded Liposphere Gel: Synergistic Combination towards Management of Psoriasis J. Control. Release 2016 243 132 145 10.1016/j.jconrel.2016.10.004 27725194

98. Mao K.-L. Fan Z.-L. Yuan J.-D. Chen P.-P. Yang J.-J. Xu J. ZhuGe D.-L. Jin B.-H. Zhu Q.-Y. Shen B.-X. Skin-Penetrating Polymeric Nanoparticles Incorporated in Silk Fibroin Hydrogel for Topical Delivery of Curcumin to Improve Its Therapeutic Effect on Psoriasis Mouse Model Colloids Surf. B Biointerfaces 2017 160 704 714 10.1016/j.colsurfb.2017.10.029 29035818

99. Kim H. Choi M.R. Jeon S.H. Jang Y. Yang Y.D. Pathophysiological Roles of Ion Channels in Epidermal Cells, Immune Cells, and Sensory Neurons in Psoriasis Int. J. Mol. Sci. 2024 25 2756 10.3390/ijms25052756 38474002 PMC10932231

100. Tabeshpour J. Banaeeyeh S. Eisvand F. Sathyapalan T. Hashemzaei M. Sahebkar A. Effects of Curcumin on Ion Channels and Pumps: A Review IUBMB Life 2019 71 812 820 10.1002/iub.2054 31020791

101. Kang D. Li B. Luo L. Jiang W. Lu Q. Rong M. Lai R. Curcumin Shows Excellent Therapeutic Effect on Psoriasis in Mouse Model Biochimie 2016 123 73 80 10.1016/j.biochi.2016.01.013 26826458

102. Reddy S. Aggarwal B.B. Curcumin Is a Non-Competitive and Selective Inhibitor of Phosphorylase Kinase FEBS Lett. 1994 341 19 22 10.1016/0014-5793(94)80232-7 7511111

103. Li L. Liu C. Fu J. Wang Y. Yang D. Peng B. Liu X. Han X. Meng Y. Feng F. CD44 Targeted Indirubin Nanocrystal-Loaded Hyaluronic Acid Hydrogel for the Treatment of Psoriasis Int. J. Biol. Macromol. 2023 243 125239 10.1016/j.ijbiomac.2023.125239 37295696

104. Zhang Y. Xia Q. Li Y. He Z. Li Z. Guo T. Wu Z. Feng N. CD44 Assists the Topical Anti-Psoriatic Efficacy of Curcumin-Loaded Hyaluronan-Modified Ethosomes: A New Strategy for Clustering Drug in Inflammatory Skin Theranostics 2019 9 48 64 10.7150/thno.29715 30662553 PMC6332788

105. Sun L. Liu Z. Wang L. Cun D. Tong H.H.Y. Yan R. Chen X. Wang R. Zheng Y. Enhanced Topical Penetration, System Exposure and Anti-Psoriasis Activity of Two Particle-Sized, Curcumin-Loaded PLGA Nanoparticles in Hydrogel J. Control. Release Off. J. Control. Release Soc. 2017 254 44 54 10.1016/j.jconrel.2017.03.385 28344018

106. Jin N. Lin J. Yang C. Wu C. He J. Chen Z. Yang Q. Chen J. Zheng G. Lv L. Enhanced Penetration and Anti-Psoriatic Efficacy of Curcumin by Improved SmartPearls Technology with the Addition of Glycyrrhizic Acid Int. J. Pharm. 2020 578 119101 10.1016/j.ijpharm.2020.119101 32006622

107. Heng M.C.Y. Song M.K. Harker J. Heng M.K. Drug-induced Suppression of Phosphorylase Kinase Activity Correlates with Resolution of Psoriasis as Assessed by Clinical, Histological and Immunohistochemical Parameters Br. J. Dermatol. 2000 143 937 949 10.1046/j.1365-2133.2000.03767.x 11069500

108. Kurd S.K. Smith N. VanVoorhees A. Troxel A.B. Badmaev V. Seykora J.T. Gelfand J.M. Oral Curcumin in the Treatment of Moderate to Severe Psoriasis Vulgaris: A Prospective Clinical Trial J. Am. Acad. Dermatol. 2008 58 625 631 10.1016/j.jaad.2007.12.035 18249471 PMC4131208

109. Asawanonda P. Klahan S.-O. Tetrahydrocurcuminoid Cream plus Targeted Narrowband UVB Phototherapy for Vitiligo: A Preliminary Randomized Controlled Study Photomed. Laser Surg. 2010 28 679 684 10.1089/pho.2009.2637 20961233

110. Vaccaro M. Bagnato G. Cristani M. Borgia F. Spatari G. Tigano V. Saja A. Guarneri F. Cannavò S.P. Gangemi S. Oxidation Products Are Increased in Patients Affected by Non-Segmental Generalized Vitiligo Arch. Dermatol. Res. 2017 309 485 490 10.1007/s00403-017-1746-z 28551758

111. Sun Y.P. Gu J.F. Tan X.B. Wang C.F. Jia X.B. Feng L. Liu J.P. Curcumin Inhibits Advanced Glycation End Product-Induced Oxidative Stress and Inflammatory Responses in Endothelial Cell Damage via Trapping Methylglyoxal Mol. Med. Rep. 2016 13 1475 1486 10.3892/mmr.2015.4725 26718010 PMC4732849

112. Ashrafizadeh M. Ahmadi Z. Mohammadinejad R. Farkhondeh T. Samarghandian S. Curcumin Activates the Nrf2 Pathway and Induces Cellular Protection against Oxidative Injury Curr. Mol. Med. 2020 20 116 133 31622191 10.2174/1566524019666191016150757

113. Jalalmanesh S. Mansouri P. Rajabi M. Monji F. Therapeutic Effects of Turmeric Topical Cream in Vitiligo: A Randomized, Double-Blind, Placebo-Controlled Pilot Study J. Cosmet. Dermatol. 2022 21 4454 4461 10.1111/jocd.14814 35104042

114. Alshaikh A.A. Bharti R.K. Spontaneous Reversal of Vitiligo, a Rare Phenomenon Reported in a Case in Saudi Arabia with an Insight into Metabolic Biochemical Derangements Medicina 2023 59 427 10.3390/medicina59030427 36984427 PMC10053937

115. Miller A.H. Raison C.L. The Role of Inflammation in Depression: From Evolutionary Imperative to Modern Treatment Target Nat. Rev. Immunol. 2016 16 22 34 10.1038/nri.2015.5 26711676 PMC5542678

116. Beurel E. Toups M. Nemeroff C.B. The Bidirectional Relationship of Depression and Inflammation: Double Trouble Neuron 2020 107 234 256 10.1016/j.neuron.2020.06.002 32553197 PMC7381373

117. Rahimifard M. Maqbool F. Moeini-Nodeh S. Niaz K. Abdollahi M. Braidy N. Nabavi S.M. Nabavi S.F. Targeting the TLR4 Signaling Pathway by Polyphenols: A Novel Therapeutic Strategy for Neuroinflammation Ageing Res. Rev. 2017 36 11 19 10.1016/j.arr.2017.02.004 28235660

118. Fan C. Song Q. Wang P. Li Y. Yang M. Liu B. Yu S.Y. Curcumin Protects against Chronic Stress-Induced Dysregulation of Neuroplasticity and Depression-like Behaviors via Suppressing IL-1β Pathway in Rats Neuroscience 2018 392 92 106 10.1016/j.neuroscience.2018.09.028 30268781

119. Zhang W. Guo Y. Han W. Yang M. Wen L. Wang K. Jiang P. Curcumin Relieves Depressive-like Behaviors via Inhibition of the NLRP3 Inflammasome and Kynurenine Pathway in Rats Suffering from Chronic Unpredictable Mild Stress Int. Immunopharmacol. 2019 67 138 144 10.1016/j.intimp.2018.12.012 30551030

120. Fattore L. Amchova P. Fadda P. Ruda-Kucerova J. Olfactory Bulbectomy Model of Depression Lowers Responding for Food in Male and Female Rats: The Modulating Role of Caloric Restriction and Response Requirement Biomedicines 2023 11 2481 10.3390/biomedicines11092481 37760922 PMC10525806

121. Xu Y. Ku B.-S. Yao H.-Y. Lin Y.-H. Ma X. Zhang Y.-H. Li X.-J. Antidepressant Effects of Curcumin in the Forced Swim Test and Olfactory Bulbectomy Models of Depression in Rats Pharmacol. Biochem. Behav. 2005 82 200 206 10.1016/j.pbb.2005.08.009 16171853

122. Wang R. Xu Y. Wu H.-L. Li Y.-B. Li Y.-H. Guo J.-B. Li X.-J. The Antidepressant Effects of Curcumin in the Forced Swimming Test Involve 5-HT1 and 5-HT2 Receptors Eur. J. Pharmacol. 2008 578 43 50 10.1016/j.ejphar.2007.08.045 17942093

123. Yang T. Nie Z. Shu H. Kuang Y. Chen X. Cheng J. Yu S. Liu H. The Role of BDNF on Neural Plasticity in Depression Front. Cell. Neurosci. 2020 14 82 10.3389/fncel.2020.00082 32351365 PMC7174655

124. Hurley L.L. Akinfiresoye L. Nwulia E. Kamiya A. Kulkarni A.A. Tizabi Y. Antidepressant-like Effects of Curcumin in WKY Rat Model of Depression Is Associated with an Increase in Hippocampal BDNF Behav. Brain Res. 2013 239 27 30 10.1016/j.bbr.2012.10.049 23142609 PMC3525727

125. Bhutani M.K. Bishnoi M. Kulkarni S.K. Anti-Depressant like Effect of Curcumin and Its Combination with Piperine in Unpredictable Chronic Stress-Induced Behavioral, Biochemical and Neurochemical Changes Pharmacol. Biochem. Behav. 2009 92 39 43 10.1016/j.pbb.2008.10.007 19000708

126. Khadrawy Y.A. Hosny E.N. Magdy M. Mohammed H.S. Antidepressant Effects of Curcumin-Coated Iron Oxide Nanoparticles in a Rat Model of Depression Eur. J. Pharmacol. 2021 908 174384 10.1016/j.ejphar.2021.174384 34324858

127. Fahmy H.M. Aboalasaad F.A. Mohamed A.S. Elhusseiny F.A. Khadrawy Y.A. Elmekawy A. Evaluation of the Therapeutic Effect of Curcumin-Conjugated Zinc Oxide Nanoparticles on Reserpine-Induced Depression in Wistar Rats Biol. Trace Elem. Res. 2024 202 2630 2644 10.1007/s12011-023-03849-z 37713054 PMC11052778

128. Chen J. Wei Y. Li N. Pi C. Zhao W. Zhong Y. Li W. Shen H. Yang Y. Zheng W. Preliminary Investigation Into the Antidepressant Effects of a Novel Curcumin Analogue (CACN136) In Vitro and In Vivo Mol. Neurobiol. 2024 1 24 10.1007/s12035-024-04363-6 39080204

129. Ng Q.X. Koh S.S.H. Chan H.W. Ho C.Y.X. Clinical Use of Curcumin in Depression: A Meta-Analysis J. Am. Med. Dir. Assoc. 2017 18 503 508 10.1016/j.jamda.2016.12.071 28236605

130. Kanchanatawan B. Tangwongchai S. Sughondhabhirom A. Suppapitiporn S. Hemrunrojn S. Carvalho A.F. Maes M. Add-on Treatment with Curcumin Has Antidepressive Effects in Thai Patients with Major Depression: Results of a Randomized Double-Blind Placebo-Controlled Study Neurotox. Res. 2018 33 621 633 10.1007/s12640-017-9860-4 29327213

131. Abu-Taweel G.M. Attia M.F. Hussein J. Mekawi E.M. Galal H.M. Ahmed E.I. Allam A.A. El-Naggar M.E. Curcumin Nanoparticles Have Potential Antioxidant Effect and Restore Tetrahydrobiopterin Levels in Experimental Diabetes Biomed. Pharmacother. 2020 131 110688 10.1016/j.biopha.2020.110688 33152905

132. Noorafshan A. Ashkani-Esfahani S. A Review of Therapeutic Effects of Curcumin Curr. Pharm. Des. 2013 19 2032 2046 23116311

133. Yallapu M.M. Nagesh P.K.B. Jaggi M. Chauhan S.C. Therapeutic Applications of Curcumin Nanoformulations AAPS J. 2015 17 1341 1356 10.1208/s12248-015-9811-z 26335307 PMC4627456

134. Rahimi H.R. Mohammadpour A.H. Dastani M. Jaafari M.R. Abnous K. Mobarhan M.G. Oskuee R.K. The Effect of Nano-Curcumin on HbA1c, Fasting Blood Glucose, and Lipid Profile in Diabetic Subjects: A Randomized Clinical Trial Avicenna J. Phytomedicine 2016 6 567 PMC5052420 27761427

135. Na L. Li Y. Pan H. Zhou X. Sun D. Meng M. Li X. Sun C. Curcuminoids Exert Glucose-lowering Effect in Type 2 Diabetes by Decreasing Serum Free Fatty Acids: A Double-blind, Placebo-controlled Trial Mol. Nutr. Food Res. 2013 57 1569 1577 10.1002/mnfr.201200131 22930403

136. Funamoto M. Shimizu K. Sunagawa Y. Katanasaka Y. Miyazaki Y. Kakeya H. Yamakage H. Satoh-Asahara N. Wada H. Hasegawa K. Effects of Highly Absorbable Curcumin in Patients with Impaired Glucose Tolerance and Non-Insulin-Dependent Diabetes Mellitus J. Diabetes Res. 2019 2019 8208237 10.1155/2019/8208237 31871950 PMC6906884

137. Panahi Y. Khalili N. Sahebi E. Namazi S. Simental-Mendía L.E. Majeed M. Sahebkar A. Effects of Curcuminoids plus Piperine on Glycemic, Hepatic and Inflammatory Biomarkers in Patients with Type 2 Diabetes Mellitus: A Randomized Double-Blind Placebo-Controlled Trial Drug Res. 2018 68 403 409 10.1055/s-0044-101752 29458218

138. Agharazi M. Gazerani S. Huntington M.K. Topical Turmeric Ointment in the Treatment of Diabetic Foot Ulcers: A Randomized, Placebo-Controlled Study Int. J. Low. Extrem. Wounds 2022 15347346221143222 10.1177/15347346221143222 36514270

139. Mokhtari M. Razzaghi R. Momen-Heravi M. The Effects of Curcumin Intake on Wound Healing and Metabolic Status in Patients with Diabetic Foot Ulcer: A Randomized, Double-blind, Placebo-controlled Trial Phyther. Res. 2021 35 2099 2107 10.1002/ptr.6957 33200488

140. Cui L. Miao J. Cui L. Cytotoxic Effect of Curcumin on Malaria Parasite Plasmodium Falciparum: Inhibition of Histone Acetylation and Generation of Reactive Oxygen Species Antimicrob. Agents Chemother. 2007 51 488 494 10.1128/AAC.01238-06 17145789 PMC1797756

141. Reddy R.C. Vatsala P.G. Keshamouni V.G. Padmanaban G. Rangarajan P.N. Curcumin for Malaria Therapy Biochem. Biophys. Res. Commun. 2005 326 472 474 10.1016/j.bbrc.2004.11.051 15582601

142. Nandakumar D.N. Nagaraj V.A. Vathsala P.G. Rangarajan P. Padmanaban G. Curcumin-Artemisinin Combination Therapy for Malaria Antimicrob. Agents Chemother. 2006 50 1859 1860 10.1128/AAC.50.5.1859-1860.2006 16641461 PMC1472230

143. Tjahjani S. Tjokropranoto R. Interaction of Alphamangostin and Curcumin with Dihydroartemisinin as Antimalaria in Vitro Proceedings of the IOP Conference Series: Earth and Environmental Science IOP Publishing Bristol, UK 2018 Volume 125 12017

144. Akide Ndunge O.B. Kilian N. Salman M.M. Cerebral Malaria and Neuronal Implications of Plasmodium Falciparum Infection: From Mechanisms to Advanced Models Adv. Sci. 2022 9 e2202944 10.1002/advs.202202944 36300890 PMC9798991

145. Aggarwal B.B. Gupta S.C. Sung B. Curcumin: An Orally Bioavailable Blocker of TNF and Other pro-Inflammatory Biomarkers Br. J. Pharmacol. 2013 169 1672 1692 10.1111/bph.12131 23425071 PMC3753829

146. Dende C. Meena J. Nagarajan P. Nagaraj V.A. Panda A.K. Padmanaban G. Nanocurcumin Is Superior to Native Curcumin in Preventing Degenerative Changes in Experimental Cerebral Malaria Sci. Rep. 2017 7 10062 10.1038/s41598-017-10672-9 28855623 PMC5577147

147. Ghosh A. Banerjee T. Bhandary S. Surolia A. Formulation of Nanotized Curcumin and Demonstration of Its Antimalarial Efficacy Int. J. Nanomed. 2014 9 5373 5387 10.2147/IJN.S62756 PMC4245089 25484584

148. Dandekar P.P. Jain R. Patil S. Dhumal R. Tiwari D. Sharma S. Vanage G. Patravale V. Curcumin-Loaded Hydrogel Nanoparticles: Application in Anti-Malarial Therapy and Toxicological Evaluation J. Pharm. Sci. 2010 99 4992 5010 10.1002/jps.22191 20821383

149. Rashidzadeh H. Salimi M. Sadighian S. Rostamizadeh K. Ramazani A. In Vivo Antiplasmodial Activity of Curcumin-Loaded Nanostructured Lipid Carriers Curr. Drug Deliv. 2019 16 923 930 10.2174/1567201816666191029121036 31663477

150. Akhtar F. Rizvi M.M.A. Kar S.K. Oral Delivery of Curcumin Bound to Chitosan Nanoparticles Cured Plasmodium Yoelii Infected Mice Biotechnol. Adv. 2012 30 310 320 10.1016/j.biotechadv.2011.05.009 21619927

151. Dos Santos R.B. Nakama K.A. Pacheco C.O. de Gomes M.G. de Souza J.F. de Souza Pinto A.C. de Oliveira F.A. da Fonseca A.L. Varotti F. Fajardo A.R. Curcumin-Loaded Nanocapsules: Influence of Surface Characteristics on Technological Parameters and Potential Antimalarial Activity Mater. Sci. Eng. C 2021 118 111356 10.1016/j.msec.2020.111356 33254976

152. Memvanga P.B. Coco R. Préat V. An Oral Malaria Therapy: Curcumin-Loaded Lipid-Based Drug Delivery Systems Combined with β-Arteether J. Control. Release 2013 172 904 913 10.1016/j.jconrel.2013.09.001 24021359

153. Khairani S. Fauziah N. Wiraswati H.L. Panigoro R. Setyowati E.Y. Berbudi A. The Potential Use of a Curcumin-Piperine Combination as an Antimalarial Agent: A Systematic Review J. Trop. Med. 2021 2021 9135617 10.1155/2021/9135617 34671402 PMC8523290

154. Schraufstätter E. Bernt H. Antibacterial Action of Curcumin and Related Compounds Nature 1949 164 456 457 10.1038/164456a0 18140450

155. Mitra A.K. Chemistry and Biomedical Applications of Cumin and Turmeric: A Review, Challenge and Perspective Chem. Afr. 2022 5 1191 1213 10.1007/s42250-022-00410-8

156. Rai D. Singh J.K. Roy N. Panda D. Curcumin Inhibits FtsZ Assembly: An Attractive Mechanism for Its Antibacterial Activity Biochem. J. 2008 410 147 155 10.1042/BJ20070891 17953519

157. Tyagi P. Singh M. Kumari H. Kumari A. Mukhopadhyay K. Bactericidal Activity of Curcumin I Is Associated with Damaging of Bacterial Membrane PLoS ONE 2015 10 e0121313 10.1371/journal.pone.0121313 25811596 PMC4374920

158. Sharifian P. Yaslianifard S. Fallah P. Aynesazi S. Bakhtiyari M. Mohammadzadeh M. Investigating the Effect of Nano-Curcumin on the Expression of Biofilm Regulatory Genes of Pseudomonas Aeruginosa Infect. Drug Resist. 2020 13 2477 2484 10.2147/IDR.S263387 32765020 PMC7382584

159. Teow S.-Y. Liew K. Ali S.A. Khoo A.S.-B. Peh S.-C. Antibacterial Action of Curcumin against Staphylococcus Aureus: A Brief Review J. Trop. Med. 2016 2016 2853045 10.1155/2016/2853045 27956904 PMC5124450

160. Zandi K. Ramedani E. Mohammadi K. Tajbakhsh S. Deilami I. Rastian Z. Fouladvand M. Yousefi F. Farshadpour F. Evaluation of Antiviral Activities of Curcumin Derivatives against HSV-1 in Vero Cell Line Nat. Prod. Commun. 2010 5 1934578X1000501220 10.1177/1934578X1000501220 21299124

161. De R. Kundu P. Swarnakar S. Ramamurthy T. Chowdhury A. Nair G.B. Mukhopadhyay A.K. Antimicrobial Activity of Curcumin against Helicobacter Pylori Isolates from India and during Infections in Mice Antimicrob. Agents Chemother. 2009 53 1592 1597 10.1128/AAC.01242-08 19204190 PMC2663130

162. Hettiarachchi S.S. Perera Y. Dunuweera S.P. Dunuweera A.N. Rajapakse S. Rajapakse R.M.G. Comparison of Antibacterial Activity of Nanocurcumin with Bulk Curcumin ACS Omega 2022 7 46494 46500 10.1021/acsomega.2c05293 36570282 PMC9773352

163. Mun S.-H. Joung D.-K. Kim Y.-S. Kang O.-H. Kim S.-B. Seo Y.-S. Kim Y.-C. Lee D.-S. Shin D.-W. Kweon K.-T. Synergistic Antibacterial Effect of Curcumin against Methicillin-Resistant Staphylococcus Aureus Phytomedicine 2013 20 714 718 10.1016/j.phymed.2013.02.006 23537748

164. Teow S.-Y. Ali S.A. Synergistic Antibacterial Activity of Curcumin with Antibiotics against Staphylococcus Aureus Pak. J. Pharm. Sci. 2015 28 2109 2114 26639480

165. Olufunmilayo E.O. Gerke-Duncan M.B. Holsinger R.M.D. Oxidative Stress and Antioxidants in Neurodegenerative Disorders Antioxidants 2023 12 517 10.3390/antiox12020517 36830075 PMC9952099

166. Wang S. Wu P. Fan Z. He X. Liu J. Li M. Chen F. Dandelion Polysaccharide Treatment Protects against Dextran Sodium Sulfate-induced Colitis by Suppressing NF-κB/NLRP3 Inflammasome-mediated Inflammation and Activating Nrf2 in Mouse Colon Food Sci. Nutr. 2023 11 7271 7282 10.1002/fsn3.3653 37970386 PMC10630811

167. Fan C. Song Q. Wang P. Li Y. Yang M. Yu S.Y. Neuroprotective Effects of Curcumin on IL-1β-Induced Neuronal Apoptosis and Depression-like Behaviors Caused by Chronic Stress in Rats Front. Cell. Neurosci. 2019 12 516 10.3389/fncel.2018.00516 30666189 PMC6330766

168. Wu J. Li Q. Wang X. Yu S. Li L. Wu X. Chen Y. Zhao J. Zhao Y. Neuroprotection by Curcumin in Ischemic Brain Injury Involves the Akt/Nrf2 Pathway PLoS ONE 2013 8 e59843 10.1371/journal.pone.0059843 23555802 PMC3610879

169. Qi X.-J. Liu X.-Y. Tang L.-M.-Y. Li P.-F. Qiu F. Yang A.-H. Anti-Depressant Effect of Curcumin-Loaded Guanidine-Chitosan Thermo-Sensitive Hydrogel by Nasal Delivery Pharm. Dev. Technol. 2020 25 316 325 10.1080/10837450.2019.1686524 31661648

170. Zbarsky V. Datla K.P. Parkar S. Rai D.K. Aruoma O.I. Dexter D.T. Neuroprotective Properties of the Natural Phenolic Antioxidants Curcumin and Naringenin but Not Quercetin and Fisetin in a 6-OHDA Model of Parkinson’s Disease Free Radic. Res. 2005 39 1119 1125 10.1080/10715760500233113 16298737

171. Agrawal S.S. Gullaiya S. Dubey V. Singh V. Kumar A. Nagar A. Tiwari P. Neurodegenerative Shielding by Curcumin and Its Derivatives on Brain Lesions Induced by 6-OHDA Model of Parkinson’s Disease in Albino Wistar Rats Cardiovasc. Psychiatry Neurol. 2012 2012 942981 10.1155/2012/942981 22928089 PMC3426182

172. Song S. Nie Q. Li Z. Du G. Curcumin Improves Neurofunctions of 6-OHDA-Induced Parkinsonian Rats Pathol. Res. Pract. 2016 212 247 251 10.1016/j.prp.2015.11.012 26922613

173. Yang J. Song S. Li J. Liang T. Neuroprotective Effect of Curcumin on Hippocampal Injury in 6-OHDA-Induced Parkinson’s Disease Rat Pathol. Res. Pract. 2014 210 357 362 10.1016/j.prp.2014.02.005 24642369

174. Liu X. Zhang H. Li C. Chen Z. Gao Q. Han M. Zhao F. Chen D. Chen Q. Hu M. The Dosage of Curcumin to Alleviate Movement Symptoms in a 6-Hydroxydopamine-Induced Parkinson’s Disease Rat Model Heliyon 2023 9 e16921 10.1016/j.heliyon.2023.e16921 37484231 PMC10360947

175. Armstrong R.A. Risk Factors for Alzheimer’s Disease Folia Neuropathol. 2019 57 87 105 10.5114/fn.2019.85929 31556570

176. Cummings J. Osse A.M.L. Cammann D. Powell J. Chen J. Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer’s Disease BioDrugs 2024 38 5 22 10.1007/s40259-023-00633-2 37955845 PMC10789674

177. Yang F. Lim G.P. Begum A.N. Ubeda O.J. Simmons M.R. Ambegaokar S.S. Chen P.P. Kayed R. Glabe C.G. Frautschy S.A. Curcumin Inhibits Formation of Amyloid Beta Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo J. Biol. Chem. 2005 280 5892 5901 10.1074/jbc.M404751200 15590663

178. Ye J. Zhang Y. Curcumin Protects against Intracellular Amyloid Toxicity in Rat Primary Neurons Int. J. Clin. Exp. Med. 2012 5 44 49 22328947 PMC3272685

179. Shi H. Yin Z. Koronyo Y. Fuchs D.-T. Sheyn J. Davis M.R. Wilson J.W. Margeta M.A. Pitts K.M. Herron S. Regulating Microglial MiR-155 Transcriptional Phenotype Alleviates Alzheimer’s-Induced Retinal Vasculopathy by Limiting Clec7a/Galectin-3(+) Neurodegenerative Microglia Acta Neuropathol. Commun. 2022 10 136 10.1186/s40478-022-01439-z 36076283 PMC9461176

180. Teter B. Morihara T. Lim G.P. Chu T. Jones M.R. Zuo X. Paul R.M. Frautschy S.A. Cole G.M. Curcumin Restores Innate Immune Alzheimer’s Disease Risk Gene Expression to Ameliorate Alzheimer Pathogenesis Neurobiol. Dis. 2019 127 432 448 10.1016/j.nbd.2019.02.015 30951849 PMC8092921

181. Small G.W. Siddarth P. Li Z. Miller K.J. Ercoli L. Emerson N.D. Martinez J. Wong K.-P. Liu J. Merrill D.A. Memory and Brain Amyloid and Tau Effects of a Bioavailable Form of Curcumin in Non-Demented Adults: A Double-Blind, Placebo-Controlled 18-Month Trial Am. J. Geriatr. Psychiatry 2018 26 266 277 10.1016/j.jagp.2017.10.010 29246725

182. Das S.S. Gopal P.M. Thomas J.V. Mohan M.C. Thomas S.C. Maliakel B.P. Krishnakumar I.M. Pulikkaparambil Sasidharan B.C. Influence of CurQfen ® -Curcumin on Cognitive Impairment: A Randomized, Double-Blinded, Placebo-Controlled, 3-Arm, 3-Sequence Comparative Study Front. Dement. 2023 2 1222708 10.3389/frdem.2023.1222708 39081970 PMC11285547

183. Rainey-Smith S.R. Brown B.M. Sohrabi H.R. Shah T. Goozee K.G. Gupta V.B. Martins R.N. Curcumin and Cognition: A Randomised, Placebo-Controlled, Double-Blind Study of Community-Dwelling Older Adults Br. J. Nutr. 2016 115 2106 2113 10.1017/S0007114516001203 27102361

184. Sharma R.A. Steward W.P. Gescher A.J. Pharmacokinetics and Pharmacodynamics of Curcumin Adv. Exp. Med. Biol. 2007 595 453 470 17569224 10.1007/978-0-387-46401-5_20

185. Wang Y.-J. Pan M.-H. Cheng A.-L. Lin L.-I. Ho Y.-S. Hsieh C.-Y. Lin J.-K. Stability of Curcumin in Buffer Solutions and Characterization of Its Degradation Products J. Pharm. Biomed. Anal. 1997 15 1867 1876 10.1016/S0731-7085(96)02024-9 9278892

186. Anand P. Kunnumakkara A.B. Newman R.A. Aggarwal B.B. Bioavailability of Curcumin: Problems and Promises Mol. Pharm. 2007 4 807 818 10.1021/mp700113r 17999464

187. Siviero A. Gallo E. Maggini V. Gori L. Mugelli A. Firenzuoli F. Vannacci A. Curcumin, a Golden Spice with a Low Bioavailability J. Herb. Med. 2015 5 57 70 10.1016/j.hermed.2015.03.001

188. Shoba G. Joy D. Joseph T. Majeed M. Rajendran R. Srinivas P. Influence of Piperine on the Pharmacokinetics of Curcumin in Animals and Human Volunteers Planta Med. 1998 64 353 356 10.1055/s-2006-957450 9619120

189. Prasad S. DuBourdieu D. Srivastava A. Kumar P. Lall R. Metal-Curcumin Complexes in Therapeutics: An Approach to Enhance Pharmacological Effects of Curcumin Int. J. Mol. Sci. 2021 22 7094 10.3390/ijms22137094 34209461 PMC8268053

190. Baek J.-S. Cho C.-W. Surface Modification of Solid Lipid Nanoparticles for Oral Delivery of Curcumin: Improvement of Bioavailability through Enhanced Cellular Uptake, and Lymphatic Uptake Eur. J. Pharm. Biopharm. 2017 117 132 140 10.1016/j.ejpb.2017.04.013 28412471

191. Hegde M. Girisa S. BharathwajChetty B. Vishwa R. Kunnumakkara A.B. Curcumin Formulations for Better Bioavailability: What We Learned from Clinical Trials Thus Far? ACS Omega 2023 8 10713 10746 10.1021/acsomega.2c07326 37008131 PMC10061533

192. Li Z. Peng S. Chen X. Zhu Y. Zou L. Liu W. Liu C. Pluronics Modified Liposomes for Curcumin Encapsulation: Sustained Release, Stability and Bioaccessibility Food Res. Int. 2018 108 246 253 10.1016/j.foodres.2018.03.048 29735054

193. Zeng L. Yang T. Yang K. Yu G. Li J. Xiang W. Chen H. Efficacy and Safety of Curcumin and Curcuma Longa Extract in the Treatment of Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trial Front. Immunol. 2022 13 891822 10.3389/fimmu.2022.891822 35935936 PMC9353077

194. Sharifi-Rad J. El Rayess Y. Rizk A.A. Sadaka C. Zgheib R. Zam W. Sestito S. Rapposelli S. Zielińska D. Setzer W.N. Turmeric and Its Major Compound Curcumin on Health: Bioactive Effects and Safety Profiles for Food, Pharmaceutical, Biotechnological and Medicinal Applications Front. Pharmacol. 2020 11 550909 10.3389/fphar.2020.01021 33041781 PMC7522354

195. Sahebkar A. Are Curcuminoids Effective C-Reactive Protein-Lowering Agents in Clinical Practice? Evidence from a Meta-Analysis Phytother. Res. 2014 28 633 642 10.1002/ptr.5045 23922235

196. Vogel A. Pelletier J. Examen Chimique de La Racine de Curcuma J. Pharm 1815 1 289 300

197. Gupta S.C. Patchva S. Koh W. Aggarwal B.B. Discovery of Curcumin, a Component of Golden Spice, and Its Miraculous Biological Activities Clin. Exp. Pharmacol. Physiol. 2012 39 283 299 10.1111/j.1440-1681.2011.05648.x 22118895 PMC3288651

198. Liju V.B. Jeena K. Kuttan R. Acute and Subchronic Toxicity as Well as Mutagenic Evaluation of Essential Oil from Turmeric ( Curcuma Longa L) Food Chem. Toxicol. 2013 53 52 61 10.1016/j.fct.2012.11.027 23201370

199. Kim D.-C. Ku S.-K. Bae J.-S. Anticoagulant Activities of Curcumin and Its Derivative BMB Rep. 2012 45 221 226 10.5483/BMBRep.2012.45.4.221 22531131

200. Shah B.H. Nawaz Z. Pertani S.A. Roomi A. Mahmood H. Saeed S.A. Gilani A.H. Inhibitory Effect of Curcumin, a Food Spice from Turmeric, on Platelet-Activating Factor-and Arachidonic Acid-Mediated Platelet Aggregation through Inhibition of Thromboxane Formation and Ca 2+ Signaling Biochem. Pharmacol. 1999 58 1167 1172 10.1016/S0006-2952(99)00206-3 10484074

201. Chaudhari S.P. Tam A.Y. Barr J.A. Curcumin: A Contact Allergen J. Clin. Aesthet. Dermatol. 2015 8 43 48 PMC4689497 26705440

202. Sathyabhama M. Priya Dharshini L.C. Karthikeyan A. Kalaiselvi S. Min T. The Credible Role of Curcumin in Oxidative Stress-Mediated Mitochondrial Dysfunction in Mammals Biomolecules 2022 12 1405 10.3390/biom12101405 36291614 PMC9599178

203. Barclay L.R.C. Vinqvist M.R. Mukai K. Goto H. Hashimoto Y. Tokunaga A. Uno H. On the Antioxidant Mechanism of Curcumin: Classical Methods Are Needed to Determine Antioxidant Mechanism and Activity Org. Lett. 2000 2 2841 2843 10.1021/ol000173t 10964379

204. Hussain T. Tan B. Yin Y. Blachier F. Tossou M.C.B. Rahu N. Oxidative Stress and Inflammation: What Polyphenols Can Do for Us? Oxid. Med. Cell. Longev. 2016 2016 7432797 10.1155/2016/7432797 27738491 PMC5055983

205. Paulraj F. Abas F. Lajis N.H. Othman I. Naidu R. Molecular Pathways Modulated by Curcumin Analogue, Diarylpentanoids in Cancer Biomolecules 2019 9 270 10.3390/biom9070270 31295798 PMC6681237

206. Giordano A. Tommonaro G. Curcumin and Cancer Nutrients 2019 11 2376 10.3390/nu11102376 31590362 PMC6835707

207. Zhou H. Beevers C.S. Huang S. The Targets of Curcumin Curr. Drug Targets 2011 12 332 347 10.2174/138945011794815356 20955148 PMC3025067

208. Zhang F. Altorki N.K. Mestre J.R. Subbaramaiah K. Dannenberg A.J. Curcumin Inhibits Cyclooxygenase-2 Transcription in Bile Acid-and Phorbol Ester-Treated Human Gastrointestinal Epithelial Cells Carcinogenesis 1999 20 445 451 10.1093/carcin/20.3.445 10190560

209. Setyono J. Harini I.M. Sarmoko S. Rujito L. Supplementation of Curcuma Domestica Extract Reduces Cox-2 and Inos Expression on Raw 264.7 Cells J. Phys. Conf. Ser. 2019 1246 12059 10.1088/1742-6596/1246/1/012059

210. Lee S.-Y. Cho S.-S. Li Y. Bae C.-S. Park K.M. Park D.-H. Anti-Inflammatory Effect of Curcuma Longa and Allium Hookeri Co-Treatment via NF-ΚB and COX-2 Pathways Sci. Rep. 2020 10 5718 10.1038/s41598-020-62749-7 32235914 PMC7109078

211. Sreejayan X.X. Rao M.N.A. Nitric Oxide Scavenging by Curcuminoids J. Pharm. Pharmacol. 1997 49 105 107 10.1111/j.2042-7158.1997.tb06761.x 9120760

212. Sreejayan N. Rao M.N. Free Radical Scavenging Activity of Curcuminoids Arzneimittelforschung 1996 46 169 171 8720307

213. Carvalho D.d.M. Takeuchi K.P. Geraldine R.M. de Moura C.J. Torres M.C.L. Production, Solubility and Antioxidant Activity of Curcumin Nanosuspension Food Sci. Technol. 2015 35 115 119 10.1590/1678-457X.6515

214. Priyadarsini K.I. Maity D.K. Naik G.H. Kumar M.S. Unnikrishnan M.K. Satav J.G. Mohan H. Role of Phenolic O-H and Methylene Hydrogen on the Free Radical Reactions and Antioxidant Activity of Curcumin Free Radic. Biol. Med. 2003 35 475 484 10.1016/S0891-5849(03)00325-3 12927597

215. Jayaprakasha G.K. Rao L.J. Sakariah K.K. Antioxidant Activities of Curcumin, Demethoxycurcumin and Bisdemethoxycurcumin Food Chem. 2006 98 720 724 10.1016/j.foodchem.2005.06.037

216. Lin X. Bai D. Wei Z. Zhang Y. Huang Y. Deng H. Huang X. Curcumin Attenuates Oxidative Stress in RAW264. 7 Cells by Increasing the Activity of Antioxidant Enzymes and Activating the Nrf2-Keap1 Pathway PLoS ONE 2019 14 e0216711 31112588 10.1371/journal.pone.0216711 PMC6528975

217. Ren L. Zhan P. Wang Q. Wang C. Liu Y. Yu Z. Zhang S. Curcumin Upregulates the Nrf2 System by Repressing Inflammatory Signaling-Mediated Keap1 Expression in Insulin-Resistant Conditions Biochem. Biophys. Res. Commun. 2019 514 691 698 10.1016/j.bbrc.2019.05.010 31078267

218. Liu F. Gao S. Yang Y. Zhao X. Fan Y. Ma W. Yang D. Yang A. Yu Y. Antitumor Activity of Curcumin by Modulation of Apoptosis and Autophagy in Human Lung Cancer A549 Cells through Inhibiting PI3K/Akt/MTOR Pathway Oncol. Rep. 2018 39 1523 1531 10.3892/or.2018.6188 29328421

219. Kuttikrishnan S. Siveen K.S. Prabhu K.S. Khan A.Q. Ahmed E.I. Akhtar S. Ali T.A. Merhi M. Dermime S. Steinhoff M. Curcumin Induces Apoptotic Cell Death via Inhibition of PI3-Kinase/AKT Pathway in B-Precursor Acute Lymphoblastic Leukemia Front. Oncol. 2019 9 484 10.3389/fonc.2019.00484 31275848 PMC6593070

220. Panahi Y. Rahimnia A. Sharafi M. Alishiri G. Saburi A. Sahebkar A. Curcuminoid Treatment for Knee Osteoarthritis: A Randomized Double-blind Placebo-controlled Trial Phyther. Res. 2014 28 1625 1631 10.1002/ptr.5174 24853120

221. Panahi Y. Saadat A. Beiraghdar F. Sahebkar A. Adjuvant Therapy with Bioavailability-Boosted Curcuminoids Suppresses Systemic Inflammation and Improves Quality of Life in Patients with Solid Tumors: A Randomized Double-Blind Placebo-Controlled Trial Phytother. Res. 2014 28 1461 1467 10.1002/ptr.5149 24648302

222. Panahi Y. Hosseini M.S. Khalili N. Naimi E. Simental-Mendía L.E. Majeed M. Sahebkar A. Effects of Curcumin on Serum Cytokine Concentrations in Subjects with Metabolic Syndrome: A Post-Hoc Analysis of a Randomized Controlled Trial Biomed. Pharmacother. 2016 82 578 582 10.1016/j.biopha.2016.05.037 27470399

223. Abe Y. Hashimoto S.H.U. Horie T. Curcumin Inhibition of Inflammatory Cytokine Production by Human Peripheral Blood Monocytes and Alveolar Macrophages Pharmacol. Res. 1999 39 41 47 10.1006/phrs.1998.0404 10051376

224. Cianciulli A. Calvello R. Porro C. Trotta T. Salvatore R. Panaro M.A. PI3k/Akt Signalling Pathway Plays a Crucial Role in the Anti-Inflammatory Effects of Curcumin in LPS-Activated Microglia Int. Immunopharmacol. 2016 36 282 290 10.1016/j.intimp.2016.05.007 27208432

225. Yadav V.S. Mishra K.P. Singh D.P. Mehrotra S. Singh V.K. Immunomodulatory Effects of Curcumin Immunopharmacol. Immunotoxicol. 2005 27 485 497 10.1080/08923970500242244 16237958

226. Li W. Wang Z. Xiao X. Han L. Wu Z. Ma Q. Cao L. Curcumin Attenuates Hyperglycemia-Driven EGF-Induced Invasive and Migratory Abilities of Pancreatic Cancer via Suppression of the ERK and AKT Pathways Oncol. Rep. 2019 41 650 658 10.3892/or.2018.6833 30542713

227. Mohan R. Sivak J. Ashton P. Russo L.A. Pham B.Q. Kasahara N. Raizman M.B. Fini M.E. Curcuminoids Inhibit the Angiogenic Response Stimulated by Fibroblast Growth Factor-2, Including Expression of Matrix Metalloproteinase Gelatinase B J. Biol. Chem. 2000 275 10405 10412 10.1074/jbc.275.14.10405 10744729

228. El-Azab M. Hishe H. Moustafa Y. El-Awady E.-S. Anti-Angiogenic Effect of Resveratrol or Curcumin in Ehrlich Ascites Carcinoma-Bearing Mice Eur. J. Pharmacol. 2011 652 7 14 10.1016/j.ejphar.2010.11.008 21114990

229. Bae M.-K. Kim S.-H. Jeong J.-W. Lee Y.M. Kim H.-S. Kim S.-R. Yun I. Bae S.-K. Kim K.-W. Curcumin Inhibits Hypoxia-Induced Angiogenesis via down-Regulation of HIF-1 Oncol. Rep. 2006 15 1557 1562 10.3892/or.15.6.1557 16685395

230. Nakamura K. Yasunaga Y. Segawa T. Ko D. Moul J.W. Srivastava S. Rhim J.S. Curcumin Down-Regulates AR Gene Expression and Activation in Prostate Cancer Cell Lines Int. J. Oncol. 2002 21 825 830 10.3892/ijo.21.4.825 12239622

231. Dorai T. Gehani N. Katz A. Therapeutic Potential of Curcumin in Human Prostate Cancer—I. Curcumin Induces Apoptosis in Both Androgen-Dependent and Androgen-Independent Prostate Cancer Cells Prostate Cancer Prostatic Dis. 2000 3 84 93 10.1038/sj.pcan.4500399 12497104

232. Saxena A.R. Ilic Z. Sripada V. Crawford D.R. Lower Concentrations of Curcumin Inhibit Her2-Akt Pathway Components in Human Breast Cancer Cells, and Other Dietary Botanicals Potentiate This and Lapatinib Inhibition Nutr. Res. 2020 78 93 104 10.1016/j.nutres.2020.05.007 32563955

233. Miyazaki K. Morine Y. Xu C. Nakasu C. Wada Y. Teraoku H. Yamada S. Saito Y. Ikemoto T. Shimada M. Curcumin-Mediated Resistance to Lenvatinib via EGFR Signaling Pathway in Hepatocellular Carcinoma Cells 2023 12 612 10.3390/cells12040612 36831279 PMC9954241

234. Lee J.-Y. Lee Y.-M. Chang G.-C. Yu S.-L. Hsieh W.-Y. Chen J.J.W. Chen H.-W. Yang P.-C. Curcumin Induces EGFR Degradation in Lung Adenocarcinoma and Modulates P38 Activation in Intestine: The Versatile Adjuvant for Gefitinib Therapy PLoS ONE 2011 6 e23756 10.1371/journal.pone.0023756 21858220 PMC3157465

235. Park Y.-G. Cho J.-H. Choi J. Ju E.-M. Adam G.O. Hwang D.-I. Lee J.-H. An S.-Y. Choi H.-K. Park C.-B. Immunomodulatory Effects of Curcuma Longa L. and Carthamus Tinctorius L. on RAW 264.7 Macrophages and Cyclophosphamide-Induced Immunosuppression C57BL/6 Mouse Models J. Funct. Foods 2022 91 105000 10.1016/j.jff.2022.105000

236. Huang M.-T. Lysz T. Ferraro T. Abidi T.F. Laskin J.D. Conney A.H. Inhibitory Effects of Curcumin on in Vitro Lipoxygenase and Cyclooxygenase Activities in Mouse Epidermis Cancer Res. 1991 51 813 819 1899046

237. Srimal R.C. Dhawan B.N. Pharmacology of Diferuloyl Methane (Curcumin), a Non-steroidal Anti-inflammatory Agent J. Pharm. Pharmacol. 1973 25 447 452 10.1111/j.2042-7158.1973.tb09131.x 4146582

238. Cao J. Han Z. Tian L. Chen K. Fan Y. Ye B. Huang W. Wang C. Huang Z. Curcumin Inhibits EMMPRIN and MMP-9 Expression through AMPK-MAPK and PKC Signaling in PMA Induced Macrophages J. Transl. Med. 2014 12 266 10.1186/s12967-014-0266-2 25241044 PMC4205290

239. Youn G.S. Kwon D.-J. Ju S.M. Choi S.Y. Park J. Curcumin Ameliorates TNF-α-Induced ICAM-1 Expression and Subsequent THP-1 Adhesiveness via the Induction of Heme Oxygenase-1 in the HaCaT Cells BMB Rep. 2013 46 410 415 10.5483/BMBRep.2013.46.8.014 23977989 PMC4133911

240. Machova Urdzikova L. Karova K. Ruzicka J. Kloudova A. Shannon C. Dubisova J. Murali R. Kubinova S. Sykova E. Jhanwar-Uniyal M. The Anti-Inflammatory Compound Curcumin Enhances Locomotor and Sensory Recovery after Spinal Cord Injury in Rats by Immunomodulation Int. J. Mol. Sci. 2015 17 49 10.3390/ijms17010049 26729105 PMC4730294

241. Binion D.G. Heidemann J. Li M.S. Nelson V.M. Otterson M.F. Rafiee P. Vascular Cell Adhesion Molecule-1 Expression in Human Intestinal Microvascular Endothelial Cells Is Regulated by PI 3-Kinase/Akt/MAPK/NF-KappaB: Inhibitory Role of Curcumin Am. J. Physiol. Gastrointest. Liver Physiol. 2009 297 G259 G268 10.1152/ajpgi.00087.2009 19520742 PMC2724083

242. Wang J. Qi L. Zheng S. Wu T. Curcumin Induces Apoptosis through the Mitochondria-Mediated Apoptotic Pathway in HT-29 Cells J. Zhejiang Univ. Sci. B 2009 10 93 102 10.1631/jzus.B0820238 19235267 PMC2644749

243. Yang Z. Li X. Peng Z. Song J. Ren J. Curcumin Down-Regulates PCNA, Cyclin D1 and Bcl-XL Expression in Human Keratinocyte Cell Lines J. Med. Coll. PLA 2010 25 321 330

244. Meena R. Kumar S. Gaharwar U.S. Rajamani P. PLGA-CTAB Curcumin Nanoparticles: Fabrication, Characterization and Molecular Basis of Anticancer Activity in Triple Negative Breast Cancer Cell Lines (MDA-MB-231 Cells) Biomed. Pharmacother. 2017 94 944 954 10.1016/j.biopha.2017.07.151 28810532

245. Dhandapani K.M. Mahesh V.B. Brann D.W. Curcumin Suppresses Growth and Chemoresistance of Human Glioblastoma Cells via AP-1 and NFkappaB Transcription Factors J. Neurochem. 2007 102 522 538 10.1111/j.1471-4159.2007.04633.x 17596214

246. Kliem C. Merling A. Giaisi M. Köhler R. Krammer P.H. Li-Weber M. Curcumin Suppresses T Cell Activation by Blocking Ca 2+ Mobilization and Nuclear Factor of Activated T Cells (NFAT) Activation J. Biol. Chem. 2012 287 10200 10209 10.1074/jbc.M111.318733 22303019 PMC3323045

247. Jung E.M. Lim J.H. Lee T.J. Park J.-W. Choi K.S. Kwon T.K. Curcumin Sensitizes Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL)-Induced Apoptosis through Reactive Oxygen Species-Mediated Upregulation of Death Receptor 5 (DR5) Carcinogenesis 2005 26 1905 1913 10.1093/carcin/bgi167 15987718

248. Chen Y.-R. Tan T.-H. Inhibition of the C-Jun N-Terminal Kinase (JNK) Signaling Pathway by Curcumin Oncogene 1998 17 173 178 10.1038/sj.onc.1201941 9674701

249. Thulasiraman P. McAndrews D.J. Mohiudddin I.Q. Curcumin Restores Sensitivity to Retinoic Acid in Triple Negative Breast Cancer Cells BMC Cancer 2014 14 724 10.1186/1471-2407-14-724 25260874 PMC4192446

250. Li Q. Sun J. Mohammadtursun N. Wu J. Dong J. Li L. Curcumin Inhibits Cigarette Smoke-Induced Inflammation via Modulating the PPARγ-NF-ΚB Signaling Pathway Food Funct. 2019 10 7983 7994 10.1039/C9FO02159K 31773117

251. Zhu T. Chen Z. Chen G. Wang D. Tang S. Deng H. Wang J. Li S. Lan J. Tong J. Curcumin Attenuates Asthmatic Airway Inflammation and Mucus Hypersecretion Involving a PPARγ-Dependent NF-ΚB Signaling Pathway in Vivo and in Vitro Mediat. Inflamm. 2019 2019 4927430 10.1155/2019/4927430 PMC6470457 31073274

252. Bradley J. TNF-mediated Inflammatory Disease J. Pathol. 2008 214 149 160 10.1002/path.2287 18161752

253. Anwar M.J. Alenezi S.K. Alhowail A.H. Molecular Insights into the Pathogenic Impact of Vitamin D Deficiency in Neurological Disorders Biomed. Pharmacother. 2023 162 114718 10.1016/j.biopha.2023.114718 37084561

254. Jang D. Lee A.-H. Shin H.-Y. Song H.-R. Park J.-H. Kang T.-B. Lee S.-R. Yang S.-H. The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics Int. J. Mol. Sci. 2021 22 2719 10.3390/ijms22052719 33800290 PMC7962638

255. Díez J.J. Hernanz A. Medina S. Bayón C. Iglesias P. Serum Concentrations of Tumour Necrosis Factor-alpha (TNF-α) and Soluble TNF-α Receptor P55 in Patients with Hypothyroidism and Hyperthyroidism before and after Normalization of Thyroid Function Clin. Endocrinol. 2002 57 515 521 10.1046/j.1365-2265.2002.01629.x 12354134

256. Tzanavari T. Giannogonas P. Karalis K.P. TNF-α and Obesity TNF Pathophysiol. 2010 11 145 156 10.1159/000289203 20173393

257. Olivera A. Moore T.W. Hu F. Brown A.P. Sun A. Liotta D.C. Snyder J.P. Yoon Y. Shim H. Marcus A.I. Inhibition of the NF-ΚB Signaling Pathway by the Curcumin Analog, 3, 5-Bis (2-Pyridinylmethylidene)-4-Piperidone (EF31): Anti-Inflammatory and Anti-Cancer Properties Int. Immunopharmacol. 2012 12 368 377 10.1016/j.intimp.2011.12.009 22197802 PMC3372981

258. Wang S.L. Li Y. Wen Y. Chen Y.F. Na L.X. Li S.T. Sun C.H. Curcumin, a Potential Inhibitor of up-Regulation of TNF-Alpha and IL-6 Induced by Palmitate in 3T3-L1 Adipocytes through NF-KappaB and JNK Pathway Biomed. Environ. Sci. 2009 22 32 39 10.1016/S0895-3988(09)60019-2 19462685

259. Panaro M.A. Corrado A. Benameur T. Paolo C.F. Cici D. Porro C. The Emerging Role of Curcumin in the Modulation of TLR-4 Signaling Pathway: Focus on Neuroprotective and Anti-Rheumatic Properties Int. J. Mol. Sci. 2020 21 2299 10.3390/ijms21072299 32225104 PMC7177421

260. Ben P. Liu J. Lu C. Xu Y. Xin Y. Fu J. Huang H. Zhang Z. Gao Y. Luo L. Curcumin Promotes Degradation of Inducible Nitric Oxide Synthase and Suppresses Its Enzyme Activity in RAW 264.7 Cells Int. Immunopharmacol. 2011 11 179 186 10.1016/j.intimp.2010.11.013 21094287

261. Ghafouri-Fard S. Shoorei H. Bahroudi Z. Hussen B.M. Talebi S.F. Taheri M. Ayatollahi S.A. Nrf2-Related Therapeutic Effects of Curcumin in Different Disorders Biomolecules 2022 12 82 10.3390/biom12010082 35053230 PMC8773597

262. Atiaa A. Abdullah A. NQO1 Enzyme and Its Role in Cellular Protection; an Insight Iberoam. J. Med. 2020 2 306 313 10.53986/ibjm.2020.0054

263. Battino M. Giampieri F. Pistollato F. Sureda A. de Oliveira M.R. Pittalà V. Fallarino F. Nabavi S.F. Atanasov A.G. Nabavi S.M. Nrf2 as Regulator of Innate Immunity: A Molecular Swiss Army Knife! Biotechnol. Adv. 2018 36 358 370 10.1016/j.biotechadv.2017.12.012 29277308

264. Vomund S. Schäfer A. Parnham M.J. Brüne B. Von Knethen A. Nrf2, the Master Regulator of Anti-Oxidative Responses Int. J. Mol. Sci. 2017 18 2772 10.3390/ijms18122772 29261130 PMC5751370

265. Ferguson B.S. Nam H. Morrison R.F. Curcumin Inhibits 3T3-L1 Preadipocyte Proliferation by Mechanisms Involving Post-Transcriptional P27 Regulation Biochem. Biophys. Rep. 2016 5 16 21 10.1016/j.bbrep.2015.11.014 26688832 PMC4680981

266. Yu C. Yang B. Najafi M. Targeting of Cancer Cell Death Mechanisms by Curcumin: Implications to Cancer Therapy Basic Clin. Pharmacol. Toxicol. 2021 129 397 415 10.1111/bcpt.13648 34473898

267. Shen Q. Hang M. Shi Y. Curcumin Boosts Natural Killer Cell-Based Immunotherapy in Impeding Progression of Hepatocellular Carcinoma Through Androgen Receptor/UL16 Binding Protein-2 Signal Sci. Adv. Mater. 2022 14 188 195 10.1166/sam.2022.4197

268. Bhattacharyya S. Md Sakib Hossain D. Mohanty S. Sankar Sen G. Chattopadhyay S. Banerjee S. Chakraborty J. Das K. Sarkar D. Das T. Curcumin Reverses T Cell-Mediated Adaptive Immune Dysfunctions in Tumor-Bearing Hosts Cell. Mol. Immunol. 2010 7 306 315 10.1038/cmi.2010.11 20305684 PMC4003225

269. Alinejad S. Khademvatan S. Amani S. Asadi N. Tappeh K.H. Yousefi E. Miandoabi T. The Effect of Curcumin on the Expression of INFγ, TNF-α, and INOS Genes in PBMCs Infected with Leishmania Major [MRHO/IR/75/ER] Infect. Disord. Drug Targets 2022 22 e040422203031 10.2174/1871526522666220404083220 35379161

270. Draghiciu O. Lubbers J. Nijman H.W. Daemen T. Myeloid Derived Suppressor Cells-An Overview of Combat Strategies to Increase Immunotherapy Efficacy Oncoimmunology 2015 4 e954829 10.4161/21624011.2014.954829 25949858 PMC4368153

271. Wang T. Wang J. Jiang H. Ni M. Zou Y. Chen Y. Wu T. Ding D. Xu H. Li X. Targeted Regulation of Tumor Microenvironment through the Inhibition of MDSCs by Curcumin Loaded Self-Assembled Nano-Filaments Mater. Today Bio 2022 15 100304 10.1016/j.mtbio.2022.100304 PMC9194645 35711288

272. Ahmad I. Hoque M. Alam S.S.M. Zughaibi T.A. Tabrez S. Curcumin and Plumbagin Synergistically Target the PI3K/Akt/MTOR Pathway: A Prospective Role in Cancer Treatment Int. J. Mol. Sci. 2023 24 6651 10.3390/ijms24076651 37047624 PMC10095292

273. Song J. Choi B. Jin E.-J. Yoon Y. Choi K.-H. Curcumin Suppresses Streptococcus Mutans Adherence to Human Tooth Surfaces and Extracellular Matrix Proteins Eur. J. Clin. Microbiol. Infect. Dis. 2012 31 1347 1352 10.1007/s10096-011-1448-y 22009290

274. Rudrappa T. Bais H.P. Curcumin, a Known Phenolic from Curcuma Longa, Attenuates the Virulence of Pseudomonas Aeruginosa PAO1 in Whole Plant and Animal Pathogenicity Models J. Agric. Food Chem. 2008 56 1955 1962 10.1021/jf072591j 18284200

275. Dai C. Lin J. Li H. Shen Z. Wang Y. Velkov T. Shen J. The Natural Product Curcumin as an Antibacterial Agent: Current Achievements and Problems Antioxidants 2022 11 459 10.3390/antiox11030459 35326110 PMC8944601

276. Kumbar V.M. Peram M.R. Kugaji M.S. Shah T. Patil S.P. Muddapur U.M. Bhat K.G. Effect of Curcumin on Growth, Biofilm Formation and Virulence Factor Gene Expression of Porphyromonas Gingivalis Odontology 2021 109 18 28 10.1007/s10266-020-00514-y 32279229

Figures, Scheme and Table