Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases
Abstract
Curcumin, a yellow pigment in the Indian spice Turmeric (Curcuma longa), which is chemically known as diferuloylmethane, was first isolated exactly two centuries ago in 1815 by two German Scientists, Vogel and Pelletier. However, according to the pubmed database, the first study on its biological activity as an antibacterial agent was published in 1949 in Nature and the first clinical trial was reported in The Lancet in 1937. Although the current database indicates almost 9000 publications on curcumin, until 1990 there were less than 100 papers published on this nutraceutical. At the molecular level, this multitargeted agent has been shown to exhibit anti-inflammatory activity through the suppression of numerous cell signalling pathways including NF-κB, STAT3, Nrf2, ROS and COX-2. Numerous studies have indicated that curcumin is a highly potent antimicrobial agent and has been shown to be active against various chronic diseases including various types of cancers, diabetes, obesity, cardiovascular, pulmonary, neurological and autoimmune diseases. Furthermore, this compound has also been shown to be synergistic with other nutraceuticals such as resveratrol, piperine, catechins, quercetin and genistein. To date, over 100 different clinical trials have been completed with curcumin, which clearly show its safety, tolerability and its effectiveness against various chronic diseases in humans. However, more clinical trials in different populations are necessary to prove its potential against different chronic diseases in humans. This review's primary focus is on lessons learnt about curcumin from clinical trials.
Linked Articles
This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc
Abbreviation
-
- MCP
-
- monocyte chemoattractant protein
Tables of Links
| TARGETS | |
|---|---|
| Enzymesa | G protein-coupled receptorsb |
| 5-LOX | CXCR4 |
| COX-2 | MCP-1 receptor (CCR2) |
| Cytosolic PLA2 | Nuclear hormone receptorsc |
| DNMTs | AR |
| ERK | ER-α |
| FAK | PPAR-γ |
| HATs | Other protein targetsd |
| HDACs | Bcl-2 |
| iNOS | Bcl-xL |
| JAK | IAP |
| JNK | TNF-α |
| ODC | XIAP |
| p38 MAPK | Catalytic receptorse |
| PKA (Akt) | EGFR |
| PKC | ROS receptors |
| uPA |
- These Tables list key protein targets and ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Southan et al., 2016) and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 (a,b,c,d,eAlexander et al., 2015a,b,c,d,e).
Introduction
Despite the substantial advances in the treatment of complex, multigenic and chronic human diseases, their occurrence rate has increased significantly in recent times (Gupta et al., 2012). A number of mono-targeted therapies, also referred to as ‘smart drugs’, have been designed over the past few years for the treatment of these chronic diseases. However, complex diseases like cardiovascular, metabolic, cancer and neurological diseases occur due to perturbations of multiple signalling pathways. Therefore, targeting a single pathway among many of the pathways involved is not likely to be effective for the prevention and treatment of these diseases (Bordoloi et al., 2016). Besides, high cost and adverse side effects are the other major disadvantages associated with these smart drugs. These limitations necessitate the urge to develop multi-targeted, cost-effective, readily available, non-toxic and highly potent agents for the management of different human diseases (Gupta et al., 2012).
Among the numerous natural remedies, turmeric has gained considerable attention due to its profound medicinal values (Prasad et al., 2014a). This agent possesses antioxidant, anti-inflammatory, anticancer, antigrowth, antiarthritic, antiatherosclerotic, antidepressant, antiaging, antidiabetic, antimicrobial, wound healing and memory-enhancing activities (Aggarwal et al., 2013a). Moreover, it exerts chemopreventive, chemosensitization and radiosensitization effects as well (Goel and Aggarwal, 2010; Gupta et al., 2011a). In traditional Indian medicine, this spice has been also used to treat different ailments such as gynecological problems, gastric problems, hepatic disorders, infectious diseases, blood disorders, acne, psoriasis, dermatitis, rash and other chronic ailments (Gupta et al., 2013a). Diverse in vivo studies have also indicated its potential against pro-inflammatory diseases, cancers, neurodegenerative diseases, depression, diabetes, obesity and atherosclerosis (Gupta et al., 2013c). Among the huge number of compounds isolated from turmeric (Tyagi et al., 2015), curcumin (a diferuloylmethane) was found to be the most widely studied compound as evinced by more than 9000 citations in the literature. It was first discovered by Vogel and Pelletier from the rhizomes of turmeric (Curcuma longa) (Prasad et al., 2014b). Structurally, it can exist in at least two tautomeric forms, keto and enol and they possess antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial and antidiabetic properties (Aggarwal et al., 2008; Goel et al., 2008; Gupta et al., 2010; Gupta et al., 2012; Aggarwal et al., 2013b; Rainey et al., 2015). These traits can possibly be attributed to the methoxy, hydroxyl, α, β-unsaturated carbonyl moiety or diketone groups present in curcumin (Aggarwal et al., 2015). Besides its safety and tolerability, cost-effectiveness is an added advantage of this compound (Shoba et al., 1998; Rasyid and Lelo, 1999; Rasyid et al., 2002; Lao et al., 2006; Tuntipopipat et al., 2006; Juan et al., 2007; Vareed et al., 2008; Shimouchi et al., 2009; Dominiak et al., 2010; Cuomo et al., 2011; Pungcharoenkul and Thongnopnua, 2011; Sasaki et al., 2011; DiSilvestro et al., 2012; Kusuhara et al., 2012; Sugawara et al., 2012; Vitaglione et al., 2012; Aggarwal et al., 2013a; Jager et al., 2014; Klickovic et al., 2014). Because of its amazing properties, curcumin is being marketed in several countries of the world in various forms (Prasad et al., 2014b).
However, the utility of curcumin is greatly hindered by its colour, lack of water solubility and low bioavailability (Anand et al., 2008). Prime factors contributing towards the low bioavailability of curcumin in both plasma and tissue might be associated with its poor absorption, rapid metabolism and rapid systemic elimination. Therefore, to enhance these, various approaches have been sought that include the use of adjuvants, liposomal curcumin, curcumin nanoparticles, curcumin phospholipid complexes, curcumin reformulated with various oils and with inhibitors of metabolism, conjugation of curcumin prodrugs and linking curcumin with polyethylene glycol (Anand et al., 2007; 2008; Goel et al., 2008; Nair et al., 2010). The use of structural analogues of curcumin and synthesis of ‘man-made’ curcumin analogues also play a role in the enhancement of its bioavailability. For instance, the natural analogues of curcumin such as demethoxycurcumin and bidemethoxycurcumin were reported to have a similar biological activity to curcumin (Kocaadam and Şanlier, 2015). Furthermore, it has been proposed that the presence of an active methylene group and β-diketone moiety causes curcumin to be unstable under physiological conditions together with its poor absorption and rapid metabolism. Supporting this proposal, more recently, different structural modifications were performed and many of the active methylene and carbonyl substituted curcumin derivatives/analogues were found to exert much improved antioxidant activity when compared with curcumin (Sahu et al., 2016). Thus, diverse synthetic derivatives of curcumin can be obtained with various chemical modifications including phenolic hydroxyl groups, acylation, alkylation, glycosylation and amino acylation to improve its bioavailability (Kocaadam and Şanlier, 2015).
Molecular targets of curcumin
Curcumin can impact a diverse range of molecular targets and signalling pathways, which augment the efficacy of existing chemotherapeutic agents (Figure 1). It can interact with a huge number of different proteins such as nuclear factor E2-related factor 2 (Nrf2), β-catenin, NF-κB, p38 MAPK, DNA (cytosine-5)-methyltransferase-1, COX-2, 5-lipoxygenase, PGE2, FOXO3, inducible NOS, ROS, cyclin D1, VEGF, glutathione, cytosolic PLA2, p-Tau (p-τ) and TNF-α. This ability of curcumin facilitiates selective modulation of multiple cell signalling pathways linked to different chronic diseases, which strongly suggest that it is a potent multi-targeted polyphenol (Anand et al., 2008; Kunnumakkara et al., 2008; Ravindran et al., 2009; Goel and Aggarwal, 2010; Hasima and Aggarwal, 2012; Aggarwal et al., 2015; Rainey et al., 2015). The common molecular targets of curcumin include transcription factors, inflammatory mediators, protein kinases and enzymes like protein reductases and histone acetyltransferase (Goel et al., 2008; Yadav and Aggarwal, 2011; Gupta et al., 2011b; 2012). A plausible mechanism through which curcumin exerts its manifold effects might be via epigenetic regulation (Tuorkey, 2014). Many recent studies have reported curcumin as a potent epigenetic regulator in different diseases, such as neurological disorders, inflammation, diabetes and different cancer types. The epigenetic regulatory roles of curcumin primarily include inhibition of DNA methyltransferases, regulation of histone modifications via effects on histone acetyltransferases and histone deacetylases and regulation of micro RNAs (Reuter et al., 2011; Boyanapalli and Tony Kong, 2015; Remely et al., 2015). Curcumin also modulates various proteosomal pathways (Hasima and Aggarwal, 2014) and impairs glycogen metabolism through selective inhibition of phosphorylase kinase (Reddy and Aggarwal, 1994). Nonetheless, it has been shown to exhibit anti-inflammatory effects by down-regulating various cytokines, such as TNF-α, IL-1, IL-6, IL-8, IL-12, monocyte chemoattractant protein (MCP)-1 (also known as CCL2) and IL-1β, and various inflammatory enzymes and transcription factors (Bharti et al., 2004; Davis et al., 2007; Aggarwal and Sung, 2009; Gupta et al., 2011a; 2014).
Numerous preclinical and clinical studies have shown the effectiveness of curcumin in the prevention and treatment of various human diseases; however, the main focus of this review is the lessons learnt from clinical trials.
Clinical studies with curcumin
Encouraging outcomes of preclinical studies have engendered ample clinical trials of curcumin to evaluate its safety and efficacy against a diverse range of human diseases (Figure 2; Tables 1 and 2). Approximately 120 clinical trials have been successfully carried out so far, involving more than 6000 human participants. In addition, there are several systematic reviews/meta-analyses based on the clinical trials of curcumin for human data (Table 2).
| Disease | Curcumin dose | Pts (#) | Clinical outcome | References |
|---|---|---|---|---|
| Safety and tolerability | ||||
| Healthy volunteers | 2 gb,d | 10 | Safe and highly bioavailable | Shoba et al., 1998 |
| 20 mgd | 12 | Safe and induced gall-bladder contraction | Rasyid and Lelo, 1999 | |
| 20, 40, 80 mgd | 12 | Safe and increased gall-bladder contraction | Rasyid et al., 2002 | |
| 0.5 g; 2 daysc | 10 | Safe and no effect on iron absorption | Tuntipopipat et al., 2006 | |
| 500–12 000 mgd | 24 | Safe and well tolerated | Lao et al., 2006 | |
| 300 mg·day−1; 6 daysb | 12 | Safe | Juan et al., 2007 | |
| 10 and 12 gd | 12 | Safe and improved absorption | Vareed et al., 2008 | |
| 500 mgb,c,d | 8 | Safe and activated bowel motility | Shimouchi et al., 2009 | |
| 150 mg·day−1; 2 weeksb | 11 | Safe and well tolerated | Dominiak et al., 2010 | |
| 0.5–6 g·day−1; 7 days | 24 | Safe and decreased lipid levels | Pungcharoenkul and Thongnopnua, 2011 | |
| 30 mga,d | 14 | Safe and bioavailable | Sasaki et al., 2011 | |
| 3 × 209–376 mg·day−1a | 9 | Safe and improved absorption | Cuomo et al., 2011 | |
| 80 mg·day−1; 4 weeks | 38 | Safe and have multiple health benefits | DiSilvestro et al., 2012 | |
| 150 mg·day−1; 8 weeks | 45 | Safe and improved BP and heart rate | Sugawara et al., 2012 | |
| 1 gd | 10 | Safe and bioavailable | Vitaglione et al., 2012 | |
| 2 gb,d | 8 | Safe and bioavailable | Kusuhara et al., 2012 | |
| 4 × 4 g; 2 daysb | 8 | Safe and highly bioavailable | Volak et al., 2013 | |
| 376 mga,d | 15 | Safe and bioavailable | Jager et al., 2014 | |
| 12 ga,d | 10 | Safe and well tolerated | Klickovic et al., 2014 | |
| Cancer | ||||
| BPH | 1 g·day−1; 24 weeksb | 61 | Reduced signs and symptoms | Ledda et al., 2012 |
| Breast | 6 g·day−1; 7 daysb | 14 | Safe and well tolerated | Bayet-Robert et al., 2010 |
| Cancerous lesions | Ointment | 62 | Reduced lesion size and pain | Kuttan et al., 1987 |
| 0.5–1.2 g·day−1; 3 months | 25 | Well tolerated and efficacious | Cheng et al., 2001 | |
| Cervical | 500 mg·day−1; 30 days | 280 | Increased HPV clearance rate | Basu et al., 2013 |
| CML | 3 × 5 g; 6 weeksc | 50 | Reduced nitric oxide levels | Ghalaut et al., 2012 |
| Colorectal | 220 mg·day−1; 29 daysa | 15 | Inhibited basal and LPS-induced PGE2 | Plummer et al., 2001 |
| 2.2 g·day−1c; 4 months | 15 | Well tolerated | Sharma et al., 2001 | |
| 0.45, 3.6 g·day−1; 4 months | 15 | Well tolerated and efficacious | Sharma et al., 2004 | |
| 0.45, 1.8, 3.6 mg·day−1; 7 days | 12 | Inhibited inflammation and DNA damage | Garcea et al., 2005 | |
| 1.08 g·day−1; 10–30 days | 26 | Improved the general health | He et al., 2011 | |
| 2 or 4 g·day−1; 30 days | 44 | 40% reduction in ACF number | Carroll et al., 2011 | |
| 2.35 g·day−1; 14 days | 26 | High levels of curcumin were recovered | Irving et al., 2013 | |
| HNSCC | 2 gd | 39 | Decreased IKKβ kinase activity in saliva | Kim et al., 2011 |
| Pancreatic | 8 g·day−1; 8 weeks | 25 | Safe, well tolerated and efficacious | Dhillon et al., 2008 |
| 8 g·day−1; 4 weeksb | 17 | Showed partial response and stable disease | Epelbaum et al., 2010 | |
| 8 g·day−1; 14 days every 3 weeksb | 21 | Safe and well tolerated | Kanai et al., 2011 | |
| 0.2–0.4 g·day−1; 9 months | 16 | Safe and well tolerated | Kanai et al., 2013 | |
| Prostate | 100 mg·day−1; 6 monthsb | 85 | Reduced serum PSA levels | Ide et al., 2010 |
| 3 g·day−1; 3 months | 40 | No significant effect | Hejazi et al., 2016 | |
| Solid tumours | 3 × 100 mg·day−1;4 monthsa | 160 | Decreased side effects of chemotherapy | Belcaro et al., 2014 |
| 180 mg·day−1; 8 weeks | 80 | Improved quality of life | Panahi et al., 2014c | |
| Cardiovascular disease | ||||
| ACS | 15–60 mg·day−1; 2 years | 75 | Reduced total and LDL cholesterol | Alwi et al., 2008 |
| AMI | 4 g·day−1; 7 days | 121 | Inhibited MI associated with CABG | Wongcharoen et al., 2012 |
| CVH | 180 gc,d | 14 | Improves postprandial endothelial function | Nakayama et al., 2014 |
| Dyslipidemia | 1 g·day−1; 30 days | 30 | Decreased triglycerides level | Mohammadi et al., 2013 |
| Metabolic and CVH | 0.9 g·day−1; 24 weeksb | 56 | No effect | Soare et al., 2014 |
| MS | 1890 mg·day−1; 12 weeks | 65 | Lowered lipid level | Yang et al., 2014 |
| 1000 mg·day−1; 8 weeksb | 100 | Effective as adjunctive therapy | Panahi et al., 2014a | |
| Inflammatory diseases | ||||
| Bronchial asthma | 500 mg·day−1; 30 days | 77 | Decreased airway obstruction | Abidi et al., 2014 |
| CKD | 2 × 824 mg·day−1; 8 weeksb | 16 | Safe and well tolerated | Moreillon et al., 2013 |
| Crohn's disease | 1.1 and 1.6 g·day−1; 1 month | 5 | Efficacious | Holt et al., 2005 |
| FAP | 3 × 480 mg·day−1; 6 monthsb | 5 | Decreased number and size of adenomas | Cruz-Correa et al., 2006 |
| Gastritis | 3 × 700 mg·day−1; 4 weeksc | 36 | No significant effect | Koosirirat et al., 2010 |
| Gingivitis | Mouthwash | 30 | Effective in mechanical periodontal therapy | Muglikar et al., 2013 |
| H. pylori infection | 2 × 30 mg·day−1; 7 days | 25 | Improved dyspeptic symptoms | Di Mario et al., 2007 |
| IBD | 1–4 g·day−1; 3 weeks | 11 | Significant decrease in relapse | Suskind et al., 2013 |
| Nephritis | 500 mg·day−1; 3 months | 24 | Decreased proteinuria, haematuria and BP | Khajehdehi et al., 2012 |
| OLP | 2000 mg·day−1; 7 weeks | 100 | Safe and well-tolerated | Chainani-Wu et al., 2007 |
| 6000 mg·day−1 | 20 | Safe, well-tolerated and efficacious | Chainani-Wu et al., 2012b | |
| 2.137 g·day−1; 30 months | 53 | Efficacious | Chainani-Wu et al., 2012a | |
| Oral mucositis | 2 × 10 drops per daya; 21 days | 7 | Well-tolerated and efficacious | Elad et al., 2013 |
| With honeyb,c | 60 | Inhibited oral mucositis | Francis and Williams, 2014 | |
| Osteoarthritis | 1 g·day−1a | 100 | Safe and efficacious | Belcaro et al., 2010a |
| 200 mga | 50 | Efficacious | Belcaro et al., 2010b | |
| 1000 mg·day−1; 3 months | 44 | Served as adjuvant therapy | Pinsornsak and Niempoog, 2012 | |
| 1500 mg·day−1; 4 weeks | 185 | As effective as ibuprofen | Kuptniratsaikul et al., 2014 | |
| 1500 mg·day−1; 3 weeks | 40 | Safe and efficacious | Panahi et al., 2014b | |
| 180 mg·day−1; 8 weeksa | 45 | Efficacious | Nakagawa et al., 2014 | |
| 2 × 126 mg·day−1; 3 months | 22 | Significant improvement | Henrotin et al., 2014 | |
| Pancreatitis | 0.5 g·day−1; 6 weeksb | 20 | Reduced MDA and increased GSH | Durgaprasad et al., 2005 |
| Peptic ulcer | 3 g·day−1; 4–12 weeks | 45 | Alleviated abdominal pain and discomfort | Prucksunand et al., 2001 |
| Periodontitis | 2% gelc | 37 | Effective in scaling and root planing | Behal et al., 2011 |
| 1%·week−1; 3 weeksa | 23 | Mild to moderate beneficiary effect | Gottumukkala et al., 2013 | |
| 1%; 1, 3 and 6 monthsa | 20 | Inhibited growth of oral bacteria | Bhatia et al., 2014 | |
| 50 mg·cm−2; 6 monthsa | 60 | Reduced plaque and gingival index scores | Gottumukkala et al., 2014 | |
| Plaque | 2 × 0.1%; 21 daysc | 100 | Prevented plaque and gingivitis | Waghmare et al., 2011 |
| Prostatitis | 200 mg·day−1; 14 daysb | 284 | Improved efficacy of prulifloxacin | Cai et al., 2009 |
| Pulmonary complication | 500 mg; 4 weeks | 89 | Safe, well-tolerated and efficacious | Panahi et al., 2015b |
| Rheumatoid arthritis | 1.2 g·day−1; 2 weeks | 18 | Reduced stiffness and joint swelling | Deodhar et al., 1980 |
| 2 × 500 mg·day−1; 8 weeksb | 45 | Reduced DAS and ACR scores | Chandran and Goel, 2012 | |
| Ulcerative colitis | 2 g·day−1; 6 months | 45 | Prevented disease relapse | Hanai et al., 2006 |
| 0.5 g·day−1; 1 year | 1 | Efficacious | Lahiff and Moss, 2011 | |
| 140 mg·day−1; 8 weeksa,b | 45 | Safe and efficacious | Singla et al., 2014 | |
| 3 g·day−1; 1 monthb | 50 | Effective, no adverse effects | Lang et al., 2015 | |
| Ulcerative proctitis | 1.1 g and 1.65 g·day−1; 1 month | 5 | Efficacious | Holt et al., 2005 |
| Uveitis | 1.125 g·day−1; 12 weeks | 53 | Efficacy equal to corticosteroid therapy | Lal et al., 1999 |
| 2 × 0.6 g·day−1; 12–18 months | 106 | Well tolerated and reduced eye discomfort | Allegri et al., 2010 | |
| Metabolic disease | ||||
| Diabetes | 5 g·day−1; 3 months | 1 | Decreased fasting blood sugar level | Srinivasan, 1972 |
| 600 mg·day−1; 8 weeks | 72 | Inhibited cytokines and oxidative stress | Usharani et al., 2008 | |
| 3 × 500 mg·day−1; 2 monthsc | 40 | Attenuated proteinuria, TGFβ and IL-8 | Khajehdehi et al., 2011 | |
| 1.5 g·day−1; 3, 6 and 9 months | 240 | Safe, well tolerated and efficacious | Chuengsamarn et al., 2012 | |
| 300 mg·day−1; 3 months | 100 | Effective, decreased serum A-FABP level | Na et al., 2014 | |
| 2 × 750 mg·day−1; 6 months | 240 | Lowered the atherogenic risks | Chuengsamarn et al., 2014 | |
| 500 mg·day−1; 15–30 days | – | Reduced albumin excretion, activated Nrf2 | Yang et al., 2015 | |
| 1 g·day−1; 4 weeksa | 25 | Decreased oedema score, improved response | Appendino et al., 2011 | |
| 500 mg·day−1; 4 weeksa | 38 | Efficacious | Steigerwalt et al., 2012 | |
| Obesity | 1 g·day−1; 30 days | 30 | Decreased oxidative stress | Sahebkar et al., 2013 |
| 1 g·day−1; 4 weeks | 30 | Improved immune response | Ganjali et al., 2014 | |
| 1 g·day−1; 30 days | 30 | Reduced anxiety | Esmaily et al., 2015 | |
| Neurological disease | ||||
| Alzheimer's disease | 2 and 4 g·day−1; 24 weeks | 33 | Patients' response yet to be published | Ringman et al., 2005 |
| 1 and 4 g·day−1; 6 months | 34 | Safe and increased vitamin E level | Baum et al., 2008 | |
| Depression | 500 mg·day−1; 5 weeks | 40 | Reduced symptoms | Bergman et al., 2013 |
| 1 g·day−1; 8 weeks | 56 | Reduced depression | Lopresti et al., 2014 | |
| 1000 mg·day−1; 6 weeks | 60 | Safe and efficacious | Sanmukhani et al., 2014 | |
| 10–1000 mg·day−1; 6 weeksb | 111 | Safe and efficacious | Panahi et al., 2015a | |
| 2 × 0.5 g·day−1; 8 weeks | 50 | Reduced IDS-SR30 score | Lopresti et al., 2015 | |
| 2 × 1 g·day−1; 6 weeks | 108 | Reduced depression | Yu et al., 2015 | |
| Skin diseases | ||||
| Psoriasis | 2 × 1%·day−1; 4 weeks | 40 | Suppressed PhK activity | Heng et al., 2000 |
| 4.5 g·day−1; 16 weeksa | 12 | Showed response rate 16.7% | Kurd et al., 2008 | |
| 2 g·day−1; 12 weeks | 63 | Effective and decreased serum IL-22 levels | Antiga et al., 2015 | |
| Radiation dermatitis | 6 g·day−1 throughout RT | 30 | Reduced severity of radiation | Ryan et al., 2013 |
| Vitiligo | 2× cream per day; 12 weeks | 10 | Improved degree of repigmentation | Asawanonda and Klahan, 2010 |
| Infectious diseases | ||||
| HIV | 2.5 g·day−1; 56 days | 40 | Well tolerated | James, 1996 |
| Tuberculosis | 6 g·day−1; 2–4 monthsa | 578 | Prevented hepatotoxicity | Adhvaryu et al., 2008 |
| Others | ||||
| Arsenic carcinogenicity | 2 × 500 mg·day−1; 3 monthsb | 286 | Reduced DNA damage | Biswas et al., 2010 |
| Cholecystectomy | 500 mg every 6 h | 50 | Improved post-operative pain | Agarwal et al., 2011 |
| CRT | 480 mg·day−1; 1 monthb | 43 | Improved graft function, reduced rejection | Shoskes et al., 2005 |
| Déjérine-Sottas | 50–75 mg·kg−1·day−1; 12 months | 1 | Improved patient's quality of life | Burns et al., 2009 |
| MGUS and SMM | 2 × 2 g·day−1; 3 months | 36 | Slowed the disease process | Golombick et al., 2012 |
| MGUS | 2 × 2 g·day−1; 3 months | 26 | Reduced paraprotein levels | Golombick et al., 2009 |
| Oxidative stress | 90 mgd | 10 | Reduced oxidative stress | Takahashi et al., 2014 |
| PMS | 2 capsules·day−1; 7 days | 70 | Attenuated severity of PMS symptoms | Khayat et al., 2015 |
| Pruritus | 1 g·day−1; 4 weeks | 96 | Safe, effective and anti-inflammatory | Panahi et al., 2012a |
| Salivary pathogens | 1.5 g·L−1 | 13 | Not effective | Araujo et al., 2012 |
| Thalassemia | 3 × 500 mg·day−1; 12 months | 21 | Ameliorated oxidative damage | Kalpravidh et al., 2010 |
| VEF | 150 mg·day−1; 8 weeks | 32 | Improved endothelial function | Akazawa et al., 2012 |
- a Curcumin formulation.
- b Combination.
- c Turmeric.
- d Administered once.
- AC, arsenic carcinogenicity; ACS, acute coronary syndrome; ACR, American College of Rheumatology; AMI, acute myocardial infarction; BPH, benign prostatic hyperplasia; CABG, coronary artery bypass graft; CBP, chronic bacterial prostatitis; CDAI, clinical disease activity index; CKD, chronic kidney disease; CML, chronic myeloid leukaemia; CP, chronic periodontitis; CRT, cadaveric renal transplantation; CVH, cardiovascular health; DM, diabetic microangiopathy; DR, diabetic retinopathy; DAS, disease activity score; FAP, familial adenomatous polyposis; GSH, glutathione; HC, hepatocellular carcinoma; HM, haematological malignancies; HNSCC, head and neck squamous cell carcinoma; IBD, inflammatory bowel disease; LN, lupus nephritis; MI, myocardial infarction; MDA, malonaldialdehyde; MDD, major depressive disorder; MGUS, monoclonal gammopathy of undetermined significance; MS, metabolic syndrome; OLP, oral lichen planus; PSA, prostate-specific antigen; PMS, premenstrual syndrome; SMM, smoldering multiple myeloma; T2D, type 2 diabetes; THC, tetrahydrocurcuminoid; UC, ulcerative colitis; VEF, vascular endothelial function.
| Disease | Publications analysed | Outcome | References |
|---|---|---|---|
| Skin health | PubMed and Embase till Aug 2015 | Benefits skin health | Vaughn et al., 2016 |
| Depressive disorder | Literature until Aug 2015 | Reduces depressive symptoms | Al-Karawi et al., 2016 |
| Circulating TNF-α | PubMed-Medline, Scopus, Web of Science, Google Scholar till Sep 2015 | Lowers circulating TNF-α | Sahebkar et al., 2016 |
| Painful conditions | Literature till Sep 2014 | Safe and effective | Sahebkar and Henrotin, 2016 |
| Musculoskeletal pain | CINAHL, Embase, CENTRAL, PubMed, Scopus, PsycINFO, Clinicaltrials.gov, unpublished studies | Analysis not completed | Gaffey et al., 2015 |
| IBD | Cochrane Library, Pubmed/Medline, PsychINFO, Scopus through Mar 2014 | Effective | Langhorst et al., 2015 |
| Dementia | Medline, Embase, Cochrane till Jul 2013 | Safe (Short term use) | Brondino et al., 2014 |
| Diabetes | Medline database in 2013 | Effective | Zhang et al., 2013 |
| Blood lipid levels | PubMed-Medline, Scopus, Ovid-AMED, Clinical trial registry, Cochrane through Sep 2012 | No effect | Sahebkar, 2014a |
| Malignant disorders | PubMed, Google J-Gate | – | Ara et al., 2016 |
| Analgesic efficacy and safety | Scopus and Medline till Sep 2014 | Safe and effective | Sahebkar and Henrotin, 2016 |
| Circulating CRP levels | PubMed/Medline and Scopus | Reduces circulating CRP levels | Sahebkar, 2014b |
- CENTRA, Cochrane Central Register of Controlled Trials; CRP, c-reactive protein; IBD, inflammatory bowel disease
Safety and adequate daily intake (ADI) value of curcumin as well as its derivatives
In general the consumption of curcumin is considered to be safe. As per JECFA (The Joint FAO/WHO Expert Committee on Food Additives) and EFSA (European Food Safety Authority) reports, the ADI value of curcumin is 0–3 mg·kg−1 (Kocaadam and Şanlier, 2015). In addition, the safety and efficacy of curcumin was evaluated in several clinical trials involving healthy human subjects. For instance, in one such study in healthy human volunteers, the effect of curcumin combined with piperine was measured; this increased the bioavailabilty of curcumin by approximately 2000% without causing any adverse effects (Shoba et al., 1998). Furthermore, curcumin was found to exhibit positive cholekinetic effect as it induced a significant contraction of the human gall-bladder (Rasyid and Lelo, 1999). At the dosage of 40 mg, curcumin evoked a 50% contraction of the gall bladder (Rasyid et al., 2002). A dose-response study was undertaken to detect the maximum tolerated dose and safety of a single dose of standardized powder extract; uniformly-milled curcumin was administered to healthy volunteers at doses ranging from 500 to 12 000 mg and it was found to be profoundly well tolerated (Lao et al., 2006). Concomitant administration of curcumin and talinolol reduced the bioavailability of talinolol possibly due to the low intraluminal curcumin concentration or an up-regulation of further ATP-binding cassette transporters in different tissues (Juan et al., 2007). Another study was attempted to evaluate the pharmacokinetics of a curcumin preparation in healthy human volunteers for up to 72 h following a single oral dose of curcumin. It was found to be absorbed after oral dosing in humans and was detected in plasma as glucuronide and sulfate conjugates (Vareed et al., 2008). Moreover, dietary turmeric was shown to activate bowel motility as well as carbohydrate colonic fermentation (Shimouchi et al., 2009). In addition, the ingestion of a capsule containing curcumin (30%), resveratrol (15%), EGCG (30%) and soybean extract (25%) was found to exert a protective effect against oxidative stress in normal healthy adults (Dominiak et al., 2010). Treatment with curcumin (500 mg·day−1) also markedly lowers serum cholesterol and triglyceride levels in healthy human subjects (Pungcharoenkul and Thongnopnua, 2011). The efficacy of curcumin dispersed with colloidal nano-particles, known as Theracurmin was also investigated in terms of absorption and was compared with that of curcumin powder. However, the former showed a much higher bioavailability and thus may be of immense use with ample clinical benefits in humans even at a very low dose (Sasaki et al., 2011). Meriva, the lecithin formulation of a standardized curcuminoid mixture also exhibited a much improved absorption and plasma curcuminoid profile at significantly lower doses (Cuomo et al., 2011). Another trial in healthy middle aged people showed that treatment with curcumin caused a marked reduction in plasma triglyceride values, salivary amylase levels, plasma β amyloid protein concentrations, plasma sICAM readings, plasma alanine amino transferase activities and increased salivary radical scavenging capacities, plasma catalase activities, plasma myeloperoxidase without increasing C-reactive protein (CRP) levels or plasma nitric oxide (DiSilvestro et al., 2012). Regular endurance exercise together with daily curcumin administration caused a marked reduction in left ventricular afterload (Sugawara et al., 2012). A formulation of curcumin in combination with a hydrophilic carrier, cellulosic derivatives and natural antioxidants was shown to enhance the bioavailability of curcumin in blood (Jager et al., 2014). On the other hand, another study indicated that the short term use of a piperine-enhanced curcuminoid preparation is ineffective at producing a clinically significant interaction involving CYP3A, CYP2C9 or the paracetamol conjugation enzymes (Volak et al., 2013). Also in another clinical trial, oral curcumin administration was linked with poor bioavailability and was shown not to increase haemoxygenase 1 (HO-1) in peripheral blood mononuclear cells (Klickovic et al., 2014).
Curcumin for cancer
Cancer is one of the prime health concerns today, affecting people of all ages worldwide. The first clinical trial on curcumin was done by Kuttan and colleagues in 1987 by enrolling 62 patients with external cancerous lesions to investigate its potential against cancer. An ethanolic extract of turmeric and an ointment of curcumin caused significant symptomatic relief in these patients along with a reduction in itching and smell. In 70% of the patients, dry lesions were observed and in a few cases, a reduction in lesion size and pain was observed (Kuttan et al., 1987). Henceforth, numerous clinical trials have been carried out using curcumin and its ability to affect multiple targets has enabled it to exert notable activities against different cancer types in human clinical trials (Gupta et al., 2012).
Cervical cancer
Cervical cancer is the second most common form of malignancy in women worldwide. Curcumin exhibits potent effects against this cancer in vitro, in vivo and in clinical settings. From an initial study, a dose of 500–12 000 mg·day−1 of curcumin was found to be safe, well tolerated and have chemopreventive properties against cervical cancer (Cheng et al., 2001). In another study, when HPV-positive cervical neoplasia patients were treated with Basant polyherbal vaginal cream (containing extracts of curcumin, reetha, amla and Aloe vera), HPV clearance rate was found to be significantly high with no adverse side effects (Basu et al., 2013). These studies showed curcumin to be a safe and efficacious compound for the prevention and treatment of cervical cancer.
Colon cancer
Colon cancer ranks third among the most commonly occurring cancers in the world. Despite significant advances in cancer therapy, mortality from colon cancer persists at the same level, highlighting the necessity of improved therapies (Nautiyal et al., 2011). The efficacy of oral curcumin (2 g or 4 g daily for 30 days) in the prevention of colorectal neoplasia was evaluated in a nonrandomized, open-label clinical trial enrolling 44 patients. The results showed a marked reduction in ACF number with 4 g dose of curcumin, which was possibly associated with its increased bioavailabity (fivefold) in plasma (Carroll et al., 2011). A dose-response study was designed to investigate the pharmacology of curcumin in humans with doses ranging from 0.45–3.6 g·day−1 up to 4 months. A dose of 3.6 g curcumin per day caused 62 and 57% decrease in inducible PGE2 production in blood samples taken 1 h after dosing on days 1 and 29, respectively with no dose limiting toxicities (Sharma et al., 2004). Similarly in another pilot dose-response study with curcuma extract in advanced colorectal cancer, the production of basal and LPS-mediated PGE2 was significantly reduced in a dose-dependent manner (Plummer et al., 2001). Administration of curcumin caused a reduction in M(1)G levels in malignant colorectal tissue, whereas COX-2 protein levels in malignant colorectal tissue remained unaltered (Garcea et al., 2005). Furthermore, curcumin treatment has a significant impact on improving the general health of colorectal cancer patients by enhancing expression of p53 molecules in tumour cells and consequently promoting the apoptosis of tumour cells (He et al., 2011). In colorectal mucosa, pharmacologically active concentrations of curcumin were achieved after administration of curcumin C3 complex (Irving et al., 2013).
Head and neck cancer
Curcumin has also been found to have potential against head and neck cancer, which generally arises in the paranasal sinuses, nasal cavity, oral cavity, pharynx and larynx. An investigation was carried out by Kim et al. to determine the potential anti-inflammatory effect of curcumin in HNSCC patients. Curcumin was found to suppress inflammatory cytokines such as IL-6, IL-8, granulocyte macrophage colony stimulating factor and TNF-α as well as IKKβ kinase in the saliva of patients. They also suggested that IKKβ kinase could be a plausible biomarker for the detection of the effect of curcumin in head and neck cancer as curcumin inhibited IKKβ kinase activity in the saliva of HNSCC patients, and this effect was strongly correlated with the reduced expression of a number of cytokines (Kim et al., 2011).
Pancreatic cancer
Pancreatic cancer is one of the most lethal human cancers and the conventional treatment approaches have had little impact on the course of this aggressive neoplasm (Li et al., 2004). However, new therapeutic strategies based on curcumin seem to hold great promise. Studies have shown that oral curcumin is safe and well-tolerated, and despite its limited absorption has clinical biological effects in pancreatic cancer patients. Its intake causes the down-regulation of NF-κB, COX-2 and phosphorylated STAT3 in peripheral blood mononuclear cells from patients with pancreatic cancer (Dhillon et al., 2008). However, a study conducted by Epelbaum et al. to investigate the activity and feasibility of gemcitabine in combination with curcumin in advanced pancreatic cancer patients, suggested that the dose of 8 g curcumin per day is inadvisable and can be reduced by combining it with systemic gemcitabine (Epelbaum et al., 2010). Furthermore, the safety and feasibility of combination therapy using curcumin and gemcitabine was evaluated in a different study; this contradicted the previous report and suggested 8 g oral curcumin daily combined with gemcitabine-based chemotherapy is extremely safe and practicable enough for pancreatic cancer patients (Kanai et al., 2011). Another group explored the safety of repeated administration of Theracurmin® in those pancreatic or biliary tract cancer patients who failed to respond to standard chemotherapy. Theracurmin® was administered orally, with standard gemcitabine-based chemotherapy, starting with a dose containing 200 mg of curcumin (Level 1) and then increasing the dose to 400 mg of curcumin (Level 2). With this regime, peak plasma curcumin levels at Level 1 was found to be 324 ng·mL−1 and, at Level 2, 440 ng·mL−1. No adverse side reactions were observed and three patients continued the treatment for nine months (Kanai et al., 2013).
Other cancers
Curcumin exhibited potential against various other cancers as well in clinical settings. In an attempt to evaluate the clinical efficacy of curcuminoid therapy, a bioavailable-boosted formulation was given to patients with solid tumours of different cancers such as colorectal, gastric, breast, sarcoma, lymphoma, prostate, bladder, oesophagus, ovary, testicles and hepatocellular carcinoma. It was observed that its supplementation suppressed systemic inflammation and significantly improved the quality of life of these patients (Panahi et al., 2014c). In a phase I clinical trial of curcumin in patients with high-risk or pre-malignant lesions of bladder cancer, oral leucoplakia, intestinal metaplasia of the stomach, uterine cervical intraepithelial neoplasm and Bowen's disease, the curcumin treatment was found to improve the histology of precancerous lesions (Cheng et al., 2001). In another study, a lecithinized delivery system of curcumin (Meriva®, Indena S.p.A. - Viale Ortles, Milano, Italy) was shown to alleviate the adverse side effects associated with the chemo- and radiotherapy of different tumours, such as colon, liver, kidney, lung and stomach (Belcaro et al., 2014). Another clinical trial found that a dose of 6 g·day−1 of curcumin for seven consecutive days in every 3 weeks in combination with a standard dose of docetaxel was safe, tolerable and highly effective against breast cancer (Bayet-Robert et al., 2010). The administration of curcumin to paediatric patients with relapsed brain tumours undergoing chemotherapy increased their response compared with the institutional controls (Wolff et al., 2012). Curcumin was also shown to possess a potent chemosensitizing effect in a study conducted with 50 chronic myeloid leukaemia patients, where the patients receiving both imatinib and curcumin showed better prognosis with reduced nitric oxide levels than the patients receiving imatinib alone (Ghalaut et al., 2012).
Curcumin for cardiovascular diseases
Cardiovascular diseases, which include acute coronary syndrome, acute myocardial infarction and dyslipidaemia, are the number one cause of mortality worldwide. There are many drugs approved for the treatment of this disease but they are not devoid of severe side effects. Therefore, the effect of curcumin has been studied in patients with this disease.
Acute coronary syndrome
Acute coronary syndrome (ACS) is used to define any group of clinical symptoms compatible with acute myocardial ischaemia (Kumar and Cannon, 2009). In a randomized controlled trial with 75 ACS patients, curcumin was evaluated for its effects on lipid levels. Curcumin was administered to the patients at increasing doses three times a day (low dose 15 mg, moderate dose 30 mg and high dose 60 mg). The findings revealed that curcumin effectively reduced the total cholesterol and low-density lipoprotein cholesterol levels in the patients at low doses when compared with the higher doses (Alwi et al., 2008).
Acute myocardial infarction
Curcuminoid was found to reduce the myocardial infarction associated with coronary artery bypass grafting (CABG) significantly. Wongcharoen et al. evaluated the effects of curcuminoids on the frequency of acute myocardial infarction after CABG. A total of 121 patients were enrolled for this trial. The curcuminoid group exhibited lower levels of post-operative C-reactive protein (CRP), malondialdehyde and N-terminal pro-B-type natriuretic peptide levels. These antioxidant and anti-inflammatory effects might contribute to the cardioprotective effects of the curcuminoids (Wongcharoen et al., 2012).
Dyslipidaemia
Dyslipidaemia is a well-established modifiable cardiovascular risk factor. Treatment of this disease is usual for the prevention of cardiovascular diseases (Cicero and Colletti, 2015). The hypolipidaemic activity of curcumin was examined in a randomized, double-blind, placebo-controlled, crossover trial. Supplementation of curcuminoid resulted in a decrease in the concentrations of serum triglycerides without causing any marked impact on the lipid profile, body mass index and body fat (Mohammadi et al., 2013).
Metabolic and cardiovascular health
Although dietary supplements have extensive health benefits, Soare et al. observed that a combination of dietary supplements had no cardiovascular or metabolic effects in non-obese relatively healthy individuals. In their study, 24 weeks of dietary supplementation did not influence arterial stiffness or endothelial function, or alter body fat measurements, blood pressure, plasma lipids, glucose, insulin, insulin-like growth factor-1 (IGF1) and markers of inflammation and oxidative stress in non-obese individuals (Soare et al., 2014). In contrast, it has been found that the consumption of curry spices rich in antioxidative compounds like curcumin and eugenol, improves postprandial endothelial function in healthy male subjects, which is beneficial for cardiovascular health. The participants who ate curry had an increased flow-mediated vasodilatation response. Moreover, the presence of spices in the curry did not significantly change the systemic and forearm haemodynamics, or any biochemical parameters (Nakayama et al., 2014).
Regular consumption of curcumin is probably an alternative way of modifying cholesterol-related parameters, as evidenced by a study that measured the effect of curcumin extract on weight, glucose and lipid profiles in patients with metabolic syndrome. At 12 weeks after intake of the curcumin extract, there was an elevation in the high-density lipoprotein cholesterol level, whereas the level of low-density lipoprotein cholesterol was decreased significantly (Yang et al., 2014). In another study conducted with 32 participants, curcumin was shown to increase the vascular endothelial function in postmenopausal women, which in turn decreases the risk of cardiovascular diseases (Akazawa et al., 2012).
Curcumin for inflammatory diseases
The effect of curcumin on different inflammatory diseases in humans, such as bronchial asthma, uveitis, periodontitis and inflammatory bowel diseases, has also been studied in detail.
Biliary diseases
The first clinical trial of curcumin in human diseases was done by Oppenheimer in 1937 to examine the effects of ‘curcumen’ or ‘curcunat’ (contains 0.1 to 0.25 g sodium curcumin and 0.1 g calcium cholate) on human biliary diseases. Healthy persons were subjected to an i.v. injection of 5% sodium curcumin solution, which resulted in rapid emptying of the gallbladder. Notably, one patient showed a complete cure throughout a long period of observation (Oppenheimer, 1937). In another study, Cholagogum F Nattermann (dried extracts from Schöllkraut and Curcuma) treatment caused an effective reduction in biliary dyskinesia (Niederau and Gopfert, 1999).
Bronchial asthma
Curcumin has also found to be highly effective against bronchial asthma. Abidi et al. (2014) investigated the effectiveness of curcumin as an add-on therapy in patients with bronchial asthma. Administration of curcumin capsules improved the mean forced expiratory volume 1 s (FEV1) values, which signifies an improvement in the airway obstruction. Moreover, improved haematological parameters were also obtained (Abidi et al., 2014).
Chronic anterior uveitis
Uveitis is a major cause of vision loss worldwide. Chronic anterior uveitis (CAU) includes a heterogeneous group of diseases, of which some are idiopathic in origin (McCluskey et al., 2000). As curcumin has shown to be effective as a treatment of diverse inflammatory conditions, a few clinical trials were attempted to evaluate its efficacy against CAU of different aetiologies. The oral administration of curcumin to CAU patients improved their health and a follow-up after 3 years indicated a 55% recurrence rate (Lal et al., 1999). Another group investigated the efficacy of oral phospholipidic curcumin on recurrent CAU of different aetiologies. The findings claimed that phospholipidic curcumin reduced the symptoms and signs of eye discomfort efficiently after a few weeks treatment in the majority of the patients (Allegri et al., 2010).
Chronic cutaneous complications
Chronic cutaneous complications are one of the major and frequent complaints of patients exposed to sulphur mustard (SM). A trial conducted by Panahi et al. investigated the effect of curcumin on serum inflammatory biomarkers such as IL-8 and hs-CRP and their association with the severity of a chronic cutaneous complication called pruritus. The results implied that curcumin is highly effective at lessening the inflammation in patients with chronic SM-induced cutaneous complications, which might account for its ability to ameliorate pruritus and improve the quality of life of these patients (Panahi et al., 2012b).
Chronic periodontitis
Curcumin, being a well-known anti-inflammatory agent, can be used to develop an effective preventive and treatment approach for chronic periodontitis. A comparative study was conducted to measure the therapeutic efficacy of chlorhexidine (CHX) chips and indigenous curcumin-based collagen as adjuncts to scaling and root planing in the management of chronic periodontitis through nonsurgical procedures. At the end of a 6 month study period, a decrease in plaque and gingival index scores and improved microbiological parameters, probing pocket depth and clinical attachment levels were observed in both CHX chips and curcumin-based collagen-treated patients (Gottumukkala et al., 2014), indicating their beneficial therapeutic effects in the nonsurgical treatment of periodontal disease. Another study carried out by the same group of investigators indicated that 1% curcumin irrigation when used as an adjunct to scaling and root planing had a mild to moderate beneficiary effect (Gottumukkala et al., 2013). In addition, 1% curcumin solution was found to cause a better resolution of inflammatory symptoms, in cases of chronic periodontitis (Suhag et al., 2007). Thus, based on the results of other experiments, a local drug-delivery system comprising 2% whole turmeric gel, which exerts high activity, can be used as an adjunct to scaling and root planing in the treatment of periodontal pockets (Behal et al., 2011).
Gingivitis
Gingivitis is one of the most common inflammatory periodontal diseases that affect more than 80% of the world's population (Pulikkotil and Nath, 2015). Curcumin therapy holds high potential as a treatment of gingivitis. As an anti-inflammatory, curcumin mouthwash was found to be almost as good as CHX and hence it may act as an efficacious adjunct to mechanical periodontal therapy (Muglikar et al., 2013). Similarly, the anti-inflammatory potential of topical curcumin was found to be comparable with that of CHX-MTZ and higher than CHX in affecting the levels of IL-1β and CCL28 (Pulikkotil and Nath, 2015). Besides curcumin, in another clinical study turmeric mouthwash was found to be useful as an adjunct to mechanical plaque control methods in the prevention of plaque and gingivitis (Waghmare et al., 2011).
Oral mucositis
Oral mucositis is a commonly occurring problem in cancer therapy. Several in vivo studies have shown that curcumin can avert oral mucositis. In clinical settings as well, a pilot study was undertaken to measure the tolerability and efficacy of a curcumin mouthwash against oral mucositis in paediatric patients receiving doxorubicin-based chemotherapy. Curcumin mouthwash resulted in decreased inflammatory scores, and the study documented no adverse reactions in the patients (Elad et al., 2013).
Oral lichen planus (OLP)
Oral lichen planus (OLP) is a chronic, mucocutaneous, immunological disease. Curcuminoids were assessed for their efficacy against OLP and found to be well tolerated (Chainani-Wu et al., 2007). Another study performed by the same group suggested curcuminoids at doses of 6000 mg·day−1 in three divided doses to be well tolerated and might be of use in regulating the signs and symptoms of OLP (Chainani-Wu et al., 2012b). Furthermore, in another controlled trial conducted with 53 patients, administration of 6000 mg·day−1 curcuminoids reduced the symptoms of OLP in 60% of the patients (Chainani-Wu et al., 2012a).
Chronic pulmonary complications
Pulmonary complications are major and frequent chronic problems of SM intoxication. Curcuminoids were found to suppress systemic inflammation in patients with chronic pulmonary complications induced by SM. This anti-inflammatory effect of curcuminoids was found be mediated through the modulation of inflammatory mediators such as IL-6, IL-8, TNF-α, TGFβ, substance P, hs-CRP, CGRP and MCP-1. Curcuminoids were also found to be safe and well tolerated throughout the trial (Panahi et al., 2015b).
Chronic kidney disease
Chronic kidney disease (CKD) is characterized by reduced kidney function, enhanced inflammation and decreased antioxidants. To evaluate the effect of curcumin against CKD in humans, a study was conducted with 16 patients. A herbal supplement composed of C. longa and Boswellia serrata or placebo was given to non-dialysis CKD patients and plasma levels of IL-6, TNF-α, glutathione peroxidase and serum CRP were measured. Curcumin was found to be safe and well tolerated and helped to reduce the levels of the inflammatory cytokine IL-6 (Moreillon et al., 2013).
Gastritis
Gastritis is caused by the production of an array of inflammatory cytokines induced by Helicobacter pylori infection in the stomach. A study conducted among H. pylori-infected gastritis patients by Koosirirat and colleagues evaluated the effect of curcumin on the production of IL-8, IL-1β, TNF-α and COX-2 in gastric mucosa. However, curcumin was ineffective at decreasing the production of these cytokines, which indicates it has a limited effect on H. pylori-induced inflammatory cytokine production. Nevertheless, other studies have reported that the symptoms of these patients with gastritis were ameliorated by the curcumin treatment (Koosirirat et al., 2010).
Inflammatory bowel disease
Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis (UC), is a type of chronic and relapsing disorder characterized by inflammation of the gastrointestinal tract (Aguas et al., 2016). Although, mortality due to IBD is not very high, it still presents a major healthcare burden. It damages the patient's quality of life to a considerable extent due to its onset in early adulthood and chronicity (Simian et al., 2016). It enhances the risk of colorectal cancer and possibly is also associated with leukaemia and lymphoma (Wheat et al., 2016).
Considering the well-established anti-inflammatory potential of curcumin, a pilot study was conducted to obtain a probable dosage of curcumin for children suffering from IBD. Curcumin was well tolerated, but a consistent increase in gassiness was reported in some patients. However, other patients showed an improvement in the symptoms of the disease (Suskind et al., 2013).
Crohn's disease
Crohn's disease is an immune-mediated IBD, which has become increasingly prevalent throughout the past decade (Lauro et al., 2016; Manuc et al., 2016). A pilot study was conducted with Crohn's disease to determine the effect of curcumin, as an addition to the existing treatments, in decreasing inflammation. This was done by reducing the doses of the other concomitant anti-inflammatory agents. Out of five patients, four showed lower Crohn's Disease Activity Index scores and sedimentation rates (Holt et al., 2005), indicating that curcumin has potential at ameliorating inflammatory Crohn's disease.
Ulcerative colitis (UC)
UC is a commonly occurring inflammatory disease and the usefulness of curcumin in the experimental models of UC has been well demonstrated. Its efficacy was investigated in a pilot study where it was evident that use of NCB-02 (a standardized curcumin preparation) as an enema caused greater improvements in disease activity in distal UC patients (Singla et al., 2014). In another trial, curcumin improved both the clinical activity index and endoscopic index and in turn suppressed the morbidity linked with UC. Therefore, curcumin could be an important, safe and effective alternative treatment for maintaining remission in quiescent UC patients (Hanai et al., 2006; Lang et al., 2015).
Osteoarthritis (OA)
The management of osteoarthritis remains a challenge and hence a safe and efficient treatment modality is much in demand. Several in vitro studies have demonstrated the beneficial effects of curcumin on cartilage in OA. Hence, a handful of clinical trials were undertaken (Henrotin et al., 2014). Panahi et al. showed that treatment with curcuminoids (1500 mg·day−1 in three divided doses) of OA patients resulted in a reduction in pain and physical function scores but not the stiffness score OA index. Thus, curcuminoids present a safe and highly efficacious treatment choice for OA (Panahi et al., 2014b). Another study also reported the efficacy of curcumin in the treatment of knee OA patients as evinced through the decrease of a cartilage specific biomarker, Coll2-1 (Henrotin et al., 2014). In addition, adjuvant therapy of curcumin with diclofenac has exhibited advantageous outcome in the treatment of primary knee OA (Pinsornsak and Niempoog, 2012). In addition, turmeric extract has also shown to be safe and effective in reducing the pain and improving the function of OA patients. In a study conducted with 367 patients, administration of Curcuma domestica extracts (1500 mg·day−1 for 4 weeks) resulted in improved osteoarthritis index, and its efficacy was found to be quite comparable with that of ibuprofen (Kuptniratsaikul et al., 2014).
To improve the efficacy of curcumin, different formulations have been used for the treatment of OA patients. Theracurmin® (manufactured by Theravalues Corporation, Kioicho, Tokyo, Japan) was used by the Nakagawa and group to evaluate its improved efficacy in the treatment of patients with knee OA. Theracurmin was shown to be effective against knee OA by lowering the knee pain visual analogue scale without causing any major toxic effects (Nakagawa et al., 2014). Another formulation Meriva, a complex of curcumin with soy phosphatidylcholine, has been found to be highly effective in the clinicomanagement of OA. The report also suggested the enhanced stability and improved absorption of curcumin taken in this form, as well as improvements in the clinical and biochemical end points in OA patients (Belcaro et al., 2010b; 2014).
Peptic ulcer
Peptic ulcer is a multifactorial disease, the complications of which remain a major challenge (Farzaei et al., 2015). There is much evidence suggesting that curcumin could play a pivotal role in the management of such ulcers. Henceforth, a phase II clinical trial to measure the effect of turmeric on the healing of peptic ulcers was performed. A few patients showed a complete absence of ulcers after the 8 weeks of treatment, whereas others did not have ulcers after 12 weeks (Prucksunand et al., 2001), indicating its great efficacy against this disease.
Rheumatoid arthritis (RA)
Curcumin has displayed potent antiarthritic effects. A pilot clinical study investigated the safety and efficacy of curcumin in active rheumatoid arthritis patients and it showed an improvement in overall DAS (disease activity score) and ACR (American College of Rheumatology) scores. The safety and superiority of curcumin treatment was well evidenced (Chandran and Goel, 2012). Moreover, the curcumin treatment was also found to reduce the stiffness and swelling in the joints of patients with RA (Hanai et al., 2006).
Curcumin for metabolic disease
Curcumin have also been shown to be very effective in the management of different metabolic diseases such as diabetes and obesity.
Diabetes
Diabetes is a cluster of metabolic diseases associated with high blood sugar levels. Several pilot studies have been carried out in human participants with curcumin to measure its effect on diabetes and associated metabolic conditions. The first study of this kind showed that curcumin could effectively lower the blood sugar levels in diabetic patients. Treatment with turmeric powder resulted in a decrease in fasting blood sugar from 1400 to 700 mg·L−1 in a patient suffering from diabetes for 16 years (Srinivasan, 1972). The intake of curcuminoids exerted a favourable effect on endothelial dysfunction along with a reduction in cytokines and markers of oxidative stress (Usharani et al., 2008). Another trial advocated curcumin's potential in delaying the development of type 2 diabetes mellitus. It ameliorated beta cell functions, elevated HOMA-β and reduced C-peptide levels (Chuengsamarn et al., 2012). The same group also reported that the intake of curcumin could reduce atherogenic risks and amend the metabolic profiles of high-risk populations (Chuengsamarn et al., 2014). Similarly, in overweight/obese type 2 diabetic patients, curcuminoids lower blood glucose levels (Na et al., 2014). Furthermore, Meriva was shown to be effective in the management of diabetic microangiopathy and retinopathy (Appendino et al., 2011; Steigerwalt et al., 2012). In a recent study, it was found that curcumin treatment improved the skeletal muscle atrophy in type 1 diabetic mice through inhibition of protein ubiquitination, inflammatory cytokines and oxidative stress (Ono et al., 2015). Another initial study indicated that a novel, chemically-modified curcumin was able to normalize wound-healing in diabetes I-induced rats by reducing the excessive collagenase-2 as well as MMP-13/collagenase-3 (Zhang et al., 2016).
Obesity
Obesity is a global health problem and is a condition where the excess fat accumulates and exerts a negative impact on health (Ganjali et al., 2014). Curcumin has proven its effectiveness in obese patients too. It reduces the symptoms of anxiety and depression associated with obesity (Esmaily et al., 2015). Curcumin modulates circulating levels of IL-1β, IL-4 and VEGF, thus exhibiting an immunomodulatory effect and also reduces oxidative stress in obese patients (Sahebkar et al., 2013; Ganjali et al., 2014).
Curcumin for neurological disease
The effect of curcumin was also studied in neurological disorders such as Alzheimer's disease and depression in humans.
Alzheimer's disease
Alzheimer's disease is a progressive neurodegenerative disorder, usually affecting people older than 65 years. A randomized, double-blind, placebo-controlled study enrolled 34 patients with Alzheimer's disease and randomly administered curcumin at two different doses (1 or 4 g) or placebo (4 g). The curcumin treatment resulted in elevated levels of vitamin E without causing any adverse reactions through the antioxidant effects of curcuma (Baum et al., 2008; Gupta et al., 2013b).
Depression
Depression is a disorder in which many dysregulated pathways have been identified. As curcumin is known to target many pathways, its effect on depression has also been studied and it was observed that treatment with curcumin altered the biomarkers of depression and also improved the mood of the patients (Lopresti et al., 2014; Lopresti et al., 2015). A study conducted by Sanmukhani et al. confirmed curcumin to be effective and safe for the treatment of patients with major depressive disorder without concurrent suicidal ideation or other psychotic disorders (Sanmukhani et al., 2014). In another randomized, double-blind, placebo-controlled study, it was observed that 4 to 8 weeks of treatment with curcumin was effective at improving several mood-related symptoms in these patients (Lopresti et al., 2014). Subsequently, the same group demonstrated that curcumin supplementation affected several biomarkers such as thromboxane B2, substance P, aldosterone, cortisol, endothelin-1 and leptin, which might be responsible for its antidepressant effect (Lopresti et al., 2015).
Curcumin for skin diseases
Curcumin has also been shown to be very effective against various skin diseases such as psoriasis and vitiligo.
Psoriasis
Psoriasis is an autoimmune disorder characterized by patches of abnormal skin. In a clinical trial, curcumin was found to exhibit an antipsoriatic effect by altering PhK activity (Heng et al., 2000). Recently, in a randomized, double-blind, placebo-controlled clinical trial, patients treated with the curcumin formulation, Meriva, showed reduced disease conditions. It also increased the anti-psoriatic effects of topical steroids in these patients when treated in combination. Thus, it was highly effective as an adjuvant therapy against psoriasis vulgaris and, notably, caused a reduction in serum levels of IL-22 (Antiga et al., 2015). Moreover, the safety and efficacy of curcumin was documented in a phase II, open-label, Simon's two-stage trial where the plaque psoriasis patients received 4.5 g of oral curcuminoid C3 complex daily. The intention-to-treat analysis response rate was found to be 16.7%, and none of the participants had to withdraw from the study due to associated adverse events (Kurd et al., 2008).
Dermatitis
A randomized, double-blind, placebo-controlled clinical trial has been conducted to investigate curcumin's potential at reducing the severity of radiation-associated dermatitis in 30 breast cancer patients. A decrease in the severity of radiation dermatitis was observed in those patients receiving 6 g·day−1 curcumin p.o. during their radiotherapy sessions (Ryan et al., 2013).
Vitiligo
Vitiligo is a chronic skin condition characterized by loss of pigmentation of the skin. The beneficial effect of curcumin on vitiligo has been demonstrated by Asawanonda and Klahan (2010); treatment with narrow band UVB plus topical tetrahydrocurcuminoid cream was found to be effective and well tolerated (Asawanonda and Klahan, 2010).
Curcumin for infectious diseases
Curcumin has also been shown to be effective in the treatment of various infectious diseases in humans.
Acquired immunodeficiency syndrome
Acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV), which interferes with and weakens the immune system. A clinical trial from New England evaluated the effectiveness of curcumin as an antiviral agent in 40 AIDS patients. The patients were allotted to either a high dose group (2.5 g·day−1) or a low-dose group in a random fashion for the treatment of 8 weeks. Though statistically insignificant, a mild increase in CD4 cells was observed in the high-dose group and a consistent decrease in the low-dose group. However, no evidence was obtained related to a decrease in viral load (James, 1996).
Curcumin for liver diseases
Curcumin exhibits effects against different liver diseases such as hepatitis B, hepatitis C, alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced hepatotoxicity, liver cancer, biliary cirrhosis and primary sclerosing cholangitis. The antioxidant and inhibitory effects of curcumin on NF-κB play a vital role in its effect against a diverse range of hepatic diseases (Nanji et al., 2003, Rivera-Espinoza and Muriel, 2009, Nabavi et al., 2014). Curcumin was shown to reduce the liver damage in several animal models of liver injury (Bruck et al., 2007). The herbal formulation comprising of C. longa and Tinospora cordifolia was found to prevent anti-tuberculosis treatment-induced hepatotoxicity significantly without causing any toxic effects (Adhvaryu et al., 2008).
Other diseases
The multitargeting potential of curcumin is extended to many other diseases as well like arsenic carcinogenicity and dyspepsia. Curcumin with its intrinsic antioxidant properties could limit the toxic effects associated with arsenic (Biswas et al., 2010). It also inhibits exercise-induced oxidative stress in humans and reduces the severity of premenstrual syndrome in women by modulating the levels of neurotransmitters and anti-inflammatory biomolecules (Takahashi et al., 2014; Khayat et al., 2015). Administration of curcuminoids to β-thalassemia/Hb E patients reduces oxidative damage (Kalpravidh et al., 2010). Furthermore, curcumin increased the quality of life in a 15-year-old Caucasian girl with Déjérine–Sottas (Burns et al., 2009). It also improves the post-operative outcomes of patients who have undergone laparoscopic cholecystectomy (Agarwal et al., 2011). A randomized controlled trial demonstrated that curcumin, due to its anti-inflammatory effects, can combat pruritus and improve the quality of life of these patients (Panahi et al., 2012a). Moreover, oral administration of curcumin suppresses the symptoms of lupus nephritis – inflammation of the kidney (Khajehdehi et al., 2012), and significantly reduces the paraprotein (a monoclonal protein) levels in the blood of patients with monoclonal gammopathy of undetermined significance (MGUS) (Golombick et al., 2009). In another study, curcumin slowed the disease progression of patients with MGUS and smouldering multiple myeloma (Golombick et al., 2012).
Synergy of curcumin with other nutraceuticals in the clinic
To attain an improved therapy with better efficacy and less toxicity, the effects of curcumin when used in combination with other safe agents have been investigated. Several clinical trials have attempted to explore the feasibility and tolerability of the combination of curcumin with various nutraceuticals. For example, oral curcumin with piperine can reverse lipid peroxidation efficiently in patients with tropical pancreatitis (Durgaprasad et al., 2005). Cruz-Correa's group have evaluated the effect of a combination therapy of curcumin and quercetin to reduce adenomas in patients with familial adenomatous polyposis. The combined treatment caused a decrease in the number and size from baseline of polyps with negligible adverse reactions and no laboratory abnormalities (Cruz-Correa et al., 2006). Rafailov and group conducted a phase I trial to evaluate the effect of a herbal preparation containing curcumin, known as ‘Zyflamend’, against prostatic intraepithelial neoplasia (PIN). The biopsy revealed benign prostatic hyperplasia alone at the end of 6 months, and after 18 months, the biopsy was negative for cancer and PIN (Rafailov et al., 2007; Sung et al., 2012). The application of Indian turmeric with honey is highly effective as a complementary therapy for oral mucositis (Francis and Williams, 2014). Moreover, Oxy-Q bioflavonoid therapy with curcumin and quercetin improves the early graft function in dialysis-dependent cadaveric kidney recipients (Shoskes et al., 2005). Likewise, in a cohort of 311 patients, Cinarepa, a mixture of various phytochemicals, including curcumin, chlorogenic acid, inulin and rosemary bud essential oil, was shown to suppress the symptoms of functional dyspepsia significantly (Sannia, 2010).
Curcumin has not only been combined with other natural compounds but also with different therapeutic drugs. In a prospective randomized study, the therapeutic effect of quercitin and curcumin (FlogMEV) in combination with prulifloxacin was assessed in chronic bacterial prostitis patients, and FlogMEV was found to improve the clinical efficacy of prulifloxacin (Cai et al., 2009). The efficacy of another 7-day non-antibiotic therapy, comprising curcumin, lactoferrin, N-acetylcysteine and pantoprazole, at eradicating H. pylori infection and reducing gastric inflammation has also been determined. However, this therapy was not particularly effective (Di Mario et al., 2007). Nevertheless, curcumin has been found to have high potential against different diseases either alone or in combination with other agents. In addition, there are more than 100 ongoing clinical trials of curcumin (Table 3); the findings of these clinical trials can be anticipated to be of immense help in providing a better understanding of curcumin's potential and its future prospects in the clinicomanagement of various human diseases.
| Disease | Dose | Pts | Phase | Affiliation | Start date |
|---|---|---|---|---|---|
| Safety and tolerability | |||||
| Healthy individuals | 2, 4 gb | 12 | I | Gary N Asher; UNC-CH USA | Mar 2011 |
| 500 mg | 23 | 0 | Jan Frank; UHOH, Germany | Oct 2011 | |
| 2790 mg·day−1; 18 months | 132 | II | Gary Small; UC, LA | Mar 2012 | |
| 80 mga | 23 | 0 | Jan Frank; UHOH, Germany | Nov 2012 | |
| NAa | 12 | I | Tetyana Pelipyagina; KGK Synergize | Apr 2015 | |
| Cancer | |||||
| ADH | 50 and 100 mg; 3 months | 30 | – | Lisa Yee; OSU, USA | June 2013 |
| Breast cancer | 500 mg | 2 | II | Andrew Mille; Emory University, USA | May 2015 |
| Curcumin gel; 4–6 ha | 180 | II | Gary Morrow, URCC NCORP | Oct 2015 | |
| Cancer | 200 mg·day−1; 28 days | 28 | I | David Hong; MDACC USA | Oct 2011 |
| 100–300 mg·m2−1; 8 weeksa | 28 | I/II | Richard Greil; Internistische Onkologie | Mar 2014 | |
| NAb | 40 | I | Aminah Jatoi; Mayo Clinic | Mar 2016 | |
| CIN | 1000 mg·day−1; 12 weeks | 14 | 0 | Carolyn Matthews; Texas Oncology | Mar 2016 |
| Colon cancer | NAb | 100 | III | Arie Figer; TASMC, Israel | Mar 2006 |
| 4 g·day−1; 30 daysa | 40 | I | Gary Asher; UNC-CH, USA | Nov 2010 | |
| NA; 7 daysb | 35 | I | Donald Miller; JGBCC, USA | Jan 2011 | |
| 2–4 g·day−1; 6yearsb | 51 | I/II | William Steward; UHL, UK | Feb 2012 | |
| 1–4 g·day−1; 4 daysb | 20 | I | Gary Asher; UNC-CH, USA | Jun 2013 | |
| 0.5,1 g·day−1; 28 daysa,b | 100 | II | Andrea DeCensi; Ente Ospedaliero Ospedali Galliera | Mar 2014 | |
| 100 mg·day−1b | 44 | II | Jeong-Heum Baek; Gachon University | May 2015 | |
| 1000 mg·day−1; 2 weeksb | 14 | 0 | John Preskitt; Texas Oncology, PA | Mar 2016 | |
| EC | 2 g·day−1; 2 weeksa | 10 | II | Frederic Amant; UZ, Belgium | Oct 2013 |
| Glioblastoma | NA | 15 | 0 | Stephan Duetzmann; Goethe University Germany | Oct 2012 |
| H&NC | 8 g·day−1; 21–28 days | 33 | 0 | Cherie-Ann Nathan; LSUHSC, USA | Jun 2010 |
| Lymphoma | NAb | 35 | II | Paolo Caimi Case; CCC, USA | Sep 2014 |
| Osteosarcoma | Curcumin powder | 24 | I/II | Manish Agarwal; TMH, India | May 2008 |
| NSCLC | 80 mg·day−1; 8 weeksa,b | 20 | I | Victor Cohen; LDI, Canada | Aug 2015 |
| Pancreatic cancer | NAb | – | III | Arber Nadir; TAU, Israel | Jun 2005 |
| Prostate cancer | NAb | 100 | II | Centre Jean Perrin | Mar 2014 |
| 120 mg·day−1; 3 daysa,b | 64 | II | Abolfazl Razzaghdoust; SBUMS, Iran | Mar 2016 | |
| Rectal cancer | 8 g·day−1b | 45 | II | Sunil Krishnan; MDACC, USA | Aug 2008 |
| Cardiovascular disease | |||||
| CVD | NAa | 21 | – | Anwar Tandar; University of Utah,USA | Jun 2013 |
| MS | 240 mg·day−1; 6 weeks | 42 | II | Jan Frank; UHOH, Germany | Jul 2013 |
| Inflammatory diseases | |||||
| RA | 1–2 × 4 cap·day−1; 2 weeks | 40 | 0 | Dinesh Khanna;UC, USA | Jan 2010 |
| 2 and 4 g·day−1; 1 montha | 45 | I | Janet Funk; UA, USA | Nov 2015 | |
| Crohn's disease | 3 g·day−1; 6 monthsb | 122 | III | Gilles Bommelaer; UCF, France | Dec 2014 |
| FAP | 2 × 3 pills·day−1; 12 months | 50 | – | Cruz-Correa; UPR, Puerto Rico | Nov 2007 |
| NA; 12 months | 50 | II | Francis Giardiello; NCI, USA | Oct 2010 | |
| Bowel syndrome | Coltect; 4 weeksa | 40 | II | Timna Naftali; TAU, Isreal | Apr 2011 |
| CP | 2 times; 4 weeks | 100 | IV | Agarwal; TKDC, India | Jan 2014 |
| Mucositis | 0.33–3 g·day−1; 4–6 weeks | 38 | I and II | Dhimant Patel; ABMC, USA | Feb 2015 |
| OSMF | Curcumin gel | 30 | II | SVSIDS; India | Dec 2013 |
| Orthodontis | Mouthwashb | 24 | I | Vitor H Panhóca; USP, Brazil | Jan 2014 |
| Osteoarthritis | 2 × 3 caps ·day−1; 3 monthsb | 22 | 0 | Caroline Castermans; CHL, Belgium | Mar 2012 |
| UC | 2 × 2 tab ·day−1; 2 months | 30 | – | Iris Dotan; TASMC, Israel | Nov 2008 |
| Curcumin capsules | 60 | III | Amit Assa; SCMCI, Israel | Sep 2016 | |
| 50–100 mg; 2 weeksb | 50 | III | Rupa Banerjee; AIG, India | Feb 2016 | |
| Metabolic disease | |||||
| Diabetes | 2 cap·day−1; 6 months | 70 | – | Alan Chous; Chous Eye Care Associates, USA | May 2012 |
| 500 mg | 50 | II/III | NNFTRI, Iran | Jul 2015 | |
| Neurological disease | |||||
| Alzheimer's disease | 2 or 3 g·day−1 | 26 | II | Fali Poncha ; JHRC, India | Oct 2009 |
| 800 mg·day−1 ; 6 monthsb | 80 | II | Sally Frautschy; VAORD, USA | Jan 2014 | |
| Schizophrenia | 720 mg·day−1 | 36 | I/II | Michael Davis; VAGLAHS, USA | Jul 2014 |
| 3 g·day−1; 6 months | 40 | IV | Vladimir Lerner; BMHC, Isreal | Jan 2015 | |
| 1200 mg·day−1; 8 weeks | 40 | II | Cenk Tek; Yale University, USA | Jan 2016 | |
| Skin disease | |||||
| Psoriasis | E2 per day; 28 daysa | 21 | I | Elorac, Inc. USA | Sep 2014 |
| Other | |||||
| AAA | 2 g·day−1; 2 days | 3500 | II | Amit Garg; LHRI, Canada | Nov 2011 |
| ADPKD | 25 mg·kg−1·day−1; 1 year | 68 | IV | Kristen Nowak; CU, USA | Nov 2015 |
| Bipolar disorder | 0.5–2 g·day−1; 3–8 weeks | 30 | II | Benjamin Goldstein; SHSC, Canada | Sep 2013 |
| Erectile dysfunction | 12 g·day−1; 8 weeksa | 44 | IV | Hyun Jun Park; PNUH, South Korea | Feb 2012 |
| ESRD | 3 cap·day−1; 8 weeks | 48 | I/II | SUMS, Iran | Apr 2011 |
| Fibromyalgia | 5 weeksa | 40 | – | Grégoire Cozon; HCL, France | Nov 2011 |
| H. Pylori infection | NAb | 150 | – | Gingold Rachel; RMC, Israel | Jan 2014 |
| Hyper prolactinoma | NA | 30 | I | Mashhad University of Medical Sciences | July 2011 |
| Inflammation | 2 capsulesb | 22 | – | Charles Couillard; LU, Canada | Oct 2013 |
| Kidney allografts | 2 mL of 12 mg·mL−1a,b | 20 | I | Kaija Salmela; HUCH, Finland | Jan 2011 |
| Kidney disease | 90 mg·day−1; 6 months | 750 | III | Matthew Weir; LHRI, Canada | Sep 2015 |
| Migraine | 4 g·day−1; 2 months | 80 | IV | TUMS, Iran | Sep 2015 |
| Multiple sclerosis | 1 g·day−1 | 2780 | II | Merck KGaA; Germany | Apr 2012 |
| NAFLD | NAa | 150 | – | Giovanni de Gaetano; Neuromed IRCCS | May 2015 |
| Prostatectomy | 1 g·day−1; 6 months | 600 | II | Yair Lotan; UTSW, USA | May 2014 |
| Proteinuria | NA | 120 | III | Magdalena Madero; Inst Nacional de Cardiología | Feb 2013 |
| Vascular ageing | 500–2000 g·day−1 | 118 | – | Douglas Seals; CU, USA | Jun 2013 |
| Vascular reactivity | – | 21 | I/II | Jean-René LUSSON; UCF, USA | Feb 2012 |
| Vascular stiffness | 200 mg·day−1 ; 7 days | 40 | I | Jamie Burr; UPEI, Canada | Nov 2014 |
- a Curcumin formulation.
- b Combination.
- AAA, abdominal aortic aneurysm; ACF, aberrant crypt foci; ADH, atypical ductal hyperplasia; ADPKD, autosomal dominant polycystic kidney disease; CIN, cervical intraepithelial neoplasia; CP, chronic periodontitis; CVD, cardiovascular disease; EC, endometrial carcinoma; ESRD, end-stage kidney disease; FAP, familial adenomatous polyposis; H&NC, head and neck cancer; MDS, myelodysplastic syndrome; MS, metabolic syndrome; NA, not available; NAFLD, non-alcoholic fatty liver disease; NSCLC, non-small cell lung cancer; OLP, oral lichen planus; OSMF, oral submucous fibrosis; RA, rheumatoid arthritis; T2D, type 2 diabetes; UC, ulcerative colitis.
Conclusions
There is an abundance of preclinical and clinical evidence indicating that curcumin has potential as a therapy for a wide variety of chronic diseases including cancer, cardiovascular, inflammatory, metabolic, neurological and skin diseases, and various infectious diseases. Unlike most pharmaceutical drugs, curcumin modulates multiple targets that affect different diseases. Safety, efficacy and affordability are some of the added advantages exhibited by this compound. There are also increasing lines of evidence suggesting it has a potent chemosensitizing effect in various cancers. Nevertheless, a few studies have reported that curcumin can function as an antagonistic as well. However, its therapeutic efficacy is hindered to a certain extent by its low bioavailability. Therefore, various strategies are being implemented, which include the development of curcumin analogues and formulations such as adjuvants, nanoparticles, liposomes, micelles and phospholipid complexes, to improve its bioavailability. In addition, several other approaches have been employed to enhance its bioavailability, which include altering the route of administering curcumin and obstructing the metabolic pathways via co-treatment with other agents. Therefore, more detailed and well-controlled clinical trials are inevitable to evaluate the efficacy of these new formulations as compared with the parental compound. Thus, the results of these further investigations are likely to increase the bioavailability, therapeutic importance and application of curcumin and make this agent a cutting edge therapeutic strategy for the prevention and treatment of a variety of chronic diseases.
Author contributions
B.B.A. and A.K. contributed to the study design and writing. D.B., G.P., J.M. and N.K.R. performed bibliographic search and artwork. S.P. contributed to proofreading and writing.
Conflict of interest
The authors declare no conflicts of interest.
