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. 2020 Oct 31;2020:2648759. doi: 10.1155/2020/2648759

Analysis of the Components in Moxa Smoke by GC-MS and Preliminary Discussion on Its Toxicity and Side Effects

Xiaoyu Xu 1,2, Si Shan 1,2,✉, Wenlei Wang 1,2, Hongning Liu 1,2
PMCID: PMC7648687  PMID: 33178311

Abstract

Moxibustion plays an important role in the prevention and treatment of diseases and the promotion of human health. In this study, the components in moxa smoke from Jiangxi Poai Biotechnology Co., Ltd., namely, Qing moxa sticks, were absorbed by five solvents (cyclohexane, ethyl acetate, n-butanol, anhydrous ethanol, and water) and identified by gas chromatography-mass spectrometry. The identification results of the smoke from the Qing moxa sticks that was absorbed in liquid are as follows: a total of 294 compounds were identified, including 139 in cyclohexane, 145 in ethyl acetate, 60 in n-butanol, 89 in anhydrous ethanol, and 77 in water, and of those, 112 toxic compounds were identified. Furthermore, Ingenuity Pathway Analysis software and the PubChem database were successfully applied to analyze the toxic compounds. There were 812 target proteins related to the toxic components, 25 molecular networks, and 54 biological pathways. The results showed that the toxic compounds of moxa smoke may have some side effects on the heart, liver, and kidney of humans. This study revealed that the components of moxa smoke are complex and diverse. Due to the findings of toxic compounds in moxa smoke, we recommend that moxibustion rooms should be equipped with ventilation equipment or enough artificial ventilation to ensure the health of patients and practitioners.

1. Introduction

Moxibustion is an important part of clinical treatment in traditional Chinese medicine. In moxibustion, wormwood or other drugs are used to place acupoints or pain points on the body surface for warming meridians and stimulating acupuncture points [1]. As people pay more attention to health, the use of moxibustion to treat diseases in China and other Asian countries is growing [2]. Heat and moxa smoke are produced during moxibustion. The heat of moxibustion has the function of assisting Yang Qi, lifting subsidence, and solidifying. Recent studies have shown that moxa smoke also has antibacterial, antitumor, antiviral, anti-inflammatory, and air purification functions [3–7]. Ancient books on Chinese Medicine contain records of the use of moxa smoke in the treatment of irritable bowel syndrome [8], inflammatory bowel disease [9], and neurological symptoms [10]. Additionally, the antioxidants in moxa smoke play an antiaging role through the penetration of heat [11].

However, some patients feel uncomfortable during moxibustion and can even have noticeable adverse reactions, such as watery eyes and coughing, which has caused people to question the safety of moxa smoke [12, 13]. Some studies have shown that there were harmful components such as monoaromatic hydrocarbons and formaldehyde in moxa smoke [14–16]. The inhalation of these substances induced eustachian tube irritation, throat itching, eye pain, tonsil swelling, and other toxic effects [12]. Therefore, it is very important to determine the toxic compounds in moxa smoke.

The aim of the present study was to analyze the components in Qing moxa smoke based on enrichment with five solvents. A set of smoke absorption devices were designed with cyclohexane, ethyl acetate, n-butanol, anhydrous ethanol, and water as absorbents with the help of an extraction pump to concentrate the moxa smoke in the solvents. The benefits of this device for enrichment of moxa smoke include: (1) moxa sticks can burn completely in the air to avoid incomplete combustion; (2) the devices can detect as many compounds as possible by increasing the concentration of moxa smoke; and (3) the use of different polar solvents can provide reference for the absorption and treatment of moxa smoke. Then, the toxic compounds were queried by the Comparative Toxicogenomics Database (CTD) [17, 18]. In addition, we aimed to estimate the toxic compounds in moxa smoke that would have an impact on the human body by applying Ingenuity Pathway Analysis (IPA) software and the PubChem database to provide an experimental basis for the safety evaluation of moxa smoke [19, 20].

2. Materials and Methods

2.1. Materials

We followed the steps outlined in our patent, “A method of using Terahertz Wave to detect the quality of moxa column,” patent number: ZL 2020 1 0000161.6, which are as follows: (1) sample placement; (2) determination of the background value; (3) measurement of the terahertz wave energy at different bands of the combustion column; (4) data processing; and (5) column quality judgment. If the terahertz wave intensity of each band is stronger than others and the waveform slightly changes, the quality is better. The results revealed which Qing moxa stick had the best quality, and that one was selected for smoke enrichment analysis [21]. Qing moxa sticks (18 × 27 ± 1 mm, Jiangxi Poai Biotechnology Co., Ltd., Poyang, China), which are widely used by the Chinese population, were used in this study. Moxa sticks were encased in Artemisia argyi (Chinese mugwort) floss, which was made of dried A. argyi leaves. The Qing moxa sticks were produced with a 10 : 1 ratio, which means that 10 kg of dried A. argyi leaves were processed into 1 kg of moxa floss. Analytical grade cyclohexane, ethyl acetate, n-butanol, and ethanol were all purchased from Guangdong Xilong Science Co., Ltd., and used as received.

2.2. Sample Preparation

A set of smoke absorption devices was designed as shown in Figure 1. With 1000 mL cyclohexane, ethyl acetate, n-butanol, anhydrous ethanol, or water as the solvent, 50 moxa sticks were burned in the air until combustion was complete. During the combustion process, the air pump control combustion speed was adjusted such that the blank flask did not fill with white smoke, so that the solvent fully absorbed the moxa smoke. The glass ball in the absorption flask had holes in it to reduce the production of bubbles and prevent the solvent from escaping. The absorption solution was emptied from the absorption flask, filtered with a 0.22 μm microporous membrane, and 2 mL of each solution was added into the sample bottle for gas chromatography-mass spectroscopy (GC-MS) analysis.

Figure 1.

Figure 1

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A smoke absorption device. (1) Smoke hood. (2) Absorption flask. (3) Blank flask. (4) Buffer flask.

2.3. GC-MS Analysis

An Agilent Technologies 7890 GC system (Agilent Technologies Inc., Palo Alto, CA, USA) coupled with an Agilent Technologies 5975 mass spectrometer (Agilent Technologies Inc.) was used for moxa smoke analysis. A HP-5MS capillary column (30 m × 0.25 mm × 0.25 μm) was used to separate compounds. High-purity helium was applied as the carrier gas. The following conditions were used: column flow rate: 1.0 mL/min; split injection, split ratio: 100 : 1; injection volume: 1 μL; and injection port temperature: 250°C. The temperature procedure was as follows: 0–3 min, 40–40°C; 3–39 min, 40–220°C; 39–43 min, 220–220°C; 43–49 min, 220–280°C; and 49–50 min, 280–280°C.

The MS working conditions were as follows: the electron ionization energy was 70 eV, the full-scan acquisition was used in the range of 50–650 m/z, the ion source temperature was 230°C, the transmission ion temperature was 280°C, and the four-stage pole temperature was 150°C. The identification of each peak in the total ion flow chromatogram was automatically retrieved from the National Institute of Standards and Technology (NIST) 11.L as the standard mass spectrometry database and verified with standard mass spectrometry. Some components were confirmed with the retention value of a standard sample. The identified components were semiquantified by comparing the peak area of each component with the total peak area, and the relative percentage of components was calculated by the peak area normalization method.

2.4. Network Toxicological Analysis

The compounds identified by the NIST 11.L were then queried for related toxicity through the CTD database (https://ctdbase.org/about/). Then, the molecular information corresponding to the toxic compounds of moxa smoke was obtained from the PubChem database (http://pubchem.ncbi.nlm.nih.gov/) [22]. In addition, the Swiss Target Prediction database (http://www.swisstargetprediction.ch/) was used to predict toxic compounds relevant targets, and exporting Uniprot ID. Next, the molecular networks of toxic compound target proteins and its biological pathways were constructed by IPA software (Qiagen, Redwood City, CA, USA).

3. Results

3.1. Total Ion Chromatogram

The total ion chromatograms (TIC) of moxa smoke from solvents by GC-MS are shown in Figure 2 [23, 24]. As shown in Figure 2, the compounds in moxa smoke were detected within 40 min.

Figure 2.

Figure 2

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Total ion chromatograms of five solvents by GC-MS. (a) Cyclohexane. (b) Ethyl acetate. (c) n-Butanol. (d) Anhydrous ethanol. (e) Water. Only compounds unique to each solvent with a relative content greater than 0.5% are tagged in the figure.

3.2. GC-MS Analysis Results

A total of 294 compounds, including 139 in cyclohexane, 145 in ethyl acetate, 60 in n-butanol, 89 in anhydrous ethanol, and 77 in water were found and identified in Qing moxa smoke. As shown in Tables 1–5, only 52 unique compounds were detected in cyclohexane smoke absorption liquid, 57 in ethyl acetate, 10 in n-butanol, 17 in anhydrous ethanol, and 47 in water, and other components were identified in more than one solvent. Toluene, pyridine, 2-methylpyridine, 2-methyl-2-cyclopenten-1-one, 2-furanmethanol, 2-acetylfuran, phenol, eucalyptol, o-cresol, indole, and biphenyl were detected in all five solvents and are shown in Figure 3, but the same components had different concentrations in different solvents. This shows that the components of moxa smoke were absorbed differently by different polar solvents.

Table 1.

Relative content (%) of unique compounds in cyclohexane.

No. Rt (min) Compound Retention index Relative content (%)
1 4.038 Bicyclo[4.1.0]hept-2-ene 706 0.033
2 4.602 4-Methyl-1,4-hexadiene 737 0.175
3 4.978 1-Methylcyclohexene 757 0.078
4 5.093 1,3,5-Heptatriene 763 0.115
5 5.290 1,7-Octadiene 774 0.048
6 5.400 2-Methyl-1-heptene 780 0.105
7 5.514 1-Octene 786 0.693
8 5.947 (E)-2-Octene 806 0.086
9 6.458 1,3-Dimethyl cyclohexene 822 0.222
10 6.647 (E,E,E)-2,4,6-Octatriene 828 0.027
11 7.111 5,6-Dimethyl-1,3-cyclohexadiene 843 0.040
12 7.749 3-Methylenecycloheptene 863 0.146
13 8.060 (1Z,2Z)-1,2-Di(ethylidene)cyclobutane 873 0.094
14 8.334 Cyclohexanol 882 0.703
15 9.025 2-Ethylpyridine 904 0.095
16 10.064 2-Methyl-1-octen-3-yne 935 0.105
17 10.166 1-Methylcycloheptene 938 0.141
18 11.164 Mesitylene 968 0.307
19 11.629 Alpha-methyl styrene 981 0.176
20 12.372 Gamma-terpinene 1004 0.227
21 12.960 1,2,4-Trimethylbenzene 1022 0.866
22 13.395 Trans-beta-methyl styrene 1035 0.371
23 14.973 1-Phenyl-2-butene 1083 0.228
24 15.181 1-Methyl-4-(prop-1-en-2-yl)benzene 1090 1.054
25 15.901 Cosmene 1112 0.163
26 16.210 2,4-Dimethylstyrene 1122 0.156
27 16.305 1-Phenyl-1-butene 1125 0.336
28 16.448 1-Allyl-2-methylbenzene 1130 0.223
29 16.749 Phenyl acetonitrile 1140 0.610
30 17.051 2,3-Dimethylphenol 1149 0.687
31 17.155 1,2,3,4-Tetramethylbenzene 1153 0.203
32 17.510 1,1a,6,6a-Tetrahydrocycloprop[a]indene 1164 0.258
33 18.241 1,2-Dimethylindan 1188 0.200
34 19.970 4-Methylindole 1247 0.200
35 20.792 7H-Benzocycloheptene 1275 0.200
36 21.045 2-(2-Hydroxyphenyl)buta-1,3-diene 1284 0.168
37 22.396 1H-Indene,2,3-dihydro-1,1,3-trimethyl 1332 0.226
38 23.401 5-Methylindole 1369 0.099
39 23.527 1,8-Cyclotetradecadiyne 1374 0.108
40 24.816 1,4-Dimethylnaphthalene 1422 0.227
41 25.073 1,4,5-Trimethylnaphthalene 1432 0.142
42 26.434 2,4,6-Trimethylbenzonitrile 1485 0.137
43 27.199 1-Phenylpyridin-2-one 1516 0.186
44 28.473 2,4-Dimethoxyacetophenone 1568 0.234
45 28.910 Spathulenol 1586 0.163
46 29.355 2-Methylbiphenyl 1605 0.114
47 30.735 (+)-γ-Gurjunene 1665 0.217
48 33.434 9-Methylene-9H-fluorene 1786 0.103
49 34.460 3,7,11,15-Tetramethyl-2-hexadecene 1835 0.062
50 34.710 2,6,10,14-Tetramethyl-2-hexadecene 1847 0.135
51 35.671 1-Nonadecene 1893 0.163
52 37.669 E-15-Heptadecenal 1993 0.123
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Table 2.

Relative content (%) of unique compounds in ethyl acetate.

No. Rt (min) Compound Retention index Relative content (%)
1 4.106 3-Methyl-butanenitrile 710 0.159
2 4.535 Dimethyl aminoacetonitrile 733 0.191
3 4.603 2,4-Dimethyl-1,3-pentadiene 737 0.152
4 5.236 3-Methylenecyclohexene 771 0.095
5 5.300 Cyclooctene 775 0.030
6 5.522 2-Octene 787 0.557
7 5.837 2,3-Dimethyl-1,4-hexadiene 802 0.120
8 5.957 (Z)-2-Octene 806 0.044
9 6.462 Pyrazine, methyl 822 0.208
10 6.869 2,5-Dimethylpyrrole 835 0.088
11 8.073 1,4-Dimethylenecyclohexane 874 0.051
12 8.411 2,3-Dimethylpyridine 885 0.166
13 9.820 3-Ethyl-1H-pyrrole 928 0.295
14 9.893 3,4-Dimethylpyridine 930 0.509
15 10.078 2-Ethyl-5,5-dimethyl-1,3-cyclopentadien 935 0.082
16 10.480 2-Methylborazine 947 0.250
17 11.291 2,5-Cyclooctadien-1-one 971 0.115
18 11.406 Benzene 975 0.060
19 11.503 Aniline 978 0.183
20 12.166 3-Methylstyrene 997 0.337
21 12.385 Alpha-phellandrene 1004 0.151
22 12.591 2-Ethyl-4-methyl-1H-pyrrole 1010 0.295
23 13.065 o-Cymene 1025 1.118
24 13.402 Allylbenzene 1035 0.309
25 15.039 3-Ethyl-o-xylene 1085 0.593
26 15.620 7-Methylbenzofuran 1103 0.383
27 15.921 Azulene 1113 0.406
28 16.454 4-Allyltoluene 1130 0.171
29 16.762 3-Ethynylaniline 1140 0.367
30 17.065 3-Methyl-1H-indene 1150 0.557
31 17.163 1,2,3,4-Tetramethylfulven 1153 0.138
32 17.523 1,4-Dihydronaphthalene 1165 0.214
33 18.254 1-Methyl-3-(1-methyl-2-propenyl)benzene 1188 0.188
34 18.501 Dihydrocarveol 1196 0.140
35 18.696 Catechol 1203 0.223
36 19.034 2,6-Dimethylundecane 1215 0.195
37 19.250 (E)-Cinnamaldehyde 1222 0.391
38 19.355 Cyclododecene 1226 0.166
39 19.758 Isoquinoline 1239 0.210
40 19.983 3-Methylindolizine 1247 0.172
41 21.057 1,11-Dodecadiene 1284 0.162
42 22.733 2-Methylhydroquinone 1345 0.174
43 22.816 Naphthalene, 1,2,3,4-tetrahydro-1, 1-dimethyl 1348 0.125
44 23.825 2-Methyl-5-(1-methylethenyl)-cyclohexanone 1385 0.131
45 23.955 3-Methylindole 1389 0.257
46 24.827 1,3-Dimethylnaphthalene 1423 0.205
47 24.930 1,6-Dimethylnaphthalene 1427 0.460
48 25.761 2-Phenyl-1,3-cyclohexadien 1459 0.104
49 28.833 Phenylephrine 1583 0.020
50 31.836 Thiazolo[5,4-f]quinolin 1713 0.158
51 32.239 1,1,2-Trimethylcycloundecane 1732 0.250
52 33.442 Phenanthrene 1787 0.116
53 34.719 3,7,11,15-Tetramethyl-2-hexadecene 1847 0.146
54 35.480 (S)-6,6-Dimethyl-2-azaspiro[4.4]non-1-ene 1884 0.158
55 37.681 3-Icosene 1994 0.179
56 39.610 10-Heneicosene (c,t) 2093 0.140
57 39.729 Heneicosane 2100 0.110
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Table 3.

Relative content (%) of unique compounds in n-butanol.

No. Rt (min) Compound Retention index Relative content (%)
1 6.843 3-Furaldehyde 834 1.167
2 9.850 3-Methylheptan-4-one 928 0.377
3 9.998 2,4-Dimethylpyridine 933 0.457
4 10.819 Limonene 957 0.442
5 12.169 Butyl butyrate 997 6.894
6 16.330 (E)-1-Phenyl-1-butene 1126 0.273
7 16.771 Benzyl(methylidyne)azanium 1140 0.559
8 18.371 cis-2-dodecene 1192 1.064
9 19.262 Tricyclo[3.3.1.0(2,8)]nona-3,6-dien-9-one 1222 0.600
10 23.958 1-Methylindolizine 1390 0.361
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Table 4.

Relative content (%) of unique compounds in anhydrous ethanol.

No. Rt (min) Compound Retention index Relative content (%)
1 5.142 Thiophene 766 0.064
2 6.488 2-Methylpyrazine 823 0.137
3 9.811 2,3-Dimethyl-1H-pyrrole 927 0.155
4 11.170 6-Methyl-6-ethylfulvene 968 0.191
5 12.724 Acrylamide 1014 0.098
6 14.877 (−)-Camphor 1080 0.477
7 14.974 2-Methyl-1-phenylpropene 1083 0.137
8 15.691 4-Pyridinol 1105 0.157
9 17.059 3-Phenyl-1,2-butadiene 1150 0.649
10 17.518 Benzo[2,3]bicyclo[3.1.0]hexane 1165 0.188
11 20.713 Citral 1272 0.283
12 21.053 4-Methyl-2H-benzopyrane 1284 0.160
13 22.331 1,7-Dimethylnaphthalene 1330 0.224
14 25.053 2,3,6-Trimethylnaphthalene 1432 0.123
15 29.065 (Z)-8-Hexadecene 1593 0.393
16 35.803 Nonadecane 1900 0.118
17 37.154 Dibutyl phthalate 1968 0.425
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Table 5.

Relative content (%) of unique compounds in water.

No. Rt (min) Compound Retention index Relative content (%)
1 4.688 Methallyl cyanide 741 0.065
2 5.083 Cyclopentanone 763 0.730
3 5.558 Tetrachloroethylene 789 0.076
4 6.010 4-Aminopyridine 808 0.470
5 6.479 2-Methylcyclopentanone 823 0.375
6 6.549 4-Methylpentanenitrile 825 0.314
7 6.679 (R)-(+)-3-Methylcyclopentanone 829 0.150
8 7.870 2,6-Dimethylpyridine 867 0.596
9 8.091 Cyclohexanone 874 0.378
10 8.420 5,5-Dimethyl-1,3-hexadiene 885 0.079
11 8.816 2-Ethylpyrazin 898 0.426
12 8.975 2,3-Dimethylpyrazine 903 0.126
13 10.000 2,5-Dimethylpyridine 933 0.497
14 10.378 5-Methylfurfural 944 1.092
15 11.178 Phenetole 968 0.185
16 11.346 1-Isopropylcyclopentene 973 0.312
17 12.121 2-Ethyl-6-methylpyridine 996 0.438
18 12.400 2-Ethyl-5-methylpyridine 1004 0.282
19 12.687 5-Ethyl-2-methylpyridine 1013 0.207
20 12.743 2-Acetyl-5-methylfuran 1015 0.095
21 13.570 1-Acetyl-2-methyl-1-cyclopentene 1040 0.378
22 14.229 2-Methyl-6-methylene-2,7-octadien-4-ol 1060 0.540
23 14.663 Sabinene hydrate 1074 0.750
24 14.803 p-Tolunitrile 1078 0.511
25 15.168 2-Methylbenzoxazole 1089 0.568
26 15.419 2,6-Dimethylphenol 1097 0.820
27 15.601 Phenylacetone 1103 0.116
28 15.698 1-Isopropyl-1-cyclohexene 1106 0.226
29 16.045 4-Ethylphenol 1117 0.681
30 16.490 Decamethylcyclopentasiloxane 1131 0.372
31 16.721 Endo-borneol 1139 2.029
32 16.918 2-Acetyltoluene 1145 0.314
33 17.065 (-)-Terpinen-4-ol 1150 2.220
34 17.262 1-(3-Methylphenyl)ethanone 1156 0.818
35 17.460 (−)-Alpha-terpineol 1163 1.438
36 17.581 (+)-Dihydrocarvone 1167 0.338
37 17.960 (+/−)-cis-piperitol 1179 0.350
38 18.027 Verbenone 1181 0.190
39 18.279 (−)-cis-carveol 1189 0.357
40 18.610 2,4-Dimethylanisole 1201 0.248
41 19.293 Piperitone 1223 0.187
42 20.994 1-Methylindan-2-one 1282 0.261
43 21.356 Dodecamethylcyclohexasiloxane 1294 0.193
44 22.485 3,3-Dimethyl-1-indanone 1336 0.233
45 23.314 Methyl eugenol 1366 0.229
46 23.669 2,3-Dimethylnaphthalene 1379 0.146
47 26.001 2,4-Di-tert-butylphenol 1468 0.644
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Figure 3.

Figure 3

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Relative contents (%) of common compounds in the five solvents.

As shown in Figure 3, the common components from moxa smoke in the five solvents included toluene (0.650%–3.872%), pyridine (0.137%–2.847%), 2-methylpyridine (0.267%–1.878%), 2-methyl-2-cyclopenten-1-one (0.412%–1.649%), 2-furanmethanol (0.526%–1.320%), 2-acetylfuran (0.266%–1.092%), phenol (2.686%–5.405%), eucalyptol (1.037%–1.605%), o-cresol (0.661%–1.419%), indole (0.780%–1.257%), and biphenyl (0.179%–0.338%). Among the above common components, the relative contents of phenol were more than 2% in all solvents. Phenol is a corrosive compound that is a strong irritant, which can lead to acute poisoning, skin ulcers, and tissue burns and can even be life-threatening [25, 26]. However, the amount of harmful substances produced by moxibustion will dictate the negative impact on the human body, and the duration of exposure to a moxa fume environment will determine if damage is caused to the body. There is no unified answer to these questions, which requires a large amount of case analysis and clinical trials.

3.3. Toxic Compounds of Moxa Smoke

The toxicity of compounds was determined based on the CTD database (https://ctdbase.org/about/), which provided abundant toxicological information for researchers. Among the 294 compounds detected in the moxa smoke absorption liquid, 112 compounds were confirmed to be toxic. Further study is needed to explore the toxicity of the 112 compounds. Table 6 provides details of the 112 toxic compounds.

Table 6.

Toxic compounds in moxa smoke.

No. Compound CAS RN Chemical ID PubChem CID
1 Toluene 108-88-3 D014050 1140
2 Pyrimidine 289-95-2 C030986 9260
3 1-Methylpyrrole 96-54-8 C096654 7304
4 Pyridine 110-86-1 C023666 1049
5 Cyclopentanone 120-92-3 C007201 8452
6 1-Octene 111-66-0 C037690 8125
7 Tetrachloroethylene 127-18-4 D013750 31373
8 Octane 111-65-9 C026728 356
9 4-Aminopyridine 504-24-5 D015761 1727
10 Ethylbenzene 100-41-4 C004912 7500
11 Styrene 100-42-5 D020058 7501
12 p-Xylene 106-42-3 C031286 7809
13 Furfural 98-01-1 D005662 7362
14 2,5-Dimethylpyrrole 625-84-3 C067286 12265
15 2-Furanmethanol 98-00-0 C012986 7361
16 2-Acetylfuran 1192-62-7 C039669 14505
17 3-Methylpyridine 108-99-6 C053603 7970
18 2,6-Dimethylpyridine 108-48-5 C013093 7937
19 o-Xylene 95-47-6 C026114 7237
20 Butyrolactone 96-48-0 D015107 7302
21 Cyclohexanone 108-94-1 C036468 7967
22 Phenyl ethyne 536-74-3 C044736 10821
23 m-Xylene 108-38-3 C031285 7929
24 Propyl benzene 103-65-1 C024268 7668
25 Nonane 111-84-2 C017573 8141
26 2-Ethylpyridine 100-71-0 C051672 7523
27 Benzaldehyde 100-52-7 C032175 240
28 Cumene 98-82-8 C015763 7406
29 2,4-Dimethylpyridine 108-47-4 C078448 7936
30 Benzofuran 271-89-6 C105430 9223
31 5-Methylfurfural 620-02-0 C048065 12097
32 Phenol 108-95-2 D019800 996
33 Limonene 138-86-3 D000077222 22311
34 3-Ethyltoluene 620-14-4 C029719 12100
35 1,2,3-Trimethylbenzene 526-73-8 C010179 10686
36 Mesitylene 108-67-8 C010219 7947
37 Phenetole 103-73-1 C079413 7674
38 Eucalyptol 470-82-6 D000077591 2758
39 Benzene 71-43-2 D001554 241
40 Aniline 62-53-3 C023650 6115
41 Alpha-methyl styrene 98-83-9 C017915 7407
42 Butyl butyrate 109-21-7 C022793 7983
43 Decane 124-18-5 C012867 15600
44 Gamma-terpinene 99-85-4 C018669 7461
45 Alpha-phellandrene 99-83-2 C005403 7460
46 5-Ethyl-2-methylpyridine 104-90-5 C019196 7728
47 o-Cresol 95-48-7 C034047 335
48 Acrylamide 79-06-1 D020106 6579
49 2-Acetyl-5-methylfuran 1193-79-9 C057528 14514
50 p-Cresol 106-44-5 C032538 2879
51 1,2,4-trimethylbenzene 95-63-6 C010313 7247
52 o-Cymene 527-84-4 C046257 10703
53 p-Cymene 99-87-6 C007210 7463
54 Guaiacol 90-05-1 D006139 460
55 m-Cresol 108-39-4 C042041 342
56 Allylbenzene 300-57-2 C102347 9309
57 Indene 95-13-6 C093581 7219
58 Acetophenone 98-86-2 C038699 7410
59 Methyl benzoate 93-58-3 C044605 7150
60 2,6-Dimethylphenol 576-26-1 C036531 11335
61 Undecane 1120-21-4 C022884 14257
62 Phenylacetone 103-79-7 C008863 7678
63 4-Pyridinol 626-64-2 C534143 12290
64 Naphthalene 91-20-3 C031721 931
65 Azulene 275-51-4 C005525 9231
66 4-Ethylphenol 123-07-9 C042291 31242
67 4-Allyltoluene 3333-13-9 C092903 76851
68 Indolizine 274-40-8 C035094 9230
69 Phenyl acetonitrile 140-29-4 C006725 8794
70 2,3-Dimethylphenol 526-75-0 C054067 10687
71 1,2,3,4-Tetramethylbenzene 488-23-3 C021246 10263
72 (−)-Alpha-terpineol 10482-56-1 C016775 443162
73 3,5-Dimethylphenol 108-68-9 C016834 7948
74 Terpinen-4-ol 562-74-3 C034019 11230
75 Dodecane 112-40-3 C007548 8182
76 Catechol 120-80-9 C034221 289
77 5,6-Dimethylbenzimidazole 582-60-5 C015158 675
78 Tridecane 629-50-5 C094074 12388
79 (E)-Cinnamaldehyde 104-55-2 C012843 637511
80 Indole 120-72-9 C030374 798
81 Isoquinoline 119-65-3 C039109 8405
82 Citral 5392-40-5 C007076 638011
83 Hydroquinone 123-31-9 C031927 785
84 Biphenyl 92-52-4 C010574 7095
85 1-Tridecene 2437-56-1 C028691 17095
86 Tetradecane 629-59-4 C024713 12389
87 2-Methylnaphthalene 91-57-6 C027384 7055
88 1-Methylnaphthalene 90-12-0 C025968 7002
89 2-Methoxy-4-vinylphenol 7786-61-0 C014245 332
90 2,6-Dimethylnaphthalene 581-42-0 C028519 11387
91 2-Methylhydroquinone 95-71-6 C062397 7253
92 Methyl eugenol 93-15-2 C005223 7127
93 5-Methylindole 614-96-0 C093726 11978
94 2,3-Dimethylnaphthalene 581-40-8 C091753 11386
95 3-Methylindole 83-34-1 D012862 6736
96 1,4-Dimethylnaphthalene 571-58-4 C031969 11304
97 2,4-Di-tert-butylphenol 96-76-4 C056559 7311
98 Dibenzofuran 132-64-9 C023614 568
99 Phenylephrine 59-42-7 D010656 6041
100 Heptadecane 629-78-7 C016486 12398
101 Spathulenol 6750-60-3 C013258 92231
102 1-Octadecene 112-88-9 C109760 8217
103 Chamazulene 529-05-5 C013872 10719
104 Phenanthrene 85-01-8 C031181 995
105 Octadecane 593-45-3 C022883 11635
106 Pinane 473-55-2 C030216 10129
107 Nonadecane 629-92-5 C061580 12401
108 Hentriacontane 630-04-6 C049203 12410
109 Methyl palmitate 112-39-0 C019012 8181
110 Ambrettolide 123-69-3 C008563 5365703
111 Dibutyl phthalate 84-74-2 D003993 3026
112 Icosane 112-95-8 C050821 8222
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3.4. Targets of Toxic Compounds

Through the PubChem database (http://pubchem.ncbi.nlm.nih.gov/), molecular information for the 112 toxic compounds in moxa smoke was identified, and the corresponding number of “Canonical SMILES” was obtained. Then, using the Swiss Target Prediction database (http://www.swisstargetprediction.ch/) to predict the 112 relevant targets of the toxic compounds, the UniProt ID was exported. In addition, the UniProt ID was analyzed with IPA software to obtain the targets of toxic compounds. There were 812 targets for the toxic compounds in moxa smoke, compared to 810 identified with the IPA database.

3.5. Molecular Networks of Toxic Compounds

The UniProt IDs of the 810 target proteins of the 112 toxic compounds were imported into the IPA bioanalysis software. Under the “tox analysis” module, IPA was used to construct the molecular networks of target proteins. A total of 25 molecular networks were constructed for 112 toxic compounds, with a maximum score of 43, as shown in Figure 4. The results showed that these target proteins were related to cell signal transduction, nucleic acid metabolism, inflammatory response, organ damage, and cell apoptosis. Therefore, this can be used to frame a correlation study on moxa smoke.

Figure 4.

Figure 4

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Molecular network with a maximum score of 43. Each node in the figure represents 1 molecule, the solid lines represent a direct interaction between two molecules, and the dotted lines represent an indirect interaction between two molecules.

3.6. Biological Pathways of Toxic Compounds

Using the “tox analysis” module in the IPA software, a total of 54 biological pathways were found for the 112 toxic compounds. The main biological pathways of the toxic compounds from moxa smoke included cardiotoxicity, hepatotoxicity, and nephrotoxicity. Consequently, the toxic compounds of moxa smoke may have some side effects on the human heart, liver, and kidneys. A heat map of the biological pathway of toxic compounds is shown in Figure 5. According to it, the pathway with the highest −log (p value) was cardiac arteriopathy, which was classified as cardiotoxicity, with a value of 79.429. Drug target molecules acting on this pathway include ABCB1, ABCC8, ACE, ADORA1, ADORA2A, ADORA2B, ADORA3, ADRA2A, ADRA2B, ADRA2C, ADRB1, ADRB2, ADRB3, ALDH5A1, ALOX5AP, AR, ASIC3, CA1, CA12, CA13, CA14, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA9, CACNA2D1, CETP, CNR1, CYP2C19, CYP2C9, DPP4, ESR1, ESR2, F10, F2, F2R, FADS1, FKBR1A, FLT1, FLT4, GAA, GABRA1∗, GABRA2∗, GABRA3∗, GABRA5∗, GABRB2∗, GABRB3∗, GABRG2∗, GLP1R, GLRA1, GRIA4, HCAR2, HMGCR, HRH2, HTT, ICAM1, INSR, ITGAL, ITGB2, KCNA5, KCNJ11, KDM1A, KDR, MTNR1A, MTNR1B, MTOR, NOS3, NPC1L1, NR3C1, NR3C2, OPRD1, OPRK1, OPRM1, PDE10A, PDE11A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE7A, PDE7B, PGR, PLA2G2A, PLA2G7, PLG, PPARA, PPARG, PRCP, PRKCH, PTGER1, PTGER2, PTGER3, PTGER4, PTGIR, PTGS1, PTGS2, RHOA, S1PR1, SCARB1, SCN10A, SCNSA, SCN9A, SELE, SERPINE1, SLC6A4, SOAT1, TBXA2R, TERT, TLR4, TNF, TNNT2∗, TSPO, TUBB1, TUBB3, VDR, VEGFA, and XDH. This also guides the development of follow-up toxicology experiments and research on the effects of moxa smoke on the organs of Sprague Dawley rats.

Figure 5.

Figure 5

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A heat map of the biological pathway of toxic compounds. The pathway scores are displayed using a purple color gradient, where darker purple corresponds to higher scores (increased statistical significance).

4. Discussion

GC-MS was applied to study the compounds in moxa smoke absorbed in five different polar solvents from Qing moxa sticks. This study found that a total of 294 compounds were identified, including 139 in cyclohexane, 145 in ethyl acetate, 60 in n-butanol, 89 in anhydrous ethanol, 77 in water, and 11 in all five polar solvents. Among the 294 compounds detected in the moxa smoke absorption liquid, 112 compounds were confirmed to be toxic. With the “tox analysis” module, IPA was used to construct molecular networks of target proteins. The results showed that these target proteins were related to cell signal transduction, nucleic acid metabolism, inflammatory response, organ damage, and cell apoptosis. At the same time, the main biological pathways of the toxic compounds from moxa smoke included cardiotoxicity, hepatotoxicity, and nephrotoxicity. The safety of smoke has become greater concern. The question of whether moxa smoke is harmless or not has become key to restricting the use of moxibustion.

At present, most studies on moxa smoke have shown that it has many pharmacological effects. A study [27] showed that the superoxide anion scavenging activity of moxa smoke was superoxide dismutase 24.4 U/mg, which was slightly higher than that of partially purified moxa extract and alkali-lignin, but lower than that of sodium ascorbate, gallic acid, and catechin, which further confirmed the antioxidant and pro-oxidative effects of moxa smoke. The methanol extract of moxa smoke has the functions of antioxidation and eliminates free radicals [28]. Another study demonstrated that moxa smoke can improve sperm concentration and promote sperm movement in rats [29]. Although it was suggested that the toxic compounds in moxa smoke were harmful to the human heart, liver, and kidneys, low and middle concentrations had no effects. Moxa smoke at higher concentrations might destroy heart, liver, and kidney function. In fact, it has been reported that moxa smoke can cause related symptoms, such as eustachian tube and throat itching, eye pain, tonsil enlargement, and other symptoms [30–33]. Tar contains two-tenths of a million of a kind of thick cyclic aromatic hydrocarbon called benzo(a)pyrene, which is a strong carcinogen [34]. In a few cases, patients undergoing moxibustion treatment or after treatment had erythema, blisters, and other hypersensitive symptoms, and these conditions disappeared after leaving the moxa smoke environment [35–37]. Research results show that moxibustion may have a greater impact on some people with chronic pharyngitis, leading to coughing due to moxa smoke allergy, but these symptoms gradually improved after ventilation [38]. Some scholars have placed rats in a dynamic exposure cabinet and observed the content of Ox-LDL in their serum. The results showed that the content of Ox-LDL decreased gradually with the increase of moxa smoke concentration, suggesting that moxa smoke can reduce the degree of platelet aggregation. Therefore, it may improve microcirculation and promote metabolism of the body. Low concentrations of moxa smoke have no noticeable damage to vascular endothelium, while medium concentrations can cause a certain degree of vascular endothelium damage [39, 40].

The moxa sticks were encased in A. argyi floss, which is made of dried A. argyi leaves. There have been many experimental studies on the toxicity of A. argyi, which were not limited to conventional acute toxicity, subacute toxicity, or chronic toxicity. Domestic scholars have conducted in-depth studies on the hepatorenal toxicity, embryonic toxicity, and genetic toxicity caused by A. argyi. The research objects were not limited to the whole animal, but also extended to the cellular level, and the intrinsic mechanism of some toxicity of A. argyi was also discussed. The relationship between quantity, time and toxicity, and a safe time span for use were also discussed. However, some of the results showed that A. argyi had hepatotoxicity, especially the essential oil of A. argyi [41, 42]. The dosage of A. argyi or moxa sticks used in toxic experiments was more than 10 to 200 times the clinical dosage. According to the results of this paper, we carried out toxicological experiment of moxa smoke in rats. We followed the steps outlined in our patent, “A device for enriching moxa smoke and its analytical method,” patent number: CN202010327163.6 [43]. Rats exposed to 756650 mg/m3 concentration of moxa smoke (concentration of moxa smoke in 50 moxa sticks) were compared with the control group, and the structure of myocardial cell, hepatic cell, and the renal tubules showed changes (Supplementary Figure S1) such as cardiac hypertrophy, degeneration and necrosis, and dilatation of renal tubules, respectively.

In a word, we should not discuss the toxicity in terms of toxicity in isolation but should comprehensively consider the clinical use characteristics of traditional Chinese medicine. However, in clinical application, we should pay attention to its “toxicity” to human body and try to avoid overuse. Therefore, moxibustion rooms should have installed ventilation equipment or the room should have adequate artificial ventilation so that the health of patients and practitioners can be guaranteed. The safety of compounds in moxa smoke needs to be further studied. The results of this study provide a basis for a safety evaluation of moxa smoke in the future.

Acknowledgments

This work was financially subsidized by the 2018 First Class Discipline Construction Project of Jiangxi Province (no. JXSYLXK-ZHYAO145). The authors thank LetPub (http://www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Data Availability

The data used to support the findings of this study are included within the article and in the supplementary figure. The prior studies (and datasets) are cited at relevant places within the text as references [21, 43].

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors' Contributions

L.H.N. conceptualized the study. S.S. and X.X.Y. contributed to methodology and formal analysis, validated the study, and wrote, reviewed, and edited the manuscript. W.W.L. provided software. X.X.Y. wrote and prepared the original draft. L.H.N was responsible for project administration. All authors have read and agreed to the published version of the manuscript.

Supplementary Materials

Supplementary Materials

Supplementary Figure S1: microscopic observations of heart, liver, and kidney pathology.

Click here for additional data file. (367.7KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Materials

Supplementary Figure S1: microscopic observations of heart, liver, and kidney pathology.

Click here for additional data file. (367.7KB, pdf)

Data Availability Statement

The data used to support the findings of this study are included within the article and in the supplementary figure. The prior studies (and datasets) are cited at relevant places within the text as references [21, 43].

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