Shikonin induces apoptosis and suppresses growth in keratinocytes via CEBP-δ upregulation

Yan, Yu; Xu, Yuanyuan; Lan, Xiaoou; Li, Xiaoying; Zhang, Xiaolan; Gao, Xing‐Hua; Geng, Long

doi:10.1016/j.intimp.2019.04.047

Cited by 26 publications

(22 citation statements)

References 36 publications

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“…Our previous study demonstrated that shikonin suppressed IL-17-induced, psoriasis-associated cytokines by inhibiting the JAK/STAT3 signaling pathway (23). Several studies suggest that shikonin and its derivatives are effective inhibitors of STAT3, which could be the possible mechanistic basis of the upregulation of CEBPD (21)(22)(23)(24)(25). IMQ can induce psoriatic-like plaques in mice by triggering the il-23/IL-17 axis (46).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Liu et al ( 24 ) found that shikonin could downregulate K17 in proliferating keratinocytes by interfering with STAT3 signaling. More recently, Yu et al ( 25 ) also demonstrated that shikonin induced G 0 /G 1 cell cycle arrest in the human HaCaT keratinocyte cell line. However, the potential effects of shikonin on the downstream mediators of the JAK/STAT3 signaling pathway are unclear.…”

Section: Introductionmentioning

confidence: 95%

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Shikonin inhibits CEBPD downregulation in IL‑17‑treated HaCaT cells and in an imiquimod‑induced psoriasis model

Lan

Wang

et al. 2020

Mol Med Rep

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Psoriasis is a chronic inflammatory skin disease characterized by well-defined scaly papules and plaques. Interleukin (IL)-17 is involved in its pathogenesis and promotes the proliferation of epidermal keratinocytes through signal transducer and activator of transcription 3 (STAT3) activation. Shikonin, a natural naphthoquinone isolated from Lithospermum erythrorhizon , possesses anti-inflammatory and immunosuppressive properties and can suppress IL-17-induced vascular endothelial growth factor expression by inhibiting the JAK/STAT3 pathway. In the present study, MTS, iCELLigence and RT-qPCR were used to determine the optimal concentration and duration of IL-17 or shikonin acting on HaCaT cells. The changes in the expression levels of genes associated with the IL-6/STAT3 pathway in differentially treated cells were analyzed via RT 2 Profiler™ PCR Array. Small interfering RNA was used to silence the expression levels of the target gene CCAAT/enhancer-binding protein δ (CEBPD). Western blotting and immunohistochemistry were used to evaluate the effect of shikonin on imiquimod-induced psoriasis in mice and the expression levels of CEBPD. Shikonin reversed IL-17-mediated downregulation of the tumor suppressor CEBPD in HaCaT cells. Moreover, low levels of CEBPD in the imiquimod-induced mouse model of psoriasis were restored by shikonin treatment, which ameliorated excessive keratinocyte proliferation. Taken together, these findings suggest that CEBPD plays a key role in the pathogenesis of psoriasis and can be targeted by shikonin as a potential therapeutic strategy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Shikonin inhibits CEBPD downregulation in IL‑17‑treated HaCaT cells and in an imiquimod‑induced psoriasis model

Lan

Wang

et al. 2020

Mol Med Rep

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“…Shikonin is a main ingredient of zicao, a chinese herbal medicine with a wide range of biological activities (J. Chen et al, 2011; X. Chen et al, 2003). Indeed, shikonin has been proved to exhibit multiple anticancer features through suppressing pyruvate kinase M2‐mediated aerobic glycolysis (X. Zhao et al, 2018), reversing the JAK/STAT3 activation (Yu et al, 2019) as well as inhibiting PKM2/STAT3/cyclinD1 signaling (Tang et al, 2018). In this study, we first systematically identified shikonin as a potent, direct, and selective IMPDH2 inhibitor and demonstrate the potential proliferation–inhibition and apoptosis‐inducing activity of shikonin in human and murine TNBC cell lines.…”

Section: Discussionmentioning

confidence: 99%

Shikonin is a novel and selective IMPDH2 inhibitor that target triple‐negative breast cancer

Wang

Chen

et al. 2020

Phytotherapy Research

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Triple‐negative breast cancer (TNBC) is heterogeneous disease with a poor prognosis. It is therefore important to explore novel therapeutic agents to improve the clinical efficacy for TNBC. The inosine 5′‐monophosphate dehydrogenase 2 (IMPDH2) is a rate‐limiting enzyme in the de novo synthesis of guanine nucleotides. It is always overexpressed in many types of tumors, including TNBC and regarded as a potential target for cancer therapy. Through screening a library of natural products, we identified shikonin, a natural bioactive component of Lithospermum erythrorhizon, is a novel and selective IMPDH2 inhibitor. Enzymatic analysis using Lineweaver–Burk plot indicates that shikonin is a competitive inhibitor of IMPDH2. The interaction between shikonin and IMDPH2 was further investigated by thermal shift assay, fluorescence quenching, and molecular docking simulation. Shikonin treatment effectively inhibits the growth of human TNBC cell line MDA‐MB‐231, and murine TNBC cell line, 4T1 in a dose‐dependent manner, which is impaired by exogenous supplementation of guanosine, a salvage pathway of purine nucleotides. Most importantly, IMPDH2 knockdown significantly reduced cell proliferation and conferred resistance to shikonin in TNBC. Collectively, our findings showed the natural product shikonin as a selective inhibitor of IMPDH2 with anti‐TNBC activity, impelling its further study in clinical trials.

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“…Astilbin was found to improve differentiation in HaCaT KCs with suppression of KRT5 and KRT14 and induction of KRT1 and KRT10 (25,26,38). In addition to anti-inflammation, Shikonin might promote apoptosis and suppresses growth in KCs (39).…”

Section: Potential Pharmacological Mechanisms Of Action Of Tcm Ingredmentioning

confidence: 96%

Evidence and potential mechanisms of traditional Chinese medicine for the treatment of psoriasis vulgaris: a systematic review and meta-analysis

Dai

et al. 2020

Journal of Dermatological Treatment

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Psoriasis vulgaris (PV) not only affects patients' skin health but also increases the risk of coronary heart disease and diabetes, which brings both physical and mental harms. Its pathogenesis is complex, and the multitarget effect of traditional Chinese medicine (TCM) is especially advantageous. Because a considerable number of randomized controlled trials related to TCM exhibit design defects, small sample size, or inadequate intervention time, so the status of TCM in the treatment of PV cannot be fully clarified. We reviewed the controlled clinical trials published over the past decade and selected 17 high-quality articles from over 2000 papers. The results suggest that TCM might be beneficial for decrease in PASI scores, thus, TCM might be an effective alternative therapy for PV management. The safety of TCM on PV was also assessed in our analysis. The more strictly designed and long-term observations of TCM for PV are supposed to be conducted in the future.

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Shikonin induces apoptosis and suppresses growth in keratinocytes via CEBP-δ upregulation

Cited by 26 publications

References 36 publications

Shikonin inhibits CEBPD downregulation in IL‑17‑treated HaCaT cells and in an imiquimod‑induced psoriasis model

Shikonin inhibits CEBPD downregulation in IL‑17‑treated HaCaT cells and in an imiquimod‑induced psoriasis model

Shikonin is a novel and selective IMPDH2 inhibitor that target triple‐negative breast cancer

Evidence and potential mechanisms of traditional Chinese medicine for the treatment of psoriasis vulgaris: a systematic review and meta-analysis

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