Immunomodulatory effects of berberine on the inflamed joint reveal new therapeutic targets for rheumatoid arthritis management

Shen, Peng; Jiao, Yang; Li, Miao; Chen, Ji Hua; Momtazi‐Borojeni, Amir Abbas

doi:10.1111/jcmm.15803

Cited by 41 publications

(27 citation statements)

References 130 publications

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“… 49 The absence of increased cell death in our experimental assay is consistent with the reported chondroprotective influence of BBR, 44 and supports the specificity of the dying influence of BBR on different cell lineages. As reported in different experimental studies, 22 , 48 , 50 we have observed a mild, but significant, transcriptional influence of BBR on genes associated with cell death and developmental cell senescence, 51 , 52 including p21 and Bak1, p53 and the tumor suppressor gene Btg1 . This moderate gene up-regulation in our in vitro assay appeared insufficient to induce apoptosis or increased SAβ-gal activity in early or late cultures at the end of the 6 hr period of treatment.…”

Section: Discussionsupporting

confidence: 81%

“…The increased chondrogenesis observed after treatments of cultures at advanced stages of cartilage differentiation might be important when considering the therapeutic influence of BBR on joint cartilage degeneration. 22 In our experimental model, BBR at initial stages of culture inhibited chondrogenesis, up-regulating pro-fibrogenic genes ( Tgfβ2 and Scleraxis ) but not Sox9 , and maintained progenitors into a fibroblastic-like state. However, the addition of BBR to the culture medium at advanced stages of culture promoted chondrogenesis, deduced by the intensification of Alcian blue specific cartilage staining and by the transcriptional up-regulation of Sox9 .…”

Section: Discussionmentioning

confidence: 71%

“… 9 Abundant evidence indicates that the anti-inflammatory effect of BBR relays in the regulation of signaling pathways associated with inflammation. 15 , 22 Cell death and cell cycle arrest of activated rheumatoid arthritis fibroblast-like synoviocytes in combination with an anti-apoptotic influence on chondrocytes were proposed to contribute also to the pharmacological effects of BBR on joint cartilage. 44 , 48 Remarkably, the induction of cell cycle arrest and apoptosis constitutes the basis for the anti-tumoral pharmacological application of BBR in a variety of tumors.…”

Section: Discussionmentioning

confidence: 99%

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Effects of Berberine on the Chondrogenic Differentiation of Embryonic Limb Skeletal Progenitors

Duarte‐Olivenza

Montero

Lorda‐Diez

2021

JIR

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Introduction Berberine (BBR) is an isoquinoline plant alkaloid with demonstrated anti-inflammatory, anti-tumor and immunosuppressive pharmacological properties that functions via multiple signaling pathways and epigenetic modulators. Numerous studies have proposed BBR as a promising therapeutic agent for joint cartilage degeneration, and other connective tissue diseases. Purpose and Methods This work aimed to evaluate the effects of BBR on the growth and differentiation of embryonic skeletal progenitors using the limb mesoderm micromass culture assay. Results Our findings show that at difference of its apoptotic influence on a variety of tumor tissues, cell death was not induced in skeletal progenitors by the addition of 12 or 25 µM BBR concentration to the culture medium. Morphological and transcriptional analysis revealed dual and opposite effects of BBR treatments on chondrogenesis depending on the stage of differentiation of the cultured progenitors. At early stage of culture, BBR was a potent chondrogenic inhibitor, while chondrogenesis was intensified in treatments at advanced stages of culture. The chondrogenic promoting effect was accompanied by a moderate upregulation of gene markers of prehypertrophic cartilage, including ColXa1 , alkaline phosphatase Alpl, Runx2 , and Indian Hedgehog Ihh . We further observed a positive transcriptional influence of BBR in the expression of DNA methyltransferase genes, Dnmt1, Dnmt3a and Dnmt3b , suggesting a potential involvement of epigenetic factors in its effects. Conclusion Our study uncovers a new pharmacological influence of BBR in cartilage differentiation that must be taken into account in designing clinical protocols for its employment in the treatment of cartilage degenerative diseases.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

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Effects of Berberine on the Chondrogenic Differentiation of Embryonic Limb Skeletal Progenitors

Duarte‐Olivenza

Montero

Lorda‐Diez

2021

JIR

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“…Berberine inhibits in ammatory proliferation of synovial cells, suppresses DC activation, regulates Th17/Treg balance, and prevents cartilage and bone destruction by regulating various signaling pathways involved in in ammatory responses, including PI3K/Akt. Such molecular targets may explore new RA treatment targets [60].…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Immune-Related Genes, Molecular Pathways and Immune Infiltration as Diagnostic and Therapeutic Candidate Targets for RA: an integrated bioinformatics-based analysis

Fang

et al. 2021

Preprint

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Relevance Rheumatoid arthritis (RA) is a systemic autoimmune disease with an aggressive, chronic synovial inflammation as the main pathological change. However, the specific etiology, pathogenesis, and related biomarkers in diagnosis and treatment are still not fully elucidated. This study attempts to provide new perspectives and insights into RA at the genetic, molecular, and cellular levels through the tenet of personalized medicine. Methods Gene expression profiles of four individual knee synovial tissues were downloaded from a comprehensive gene expression database, R language was used to screen for significantly differentially expressed genes (DEGs), Gene Ontology Enrichment Analysis, Kyoto Gene Encyclopedia, and Gene Set Enrichment Analysis were performed to analyze the biological functions and signaling pathways of these DEGs, STRING online database was used to establish protein-protein interaction networks, Cytoscape software to obtain ten hub genes, Goplot to get six inflammatory immune-related hub genes, and CIBERSORT algorithm to impute immune infiltration. Results Molecular pathways that play important roles in RA were obtained: Toll-like receptors, AMPK, MAPK, TNF, FoxO, TGF-beta, PI3K and NF-κB pathways, Ten hub genes: Ccr1, Ccr2, Ccr5, Ccr7, Cxcl5, Cxcl6, Cxcl13, Ccl13, Adcy2, and Pnoc. among which Adcy2 and Pnoc have not been reported in RA studies, suggesting that they may be worthy targets for further study. It was also found that among the synoviocytes in RA, the proportions of plasma cells, CD8 T cells, follicular helper T cells, monocytes, γ delta T cells, and M0 macrophages were higher, while the proportions of CD4 memory resting T cells, regulatory T cells (Tregs), activated NK cells, resting dendritic cells, M1 macrophages, eosinophils, activated mast cells, resting mast cells were lower in proportion, and each cell played an important role in RA. Conclusions This study may help understand the key genes, molecular pathways, the role of inflammatory immune infiltrating cells in RA’s pathogenesis and provide new targets and ideas for the diagnosis and personalized treatment of RA.

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“…In regard to RA specifically, BBR has been successful at treating clinically apparent CIA and other RA animal models in vivo through a number of suggested mechanisms, such as (a) dendritic cell apoptosis [24], (b) interference with MAPK signaling via inhibition of p-ERK, p-38, and p-JNK [25,32], (c) attenuation of T h 17 activity via inducing cortistatin in the gut [27], (d) restoration of the balance between T reg /T h 17 cells [26], (e) the suppression of T h 17 differentiation/proliferation through inhibition of CD169 and the RORγt transcription factor, (f) induction of T reg differentiation through aryl hydrocarbon receptor (AhR) activation [33], (g) and promotion of anti-inflammatory M2 macrophage polarization through upregulation of p-AMPK and inhibition of HIF1α [34]. A more detailed account of the anti-inflammatory actions of BBR in the context of rheumatoid arthritis can be found in the recent review by Shen et al (2020) [35].…”

Section: Introductionmentioning

confidence: 99%

Berberine Delays Onset of Collagen-Induced Arthritis through T Cell Suppression

Vita

Aljobaily

Lyons

et al. 2021

IJMS

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There is evidence that berberine (BBR), a clinically relevant plant compound, ameliorates clinically apparent collagen-induced arthritis (CIA) in vivo. However, to date, there are no studies involving the use of BBR which explore its prophylactic potential in this model of rheumatoid arthritis (RA). The aim of this study was to determine if prophylactic BBR use during the preclinical phase of collagen-induced arthritis would delay arthritic symptom onset, and to characterize the cellular mechanism underlying such an effect. DBA/1J mice were injected with an emulsion of bovine type II collagen (CII) and complete Freund’s adjuvant (day 0) and a booster injection of CII in incomplete Freund’s adjuvant (day 18) to induce arthritis. Mice were then given i.p. injections of 1 mg/kg/day of BBR or PBS (vehicle with 0.01% DMSO) from days 0 to 28, were left untreated (CIA control), or were in a non-arthritic control group (n = 15 per group). Incidence of arthritis in BBR-treated mice was 50%, compared to 90% in both the CIA and PBS controls. Populations of B and T cells from the spleens and draining lymph nodes of mice were examined on day 14 (n = 5 per group) and day 28 (n = 10 per group). BBR-treated mice had significantly reduced populations of CD4+Th and CD4+CXCR5+ Tfh cells, and an increased proportion of Foxp3+ Treg at days 14 and 28, as well as reduced expression of co-stimulatory molecules CD28 and CD154 at both endpoints. The effect seen on T cell populations and co-stimulatory molecule expression in BBR-treated mice was not mirrored in CD19+ B cells. Additionally, BBR-treated mice experienced reduced anti-CII IgG2a and anti-CII total IgG serum concentrations. These results indicate a potential role for BBR as a prophylactic supplement for RA, and that its effect may be mediated specifically through T cell suppression. However, the cellular effector involved raises concern for BBR prophylactic use in the context of vaccine efficacy and other primary adaptive immune responses.

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Immunomodulatory effects of berberine on the inflamed joint reveal new therapeutic targets for rheumatoid arthritis management

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 41 publications

References 130 publications

Effects of Berberine on the Chondrogenic Differentiation of Embryonic Limb Skeletal Progenitors

Effects of Berberine on the Chondrogenic Differentiation of Embryonic Limb Skeletal Progenitors

Identification of Key Immune-Related Genes, Molecular Pathways and Immune Infiltration as Diagnostic and Therapeutic Candidate Targets for RA: an integrated bioinformatics-based analysis

Berberine Delays Onset of Collagen-Induced Arthritis through T Cell Suppression

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