Curcumin

Curcumin also called Curcuma longa, Indian saffron, diarylheptanoid or diferuloylmethane, is a natural bright yellow pigment obtained from the tubers of turmeric (Curcuma longa plant) in the ginger family, is native to Southeast Asia and is grown commercially in that region, primarily in India ¹, ², ³. Curcumin is a well-known antioxidant due to its reactive oxygen species (ROS) scavenging property. Curcumin comprises between 1% and 6% by dry weight of whole turmeric extracts, other components being starch, fats, proteins, fiber, vitamins, minerals, and water ⁴. Turmeric is used as a culinary spice and traditional medicine. The turmeric root can be dried and made into capsules, tablets, extracts, powders or teas. Or it can be made into a paste to apply to the skin.  Turmeric’s main active component — curcumin — is what gives a yellowish color to curry powder and is a major ingredient in curry powders common in many Indian and Asian dishes, and it is also used as a coloring for foods, fabrics and cosmetics. The extract of turmeric contains three major curcuminoids (Figure 1): Curcumin (60–70%), demethoxycurcumin (20–27%), and bisdemethoxycurcumin (10–15%) ⁵. The activities of turmeric are commonly attributed to curcuminoids (curcumin, demethoxycurcumin and others). Commercial preparations of turmeric and curcumin vary widely in curcuminoid content. The antiinflammatory effects of turmeric and curcumin are thought to be mediated by inhibition of leukotriene synthesis. Curcumin has also been reported to have anti-cancer effects mediated by inhibition of intracellular kinases. Turmeric and curcumin are under active investigation as antiinflammatory and anti-cancer agents, for treatment of diabetes and hyperlipidemia and as therapy of liver diseases including nonalcoholic steatohepatitis (NASH) ⁶. The scientific bases for the purported effects of turmeric and curcumin are not well established and rigorous proof of their effictiveness in any medical condition is lacking.

Turmeric may be unsafe for use during pregnancy in amounts greater than those commonly found in food. Little is known about whether it’s safe to use turmeric in amounts greater than those commonly found in food while breastfeeding. In one study, high doses of curcumin (8000 mg/day) do not cause side effects ⁷. In another study, curcumin was administered at doses up to 12 g/day for three months with no apparent toxicity ⁸. However, some studies have found that high concentrations of curcumin have some side effects. Tanwar et al ⁹ found that curcumin had antioxidant effects at lower concentrations (100 or 200 mg/kg/day), but curcumin had side effects of promoting lipid peroxidation at higher concentrations (400 mg/kg/day) in a rat model of myocardial necrosis induced by isoprenaline. In another study, Sun et al ¹⁰ found that curcumin (75 mg/kg/day) can induce histone hypoacetylation and inhibit the expression of transcription factors such as GATA4 early in heart development, ultimately leading to defects in heart development, such as thinning of the ventricular wall and septum. In general, curcumin may be detrimental to embryonic heart development during early pregnancy ¹⁰. Clinically, the common side effects of curcumin are flatulence, changes in liver enzymes and blood biochemical parameters ¹¹, ¹². The metabolism and lipid-lowering effects of curcumin are mainly carried out in the liver, which may be the main reason for the increase of liver enzymes ¹³.

Curcumin has been consumed for hundreds of years and is considered pharmacologically safe when taken at doses up to 100 mg/day ¹⁴, ¹⁵, ¹⁶. According to the Joint Food and Agriculture Organization/The World Health Organization (JECFA) report on food additives, the Acceptable Daily Intake Level (ADI) of curcumin is 0 to 0.1 mg/kg body weight ¹⁷. In clinical trials, curcumin was found to be safe and effective. In a randomized and controlled clinical trial involving patients with arthritis, curcumin was administered in doses ranging from 120 to 1500 mg for 4 to 36 weeks, reduced inflammation and pain levels, and was shown to be a safe treatment method ¹⁸. Also, in a clinical study comparing the administration of curcumin 500 mg (BCM-95®) 3 times/day and diclofenac 50 mg, 2 times/day for 28 days in patients with knee osteoarthritis, patients that received curcumin presented similar improvement in the severity of pain, reduction in flatulence episodes, no requirement of H2 blockers, weight reduction, and anti-ulcer effects, proving to be a very safe treatment method presenting a 13% adverse effect rate versus 38% in the diclofenac group ¹⁹. Furthermore, in chronic kidney disease subjects, supplementation with 500 mg of curcumin tablets, two times/day for six months, reduced plasma pro-inflammatory mediators and lipid peroxidation. During the long-term administration treatment, no serious adverse events were observed, confirming the safety profile of curcumin ²⁰. In addition, in patients with non-alcoholic fatty liver disease (NAFLD), curcumin supplementation of 1000 mg/day in two doses for eight weeks was considered safe and well tolerated with no report of severe adverse events during the treatment ²¹. The US Food and Drug Administration (FDA) approved the curcumin as a “generally safe” (GRAS) compound ²².

Historically, turmeric was used in Ayurveda and other traditional Indian medical systems, as well as Eastern Asian medical systems such as traditional Chinese medicine. In India, it was traditionally used for disorders of the skin, upper respiratory tract infections, joints, indigestion and liver diseases. Today, curcumin and its derivatives (curcuminoids) have received immense attention due to their biofunctional properties such as antioxidant, anti-inflammatory, immune regulatory, antiviral, antifungal, antibacterial, anticancer, antidiabetic, neuro-protective, cardiovascular protective, and hepatoprotective effects ²³, ²⁴, ²⁵, ²⁶. These properties are attributed to the key elements in the curcumin structure ²⁷. Turmeric is currently being promoted as a dietary supplement for a variety of conditions, including arthritis, digestive disorders, respiratory infections, allergies, liver disease, depression, and many others.

The metabolism of curcumin is critical for its potent biological activities as well as the beneficial effects on health ²⁸. In the mammalian body, curcumin can be presented in three major forms and they are free, conjugated, and reduced curcumin states (see Figure 3) ²⁹. Oral administration mainly metabolizes curcumin into the conjugated curcumin via glucuronidation and sulfation. Especially, the finding demonstrates that the gastrointestinal tract plays an important role in the glucuronidation of curcuminoids in human ³⁰. In addition, intravenous or intraperitoneal administration leads to the reduction of curcumin into dihydrocurcumin, tetrahydrocurcumin, and hexahydrocurcumin ³¹. However, minor free and intact curcumin can be detected in plasma after the administration ³². On the other hand, the metabolism of curcuminoids mainly leads to reductive metabolites, for example, hexahydrocurcuminoids are the major reductive metabolites observed in both male and female rat liver ³³.

So far, both pre-clinical and clinical studies of curcumin administration via the oral route have demonstrated the poor biodistribution of curcumin ³⁴, ³⁵. A typical example is a pharmacokinetic investigation performed on healthy human subjects, which revealed that even after high oral-dosage administration (Cmax) of 10 g and 12 g of curcumin, only 2.30 and 1.73 μg/mL of curcumin were found in the blood. This means curcumin undergoes several physiological changes as it passes through the liver and gut ³⁶. Due to the low chemical stability and poor bioavailability of curcumin, more attention has been paid to its metabolites ³⁷. Although the major structure of its metabolites is consistent with curcumin, the minor differences in the structure of metabolites improve their chemical stability. For example, the hexahydrocurcumin has the same phenolic groups or diketo moieties as curcumin, but has no olefinic double bonds, leading to hexahydrocurcumin being more stable than curcumin at a physiological pH of 7.4 ³⁸. In the intestine, the absorption of curcumin is poor, while the reductive and conjugated curcumin metabolites show moderate absorption ³⁹. Hence, it is hypothesized that the biological effects of curcumin in tissues, such as liver and kidney, may be attributed to the curcumin metabolites ⁴⁰. However, the metabolism or degradation of curcumin can affect the bioactivity of curcumin. A finding shows that curcumin induces arrest in the G2/M phase and mitotic catastrophe in three human cancer cell lines, while the reductive metabolism and chemical degradation inactivate the ability of curcumin to cause cancer cell death ⁴¹.

The relationship between curcumin and microbiota (community of micro-organisms) plays an important role in the gastrointestinal metabolism of curcumin ⁴². The main metabolic process in human intestinal microbiota includes demethoxylation, reduction, hydroxylation, methylation, and acetylation ⁴³. A study used the bacteria strain, Bacillus megaterium DCMB-002, isolated from mice feces to treat with curcumin, and the bacteria have been found to transform curcumin into various metabolites ⁴⁴. In addition, the human intestinal bacteria, Blautia sp. MRG-PMF1, have been reported to biotransform curcumin via the methyl aryl ether cleavage reaction ⁴⁵.

Figure 1. Three major curcuminoids in turmeric and their chemical structures

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Figure 2. Curcumin chemical structure

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Curcumin metabolism and degradation

Following oral administration of curcumin, it is metabolized extensively. It has been reported that the phase 1 reduction reaction and phase 2 conjugation reaction were the major metabolic pathways of curcumin in animals, and dihydrocurcumin, tetrahydrocurcumin, octahydrocurcumin, and hexahydrocurcumin were the main metabolites in phase 1 ⁴⁸. There is some evidence indicating that metabolites are the major contributors of the pharmacological activity of curcumin. For instance, dihydrocurcumin diminished lipid accumulation, oxidative stress, and insulin resistance in oleic acid-induced L02 and HepG2 cells ⁴⁹.

Figure 3. Metabolic pathways of curcumin

Footnotes: Oral administration mainly metabolizes curcumin into conjugated curcumin, while intravenous or intraperitoneal administration mainly leads to reduced curcumin. In addition, minor free and intact curcumin can be detected in plasma after any administration.

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Tetrahydrocurcumin, another metabolite of curcumin, has been reported to show a wide range of therapeutic properties ⁵⁰, ⁵¹. The properties of tetrahydrocurcumin metabolite are comparable to those of curcumin. However, studies revealed that Tetrahydrocurcumin is more potent than curcumin as an anti-inflammatory, antioxidant, neuroprotective agent and anti-cancer ⁵⁰. Several lines of evidence demonstrated that tetrahydrocurcumin has higher antioxidant activity and upregulates the antioxidant enzymes in different pathological conditions including atherosclerosis ⁵², diabetes ⁵³, hyperlipidemia ⁵⁴, and neurotoxicity ⁵⁵. Having additional hydrogen molecules, Tetrahydrocurcumin is more hydrophilic than curcumin ⁵⁶ and pharmacokinetic assessments reveal that it is more stable than curcumin in 0.1 M phosphate buffers at neutral pH and plasma ⁵⁷. Furthermore, Tetrahydrocurcumin half-life in test tube studies is significantly longer than that of curcumin ⁵⁸. Together, these properties suggest that Tetrahydrocurcumin may be more potent and efficacious against human diseases than curcumin, owing to its distinct chemical properties and stability. Recent studies showed that curcumin quickly degrades in aqueous buffer and some degradation compounds are produced ⁵⁹ comprising alkaline hydrolysis products (ferulic acid, vanillin, ferulaldehyde, and feruloyl methane) which are formed through ahydroxyl ion (OH-)-mediated hydrolysis reaction ⁶⁰ and autoxidation products (bicyclopentadione), are formed through a radical-mediated process ⁶¹. Evidence suggests that curcumin mostly degrades via oxidation pathway rather than through hydrolysis ⁵⁹. Although some of these degradation products are biologically active, they are noticeably less-active in comparison to curcumin ⁵⁹, supporting the idea that chemical degradation of curcumin has a limited contribution to its biological and pharmacological activities ¹.

Curcumin health benefits

Much research has been done on substances from turmeric, overall, several clinical trials have demonstrated the beneficial effects of curcumin in patients with inflammation, cardiovascular diseases, metabolic syndrome, or diabetes ⁶². Turmeric and curcumin have a variety of interesting biological activities, but they’re challenging to study because curcumin is unstable (it easily changes into other substances) and has low bioavailability (not much of it reaches the bloodstream) when it’s taken orally. For instance, the dose of curcumin given orally is 8 g/day in humans, and the data shows that curcumin is rapidly transformed into metabolites, resulting in a low level of free curcumin in plasma (<2.5 ng/mL) ⁶³. The poor aqueous solubility and low bioavailability of curcumin are considered as the main obstacles to its clinical development, and the metabolites and derivatives may be responsible for the biological activities rather than free curcumin ⁶⁴. To enhance the stability and bioavailability of curcumin, many studies focus on modifications of curcumin and its delivery systems, such as nanoparticles, micellation, and conjugation with other materials ⁶⁵. Such modifications can increase its stability, solubility, in vivo uptake, bioactivity, and safety ⁶⁶. In addition, curcumin products may differ in composition or contain more substances than expected, which makes the results of research on these products difficult to understand and compare. Because the actions of turmeric and its components in people are complex and not well understood, no clear conclusions have been reached about whether these substances have benefits for health conditions. Curcumin (turmeric) has been widely used as a common household remedy for cough, sore throat and respiratory ailments in Asia.

In the past five years, some clinical trials have been conducted to investigate the effects of curcumin on patients with several diseases, such as metabolic syndromes, diabetes, arthritis, and gut inflammation ⁶⁷. In clinical trials, curcumin is often used in combination with other agents or alone with delivery systems, such as nanoparticles and liposomal encapsulation ⁶⁸, ⁶⁹.

Oxidative stress plays an important role in the progression of nondiabetic or diabetic proteinuric kidney disease. Specifically, a randomized double-blind placebo-controlled clinical trial was performed to evaluate the antioxidant effects of curcumin on chronic kidney disease (CKD). One hundred and one patients with nondiabetic or diabetic proteinuric chronic kidney disease received a placebo or 320 mg of curcumin per day for eight weeks. Results showed that curcumin attenuates lipid peroxidation in plasma in patients with nondiabetic proteinuric CKD and improved the antioxidant capacity in patients with diabetic proteinuric chronic kidney disease ⁷⁰.

Due to its anti-inflammatory activity, curcumin could provide an improvement on inflammatory diseases. Thirty-six patients with rheumatoid arthritis (RA, a chronic systemic inflammatory disorder) were randomly assigned to receive a placebo, 250mg, or 500 mg of curcumin twice daily for 90 days. At the end of the study, the clinical markers of inflammation, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) values, were significantly improved in the groups receiving curcumin ⁷¹. In addition, the effects of curcumin on osteoarthritis (OA) were evaluated, and 22 patients with knee osteoarthritis took three caps of bio-optimized curcumin twice a day. The treatment with curcumin significantly reduced the serum levels of Coll2-1, a cartilage-specific biomarker, attenuating knee osteoarthritis ⁷². Psoriasis vulgaris is a common chronic inflammatory disease. Sixty-three patients with mild-to-moderate psoriasis vulgaris were treated with 2 g of topical steroids and oral curcumin per day, or with topical steroids alone for 12 weeks. In patients treated with oral curcumin, the psoriasis area and severity index values and serum levels of IL-22 were significantly reduced and the inflammation progression was ameliorated ⁷³. Similarly, patients with moderate-to-severe psoriasis were treated orally with 0.4 mg/kg of acitretin and 3 g of nanocurcumin or only with acitretin every day for 12 weeks. It resulted in reduced psoriasis area and severity index values and unchanged cholesterol serum levels in patients treated with curcumin and acitretin ⁶⁹. Furthermore, migraines are characterized by high levels of IL-6 and CRP, which disrupt the integrity of the blood-brain barrier and induce neurogenic inflammation. Eighty episodic migraine patients were randomized to receive a combination of omega-3 fatty acids (2500 mg) and nanocurcumin (80 mg) or omega-3 alone or nanocurcumin alone for two months. Notably, the combination of nanocurcumin and omega-3 downregulated IL-6 mRNA and decreased the serum levels of IL-6 as well as high sensitivity CRP (hs-CRP) ⁷⁴.

Curcumin supplements are considered as a preventive agent and an adjuvant therapy of cancers. Oral leukoplakia is a potentially malignant lesion of the oral cavity. Subjects with oral leukoplakia (n = 223) randomly took orally 3.6 g of curcumin (n = 111) or a placebo (n = 112) daily for six months. The primary endpoint was a clinical response obtained by bi-dimensional measurement of the leukoplakia size at six months of recruitment. At the end of the study, the treatment with curcumin had no safety concerns and the subjects were well tolerated and given a durable clinical response for six months ⁷⁵. Additionally, curcumin has been reported to have antitumor effects on glioblastoma cells in human. Thirteen glioblastoma patients received 70 mg of micellar curcuminoids, consisting of curcumin, demethoxycurcumin, and bis-demethoxycurcumin, three times per day for four days. After the intervention of curcuminoids, the mean ratio of phosphocreatine to inorganic phosphate decreased, and the mean intratumoral pH increased, attenuating intratumoral energy metabolism ⁷⁶.

In clinical trials, curcumin has also been demonstrated to show protection against cardiovascular diseases. The progression of atherosclerosis can be accelerated by alpha 1-antitrypsin-low-density lipoprotein (AT-LDL). Subjects with stages I-II chronic obstructive pulmonary disease (COPD) were randomly treated with 90 mg of Theracurmin (R) (a highly absorptive curcumin using a drug delivery system) or a placebo twice a day for 24 weeks. The level of atherosclerotic low-density lipoprotein (LDL or “bad cholesterol”) was significantly lower in the curcumin group compared with the placebo group ⁷⁷. The curcumin extract was evidenced to have a lipid-lowering effect via a clinical trial of 65 patients with metabolic syndromes. Patients were randomized into two groups to take a 630 mg curcumin extract capsule or a placebo capsule thrice daily for 12 weeks. The level of high-density lipoprotein cholesterol (HDL or “good cholesterol”) were significantly increased, and the levels of LDL and triglycerides were significantly reduced after curcumin extract treatment for 12 weeks ⁷⁸. A six-month clinical trial with type 2 diabetic patients shows that curcumin intervention significantly reduces pulse wave velocity, increases the level of serum adiponectin, and decreases the level of leptin, lowering the atherogenic risks ⁷⁹. A randomized double-blind placebo-controlled trial including 33 patients with coronary artery disease revealed that the intake of curcumin significantly ameliorates dyslipidemia in patients. Curcumin was observed to control the blood lipid levels by decreasing the serum levels of triglycerides, LDL-cholesterol, and very low density lipoprotein-cholesterol (VLDL-C) ⁸⁰.

Curcumin supplementation may exert beneficial effects on the management of diabetes. In an open-label, randomized control trial, eight type-2 diabetic patients were treated with curcumin capsules on glyburide therapy for 10 days. Results show that the levels of blood glucose, LDL, VLDL, and triglycerides were decreased significantly, and the content of HDL was increased. The findings indicate that the combination of curcumin capsules with glyburide contributes to better glycemic control in diabetic patients ⁸¹. In addition, 70 type-2 diabetic patients randomly received 80 mg of nano-micelle curcumin or a placebo daily for three months, and in the group with nano-micelle curcumin, a significant decrease was observed in glycated hemoglobin (HbA1C) and fasting blood glucose (FBG) which are biochemical parameters related to diabetes ⁸².

Anticancer activity of curcumin

Curcumin is shown to have anticancer potential for the prevention and treatment of different cancers ⁸³. The underlying anticancer mechanisms of curcumin mainly depend on the inhibition of cancer cell growth, induction of cancer cell apoptosis, and suppression of cancer cell metastasis ⁸⁴. Curcumin disturbs the balance in the mitochondrial membrane potential, leading to enhanced suppression of the Bcl-xL protein ⁸⁵. The extrinsic apoptotic pathway works through increasing the death receptors (DRs) on cells and triggering the tumor necrosis factor (TNF)-related apoptosis. Curcumin also contributes to this pathway by upregulating the expression of death receptors DR 4 and DR 5 ⁸⁶. Test tube studies showed a remarkable ability of curcumin and its derivatives to induce apoptosis in different cell lines by inhibiting or downregulating intracellular transcription factors. These factors include NF-κB, activator protein 1 (AP-1), cyclooxygenase II (COX-2), nitric oxide synthase, matrix metalloproteinase-9 (MMP-9), and STAT3 ⁸⁷. A recent work has found a new anticancer mechanism for curcumin by decreasing the glucose uptake and lactate production (Warburg effect) in cancer cells via downregulation of pyruvate kinase M2 (PKM2). The inhibition of PKM2 was achieved by suppressing the mammalian target of rapamycin-hypoxia-inducible factor 1α (TOR-HIF1α) ⁸⁸. Several studies have investigated the ability of curcumin and its derivatives to suppress multiple different carcinomas by interacting with different molecular targets.

Curcumin is also considered as an auxiliary agent, and intensifies the therapeutic effects of other cancer treatments ⁴⁶. When used in radiation therapy, curcumin prevents radiation-induced activation of the NF-κB pathway, increases sensitivity to ionizing radiation and apoptosis of tumor cells, and decreases tumor cell proliferation, improving anticancer efficacy ⁸⁹. Moreover, the addition of curcumin is found to potentiate 5-fluorouracil-induced reduction of proliferation and invasion in colorectal cancer cells ⁹⁰ and curcumin enhances the chemosensitivity of colorectal cancer cells to 5-fluorouracil and induces apoptosis. These effects are speculated to be associated with the downregulation of NF-κB activation, inhibition of AMP-activated protein kinase (AMPK)/unc-51-like kinase (ULK1)-dependent autophagy, and the suppression of Akt activity ⁹¹.

Prostate cancer

A recent estimate reported by the American Cancer Society revealed that 2.9 million men have been diagnosed with prostate cancer in the United States ⁹², making it the second leading cause of cancer death in men ⁹³. Curcumin has shown a strong ability to inhibit proliferation and induce apoptosis in prostate cancer both in vitro and in vivo ⁹⁴ by interfering with a number of cellular pathways, including mitogen-activated protein kinase (MAPK), epidermal growth factor receptor (EGFR), and nuclear factor κ (NFκB) ⁹⁵. A recent study has revealed the ability of curcumin to activate protein kinase D1 (PKD1), leading to attenuation of the oncogenic signaling by β-catenin and MAPK [100] and consequent inhibition of prostate cancer ⁹⁶. Moreover, PKD1 was found to be severely downregulated following progression from androgen-dependent to androgen-independent prostate cancer ⁹⁶ and to affect the motility and invasion of prostate cancer via interaction with E-cadherin ⁹⁷. Therefore, it has been considered as a new therapeutic target for cancer in general and for prostate cancer in particular ⁹⁸. In addition to curcumin, some of its derivatives have also shown anticancer activity against prostate cancer. Metallo-curcumin conjugated DNA complexes exhibited significant toxicity to prostate cancer cells (PC3, 22Rv1, TRAMP-C1, LNCaP, and DU145) ⁹⁹. Dimethyl curcumin (ASC-J9) has also shown very good activity in enhancing androgen receptor degradation in androgen-dependent prostate cancer ¹⁰⁰.

Colorectal cancer

Colorectal cancer comes third behind prostate cancer and lung cancer as the most common form of malignant cancer ¹⁰¹. Although patients diagnosed with colorectal carcinoma undertake surgical removal of the tumor tissue along with chemotherapy, more than half of the patients suffer from relapses ¹⁰². Administration of curcumin was found to reduce M (1) G levels in the malignant colorectal cells without changing COX-2 protein levels ¹⁰³. In addition, curcumin treatment was able to downregulate miR-21 gene, which is overexpressed in colorectal cancer cells, by inhibiting AP-1 (activator protein) binding to miR-21 promoter ⁹⁷. Treating HCT 116 colorectal cancer cells with curcumin resulted in a cell cycle arrest in the G2/M phase via miR-21 gene regulation and inhibited the tumor tissue growth ⁹⁷. However, an in vivo study in mice with colorectal cancer demonstrated an improved response to radiation therapy when combined with curcumin due to its ability to target nuclear factor (NF-κB) ¹⁰⁴. Another study has managed to enhance curcumin inhibition activity against colon cancer cells by combining it with ERRP, a pan-erb B inhibitor ¹⁰⁵.

In a study in which 15 patients with advanced chemotherapy-resistant colorectal cancer were given curcumin extract in capsular form daily for up to 4 months, the intake of 440 mg/day of turmeric capsule for 29 days resulted in a reduction of lymphocytic glutathione S-transferase (GST) activity by 59%. However, the same effect was not observed at higher doses and it was emphasized that 2.2 g/day of turmeric (containing 180 mg of curcumin), which is thought to be safe, may be given to the patients, but larger clinical studies should be performed ¹⁰⁶. In another study conducted by Sharma et al. ¹⁰⁷, 15 patients with advanced chemotherapy-resistant colorectal cancer were given 0.45 to 3.6 g of curcumin per day for up to 4 months and it was found that 3.6 g of curcumin significantly reduced inducible Prostaglandin E2 (PGE2) production by 62% and 57%, respectively in the blood samples on the 1stand 29thdays. In the study of Garcea et al. ¹⁰⁸, curcumin capsules were given to individuals with colorectal cancer for 7 days (3.6 g/day, 1.8 g/day or 0.45 g/day) and the levels of M(1)G, which are adenomatous burden indicators, were found two and a half times higher in the malign tissue than the normal tissue. Curcumin sulfate and curcumin glucuronide were detected in the tissue of these patients. The result of the study showed that the daily dose of 3.6 g curcumin reduced M(1)G levels in malignant colorectal tissues but did not affect the cyclooxygenase-2 (COX-2) enzyme levels. Studies show evidence of effect of curcumin on colorectal cancer, however, more clinical studies are needed for clearer results on this subject.

More recently, the safety and efficacy of curcumin in familial adenomatous polyposis was evaluated in a double-blinded randomized trial by Cruz-Correa et al. ¹⁰⁹. In this study, 44 patients with familial adenomatous polyposis with at least five intestinal adenomatous polyps who had not undergone colectomy were included in this trial and were randomly allocated to two groups receiving either pure curcumin (3 g per day orally) or placebo for 12 months. The main outcome measures were the number and size of lower gastrointestinal tract polyps, which were assessed every four months for one year. At the end of the study, no significant difference was found in the mean number or mean size of polyps between the curcumin group and the placebo group. The adverse effects were very few, and not significantly different from the placebo group. These results show the low efficacy but high safety of oral curcumin at the administered dose in patients with familial adenomatous polyposis ¹⁰⁹.

Pancreatic cancer

In a 2010 study by Epelbaum et al. ¹¹⁰, patients with either advanced local or metastatic pancreatic cancer were treated with a combination of curcumin (8 g/day per oral) and gemcitabine (1000 mg/m2 intravenous once per week) for three out of four weeks of each chemotherapy cycle. The primary outcome was time to tumor progression and the main secondary outcome was toxicity profile. In the study, eight out of seventeen patients were noncompliant with curcumin due to abdominal pain, five of which discontinued treatment before two weeks and three received adjusted doses of curcumin for the rest of the study (4 g/day). One patient died during the first cycle due to cardiac problems not associated with curcumin. One patient developed grade II neutropenia and one patient grade I thrombocytopenia. The time to tumor progression was between one and twelve months (median two months), and the overall survival time was between one and 24 months (median 6). Based on these results, they concluded that the combination therapy with curcumin and gemcitabine in pancreatic cancer is feasible; however, the dose of curcumin should be less than 8 g/day ¹¹⁰.

Head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common form of cancer worldwide, with more than 30,000 diagnosed cases every year ¹¹¹. Head and neck squamous cell carcinoma generally arises in the oral cavity, paranasal cavities, larynx, and pharynx ¹¹². In vitro studies of curcumin in different head and neck cancer cell lines have proven its ability to inhibit cell growth due to its effects on a number of cellular pathways involved in cell proliferation, most notably NF-κB and STAT3, which are found to be overexpressed in several head and neck carcinomas ¹¹³. Curcumin was shown to downregulate NF-κB and inhibit the interleukin-6 (IL-6)-mediated phosphorylation of STAT3, thus inhibiting the proliferation of the cancer cells ¹¹⁴.

Kim et al. ¹¹⁵ performed a pilot study in patients with head and neck squamous cell carcinoma to determine the effect of curcumin on inhibiting IκB kinase β (IκKβ) activity and suppressing the proinflammatory cytokines. The patients were asked to chew curcumin tablets (2 mg), their saliva samples were collected before and after chewing the tablets, and the IκKβ activity was measured, as well as the levels of salivary cytokines interleukin (IL)-6 and IL-8. Curcumin resulted in a reduction in IκKβ activity in the salivary cells of head and neck squamous cell carcinoma patients. There was a brief reduction in IL-8 expression in eight of 21 post-curcumin samples; however, this reduction was not statistically significant. On the other hand, there was a marked decrease in the expression of other cytokines, including IL-10, IFN-γ, IL-12p70, and IL-2 clustered together, and also granulocyte macrophage colony stimulating factor (GMCSF) and TNF-α clustered together. These results show the inhibitory effect of curcumin on IκKβ activity in the salivary cells of patients with head and neck squamous cell carcinoma; therefore, they suggested considering IκKβ as a biomarker for detecting the effect of curcumin in head and neck cancer ¹¹⁵.

Breast cancer

Breast cancer is a leading cause of death in women ¹¹⁶. Despite lumpectomy, radiation therapy, chemotherapy, and endocrine therapy, the recurrence rate of breast cancer has been reported to be still high based on a meta-analysis of 21 retrospective studies ¹¹⁷. Therefore, there is still a need for more efficient therapeutic strategies. In a study on MCF-10A human mammary epithelial cells and MCF-7 breast cancer cells [114], a tangible drop in telomerase activity was observed as a result of treatment with curcumin in a concentration-dependent manner which was correlated to downregulation of hTERT by curcumin but not through the c-Myc mRNA pathway ¹¹⁸. The effect of curcumin on cell-cycle regulatory proteins, matrix metalloproteinases and NF-κB was evaluated in MDA-MB-231 and BT-483 breast cancer cell lines ¹¹⁹. In agreement with the previous studies on other breast cancer cell lines, this study also confirmed the ability of curcumin to downregulate NF-κB, leading to an antiproliferative effect ¹²⁰. However, a decrease in cyclic D1 in MDA-MB-231 cells and a decrease in CDK4 BT-483 were observed after treatment with curcumin ¹¹⁹. Combining arabinogalactan and curcumin enhanced apoptosis induction by increasing ROS levels, disturbing the mitochondrial membrane and decreasing glutathione in MDA-MB-231 cell line ¹²¹. Moreover, curcumin led to the inhibition of breast tumor via overexpression of the p53 gene and reduction of antigen ki-67 levels ¹²¹. Another study on MDA-MB-231 cells has shown that curcumin also inhibits inflammatory cytokines CXCL1/2. Inhibiting CXCL1 and 2 by curcumin results in inhibiting the expression of a series of metastasis-promoting genes such as chemotactic receptor CXCR4 ¹²². Dimethyl curcumin (ASC-J9) has also been reported to be effective against estrogen-dependent breast cancer via inhibiting several types of steroid receptors ¹²³.

Bayet-Robert et al. ¹²⁴ evaluated the feasibility and tolerability of a combination of curcumin and docetaxel in 14 patients with metastatic or locoregionally recurrent advanced breast cancer in an open-label phase 1 dose escalation clinical trial. The patients received an I.V. infusion of Docetaxel (100 mg/m²) every three weeks for six chemotherapy cycles, and oral curcumin (starting from 500 mg/day and increased until a dose-limiting toxicity would occur) for seven consecutive days in each cycle (from five days before to two days after administration of docetaxel). The primary endpoint was the maximal tolerated dose of curcumin when administered in combination with a standard dose of docetaxel in the patients. Secondary outcomes were toxicity, safety, and clinical response to the combination therapy, as well as levels of CEA tumor marker and vascular endothelial growth factor (VEGF) as a positive endogenous modulator of angiogenesis.

The maximal tolerated dose of curcumin was found to be 8 g/day as in higher doses, dose-limiting toxicities (neutropenia, anemia, and severe diarrhea) were observed, leading to the discontinuation of the trial in two patients. Other toxicities (oral cavity mucositis, hand-foot syndrome, nail changes, dermal changes, conjunctivitis, and fatigue) were either not persistent or were treated easily so did not affect the continuation of the trial. However, due to noncompliance of a number of patients with the doses higher than 6 g/day, in the end, this dose was recommended as the maximal tolerated dose to be considered for phase 2 clinical trials. In terms of clinical and biological response (decrease in CEA tumor marker across the treatment and regression of nonmeasurable lesions), some degree of improvement was observed in most patients, with five patients showing a partial response to treatment and three patients having stable disease at least six weeks after the last cycle of treatment. No disease progression was observed in any of the patients. Moreover, curcumin/docetaxel combination significantly decreased the levels of VEGF after three cycles of treatment ¹²⁴.

Brain cancer and glioblastoma

Glioblastoma (GBM) is the most common malignant brain cancer in humans, accounting for about 15% of all central nervous system tumors ¹²⁵. In the treatment of brain tumors and glioblastoma, surgical intervention and radiation therapy are limited due to infiltration of cancer cells into the healthy brain, leading to damaging effects after treatment ¹²⁶. Therefore, alternative therapies using naturally derived compounds such as curcumin with less side effects than the conventional treatments are receiving more attention. Curcumin has multiple molecular targets, therefore, combating brain tumors may take different cellular pathways, including apoptosis, autophagy, angiogenesis, invasion, and metastasis ¹²⁵. Although penetrating the blood–brain barrier (BBB) is considered the rate-limiting step for many anticancer agents, curcumin was able to cross the blood–brain barrier in high levels ¹²⁷. Moreover, an animal study using human glioma U-87 cells xenografted into athymic mice showed that curcumin is able to suppress glioma angiogenesis through inhibiting MMP-9 and downregulating endothelial cell markers (CD31 and CD105 mRNA) ¹²⁷. Curcumin was also able to induce G2/M cell cycle arrest by increasing protein kinase 1 (DAPK1) in U-251 malignant glioblastoma cells, which indicates that suppressing DAPK1 by curcumin does not only induce cell arrest but also inhibits STAT3 and NF-κB and activates caspase-3 ¹²⁸.

Antioxidant activity of curcumin

The imbalance between free radicals and the body’s defense system against oxidative stress can cause various chronic diseases ¹²⁹. An excessive production of reactive oxygen species (ROS) can induce oxidative stress and damage essential biomolecules, while antioxidants, including antioxidant enzymes and antioxidant compounds, can protect the human body from free radicals and ROS effects, attenuating the progress of many chronic diseases ¹³⁰. Both in vitro and in vivo studies have revealed the antioxidant activity of curcumin contributes to its diverse therapeutic effects. The research on the chemical structure of curcumin shows that electron-donating groups of curcumin, especially the phenolic hydroxyl group, are the main contributors to its antioxidant activity ¹³¹.

Curcumin mainly reduces the oxidative stress by scavenging free radicals ¹³². Studies have shown that curcumin can directly remove the excessive free radicals and prevent ROS production ¹³³. In A549 cells with influenza A virus (IAV)-induced oxidant stress, curcumin treatment is found to inhibit the production of ROS as well as the activation of toll-like receptor, which may be responsible for the suppression of influenza A virus infection ¹³⁴. Quinocetone causes genotoxicity and oxidative stress in human hepatocyte L02 cells, and curcumin pretreatment markedly inhibits excessive ROS generation, with the suppression of the decrease in the activity of antioxidant enzymes, like superoxide dismutase (SOD), and levels of antioxidant constituents, such as glutathione (GSH) ¹³⁵. In addition, in diabetic mice, curcumin treatment inhibits ROS production and hyperglycemia-induced oxidative stress by restoring the functions of DNA methyltransferase (DNMT) ¹³⁶.

On the other hand, curcumin can also increase the activities of antioxidant enzymes. Treatment of curcumin significantly increases the activity of paraoxonase 1 arylesterase (PON1), reduces the susceptibility of low-density lipoprotein (LDL or “bad cholesterol”) oxidation, and restores the abnormal biochemical parameters caused by HgCl2 ¹³⁷. Additionally, the administration of curcumin results in amelioration of aflatoxin B1-induced effects via increases in the level of GSH, gene expression, and activities of antioxidant enzymes, such as catalase, SOD, glutathione peroxidase (GSH-Px), and glutathione-S-transferase ¹³⁸. Furthermore, curcumin significantly reverses the decreased activity of SOD induced by zymosan and attenuates the increase of the level of malondialdehyde (MDA) ¹³⁹. In allergic rhinitis, the curcumin fed rats show higher tissue GSH levels in inferior turbinate tissues and GSH-Px activity in serum than those of the control ¹⁴⁰. In addition, curcumin increases the glutathione level in erythrocytes and plasma, while simultaneously decreases the oxidant potential of plasma ¹⁴¹. Furthermore, an in vitro study indicates that curcumin blocks nuclear factor κB (NF-κB) activation due to its antioxidant activity ¹⁴².

Considering the potent antioxidant activity, curcumin has been found to scavenge free radicals, restore abnormal alternations induced by external factors, and repress transcription factors related to oxidation. These effects help reduce oxidative stress and lower the risk of various chronic diseases. However, it should be pointed out that a compound with antioxidant activity in test tube study cannot represent an effective antioxidant in vivo, and it can be a pro-oxidant under certain conditions, showing no health benefits ¹⁴³.

Anti-inflammatory activity of curcumin

Curcumin can also protect against inflammation effectively via modulating pro-inflammatory cytokines and related signaling pathways, such as NF-κB, peroxisome proliferator-activated receptor-gamma (PPAR-γ), and myeloid differentiation protein 2-TLR 4 co-receptor (TLR4-MD2) signaling pathways ¹⁴⁴. The inflammatory response is often accompanied by the excessive production of pro-inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). Therefore, the downregulation of proinflammatory cytokines may effectively reduce the incidence of inflammation ¹⁴⁵. Pretreatment of curcumin on human genital epithelial cells abrogates the glycoprotein 120-mediated upregulation of the pro-inflammatory cytokines, TNF-α, and IL-6, as well as the chemokines, IL-8, RANTES (regulated on activation, normal T cell expressed, and secreted), and interferon γ-induced protein-10 (IP-10) ¹⁴⁶. Moreover, curcumin-loaded solid lipid nanoparticles can effectively decrease the expression of serum pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β ¹⁴⁷. Also, the liposomal curcumin complex effectively decreases pro-inflammatory cytokine and chemokine expression in synovial fibroblasts and macrophages without affecting cell viability, showing less toxicity compared to free curcumin ¹⁴⁸: Toxicity and biological activity in synovial fibroblasts and macrophages. In Vivo. 2016;30:413–419.)). The degradation product of curcumin, 4-vinyl guaiacol, has been reported to decrease IL-6 gene expression in lipopolysaccharide (LPS)-stimulated mice macrophages ¹⁴⁹.

The upregulation of anti-inflammatory cytokines is also essential for the reduction of the inflammatory response. Results show that curcumin can inhibit inflammation and increase M2-like macrophages in white adipose tissues, promoting the production of anti-inflammatory cytokines ¹⁵⁰. Moreover, the animal study reveals that curcumin exhibits antiepileptogenic effects by upregulating the gene expression of anti-inflammatory cytokines, such as interleukin 10 receptor (IL-10R), chemokine (C-X-C motif) ligand 16 (CXCL16), and CXCL17 ¹⁵¹. In cultured macrophages, it is observed that macrophages uptake the curcumin-loaded nanoparticles, and significantly increase the release of anti-inflammatory factors, including transforming growth factor-beta (TGF-β) and IL-10 ¹⁵². In summary, curcumin exhibits anti-inflammatory activity via the regulation of pro-inflammatory cytokines, such as IL-6, TNF-α, and IL-1β, as well as anti-inflammatory cytokines, such as IL-10 and TGF-β.

The anti-inflammatory property of curcumin is also involved in other signaling pathways. Curcumin is also found to induce degranulation in human neutrophils by increasing the cell surface expression of cluster of differentiation 35 (CD35) (secretory vesicle), CD63 (azurophilic granules), and CD66b (gelatinase granules) ¹⁵³. The control of neutrophils may be a potential anti-inflammatory mechanism of curcumin. In addition, curcumin exhibits anti-inflammatory activity via the PPAR-γ. A study finds that curcumin decreases the production of NO and suppresses the proliferation of vascular smooth muscle cells by elevating PPAR-γ activity, so as to attenuate angiotensin II-induced inflammatory responses ¹⁵⁴. Additionally, it has been reported that the TLR4-MD2 signaling complex is inhibited by curcumin and its analogs. It is supposed that curcumin and its analogs can compete with lipopolysaccharide for binding on MD2 and finally reduce the inflammation ¹⁴⁴. Overall, curcumin also exhibits anti-inflammatory activity by interacting with inflammation-related signaling pathways, such as NF-κB, PPAR-γ, and TLR4-MD2 signaling pathways.

Immune-regulatory activity of curcumin

Numerous studies have indicated that curcumin is beneficial to the immune system, and it interacts with immune cells to protect against immune-related diseases by modulating various immune cells, such as various T lymphocyte subsets, macrophages, dendritic cells, B lymphocytes, and natural killer cells, and improving the aberrant alternations of immunological parameters ¹⁵⁵. Curcumin can reduce the numbers of neutrophil and eosinophil, and increase the lymphocyte counts ¹⁵⁶. In addition, Th1 cells produce IFN-γ, TNF-α, and IL-1β, while Th2 cells produce IL-4, IL-10, and TGF-β. Th17 cells can produce IL-17, and the immune suppressive Treg cells can prevent autoimmune disease. The balance of this subpopulation of T cells is crucial for the modulation of the immune system ¹⁵⁷. Meanwhile, pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages correspond to Th1 and Th2 cells, respectively. The levels of M1 and M2 macrophages are of great importance for the immune system homeostasis ¹⁵⁸. Curcumin poses a stimulatory effect on Th1 cells and an inhibitory effect on Th2 cells, regulating the Th1/Th2 balance in ovalbumin-sensitized rats. Curcumin exhibits protective effects against immunotoxicity induced by 2-amino-3-methylimidazole (4,5-f) quinoline, which diminishes the percentage of blood lymphocytes ¹⁵⁹. It has also been reported that curcumin attenuates experimental autoimmune myasthenia gravis via the regulation of various immune cells ¹⁶⁰. Specifically, it inhibits the expression of T cell co-stimulatory molecules, shifts the balance from Th1/Th17 toward Th2/Treg, increases the number of NKR-P1+ cells, and promotes the differentiation of B cells into a subset of B10 cells. Also, an in vitro study of bone marrow-derived mesenchymal stem cells with curcumin shows an increasing trend towards M2 macrophage polarization, providing a favorable immune microenvironment for cutaneous wound healing ¹⁵⁸. Moreover, curcumin mediates a lower level of macrophage infiltration and inhibits NF-κB activation in macrophages ¹⁶¹. An in silico study indicates that the antioxidant property and strong binding affinity with CD4 and CD8 receptors of curcumin inhibit the thymic apoptosis induced by deltamethrin ¹⁶². Furthermore, curcumin has been reported to provide a protection of immunity by reversing type-2 cytokine bias, reducing the Treg cell population, and inhibiting T cell apoptosis ¹⁶³.

In fish fed with the dietary curcumin, it has been observed that the lysozyme activity, total IgG, and IgM levels increase after curcumin treatment, suggesting an effect on improving the immune responses to Aeromonas hydrophila ¹⁶⁴. For the weaned piglets orally administered with the enterotoxigenic Escherichia coli, the treatment of curcumin increases the secretory immunoglobulin (sIgA), improving the immune status ¹⁶⁵. Moreover, curcumin is able to modulate the production of immune mediators. For example, it can induce the increase of IFN-γ as well as the decrease of IL-1β, IL-4, IL-6, IL-17A, and TNF-α ¹⁶⁶.

Overall, curcumin mainly improves the immune system via the interaction with immune cells, such as lymphocytes and macrophages. Also, curcumin induces immune responses by modulating immune molecules, such as IgG, IgM, and sIgA.

Neuroprotective activity of curcumin

Curcumin has shown the potential as a neuroprotective agent due to its antioxidant and anti-inflammatory activities and the ability to maintain the chemical balance in the brain ¹³². Scientists have revealed that curcumin pretreatment is effective to reduce H2O2-induced neurotoxicity in PC12 cells by attenuating caspase activation, poly (ADP-ribose) polymerase (PARP) cleavage, DNA damage, and the accumulation of ROS, and dysregulation of the MAPK and Akt pathways. These protective effects can be used in the therapy for human neurodegenerative diseases ¹⁶⁷. Furthermore, the neuroprotective property of curcumin can reduce H2O2-induced damage in the SH-SY5Y human neuroblastoma cell line, and enhance cell viability ¹⁶⁸. Anti-neuroinflammatory results elucidate that curcumin inhibits the secretion of pro-inflammatory mediators and cytokines, induces HO-1 transcription and translation, and modulates NF-κB and MAPK signaling pathways, reducing inflammation in microglial cells ¹⁶⁹. The suppression of inflammation by curcumin leads to the reduction in astrocyte hypertrophy and the activation of microglia in the hippocampus, contributing to a better memory and mood function ¹⁷⁰. Furthermore, the pretreatment of curcumin is also effective to attenuate brain trauma and improve neurological function, alleviate neuropathic pain, mitigate axonal injury, and protect against ischemia and reperfusion injury ¹⁷¹.

Test tube and animal studies have shown the potential of curcumin as an adjuvant for the treatment of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. In neurodegenerative diseases, curcumin treatment can bind to some proteins or limit the aggregation of other protein to maintain homeostasis of the inflammatory system and facilitate the heat shock system ¹⁷². Numerous studies acknowledge that the accumulation of amyloid-β protein and hyperphosphorylated tau proteins is the hallmark of Alzheimer’s disease. Curcumin may directly bind to PPAR-γ and increase transcriptional activity and protein levels of PPAR-γ, which alleviates amyloid-β-induced neuroinflammation and improves neuronal status in the rat model of Alzheimer’s disease ¹⁷³. The toxicity of the amyloid-β peptide damages spatial learning and memory through the c-Jun N-terminal kinase (JNK) signaling pathway in Alzheimer’s disease. After treating with curcumin, Alzheimer’s disease rats show restored spatial learning and memory deficits, and JNK-3 phosphorylation is inhibited ¹⁷⁴. In mice with Alzheimer’s disease, active avoidance and locomotor activity are improved by curcumin, which protects against neurodegeneration ¹⁷⁵. For Parkinson’s disease, increasing evidence indicates that the accumulation of α-synuclein protein plays a vital role in the occurrence of Parkinson’s disease ¹⁷⁶, suggesting that curcumin can reduce the accumulation of A53T α-synuclein by downregulating the mTOR/ribosomal protein S6 kinase (p70S6K) signaling, and restoring macroautophagy. Curcumin prevents α-synuclein from aggregating in the dopaminergic neurons at both the gene level and protein expression level ¹⁷⁷. Meanwhile, curcumin inhibits astrocytic activation, and reduces iron deposition on the dopaminergic neurons. Moreover, the cognitive function is impaired in mice with Parkinson’s disease, while curcumin treatment in mice reduces the enhanced acetylcholine esterase enzyme levels, and restores the moto deficits, improving the cognitive functions ¹⁷⁸. Curcumin provides protection for neurons by reducing p-p28 expression, caspase-3 activation, and toxic quinoprotein formation in 6-hydroxydopamine treated SH-SY5Y cells, ameliorating oxidative stress-related neurodegeneration, like Parkinson’s disease ¹⁷⁹.

It has been documented that the exposure to some heavy metals, medications, and chemicals can induce nerve injuries, and even neuropathology of several neurodegenerative disorders. Curcumin diminishes copper-induced neurotoxicity in vivo by upregulating tyrosine hydroxylase expression and restoring locomotor performance ¹⁸⁰. In addition, curcumin treatment can ameliorate arsenic-induced mitochondrial dysfunctions and modulate proteins related to apoptosis to reduce cholinergic deficits ¹⁸¹. Additionally, curcumin has been reported to abrogate the neurotoxicity induced by some drugs. For example, curcumin is found to remarkably ameliorate the abnormal alternations caused by cisplatin, including thermal hypoalgesia, reduced sciatic motor nerve conduction velocity, and nuclear and nucleolar atrophy with the loss of neurons ¹⁸². Bupivacaine, a widely-used anesthetic, has neurotoxicity in SH-SY5Y cells, and curcumin has been observed to protect against neuronal injury by increasing the level of Akt phosphorylation ¹⁸³. With the intervention of curcumin on pregnant mice, cultured neurons, and neural progenitor cells, results show that curcumin can mitigate the toxic effects of celecoxib on fetal brain development by suppressing the proliferation of neuronal progenitor cells via activation of the Wnt/β-catenin pathway ¹⁸⁴. Furthermore, the treatment of curcumin has been reported to reduce colistin-induced neurotoxicity in neuroblastoma-2a through regulating NF-κB signaling, leading to antioxidative and anti-apoptotic responses ¹⁸⁵. Furthermore, toxic chemicals, like quinolinic acid, also impair the nervous system. Curcumin prevents rotation behavior, striatal morphological alterations, and neurodegeneration induced by quinolinic acid, and activates the Nrf2 cytoprotective pathway to induce antioxidant responses ¹⁸⁶.

Cardiovascular protection

It has been documented that the intake of curcumin is beneficial to cardiovascular diseases ¹⁸⁷. Curcumin can protect heart muscle cells (cardiomyocytes). For instance, curcumin protects against norepinephrine-induced hypertrophic stress and maintains extracellular matrix remodeling by inhibiting the increased collagen content under hypertrophic stress, and suppressing enhanced gelatinase B expression and gelatinolytic activity in H9c2 cardiomyocytes ¹⁸⁸. It has also been found that curcumin prevents cardiomyocytes from norepinephrine-induced apoptosis and restores their physiological status ¹⁸⁹. In addition, the administration of curcumin can attenuate the cytotoxicity of hemiscorpius lepturus venom, which damages the mitochondrial respiratory chain and results in ATP depletion, death signaling, and consequent cardiomyocytes apoptosis ¹⁹⁰. Furthermore, curcumin increases the viability of H9c2 cardiomyoblasts exposed to H2O2 by upregulating the HO-1 protein, inhibiting cleaved caspase-3 protein expression, and increasing the Bcl-2/Bax ratio ¹⁹¹. Additionally, curcumin prevents cardiomyocytes from high glucose-induced apoptosis via the inhibition of NADPH-mediated oxidative stress by modulating the PI3K/Akt signaling pathway ¹⁸⁷.

It is reported that curcumin can ameliorate cardiac hypertrophy and preserve cardiac function by upregulating Na+/Ca2+ exchanger expression levels. The left ventricle (LV) end-systolic and diastolic dimensions are reduced, and the LV ejection fraction and LV fractional shortening are enhanced in vivo by curcumin ¹⁹². Another work uses high doses of glucose and insulin to induce hypertrophy in cardiomyocytes and the treatment of curcumin decreases the increased ANF mRNA expression, total protein content, and cell surface area, resulting in attenuated cardiomyocyte hypertrophy ¹⁹³. Meanwhile, curcumin increases PPAR-γ and Akt protein expressions, endothelial NO synthase (eNOS) mRNA expression, eNOS content, and NO concentration in cardiomyocytes. Curcumin is also found to suppress hypertrophic responses in cardiomyocytes by disrupting the formations of the zinc finger transcription factor, GATA4, and functional proteins, such as intrinsic histone acetyltransferase, and p300 ¹⁹⁴. Additionally, curcumin can attenuate chronic heart failure by increasing Dickkopf-related protein 3, p38 MAPK, JNK, and apoptosis signal-regulating kinase 1 (ASK1) ¹⁹⁵. Moreover, curcumin has been demonstrated to have hypocholesterolemic activity both in vitro and in vivo. Curcumin treatment is found to reduce cholesterol absorption in Caco-2 cells via downregulation of expressions of Niemann-Pick C1-like 1 (NPC1L1) and sterol regulatory element binding protein-2 (SREBP-2) ¹⁹⁶.

The occurrence of cardiovascular diseases is closely related with unbalanced diets. For curcumin, it protects the cardiomyocytes from injuries, and decreases cardiac hypertrophy, chronic heart failure, and cholesterol absorption.

Anti-diabetic effect of curcumin

Diabetes mellitus has reached pandemic status and there have been numerous studies on the development of anti-diabetic drugs with fewer side effects ¹⁹⁷. Curcumin has been found to exhibit promising anti-diabetic activity, and curcumin intervention on prediabetic individuals can significantly lower the risk of developing type 2 diabetes ¹⁹⁸. Additionally, curcumin can be a potential alternative to prevent and treat diabetes as well as certain complications, such as diabetic retinopathy ¹⁹⁹.

The anti-diabetic activity of curcumin commonly reflects on the control of hyperglycemia by downregulating α-glucosidase and α-amylase activity. In addition, curcumin is beneficial for insulin-producing and insulin-responsive tissue, such as liver, skeletal muscle, and adipose tissues ²⁰⁰. Molecular docking in silico shows that curcumin poses a better inhibitory effect on α-amylase than other natural compounds, such as quercetin and berberine ²⁰¹. After hyperglycaemic rats were administered with curcumin, the mean blood glucose level was significantly reduced ²⁰². Additionally, the glucose tolerance and insulin sensitivity of diabetic rats were enhanced after being treated with curcumin ²⁰³. Meanwhile, the levels of Akt phosphorylation and glucose transporter type 4 (GLUT4) translocation in skeletal muscles are increased by curcumin. Moreover, in diabetic mice treated with curcumin for 12 weeks, pancreatic islets have no lymphocytes infiltration and there is an increase in the numbers of small islets of Langerhans near the ducts in the pancreas, which indicates an improvement of pancreatic islets ²⁰⁴.

Liver protective effect of curcumin

Numerous studies indicate that curcumin exhibits hepatoprotective effects on acute and chronic liver injuries induced by pollutants, drugs, and alcohol, nonalcoholic fatty liver disease, and liver fibrosis ²⁰⁵. Carbon tetrachloride (CCl4), a well-known hepatotoxin pollutant, can induce acute or chronic liver injuries, and result in a high level of ROS, mitochondrial dysfunction, and cellular apoptosis ²⁰⁶. Nanoparticulated curcumin has been evidenced to maintain cellular ROS levels, increase cellular antioxidant enzymes, prevent excessive mitochondrial destruction, and decrease fatty changes and inflammation in CCl4-treated rat hepatocytes ²⁰⁷. Enzymes, such as aspartate aminotransferase (AST) and alanine transaminase (ALT), in serum, are the main liver transaminases for liver damage assessment, and the hepatic GSH content indicates oxidative stress in the liver ²⁰⁸. Turmeric extract and curcumin are found to suppress CCl4-induced hepatic oxidative stress. They decrease the activities of serum aspartate aminotransferase (AST) and alanine transaminase (ALT) and the level of lipid peroxidase, while increasing the hepatic GSH content ²⁰⁹. Additionally, curcumin is able to reduce the number of apoptotic hepatocytes induced by cadmium accumulation ²¹⁰.

Curcumin has been reported to ameliorate streptozotocin-induced liver injury of diabetic rats by decreasing hepatic endoplasmic reticulum stress marker protein and the sub-arm of unfolded protein response signaling protein, and inhibiting TNF-α, IL1β, phospho-p38 MAPK, and ASK1 in liver ²¹¹. Paracetamol-induced mitochondrial dysfunction in hepatocytes is also attenuated by curcumin. It decreases oxygen consumption in the membrane potential, ATP synthesis, aconitase activity, and the activity of respiratory complexes, I, III, and IV ²¹².

Alcoholic liver disease is characterized by the disturbance of alcohol and lipid metabolism. A metabolomic pathway analysis shows that curcumin attenuates ethanol-induced liver injury by inhibiting the biosynthesis of unsaturated fatty acids, and interconversions of pentose and glucuronate ²¹³. In addition, curcumin dose-dependently attenuates the hepatocyte necroptosis and alcohol-induced decrease in hepatic Nrf2 expression in alcoholic mice ²¹⁴.

Recently, curcumin has been reported to possess therapeutic efficacy in nonalcoholic fatty liver disease (NAFLD) experimental models, including non-alcoholic steatohepatitis (NASH) ²¹⁵. Oral administration of curcumin effectively protects against the progression of NAFLD induced by a high-fat diet through alternations in the metabolism, and the intrahepatic CD4+ cell accumulation ²¹⁶. Furthermore, high mobility group box 1 (HMGB1) is demonstrated to interact with TLR4, and induce nuclear translocation of activated NF-κB, releasing pro-inflammatory cytokines ²¹⁷. Curcumin can reduce cytoplasmic translocation of HMGB1, the level of TLR4 protein expression, and the nuclear translocation of NF-κB ²¹⁸. Moreover, some studies elucidate that curcumin exhibits its hepatoprotective property by inhibiting transient receptor potential melastatin 2 (TRPM2) channels, and curcumin can restore Ca2+ levels, reduce oxidative stress, and lower the risk of NASH ²¹⁹.

Further investigations reveal that curcumin inhibits the angiogenesis in liver fibrosis. Curcumin reduces the angiogenic properties of hepatic stellate cells, disrupts the platelet-derived growth factor- receptor (PDGF-R)/ERK and mammalian target of rapamycin (mTOR) pathways, and regulates activation of PPAR-γ ²²⁰. In addition, curcumin can suppress liver fibrosis via miRNA-mediated epigenetic regulation. It has been reported that curcumin upregulates miR-29b expression with the downregulation of DNA methyltransferase 3b as well as the upregulation of PTEN, which inhibits the activated hepatic stellate cells ²²¹.

Is curcumin safe?

Turmeric and curcumin may be unsafe for use during pregnancy in amounts greater than those commonly found in food. Little is known about whether it’s safe to use turmeric in amounts greater than those commonly found in food while breastfeeding. Curcumin has been consumed for hundreds of years and is considered pharmacologically safe when taken at doses up to 100 mg/day ¹⁴, ¹⁵, ¹⁶. Several studies including preclinical and clinical evaluated the safety of curcumin ²²², ²²³, ²²⁴. The maximum proposed dose of curcumin varies, ranging from daily consumption of 3 mg/kg to 10 g ²²⁵. In a clinical study, no serious adverse effect was observed in any of the healthy subjects who used a daily dose of 12 g ²²⁶. In one study, high doses of curcumin (8000 mg/day) do not cause side effects ⁷. In another study, curcumin was administered at doses up to 12 g/day for three months with no apparent toxicity ⁸. However, some studies have found that high concentrations of curcumin have some side effects. Tanwar et al ⁹ found that curcumin had antioxidant effects at lower concentrations (100 or 200 mg/kg/day), but curcumin had side effects of promoting lipid peroxidation at higher concentrations (400 mg/kg/day) in a rat model of myocardial necrosis induced by isoprenaline. In another study, Sun et al ¹⁰ found that curcumin (75 mg/kg/day) can induce histone hypoacetylation and inhibit the expression of transcription factors such as GATA4 early in heart development, ultimately leading to defects in heart development, such as thinning of the ventricular wall and septum. In general, curcumin may be detrimental to embryonic heart development during early pregnancy ¹⁰. Clinically, the common side effects of curcumin are flatulence, changes in liver enzymes and blood biochemical parameters ¹¹, ¹². The metabolism and lipid-lowering effects of curcumin are mainly carried out in the liver, which may be the main reason for the increase of liver enzymes ¹³.

According to the Joint Food and Agriculture Organization/The World Health Organization (JECFA) report on food additives, the Acceptable Daily Intake Level (ADI) of curcumin is 0 to 0.1 mg/kg body weight ¹⁷. In clinical trials, curcumin was found to be safe and effective. In a randomized and controlled clinical trial involving patients with arthritis, curcumin was administered in doses ranging from 120 to 1500 mg for 4 to 36 weeks, reduced inflammation and pain levels, and was shown to be a safe treatment method ¹⁸. Also, in a clinical study comparing the administration of curcumin 500 mg (BCM-95®) 3 times/day and diclofenac 50 mg, 2 times/day for 28 days in patients with knee osteoarthritis, patients that received curcumin presented similar improvement in the severity of pain, reduction in flatulence episodes, no requirement of H2 blockers, weight reduction, and anti-ulcer effects, proving to be a very safe treatment method presenting a 13% adverse effect rate versus 38% in the diclofenac group ¹⁹. Furthermore, in chronic kidney disease subjects, supplementation with 500 mg of curcumin tablets, two times/day for six months, reduced plasma pro-inflammatory mediators and lipid peroxidation. During the long-term administration treatment, no serious adverse events were observed, confirming the safety profile of curcumin ²⁰. In addition, in patients with non-alcoholic fatty liver disease (NAFLD), curcumin supplementation of 1000 mg/day in two doses for eight weeks was considered safe and well tolerated with no report of severe adverse events during the treatment ²¹. The US Food and Drug Administration (FDA) approved the curcumin as a “generally safe” (GRAS) compound ²².

According to the literature, curcumin didn’t show mutagenic and genotoxic effects and is safe in pregnant animals ¹. However, more studies in humans are needed. In addition, animal studies didn’t report reproductive toxicity of curcumin following oral administration. Curcumin was safe even at the high doses: in a phase 1 human trial 25 subjects used up to 8000 mg of curcumin per day for 3 months without showing toxicity. Five other human trials using 1125–2500 mg of curcumin per day have also found it to be safe as well as in another study in which it was used 6 g/day orally for 4–7 weeks ²²⁷.

In addition, a good safety profile has been reported for curcumin in patients with cardiovascular risk factors or pre-malignant lesions of internal organs who took a dose of curcumin ranging from 500 to 8000 mg/day for a 3 months period ²²⁸, ²²⁴. This safety has been observed in patients with different cancers, including colorectal (taking, ranging from 36 to 180 mg/day for up to 4 months), breast (taking up to 6000 mg/day) and pancreatic cancer (taking 8000 mg/day of curcumin for 2 months) ²²⁹, ²³⁰, ²³¹.

Having in mind that the majority of studies reporting curcumin safety has been performed for short periods of time so far and, there is not complete evidence regarding the consequences of long term administration of curcumin ¹. Therefore, clinical trials and more studies are needed specially on new formulations and in long term use to find out all aspects of toxicity of curcumin.

Only limited side effects such as gastrointestinal upsets have been stated in human. In addition, abdominal pain has also been reported followed by curcumin consumption at a dose of 8000 mg/day in patients with pancreatic cancer ¹¹⁰. These gastrointestinal side effects might be related to the curcumin-induced cyclooxygenase (COX) inhibition and the subsequent inhibition of prostaglandin (PG) synthesis and/or its influence on the composition of the gut microbiome, which needs further study to be established. In addition to gastrointestinal side effects, a mild headache or nausea have been reported in few patients affected by primary sclerosing cholangitis taking curcumin in dose of up to 1400 mg/day ²³².

Furthermore, recent reports of liver diseases related to curcumin attracted the medical community’s attention to its possible liver toxicity ²³³. Whether this effect belongs to curcumin molecule or other possible contamination has to be clarified.

Evaluating the other routes of administration, in a short-term intravenous dosing of liposomal formulation, curcumin has been shown to be safe up to a dose of 120 mg/m² on healthy subjects in a clinical trial, while in a dose escalation study in patients with metastatic cancer a dose of 300 mg/m² over 6 h reported to be the maximum tolerated dosage ²³⁴, ²³⁵. One case of hemolysis and one death associated with intravenous curcumin preparations have been reported, indicating that regarding the safety of intravenous administration of curcumin, further studies and data are needed ²³⁵, ²³⁶, ²³⁷.

Curcumin and turmeric summary

In light of the instability of curcumin, many animals and human studies, especially preclinical trails, still support the therapeutic and protective effects of curcumin, while more clinical trials are necessary to clarify its effects on human. Although there is still a debate about curcumin beneficial effects on humans, numerous preclinical studies still support its health benefits due to their versatile bioactivity. Therefore, curcumin can be still a good natural ingredient for the development of relevant functional foods as promising alternatives for the prevention of certain chronic diseases.

In conclusion, curcumin has been reported to exhibit versatile bioactivity and provide diverse health benefits to humans, such as antioxidant, anti-inflammatory, and anticancer activities. Furthermore, it is promising to use the nanotechnology to encapsulate curcumin to improve its stability, bioavailability, bioactivity, and health benefits.

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