Anti-angiogenic effect of Shikonin in rheumatoid arthritis by downregulating PI3K/AKT and MAPKs signaling pathways

Liu, Chunfang; He, Lianhua; Wang, Jingxia; Wang, Qianqian; Sun, Congcong; Li, Yiqun; Jia, Ke-Xin; Wang, Jinxia; Xu, Tengteng; Ming, Rui-Rui; Wang, Qingwen; Lin, Na

doi:10.1016/j.jep.2020.113039

Cited by 77 publications

(40 citation statements)

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“…Synovitis hyperplasia and angiogenesis are two important pathological links in RA, which play an important role in the progress of RA [ 28 ]. Our previous research have proved that angiogenesis plays an significant role in RA, SKN and Ermiao San can effectively inhibit synovial angiogenesis in RA [ 20 , 21 ]. Some studies have confirmed that SKN can act on synovial cells [ 5 , 6 ], but its specific target is unclear, which is the focus of our article.…”

Section: Discussionmentioning

confidence: 99%

“…The hind knees, liver, kidney and testis were achieved and dissected into sections for pathological measurement, and stained with hematoxylin and eosin (HE) while the front knees were used for western blot. As described previously, histopathologic severity was measured using three different parameters [ 20 – 22 ]: synovial hyperplasia, synovitis, cartilage damage and bone erosion. Each parameter was measured by two independent observers at 0–3 (0, normal; 3, severe).…”

Section: Methodsmentioning

confidence: 99%

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Shikonin attenuates rheumatoid arthritis by targeting SOCS1/JAK/STAT signaling pathway of fibroblast like synoviocytes

Luan

et al. 2021

Chin Med

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Background Rheumatoid arthritis is a progressive and systemic autoimmune disease seriously compromises human health. Fibroblast like synoviocytes are the major effectors of proliferation and inflammation in rheumatoid arthritis synovial tissue. Shikonin has anti-inflammatory and immunomodulatory activities. But, its role on synovitis of rheumatoid arthritis is unknown. Methods The DBA/1 male mice were randomly divided into the following three groups (n = 6): (1) the normal control group of mice, (2) the CIA (collagen-induced arthritis) group in which mice suffered from arthritis induced by collagen, (3) the SKN (shikonin) group of mice which got arthritis and given intragastrically with shikonin 4 mg/kg per day continuously for 20 days,(4) the MTX (methotrexate) group of mice which got arthritis and orally administration with shikonin 0.5  mg/kg once two days continuously for 20 days. The therapeutic effect of shikonin on collagen induced arthritis mice was tested by arthritis incidence rate, arthritis score and inflammatory joint histopathology. The invasion, adhesion and migration of fibroblast like synoviocytes induced by tumor necrosis factor-α were applied to measure the anti-synovitis role of shikonin. The effect of shikonin on expression of interleukin-6, interleukin-1β and tumor necrosis factor-α was measured by enzyme linked immunosorbent assay. The interaction between shikonin and suppressor of cytokine signaling 1 was verified by molecular docking. The signaling pathways activated by shikonin were measured by western blot. Results Shikonin decreased the arthritis score and arthritis incidence, and inhibited inflammation of inflamed joints in collagen induced arthritis mice. And shikonin reduced the number of vimentin+cells in collagen induced arthritis mice inflamed joints. Meanwhile, shikonin suppressed tumor necrosis factor-α-induced invasion, adhesion and migration of fibroblast like synoviocytes and reduced the expression of interleukin-6, interleukin-1β and tumor necrosis factor-α. And we found that shikonin targeted suppressor of cytokine signaling 1. More interestingly, shikonin blocked the phosphorylation of Janus kinase 1/signal transducer andactivator of transcription 1/signal transducer andactivator of transcription 6 in synovial tissues and in fibroblast like synoviocytes. Conclusion Shikonin represents a promising new anti-rheumatoid arthritis drug candidate that has anti-synovitis effect in collagen induced arthritis mice and inhibits tumor necrosis factor-α-induced fibroblast like synoviocytes by targeting suppressor of cytokine signaling 1/ Janus kinase/signal transducer andactivator of transcription signaling pathway. These findings demonstrate that shikonin has anti-synovitis effect and has great potential to be a new drug for the treatment of rheumatoid arthritis.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Shikonin attenuates rheumatoid arthritis by targeting SOCS1/JAK/STAT signaling pathway of fibroblast like synoviocytes

Luan

et al. 2021

Chin Med

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“…The PI3K/AKT signaling pathway is activated and up-regulated in RA. Shikonin(SKN) down-regulates PI3K and Akt's expression, inhibiting the phosphorylation and gene-level signaling molecules such as ERK1/2, JNK1/2, and p38, and exerts anti-RA angiogenic effects [58]. Cinnamaldehyde (CA) can block PI3K/AKT signaling pathway and inhibit the proliferation and in ltration of rheumatoid synovial cells, which has potential therapeutic effects on RA [59].…”

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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“…guttata Bunge in the Chinese Pharmacopoeia (2020 version). Shikonin and its derivatives, red naphthoquinones, are widely found in the epidermis of the roots of Arnebiae Radix ( Zhan et al, 2015 ) and have been widely demonstrated to possess various biological activities, such as anti-inflammatory ( Fu et al, 2016 ; Sun et al, 2017 ; Guo et al, 2019 ), antibacterial ( Zhao et al, 2017 ; Huang et al, 2020 ), and antiangiogenic ( Liu C. et al, 2020 ) activities. Recently, it was reported that shikonin and its derivatives could induce apoptosis of many types of cancer cells and exhibit anticancer activities and antitumorigenic properties ( Liao et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Authentication of Three Source Spices of Arnebiae Radix Using DNA Barcoding and HPLC

Ren

et al. 2021

Front. Pharmacol.

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Arnebia decumbens (Vent.) Coss. et Kralik, A. euchroma (Royle) Johnst and A. guttata Bunge, three commonly used traditional Chinese medicinal plants have been widely used for the clinical treatment of inflammatory diseases caused by fungal, bacterial, oxidation, and other related pathogens. However, precise identification at the similar species level is usually challenging due to the influence of the source of medicinal materials, traditional ethnic medicine and medicinal habits. Here we developed a comprehensive and efficient identification system for three source spices of Arnebiae Radix based on DNA barcoding and HPLC fingerprinting. A total of 599 samples from thirty-five wild populations were collected and identified by using DNA barcodes of ITS2 regions, and the chemotypes of seven naphthoquinoneswere revealed by HPLC quantitative analysis including principal component analysis and hierarchical clustering analysis. Our results showed that the ITS2 sequences can distinguish three source spices of Arnebiae Radix from adulterants. However, it was difficult to identify them by HPLC-specific chromatograms combined with chemometric analysis. These results indicated that DNA barcoding was a more powerful method than HPLC fingerprinting for the identification of related species that were genetically similar. DNA barcoding analysis could be a promising and reliable tool to accurately confirm the identities of medicinal materials, especially for those whose sources are multiple and difficult to be identified by conventional chromatography.

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Anti-angiogenic effect of Shikonin in rheumatoid arthritis by downregulating PI3K/AKT and MAPKs signaling pathways

Cited by 77 publications

References 38 publications

Shikonin attenuates rheumatoid arthritis by targeting SOCS1/JAK/STAT signaling pathway of fibroblast like synoviocytes

Shikonin attenuates rheumatoid arthritis by targeting SOCS1/JAK/STAT signaling pathway of fibroblast like synoviocytes

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

Authentication of Three Source Spices of Arnebiae Radix Using DNA Barcoding and HPLC

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