Multifunctional Curcumin Mediate Multitherapeutic Effects

Molecular targets of curcumin action

Several findings have demonstrated that curcumin binds to different molecular targets and affects cell-signaling pathways. Curcumin is highly anti-inflammatory compound and interacts with pro-inflammatory chemokines and cytokines. It is an important inhibitor of myeloid differentiation protein 2, alpha 1-acid glycoprotein, various enzymes including xanthine oxidase, histone acetyltransferases, lipoxygenase (LOX), cyclooxygenase (COX), inducible nitric oxide synthase (iNOS), histone deacetylases, human immunodeficiency virus type 1 protease and integrase, DNA methyltransferases and -polymerase, protein reductases and kinases (glycogen synthase kinase [GSK-3β], protein kinase C [PKC], phosphorylase-3 kinase, focal adhesion kinase [FAK]), aldose reductase, thioredoxinreductase, and antiapoptotic proteins including B-cell lymphoma 2 (Bcl2), and B-cell lymphoma-extra-large (Bcl-xL). Curcumin has also the ability to inhibit cytokines like interleukins IL-1, IL-2, IL-6, IL-8, IL-12, tumor necrosis factor-alpha (TNF-α), mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinases (JNK), and can bind directly with DNA, RNA, proteins (immunoglobulin, albumins, caseins, and divalent metal ions (copper, iron, zinc, and manganese; Shehzad and others 2012, 2013a, 2013b; Gupta and others 2011). Various transcription factors binds indirectly to curcumin including activator protein-1 (AP-1), β-catenin, peroxisome proliferator-activated receptor gamma (PPARγ), and signal transducer and activator of transcription (STAT) proteins (Shehzad and others 2010). It has been shown that curcumin prevents nuclear factor-kappa B (NF-κB) recruitment by downregulating matrix metalloproteinases (MMPs) secretions expressions of carboxylases and apoptosis inhibiting proteins like caspase-3 and Bcl-2 family proteins Bcl2 and Bcl-xLin culture of human tenocytes (Buhrmann and others 2011). Curcumin has also been found to suppress vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 (iCAM-1) expression by inhibiting TNF-α, monocyte chemoattractant protein-1 (MCP-1), IL-6, IL-8, and NF-κB activation in human ectopic inflammatory endometriotic stromal cells (Kim and others 2012ab). It reduces the levels of inflammatory markers macrophage inflammatory protein 1-alpha (MIP-1α), COX-2, 5-LOX, adhesion molecules, and C-reactive protein (CXCR-4; Julie and Jurenka 2009). Curcumin has been found to promote the expression of p53, p21, Bax, and reactive oxygen species (ROS), resulting in decrease in mitochondrial membrane potential (Goel and Aggarwal 2010).Thus, broad range modulation of molecular targets provide molecular basis for the therapeutic action of curcumin against wide range of diseases.

Curcumin health effects

Curcumin therapeutic effects include its efficacy against numerous diseases like asthma, scleroderma, IBD, psoriasis, rheumatoid arthritis, neurodegenerative diseases, renal ischemia, and cancers. The therapeutic potential of curcumin in various diseases has been summarized under the following headings.

Cancers

According to centers for disease control and prevention (CTC), 14.1 million new cases have been diagnosed in 2012 and it is expected to increase to 19.3 million by 2025 (Torre and others 2015). Cancer is a multifaceted disease characterized by gradual accumulation of gene mutations at genetic and epigenetic level followed by abnormal cell proliferation and growth. In all cancer types, inflammation is a major component of initiation and progression. Curcumin's anti-inflammatory and anticancer activity has wide range of therapeutic effect in various cancers. Studies have shown that curcumin interacts with multiple molecular targets and effective against various cancers including gastric cancer, colorectal cancer, breast cancer, hepatic cancer, intestinal cancer, pancreatic cancer, kidney cancer, bone cancer, and brain cancer (Padhye and others 2009). Curcumin has the ability to inhibit pro-inflammatory enzymes including COX-2 and iNOS in colorectal cancers when administered orally (Aggarwal and others 2009). Curcumin inhibits COX-2 activity by direct binding through Ala516, Val116, Val523, and Tyr355, whereas COX-1 activity is blocked by direct binding through Ser15. Curcumin also suppressed COX-2-induced prostaglandin E2 (PGE₂) expression through hydrogen bonding with Ala562 (Aggarwal and others 2009). Furthermore, cytokines, protein kinases, and growth factors play an important role in tumor progression, cell proliferation, and transformation. Curcumin has been shown to suppress inflammatory cytokines including vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2) oncoprotein, TNF-α, and IL-1, IL-2, IL-6, IL-8, and IL-12), and the activation of NF-κB (Park and others 2005). T-cell factor (TCF), β-catenin, and lymphoid enhancer factor are well-known targets for many anticancer agents which can be targeted using curcumin by overexpressing TCF-4 in cancer cell lines and by decreasing nuclear translocation of β-catenin (Shehzad and others 2010). Curcumin treatment also suppressed MMP-2, -9, and -14, STAT-3, and NF-κB as well as downregulated expression of chemokine CC motif ligand 2 (CCl2), which are associated with tumor growth, invasion, and metastasis (Sa and Das 2008). Curcumin has been shown to induce apoptosis by modulating Bax/Bcl-2 with generation of ROS with an enhancement of TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis. Induction of poly-ADP ribose polymerase (PARP) cleavage and activation of caspase-7, caspase-9 by downregulation of inflammatory markers, inhibition of PKC, epidermal growth factor (EGF)-receptor tyrosine kinase, association of cyclin D1 with cyclin-dependent kinase 4/6 (CDK4/CDK6), downregulation of protein activated kinase 1 (PAK1), and phosphorylation of CDK-mediated retinoblastoma protein (pRb) have been shown to suppress cancer cell proliferation (Shehzad and others 2013ab).

In a randomized double-blind placebo-controlled parallel group trial has shown that an adjunctive therapy with curcumin improves the symptoms in patients of dyspepsia and peptic ulcer (Khonche and Biglarian 2016). Phase I and II study revealed that combination therapy of gemcitabine based chemotherapy and 8 g oral curcumin is proved feasible and safe in patients with pancreatic cancer (Kanai and others 2011). Another phase II clinical trial on 25 patients with advanced pancreatic cancer has also confirmed the safety and efficacy of curcumin despite its low biological absorption (Dhillon and others 2008). Curcumin also reduced the sensitivity of radiation dermatitis in breast cancer patients receiving radiotherapy as observed in a randomized, double-blind, placebo-controlled clinical trial on 30 patients. About 95% patients show the adverse effect of radiotherapy in the form of radiation dermatitis. Curcumin significantly alleviated the symptoms of radiation dermatitis in cancer patients (Ryan and others 2013). Phase I trial on women with cervical neoplasia has shown that intravaginal curcumin is safe and well tolerated. Dose-escalation phase I trial was conducted on 13 women patients with age range of 18 to 45 years. No severe adverse effects of curcumin has observed (Gattoc and others 2016). Several phase I and II clinical trials has shown that curcumin inhibits angiogenesis, proliferation, invasion, and metastasis in different cancers by inhibiting various molecular pathways (Kunnumakkara and others 2008). A combination treatment of curcumin with quercetin is also effective in familial adenomatous polyposis (FAP) in 5 patients. A dose of 480 mg curcumin and 20 mg quercetin decreased the size and number of ileal and rectal adenomas in patients as compared with baseline (Cruz-Correa and others 2006). A phase I clinical trial as a dose escalation study is also conducted on 15 patients with colorectal cancer to evaluate the pharmacology of the curcumin. A daily dose of 0.45 to 3.6 g has been given to patients for 4 mo. Its anticancer activity is observed and is related with inhibition of PGE₂ production, induction of glutathione transferase enzymes, and suppression of oxidative DNA adduct formation (Sharma and others 2004).

Diabetes

About 422 million people have been suffering from diabetes worldwide (NCD Risk Factor Collaboration 2016ab). Diabetes is a hyperglycemic metabolic disorder that affects liver, heart, kidneys, and even brain. It is well known that diabetes results as a damage of pancreatic beta cells followed by insulin resistance and hyperglycemia. Diabetes is initiated and progressed by recruitment and execution of different cytokines, transcription factors, and enzymes (Zaccardi and others 2016). Curcumin has many beneficial roles regarding pancreatic cells. Curcumin treatment reduced ROS production and increased viability of islet cells mediated through the inhibition of PARP in streptozotocin (STZ)-induced diabetic mice inhibiting the islet cell damage (Meghana and others 2007; Kanitkar and others 2008). Curcumin also normalized pancreatic glucose transporter 2 (GLUT2) levels, glucose clearance, and cytokine (TNF-α, IL-1β, and interferon-γ)-induced NF-κB translocation by inhibiting phosphorylation of IκBα (Shehzad and others 2011).

Curcumin is anti-inflammatory and anti-oxidant agent, which has the ability to reduce the blood glucose level by suppressing inflammation due to hyperglycemia, stimulating  glucose uptake, activating adenosine monophosphate kinase (AMPK), upregulation of GLUT2, GLUT3, and GLUT4 genes expressions, stimulating insulin secretion from pancreatic tissues, promoting the PPAR ligand-binding activity, reducing insulin resistance, and improving pancreatic cell functioning (Ghorbani  and others 2014). It has been reported that 0.5% administration of curcumin ameliorated the fasting blood glucose, urine volume, and urine sugar in STZ-induced diabetic rats (Chougala and others 2012). In same type of diabetic model, curcumin treatment reduced infiltration of macrophage in the kidneys of diabetic rats, suppressed the expression of proinflammatory cytokines (TNF-α and IL-1β), IκBα degradation, and inhibited NF-κB activity (Soetikno and others 2011). Curcumin treatment suppressed hyperlipidemia by reducing cholesterol levels, free fatty acids, phospholipids, very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) expressions in control and experimental type 2 diabetic rats (Pari and Murugan 2007). Curcumin can prevent oxidative stress-induced liver damage through modulation of anti-oxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and nicotinamide adenine dinucleotide phosphate (Lin and others 2012). Curcumin has been reported to display protective effects against hyperalgesia in diabetic mice by inhibiting TNF-α release in dose-dependent manner and found effective in reducing thermal sensational pain (Mrudula and others 2007). Curcumin also displayed renoprotective effects in diabetic nephropathy (DN) by reducing IL-1β, cleaved caspase-1, and NLR family pyrin domain containing 3 protein in db/db mice (Lu and others 2017). Curcumin inhibited lipid accumulation and oxidative stress in kidneys through activation of AMPK and nuclear factor erythroid 2-related factor 2 signaling in Otsuka–Long–Evans–Tokushima Fatty rats (Kim and others 2016). Curcumin also suppressed the activation of inflammatory gene by reversing phosphorylation of caveolin-1 Tyr(14) that suppressed Toll-like receptors (TLR4) activation (Sun and others 2014. In another study, STZ-induced diabetic rats excreted less creatine, urea, albumin, and inorganic phosphorus when fed with dietary curcumin for a period of 8 wk. This treatment also reduced weight of the liver and products of lipid peroxidation in plasma and urine (Alwi and others 2008).

Diabetic patients have several complications like liver diseases, coronary, and pancreatic dysfunction. Curcumin not only treated diabetes but also improved the adverse conditions. In clinical trials of 63 coronary syndrome patients, oral administration of curcumin for a period of 2 mo reduced total cholesterol level and LDL cholesterol level even with the low doses of 45 mg/d (Premanand and others 2006). Supplementation of curcuminoids decreased fasting blood glucose and insulin resistance index in a completed trial on 100 type 2 diabetic patients, with significant reduction in serum total free fatty acids, triglycerides, and an increase in lipoprotein lipase activity (Na and others 2013).

Obesity

Obesity is one of the serious health problems around the world. Approximately 600 million people are obese worldwide since 2014 (NCD Risk Factors Collaboration 2016a,2016b). It is caused by abnormal increase in weight of the body leading to adverse health issues and overall quality of life. Obesity is also considered the major cause of cancer, type 2 diabetes, liver abnormalities, and cardiovascular disease (CVD; Ahn and others 2010). Studies have shown that curcumin has the ability to inhibit protein expression related to obesity such as Wnt/β-catenin and MAPK, which resulted into upregulation of cyclin D1 and c-MycmRNA levels. Curcumin treatment inhibited GSK-3β, casein kinase 1-alpha, and axin through suppression of β-catenin phosphorylation and extracellular signal–regulated kinases, JNK, and p38 (Ejaz and others 2009). These components are believed to cause the differentiation of 3T3-L1 cells into adipocytes. Curcumin has shown an important role in decreasing angiogenesis and adipogenesis by lowering cholesterol level and suppressing CCAAT/enhancer binding protein alpha and PPAR expression (He and others 2012). Curcumin has also shown beneficial effect in high-fat diet fed C57BL/6J by reducing the expression of lipogenic gene in the liver and the inflammatory response in the adipose tissue (Shao and others 2012). Curcumin treatment suppressed macrophage recruitment in adipose tissue, leptin, and leptin receptor levels in obesity disorder when associated with inflammation (Wang and others 2014).

The effect of curcuminoid supplementation (1 g/d for 30 d) was investigated in 30 obese individuals in a randomized crossover trial. Results have shown significant reduction in serum triglycerides concentrations but there was no significant effect on other lipid profile parameters such as cholesterol, LDL, and HDL (Mohammadi and others 2013).

Cardiovascular diseases

About 17.6 million people died from CVDs worldwide in 2012 (McAloon and others 2016). Atherosclerosis is one of the major inflammatory CVD which involves damage of arterial wall due to oxidative stress, LDL oxidation, and cholesterol deposition leading to the formation of plaques inside the arteries (Bergheanu and others 2017; Förstermann and others 2017).

Curcumin being an anti-inflammatory agent can be used to treat inflammatory atherosclerosis by triggering heme-oxygenase-1 (HO-1) via stimulation of antioxidant responsive element (ARE) and hinders differentiation of endothelial and smooth cells of vessels. In aortic and vascular smooth muscle cells, Curcumin plays anti-inflammatory role by upregulation of p21 and downregulation of TNF-α cells through HO-1 enzyme release (Shehzad and others 2013b). Curcumin was found to protect failure of sensitive heart by enhancing systolic heart function in salt sensitive Dah1 rats (Duan and others 2012). Curcumin has been used for the treatment of myocardial ischemiain Sprague–Dawley rat. Curcumin interacts with JAK/STAT-3 pathway, caspase, and Bcl-2 pathways resulting in decrease in number of apoptotic cardiomyocytes and lactate dehydrogenase release into the coronary flow thus assists in an overall improvement in post-ischemic cardiac function (Kim and others 2012ab). Curcumin has also been reported to prevent damage in abdominal aortic a-neuronal-systemby suppressing AP-1 and NF-κB binding ability to DNA, impedes the release of IL-6 and IL-1ß, and inhibits MMP-9 and MCP-1 in aortic tissues (Morimoto and others 2010).

Neurodegenerative diseases

About 47.5 million people were suffering from dementia worldwide in 2015 and the figure is expected to increase in the near future with 7.7 million new cases every year (Qiu and Fratiglioni 2017). Neurodegenerative diseases are caused by abnormal regulation of noxious proteins and injured neurons. Free radicals cause protein, lipid and DNA damage, tissue injury, inflammation, and cellular apoptosis (Lagouge and Larsson 2013). Increased ROS generation modulates protein expression and highly oxidized proteins endogenously inhibit the proteasomal activity leading to aberrant accumulation of proteins such as ß-amyloid in Alzheimer disease (AD; Follett and others 2016; Höhn and others 2016), huntingtin in huntingtin disease (HD; Bates 2003) and α-synuclein in Parkinson disease (PD; Follett and other 2016), resulting in the progression and development of neurological diseases.

Studies has shown that nanocurcumin has significantly lowered the levels of IL-1β and oxidized proteins in the AD transgenic Tg2576 mouse brain, with considerable decrease in the levels of plaque burden and soluble Aβ peptide (Cheng and others 2013). In 6-hydroxydopamine (6-OHDA) model of PD, curcumin treatment has shown neuroprotective effects by elevating level of antioxidant enzymes such as GPx and SOD, dopamine, and acetylcholine levels and by reducing malonaldehyde (MDA) levels (Song and others 2016). Curcumin treatment in animal model of MS (experimental autoimmune encephalomyelitis) inhibited the development and differentiation of Th17 cells through the downregulation of IL-21, IL-6, STAT-3, and NF-кB phosphorylation (Xie and others 2009). In same MS model, curcumin inhibited apoptosis by protecting mitochondrial damage (Feng and others 2014). Haloperidol administration increases tongue protrusion, facial jerking, and vacuous chewing movements by modulating their antioxidant system. However, curcumin pretreatment showed dose-dependent repressed effects by reducing serotonin, norepinephrine, and dopamine levels in the subcortical and cortical regions in rats (Bishnoi and others 2008).

Curcumin has been shown anti-nociceptive action against neuropathic pain in animal models. In a canonical model of neuropathic pain, chronic construction injury was made by ligating the sciatic nerve in mice. To assess the mechanical allodynia or thermal hyperalgesia, von Frey hair or hot plate test was used, respectively. Oral administration of curcumin (5, 15, and 45 mg/kg) twice a day for 3 wk improved allodynia and thermal hyperalgesia in chronic construction injury by increasing the monoamine metabolite. Reduction of serotonin by p-cholorophenylalanine and chemical removal of descending noradrenaline by 6-hydroxydopamine interfere with the antinociceptive action of the curcumin. ß2-Adrenoreceptor antagonist ICI 118, 551, and delta opioid receptor antagonist naltrindole destruct the curcumin anti-allodynic action. 5HT-1A receptor antagonist WAY 100635 along with the irreversible mu-opioid receptor antagonist ß-funaltrexamine has abolished the curcumin's anti-hyperalgesic action. It is resulted that descending monoamine system along with spinal ß2 adrenoreceptor and 5HT-1A receptors are very crucial for the nociceptive action of curcumin in neuropathic pain (Zhao and others 2012). A 6-mo randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin on Alzheimer's patients has shown its safety and efficacy (Baum and others 2008).

Allergy and bronchial asthma

A total of 25.7 million people globally were suffering from asthma in 2010 (Loftus and Wise 2016). Inflammatory cytokines mediates pro-inflammatory diseases like allergy and asthma. It has been reported that repression of mast cell histamine by using curcumin can provide protection from different allergies (Kurup and others 2007). In curcumin, a functional group of hydroxyl in diferuloyl methane has shown decreased allergic reactions, increased antioxidant levels, and improved constricted airways in allergy and asthma model (Kurup and Barrios 2008).

In mouse model of asthma, curcumin alleviated airway inflammation by reducing goblet cell hyperplasia, inflammatory cells accumulation, and mucous secretion by blocking lipopolysaccharide upregulated expression of TNF-α, IL-6, and IL-1β (Liu and others 2015). Intranasal administration of curcumin in murine model of chronic asthma prevented inflammatory cells accumulation to the airways, structural changes associated with chronic asthma such as thickening of peribronchial and airway smooth muscle and epithelial lining sloughing off (Chauhan and others 2014). Curcumin treatment significantly reduced the inflammation in ovalbumin induced allergic asthma model, by regulating Treg/Th17 balance (Ma and others 2013). Furthermore, in chronic obstructive pulmonary disease (COPD) and asthma, oxidative stress disruption results in the resistance to steroid therapy through the unbalanced acetylation and deacetylation of histone deacetylase and activation of NF-κB. Curcumin scavenges free radicals like O₂ and NO, acting as a powerful antioxidant through decreased activation of NF-κB, MAPK, and downregulates pro-inflammatory mediators like growth factor receptor genes, MMPs, and adhesion molecules in inflammatory lung disease (Biswas and Rahman 2008).

Rheumatoid arthritis and osteoarthritis

Approximately 13 million American and almost 1% of world population is being affected by rheumatoid arthritis (RA). RA is an inflammatory and autoimmune disorder of cartilage and bones causing body joint distortion, demolition, and loss of function (Shiozawa and Tsumiyama 2009). The interaction of environmental and genetic factors starts a cascade of immune reactions in cartilage and bones resulting in body joint distortion, demolition, and loss of function (Gibofsky 2012). Osteoarthritis is the most common form of arthropathy that is characterized by subsequent malfunction of different structural cartilage and degeneration of articular cartilage because of combination of biochemical, biomechanical, physiological, and genetic processes (Loeser and others 2012). Curcumin inhibited IL-1β induced AKT and NF-κB activation in fibroblast-like synoviocytes, by suppressing phosphorylation of IκBα and its degradation, which has been correlated with downregulation of MMP-9 and COX-2 (Moon and others 2010; Shakibaei and others 2007). Curcumin treatment potentially reduced the severity of collagen-induced arthritis in mouse model by decreasing serum B-cell-activating factor belonging to the TNF family production and serum IL-6 and IFN-γ (Huang and others 2013). A randomized clinical trial was conducted based on Western Ontario McMaster universities osteoarthritis index (WOMAC) and pain visual analogue score (PVAS) to evaluate the efficacy of curcumin against arthritis. Randomized controlled trial has shown the trimming of PVAS, whereas the meta-analysis has revealed the reduction of WOMAC by curcumin. This randomized controlled trial provides the evidence of efficacy for the treatment of arthritis by the curcumin (Daily and others 2016). Curcuma domestica is also as safe and efficient as ibuprofen for the patients with knee arthritis. A study is carried out on 367 subjects with primary knee osteoarthritis. WOMAC total were main outcome. Most of the subjects were satisfied with the treatment and side effects were the same as ibuprofen. Overall, curcuma domestica efficacy was comparable with the ibuprofen (Kuptniratsaikul and other 2014).

Inflammatory bowel disease

The incidence of IBD continues to rise in the world with 2.5 to 3 million people in Europe only (Burisch and Munkholm 2013). It is a disorder of the immune system with debilitating involvement of chronic inflammation of digestive tract, including Crohn's disease (CD) and ulcerative colitis (UC). In some chemically induced colitis in vitro and in vivo models, curcumin has been found to reduce colitis (Larmonier and others 2011). In various experimental models of IBD, curcumin not only prevented translocations of NF-κB but also inhibited 5-LOX, iNOS, and COX-2 expression in IBD and suppressed TLR4-induced NF-κB activation (Baliga and others 2012).

The curcumin treatment results were investigated on 5 approved patients with UC/proctitis (treated with 550 mg of curcumin [DFM 100; 99.5% pure1] twice daily for 1 mo and then 550 mg 3 times daily for another month) and 5 patients with CD 360 mg 3 times daily for 1 mo and then 360 mg (4 capsules) 4 times daily for the remaining 2 mo). The UC/proctitis group has reduced erythrocyte sedimentation rate and CD activity index (CDAI), whereas in CD a protein, C-reactive protein was observed. Reduction of cramping, abdominal pain, diarrhea with improved bowel movements were observed with curcumin treatment (Holt and others 2005. Curcumin along with fennel essential oil has significant response in patients with irritable bowel syndrome (Portincasa and others 2016). All these evidences show curcumin efficacy for the prevention and treatment of IBD.

Renal ischemia

Renal ischemia also known as ischemia reperfusion injury (IRI) is an interconnected and complex result of renal transplantation, mainly caused by poor prognosis and resulting in acute kidney injuries. This disease is characterized by an increase in inflammatory markers in kidney as a result of NF-κB activation and oxidative stress (Patschan and others 2012). According to the meta-analysis of 312 studies, it is estimated that almost 50 million patients lead to the acute kidney injury that is more common in intensive care unit patients and after cardiac surgery (Naves and others 2015). The antirenal ischemia role of curcumin has been well observed. In albino Wistar rats, curcumin was shown to decrease in blood urea, serum creatinine, and nitrogen levels. It also caused   inhibition of the caspase-3, malonaldehyde, lactose dehydrogenase myeloperoxide, and IFN-γ together with enhanced IL-1 (Liu and others 2016). Curcumin pretreatment attenuated both myocardial and renal injuries in Sprague–Dawley rats by reducing inflammatory response (Chen and others 2013). Curcumin has shown to induce apoptosis in C57/B6 mice through downregulation of TNF-α, heat shock protein-70, and TLR-4 expression, with maintaining normal levels of serum creatinine and improved injury healing. Curcumin also reduced superoxide generation and enhanced SOD through the suppression of phospho-S6 ribosomal protein, NF-κB, and MAPK. It also inhibited inflammatory chemokine activation and neutrophil infiltration in the renal IRI (Rogers and others 2012). Curcumin has been shown to increase level of antioxidant enzyme such as GPx, SOD, catalase (CAT) and by reducing level of oxidation products such asNO, MDA, and protein carbonyl (PC), against IRI in rat kidney (Bayrak and others 2008). These studies have revealed the curcumin role for the protection or prevention of IRI through its anti-inflammatory action.

Scleroderma

Prevalence of scleroderma varies according to location and geographical position, as in South Australia 232.2 and in England 88 is the prevalence per million (Barnes and Mayes 2012). Scleroderma is an autoimmune rheumatic disease that typically results in skin fibrosis, vasculopathy, and fibrosis of other organs, with an abnormal regulation of inflammatory cytokines involved in fibrosis and angiogenesis (Hunzelmann and Krieg 2010). Curcumin selectively inhibited the transforming growth factor beta (TGF-ß)-induced Smad2 phosphorylation and in patient cells of systemic scleroderma, it induced apoptosis through upregulation of TGF-ß-induced factor (TGIF). Upregulation of TGIF might be due to decrease ubiquitination of TGIF, as TGIF is a negative regulator of TGF-ß signaling, thus inhibiting TGF-β (Song and others 2011).

Psoriasis

The incidence of psoriasis varies according to geographic location and age. It is more frequent in countries that are distant from the equator and 78.9/100000 persons per year in the United States only (Parisi and others 2013). Psoriasis is a chronic inflammatory disease causing inflammation of skin by abnormal proliferation and differentiation of keratinocytes and have various inflammatory markers including survivin, NF-κB, TNF-α, and STAT-3 (Abdou and Hanout 2008; Gunduz and others 2012). Studies have suggested that curcumin may provide protection against psoriasis in psoriatic keratinocytes, by decreasing the pro-inflammatory cytokines expression and inhibiting the keratinocyte proliferation (Sun and others 2013). Recently, it has been shown that in TNF-α stimulated HaCaT cells, curcumin treatment inhibited production of IL-6/IL-8 and induced apoptosis through the downregulation of anti-apoptotic proteins such as Bcl-xL and inhibitor of apoptosis protein 1 and 2 (IAP1, IAP2) with inhibition of NF-κB subunit p65 activation. These results show that curcumin can be used to treat psoriasis (Sun and others 2012). Oral administration of curcuminoid C3 complex (4.5 g/d) to patients with plaque psoriasis showed that it is well tolerated by patients; however, efficacy of the drug was low as compared to in vitro studies (Kurd and others 2008).

Curcumin clinical study

Efficacy, safety, and pharmacokinetics of curcumin has been addressed in various cancers both in vitro and in vivo studies (Shehzad and others 2013a). In recent clinical trials, curcumin has been used alone or in combination with other synthetic and natural agents in human subjects including preneoplastic diseases, neoplastic such as pancreatic cancer, multiple myeloma, and colon cancer, and myelodysplastic syndromes (Syng-Ai and others 2004). A post hoc analysis of randomized controlled trial was conducted on 117 patients of metabolic syndrome recruited according to the inclusion criteria defined by the Natl. Cholestrol Education Program Adult Treatment Panel III guidelines. Group statistics and analysis have shown considerable reduction in IL-6, MCP-1, TNF-α, and TGF-β. Result of this study has confirmed the potential of curcumin to decrease the serum concentration of pro-inflammatory cytokines in patients with metabolic syndrome (Panahi and others 2016). Curcumin anti-inflammatory activity has also been observed in various inflammatory disorders including cancer, hyperglycemia, arthritis, dermatitis, cystic fibrosis, cardiovascular and liver diseases, several brain diseases like schizophrenia, Alzheimer and various pathological conditions of orthodontics and periodontics summarized in Table 1.

Curcumin limitations

Although curcumin has a potential to treat numerous human disorders including cancers, but its poor bioavailability because of poor absorption, rapid metabolism, and systemic elimination limits its therapeutic efficacy (Anand and others 2007). After oral administration, its decreased bioavailability supports its short half-life and extremely low serum levels. According to several in vitro studies on cancer cells, it has been shown that cancer cells are unable to die until they receive curcumin concentration in micro-molar range 5 to 50 μM, for few hours, whereas the plasma concentrations of curcumin involving high oral doses are relatively very low, mainly in nanomolar range. High concentrations of curcumin cannot be maintained in tissues and plasma because of the fact that curcumin undergoes extensive metabolism in liver and intestines after oral ingestion. This counts for main hindrance for the clinical development of oral curcumin. The low clinical efficacy in case of diseases including cardiovascular and AD have been shown in a study (Shoba and others 1998), whereas for cancers the poor prolonged delivery of curcumin at high doses and reduced bioavailability accounts for viable cancer cells even in treated conditions (Sasaki and others 2011). Various methods to improve levels of curcumin are also linked with the increased toxicity under specific conditions. Goodpasture and Arrighi (1976) reported a dose- and time-dependent induction of chromosome aberrations in various mammalian cell lines at concentrations of 10 μg/mL. Since then various studies have confirmed the DNA damage associated with more or less similar concentration of curcumin raising concern about its safety. These effects may involve several possible mechanisms including ROS, that is, hydrogen peroxide and superoxide anion, which plays an important role in the progression of cancer and other diseases as explained earlier (Cerutti 1985). This is due to the presence of 2 a-b-unsaturated ketones in the structure of curcumin which reacts with exposed thiol groups of cysteine residues of proteins resulting in the production of ROS (Fang and others 2005), resulting in DNA damage. Curcumin could also produce undesired increase of drugs in plasma, as in one of the study it has been shown to inhibit the drug-metabolizing enzymes (cytochrome P450, UDP-glucuronosyltransferase, and glutathione-S-transferase; Mancuso and Barone 2009). Other safety issues involve the role of curcumin as active iron chelator in vivo causing iron deficiency anemia in mice 58, making it ineffective in people with iron suboptimal levels.

Curcumin is a safe drug and well tolerated at doses up to 8 g/d, but doses ranging from 0.9 to 3.6 g/d for 1 to 4 mo has undesirable effects including nausea, diarrhea, and an increase in amounts of lactate dehydrogenase and serum alkaline phosphatase (Sharma and others 2004). In addition, chest tightness, gastrointestinal upset, skin rashes, and inflamed skin has been reported in patients with long-term exposure to curcumin. In double-blind placebo-controlled study of 24 wk, tolerability of 2 to 4 g/d of curcumin (oral administration) was examined in patients with mild to moderate AD. Five patients were dropped out of the study because of GIT side effects and no significant effect of curcumin was observed in others (Ringman and others 2012). In phase II trial, oral administration of curcumin (8 g/d) in patients with advanced pancreatic cancer, although shown well tolerability but considerable interpatient variable plasma curcumin level and drug level peaks (22 to 45 ng/mL) were observed (Dihllon and others 2008). Oral administration of 2 to 4 g doses of solid lipid curcumin particles in patients with last-stage osteosarcoma and in healthy individuals has been evaluated. Dose–plasma concentration relationship has shown high interpatient pharmacokinetics variability and nonlinear dose effect, which determines potentially complex absorption kinetics of curcumin (Gota and others 2010). The lack of established doses and long-term toxicity studies in humans should be considered as the fact and curcumin as a common dietary constituent with no toxicity in short-term study is not enough to prove its safety. Recently, curcumin has been reported as panassay interference compounds and invalid metabolic panaceas in literature. Curcumin is also lacking specific targets with clear mechanism of action, chemical stability, and absorption, distribution, metabolism, excretion, and toxicology (Nelson and others 2017). Sometimes false-positive and false-negative results may occur, as turmeric is the mixture of closely related components. It is also possible that we may detect encouraging biological effects of one component but link it to the activity of wrong component. So, in order to develop curcumin as an effective drug, its benefit–risk ratio should be fully researched and acknowledged.