The synchronized feature of Saururus chinensis and gut microbiota against T2DM, NAFLD, obesity and hypertension via integrated pharmacology

Figures & data

Figure 1. The workflow of this study.

Table 1. The profiling of chemical compounds in Saururus chinensis (SC).

No.	Compounds	PubChem ID	RT (min)	Area (%)	Classification
1	3-Methyl-2,3-dihydrofuran	102677	3.89	0.24	Dihydrofurans
2	4H-Pyran-4-one	7968	4.26	0.20	Pyrans
3	4-Thujanol	62367	4.31	0.74	Prenol lipids
4	A902158	119838	4.77	1.01	Pyrans
5	1-Benzofuran	6918602	5.35	0.13	Carboxylic acids and derivatives
6	Aes-103	237332	5.51	0.39	Organooxygen compounds
7	Safrole	5144	5.75	0.23	Benzodioxoles
8	alpha-Cubebene	56609	6.07	0.42	Organonitrogen compounds
9	3-Pyrazolidinone, 1,4-dimethyl	437722	6.20	0.09	Azolidines
10	Ylangene	6432119	6.27	0.26	Prenol lipids
11	Germacrene D	5373727	6.33	0.30	Prenol lipids
12	Caryophyllene	5281515	6.55	0.33	Prenol lipids
13	cis-Isoeugenol	1549041	6.68	0.89	Phenols
14	Isoeugenol	853433	6.75	0.22	Phenols
15	alpha-Amorphene	101708	6.81	0.58	Prenol lipids
16	Octane, 3,5-dimethyl-	139989	6.89	1.02	Saturated hydrocarbons
17	Ethyl 2-chloroacetate	7751	6.94	1.29	Carboxylic acids and derivatives
18	Calamenene	6429077	7.05	2.44	Prenol lipids
19	1,4-Cadinadiene	519298	7.12	0.47	Prenol lipids
20	3-Piperidinol, 1,4-dimethyl-, cis-	91691522	7.19	0.34	Piperidines
21	NA0392	5375880	7.25	0.15	Stilbenes
22	Ethylisobutyrate	7342	7.31	0.21	Carboxylic acids and derivatives
23	3,6,6-trimethyl-3,4,5,7,8,9-hexahydro-1H-2-benzoxepine	85838875	7.40	0.32	Organooxygen compounds
24	3-Tetradecen-5-yne, (E)-	5367444	7.42	0.47	Unsaturated hydrocarbons
25	Limonene dioxide	232703	7.56	0.23	Oxepanes
26	Isocaryophyllene	5281522	7.60	0.32	Prenol lipids
27	gamma-Dihydroionone	114558	7.68	0.25	Prenol lipids
28	Kinic acid	1064	7.76	1.99	Organooxygen compounds
29	1-(1-Ethyl-4-piperidinyl)ethanamine	541500	7.99	0.67	Piperidines
30	Ethylene bromohydrin	10898	8.09	0.33	Halohydrins
31	Citronellol acetate	9017	8.48	0.51	Fatty Acyls
32	Ledol	92812	8.52	0.34	Prenol lipids
33	9-Octadecyne	141998	8.56	0.56	Unsaturated hydrocarbons
34	Vulgarol A	91746444	8.63	0.29	Prenol lipids
35	Hexadecanoic acid, methyl ester	8181	8.73	0.37	Fatty Acyls
36	Aromadendrane (DTXSID60880789)	520381	8.80	0.39	Prenol lipids
37	Hexadecanoic acid	985	8.914, 9.337	0.96	Fatty Acyls
38	Oplopenone	6429350	8.98	0.26	Prenol lipids
39	4α,5α-Epoxycholestane	537014	9.366, 10.000, 10.346	2.74	Steroids and steroid derivatives
40	Linolenic acid, methyl ester	5319706	9.42	0.22	Fatty Acyls
41	Phytol	5366244	8.385, 9.452	3.28	Prenol lipids
42	Linolenic acid	5280934	9.60	0.59	Fatty Acyls
43	4-Hexadecen-6-yne, (E)-	5365640	9.65	0.41	Unsaturated hydrocarbons
44	[2,6,6-Trimethyl-4-(3-methyl-2-butenyl)-1-cyclohexen-1-yl]methanol #	550198	9.74	1.09	Organooxygen compounds
45	Patchoulane	29408	10.048, 10.539	1.21	Prenol lipids
46	Bicyclo[6.1.0]nonane, 9-(1-methylethylidene)-	534869	10.114, 10.683	0.82	Unsaturated hydrocarbons
47	Dodecahydro-as-indaceno[4,5-b]oxirene #	101667823	10.18	0.63	Oxepanes
48	1,5,9-Decatriene, 2,3,5,8-tetramethyl-	5365881	10.41	3.40	Unsaturated hydrocarbons
49	5-Methyl-6-phenyl-1,3-oxazinane-2-thione #	5370596	10.81	1.17	Benzene and substituted derivatives
50	2-Palmitoylglycerol	123409	10.71	2.91	Glycerolipids
51	STK734327	584789	11.37	0.88	Diazanaphthalenes
52	Cedran-diol, 8S,14-	45850912	11.42	0.51	Carboxylic acids and derivatives
53	Macelignan	10404245	11.50	1.54	Dibenzylbutane lignans
54	Methyl homovanillate	343303	11.61	9.97	Pyridines and derivatives
55	ChemDiv2_002275	586231	11.68	0.92	Phenols
56	1,7,7-Trimethylbicyclo[2.2.1]hept-2-yl 3-methylenecyclopentanecarboxylate	557320	11.73	0.88	Prenol lipids
57	Dehydrodiisoeugenol	5379033	11.84	3.37	2-arylbenzofuran flavonoids
58	Dehydrodieugenol	165225	11.87	3.33	Benzene and substituted derivatives
59	1H-Indene, 5-butyl-6-hexyloctahydro-	535091	12.18	0.44	Polycyclic hydrocarbons
60	Phenol, 2-methoxy-3-(2-propenyl)-	596373	12.24	0.59	Phenols
61	Pyrethrone	5373801	12.29	0.33	Organooxygen compounds
62	Phenol, 2-methoxy-6-(1-propenyl)-	101959	12.35	1.35	Phenols
63	Phenol, 2-(1-methyl-2-buthenyl)-4-methoxy-	5286356	12.414, 12.452	3.81	Phenols
64	3-Butylpyridine 1-oxide	573221	12.68	5.60	Pyridines and derivatives
65	Piclamilast	154575	12.87	4.41	Benzene and substituted derivatives
66	Galgravin	101749	13.40	1.68	Furanoid lignans
67	DTXSID00336513	534242	13.89	0.48	Pyrazolopyrimidines
68	6-prop-2-enyl-1,3-benzodioxol-5-ol	601267	14.11	0.39	Benzodioxoles
69	3,4-Dimethoxyphenylalanine	275285	14.59	7.50	Carboxylic acids and derivatives
70	Stigmasta-5,22-dien-3-ol	6432745	16.14	0.33	Steroids and steroid derivatives
71	Stigmast-5-en-3-ol	6432744	16.91	1.14	Steroids and steroid derivatives

RT: retention time.

Table 2. The physicochemical properties of chemical constituents.

No.	Compounds	Lipinski’s rule
		MW	HBA	HBD	MLog P	Lipinski’s violations	Bioavailability score	TPSA (Å^2)
		<500	<10	≤5	≤4.15	≤1	>0.1	<140
1	3-Methyl-2,3-dihydrofuran	84.12	1	0	0.62	0	0.55	9.23
2	4H-Pyran-4-one	96.08	2	0	−0.6	0	0.55	30.21
3	4-Thujanol	154.25	1	1	2.45	0	0.55	20.23
4	A902158	144.13	4	2	−1.77	0	0.85	66.76
5	1-Benzofuran	540.63	8	2	0.35	1	0.55	147.06
6	Aes-103	126.11	3	1	−1.06	0	0.55	50.44
7	Safrole	162.19	2	0	2.02	0	0.55	18.46
8	alpha-Cubebene	204.35	0	0	5.65	1	0.55	0.00
9	3-Pyrazolidinone, 1,4-dimethyl	114.15	2	1	0.03	0	0.55	32.34
10	Ylangene	204.35	0	0	5.65	1	0.55	0.00
11	Germacrene D	204.35	0	0	4.53	1	0.55	0.00
12	Caryophyllene	204.35	0	0	4.63	1	0.55	0.00
13	cis-Isoeugenol	164.20	2	1	2.01	0	0.55	29.46
14	Isoeugenol	164.20	2	1	2.01	0	0.55	29.46
15	alpha-Amorphene	204.35	0	0	4.63	1	0.55	69.04
16	Octane, 3,5-dimethyl-	142.28	0	0	4.82	1	0.55	50.18
17	Ethyl 2-chloroacetate	122.55	2	0	0.86	0	0.55	26.30
18	Calamenene	202.34	0	0	5.45	1	0.55	0.00
19	1,4-Cadinadiene	204.35	0	0	4.63	1	0.55	0.00
20	3-Piperidinol, 1,4-dimethyl-, cis-	129.20	2	1	0.57	0	0.55	23.47
21	NA0392	208.30	0	0	5.75	1	0.55	0.00
22	Ethylisobutyrate	116.16	2	0	1.27	0	0.55	26.30
23	3,6,6-Trimethyl-3,4,5,7,8,9-hexahydro-1H-2-benzoxepine	194.31	1	0	3.15	0	0.55	9.23
24	3-Tetradecen-5-yne, (E)-	192.34	0	0	5.68	1	0.55	0.00
25	Limonene dioxide	168.23	2	0	1.52	0	0.55	25.06
26	Isocaryophyllene	204.35	0	0	4.63	1	0.55	0.00
27	gamma-Dihydroionone	194.31	1	0	3.04	0	0.55	17.07
28	Kinic acid	192.17	6	5	−2.14	0	0.55	118.22
29	1-(1-Ethyl-4-piperidinyl)ethanamine	156.27	2	1	1.22	0	0.55	29.26
30	Ethylene bromohydrin	124.96	1	1	0.53	0	0.55	20.23
31	Citronellol acetate	198.30	2	0	3.04	0	0.55	26.30
32	Ledol	222.37	1	1	3.81	0	0.55	3.81
33	9-Octadecyne	250.46	0	0	6.77	1	0.55	0.00
34	Vulgarol A	308.50	2	2	3.93	0	0.55	40.46
35	Hexadecanoic acid, methyl ester	270.45	2	0	4.44	1	0.55	26.30
36	Aromadendrane (DTXSID60880789)	206.37	0	0	5.8	1	0.55	0.00
37	Hexadecanoic acid	256.42	2	1	4.19	1	0.85	37.30
38	Oplopenone	220.35	1	0	3.56	0	0.55	3.56
39	4α, 5α-Epoxycholestane	386.65	1	0	6.48	1	0.55	12.53
40	Linolenic acid, methyl ester	292.46	2	0	4.61	1	0.55	26.30
41	Phytol	296.53	1	1	5.25	1	0.55	20.23
42	Linolenic acid	278.43	2	1	4.38	1	0.85	37.30
43	4-Hexadecen-6-yne, (E)-	220.39	0	0	6.18	1	0.55	0.00
44	[2,6,6-Trimethyl-4-(3-methyl-2-butenyl)-1-cyclohexen-1-yl]methanol #	222.37	1	1	3.56	0	0.55	20.23
45	Patchoulane	206.37	0	0	5.8	1	0.55	0.00
46	Bicyclo[6.1.0]nonane, 9-(1-methylethylidene)-	164.29	0	0	4.86	1	0.55	0.00
47	Dodecahydro-as-indaceno[4,5-b]oxirene #	178.27	1	0	3.02	0	0.55	12.53
48	1,5,9-Decatriene, 2,3,5,8-tetramethyl-	192.34	0	0	4.67	1	0.55	0.00
49	5-Methyl-6-phenyl-1,3-oxazinane-2-thione #	207.29	1	1	1.78	0	0.55	53.35
50	2-Palmitoylglycerol	330.50	4	2	3.18	0	0.55	66.76
51	STK734327	326.37	4	0	2.5	0	0.55	78.65
52	Cedran-diol, 8S,14-	345.39	6	1	1.22	0	0.55	76.83
53	Macelignan	328.40	4	1	3.21	0	0.55	47.92
54	Methyl homovanillate	435.39	7	3	0.92	0	0.55	143.48
55	ChemDiv2_002275	221.30	3	2	1.67	0	0.55	41.49
56	1,7,7-Trimethylbicyclo[2.2.1]hept-2-yl 3-methylenecyclopentanecarboxylate	262.39	2	0	3.94	0	0.55	26.30
57	Dehydrodiisoeugenol	326.39	4	1	2.73	0	0.55	47.92
58	Dehydrodieugenol	326.39	4	2	3.04	0	0.55	58.92
59	1H-Indene, 5-butyl-6-hexyloctahydro-	264.49	0	0	6.76	1	0.55	0.00
60	Phenol, 2-methoxy-3-(2-propenyl)-	164.20	2	1	2.01	0	0.55	29.46
61	Pyrethrone	162.23	1	0	2.3	0	0.55	17.07
62	Phenol, 2-methoxy-6-(1-propenyl)-	164.20	2	1	2.01	0	0.55	2.01
63	Phenol, 2-(1-methyl-2-buthenyl)-4-methoxy-	192.25	2	1	2.58	0	0.55	2.58
64	3-Butylpyridine 1-oxide	151.21	1	0	1.95	0	0.55	25.46
65	Piclamilast	381.25	4	1	2.84	0	0.55	60.45
66	Galgravin	372.45	5	0	2.42	0	0.55	46.15
67	DTXSID00336513	203.24	3	2	0.78	0	0.55	66.49
68	6-prop-2-enyl-1,3-benzodioxol-5-ol	178.18	3	1	1.41	0	0.55	38.69
69	3,4-Dimethoxyphenylalanine	225.24	5	2	−1.66	0	0.55	81.78
70	Stigmasta-5,22-dien-3-ol	412.69	1	1	6.62	1	0.55	20.23
71	Stigmast-5-en-3-ol	414.71	1	1	6.73	1	0.55	20.23

MW: molecular weight; HBA: hydrogen bonding acceptor; HBD: hydrogen bonding donor; MLog P: Moriguchi octanol–water partition coefficient; TPSA: topological polar surface area.

Table 3. The topological analysis of final targets.

No.	Target	DC	BC	CC	No.	Target	DC	BC	CC
1	TNF	60	1182	0.0090	44	SCD	12	13	0.0058
2	PPARG	50	699	0.0083	45	NOX1	12	1	0.0058
3	MAPK3	42	383	0.0075	46	NOS1	12	4	0.0058
4	EGFR	38	413	0.0075	47	NR1H3	11	3	0.0058
5	HIF1A	41	298	0.0074	48	ALOX5	10	215	0.0057
6	ESR1	37	292	0.0074	49	FABP4	11	43	0.0057
7	CASP3	38	163	0.0074	50	F2R	9	7	0.0057
8	PPARA	33	391	0.0072	51	ROCK1	9	1	0.0057
9	SIRT1	33	214	0.0071	52	TTR	9	14	0.0057
10	TLR4	33	156	0.0071	53	ERN1	9	0	0.0057
11	CYP3A4	27	270	0.0068	54	MIF	9	20	0.0057
12	NFE2L2	28	106	0.0068	55	F2	9	18	0.0056
13	APP	27	177	0.0067	56	CNR1	7	22	0.0055
14	CASP1	24	56	0.0066	57	THRB	6	2	0.0055
15	MAPK1	25	87	0.0065	58	NR1I3	11	19	0.0055
16	CYP1A1	22	197	0.0065	59	CYP17A1	11	7	0.0055
17	MAPK14	22	129	0.0065	60	CTSS	10	4	0.0055
18	PRKCA	20	136	0.0065	61	EDNRA	6	2	0.0055
19	MPO	23	113	0.0065	62	COL18A1	6	1	0.0055
20	NOS3	23	44	0.0065	63	CYP2D6	13	39	0.0054
21	PTPRC	21	39	0.0065	64	ANPEP	7	2	0.0054
22	ESR2	21	65	0.0064	65	SPHK2	4	0	0.0054
23	AR	20	130	0.0064	66	CES1	6	5	0.0053
24	ABCB1	18	59	0.0063	67	PLA2G7	4	2	0.0053
25	IGF1R	19	49	0.0063	68	GCK	9	170	0.0053
26	PPARD	20	48	0.0063	69	CASR	6	4	0.0053
27	CYP1A2	21	133	0.0063	70	CYP1B1	13	38	0.0053
28	NR1H4	20	63	0.0063	71	P2RX7	5	0	0.0053
29	IL2	19	23	0.0063	72	HTR2A	9	69	0.0053
30	PTGS1	17	174	0.0063	73	CPT2	7	0	0.0052
31	CYP19A1	17	30	0.0063	74	SIRT2	4	0	0.0052
32	CTSB	18	41	0.0062	75	AHR	7	3	0.0050
33	G6PD	14	55	0.0061	76	ACKR3	4	21	0.0048
34	MAOA	12	185	0.0061	77	GLI2	2	0	0.0047
35	NOS2	16	10	0.0061	78	ADH1B	4	5	0.0047
36	TRPV1	13	67	0.0061	79	NAAA	3	0	0.0047
37	CYP27B1	14	48	0.0061	80	ADRA2B	3	15	0.0045
38	INSR	12	19	0.0060	81	HTR2B	3	2	0.0045
39	CPT1A	14	19	0.0059	82	ALOX12	3	0	0.0043
40	ALOX15	8	52	0.0059	83	ADRA1A	4	19	0.0043
41	SHBG	9	7	0.0059	84	GSTK1	2	0	0.0042
42	MET	10	4	0.0058	85	OXER1	1	0	0.0039
43	GPBAR1	8	14	0.0058	86	GLB1	1	0	0.0037

DC: degree of centrality; BC: betweenness centrality; CC: closeness centrality.

Table 4. The description of key signalling pathways related to T2DM, NAFLD, OB and HT.

KEGG ID and description	Target	False discovery rate
hsa03320: PPAR signalling pathway	PPARA, PPARD, PPARG, NR1H3, FABP4, SCD, CPT1A, CPT2	0.0000001160
hsa04370: VEGF signalling pathway	MAPK1, MAPK3, MAPK14, PRKCA, NOS3, SPHK2	0.0000038400
hsa04917: prolactin signalling pathway	MAPK1, MAPK3, MAPK14, ESR1, ESR2, CYP17A1	0.0000007060
hsa04066: HIF-1 signalling pathway	MAPK1, MAPK3, PRKCA, IGF1R, EGFR, TLR4, HIF1A, NOS2, NOS3, INSR	0.0000000047
hsa04664: Fc epsilon RI signalling pathway	MAPK1, MAPK3, MAPK14, TNF, PRKCA	0.0000070200
hsa04933: AGE-RAGE signalling pathway in diabetic complications	MAPK1, MAPK3, MAPK14, TNF, PRKCA, NOX1, CASP3, NOS3	0.0000004030
hsa04071: sphingolipid signalling pathway	MAPK1, MAPK3, MAPK14, TNF, PRKCA, NOS3, ROCK1, SPHK2	0.0000011800
hsa04020: calcium signalling pathway	NOS1, NOS2, NOS3, SPHK2, EDNRA, F2R, P2RX7, EGFR, PRKCA, ADRA1A, HTR2A, HTR2B	0.0000000052
hsa04926: relaxin signalling pathway	MAPK1, MAPK3, MAPK14, NOS1, NOS2, NOS3, PRKCA, EGFR	0.0000017800
hsa04660: T cell receptor signalling pathway	MAPK1, MAPK3, MAPK14, TNF, PTPRC, IL2	0.0000467000
hsa04152: AMPK signalling pathway	PPARG, IGF1R, SIRT1, INSR, SCD, CPT1A, ADRA1A	0.0000125000
hsa04625: C-type lectin receptor signalling pathway	MAPK1, MAPK3, MAPK14, TNF, IL2, CASP1	0.0000483000
hsa04912: GnRH signalling pathway	MAPK1, MAPK3, MAPK14, PRKCA, EGFR	0.0002300000
hsa04072: phospholipase D signalling pathway	MAPK1, MAPK14, SPHK2, F2R, F2, EGFR, PRKCA, INSR	0.0000046600
hsa04068: FoxO signalling pathway	MAPK1, MAPK3, MAPK14, SIRT1, INSR, IGF1R, EGFR	0.0000162000
hsa04657: IL-17 signalling pathway	MAPK1, MAPK3, MAPK14, TNF, CASP3	0.0002600000
hsa04621: NOD-like receptor signalling pathway	MAPK1, MAPK3, MAPK14, P2RX7, TNF, TLR4, CASP1, CASR	0.0000016200
hsa04015: Rap1 signalling pathway	MAPK1, MAPK3, MAPK14, F2R, MET, EGFR, PRKCA, IGF1R, INSR, CNR1	0.0000006020
hsa04919: thyroid hormone signalling pathway	MAPK1, MAPK3, HIF1A, PRKCA, ESR1, THRB	0.0001000000
hsa04620: Toll-like receptor signalling pathway	MAPK1, MAPK3, MAPK14, TNF, TLR4	0.0003800000
hsa04022: cGMP-PKG signalling pathway	MAPK1, MAPK3, EDNRA, INSR, NOS3, ROCK1, ADRA1A, ADRA2B	0.0000083000
hsa04012: ErbB signalling pathway	MAPK1, MAPK3, PRKCA, EGFR	0.0017000000
hsa04915: oestrogen signalling pathway	MAPK1, MAPK3, ESR1, ESR2, EGFR, NOS3	0.0001600000
hsa04371: apelin signalling pathway	MAPK1, MAPK3, NOS1, NOS2, NOS3, SPHK2	0.0001600000
hsa04668: TNF signalling pathway	MAPK1, MAPK3, MAPK14, TNF, CASP3	0.0005800000
hsa04350: TGF-beta signalling pathway	MAPK1, MAPK3, TNF, ROCK1	0.0024000000
hsa04920: adipocytokine signalling pathway	TNF, PPARA, CPT1A	0.0093000000
hsa04921: oxytocin signalling pathway	MAPK1, MAPK3, PRKCA, EGFR, NOS3, ROCK1	0.0002400000
hsa04150: mTOR signalling pathway	MAPK1, MAPK3, TNF, PRKCA, IGF1R, INSR	0.0002600000
hsa04922: glucagon signalling pathway	PPARA, SIRT1, GCK, CPT1A	0.0032000000
hsa04010: MAPK signalling pathway	MAPK1, MAPK3, MAPK14, TNF, PRKCA, EGFR, MET, IGF1R, INSR	0.0000070200
hsa04151: PI3K-Akt signalling pathway	MAPK1, MAPK3, F2R, INSR, NOS3, IL2, IGF1R, PRKCA, TLR4, EGFR, MET	0.0000052100
hsa04014: Ras signalling pathway	MAPK1, MAPK3, INSR, IGF1R, PRKCA, EGFR, MET	0.0002900000
hsa04910: insulin signalling pathway	MAPK1, MAPK3, INSR, GCK	0.0078000000
hsa04024: cAMP signalling pathway	MAPK1, MAPK3, F2R, EDNRA, ROCK1, PPARA	0.0011000000
hsa04722: neurotrophin signalling pathway	MAPK1, MAPK3, MAPK14	0.0297000000

Figure 3. (A) SC, GM, signalling pathway, target, metabolite (SGSTM) network (61 nodes and 106 edges). (B) MAPK1-STK734327 conformer (–7.7 kcal/mol). (C) The value of energy gap from eight compounds in this study. Yellow arrow bar: a key compound from SC.

Table 5. The chemical reactivity parameters of eight key compounds in this study.

No.	Molecules	LUMO	HOMO	EGAP (eV)	ɳ (eV)	S (eV)	χ (eV)
1	STK734327	−0.04862	−0.21524	−0.16662	0.08331	12.00336	−0.08331
2	Piclamilast	−0.06683	−0.23974	−0.17291	0.08646	11.56671	−0.08646
3	Equol	−0.00968	−0.20919	−0.19951	0.09976	10.02456	−0.09976
4	Kinic acid	−0.04654	−0.24838	−0.20184	0.10092	9.90884	−0.10092
5	3,6,6-Trimethyl-3,4,5,7,8,9-hexahydro-1H-2-benzoxepine	0.01814	−0.21889	−0.23703	0.11852	8.43775	−0.11852
6	Stigmasta-5,22-dien-3-ol	0.02578	−0.22797	−0.25375	0.12688	7.88177	−0.12688
7	4α,5α-Epoxycholestane	0.06884	−0.24254	−0.31138	0.15569	6.42302	−0.15569
8	Aromadendrane	0.07927	−0.24213	−0.32140	0.16070	6.22278	−0.16070

Figure 4. The key findings of this study.

Data availability statement

All data generated or analysed during this study are included in this published article (and its Supplementary Information files).