Chemical composition and biological activities of volatile oil isolated from Curcumae rhizoma

Wenhn Wng,Yibo Wng,Yuntin Xing,Xinyo Wng,Gunyi Zho,Yu Chen,＊

a School of Life Science and Biopharmaceutics,Shenyang Pharmaceutical University,Shenyang 110016,China;

b National Health Commission Key Laboratory of Parasitic Disease Control and Prevention,Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology,Jiangsu Provincial Medical Key Laboratory,Jiangsu Institute of Parasitic Diseases,Wuxi 214064,China;

c School of Business,Liaoning University,Shenyang 110136,China

Abstract Curcumae rhizoma (C.rhizoma),the rhizome of Curcuma Longa L.,Curcuma kwangsiensis L.and Curcuma wenyujin L.in the ginger family,is a treasure in traditional Chinese medicine.It has the effect of promoting qi and breaking blood,eliminating accumulation and relieving pain.With the development of modern medicine,the active ingredients and therapeutic mechanism of C.rhizoma have been gradually revealed.In this paper,the chemical composition and biological activities of volatile oil isolated from C.rhizoma are reviewed in detail,aiming to provide reference for further utilization of C.rhizoma volatile oil and provide more effective drug options for clinical treatment.

Keywords: Curcumae rhizoma;chemical composition;biological activity

1 Introduction

Curcumae rhizoma(C.rhizoma),the rhizome of the ginger family plantsCurcuma LongaL.,Curcuma kwangsiensisL.andCurcuma wenyujinL.,is a type of traditional Chinese medicine with important medicinal value.It has wide clinical applications.It has the effects of promoting Qi and breaking blood stasis,eliminating food retention and alleviating pain.It is often used to treat symptoms such as blood stasis and heartache,food retention,abdominal pain,blood stasis and menstrual disorders [1,2].Modern medical research has further revealed the biological activity ofC.rhizoma.Volatile oil inC.rhizomais a major chemical component,which has various functions such as antioxidant,antiviral,antibacterial,anti-inflammatory,and antitumor effects [3].These biological activities makeC.rhizomawidely applicable and extremely potential for clinical practice.This article reviews the chemical composition and biological activities of the essential oil fromC.rhizoma,with a view to provide references for its future application in clinical practice.By deeply understanding the chemical composition and biological activity of this traditional Chinese medicine,researchers can better recognize and use it,and even provide more effective drug options for clinical treatment.

2 Chemical compositions

Relevant literature shows that the volatile oil ofC.rhizomacontains a rich variety of compounds.The volatile oil ofC.rhizomaincludes sesquiterpenes,aromatic hydrocarbons and their derivatives,monoterpenes,aliphatic hydrocarbons and their derivatives,etc.

2.1 Sesquiterpenoids

Sesquiterpenoids are the most diverse components in the volatile oil ofC.rhizoma,and have obvious curative effects in the treatment of cardiovascular system and liver diseases.The sesquiterpenoid components include bergamotol (1),β-caryophyllene (2),β-elemene (3),(+)-germacrene D (4),(-)-elemene (5),(+)-selinene (6),(E)-isovalencenol (7),curzerenone (8),furanodienone (9),(1aR,4E,10aR)-1a,3,6,10a-tetrahydro-1a,5,9 trimethyloxireno[4,5]cyclodeca [1,2-b]furan-10(2H)-one (10),(+/-)-δ-elemene (11),eudesma-3,7(11)-diene (12),humulenelepoxide (13),isofuranodienone (14),(-)-calamenene (15),(-)-epiglobulol (16),(1S,6β)-1β-methyl-4-(1-methylethylidene)-7β-(3-oxobutyl)bicyclo[4.1.0]heptan-3-one (17),germacrone (18),spathulenol (19),costol (20),(-)-globulol (21),caryophyllene oxide (22),hydroxyvalerenic acid (23),guaiene (24),3-cubebene (25),α-guaiene (26),α-caryophyllene (27),eremophilene (28),and (-)-α-cubebene (29) [4].The structural formulas of these sesquiterpenoids are shown in Fig.1.

Fig.1 Structural formulas of sesquiterpenoids in C.rhizoma

Continued fig.1

2.2 Aromatic hydrocarbons and their derivatives

Some aromatic hydrocarbons and their derivatives have antibacterial and anti-tumor effects,which provide many drug design ideas for the pharmaceutical field.The aromatic hydrocarbon and their derivative components include 3'-methylacetophenone (30),4'-methylacetophenone(31),4,7-dimethyl-1-benzofuran (32),1-ethyl-4-isopropylbenzene (33),2-ethyl-6-methylphenol (34),methyl eugeno l (35),and 4-ethenyl-1,2-dimethylbenzene (36) [5].The structural formulas of these aromatic hydrocarbons and their derivatives are shown in Fig.2.

Fig.2 Structural formulas of aromatic hydrocarbons and their derivatives in C.rhizoma

2.3 Monoterpenoids

As one kind of the main chemical components ofC.rhizoma,monoterpenoids have a wide range of biological activities.According to the database,monoterpenoids have a close relationship with tumor-related targets.Related literature shows that monoterpenoids have anti-inflammatory,antiviral and antibacterial effects.The monoterpenoid components include (-)-cis-carveol (37),4-methyl-2-prop-2-enylphenol (38),1-methyl-4-(1-methylehyl)-2-cyclohexen-1-ol (39),2,3,3-trimethylbicyclo (2.2.1)heptan-2-ol (40),isothujol (41),1,8-cineole (42),(-)-α-terpineol (43),1-methyl-4-(2-methyloxiranyl)-7-oxabicyclo[4.1.0]heptane (44),α-pinene (45),β-pinene (46),β-phellandrene (47),terpinolene (48),4-thujanol (49),2-methylisoborneol (50),(-)-α-pinene (51),verbenone (52),borneol (53),isoborneol (54),3-carene (55),terpinen-4-ol (56),(-)-camphor (57),and cyclodecanone (58) [6,7].The structural formulas of these monoterpenoids are shown in Fig.3.

Fig.3 Structural formulas of monoterpenoids in C.rhizoma

2.4 Aliphatic hydrocarbons and their derivatives

Aliphatic hydrocarbons and their derivatives have anti-inflammatory,analgesic,and other biological activities.Their unique chemical structure makes them important in drug synthesis.The aliphatic hydrocarbon and their derivative components include acetic acid-2-nonyl ester (59),3-nonanone (60),2-butanone (61),2-heptanol (62),2,3,4,5,6,7-hexahydroinden-1-one (63),2-undecanone (64),bornyl acetate (65),and 2-octanol (66) [8,9].The structural formulas of these aliphatic hydrocarbons and their derivatives are shown in Fig.4.

Fig.4 Structural formulas of aliphatic hydrocarbons and their derivatives in C.rhizoma

3 Pharmacological activities

3.1 Antitumor activity

C.rhizomaoil,especially curcumenol inside,shows good efficacy in the treatment of breast cancer [10],lung cancer [11],gastric cancer [12],and colon cancer [13].It is reported that volatile oil ofC.rhizomapromotes the occurrence of apoptosis of tumor cells by regulating the transduction of related apoptotic signals and the expression of related genes and proteins,and inhibit the occurrence and development of tumor cells by interfering with the cell cycle [14].In addition,tumor cells activate the inhibitory pathway in T cells by expressing corresponding ligands and binding with them.C.rhizomaoil inhibits immune cell function or apoptosis [15].Taking lung cancer as an example,mice were randomly divided into three groups: negative control group (injection of normal saline),positive control group (injection of fluorouracil 0.2 mL,20 mg/mL),and treatment group (injection ofC.rhizomaoil 0.2 mL,100 mg/mL).Each group of mice received the drug once a day for 3 w.The mice were killed on the next day after drug withdrawal,and the tumor inhibition rate was calculated.At the same time,tumor samples of mice in the treatment group and the negative control group were also collected for PCNA (Proliferating cell nuclear antigen) and RB (Retinoblastoma protein) protein immunohistochemical staining.PBS (phosphate buffer saline) was used to replace antibody as negative control and positive pairs.During observation,several fields (total number of cells greater than 1000) were randomly selected for each case,and the PCNA positive index (PCNA LI) and the mean value of RB LI were calculated.The results showed thatC.rhizomaoil had significant antitumor effect on Lewis lung cancer mice.C.rhizomaoil may affect tumor growth by down-regulating PCNA and up-regulating RB protein expression.In addition,the inhibitory effect ofC.rhizomaoil on cell proliferation is similar to that of 5-FU,and it has good clinical antitumor effect [16].Network pharmacological investigation shows that curcumenol and other components of the volatile oil ofC.rhizomaact on multiple targets such as ESR1 and PIK3CA,and exert anti-tumor effects by regulating multiple signaling pathways such as cancer pathway,TNF signaling pathway and PI3K signaling pathway [17].It also indicates that curcumenol regulates more than 100 targets to affect glutamine metabolism,such as MAPK1 and HSP90AA1.The protein interaction network shows that curcumenol has a high affinity with multiple targets.The research reveals the potential signaling pathways and biological processes,and provides theoretical basis for medical applications.The pharmacological research ofβ-elemene is more in-depth.β-elemene directly kills tumor cells,and conventional dose has no effect on normal cells,such as peripheral blood leukocytes.By interfering with the growth and metabolism of tumor cells,it induces rapid apoptosis of tumor cells.It acts on the regulatory points of S phase,G2phase and M phase of the cell cycle,blocks S phase cells to enter G2+M phase,reduces the ability of tumor cell division and inhibits its proliferation.

3.2 Antioxidant activity

First,1 mL of the crude extract sample with a concentration of 1 g/L and 1 mL of DPPH solution with a concentration of 1.333 g/L were added to the same test tube,shook well,and reacted at room temperature in the dark for 20 min away from light.The absorbance Ai was measured at 517 nm with anhydrous ethanol as the blank.Then,1 mL 1.333 g/L DPPH (diphenylpicrophenylhydrazine) solution was mixed with 1 mL anhydrous ethanol,shook well,and reacted at room temperature in the dark for 20 min,and the absorbance was measured at 517 nm with anhydrous ethanol as the blank.After that 1 mL of the sample with a concentration of 1 g/L was mixed with 1 mL of anhydrous ethanol,shook well,and reacted at room temperature in the dark for 20 min,and the absorbance was measured at 517 nm with anhydrous ethanol as the blank.The results showed that at the concentration of 1 g/L,C.rhizomahas a strong antioxidant activity,with the scavenging rate of DPPH free radicals exceeding 90% [18].Natural phenolic compounds,such as 2-ethyl-6-methylphenol,have antioxidant activity.At the same time,the essential oil of dry leaf and fresh leaf in the volatile oil ofC.rhizomaalso showed strong anti-linoleic acid lipid peroxidation and antioxidation effects [19].

3.3 Antibacterial and antiviral activity

Researchers dilutedC.rhizomaoil into different concentrations with acetone as the solvent,and investigated the inhibitory effect of acetone and sterile water on spore germination of four fungi(Rhizoctonia pinicola,Curiospora zeae,Anthrax gelatinae,and rice blast fungus) at the concentration of 6.25-50μmol/L (using acetone and sterile water as the control) [20].The results showed that the inhibition rate of spore germination of the four fungi was lower than that of the control group,and the IC50value from small to large was as follows:R.pinicola(6.8μmol/L),C.zeae(16.6μmol/L),A.gelatinae(17.0μmol/L),and rice blast fungus (27.6μmol/L).In addition,the study also found that the oil of GuangxiC.rhizomaturmeric acted on fungi,making their cell walls and organelles disappear,and thus affecting the growth of fungal mycelia.

Huang Huifeng et al.studied the antibacterial activity ofC.wenyujinoil against bacteria [21].They found thatC.wenyujinoil had better antibacterial activity againstEscherichia coliandStaphylococcus aureus,and the residue oil also had better antibacterial activity againstTetracococcus,Escherichia coliandStaphylococcus aureus,and the antibacterial activity of the residue oil was generally stronger than that ofC.wenyujinoil.In addition,C.wenyujinturmeric leaf essential oil has an inhibitory effect onS.aureus,E.coli,Bacillus subtilisandSalmonella,and the inhibitory effect increases with the increase of concentration [19].

Curcuma Longa L.turmeric oil has antiviral effects.It inhibits the proliferation and growth of cervical cancer cell lines SiHa,Ca Ski and cervical immoribile cell H8 by inhibiting the expression of human papilloma virus (HPV) 16 subtype E6E7 [22].

3.4 Analgesic and anti-inflammatory activity

The analgesic effect was observed in the experimental pain model of mice induced by hot plate method and glacial acetic acid,and the antiinflammatory effect was observed in the model of ear swelling induced by xylene,increased capillary permeability induced by glacial acetic acid and cotton ball granuloma hyperplasia in mice [23].The results show that the extract ofC.rhizomahas analgesic and anti-inflammatory functions.Gu Ying et al.also confirmed thatC.rhizomaoil could be used in the treatment of acute erosive esophagitis,and played a safe and effective role in alleviating esophageal inflammation [24].In addition,GuangxiC.rhizomahas strong antiinflammatory and analgesic effects [25].It has exhibited anti-fibrosis effect,which may be realized by inhibiting the expression of inflammatory factors such as interleukin (IL-1β).In the study of mouse mononuclear macrophage leukemia cells (RAW 264.7),the phenotypic activation of lipopolysaccharide (LPS) demonstrated the antiinflammatory and antifibrotic effects of curcumenol.

3.5 Other pharmacological activities

Chen JM et al.found thatC.rhizomawater decoction,formula particles andC.rhizomaoil all had good anti-dysmenorrhea effects [26].Li Shengsheng et al.studiedβ-elemene isolated fromC.rhizomaoil,and found that it inhibited GEF expression in hepatic stele cells,up-regulated the expression of GDIβ,and interfered with GEF/Gdiβ-Rho related kinase (ROCK) pathway,thus playing an anti-liver fibrosis role [27].In addition,curcuma dione is one of the effective components of curcuma oil,which increases blood flow by changing the coagulation time and thrombin activity,inhibits platelet aggregation,and effectively prevents the occurrence of thrombus [28].

4 Conclusion

The chemical constituents and pharmacological effects ofC.rhizomaoil were reviewed in this paper.In this common Chinese medicine,volatile oil ofC.rhizomais an indispensable pharmaceutical constituent,which plays an effective role in the treatment of many diseases.Studies have found that volatile oil ofC.rhizomahas many pharmacological effects,such as anti-inflammatory,analgesic,antibacterial and antiviral,detumescence,liver protection,and anti-tumor and lipid regulation.In clinical application,volatile oil ofC.rhizomais used to treat dysmenorrhea,headache,hepatitis,liver cirrhosis,tumor and other diseases,and it is also used for health care.Considering the molecular biological characteristics of curcuma and other substances inC.rhizoma,together with modern therapies,we make some suggestions for the medicinal use of curcuma.Firstly,since the active ingredients in the extract ofC.rhizomacan inhibit tumor growth and CAR T cell therapy can eliminate tumor cells,the combination of the two might achieve synergistic anti-tumor effect and improve the therapeutic effect.Secondly,sinceC.rhizomais a typical anti-inflammatory drug that can reduce the inflammatory response that CAR T therapy can trigger,such as cytokine release syndrome(CRS),by inhibiting the production of interleukin(IL-1),it might reduce the risk of complications of CAR-T therapy and improve patient tolerance.Thirdly,sinceC.rhizomaoil can change the tumor microenvironment,such as inhibiting tumor angiogenesis and promoting tumor cell apoptosis,it might improve the permeability and activity of CAR T cells in tumor tissues and enhance the efficacy.This feature can also be applied to the interaction with traditional chemotherapy drugs.For example,curcumenol can be combined with traditional chemotherapy drugs,such as anthracycline and platinum,to enhance the effect of chemotherapy.Curcumenol has anti-tumor angiogenesis effect,can reduce tumor growth rate,and inhibit tumor growth together with chemotherapy drugs.But,takingC.rhizomavolatile oil may cause gastrointestinal discomfort in some people.C.rhizomais warm in nature.Taken for a long time,it may lead to body fluid depletion,aggravate the symptoms of patients with stomach Yin deficiency,and cause acid reflux,nausea,vomiting and other discomfort.Therefore,patients with weak physique and stomach Yin deficiency can not takeC.rhizomafor a long time.In the future,the researchers onC.rhizomaoil should dig more effective components,explore the mechanism of action,and optimize the preparation technology.In addition,the application ofC.rhizomaoil in a wider range of fields should be further expanded.

Acknowledgements

This work was financially supported by National Nature Science Foundation of China(81973284),Scientific Research Foundation of the Education Department of Liaoning Province(LJKZ0944) and Jiangsu Province Capability Improvement Project through Science,Technology and Education (ZDXYS202207).