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Combined Cornus Officinalis and Paeonia Lactiflora Pall Therapy Alleviates Rheumatoid Arthritis by Regulating Synovial Apoptosis via AMPK-Mediated Mitochondrial Fission - PubMed

  • ️Fri Jan 01 2021

Combined Cornus Officinalis and Paeonia Lactiflora Pall Therapy Alleviates Rheumatoid Arthritis by Regulating Synovial Apoptosis via AMPK-Mediated Mitochondrial Fission

Lichuang Huang et al. Front Pharmacol. 2021.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to cartilage destruction and bone erosion. In-depth exploration of the pathogenesis of RA and the development of effective therapeutic drugs are of important clinical and social value. Herein, we explored the medicinal value of Cornus officinalis Sieb. and Paeonia lactiflora Pall. in RA treatment using a rat model of collagen-induced arthritis (CIA). We compared the therapeutic effect of Cornus officinalis and Paeonia lactiflora with that of their main active compounds, ursolic acid and paeoniflorin, respectively. We demonstrated that the combination of Cornus officinalis and Paeonia lactiflora effectively inhibited the release of factors associated with oxidative stress and inflammation during RA, therein ameliorating the symptoms and suppressing the progression of RA. We further showed that the underlying mechanisms may be related to the regulation of apoptosis in synovial tissues, and we investigated the potential involvement of AMPK-mediated mitochondrial dynamics in the therapeutic action of the two drugs and their active components.

Keywords: inflammation; oxidative stress; paeoniflorin; synovial tissue; ursolic acid.

Copyright © 2021 Huang, Hu, Shao, Wu, Zhang and Cao.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1

Validation of CIA model establishment. (A) To induce CIA, Sprague-Dawley rats were given an initial injection of CFA containing collagen II (day 0). After 7 days, boost immunization was induced via CFA injection. Drug administration began on day 14 and continued daily for 20 days. The rats were sacrificed on day 34. (B) Macroscopic observation of toe swelling on day 0 (CIA initiation), day 14 (beginning of drug treatment), and day 34 (end of drug treatment). (C) Toe volume was measured on day 0, 4, 7, 12, 14, 24, 32, and 34. (D) Relative toe swelling was calculated using the following equation (Vx–V0)/V0 × 100%, where Vx is the toe volume measured on day x and V0 is the initial toe volume of the respective drug treatment group measured on day 0. All data are expressed as the mean ± standard deviation (n = 3 rats). #p < 0.05; Δ, ΔΔ, and ΔΔΔ denote p < 0.05 compared to day 4, 7, and 12, respectively, in the same drug treatment group; *, **, and *** denote p < 0.05 compared to day 14, 24, and 32, respectively, in the same drug treatment group. Low, medium, and high doses of COR and PAE were administered, but the medium doses (COR-M and PAE-M) were selected as representatives for analysis. CIA: collagen-induced arthritis; COR: Cornus officinalis; PAE: Paeonia lactiflora; PF: paeoniflorin; UA: ursolic acid; DEX: dexamethasone.

FIGURE 2
FIGURE 2

Effect of drug treatment on joint tissue morphology and apoptosis. Sprague-Dawley rats were induced by CIA for 14 days and subjected to daily drug administration at various doses for 20 consecutive days. (A) HE staining of the histopathology of joint tissues (scale bar, 50 μm). Eosinophils are indicated by black arrows and lymphocytes are indicated by red arrows. (B) Evaluation of inflammation score from the images of HE staining. (C) TUNEL staining of joint tissue apoptosis. Brown staining indicates apoptotic cells (scale bar, 50 μm). (D) Evaluation of the proportion of apoptotic cells from the images of TUNEL staining. All data are expressed as the mean ± standard deviation (n = 3 sections). *p < 0.05. Low, medium, and high doses of COR and PAE were administered, but the medium doses (COR-M and PAE-M) were selected as representatives for analysis. CIA: collagen-induced arthritis; COR: Cornus officinalis; PAE: Paeonia lactiflora; PF: paeoniflorin; UA: ursolic acid; DEX: dexamethasone.

FIGURE 3
FIGURE 3

Effect of drug treatment on inflammatory cytokine secretion and oxidative defense in CIA-induced rats. Sprague-Dawley rats were induced by CIA for 14 days and subjected to daily drug administration at various doses for 20 consecutive days. (A) ELISA detection of the serum content of TNF-α, IL-1β, IL-6, and IL-10. (B) Biochemical detection of the content of MDA, SOD, and NO in the serum and synovial tissues. All data are expressed as the mean ± standard deviation (n = 3). *p < 0.05. Low, medium, and high doses of COR and PAE were administered, and dose response was analyzed. CIA: collagen-induced arthritis; COR: Cornus officinalis; PAE: Paeonia lactiflora; PF: paeoniflorin; UA: ursolic acid; DEX: dexamethasone; MDA: malondialdehyde; SOD: superoxide dismutase; NO: nitric oxide.

FIGURE 4
FIGURE 4

Effect of drug treatment on the expression of proteins associated with apoptosis in CIA-induced rats. Sprague-Dawley rats were induced by CIA for 14 days and subjected to daily drug administration at various doses for 20 consecutive days. Western blot detection and quantification of the expression of apoptosis-related proteins (Bax, Bcl-2, cleaved caspase-3, and cytochrome-c) in synovial tissues. All protein expression was normalized to that of GAPDH as a housekeeping control. All data are expressed as the mean ± standard deviation (n = 3). *p < 0.05. Low, medium, and high doses of COR and PAE were administered, and dose response was analyzed. CIA: collagen-induced arthritis; COR: Cornus officinalis; PAE: Paeonia lactiflora; PF: paeoniflorin; UA: ursolic acid; DEX: dexamethasone; GAPDH: glyceraldehyde 3-phosphate dehydrogenase.

FIGURE 5
FIGURE 5

Effect of drug treatment on the expression of proteins associated with mitochondrial function and AMPK signaling in CIA-induced rats. Sprague-Dawley rats were induced by CIA for 14 days and subjected to daily drug administration at various doses for 20 consecutive days. (A) Western blot detection and quantification of the expression of mitochondrial function-related proteins (Drp1, Drp1 phosphorylation at Ser616 and Ser637, MTFP1, and MFN2) in synovial tissues. (B) Western blot detection and quantification of the expression of AMPK in its non-phosphorylated and phosphorylated form in synovial tissues. All protein expression was normalized to that of GAPDH as a housekeeping control. All data are expressed as the mean ± standard deviation (n = 3). *p < 0.05. Low, medium, and high doses of COR and PAE were administered, and dose response was analyzed. CIA: collagen-induced arthritis; COR: Cornus officinalis; PAE: Paeonia lactiflora; PF: paeoniflorin; UA: ursolic acid; DEX: dexamethasone; Drp1: dynamin-related protein 1; MTFN1: mitochondrial fission process protein 1; MFN2: mitofusin 2; AMPK: AMP-activated protein kinase; GAPDH: glyceraldehyde 3-phosphate dehydrogenase.

FIGURE 6
FIGURE 6

Transmission electron microscopy of mitochondrial morphology in synovial tissues. Sprague-Dawley rats were induced by CIA for 14 days and subjected to daily drug administration at various doses for 20 consecutive days. Selected areas in the microscopic images were magnified to show details of mitochondrial structure (scale bar, 500 nm). Arrows marked by “Fi” indicate areas where mitochondrial fission has occurred. Low, medium, and high doses of COR and PAE were administered, but the medium doses (COR-M and PAE-M) were selected as representatives for analysis. CIA: collagen-induced arthritis; COR: Cornus officinalis; PAE: Paeonia lactiflora; PF: paeoniflorin; UA: ursolic acid; DEX: dexamethasone.

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