Effect on serum metabolomics of rats with premature ovarian insufficiency by Zhibian (BL54) through Shuidao (ST28) acupuncture

doi:10.19852/j.cnki.jtcm.20231226.001

Abstract

Abstract:

OBJECTIVE: To analyze the serum metabolic targets of the "Zhibian (BL54) through Shuidao (ST28)" acupuncture technique in cyclophosphamide (CTX)-induced premature ovarian insufficiency (POI) model rats and to elucidate the potential molecular mechanism of acupuncture in improving POI.

METHODS: We used an intraperitoneal injection of CTX to establish the POI rat model (POI group) and compared serum hormone levels and ovarian histopathological changes to evaluate the effect of the Zhibian (BL54) through Shuidao (ST28) technique (ZS + POI group) on ovarian function. Then, nontargeted metabolomics was performed using rat serum by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS).

RESULTS: After acupuncture intervention, the serum hormone levels and ovarian pathological morphology of POI rats were effectively improved. Moreover, UPLC-Q-TOF/MS results showed that the ZS + POI group showed a significant reversal of the levels of 6 differential metabolites. Among them, the levels of four serum metabolic markers, divanillyltetrahydrofuran ferulate, trans-ferulic acid, tryptamine, and neuraminic acid, increased significantly. Further analysis of biological effects showed that all metabolites were involved in the regulation of reproductive hormone levels and antioxidant and antiapoptotic effects.

CONCLUSIONS: The "Zhibian (BL54) through Shuidao (ST28)" acupuncture method may improve the ovarian function of POI rats by regulating serum metabolite markers to exert antioxidant and antiapoptotic effects, which provides a theoretical basis for the clinical application of acupuncture in the treatment of POI.

Key words: acupuncture, premature ovarian insufficiency, metabolomics, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, Zhibian (BL54) through Shuidao (ST28)

YAN Jing, FENG Huimin, QIU Fang, WANG Haijun, YIN Luyun, JIN Xiaofei, ZHAO Jiyu, WANG Hongyang, YAN Xiaoqin. Effect on serum metabolomics of rats with premature ovarian insufficiency by Zhibian (BL54) through Shuidao (ST28) acupuncture[J]. Journal of Traditional Chinese Medicine, 2024, 44(4): 722-733.

Figures/Tables 8

Table 1 Changes in body weight of rats (g, $\bar{x}±s$)

Group	n	Before modeling	After modeling	Post intervention
Control	12	245±7	266±11	316±15
POI	12	244±10	253±11^a	286±13^b
SA+POI	12	244±7	255±12^a	288±13
ZS+POI	12	244±9	255±14^a	301±17^c

Table 2 Changes in serum hormone levels ($\bar{x}±s$)

Group	n	After modeling			Post-intervention
Group	n	FSH (IU/L)	LH (mIU/mL)	E₂ (pmol/L)	FSH (IU/L)	LH (mIU/mL)	E₂ (pmol/L)
Control	12	3.1±0.9	22.7±6.7	39.3±9.8	4.0±1.1	20.9±5.0	43.7±6.1
POI	12	6.0±1.3^a	36.7±5.4^a	26.0±8.7^a	7.4±1.4^a	36.3±4.2^a	28.0±6.0^a
SA+POI	12	5.8±0.9^a	38.8±5.1^a	29.6±6.5^a	7.3±0.9	35.2±4.4	30.6±6.1
ZS+POI	12	6.3±0.9^a	36.8±6.2^a	27.1±8.6^a	6.1±0.9^b	30.3±4.4^b	38.0±7.0^b

Figure 1 ovarian tissue morphology A: gross ovarian tissue specimen in control group; B: gross ovarian tissue specimen in POI group; C: gross ovarian tissue specimen in SA + POI group; D: gross ovarian tissue specimen in ZS + POI group; E: pathomorphological change ovarian tissue in control group; F: pathomorphological change ovarian tissue in POI group; G: pathomorphological change ovarian tissue in SA + POI group; H: pathomorphological change of ovarian tissue in ZS + POI group (HE, × 200). Control: normal feeding, without any treatment. POI: POI model was induced by intraperitoneal injection of CTX (2 mg/mL) for 15 d; SA+POI: sham acupuncture intervention in CTX-induced POI rats for 4 weeks; ZS + POI: Zhibian (BL54) through Shuidao (ST28) acupuncture intervention in CTX-induced POI rats for 4 weeks. PF: primary follicle; EA: early antral follicle; AF: atresia follicle; HE: hematoxylin-eosin staining; POI: premature ovarian insufficiency; CTX: cyclophosphamide; SA: sham acupuncture; ZS: Zhibian (BL54) through Shuidao (ST28) acupuncture.

Table 3 Changes in ovarian weight and coefficient ($\bar{x}±s$)

Group	n	Left ovary		Right ovary
Group	n	Weight (mg)	Coefficient (mg/g)	Weight (mg)	Coefficient (mg/g)
Control	12	73.333±6.513	0.233±0.023	71.667±12.673	0.227±0.037
POI	12	44.167±12.401^a	0.153±0.039^a	45.000±7.977^a	0.157±0.026^a
SA+POI	12	45.833±9.962	0.159±0.033	43.333±10.731	0.150±0.032
ZS+POI	12	56.667±6.513^b	0.188±0.020^b	58.333±11.146^b	0.194±0.037^b

Figure 2 OPLS-DA score plots and model replacement test plots of rat serum samples A: OPLS-DA score plot and model replacement test plot of the control group vs the POI group in positive ion mode; B: OPLS-DA score plot and model replacement test plot of the control group vs the POI group in negative ion mode; C: OPLS-DA score plot and model replacement test plot of the POI group vs the ZS + POI group in positive ion mode; D: OPLS-DA score plot and model replacement test plot of the POI group vs the ZS+POI group in negative ion mode; A1, B1, C1, D1: OPLS-DA score plot; A2, B2, C2, D2: model replacement test plot. In the OPLS-DA score plots, the x-axis (t1) represents the prediction component (intergroup difference component), the y-axis (t2) represents the orthogonal component (intragroup difference component), and the percentage of the horizontal y-axis represents the proportion of this component in the total variance. In the model replacement test plots, the x-axis represents the correlation between the permutation group and the original model group, the y-axis represents the value of R2Y or Q2Y (where R2γ and Q2γ with 1 in the x-axis are the values of the original model), the blue point and the red point represent the R2γ and Q2γ of the replaced model, respectively, and the imaginary line is the fitted regression line. Control: normal feeding, without any treatment; POI: POI model was induced by intraperitoneal injection of CTX (2 mg/mL) for 15 d; ZS+POI: Zhibian (BL54) through Shuidao (ST28) acupuncture intervention in CTX-induced POI rats for 4 weeks. ESI: electron spray ionization; RMSEE: root mean square error, pre: number of predicted components, ort: number of orthogonal components; OPLS-DA: orthogonal partial least squares-discrimination analysis; POI: premature ovarian insufficiency; CTX: cyclophosphamide; ZS: Zhibian (BL54) through Shuidao (ST28) acupuncture.

Figure 3 Screening of metabolic differentials and KEGG pathway enrichment maps in serum of POI model intervened by acupuncture intervention A: volcano map in positive ion mode, B: volcano map in negative ion mode, C: KEGG pathway enrichment map in positive ion mode, D: KEGG pathway enrichment map in negative ion mode. In the volcano map, the x-axis represents the difference multiple, the y-axis represents the P-value, and the scatter size represents the VIP value. Blue dots indicate down-regulation, red dots indicate up-regulation, and gray dots indicate no significant difference. In the KEGG pathway enrichment map, the x-axis is the ratio of the number of differential metabolites to the total number of metabolites, and the y-axis is the name of the pathway. The larger the point, the more the number of metabolites enriched, and the redder the color of the point, the more significant the enrichment pathway. KEGG: Kyoto Encyclopedia of Genes and Genomes; POI: premature ovarian insufficiency.

Table 4 Effect of "Zhibian (BL54) through Shuidao (ST28)" acupuncture on potential biomarkers in the serum of rats with POI

Name	Formula	Mass-to-charge ratio (m/z)	RT (min)	Control vs POI				POI vs ZS+POI
Name	Formula	Mass-to-charge ratio (m/z)	RT (min)	FC	P value	VIP	Trend		FC	P value	VIP	Trend
Divanillyltetrahydrofuran ferulate	C30H32O8	1099.4293	11.4854	0.2409	0.0001	2.1464	↓^a	4.4102		0.0000	2.2110	↑^c
Rolitetracycline	C27H33N3O8	1099.4546	13.5905	0.1087	0.0011	2.0491	↓^b	6.5169		0.0000	2.1883	↑^c
Trans-ferulic acid	C10H10O4	239.0564	2.9167	0.6022	0.0006	1.9304	↓^a	1.5964		0.0027	1.8209	↑^b
Tryptamine	C10H12N2	159.0912	2.4098	0.7189	0.0023	1.8795	↓^b	4.2828		0.0000	2.2682	↑^c
Neuraminic acid	C9H17NO8	288.0653	2.0602	0.4761	0.0038	1.8148	↓^b	1.6599		0.0095	1.6740	↑^b
Eupatilin	C18H16O7	343.0840	4.2009	0.5563	0.0030	1.7867	↓^b	2.0420		0.0015	1.8760	↑^b

Figure 4 ROC curve and box plot of acupuncture on potential biomarkers in serum of rats with POI A: divanillyltetrahydrofuran ferulate; B: trans-ferulic acid; C: tryptamine; D: neuraminic acid. Each plot represents the ROC curve and metabolic box plot of the same metabolite in the Control vs POI group (above) and ZS + POI vs POI group (below). A1, B1, C1, D1: ROC curve plot in the Control vs POI group; A2, B2, C2, D2: box plot in the Control vs POI group; A3, B3, C3, D3: ROC curve plot in the ZS+POI vs POI group; A4, B4, C4, D4: box plot in the ZS + POI vs POI group. In the ROC curve plot, the area surrounded by the blue dot solid line and the straight line (x = 1, y = 0) is AUC, the closer the AUC value is to 1, the higher the accuracy of the prediction. In the box plot, the content distribution of metabolites in each group was shown. Control: normal feeding, without any treatment; POI: POI model was induced by intraperitoneal injection of CTX (2 mg/mL) for 15 d; SA + POI: sham acupuncture intervention in CTX-induced POI rats for 4 weeks; ZS + POI: Zhibian (BL54) through Shuidao (ST28) acupuncture intervention in CTX-induced POI rats for 4 weeks. ROC: receiver operating characteristic curve; POI: premature ovarian insufficiency; ZS: Zhibian (BL54) through Shuidao (ST28) acupuncture; AUC: area under roc; CTX: cyclophosphamide.

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