Protective effect of Dan Ze mixture (丹泽合剂) against lipotoxic cardiomyopathy through activating B-cell lymphoma-2 adenovirus E1B 19 kDa-interacting protein 3/mitophagy signaling pathway

doi:10.19852/j.cnki.jtcm.2025.03.010

Journal of Traditional Chinese Medicine ›› 2025, Vol. 45 ›› Issue (3): 538-551.DOI: 10.19852/j.cnki.jtcm.2025.03.010

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Protective effect of Dan Ze mixture (丹泽合剂) against lipotoxic cardiomyopathy through activating B-cell lymphoma-2 adenovirus E1B 19 kDa-interacting protein 3/mitophagy signaling pathway

SHI Cheng¹, CHEN Jian², ZHANG Yufang³, GAO Ya³, LI Dantong³, YUE Shijun³(), ZHANG Yixin⁴()

1 College of Basic Medical Sciences, College of Pharmacy, Hebei University of Chinese Medicine, International Joint Research Center on Resource Utilization and Quality Evaluation of Traditional Chinese Medicine of Hebei Province, Hebei Technology Innovation Center of Chinese Medicine Formulation, Shijiazhuang 050200, China
2 College of Basic Medical Sciences, International Joint Research Center on Resource Utilization and Quality Evaluation of Traditional Chinese Medicine of Hebei Province, Hebei Technology Innovation Center of Chinese Medicine Formulation, Shijiazhuang 050200, China
3 College of Pharmacy, Hebei University of Chinese MediCollege of Basic Medical Sciences, International Joint Research Center on Resource Utilization and Quality Evaluation of Traditional Chinese Medicine of Hebei Province, Hebei Technology Innovation Center of Chinese Medicine Formulation, Shijiazhuang 050200, China
4 College of Pharmacy, Hebei University of Chinese Medicine, International Joint Research Center on Resource Utilization and Quality Evaluation of Traditional Chinese Medicine of Hebei Province, Hebei Technology Innovation Center of Chinese Medicine Formulation, Shijiazhuang 050200, China

Received:2024-07-27 Accepted:2024-11-02 Online:2025-06-15 Published:2025-05-21
Contact: Prof. YUE Shijun, Department of Clinical Pharmacology of Traditional Chinese Medicine, College of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, China. shijun_yue@163.com;Prof. ZHANG Yixin, Department of Clinical Pharmacology of Traditional Chinese Medicine, College of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, China. hbzyx123@163.com,Telephone: +86-18732109076
About author:
SHI Cheng and CHEN Jian are co-first authors and contributed equally to this work
Supported by:
Scientific Research Project of Hebei Province Administration of Traditional Chinese Medicine: to Explore the Protective Effect and Mechanism of Zexie Decoction on Lipotoxic Cardiomyopathy based on the p-mitogen-activated protein kinases/ Peroxisome proliferator-activated receptor γ coactivator 1-alpha (pMAPK/PGC-1α) Signaling Pathway(2022096);Medical Science Research Project of Hebei Province: the Effect of 23-acetyl Alismol-B on Mitochondrial Function in Palmitic Acid-induced H9c2 Cells Was Investigated based on the Ca²⁺-Cyclic Adenosine Monophosphate (cAMP)-Response Element Binding Protein/cAMP Response Element (CREB/CRE)-PGC-1α Signaling Pathway(20221490);Hebei province natural science fund project: Study on the Mechanism of Danshen Zexie Decoction in Activating Nuclear Factor Erythroid 2-related Factor 2 Signaling Pathway to Trigger 0mi/HtrA2, Restoring Autophagic Flux and Enhancing Metabolism-Related Fatty Liver Disease(H2023423064);Hebei graduate student innovation ability funding training project: to Investigate the Protective Effects and Underlying Mechanisms of Zexie Decoction on Lipotoxic Cardiomyopathy, with A Focus on the PGC-1a Signaling Pathway(CXZZBS2022096)

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Abstract

Abstract:

OBJECTIVE: To investigate the mechanism of Dan Ze mixture (丹泽合剂, DZM) in the treatment of lipotoxic cardiomyopathy.
METHODS: Ultra-performance liquid chromatography tandem mass spectrometry was employed to characterize the serum migration constituents of DZM. A lipotoxic cardiomyopathy rat model was established through high-fat diet and intervened by different doses of DZM. The cardiac function was assessed using echocardiography, and hematoxylin and eosin, oil red O, and Masson staining were conducted to evaluate morphological changes, lipid accumulation, and fibrosis in myocardial tissue. Serum myocardial enzyme activity, lipid levels, and lipid content of myocardial tissue were measured, while fluorescent staining and colorimetry were used to assess oxidation levels in myocardial tissue. Mitochondrial membrane potential was detected by 5,5’, 6,6’-Tetrachloro-1,1’,3,3’-tetraethyl-imidacarbocyanineio-dide (JC-1). Transmission electron microscopy was employed to observe ultrastructure and mitochondrial structure changes in myocardial tissue. Fluorescence double staining and colocalization were utilized to observe the binding of autophagosomes and mitochondria, while immunohistochemical staining was used to detect the expression of mitophagy-related proteins. Terminal deoxynucleoitidyl transferase mediated nick end labeling staining was employed for the identification of apoptosis in myocardial tissue, while quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot were utilized for the detection of apoptosis, B-cell lymphoma-2 adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)/ mitophagy signaling pathway-related genes and proteins. In palmitic acid-induced Rat H9C2 cardiomyocytes (H9c2) cells, various cellular parameters including cell viability, lactate dehydrogenase release, apoptosis rate, oxidative stress level, mitochondrial structure and function, and mitophagy level were assessed after the treatment of DZM drug-containing serum for a duration of 24 h. The cellular expressions of BNIP3/mitophagy signaling pathway relevant genes and proteins were further evaluated using qRT-PCR and Western blot techniques.
RESULTS: A total of 295 prototypes (e.g., phenolic acids, quinones, terpenoids) were identified in serum of rats after oral administration of DZM. In vivo, DZM therapy has been shown to effectively enhance cardiac function, mitigate high-fat diet-induced myocardial structural damage and lipid accumulation. Furthermore, DZM has demonstrated the ability to reduce lipid levels, attenuate cell apoptosis, combat oxidative stress, enhance mitochondrial structure and function, and activate the BNIP3/mitophagy signaling pathway. Furthermore, the silencing of BNIP3 has been shown to exacerbate palmitic acid-induced damages in H9c2 cells, while inhibiting the BNIP3/mitophagy signaling pathway can mitigate the inhibitory effects of DZM on palmitic acid-induced apoptosis, lipid deposition and oxidative stress.
CONCLUSION: This study presents preliminary evidence for the therapeutic efficacy of DZM on lipotoxic cardiomyopathy through the activating BNIP3/mitophagy signaling pathway.

Key words: mitophagy, signal transduction, Dan Ze mixture, lipotoxic cardiomyopathy, mitochondrial autophagy, Bcl2/adenovirus E1B gene 19 kDa protein-interacting protein 3

SHI Cheng, CHEN Jian, ZHANG Yufang, GAO Ya, LI Dantong, YUE Shijun, ZHANG Yixin. Protective effect of Dan Ze mixture (丹泽合剂) against lipotoxic cardiomyopathy through activating B-cell lymphoma-2 adenovirus E1B 19 kDa-interacting protein 3/mitophagy signaling pathway[J]. Journal of Traditional Chinese Medicine, 2025, 45(3): 538-551.

Figures/Tables 11

Figure 1 DZM alleviated myocardial injury and fibrosis, reduced myocardial cell apoptosis and inhibited oxidative damage A: HE staining of myocardial tissue (× 200). A1: control group; A2: model group; A3: Ator group; A4: L-DZM group; A5: M-DZM group; A6: H-DZM group; B: Masson staining of myocardial tissue (× 200). B1: control group; B2: model group; B3: Ator group; B4: L-DZM group; B5: M-DZM group; B6: H-DZM group; C: oil O staining of myocardial tissue (× 200). C1: control group; C2: model group; C3: Ator group; C4: L-DZM group; C5: M-DZM group; C6: H-DZM group; D: TUNEL staining of myocardial tissue (× 200). D1: control group; D2: model group; D3: Ator group; D4: L-DZM group; D5: M-DZM group; D6: H-DZM group; E: Western blot analysis of Bcl-2 and Bax in rats. F: Bcl-2 and Bax mRNA expression were detected by qRT-PCR. F1: Bcl-2 mRNA; F2: Bax mRNA. G: ROS fluorescence staining in myocardial tissue (× 400). G1: control group; G2: model group; G3: Ator group; G4: L-DZM group; G5: M-DZM group; G6: H-DZM group. Control group: gavage of normal saline; Model group: high fat feed for 26 weeks + gavage of normal saline for 6 weeks; Ator group: high fat feed + gavage of Ator (2.1 g/kg) for 6 weeks; L-DZM group: high fat feed + gavage of DZM (6.3 g/kg) for 6 weeks ; M-DZM group: high fat feed 26 weeks + gavage of DZM (12.6 g/kg) for 6 weeks; H-DZM group: high fat feed 26 weeks + gavage of DZM (25.2 g/kg) for 6 weeks. DZM: Dan Ze mixture; HE: hematoxylin and eosin; Ator: atorvastatin; L-DZM: low dose of DZM; M-DZM: middle dose of DZM; H-DZM: high dose of DZM; TUNEL: terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling; Bcl-2: B-cell lymphoma-2; Bax: Bcl-2-associated X. GAPDH: glyceraldehyde-3-phosphatedehydrogenase; ROS: reactive oxygen species. One-way analysis of variance tests were used among these groups. Data were shown as the mean ± standard error of mean (n = 8). Compared with control group, aP < 0.05; compared with model group, bP < 0.05; compared with Ator group, cP < 0.05; compared with L-DZM group, dP < 0.05; compared with M-DZM group, eP < 0.05.

Table 1 Effect of DZM on serum myocardial enzymes in rats with lipotoxic cardiomyopathy (U/L)

Group	n	CK	CK-MB	LDH	α-HBDH
Control	8	1041±45	772±31	647±14	216±6
Model	8	2276±60^a	1196±16^a	974±25^a	419±4^a
Ator	8	1075±74^b	951±27^b	643±24^b	242±8^b
L-DZM	8	1484±35^bc	919±19^b	795±17^bc	311±5^bc
M-DZM	8	1228±70^bd	839±35^bc	737±14^b	292±6^bc
H-DZM	8	1138±27^bd	740±20^bcd	555±35^bde	265±12^bd

Table 2 Effect of DZM on cardiac function of rats with lipotoxic cardiomyopathy

Group	n	LVEDd (mm)	LVEDs (mm)	EF (%)	FS (%)
Control	3	7.36±0.08	3.16±0.15	85.63±1.14	57.19±1.70
Model	3	8.17±0.16^a	4.73±0.15^a	69.76±1.17^a	38.88±1.02^a
Ator	3	7.15±0.12^b	3.94±0.06^b	76.43±0.76^b	46.19±0.64^b
L-DZM	3	8.07±0.27	4.38±0.25	74.85±2.13	46.06±1.89^b
M-DZM	3	7.82±0.20	4.44±0.20	74.93±2.11	46.15±1.94^b
H-DZM	3	7.01±0.09^b	3.73±0.10^b	79.28±0.86^b	46.79±1.02^b

Table 3 Effect of DZM on blood lipid in rats with lipotoxic cardiomyopathy (mmol/L)

Group	n	TC	TG	LDL	FFA	HDL
Control	8	1.547±0.076	0.126±0.004	0.503±0.017	212.500±14.130	0.900±0.045
Model	8	2.325±0.050^a	0.846±0.008^a	1.595±0.078^a	443.100±17.660^a	0.466±0.016^a
Ator	8	1.636±0.066^b	0.152±0.005^b	0.742±0.036^b	288.500±23.670^b	0.751±0.025^b
L-DZM	8	1.837±0.025^b	0.205±0.013^bd	0.940±0.018^bd	316.600±14.070^b	0.614±0.015^bd
M-DZM	8	1.614±0.056^b	0.146±0.008^bc	0.852±0.016^b	285.100±7.974^b	0.664±0.022^b
H-DZM	8	1.540±0.033^bc	0.125±0.003^bc	0.637±0.011^bce	210.200±9.895^bcde	0.898±0.021^bcde

Table 4 Effect of DZM on SOD, GSH and MDA level in serum of rats with lipotoxic cardiomyopathy

Group	n	SOD (U/mgprot)	GSH (μmol/grot)	MDA (μmol/grot^-)
Control	8	24.29±0.63	72.38±1.84	22.56±0.98
Model	8	7.33±0.14^a	12.40±0.46^a	85.44±2.60^a
Ator	8	21.95±0.71^b	62.74±1.76^b	34.34±1.10^b
L-DZM	8	10.74±0.27^bc	25.71±0.50^bc	66.07±1.32^bc
M-DZM	8	14.12±0.27^bcd	36.30±0.79^bcd	57.26±1.39^bcd
H-DZM	8	16.76±0.28^bcde	45.93±0.72^bcde	44.48±0.74^bcde

Table 5 Effect of DZM on apoptosis-related gene in PA-induced H9c2 cell

Group	n	Bcl-2 mRNA	Bax mRNA
Control	8	1.001±0.015	1.001±0.011
Model	8	0.565±0.022^a	1.537±0.056^a
DZM	8	1.689±0.036^b	0.331±0.012^b
DZM+si-BNIP3	8	1.026±0.046^bc	0.647±0.042^bc
Si-BNIP3	8	0.648±0.021^cd	1.661±0.031^cd

Figure 2 DZM improved the mitochondria structure and function of myocardial tissue and enhanced mitochondrial autophagy A: myocardial tissue and mitochondrial ultrastructure were detected by transmission electron microscope (× 2500). A1: control group; A2: model group; A3: Ator group; A4: L-DZM group; A5: M-DZM group; A6: H-DZM group; B: JC-1 of mitochondrial membrane potential. B1: control group; B2: model group; B3: Ator group; B4: L-DZM group; B5: M-DZM group; B6: H-DZM group; C: Myocardial tissue immunofluorescence co-localization of LC3 and PHB2 (× 400). C1: LC3 fluorescent staining in normal group; C2: PHB2 fluorescent staining in normal group C3: Nuclear fluorescence staining in normal group C4: immunofluorescence co-localization of LC3 and PHB2 in normal group; C5: LC3 fluorescent staining in model group; C6: PHB2 fluorescent staining in model group; C7: Nuclear fluorescence staining in model group; C8: immunofluorescence co-localization of LC3 and PHB2 in model group; C9: LC3 fluorescent staining in Ator group; C10: PHB2 fluorescent staining in Ator group; C11: Nuclear fluorescence staining in Ator group; C12: immunofluorescence co-localization of LC3 and PHB2 in Ator group; C13: LC3 fluorescent staining in L-DZM group; C14: PHB2 fluorescent staining in L-DZM group; C15: Nuclear fluorescence staining in L-DZM group; C16: immunofluorescence co-localization of LC3 and PHB2 in L-DZM group; C17: LC3 fluorescent staining in M-DZM group; C18: PHB2 fluorescent staining in M-DZM group; C19: Nuclear fluorescence staining in M-DZM group; C20: immunofluorescence co-localization of LC3 and PHB2 in M-DZM group; C21: LC3 fluorescent staining in M-DZM group; C22: PHB2 fluorescent staining in M-DZM group; C23: Nuclear fluorescence staining in M-DZM group; C24: immunofluorescence co-localization of LC3 and PHB2 in M-DZM group. Control group: gavage of normal saline; Model group: high fat feed for 26 weeks + gavage of normal saline for 6 weeks; Ator group: high fat feed + gavage of Ator (2.1 g/kg) for 6 weeks; L-DZM group: high fat feed + gavage of DZM (6.3 g/kg) for 6 weeks ; M-DZM group: high fat feed 26 weeks + gavage of DZM (12.6 g/kg) for 6 weeks; H-DZM group: high fat feed 26 weeks + gavage of DZM (25.2 g/kg) for 6 weeks. DZM: Dan Ze mixture; Ator: Atorvastatin; L-DZM: low dose of DZM; M-DZM: middle dose of DZM; H-DZM: high dose of DZM; LC3: L Chain 3; PHB2: prohibitin 2; JC-1: 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide.

Figure 3 DZM regulates the positive expression of mitochondrial autophagy related proteins and the expression of BNIP3/ mitochondrial autophagy pathway related genes and proteins A: myocardial tissue immunofluorescence staining of p62 (× 400). A1: control group; A2: model group; A3: Ator group; A4: L-DZM group; A5: M-DZM group; A6: H-DZM group; B: myocardial tissue immunofluorescence staining of Tom20 (× 400). B1: control group; B2: model group; B3: Ator group; B4: L-DZM group; B5: M-DZM group; B6: H-DZM group; C: myocardial tissue immunofluorescence staining of HSP60 (× 400). C1: control group; C2: model group; C3: Ator group; C4: L-DZM group; C5: M-DZM group; C6: H-DZM group; D: myocardial tissue immunofluorescence staining of PHB2 (× 400). D1: control group; D2: model group; D3: Ator group; D4: L-DZM group; D5: M-DZM group; D6: H-DZM group; E: BNIP3/ mitochondrial autophagy pathway related proteins. F: BNIP3/ mitochondrial autophagy pathway related genes. F1: BNIP3 mRNA; F2: Beclin-1 mRNA; F3: p62 mRNA; F4: LC3 mRNA; F5: PHB2 mRNA. Control group: gavage of normal saline; Model group: high fat feed for 26 weeks + gavage of normal saline for 6 weeks; Ator group: high fat feed + gavage of Ator (2.1 g/kg) for 6 weeks; L-DZM group: high fat feed + gavage of DZM (6.3 g/kg) for 6 weeks ; M-DZM group: high fat feed 26 weeks + gavage of DZM (12.6 g/kg) for 6 weeks; H-DZM group: high fat feed 26 weeks + gavage of DZM (25.2 g/kg) for 6 weeks. DZM: Dan Ze mixture; Ator: atorvastatin; L-DZM: low dose of DZM; M-DZM: middle dose of DZM; H-DZM: high dose of DZM; BNIP3: B-cell lymphoma-2/adenovirus E1B gene 19 kDa protein-interacting protein 3; Beclin-1: myosin-like BCL2 interacting protein; p62: sequestosome-1; LC3: L Chain 3; PHB2: prohibitin 2; Tom20: mitochondrial membrane 20; HSP60: heat shock protein 60. GAPDH: glyceraldehyde-3-phosphatedehydrogenase. One-way analysis of variance tests were used among these groups. Data were shown as the mean ± standard error of mean (n = 3). Compared with control group, aP < 0.05; compared with model group, bP < 0.05; compared with Ator group, cP < 0.05; compared with L-DZM group, dP < 0.05; compared with M-DZM group, eP < 0.05.

Figure 4 DZM improved the accumulation of lipid droplets in H9c2 cells induced by PA, regulated the expression of genes and proteins related to BNIP3/ mitochondrial autophagy pathway, improved mitochondrial structure and function, and alleviated cell apoptosis A: Oil red O staining of H9c2 cells (× 400). A1: control group; A2: model group; A3: DZM group; A4: DZM+si-BNIP3 group; A5: si-BNIP3group. B: BNIP3/ mitochondrial autophagy pathway related proteins. C: H9c2 cell apoptosis was detected by flow cytometry. C1: control group; C2: model group; C3: DZM group; C4: DZM + si-BNIP3 group; C5: si-BNIP3group. D: Western blot analysis of Bcl-2 and Bax. E: PA-induced H9c2 cell mitochondrial ultrastructure and autophagosome count were assessed via transmission electron microscopy (× 5000). E1: control group; E2: model group; E3: DZM group; E4: DZM + si-BNIP3 group; E5: si-BNIP3 group. F: JC-1 of mitochondrial membrane potential. F1: control group; F2: model group; F3: DZM group; F4: DZM + si-BNIP3 group; G5: si-BNIP3group. control group: conventional culture; model group: palmitic acid incubation for 24 h; DZM group: palmitic acid + DZM incubation for 24 h; DZM + si-BNIP3 group: palmitic acid + DZM incubation + Silence the BNIP3 gene expression for 24 h; si-BNIP3group: palmitic acid + Silence the BNIP3 gene expression for 24 h. DZM: Dan Ze mixture medicated serum; Bcl-2: B-cell lymphoma-2; Bax: Bcl-2-Associated X; BNIP3: B-cell lymphoma-2/adenovirus E1B gene 19 kDa protein-interacting protein 3; Beclin-1: myosin-like BCL2 interacting protein; p62: Sequestosome-1; LC3: L Chain 3; PHB2: prohibitin 2; GAPDH: glyceraldehyde-3-phosphatedehydrogenase; JC-1: 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide.

Table 6 Effect of DZM on the expression of mitochondrial autophagy related genes in PA-induced H9c2 cell

Group	n	BNIP3 mRNA	Beclin-1 mRNA	P62 mRNA	LC3Ⅱ/Ⅰ mRNA	PHB2 mRNA
Control	8	1.005±0.036	1.000±0.012	1.000±0.010	1.008±0.043	1.002±0.021
Model	8	0.651±0.065^a	0.456±0.046^a	1.618±0.053^a	0.447±0.025^a	0.296±0.019^a
DZM	8	1.905±0.022^b	1.922±0.016^b	0.755±0.049^b	1.443±0.055^b	1.881±0.025^b
DZM+si-BNIP3	8	1.226±0.026^bc	1.244±0.025^bc	1.123±0.028^bc	1.154±0.019^bc	1.253±0.032^bc
Si-BNIP3	8	0.580±0.018^cd	0.460±0.015^cd	1.853±0.026^bcd	0.270±0.009^bcd	0.340±0.014^cd

Table 7 Effect of DZM on the level of SOD, MDA and GSH in PA-induced H9c2 cell

Group	n	SOD (U/mL)	GSH (mg/L)	MDA (nmol/mL)
Control	8	157.80±7.39	5.80±0.26	1.47±0.06
Model	8	64.82±1.89^a	1.77±0.17^a	3.63±0.07^a
DZM	8	116.60±3.58^b	4.62±0.26^b	2.04±0.06^b
DZM+si-BNIP3	8	91.26±2.51^bc	3.05±0.26^#c	2.72±0.13^bc
Si-BNIP3	8	39.66±1.84^bcd	0.73±0.08^#cd	5.11±0.13^bcd

References 49.

1.	Han J, Kaufman RJ. The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res 2016; 57: 1329-38. DOI PMID
2.	Nordin N, Majid NA, Hashim NM, Rahman MA, Hassan Z, Ali HM. Liriodenine, an aporphine alkaloid from Enicosanthellum pulchrum, inhibits proliferation of human ovarian cancer cells through induction of apoptosis via the mitoch-ondrial signaling pathway and blocking cell cycle progression. Drug Des Devel Ther 2015; 9: 1437-48.
3.	Dewald O, Sharma S, Adrogue J, et al. Down regulation of peroxisome proliferator-activated receptor-alpha gene expression in a mouse model of ischemic cardiomyopathy is dependent on reactive oxygen species and prevents lipotoxicity. Circulation 2005; 112: 407-15.
4.	Berardi DE, Bock-Hughes A, Terry AR, Drake LE, Bozek G, Macleod KF. Lipid droplet turnover at the lysosome inhibits growth of hepatocellular carcinoma in a BNIP3-dependent manner. Sci Adv 2022; 8: eabo2510.
5.	Roth GA, Mensah GA, Johnson CO, et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study. J Am Coll Cardiol 2020; 76: 2982-3021. DOI PMID
6.	Wang B, Wang Y, Zhang J, et al. ROS-induced lipid peroxidation modulates cell death outcome: mechanisms behind apoptosis, autophagy, and ferroptosis. Arch Toxicol 2023; 97: 1439-51. DOI PMID
7.	Zheng P, Ma W, Gu Y, et al. High-fat diet causes mitochondrial damage and down regulation of mitofusin-2 and optic atrophy-1 in multiple organs. J Clin Biochem Nutr 2023; 73: 61-76. DOI PMID
8.	Tong M, Saito T, Zhai P, et al. Mitophagy is essential for maintaining cardiac function during high fat diet-induced diabetic cardiomyopathy. Circ Res 2019; 124: 1360-71. DOI PMID
9.	Lin Q, Li S, Jiang N, et al. Inhibiting NLRP3 inflammasome attenuates apoptosis in contrast-induced acute kidney injury through the upregulation of HIF1A and BNIP3-mediated mitophagy. Autophagy 2021; 17: 2975-90.
10.	Ni H, Liu R, Zhou Z, Jiang B, Wang B. Parkin enhances sensitivity of paclitaxel to nasopharyngeal carcinoma by activating BNIP3/NIX-mediated mitochondrial autophagy. Chin J Physiol 2023; 66: 503-15. DOI PMID
11.	Sun LL, Shao YN, You MX, Li CH. ROS-mediated BNIP3-dependent mitophagy promotes coelomocyte survival in Apostichopus japonicus in response to Vibrio splendidus infection. Zool Res 2022; 43: 285-300.
12.	Zhang H, Yin C, Liu X, et al. Prohibitin 2/PHB 2 in parkin-mediated mitophagy: a potential therapeutic target for non-small cell lung carcinoma. Med Sci Monit 2020; 26: e923227.
13.	Chen Y, Fan L, Zhang T, et al. Effectiveness of Zhuling decoction on diuretic resistance in patients with heart failure: a randomized, controlled trial. Zhong Hua Zhong Yi Yao Za Zhi 2022; 42: 439-45.
14.	Wang C, Wu Q, Li P, et al. Effect of Traditional Chinese Medicine combined with Western Medicine on blood lipid levels and inflammatory factors in patients with angina pectoris in coronary heart disease identified as intermingled phlegm and blood stasis syndrome: a network Meta-analysis. Zhong Hua Zhong Yi Yao Za Zhi 2023; 43: 640-49.
15.	Le ZY, Qin X, Fang N, Yu SG. Effects of Rhizoma alismatis decoction on hemodynamics in rats with myocardial ischemia reperfusion injury. Hubei Zhong Yi Yao Da Xue Xue Bao 2012; 14: 3-5.
16.	Li Z, Liu M, Chen M, et al. Clinical effect of Danshen decoction in patients with heart failure: a systematic review and Meta-analysis of randomized controlled trials. PLoS One 2023; 18: e284877.
17.	Liu M, Yanneng X, Yang G, Li Z, Luo G, Yang S. Danshen decoction in the treatment of hyperlipidemia: a systematic review and Meta-analysis protocol of randomized controlled trials. Evid Based Complement Alternat Med 2022; 2022: 2392652.
18.	Biao Y, Chen J, Liu C, et al. Protective effect of Danshen Zexie decoction against non-alcoholic fatty liver disease through inhibition of ROS/NLRP3/IL-1beta pathway by Nrf 2 signaling activation. Front Pharmacol 2022; 13: 877924.
19.	Zhang F, Wu J, Ruan H, et al. Zexie decoction alleviates non-alcoholic fatty liver disease in rats: the study of genes, lipids, and gut microbiotas. Biochem Biophys Res Commun 2022; 632: 129-38.
20.	Li AZ. Clinical efficacy of Zexie decoction in the treatment of hyperlipidemia. Lin Chuang He Li Yong Yao Za Zhi 2018; 11: 114-5.
21.	Wang J, Xu P, Xie X, et al. DBZ (Danshensu Bingpian Zhi), a novel natural compound derivative, attenuates atherosclerosis in apolipoprotein E-deficient mice. J Am Heart Assoc 2017; 6: e006297.
22.	Younis NS. Doxorubicin-induced cardiac abnormalities in rats: attenuation via sandalwood oil. Pharmacology 2020; 105: 522-30.
23.	Wang MY, Gao G, Li EW, et al. Mechanism of Zexie Decoction in improvement of nonalcoholic fatty liver disease based on LKB1/AMPK/PGC-1α pathway. Zhong Guo Zhong Yao Za Zhi 2022; 47: 453-60.
24.	Zhao Y, Shao C, Zhou H, et al. Salvianolic acid B inhibits atherosclerosis and TNF-alpha-induced inflammation by regulating NF-κB/NLRP3 signaling pathway. Phytomedicine 2023; 119: 155002.
25.	Xiong H, Li N, Zhao L, et al. Integrated serum pharmacochemistry, metabolomics, and network pharmacology to reveal the material basis and mechanism of Danggui Shaoyao San in the treatment of primary dysmenorrhea. Front Pharmacol 2022; 13: 942955.
26.	Chen W, Gong L, Guo Z, et al. A novel integrated method for large-scale detection, identification, and quantification of widely targeted metabolites: application in the study of rice metabolomics. Mol Plant 2013; 6: 1769-80. DOI PMID
27.	Li S, Qian X, Gong J, et al. Exercise training reverses lipotoxicity-induced cardiomyopathy by inhibiting HMGCS2. Med Sci Sports Exerc 2021; 1: 47-57.
28.	Chen Q. Pharmacology Research Methodology of Chinese Medicine (3th edition): People's Medical Publishing House, 2011: 122-3.
29.	Cai XJ, Zhang XH, Wang FW. Curative effect of Danshen decoction on chronic pulmonary heart disease and its influence on blood gas index and heart function. Zhejiang Zhong Yi Yao Da Xue Xue Bao 2015; 50: 555-6.
30.	Yang Z, Chen Y, Yan Z, et al. Inhibition of TLR4/MAPKs pathway contributes to the protection of salvianolic acid a against lipotoxicity-induced myocardial damage in cardiomyocytes and obese mice. Front Pharmacol 2021; 12: 627123.
31.	Xiang Y, Liang X, Bao CY, et al. The role of luteolin in regulating the endoplasmic reticulum stress-mitochondrial apoptosis pathway in lipotoxic myocardial injury. Hubei Zhong Yi Yao Da Xue Xue Bao 2023; 37: 185-9+195+180.
32.	Wang F, Neumann D, Kapsokalyvas D, et al. Specific compounds derived from Traditional Chinese Medicine ameliorate lipid-induced contractile dysfunction in cardiomyocytes. Int J Mol Sci 2024; 25: 8131.
33.	Nakamura M, Liu T, Husain S, et al. Glycogen synthase kinase-3alpha promotes fatty acid uptake and lipotoxic cardiomyopathy. Cell Metab 2019; 29: 1119-34.
34.	Zhou C, Yin X. Wogonin ameliorated obesity-induced lipid metabolism disorders and cardiac injury via suppressing pyroptosis and deactivating IL-17 signaling pathway. Am J Chin Med 2022; 50: 1553-64.
35.	Ren BC, Zhang YF, Liu SS, et al. Curcumin alleviates oxidative stress and inhibits apoptosis in diabetic cardiomyopathy via Sirt1-Foxo1 and PI3K-Akt signalling pathways. J Cell Mol Med 2020; 24: 12355-67.
36.	Yen PT, Huang SE, Hsu JH, et al. Anti-inflammatory and anti-oxidative effects of puerarin in postmenopausal cardioprotection: roles of Akt and heme oxygenase-1. Am J Chin Med 2023; 51: 149-68.
37.	Fu JJ, Duan JK, LI H. The crosstalk between autophagy and apoptosis. Sheng Ming De Hua Xue 2014; 5: 649-53.
38.	Zhang J, Wang Y, Bao C, et al. Curcumin-loaded PEG-PDLLA nanoparticles for attenuating palmitate-induced oxidative stress and cardiomyocyte apoptosis through AMPK pathway. Int J Mol Med 2019; 44: 672-82.
39.	Chen D, Li X, Zhang L, Zhu M, Gao L. A high-fat diet impairs mitochondrial biogenesis, mitochondrial dynamics, and the respiratory chain complex in rat myocardial tissues. J Cell Biochem 2018; 119: 9602. DOI PMID
40.	Chiu TH, Ku CW, Ho TJ, et al. Schisanhenol attenuates OxLDL-induced endothelial dysfunction via an AMPK-dependent mechanism. Am J Chin Med 2023; 51: 1459-75.
41.	Shao D, Kolwicz SJ, Wang P, et al. Increasing fatty acid oxidation prevents high-fat diet-induced cardiomyopathy through regulating parkin-mediated mitophagy. Circulation 2020; 142: 983-97. DOI PMID
42.	Zhang Y, Fang Q, Wang H, et al. Increased mitophagy protects cochlear hair cells from aminoglycoside-induced damage. Autophagy 2023; 19: 75-91.
43.	Hsu WT, Chen YH, Yang HB, Lin JG, Hung SY. Electroacupuncture improves motor symptoms of parkinson's disease and promotes neuronal autophagy activity in mouse brain. Am J Chin Med 2020; 48: 1651-69.
44.	Jeong SJ, Zhang X, Rodriguez-Velez A, Evans TD, Razani B. p62/SQSTM1 and selective autophagy in cardiometabolic diseases. Antioxid Redox Signal 2019; 31: 458-71.
45.	Wei Y, Chiang WC, Sumpter R Jr, Mishra P, Levine B. Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell 2017; 168: 224-38. DOI PMID
46.	Liu L, Bai F, Song H, Xiao R, et al. Upregulation of TIPE 1 in tubular epithelial cell aggravates diabetic nephropathy by disrupting PHB2 mediated mitophagy. Redox Biol 2022; 50: 102260.
47.	Shang C, Liu Z, Zhu Y, et al. SARS-CoV-2 causes mitochondrial dysfunction and mitophagy impairment. Front Microbiol 2021; 12: 780768.
48.	Yang X, Jiang T, Wang Y, Guo L. The role and mechanism of SIRT1 in resveratrol-regulated osteoblast autophagy in osteoporosis rats. Sci Rep 2019; 9: 18424. DOI PMID
49.	Martinez-Vicente M. Neuronal mitophagy in neurodegenerative diseases. Front Mol Neurosci 2017; 10: 64. DOI PMID

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Protective effect of Dan Ze mixture (丹泽合剂) against lipotoxic cardiomyopathy through activating B-cell lymphoma-2 adenovirus E1B 19 kDa-interacting protein 3/mitophagy signaling pathway

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