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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 8
| Issue : 4 | Page : 463-490 |
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A review: The phytochemistry, pharmacology, and pharmacokinetics of Curcumae Longae Rhizoma (Turmeric)
Song-Tao Liu, Sen-Wang Zheng, A-Jiao Hou, Jia-Xu Zhang, Song Wang, Xue-Jiao Wang, Huan Yu, Liu Yang
Key Laboratory of Basic and Application Research of Beiyao (Heilongjiang University of Chinese Medicine), Ministry of Education, Harbin 150040, China
| Date of Submission | 29-Jun-2021 |
| Date of Acceptance | 23-Aug-2021 |
| Date of Web Publication | 21-Jul-2022 |
Correspondence Address:
Dr. Liu Yang
Key Laboratory of Chinese Materia Medica, Heilongjiang University of Chinese Medicine, Ministry of Education, Harbin
China
 Source of Support: None, Conflict of Interest: None  | 2 |
DOI: 10.4103/2311-8571.351523
Curcumae Longae Rhizoma (CLR) is the rhizome of Curcuma longa L. Pharmacological studies show that CLR can be used to treat cervical cancer, lung cancer, lupus nephritis, and other conditions. In this paper, we review botany, traditional application, phytochemistry, pharmacological activity, and pharmacokinetics of CLR. The literature from 1981 to date was entirely collected from online databases, such as Web of Science, Google Scholar, China Academic Journals full-text database (CNKI), Wiley, Springer, PubMed, and ScienceDirect. The data were also obtained from ancient books, theses and dissertations, and Flora Reipublicae Popularis Sinicae. There are a total of 275 compounds that have been isolated from CLR, including phenolic compounds, volatile oils, and others. The therapeutic effect of turmeric has been expanded from breaking blood and activating qi in the traditional sense to antitumor, anti-inflammatory, antioxidation, neuroprotection, antibacterial, hypolipidemic effects, and other benefits. However, the active ingredients and mechanisms of action related to relieving disease remain ill defined, which requires more in-depth research and verification at a clinical level.
Keywords: Botany, Curcumae Longae Rhizoma, pharmacokinetics, pharmacology, phytochemistry, traditional uses
How to cite this article:
Liu ST, Zheng SW, Hou AJ, Zhang JX, Wang S, Wang XJ, Yu H, Yang L. A review: The phytochemistry, pharmacology, and pharmacokinetics of Curcumae Longae Rhizoma (Turmeric). World J Tradit Chin Med 2022;8:463-90 |
How to cite this URL:
Liu ST, Zheng SW, Hou AJ, Zhang JX, Wang S, Wang XJ, Yu H, Yang L. A review: The phytochemistry, pharmacology, and pharmacokinetics of Curcumae Longae Rhizoma (Turmeric). World J Tradit Chin Med [serial online] 2022 [cited 2023 Dec 1];8:463-90. Available from: https://www.wjtcm.net/text.asp?2022/8/4/463/351523 |
| Introduction | |  |
Curcumae Longae Rhizoma (CLR) is the irregularly oval or cylindrically shaped, dried rhizome of Curcuma longa L. (CLL) and belongs to the Zingiberaceae family. Turmeric is often used as a medicine or condiment worldwide. Its cultivation areas are mainly in the tropical regions of Asia, including India, Bangladesh, China, Thailand, and other countries.[1] In Bangladesh, people refer to it as “holud.” In India where it is known as “haldi” or “golden spice,” it is not only used in traditional medicine but also widely used in Hindu religious ceremonies, food, daily chemicals, and other areas.[141] People in India conventionally used turmeric as a spice and condiment and later began to use it for the treatment of anemia, measles, chickenpox, rheumatism, anorexia, rhinitis, cough, and even insect repellent. It is now an integral component of Ayurvedic medicine.[2] In China, turmeric is called Jiang Huang (姜黄) because of its ginger-like shape and bright yellow. Pharmacopoeia records that turmeric tastes pungent and bitter, while being mild in nature. It can enter the spleen and liver meridians and has the effect of improving blood circulation and activating qi, dredging meridians, and relieving pain. It is used in traditional Chinese medicine (TCM) to treat conditions such as chest, shoulder and arm pain, dysmenorrhea, amenorrhea, rheumatism, and swelling and pain from falls.[3] Xin Xiu Ben Cao (新修本草) records that “turmeric is the main confidant, which leads to stagnation, lower qi, broken blood, wind–heat removal, and carbuncle swelling elimination. The skill is stronger than Yu Jin.” This means that turmeric has a positive effect on regulating blood gas, and optimal blood gas is the key to regulating meridians and exerting its efficacy.[4] CLL is a type of medicinal and edible plant, which possesses aboveground and underground parts. People usually discard the leaves and primarily use its rhizome part. Studies have shown that the leaves may have no medicinal value.[5] CLL is mainly distributed in Sichuan, the Fujian province in China, and is also found in Jiangxi, Hunan, Shaanxi, and Yunnan. Phytochemical studies show that CLL contains mainly phenolic turmeric acids, sterols, diterpenoids, and a few trace elements. More than 275 types of components have been identified and isolated from turmeric. Pharmacological studies have shown that CLR can be used for the treatment of various diseases and conditions – such as antitumor, anti-inflammatory, antioxidation, neuroprotection, antibacterial, and blood lipid-lowering remedies.[6],[7],[8],[9],[10],[11] In addition, it can be used to treat gastrointestinal diseases – especially bile and liver diseases, sinusitis, joint pain, fatigue, sprains, boils, scabies, insect bites, and other ailments and diseases.[12]
Over the past few years, researchers in China and abroad have studied turmeric using modern technology and methods. However, clinical applications of CLR recorded in traditional medical books still require deep excavation and evaluation from a scientific perspective. The research on the aerial parts of CLL was rarely reported, and its leaves may contain some undiscovered new compounds that should be studied in more detail to avoid a waste of resources. Furthermore, investigations into the scientific mechanism underlying its therapeutic effects are incomplete, and future researchers should further study the pharmacological action mechanisms of CLR to ensure its safe clinical application. In this paper – the botany, ethnopharmacology, phytochemistry, pharmacological action, and pharmacokinetics of CLR are summarized. We not only reviewed the research progress on CLR in recent decades from various angles but also determined the inadequacies of the current studies and put forward the relevant problem-solving options to address them. We aim to provide a material basis for further development and utilization of CLR to fully tap the medicinal potential of turmeric.
| Botany | | |
CLL., a perennial herb, has long and wide leaves growing directly from the base of the plant, and its rhizomes are well developed. There are about 80 species of Curcuma in the world and more than 10 species in China. The earliest record of CLR can be traced back to Xin Xiu Ben Cao (新修本草): The roots and leaves of CLL are similar to Curcuma wenyujin. The buds grow in spring and bloom in summer, but it bears no fruits. The colors of the roots are yellow, blue, and white.[4] The plant has well-developed, underground, fleshy rhizomes and constitutes the medicinal parts, while the aboveground parts wither in winter.
CLL can easily be distinguished by its appearance. Images of CLL and CLR are shown in [Figure 1]. The morphological characteristics are as follows.[140] the rhizome is thick, and the end expands to grow into an oval- or spindle-shaped new rhizome, which is grayish brown; the rhizome is ovate and yellow inside; lateral rhizomes are cylindrical, red, and yellow; the leaf blade is elliptical or narrow, 20–45 cm in length, and 6–15 cm in width. The petiole is approximately half as long as the leaf blade sometimes several times as long. The leaf sheath is wide and about the same length as the petiole. Spikes are dense and 13–19 cm in length. The total pedicel length is 20–30 cm; bracts are broadly ovoid, with each bract containing several small flowers; the top bracts are ovate or narrowly ovate, and there are no flowers in the axils. The stamens are rectangular, the filaments are flat and wide, and the lateral staminodes are long and oval. The capsule is membranous, spherical, and three-valved. The seed is oval shaped with an aril. The flowering period lasts from August to November.[13]
CLL is suited to grow in a warm and humid environment with abundant sunshine and rainfall but is unsuited to severe cold and frost, drought, and waterlogging. It is mainly distributed in tropical Asia – including China, India, and Thailand. The harvest season of turmeric is generally in the late December, at which time the rhizomes contain the highest content of curcuminoids and exhibit the best efficacy.[14]
| Ethnopharmacology | | |
Turmeric has been used in China for thousands of years and is recorded in several books of Chinese medicine. These include Xin Xiu Ben Cao (新修本草), Sheng Ji Zong Lu (圣济总录), Pu Ji Fang (普济方), and Ben Cao Gang Mu Shi Yi (本草纲目拾遗).[128],[129],[130],[131] TCM believes that turmeric relieves pain, alleviates blood stasis, relieves depression, activates qi, benefits the gallbladder, clears the heart, eliminates body-waste stagnation, and dredges channels.[15] It can be used not only as a medicine but also as a dietary supplement. Pharmacopoeia records that it can quickly promote blood circulation and qi movement, clear channels, and relieve pain, and it can be used for the treatment of chest, shoulder, and arm pain, dysmenorrhea, amenorrhea, traumatic injury, rheumatism, and other ailments. The usual dosage is 3–10 g. The use of turmeric was recorded in the Harappa civilization as early as 3000 BC.[16] CLL is also popular in India as a medicinal plant. People use it to treat various illnesses, from arthritis to indigestion to various skin diseases.[17] In China, there are numerous records of turmeric in medical books.
The book of Ben Cao Tu Jing (本草图经)[132] in the Song Dynasty mentioned that CLR could treat flatulence and postpartum septicemia.
According to Ben Cao Jing Shu (本草经疏)[133] in the Ming Dynasty, the use of turmeric was banned if the etiology was blood deficiency, arm pain, and abdominal pain, instead of blood stasis and swelling due to qi and plastic. If people consumed it by mistake, it would negatively affect the blood and the disease would worsen.
Ben Cao Qiu Yuan (本草求原)[134] of the Jin Dynasty recorded that CLR could accelerate the movement of qi in the body. If the gas was biochemical, the body fluid would flow in the three Yin San Yang, while the clear one would be injected into the lung, and the turbid one would be injected into the meridian and slip into the sea. The blood would circulate on its own, to regulate the qi and disperse the knot, and then be released.
Ben Cao Gang Mu Shi Yi (本草纲目拾遗), written in the Ming Dynasty, reported that authentic turmeric is that which has been planted for more than 3 years. It can produce and develop flowers in the rhizosphere just like Schima superba. Rhizomes are hard and pungent, which is similar to Curcumae Rhizoma and Curcumae Radix. The smell and other characteristics of turmeric were described clearly in this book.
According to the Ben Cao Qiu Zhen (本草求真)[135] of the Qing Dynasty, the function of CLR is similar to that of Curcuma aromatica, Curcuma zedoaria, Trigonobalanus, and Corydalis yanhusuo. C. aromatica can enter the heart and purge the blood of heart cells, and C. zedoaria enters the liver to treat blood in qi. Trigonobalanus enters the liver to treat qi in blood, and C. yanhusuo divides qi from heart and liver blood, while qi divides blood. In addition, CLR enters the spleen, which not only cures blood in qi but also restores qi ear in the blood. Chen Zangqi declared that CLR was less pungent and more bitter, with a better nature than C. aromatica. It can quickly promote blood circulation and qi movement. It can treat suffocation and gas accumulation, blood stasis, and blood-closed carbuncles. The book also describes the differences between turmeric plants.
The medicine books of Xin Xiu Ben Cao (新修本草) point out that the leaves and rhizomes of CLL are like Curcumae Radix. CLL produces flower buds in the early spring and blooms in summer, without bearing any seeds. Roots are yellow, green, and white. The taste of the leaves is less bitter than that of the rhizomes (similar to that of Curcumae Radix), but the flowers are different. C. longa, Curcumae Rhizoma, and Curcumae Radix all come from the Curcuma family. They have similar basic sources but different chemical compositions and pharmacological effects. However, referring to ancient books, it has been found that they were used interchangeably in ancient times, and their relationship is confusing. Currently, despite existing literature distinguishing them using fingerprint and modern analysis methods, unified evaluation is lacking.
Turmeric is mostly used alone in practical application, but it can play a better role in combination with other herbs. These formulations follow the rule of “Jun Chen Zuo Shi.”[142] It is more effective in reducing adverse effects and toxicity and improving the therapeutic of herbs.[143] For example, the common formulae include Qiwei Jianghuang Chaji, Jiuwei Gantai Jiaonang, Wuhuang Yangyin Keli, Huazheng Huisheng Pian, and Fengtong'an Jiaonang, which carry the functions of clearing away heat and dampness, dispelling wind and relieving itching, removing blood stasis and dredging collaterals, soothing the liver and invigorating the spleen, eliminating phlegm, and benefiting qi and nourishing yin, among other uses. It can be used for treating symptoms caused by blood stasis, frequent micturition, spontaneous perspiration, night sweats, palpitations, insomnia, obesity, depression, vexation, acne caused by damp heat and depressed skin, as well as other similar conditions. The prescriptions of CLR are summarized in [Table 1].
In modern times, turmeric extract is also used in the cosmetic field because it possesses antiwrinkle and skin-beautifying effects. It is also used as an additive in food and dyes. Turmeric residue can produce turmeric starch, ferment unpleasant wine, and be directly used as feed. The comprehensive utilization of turmeric can promote the development of the food, chemical, spice, and pharmaceutical industries and therefore offers valuable economic benefits.
| Phytochemistry | | |
Several chemical components have been extracted from CLR, which have been widely investigated by researchers. To date, more than 275 compounds have been isolated and identified, including primarily phenolic compounds, volatile oils, trace elements, and other components.[18] In this section, we summarize the chemical constituents obtained.
Phenolic compounds
The main active components in CLR are phenolic compounds and volatile oils, both of which have good therapeutic and medicinal effects, and curcumin is currently the main research target. Curcumin is a type of polybasic phenolic acid compound with a β-diketone symmetrical structure, which consists of 1–2 phenolic groups, two α-, β-unsaturated ketone double bonds, one β-diketone, and a central active methylene group.[19] The 2020 version of Pharmacopoeia stipulates that the content of curcumin in turmeric should not be less than 1.0%. The first separation of curcumin compounds can be traced back to 1815, and the chemical structure of the bis-feruloyl methane component was identified in 1910.[20] At present, more than 30 kinds of natural curcumin compounds have been isolated from turmeric.[21] Among them, the highest content is found in three components, including curcumin I, curcumin II, and curcumin III.[22] Pharmacological studies show that curcumin has anticancer, anti-inflammation, and antioxidation pharmacological properties, also reduces blood lipid levels, offers neuroprotection, and provides other pharmacological protection.[23]
With a focus on “search-location-purification-identification,” Li et al. identified a new compound with a curcumin skeleton structure from a 95% methanol extract of Curcumae Rhizoma named curcuterpene G (3,4′′′-epoxy-5′′′-C-(1α,2β,3β-bisabola-4,10-diene-9-one)-(2 → 5′′′)-curcumin) by using Liquid Chromatograph-Mass Spectrometer (LC-MS) analysis, MCI (Macroporous Resin) MCI pore resin, ODS-C18 reversed-phase column chromatography, and (Reversed Phase-High Performance Liquid) RP-HPLC.[24] Bai et al. used various column chromatography approaches to separate the yellow-pigmented compound 1,5-bis (4-hydroxyphenyl)-penta-(1E,4E)-1,4-diene-3-one from the ethanol extract of C. longa for the first time.[25] Cui et al. used silica gel column chromatography, Sephadex LH-20 gel column chromatography, and HPLC to separate 13 components from the n-butanol fraction of 95% ethanol extract of CLR, among which isocyclic demethoxycurcumin was isolated for the first time.[26] Li et al. reported 19 diphenyl heptanes and 3 diphenyl ketones.[18] Wei et al. found through HPLC comparative analysis that the aerial parts of CLL do not contain curcumin, so it may have no pharmacological value. This may be one of the reasons why ancient people abandoned it completely.[5] We summarize the phenolic compounds of CLR in [Table 2], and the structures are shown in [Figure 2].
Volatile oils
There are various components in CLR, of which volatile oils are one of the main active components. Its content can reach approximately 7% (ml/g) in the turmeric. Modern research shows that the volatile oil has various kinds of pharmacological activities such as antitumor, antithrombosis, antioxidation, antibacterial, and anti-inflammatory effects.[27] It has been widely used in medicine, food, cosmetics, and other fields. However, the components of volatile oil are complex. Differences in plant variety, cultivation areas, and processing and extraction methods result in marked differences in the chemical components and relative content percentage of volatile oil from CLR.[28] Yang et al. analyzed the chemical components of turmeric volatile oil from Sichuan, Hainan, Thailand, and Vietnam using gas chromatography-mass spectrometry (GC-MS) and identified 50 components. The investigation revealed that the content of turmeric was lower in domestic volatile oil than in that imported from Southeast Asia.[29] Qiang et al. extracted volatile oil using steam distillation and analyzed the components of the extracted volatile oil using headspace solid-phase microextraction combined with GC-MS. Among them, 51 components were identified, and the relative percentage of these components accounted for 98.41% of volatile oil components. At the same time, a new compound, β-cedrene, was discovered.[30] Zeng et al. separated and identified the ethanol extract of CLR and obtained six sesquiterpenes including turmeronol A, turmeronol B, bisabolone, 8-hydroxyl-ar-turmerone, bisabolone-9-one, (6S)-2-methyl-6-[(1R,5S) 4-methene-5-hydroxyl-2-cyclohexen-2-hepten-4-one].[31] Chen et al. used GC-MS to compare the volatile components extracted from dried and raw turmeric using steam distillation and Soxhlet extraction with petroleum ether as the solvent. Five common components were identified with relative content exceeding 4%: α-curcumene, aromatic ginger flavone, β-sesquiterpene, α-ginger flavone, and β-ginger flavone.[32] Gounder and Lingamallu extracted the volatile oil from CLR using fresh and dried plants (from India) and obtained 28 and 14 components, respectively, most of which were sesquiterpenes, and the main components were aromatic ginger flavone (21.0% and 30.3%), α-ginger flavone (33.5% and 26.5%), and β-ginger flavone (11.5%).[33] Zou et al. analyzed 71 components from the volatile oil of CLR using GC-MS, among which the main components were turmeric flavone, Curcuma new ketone, ginger flavone, and so on.[34] Fang et al. analyzed CLR from Guangdong, Sichuan, Fujian, Yunnan, and Hainan using the ultrasonic method and extracted its methanol and petroleum ether fractions. This approach yielded 47 chemical components identified using LC-MS (Liquid Chromatograph-Mass Spectrometer) and GC-MS. On comparing the content of compounds from different habitats, it was found that there were differences in the methanol fractions, petroleum ether fractions, and contents of CLR, and the content of total ginger flavonoids in CLR decreased first and then increased with increased latitude.[35] We summarize the volatile oil compounds of CLR in [Table 3], and the structures are shown in [Figure 3].
Other components
In addition to the above components, CLR contains low levels of diterpenes, saccharides, sterols, flavonoids, organic acids, and trace elements. Afzal et al. isolated 4 diterpenoids and 3 triterpenoids from CLR.[36] The saccharides in CLR include 1.1% arabinose, 12% fructose, and 28% glucose. There are also acidic polysaccharides A, B, C, and D. CLR also contains sterols such as β-sitosterol, fatty acid, oleoresin, mono-dilute acid, and di-dilute acid. Flavonoids isolated and identified from CLR include dihydroflavonols, flavones, flavonols, and their aglycones myricetin, lutein, quercetin, apigenin, and kaempferol.[37],[38],[39] Furthermore, organic acids isolated from CLR include salicylic, veratric, ferulic, syringic, cinnamic, sinapic, chlorogenic, m-hydroxybenzoic, and p-hydroxybenzoic types of acids.[40] In addition, it contained succinic acid and protocatechuic acid.[41] Chen et al. determined 19 inorganic elements, namely Li, B, Mg, Al, P, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Sr, Ba, Cd, and Pb from turmeric using MS (Inductively Coupled Plasma-Mass Spectrometry) ICP-MS and (Inductively Coupled Plasma-atomic emission spectrometry) ICP-AES.[42] We summarize the other compounds of CLR in [Table 4], and the structures are shown in [Figure 4]. | Figure 4: Structures of the other ingredients in Curcumae Longae Rhizoma
Click here to view |
| Pharmacology | | |
As a natural medicine, the pharmacological activity of CLR has surpassed the category of “breaking blood and activating qi, dredging meridians, and relieving pain” in TCM theory and has become a new area of interest in natural medicine research. Published scientific literature has shown that CLR possesses antitumor, anti-inflammatory, antioxidation, neuroprotection, antibacterial, and hypolipidemic functions. Chemotherapeutic drugs take effect quickly and can rapidly affect the patient's condition. However, they may elicit adverse reactions and lead to the development of drug resistance.[144] In contrast, TCM can achieve better therapeutic effects using multichannel and multitarget strategies.[145]
Antitumor effects
In recent years, Chinese medicine has demonstrated unique advantages in treating tumors. Numerous preclinical cell and animal experiments have shown that turmeric volatile oil and curcumin have therapeutic effects on pancreatic, gastric, colorectal, prostate, liver, skin, breast, and oral cancers.[44] CLR can be used not only as a chemotherapy drug but also as a tumor-preventive drug. Its anticancer mechanism acts at various stages in the development of cancer and inhibits tumor-related factors in different ways.[45] Therefore, CLR has become a research hotspot in China and abroad.
In 1985, Kuttan et al. discovered that CLR could inhibit the growth of animal tumors in vivo and in vitro and determined that its antitumor active component was curcumin. It was proved that curcumin could be used as an anticancer and antimutagenic agent.[46] Subsequently, the antitumor effect of curcumin was widely studied. Experiments by Xu et al. revealed that curcumin inhibited the proliferation of human gastric cancer MGC803, human liver cancer Bel7402, and human erythroleukemia K562 cells and had a significant antitumor effect on mouse melanoma B16 and Ehrlich ascites carcinoma-transplanted tumor in vivo.[47] Chen et al. found that pure curcumin has certain inhibitory effects on H22 tumor cells, but the water extract of turmeric has no obvious inhibitory effect, which may be related to the difference in curcumin content in the water extract, the interference of other components on curcumin's anticancer properties, or the loss of volatile oil components with anticancer effects in the process of water extraction.[48] Sun et al. studied the antitumor activity of turmeric extract emulsion in vivo and found that the injection of turmeric oil extract emulsion inhibits the growth of tumors in transplanted melanoma-bearing and glioma-bearing mice (intracranial inoculation) in a dose-dependent manner; the effect of intravenous administration twice a day on mice with glioma is better, indicating that turmeric oil extract emulsion has anticancer effects and can pass the blood–brain barrier.[49] Puliyappadamba et al. studied the anticancer effect of curcumin on lung cancer cells and found that curcumin can downregulate nuclear factor kappa-B (NF-κB), protein kinase B (Akt), B-cell lymphoma/leukemia-2 (Bcl-2), and mitogen-activated protein kinases (MAPKs) in lung cancer cell lines H1299 (p53−/−) induced by nicotine. The activation of survival signals such as activator protein 1 and inhibitor of apoptosis protein revealed that nicotine is a harmful carcinogen, especially in patients with lung cancer with impaired tumor protein 53 status, and determined that curcumin is a potential chemopreventive agent.[50]
Qin and Chen used human umbilical vein endothelial cells (HUVECs) and chick embryo allantoic membrane-transplanted tumor as models to investigate the effect of curcumin on angiogenesis and the possible mechanism of inhibiting melanoma growth. The experimental results showed that turmeric could inhibit the migration number of HUVECs induced by vascular endothelial growth factors (VEGF) in a dose-dependent manner (8–5 μmol·L− 1) and inhibit angiogenesis in vivo. At the same time, it can inhibit the growth of melanoma B16F10 in vivo at 20 mg·L− 1 by blocking the proliferation and migration of HUVECs and reducing the expression of VEGF receptor 2 and matrix metalloproteinase (MMP-2) protein.[51] Liu et al. discussed the effect of curcumin on dimethylhydrazine-induced colorectal cancer in rats at the cellular and organism levels. The results revealed that the cancer inhibition rate of the curcumin group was 26.46%, and the expression of peroxisome proliferator-activated receptor γ (PPARγ) was enhanced (P < 0.05). In vitro, curcumin also inhibits the proliferation of human colon cancer cell line HT29 in a dose–time-dependent manner, and the effect is stronger than that of the GW9662 intervention group, which proves that curcumin controls colorectal cancer by regulating the PPARγ pathway.[52] Tang et al. studied the effect of curcumin on multidrug resistance (MDR) of human gastric cancer drug-resistant cell line SGC7901/VCR. The experiment showed that SGC7901/VCR cell line was more sensitive to drugs, which may be related to the activation of caspase-3 in SGC7901/VCR cells and the decrease of P-glycoprotein (P-gp) function and expression, indicating that curcumin was an MDR regulator of drug-resistant gastric cancer cells.[53]
Esophageal cancer is the sixth most common cancer in the world. It is estimated that approximately 200,000 people in the world die from esophageal cancer annually, and the disease greatly endangers people's lives and health.[54] Wang explored the mechanism of curcumin reversing the MDR of the esophageal cancer cell line vincristine VCR. Experiments showed that a small dose of curcumin combined with vincristine VCR could significantly increase the sensitivity of Eca-109/VCR cells to VCR and effectively reverse the drug resistance of Eca-109/VCR cells. The mechanism may be by inhibiting the p38 MAPK signaling pathway. The expression of p38 MAPK mRNA, excision repair cross-completion gene 1 mRNA, MDR mRNA, p38 MAPK, p-p38 MAPK, P-gp, and other proteins were downregulated to achieve the goal.[55] Zhao et al. studied the anticancer effect of turmeric volatile oil on human lung cancer A549 cells. Experiments showed that turmeric volatile oil could inhibit tumor growth in a time–dose-dependent manner, which showed that the structure of tumor cells was deformed, the nucleus shrunken, the amount of apoptosis increased, and the migration ability of A549 cells in vitro obviously inhibited.[56] This experiment provides the possibility for exploring new antitumor candidate drugs further and offers the basis for the development and research of anticancer drugs.
Cervical cancer is a common malignant tumor which occurs in the cervical, vaginal, or transitional zone. Wei et al. explored the effect of curcumin on cervical cancer tumors transplanted subcutaneously within mice. The results showed that the tumor volume of mice in the experimental group was significantly reduced, the tumor quality was decreased, the NO produced by tumor cells was decreased, and the levels of the tumor marker molecules MMP-2, MMP-9, and VEGF were all decreased (P < 0.01), which indicated that curcumin had antitumor protection effects on mice with subcutaneously transplanted cervical cancer that inhibited tumor growth.[57] Hong et al. discussed the effect and mechanism of curcumin on mice with cervical cancer from the perspective of pathway analysis. The experimental results revealed that the tumor inhibition rate of mice in the CLR group increased, while the thymus, splenic, and apoptosis indexes of tumor cells in the experimental group were higher than those in the model group, indicating that curcumin could significantly inhibit the growth of transplanted tumors in mice with cervical cancer, induce apoptosis of tumor cells, and enhance the immune function against cervical cancer in mice. The mechanism may be related to the inhibition of an epidermal growth factor receptor-signal transducer and activator of transcription 3 (STAT3) signal transduction.[58]
As already noted, CLR has the efficacy of breaking blood and activating qi, which is considered by TCM to be able to eliminate tumors. Modern pharmacological studies also show that CLR, as a candidate of anticancer drugs, has an inhibitory effect on various cancers. It can be targeted to multiple molecular pathways such as phosphate and tension homology deleted on chromosome ten (PTEN), VEGF-A, and phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) and also assists western medicines in eliminating drug resistance of tumor cells. However, most of the above studies were conducted at cell and organism level and lack clinical validation, which make the results insufficient. In follow-up studies, researchers can strengthen the related research on clinical trials or establish more experiments and animal models in vivo and in vitro to further explore the antitumor mechanism of the compounds in CLR so that it can be widely popularized and applied as an auxiliary drug in clinical antitumor treatment.
Anti-inflammation effects
Inflammation is a defensive response of the body to stimulation, which is characterized by redness, swelling, heat, pain, and dysfunction. Inflammation is subdivided into the infectious and noninfectious types. Usually, inflammation is beneficial and an automatic defense response of the human body. Sometimes, inflammation can be harmful, notably causing attacks on own tissues and inflammation in transparent tissues, among the examples. CLR is a Chinese herbal medicine and an anti-inflammatory drug recorded in the literature.[59] The anti-inflammatory effects are mainly achieved by reducing the expression and secretion of inflammatory cytokines, mediating a variety of inflammatory signaling pathways, and regulating inflammation-related cell functions.
Kim et al. studied the effect of curcumin on Janus tyrosine kinase-STAT (JAK-STAT) signaling pathways in activated brain microglia. They found that curcumin can inhibit the phosphorylation of JAK1 and JAK2 by increasing the phosphorylation of SRC homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) and its connection with JAK1 and JAK2, thus inhibiting the JAK-STAT signaling pathway and alleviating inflammatory reaction.[60] This study found a new anti-inflammatory mechanism, which offers a novel approach for the treatment of brain injury and chronic inflammation.
Hu et al. studied the effect of a turmeric decoction on experimental synovitis in rats. The experimental results showed that compared with the normal group, the extent of swelling of the ankle joint in the turmeric group was significantly reduced (P < 0.05). In addition, congestion of synovial tissue and inflammatory cell infiltration of rats were reduced, which indicated that turmeric could improve inflammation in experimental rats.[61] However, in this experiment, the anti-inflammatory mechanism of CLR was not studied in-depth, and no positive drug group was set for comparison, which may be the point at which the experiment needed to be supplemented.
NF-κB is an important nuclear transcription factor, which plays an important regulatory role in inflammatory, stress, and immune responses.[62] Curcumin can effectively inhibit inflammation by inhibiting this pathway. Han et al. studied the effect of curcumin on rats with experimental autoimmune neuritis (EAN). The experimental results showed that curcumin could reduce the accumulation of inflammatory cells. Inhibition of the expression of the inflammation-related factors interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-17 in the peripheral nervous system (PNS) can change the differentiation of helper T-cells by reducing IFN-γ + CD4 + Th1 cells in the lymph nodes and spleen. The experimental results show that curcumin can be used as a candidate drug for EAN.[63] Liu et al. studied the effect of curcumin on lupus nephritis and its possible mechanism. The experiment showed that the levels of urinary protein, renal function indexes, selective catalytic reduction, and blood urea nitrogen in MRL/Lpr mice were significantly decreased, the level of the anti-dsDNA antibody of the systemic lupus erythematosus marker in serum was significantly decreased, and the protein expression of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3), and caspase-1 was inhibited. The mechanism may be related to the inhibition of the NF-κB signaling pathway and the activation of the NLRP3 inflammatory corpuscle.[64]
Although curcumin demonstrates strong anti-inflammatory activity, its water solubility is poor, it is unstable under physiological conditions, it metabolizes rapidly in vivo, and it is easy to decompose under alkaline conditions, which leads to low bioavailability and poor effective absorption.[65] To overcome this problem, Luis et al. studied the anti-inflammatory effect of curcumin coated with different gel carriers on mouse ear edema induced by 12-o-tetradecanoylphorbol 13-acetate (TPA). The experimental results showed that the anti-inflammatory activity of curcumin coated with organogels was 45.9%, that of curcumin coated with nanogels was 61.8%, that of curcumin without coating, namely free curcumin (FC), was 33.2%, and that of curcumin coated with hydrogel was 28.1%.[66] The gel system was nontoxic in vivo and easy to manufacture, and it also greatly improved the utilization rate of curcumin.
Symptoms of inflammation include redness, swelling, heat, and pain. As indicated, TCM believes that turmeric can activate qi and blood, dredge meridians, and relieve pain, thus eliminating inflammation. Phytochemical studies have shown that the phenylacryloyl group in curcumin compounds is essential for anti-inflammation. Pharmacological experiments show that CLR can inhibit the activity of inflammation-related enzymes such as Cox-2 and iNOS and inhibit the production of inflammatory factors such as TNF-α, IL-1, IL-1β, IL-2, IL-6, IL-8, IL-12, IL-13, IL-17, and IFN-γ. However, the above experiments lack dose-dependent studies, and the maximum safe dose and the minimum effective dose have not been studied yet. In addition, only NF-κB involved in the anti-inflammatory pathway of turmeric is mentioned. Future researchers can perform in-depth studies of the JAK2/STAT3 pathway, c-Jun N-terminal kinase/MAPK pathway, and extracellular regulated protein kinases-cAMP-response element binding protein pathway, among other similar pathways. At the same time, the anti-inflammatory effects of volatile oil components require further investigation.
Antioxidation effects
Curcumin compounds in CLR have strong antioxidant activity. Xu et al. homogenized the brain, heart, liver, kidney, and spleen of NIH (National Institutes of Health) NIH mice. After adding curcumin, a significant antagonistic effect emerged on lipid peroxidation of the five organs in a dose-dependent manner, indicating that curcumin has an antioxidant function.[67] However, this experiment has not been verified in vivo.
The antioxidant activity of curcumin is closely related to the content of glutathione (GSH) in cells. GSH is a small molecule sulfhydryl compound synthesized in cells, which has antioxidant and detoxification effects. Zheng et al. found that curcumin, as an antioxidant, could increase the expression of the glutamate-cysteine ligase gene, increase the intracellular GSH content, and reduce the oxidative stress reaction, thus inhibiting the activation of hepatic stellate cells.[68] The antioxidant activity of curcumin was mainly achieved by promoting GSH synthesis. This experiment elucidated a new antioxidant mechanism. However, this conclusion is drawn from the in vitro experiment, and it needs to be validated in vivo. Therefore, the effect of curcumin on (Hepatic stellate cells) HSC activation in vivo may not be fully reflected.
Under normal conditions, the defense system of oxides and antioxidants in organisms is balanced, thus ensuring the normal operation of metabolism. When the balance of oxide and the antioxidant defense system is destroyed, it causes oxidative stress, and intracellular oxidative stress will cause serious metabolic disorders.[69] Huang studied the effects of curcumin with a model of different concentrations on H2O2-induced oxidative stress in bone marrow mesenchymal stem cells. It was found that curcumin with a concentration of 12.5 μmol/L can exert the greatest antioxidative stress effect, and its mechanism may be related to activation of the mechanistic target of rapamycin (mTOR) pathway, the antiapoptosis promoting proteins Bcl-2, p-mTOR, p-P70S6K, and p-S6, and decreased expression of Bcl-2-associated X protein.[70]
Shakeri et al. treated asthma model rats with turmeric extract and curcumin, and the symptoms of rats were alleviated, while the levels of superoxide dismutase (SOD), catalase (CAT), and sulfhydryl groups in rats were increased, and the total number of white blood cells and lymphocytes, nitric oxide-2, nitric oxide-3, and malondialdehyde (MDA) levels were decreased. The therapeutic effect was equivalent to that of the positive drug dexamethasone, indicating that turmeric and its main component curcumin had preventive treatment potential for oxidative stress in asthma symptoms.[71] Xiao et al. explored the antioxidant capacity of curcumin using various differentiated rat adrenal pheochromocytoma cells (PC12 cells) as models. Experiments showed that curcumin could enhance the activities of antioxidant enzymes in cells, such as SOD, CAT, and glutathione peroxidase. It could upregulate the expression of genes to improve the total antioxidant capacity of PC12 cells, reduce the level of reactive oxygen species, and promote the redox balance of cells. Therefore, curcumin at a certain concentration could have an antioxidative effect in PC12 cells.[72]
However, the above experiments only studied the antioxidant capacity of turmeric at the cell and organism level, and researchers should continue to verify it clinically in the future. Moreover, researchers only regard curcumin as the most important antioxidant component in turmeric, which cannot reflect the complete activity of turmeric. There may be thousands of components in turmeric, including antioxidant components; further, it may contain components without antioxidant activity or those that promote oxidation. Future studies can use spectrum-effect relationships to screen out more components with antioxidant activity. In addition, studies have shown that the ethanol extract of the CLL fruit has strong antioxidant activity, but researchers have not regarded it as a medicinal part – yet, its utilization may alleviate the shortage of CLL resources. Finally, as a natural antioxidant, turmeric has the advantages of low toxicity and easy access, and it can also be added to food for use. In the future, people should pay attention to the application of turmeric as a food-borne antioxidant and further study its antioxidant functions and mechanisms, to provide a theoretical basis for the prevention and treatment of oxidative stress-related diseases.
Neuroprotective effects
Curcumin has potential applicability in brain protection and the treatment of cerebrovascular diseases. owing to its good antioxidant and anti-inflammatory effects. Zhang et al. studied the protective effect of curcumin on HUVEC injury induced by TNF-α. The results showed that the morphology of HUVEC treated with curcumin did not change significantly, while apoptotic bodies decreased significantly, which may be achieved by downregulating the gene expression of caspase-3.[73] Susana et al. studied the protective effect of curcumin on the hemin-induced death of cerebellar granule neurons (CGNs) of the rats. The research showed that curcumin could promote the expression of heme oxygenase-1 (HO-1), glutathione transferase (GSH), and oxidized glutathione disulfide (GSSG) in CGNs, increase the activities of glutathione reductase (GR), glutathione-S transferase (GST), and SOD in CGNs, and induce translocation of nuclear factor-erythroid-factor 2-related factor 2 (Nrf2) into the nucleus to play a neuroprotective role.[74]
Depression is a kind of psychological disorder characterized by significant and lasting melancholy and lack of interest. The disease seriously affects quality of life, and in recent years, cases of depression have shown an increasing trend. Zhang et al. studied the antidepressant effect of curcumin on chronic, unpredictable, and mild stress (CUMS)-induced depression in a rat model. The results showed that curcumin could inhibit brain-derived neurological factor (BDNF). The decrease of postsynaptic density protein 95 (PSD-95) and synaptophysin (SYN) expression in lateral amygdala (LA) could improve depression behavior, which offers a novel perspective for the clinical treatment of depression.[75] Deng et al. further studied the effect of curcumin on CUMS depression in a rat model and discussed the central nervous protection of curcumin on chronic stress in rats. The experiment showed that the sugar water preference of curcumin-treated rats increased, the immobility time shortened, the serum corticosterone level decreased significantly, the expression of BDNF, PSD-95, and SYN protein in the hippocampus increased significantly, the apoptosis index in tissue sections decreased significantly, and depression-like behavior was alleviated. It proved the potential antidepressant effect of curcumin, which may be related to regulating the hypothalamic–pituitary–adrenal axis to reduce serum corticosterone levels, improving synaptic plasticity, and exerting an antiapoptosis effect.[76]
Yang et al. studied the neuroprotective effect of curcumin on the rat model of traumatic brain injury (TBI) caused by heavy impact. The experiment showed that compared to the solvent group, in the curcumin treatment group, the score of the modified neurological impairment scale was significantly lower (P < 0.05), the level of phosphorylated PI3K/AKT was significantly higher (P < 0.05), the injured area of the brain tissue was reduced (P < 0.05), and the apoptosis rate of neurons was significantly reduced (P < 0.05). The expression levels of LC3 and beclin-1 increased significantly (P < 0.05), while that of P62 decreased significantly (P < 0.05). The experiment showed that curcumin could significantly improve the nerve function of rats with TBI, and the mechanism may involve autophagy that is activated through the PI3K/AKT signaling pathway.[77] However, the protein related to the PI3K/AKT signaling pathway did not change significantly in this experiment, but the phosphorylation level of PI3K/AKT increased significantly, and autophagy appeared. Therefore, the mechanism of activating the PI3K/AKT signaling pathway remains to be explored.
The above experiments have proved that turmeric has neuroprotective function, and it can cure depression, brain injury, death of CGNs, and related diseases. However, due to the complexity of the human brain, and the fact that these experiments have not been verified clinically, the specific effect needs to be explored further. In addition, there were no positive or negative control groups in these experiments. Future research can employ pregabalin, nicotinamide, donepezil hydrochloride, mecobalamin, and metformin as positive controls to improve the experimental data. Furthermore, network pharmacology can be used to link the target genes of active ingredients of CLR and neurological diseases to explore more target pathways and proteins. This may lay a foundation for the treatment of neurological diseases such as Alzheimer's and Parkinson's disease.
Antibacterial effects
De et al. explored the bacteriostatic effect and mechanism of curcumin on Helicobacter pylori through in vitro and in vivo experiments and found that curcumin not only inhibited the reproduction of H. pylori in vitro but also reduced the stomach injury caused by H. pylori infection. In addition, they found that the bacteriostatic mechanism of curcumin did not always depend on the shikimate pathway, which provided a new mechanism for curcumin to resist H. pylori infection in the future. However, this experiment still needs clinical application.[78]
Tyagi et al. studied the antibacterial activity of curcumin against Gram-positive and Gram-negative bacteria. It was found that curcumin had antibacterial effects on Staphylococcus aureus and Enterococcus faecalis, Escherichia More Details coli, and Pseudomonas aeruginosa by destroying the permeability of bacterial cell membranes in a dose–time-dependent manner, which was also related to its antioxidant and anti-inflammatory activities.[79] However, curcumin could only kill bacteria at high concentration in this study, so its effect is not strong in practical application. Therefore, we can try to modify its structure or add a coating gel to enhance its antibacterial effect in the future.
Alihosseini et al. studied the synergistic antibacterial activity of curcumin and ampicillin against P. aeruginosa, S. aureus, E. coli, Corynebacterium diphtheria, Bacillus subtilis, and methicillin-resistant S. aureus. Experiments showed that the antibacterial activity of solid lipid nanoparticles was enhanced and the minimum inhibition concentration was reduced. The use of nanotechnology could reduce the dosage of antibiotics and reduce the drug resistance of certain strains.[80] Li et al. found that curcumin glucoside, curcumin disaccharide glycoside, and curcumin had inhibitory effects on penicillin-sensitive strains, intermediate strains, and drug-resistant strains of Streptococcus pneumoniae, respectively, and the inhibitory areas exceeded the penicillin G group and the inhibitory areas on drug-resistant strains all exceeded 20 mm. The mechanism of action may involve the inhibition of penicillin-binding proteins, destruction of the integrity of the bacterial cell wall, and selective permeation of the envelope, which eventually leads to bacterial death.[81]
The above experiments show that curcumin in turmeric can not only inhibit and kill bacteria but may also reduce the emergence of bacterial resistance and the side effects of western medicine. COVID-19, which broke out at the end of 2019, has evolved into a global pandemic. A large number of clinical trials are being carried out around the world, but a specific drug has not yet appeared. Studies have shown that curcumin has inhibitory effects on the homologous porcine transmissible gastroenteritis virus,[127] and because of its convenient access and minimal side effects, it may become a candidate drug for treating COVID-19.
Hypolipidemic effects
As stated before, CLR is a commonly used medicine for promoting blood circulation and removing blood stasis and has the functions of breaking blood and activating qi, dredging channels, and relieving pain. Its function of reducing blood lipids has been supported by the TCM theory, clinical application, and experimental research. Wan studied the effects of different compatibility ratios of ethanol extracts of rhubarb and turmeric on experimental mice with hyperlipidemia. Experiments showed that all three compatibility ratios had the effect of reducing blood lipids, and the compatibility ratio of rhubarb and turmeric at 1:2 was better than that of the equal ratio group and rhubarb and turmeric group at 2:1. This experiment provides some evidence for further studying the difference of the effects of Chinese medicine in combination with other drugs.[82] However, the principle of the lipid-lowering effect of rhubarb and turmeric in the experiment needs further exploration. Singh et al. found that turmeric volatile oil could play an antihyperlipidemic role by regulating the genes involved in lipid metabolism and transportation and PPARα. At the same time, it could regulate liver X receptor α and reduce lipid-induced oxidative stress, platelet activation, and vascular dysfunction. It could also reduce accelerated atherosclerosis, inflammation, and macrophage foam cell formation caused by arterial injury.[83]
Chen et al. studied the effect of propolis combined with turmeric extract on blood lipid in hyperlipidemia model rats. The results showed that propolis combined with turmeric extract in low-, medium-, and high-dose groups could reduce the contents of serum total cholesterol (TC) and serum total triglyceride (TG) in rats with hyperlipidemia, but propolis or turmeric extract alone had no significant effect. Compared with the water control group, the content of high-density lipoprotein cholesterol (HDL-C) in the middle- and high-dose groups increased significantly (P < 0.05). The results showed that propolis and turmeric extract were effective in lowering serum TC and serum TG, as well as increasing serum HDL-C and other hyperlipidemia-related indexes, and had obvious lipid-lowering effects.[84] This study provides a scientific basis for the clinical application and product development of propolis combined with turmeric. Statins are lipid-lowering drugs that can be taken over a long time. However, the risk of cardiovascular and cerebrovascular diseases induced by statins has gradually increased in recent years. As extracts of TCMs and natural medicines have a relatively small incidence of adverse reactions, combined drugs have gradually been used in favor of statins. Hai et al. studied the effect of turmeric extract combined with atorvastatin calcium on reducing blood lipid in a hyperlipidemia mice model established by a high-fat diet. The results showed that the turmeric extract group, atorvastatin calcium group, and combined group showed different degrees of blood lipid-reducing effect in the serum of mice with hyperlipidemia. The combination of turmeric extract and atorvastatin calcium was superior to a single drug in the four indexes of serum TC, TG, HDL-C, and low-density lipoprotein cholesterol (LDL-C), which may be related to their deficiency in specific pharmacodynamic indexes.[85] Further studies are necessary to verify whether the combination of turmeric extract and atorvastatin calcium can achieve the same result in the clinical treatment of hyperlipidemia.
Wen and Zou studied the effect of β-cyclodextrin inclusion with curcumin on the lipid-lowering function of patients with hyperlipidemia. After 2 months of medication-related observation on 228 patients, the related indexes were determined. After the test, the contents of serum TC, TG, and LDL-C decreased, while the HDL-C level increased. The total effective rate of auxiliary lipid-lowering was 55.3%, which indicated that the sample had an auxiliary lipid-lowering function.[86]
Others
Paraquat (PQ) is an organic heterocyclic contact defoliant and herbicide widely used in the world at present and can produce a large amount of mitochondrial peroxide and induce insulin resistance and a disorder of blood glucose metabolism. Yang et al. discussed the effect and pharmacological mechanism of curcumin on paraquat oxidative stress-induced insulin resistance in mice. The experimental results showed that protein kinase B (PKB) phosphorylation was enhanced, the PTEN level of the insulin signal suppressor protein was decreased, MDA level in muscle tissue and mitochondria of mice returned to normal levels, and Nrf2 nuclear translocation and its specific regulation of quinone oxidoreductase 1 (NQO-1) protein increased. The inflammatory signal inhibitory protein IκBα increased to a certain extent, which indicated that curcumin could resist the disorder of glucose metabolism caused by PQ environmental pollutants, and its effect of relieving insulin resistance in mice was related to enhancing the muscle insulin signal and activating the Nrf2 antioxidant system.[87]
CLR is often used in the treatment of rheumatism and arthralgia. Yin et al. studied the effect of turmeric alcohol extract on reducing uric acid in mice with hyperuricemia induced by hypoxanthine and potassium oxazine. The experimental results showed that turmeric alcohol extract of 2.6 g/kg could reduce serum uric acid, inhibit liver xanthine oxidase, and promote urine uric acid excretion, which indicated that turmeric could reduce uric acid production, promote urine uric acid excretion by inhibiting xanthine oxidase activity in the liver tissue, and treat gout.[88]
Fibrosis is a kind of pathological change in which fibrous connective tissue increases and parenchymal cells decrease in organs and tissues. Progression of fibrosis can lead to the destruction of organ structure, functional decline, and even failure. Xue et al. studied the effect of curcumin on a bleomycin-induced pulmonary fibrosis model in rats. The results showed that the content of transforming growth factor beta 1 (TGF-β1) in lung tissue protein decreased to a certain extent after 200 mg/kg/day curcumin was administered, which was similar to the results of the positive drug control group – indicating that curcumin has certain preventive and therapeutic effects on pulmonary interstitial fibrosis in rats. It may be achieved by inhibiting the expression of TGF-β1 in lung tissue.[89] This experiment has good development prospects, but the formation of pulmonary fibrosis is a chronic and complex process, so the experimental results need to be tested clinically over an extended time period. Liu et al. found that CLR could be used to treat coronary microembolization-induced myocardial injury, which may be related to its induced decrease of myocardial apoptosis and inhibition of myocarditis reaction mediated by the Toll-like-receptor 4/myeloid differentiation factor 88/NF-κB signaling pathway.[90] In addition, turmeric is also used to treat dermatitis, gastrointestinal ulcer, retinopathy, cerebral infarction, acute lung injury, allergic rhinitis, and other diseases. The pharmacological activities of CLR are listed in [Table 5].
| Pharmacokinetics | | |
Curcumin has low solubility in water, short plasma half-life, easy metabolism, and poor absorption, which leads to its low bioavailability. The study of its pharmacokinetics in vivo is helpful in providing a theoretical basis for the preparation and clinical application of different formulations of curcumin. Sun et al. studied the kinetic characteristics of curcumin liposome administered intravenously in rabbits and orally in rats. Experiments showed that curcumin liposome injection conformed to the two-compartment model, and compared with FC, it had the advantages of fast distribution, strong action, slow elimination, and long action time. Compared with curcumin suspension, the curcumin liposome oral liquid had the advantages of fast absorption, slow elimination, high concentration in blood, and wide distribution in tissues.[91] Schiborr et al. found that the curcumin content in the brain of mice was 4–5 μg·g− 1 after intraperitoneal injection of curcumin for 30 min, while the curcumin content in the plasma, livers, and brains of mice in a gastric perfusion group was lower than the detection limit.[92] Zhang et al. measured the concentration of curcumin in rat plasma under different administration routes and calculated its bioavailability. The results showed that the elimination half-life of curcumin given by intravenous administration was 11.96 ± 2.64 min, compared with that given by intragastric administration (90.79 ± 11.55 min) and intraperitoneal injection (159.28 ± 18.12 min). The rats were administered curcumin by gavage (200 mg/kg), intraperitoneal injection (20 mg/kg), and sublingual vein (10 mg/kg), and their Cmax values were 3.58 ± 0.58, 1.01 ± 0.12, and 0.67 ± 0.06 mg/L, respectively, with area under characteristic (AUC) readings of 86.36, 73.39, and 104.62 mg/L·min, respectively. The bioavailability of curcumin with oral administration was 4.13% and that with intraperitoneal injection was 35.07%. This shows that the absorption rate of active ingredients can be increased by changing the mode of administration of curcumin to the injection method.[93]
Huang et al. studied the pharmacokinetics of a curcumin-povidone solid dispersion in mice after intragastric administration. The results showed that it conformed to the two-compartment open model. Three hours following intragastric administration, the absorption rate of curcumin suspension was 11.8% ± 2.2%, while the absorption rate of curcumin solid dispersion solution achieved was 79.7% ± 2.1%. The results show that the absorption rate of the curcumin solid dispersion solution is 6.75 times higher than the curcumin suspension (P < 0.01).[94] The former can significantly increase the bioavailability of curcumin and the blood drug concentration is higher. Chen et al. created curcumin nanoparticles and compared their effects on mice with Alzheimer's disease with those of curcumin micropowder. The experimental results showed that curcumin nanoparticles effectively increased the blood concentration of curcumin, and the brain AUC and residence time increased sixfold, indicating that the new dosage form can increase the absorption of curcumin in vivo.[95] Lu et al. found that gavage administration of Tmax, Cmax, T½, and AUC of curcumin nanopreparation and dispersion were 120 min, 0.14 μg/mL, 2310 min, and 246.80 min·μg/ml and 30 min, 0.12 μg/mL, 1733 min, and 155.31 min·μg/ml, respectively. In contrast, Cmax, T½, and AUC were 1.83 μg/mL, 365 min, 103.22 min·μg/ml, and 12.15 μg/mL, 6930 min, and 331.09 min·μg/ml, respectively, after intravenous injection of curcumin nanopreparation and its dispersion. This showed that the bioavailability of nanopreparation by intragastric administration was optimal and that of intravenous dispersion was ideal.[96]
Turmeric has low bioavailability in vivo owing to its structure and solubility characteristics. Many researchers have worked in this field and designed various dosage forms; however, a few shortcomings remain, such as high levels of traditional dosage forms and potential toxicity of new dosage forms. Therefore, the mechanism to design dosage forms with low cost, convenience, environmental protection, safety, and good kinetic characteristics in the future needs further exploration and research by pharmaceutical workers.
| Conclusions and Perspectives | | |
In this paper, the characteristics of turmeric in botany, traditional application, pharmacological activity, and pharmacokinetics were comprehensively described. More than 275 components isolated till date are summarized, and their structures are attached, which has certain comprehensive reference value. In the pharmacological aspect – the antitumor, anti-inflammatory, antioxidant, hypolipidemic, antibacterial, and neuroprotective effects of CLR were studied. This in-depth and comprehensive summary has never been reported in the literature. After decades of efforts, we have an in-depth understanding of the physicochemical and therapeutic properties of turmeric. However, with these achievements, we find that our understanding is insufficient in the research of CLR.
First, research on turmeric processing is rarely seen nowadays. The processing methods of turmeric in Pharmacopoeia only dealt with removing impurities, slight soaking, washing, moistening thoroughly, cutting into thick slices, and drying. Priority was given to its raw use. In ancient times, people also used a variety of other processing methods, such as simmering in wet paper, parching to dryness, parching with wine and vinegar, and soaking rice in water. Other processing methods may have been eliminated for reasons of clinical inefficacy or other reasons, which merits further discussion.
Second, curcumin compounds are the main active ingredients in CLR but have poor solubility and low bioavailability. In recent years, many researchers have focused on a drug delivery system and preparation technology to overcome the limitations and have made some progress. However, the activity of curcumin in vivo is closely related to the activity of its metabolites. On the basis of improving bioavailability and promoting curcumin absorption, future research should focus on the metabolites and metabolic pathways in vivo. At the same time, there should be studies on the new drug-loaded materials that are simple to produce and that can be used in industrial mass production.
Third, the pharmacological effects of TCM come from the chemical substances with specific activities contained in TCM. CLR, as a kind of Chinese herbal medicine, contains thousands of chemical components. At present, more than 275 components such as phenols, volatile oils, diterpenes, flavonoids, and saccharides have been identified and isolated, but this is not the end point of research into its chemical composition. Currently, most researchers concentrate primarily on the rhizomes and components such as curcumin and volatile oils. To better develop and utilize CLR and explore its potential applicability, future researchers should investigate further chemical components in the aerial parts of CLL. Although the leaf does not contain curcumin, it may contain other useful components. Investigators should also explore other components such as saccharides and flavonoids. This may provide help for research into its pharmacodynamic substances. It is believed that with the development of new technologies, new active compounds in CLR will be discovered soon.
Fourth, the pharmacological effects of CLR are extensive, but most experiments have only investigated the in vitro activity. The pharmacokinetics and specific mechanisms of CLR in the human body have not been uniformly demonstrated, and there are different opinions on the targets and pathways of drug action. It is hoped that future work can focus on the specific mechanisms of various pharmacological effects of turmeric. In addition, with the drug research delving thoroughly into the cellular and molecular level, it may be possible to explore and verify the biological activities of different components by combining the current transcriptomics or network pharmacology methods, which are of great significance for the development of turmeric plants and guidance on rational drug use.
Finally, there are various difficulties in fundamentally improving the quality of turmeric. For example, the research on the protection, development, and utilization of turmeric germplasm resources lacks systematic collection and collation. In addition, due to the excessive digging and destruction of the natural environment, the resources of wild medicinal plants of CLL in China are decreasing continuously. Moreover, only a single species of turmeric is cultivated by humans, so the breeding of high-quality turmeric germplasm cannot be sustained. In short, there is a lack of high-quality varieties with commercialization value in the production of turmeric. Therefore, in the future, the investigation and collection of domestic curcumin medicinal plant resources and the evaluation and screening of excellent resources should be strengthened, which is conducive to the rational development and utilization of curcumin plant reserves.
In summary, this paper reviewed CLR from the perspectives of botany, ethnopharmacology, phytochemistry, pharmacology, and pharmacokinetics, hoping to provide convenience for future researchers and to promote the development of active lead compounds and innovative drugs. It is believed that with the development of science and technology and the deepening of research, people will have a deeper understanding of turmeric.
Financial support and sponsorship
This work was supported by the Graduate Innovative Research Project Foundation of Heilongjiang University of Chinese Medicine (No. 2022yjscx059); the Natural Science Foundation of Heilongjiang Province [No. LH2021H097]; the National Natural Science Foundation Matching Project (No. 2018PT02); the National Natural Science Foundation of China (No. 81703684, 81803690, and 81973604); The Special Funds from the Central Finance to Support the Development of Local Universities, the scientific research project of Heilongjiang Provincial Health Commission (No.20211313050171).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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