Compound Yuye Decoction protects diabetic rats against cardiomyopathy by inhibiting myocardial apoptosis and inflammation via regulating the PI3K/Akt signaling pathway

doi:10.12122/j.issn.1673-4254.2024.07.10

Abstract

Abstract:

Objective To explore the therapeutic mechanism of compound Yuye Decoction against diabetic cardiomyopathy (DCM). Methods Drugbank, Gene Cards, OMIM and PharmGKb databases were used to obtain DCM-related targets, and the core targets were identified and functionally annotated by protein-protein interaction network analysis followed by GO and KEGG enrichment analysis. The "Traditional Chinese Medicine-Key Component-Key Target-Key Pathway" network was constructed using Cytoscape 3.9.1, and molecular docking was carried out for the key components and the core targets. In the animal experiment, Wistar rat models of DCM were treated with normal saline or Yuye Decoction by gavage at low (0.29 g/kg) and high (1.15 g/kg) doses for 8 weeks, and the changes in cardiac electrophysiology and histopathology were evaluated. The changes in serum levels of LDH, CK, and CK-MB were examined, and myocardial expressions of PI3K, P-PI3K, Akt, P-AKT, BAX, IL-6, and TNF-α were detected using Western blotting. Results We identified 61 active compounds in Yuye Decoction with 1057 targets, 3682 DCM-related disease targets, and 551 common targets between them. Enrichment of the core targets suggested that apoptosis, inflammation and the PI3K/Akt pathways were the key signaling pathways for DCM treatment. Molecular docking studies showed that the active components in Yuye Decoction including gold amidohydroxyethyl ester and kaempferol had strong binding activities with AKT1 and PIK3R1. In DCM rat models, treatment with Yuye Decoction significantly alleviated myocardial pathologies, reduced serum levels of LDH, CK and CK-MB, lowered myocardial expressions of BAX, IL-6 and TNF-α, and increased the expressions of P-PI3K and P-AKT. Conclusion The therapeutic effect of compound Yuye Decoction against DCM is mediated by its multiple active components that act on multiple targets and pathways to inhibit cardiomyocyte apoptosis and inflammatory response by regulating the PI3K/Akt signaling pathway.

Key words: network pharmacology, compound Yuye Decoction, diabetic cardiomyopathy

Wenxiang ZHANG, Huixian GU, Pengde CHEN, Siyu WU, Hongyan MA, Lan YAO. Compound Yuye Decoction protects diabetic rats against cardiomyopathy by inhibiting myocardial apoptosis and inflammation via regulating the PI3K/Akt signaling pathway[J]. Journal of Southern Medical University, 2024, 44(7): 1306-1314.

Figures/Tables 14

Fig.1 Potential target map of Yuye decoction for treatment of diabetic cardiomyopathy (DCM).

Fig.2 Core targets of Yuye Decoction for treatment of DCM.

Fig.3 GO enrichment analysis of Yuye Decoction for treatment of DCM.

Fig.4 KEGG pathway enrichment analysis of Yuye Decoction for DCM treatment.

Fig.5 Core pathway-target-component diagram of Yuye Decoction for DCM treatment.

Tab.1 Top 15 key active components in Yuye Decoction for DCM treatment

MOL ID	Name	Degree	Intermittivity	Compactedness
MOL008974	Gomisin G	19	0.0428	0.4079
MOL005317	Deoxyharringtonine	17	0.0472	0.4056
MOL008992	Schisandrin C	16	0.0279	0.4079
MOL008968	Schisandrin B	16	0.0209	0.3902
MOL008957	Schisantherin B	16	0.0204	0.3902
MOL000631	Trans-coumartol tyramide	16	0.0443	0.3881
MOL000239	Kumatakenin	16	0.0304	0.4079
MOL008956	Angeloylgomisin O	14	0.0249	0.4056
MOL000422	Kaempferol	14	0.0172	0.4034
MOL000371	Nessen incense pea rosewood phenol	14	0.0363	0.4011
MOL001677	Gold amidohydroxyethyl ester	13	0.0371	0.3702
MOL005429	Hancinol	13	0.0313	0.3840
MOL000322	Kadsurenone	13	0.0176	0.3989
MOL000310	Denudatin B	13	0.0176	0.3989
MOL000098	Quercetol	12	0.0110	0.3967

Tab.2 Docking results of the key components and core targets of Yuye Decoction for DCM

MOL ID	Name	LibDockScore
MOL ID	Name	AKT1	PIK3R1
MOL001677	Gold amidohydroxyethyl ester	142.621	126.014
MOL005317	Deoxyharringtonine	126.451	118.734
MOL000631	Trans-coumartol tyramide	122.132	123.650
MOL000422	Kaempferol	110.677	96.605
MOL000310	Denudatin B	106.976	110.867

Fig.6 Docking diagrams of the compounds and target molecules in compound Yuye Decoction. A: Asperglaucide docked to AKT1. B: Kaempferol docked to AKT1. C: Coumaroyltyramine docked to PIK3R1. D: Deoxyharringtonine docked to PIK3R1. a, b, and c present the 3D docking diagrams, and d presents the 2D docking diagrams.

Fig.7 Changes in blood glucose level during the 8-week treatment in each group. *P<0.05 vs NC; #P<0.05 vs MOD.

Fig.8 HE staining of myocardial tissues of rats in normal group (A), model group (B), YYT-low group (C), and YYT-high group (D).

Tab.3 Cardiac electrophysiological indexes of the rats in the 4 groups (Mean±SD, n=6)

Group	HR(BMP)	Q-T Interval(ms)	ST(mV)
NC	294.67±27.11	62.67±5.39	0.07±0.01
MOD	478.00±89.23*	78.83±7.49*	0.19±0.03*
YYT-low	320.83±89.32^#	75.83±4.62*	0.11±0.05^#
YYT-high	333.50±102.22^#	68.67±6.98^#	0.08±0.01^#

Tab.4 Changes in serum CK, CK-MB and LDH levels of the rats in each group (Mean±SD, n=5, U/L)

Group	CK	CK-MB	LDH
NC	625.54±71.33	80.1.70±170.14	1042.26±112.50
MOD	988.08±80.05*	1164.86±98.16*	1572.58±176.07*
YYT-low	876.92±101.63	1081.84±228.72	1376.28±167.55
YYT-high	711.28±76.25^#	853.46±219.86^#	1145.22±244.03^#

Fig.9 Expression of apoptosis and inflammation-related proteins in the myocardium of rats in each group. *P<0.05 vs NC; #P<0.05 vs MOD.

Fig.10 Expression of AKT-related proteins in the myocardium of the rats in each group. *P<0.05 vs NC; #P<0.05 vs MOD.

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