Abstract
The rhizome of turmeric (Curcuma longa L.) has been used as an herbal medicine, coloring agent, spice, and food additive for thousands of years in different parts of the world particularly in Asian countries. It has been used for a range of diseases in many traditional medical schools, including Islamic traditional medicine, Chinese traditional medicine, and Ayurveda. It has been used mainly for digestive problems, as a cardio-, hepato-, and neuroprotective agent as well as in many inflammatory conditions such as arthritis and for enhancing immune system. Curcumin, a diarylheptanoid derivative found in turmeric, has anti-inflammatory, antioxidant, and anticancer properties; controls obesity and metabolic problems; and improves memory and mood disorders. Therapeutically, curcumin exhibits promising potential in preclinical and clinical studies and is currently in human trials for a variety of conditions, including metabolic syndrome, nonalcoholic fatty liver disease, rheumatoid arthritis, migraine, premenstrual syndrome, ulcerative colitis, knee osteoarthritis, polycystic ovarian syndrome, atherosclerosis, liver cirrhosis, amyotrophic lateral sclerosis, depression, psoriasis, and Alzheimer’s disease. Among all beneficial activities reported for curcumin, the research toward the obesity and metabolic-preventing/suppressing aspects of curcumin is growing. These findings emphasize that most of the traditional applications of turmeric is due to the presence of its key constituent, curcumin. According to the traditional background of turmeric use and clinical values of curcumin, further preclinical studies for unstudied properties and clinical studies with larger sample sizes for confirmed activities are expected.
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Keywords
- Turmeric
- Curcuma longa
- Zingiberaceae
- curcumin
- traditional medicine
- clinical trials
- hepato-protective
- cardioprotective
- neuroprotective
2.1 Introduction
Turmeric, belonging to Zingiberaceae family, is a perennial plant growing up to one meter high with oblong or cylindrical rhizomes. The rhizomes , being externally brown, consists of an egg-shaped primary rhizome called the “tuber” and several branched secondary rhizomes called the “rhizome.” The internal color of the rhizomes ranges from yellow to yellow-orange. This yellow color is due to the presence of pigments known as curcuminoids, which possess diverse pharmacological activities [1]. Chemically, curcuminoids known as diarylheptanoids consist of two aryl groups which are connected to each other via a chain with seven carbons. Curcumin (diferuloylmethane) is the most important bioactive curcuminoids. However, there exist other curcuminoids like desmethoxycurcumin and bisdesmethoxycurcumin in turmeric rhizome (Fig. 2.1) [2]. According to preliminary, preclinical, and clinical studies, the yellow pigment curcumin possesses a worthy pharmacology including anti-inflammatory [3, 4], immunomodulatory [5], antioxidant [6], hypolipidaemic [7], antimicrobial [8], anticarcinogenic [9], antitumor [10, 11, 12], radioprotective [13], neuroprotective [14], hepato-protective [15], nephroprotective [16], cardio-protective [17], and vasoprotective activities. Curcumin has been shown to interact with a wide range of biochemical pathways and influence a variety of molecular targets such as cytokines [18], transcription factors [19], kinases [20], growth factors [21], and microRNAs [22].
The chemical structure of the main curcuminoids (the key constituents of turmeric)
Turmeric, also known as Indian saffron, has a long history of use as an herbal medicine, spice, and a coloring agent [23]. The first record of turmeric use dates back to 600 BC in an Assyrian herbal. It was also mentioned by famous Greek physician, Dioscorides, and many traditional scholars in Islamic traditional medicine (ITM) [24,25,26,27,28,29,30,31,32,33,34,35,36,37]. It has also a long-standing reputation in Chinese traditional medicine (TCM), Ayurveda, and different folk medicines around the world [38]. It has been traditionally used for the treatment of a range of diseases including skin disorders (topically) and poor digestion and liver function (internally) [38]. As the knowledge from traditional medicine is a guide for the scientists in the field of natural product–based drug discovery, we decided to investigate the medicinal applications of turmeric in different systems of traditional medicine and the pharmacological activities of curcumin in modern medicine to see the progress from ancient medicine to current clinical trials.
2.2 Traditional View
Turmeric has a long history of medical use in many cultures, particularly in Asia. Turmeric is originally a plant from India and South-East Asia, but nowadays it is cultivated in different regions of the world. However, India is still the largest producer of this valuable plant. Several traditional textbooks [24,25,26,27,28,29,30,31,32,33,34,35,36,37] and electronic scientific literature were searched to find the applications of turmeric in ancient times.
2.2.1 Turmeric in Islamic Traditional Medicine (ITM)
Turmeric, known as Zardchoobeh in Farsi (Persian language) and Hūrd, Kūrkūm, ʿOruqṢūfer, ʿOruqal-ṢabaghinKabir in Arabic, refers to Curcumalonga L. [Syn. C. domestica Valeton] in ITM textbooks. The latter name has made many of the ITM scientists a bit confused since Chelidoniummajus L. is called ʿOruqal-Ṣabaghin Ṣaghir. Some authors do not distinguish between these two names regardless of the suffixes Kabir or Ṣaghir. Even, some scientists believe that ʿOruqal-Ṣabaghin is the name of Rubiatinctorum L.
According to turmeric monographs in the most important textbooks of Islamic medicine, it is deduced that most authors consider it as warm and dry in the second degree and others in the third degree. Pharmacologically, different parts of turmeric plants have been prescribed by ITM physicians to manage various health problems particularly, inflammatory-related disorders. For example, the wood of turmeric has been used for the treatment of toothache. Its extract has been applied for eye problems such as cataract and corneal opacity as well as strengthening eyesight. It was administered topically to relieve the aches in the joints. Putting turmeric powder on wet and infectious wounds can dry them out.Topical administration of turmeric is useful for treating scabies, moist scabies, and herpes. In addition, this spice has been highly recommended for obstructive jaundice (caused by bile duct obstruction), cardiac problems like tachycardia, and nervous system–related problems such as epilepsy and paralysis [24,25,26,27,28,29,30,31,32,33,34,35,36,37].
2.2.2 Indian Traditional Medicine (Ayurveda)
Turmeric is commonly called “Haldi” in north India, and “Manjal” in the south [39]. In India, turmeric is used for a range of diseases similar to ITM. Indian people has used turmeric as a gastric tonic, as well as a blood purifier, digestive, anti-fever, and wound healing agent. It is also used for pregnancy nausea and skin and liver disease. It has been externally used to relieve conjunctivitis, skin infections, arthritis, hemorrhoids, and eczema. In addition, Indian women apply turmeric on their skin to reduce hair growth [39, 40].
2.2.3 Traditional Chinese Medicine (TCM)
In TCM, a range ofapplications have been reported for turmeric rhizome and tuber. Turmeric rhizomes, being a blood and Qi (vital energy) stimulant, have been used as an analgesic, painkiller, and wound healing agent. It has been prescribed for treating jaundice, chest and abdominal pain and swelling, frozen scapula, postpartum abdominal pain, and amenorrhea. Turmeric tuber, known as Yu Jin, is spicy and bitter and has been used in hot conditions like viral hepatitis since it is considered as a cooling agent. Ithas been used to relieve menstrual pain, heal traumatic injuries, treat enlarged liver cirrhosis, and treat mental problems like mania and epilepsy [41].
2.2.4 Traditional Thai Medicine (TTM)
In TTM, turmeric has been used in cases of gastrointestinal ulcers, anal hemorrhoids, vaginal hemorrhoids, skin diseases, ringworms, and insect bites and for the prevention of gonorrhea and common colds [23].
2.3 Clinical View
The biological and pharmacological effects of curcumin have been described by several in vitro and in vivo studies, showing the potential antioxidant, anti-inflammatory, cardio-protective, anti-microbial, nephro-protective, hepato-protective, hypoglycaemic, immunomodulatory, and anti-rheumatic activities of this valuable compound [37]. Because of potent activities and rare serious side effects of curcumin observed in many preclinical studies, there have been a growing trend in clinical trials on curcumin in the last two decades. A search through scientific databases PubMed and Scopus using the words “curcumin” and “clinical trial” or “trial” yielded a total of 262 articles of which 175 are included in the present paper (Table 2.1). Other articles were systematic reviews, meta-analysis, or irrelevant topics. Similar to in vitro and animal studies, various human trials have shown anti-inflammatory, antioxidant, cardio-protective, antimicrobial properties (especially topically), and tissue protection effects including neuroprotective and hepato-protective activities for curcuminoids (Table 2.1).
2.3.1 Anti-Inflammatory and Antioxidant Activities
The anti-inflammatory activity of curcumin, being reported for the first time in 1971, has been investigated in many preclinical and clinical trials so far [41, 42]. In many cases, curcumin exerts its beneficial activity via decreasing acute or chronic inflammatory responses (Table 2.1). Curcumin inhibits the production of pro-inflammatorymonocyte/macrophage-derived cytokines such as interleukin-8 (IL-8), monocyte inflammatory protein-1(MIP-1), monocyte chemotactic protein-1 (MCP-1), IL-1b, and tumor necrosis factor-α (TNF-α) in several in vitro studies. Also, in vivo studies demonstrated the beneficial effect of curcumin on adipose tissue through the inhibition of several pro–inflammatory mediators, such as MCP-1, IL-1β, TNFα, IL-6, and cyclooxygenase 2 (COX2) [6, 43].
The clinical trials also support the benefit of curcumin in the treatment of acute and chronic inflammatory problems including advanced chronic kidney disease with hemodialysis [19, 44], cardiovascular diseases, rheumatoid arthritis [45], migraine [46,47,48], premenstrual syndrome (PMS) [49], mastitis [50], radiation dermatitis [51], postmenopausal syndrome [52], ulcerative colitis [53], chronic pulmonary complications of sulfur mustard (CPC-SM) [54, 55], metabolic syndrome (MeS) [56], knee osteoarthritis (KOA) [57, 58], and chronic SM-induced pruritic skin lesions [59] via suppressing the production of cytokines including IL-1β, IL-4, IL-6, IL-8, and TNF-α [60].
The protective effect of curcumin against oxidative damage has been proven in several cell lines and animal models. Curcumin reduces lipid peroxidation through the normalization of antioxidant enzyme levels, such as superoxide dismutase, catalase, and glutathione peroxidase (Gpx). It is a free radical scavenger of hydroxyl (OH) and nitric oxide (NO) radicals, protects DNA against oxidative injury, and reduces reactive oxygen species (ROS). Moreover, it can activate other cellular antioxidants such as heme oxygenase-1, NADPH:quinone oxidoreductase-1 and glutathione, upregulated Nrf2-ARE-regulated pathways [6, 61,62,63].
A systematic review and meta-analysis of curcumin in the management of inflammatory and oxidative stress markers concluded that there was a significant tendencyin favor of taking curcumin-containing supplements through a significant reduction in IL-6, high sensitive c-reactive protein(hs-CRP), and malondialdehyde (MDA) levels [64]. Another meta-analysis found that consumption of curcumin for 4 weeks or longer may play an antioxidative role by reducing circulating MDA concentrations and increasing superoxide dismutase (SOD) activity and the effect is greater when combined with piperine [65].
2.3.2 Metabolic Disorders
Metabolic disorders have been one of the major health problems in recent decades in both developed and developing countries. Interestingly, many of the studied clinical trials have been focused on investigating the effects of curcumin on different components of metabolic problems [56, 63, 66,67,68,69]. Accordingly, most of these studies have shown the beneficial effects of curcumin on regulating glucose and lipid contents of people with MeS or subjects prone to it. In the following paragraphs, the effects of curcumin are discussed in two main categories, namely, its cardio- and hepato-protective activities.
2.3.2.1 Cardio- and Vaso-Protective
Curcumin is gaining growing interest in the scientific community for treating cardiovascular problems. Curcumin has cardio-protective activities through different mechanisms and multiple molecular targets mainly due to its exogenous and endogenous antioxidant capabilities (Table 2.1). In particular, curcumin is involved in the regulation of lipid and glucose metabolism. Therefore, curcumin exerts its cardio-protective activity either through decreasing blood glucose levels via increasing insulin sensitivity and secretion [70,71,72] and decreasing insulin resistance or by regulating lipid metabolism such as decreasing triglycerides (TG), low density lipoprotein (LDL) and increasing high density lipoprotein (HDL) levels as well as decreasing obesity risk factors including body mass index (BMI), waist and hip circumferences [63, 73,74,75]. Curcumin regulates gene expression of PPAR-γ and LDL receptor, decreases serum CRP, adhesion molecule VCAM-1, creatine kinase-MB (CK-MB), leptin and cortisol, and increases serum adiponectin (Table 2.1).
Owing to the extensive clinical studies on curcumin, there are a large number of systematic reviews and meta-analysis from published works. Most of these analyses emphasized on the beneficial effects of curcumin in regulating blood glucose and lipid levels though there are some inconsistencies in the results. For instance, a meta-analysis, published in 2017, included seven double-blind, randomized, controlled trials (n = 649) of curcumin for dyslipidemia. Curcumin significantly reduced serum LDL-C and TG levels as compared to those in the control group though serum HDL-C levels were not obviously improved [76]. A systematic review of the efficacy of curcumin in patients with MeS concluded that curcumin appears to reduceTG, and total cholesterol (TC) , as well as fasting glucose levels, homeostasis model of assessment-estimated insulin resistance (HOMA-IR), glycosylated hemoglobin (HbA1c) while no significant effects on HDL and LDL cholesterol levels [77]. A systematic review and meta-analysis of the role of curcumin as an adjunct therapy in patients with MeS found seven clinical trials published up to late 2018. Data analysis showed that curcumin can significantly improve FBG, TG, HDL-C, and diastolic blood pressure levels [56]. In another systematic review studying eleven clinical trials on curcumin given to patients with disglycemia found benefit in improving FBG and HbA1c compared with placebo but not HOMA-IR [71]. A systematic review and meta-analysis of seven clinical trials investigating the effects of curcumin glucose profile in prediabetic patients revealed that curcumin can significantly reduce HbA1c and FBG [78].
In addition to direct effects of curcumin on blood glucose and lipid levels, curcumin appears to increase adiponectin and decrease leptin content. A 2019 systematic review of randomized, double–blind clinical trials identified six studies and concluded that curcumin supplementation significantly increased adiponectin concentrations in comparison with placebo. Greater effects on adiponectin were observed in trials lasting ≤10 weeks [79]. Another systematic review also published in 2019 investigated the influence of curcumin intake on weight loss among patients with MeS and related disorders. Eighteen clinical studies were identified from up to 2018 involving a total of 1604 patients. Curcumin intake significantly reduced BMI, weight, waist circumference (WC), as well as leptin levels and increased adiponectin levels [66].
2.3.2.2 Hepato-Protective
Curcumin has demonstrated promising hepato-protective activity through decreasing serum liver enzyme levels such as AST (aspartate aminotransferase) and ALT (alanine aminotransferase) [80], improving BMI, WC and hip circumference (HC) [81], decreasing liver fat content [69], and improving serum concentrations of TNF-α, MCP-1 and epidermal growth factor (EGF).
Among the reviewed clinical trials investigating the hepato-protective activities of curcumin, nonalcoholic fatty liver disease (NAFLD) is the most studied disorder. Unfortunately, NAFLD, a major cause of liver-related morbidity, is prevailing due to the rising epidemic of obesity. A systematic review and meta-analysis of curcumin versus placebo in the treatment of NAFLD concluded that curcumin supplementation significantly reduced BMI and WC [73]. Another meta-analysis found that curcumin supplementation in NAFLD patients makes a significant reduction in ALT, AST, serum TC, LDL, FBG, HOMA-IR, serum insulin, and WC [68]. Similarly, a meta-analysis that included 4 RCTs with a total of 229 NAFLD patients found that curcumin decreases LDL-C, TG, fasting blood sugar (FBS), HOMA-IR, weight, and AST levels compared with placebo [69].
2.3.3 Neuroprotective and Antidepressant
Neuroprotective potential of curcumin thought to be largely mediated by antioxidantmechanisms, anti-inflammatory responses such as inhibition of cytokine production [82], and reducing amyloid and tau accumulation in brain regions. Several clinical trials have examined the effects of curcumin supplementation on nervous system–related disorders like age-related cognitive decline, dementia, depression, and mood disorders. As it is shown in Table 2.1, curcumin supplementation has neuroprotective effects in a wide range of diseases including diabetic polyneuropathy, amyotrophic lateral sclerosis (ALS), migraine, Alzheimer’s disease, depression, and neurological symptoms associated with PMS.
Among all neuroprotective activities reported for curcumin, the efficacy of curcumin in Alzheimer’s disease and depression is receiving considerable research attention. In vitro and in vivo studies show that curcumin can significantly inhibit monoamine oxidase MAO-A and MAO-B activities in a dose-dependent manner, increase serotonin, noradrenaline, and dopamine levels markedly. A recent meta-analysis of six clinical trials with a total of 289 subjects showed that curcumin improved the memory and cognitive function in elderly people [83]. A meta-analysis evaluating the efficacy and safety of curcumin for the treatment of depression concluded a significant effect of curcumin in ameliorating depressive symptoms. Out of all six included trials, significant anti-anxiety effects were observed in 3 of the trials [84]. Another meta-analysis of six clinical trials, up to 2015, on curcumin in patients with major depression found that although there is a significant reduction of depression symptoms in all the patients, curcumin had the highest effect when given to middle-aged patients, for longer duration of administration, and at higher doses [85]. The anti-depressant and anti-anxiety activities of curcumin have also been confirmed by a recent meta-analysis of nine clinical trials [86].
2.3.4 Indications Supported by Both Traditional Medicine and Clinical Trials
From applications of turmeric in different systems of traditional medicine and the observed clinical efficacy and safety of curcumin in several trials, it can be concluded that there is a correlation between the data extracted from both sources. As indicated in the section “traditional view,” turmeric is mostly used in inflammatory and oxidative conditions and has been prescribed as a heart, liver, and neurological tonic as well as digestive problems in ITM, TCM, and Ayurveda. Islamic and Chinese traditional medicines and Ayurveda as the ancient schools of medicine have a large contribution to the distribution of old medicine to the modern world. The prescriptions in these schools, mostly being based on phytotherapy, are full of clues to find lead compounds with great medicinal properties. For instance, in ITM like many other medical systems, herbs have provided the basis for solving health problems. In this medical system, considerable respect was paid to the qualities of individual herbs. Physicians were familiar with the nature of each remedy, its actions, energy pattern, indications, and duration of action. Moreover, they were expected to understand the specific relationships of the herbal medicine to the organs, its toxicity contraindications, and antidotes, types of preparation that can be made, its dosage, administration and even its natural habitat. There were many outstanding physicians who made their scientific knowledge about the medicinal herbs written as Materia Medica. Persians ar-Rhazi (Rhazes), al-Majusi (Haly Abbas), and Ibn-Sina (Avicenna) were among the well-known physician who did notable developments. They were not only well familiar with the theoretical aspects of phytotherapy but also in practice [41, 87]. Turmeric is one of the well-known spices and medicinal herbs with many monographs written about its characteristics and medicinal values. It is almost mentioned in all ITM medicinal textbooks [87]. Curcuminoids are the yellow pigments in turmeric. Curcumin is the most important bioactive curcuminoids. As discussed in the previous sections, there are thousands of articles investigating the pharmacological activities of curcumin. Interestingly, the trend of clinical trials is toward to the claimed traditional uses. In the case of cardiovascular, metabolic, gastrointestinal, and neurological disorders, curcumin shows promising activities. It has also shown beneficial activities in inflammatory conditions and as a chemopreventive agent. Thus, it can be concluded that most of the reported traditional properties of turmeric are because of the presence of curcumin.
Taken together, curcumin is a promising lead compound for therapeutically purposes. Further research projects including in vitro and in vivo studies for the undetermined potential activities of curcumin as well as clinical trials for the potent properties reported in preliminary studies are expected. In addition, for the activities investigated in many human trials with positive results, more comprehensive studies are necessary.
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The authors are grateful to Mashhad University of Medical Sciences (MUMS) for help and supports.
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Akaberi, M., Sahebkar, A., Emami, S.A. (2021). Turmeric and Curcumin: From Traditional to Modern Medicine. In: Guest, P.C. (eds) Studies on Biomarkers and New Targets in Aging Research in Iran. Advances in Experimental Medicine and Biology(), vol 1291. Springer, Cham. https://doi.org/10.1007/978-3-030-56153-6_2
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