Pharmaceutics
·
2024
·Vol. 16
·期 12
·1543
·
IF 4.9
Min Li,Wenying Li,Fang Xu,Yiping Pu,Jianguang Li
Background:L-Shikonin, an active component of Arnebia euchroma (Royle) Johnst., has remarkable pharmacological effects, particularly in its anti-tumour activity. Nonetheless, the specific targets and mechanisms of action remain to be further explored.Methods:A novel Fe3O4@L-Shikoninwas designed and synthesized in this study by linking Fe3O4andL-Shikoninthrough benzophenone. Fe3O4@L-Shikoninwas characterized using several techniques, including scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), and drug removal methods, to determine the content ofL-Shikoninon the surface of the magnetic particles. Target hooking technology was utilized to identify the target proteins of the compound in melanoma. The synthesized Fe3O4@L-Shikoninwas co-incubated with A375 cell lysate, followed by the target proteins, which were purified by magnetic enrichment using magnetic microspheres and identified by high-resolution mass spectrometry.Results:AutoDock Vina software was employed for molecular docking analysis, where it was found thatL-Shikonintargets RPN1, CPEB4, and HNRNPUL1 proteins. Subsequently, A375 cells were treated withL-Shikoninat different concentrations (2.5, 5.0, 10.0 μM) for 48 h, and the expressions of the three proteins were observed. The results showed a significant reduction in the relative expression of CPEB4 in the high-dose group compared to the control group (p< 0.01). Moreover, the relative expression of HNRNPUL1 was decreased in the medium- and high-dose groups (p< 0.05).Conclusions:This study initially revealed from the source thatL-Shikoninmay regulate melanoma-specific markers, melanosomes, tyrosine kinases related to abnormal tyrosine metabolism, and melanoma through multiple targets such as CPEB4 and HNRNPUL1. Proliferation and metastasis work together to exert an anti-melanoma mechanism, which provides a new idea for the follow-up study of the molecular pharmacological mechanism of the complex system of total naphthoquinones inArnebia euchroma(Royle) Johns.
研究领域:
药理学
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肿瘤学
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分子生物学
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材料科学
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DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2023
·
IF 3.6
Chen Xiaohui,Lin Shengrong,Liang Yunbang,Xue Xiaomin,Yasen Miersalijiang
Shikonin is a natural product with antioxidant and anti-inflammatory activities. The biological activity of shikonin is still not fully understood, as well as its association with innate immunity and immune and inflammatory bowel disease (IBD) in humans. In this study, the toxicity of shikonin on Raw264.7 cells was assayed by MTT, and polarization of inflammatory macrophages was determined by flow cytometry. The results showed that shikonin can inhibit the polarization of macrophages towards M1 type and significantly inhibited the production of NO in the concentration range of 0.5–1 μM. In addition, after treatment with shikonin, the production of IL-1β and TNF-α was significantly decreased. After shikonin administration, the body weight loss and decrease of colon length were significantly suppressed in DSS-treated colitis C57BL/6 mice. The pro-inflammatory cytokines TNF-α and IL-1β in colonic homogenate were significantly decreased. Shikonin treatment resulted in a notable improvement in the histopathological manifestations in DSS-treated animals at 25/50 mg/kg. Meanwhile, we found that shikonin can regulate differentiation of T helper 17 cell (Th17)/regulatory T cell (Treg), thereby regulating the balance of Th17/Treg cells and exerting an anti-inflammatory effect in IBD animal models. In conclusion, we found that shikonin protects against DSS-induced acute colitis by, among other things, reducing immune cell infiltration, polarizing macrophages, and regulating Th17/Treg differentiation, as well as by downregulating the release of inflammatory cytokines. These findings showed that shikonin can improve inflammation by affecting macrophage polarization. Our experimental data provide experimental evidence and theory basis for research on anti-inflammatory effects for the shikonin as health or functional food. Graphical Abstract
研究领域:
免疫学
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药理学
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消化病学
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DOI
PubMed
高影响因子
COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING
·
2024
·Vol. 27
·期 13
·1919-1929
·
IF 1.6
Zhang Fei,Chu Mingliang,Liu Jiemin,Zhao Qi,Zhu Yanqiu,Wu Xuefang
Aim: The study aimed to study the potential roles and mechanisms of shikonin in gastric cancer by network pharmacology and biological experiments. Methods: The key genes and targets of shikonin in gastric cancer were predicted by network pharmacology and molecular docking study.
The effect of shikonin on the proliferation, migration, and invasion of gastric cancer cells was detected by the CCK8 method, and wound healing and transwell assays. The expression levels of c-Myc and Yap-1 were detected via western blotting in gastric cancer cells after shikonin intervention.
Results: The results of network pharmacology revealed the key target genes of shikonin on gastric cancer cells to be c-Myc, Yap-1, AKT1, etc. GO and KEGG analysis showed regulation of cell migration, proliferation, adhesion, and other biological processes, including the PI3K-Akt signaling
pathway, HIF-1 signaling pathway, necroptosis, and other cancer pathways. Molecular docking showed shikonin to be most closely combined with protooncogenes c-Myc and Yap-1. In vitro experiments showed that the proliferation rate, migration, and invasion ability of the gastric cancer cell group
decreased significantly after shikonin intervention for 24h. The expression levels of c-Myc and Yap-1 in gastric cancer cells were found to be significantly decreased after shikonin intervention. Conclusion: This study showed protooncogenes c-Myc and Yap-1 to be the core target genes
of shikonin on gastric cancer cells. Shikonin may suppress gastric cancer cells by inhibiting the protooncogenes c-Myc and Yap-1. This suggests that shikonin may be a good candidate for the treatment of gastric cancer.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
LANGMUIR
·
2025
·
IF 3.9
Zhiyuan Liu,Yaxuan Huang,Rui Sun,Nan Li,Fengyun Xu,Wei Zhang,Wenke Zhang
Shikonin (SHK) is a potential chemotherapy drug for the treatment of breast cancer. However, the poor water solubility, as well as the lack of tumor targeting, restricts the practical application of SHK molecules. In addition, chemotherapy alone is no longer sufficient for current clinical treatment, and it needs to be combined with other therapeutical methods. Here, using our previously developed shikonin-disulfide bond-poly(ethylene glycol) compound (referred to as SHK-SS-PEG) as a chemotherapy molecule that responds to reduced glutathione (GSH), a SHK-SS-PEG-functionalized multiwall carbon nanotubes (MWCNTs) system (SHK-SS-PEG/MWCNTs) was prepared by physical interaction. Such a system exhibits both chemotherapy and photothermal therapy for breast cancer. The physical adsorption of SHK-SS-PEG on the MWCNTs causes them to have good dispersion and storage stability for up to 3 months in aqueous solution and possess excellent photothermal conversion performance of MWCNTs. In addition, the drug release rate of SHK-SS-PEG/MWCNTs in MCF-7 cells as triggered by a near-infrared (NIR) laser was increased by 2-fold compared with that of nonirradiated cells. In vitro antitumor studies demonstrated that SHK-SS-PEG/MWCNTs had a combined effect of chemotherapy and photothermal therapy. The mortality of MCF-7 cells treated with SHK-SS-PEG/MWCNTs ([MWCNTs] = 75 μg/mL) under 808 nm NIR laser irradiation was as high as 87.78%, which was 34.39% and 28.31% higher than that of the SHK-SS-PEG/MWCNTs group without NIR laser irradiation and the MWCNTs group irradiated with NIR laser at the same equivalent concentration, respectively. These results indicated that SHK-SS-PEG/MWCNTs combined with an 808 nm NIR laser were an ideal antitumor system.
研究领域:
纳米医学
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肿瘤学
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药剂学
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产品关联
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2019
·
IF 3.743
Hongli Guo,Jieyu Sun,Deyi Li,Yahui Hu,Xiaowen Yu,Hu Hua,Xia Jing,Feng Chen,Zhanjun Jia,Jing Xu
Acetaminophen (APAP) overdose causes acute liver injury and leads to fatal liver damage. However, the therapies are quite limited. Shikonin is a natural product with antioxidant and anti-inflammatory activities. In the present study, the hepatoprotective effects and the underlying mechanisms of shikonin in APAP-induced hepatotoxicity in vivo and in vitro were investigated. APAP-induced acute liver injury and shikonin pretreatment models were established in vivo and in vitro, as evidenced by serum hepatic enzymes, histological changes, oxidative stress indicators and proinflammatory cytokines. The results revealed that shikonin pretreatment prevented the elevation of serum alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels and markedly reduced APAP-induced histological alterations in liver tissues. Additionally, shikonin restored superoxide dismutase (SOD) expression and glutathione (GSH) content in line with the blockade of oxidative stress. The changes in gene expression involved in oxidative stress including methionine sulfoxide reductase (such as MsrA and MsrB1), heme oxygenase-1 (HO-1), SOD2 and cytochrome P450 2E1 (CYP2E1), were markedly reversed after shikonin therapy. Furthermore, shikonin markedly attenuated the APAP-induced production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) and suppressed the expression of genes related to inflammation. In AML-12 cells, shikonin pretreatment decreased APAP-induced cytotoxicity as measured by CCK-8 assay and LDH release. The changes in gene expression involved in oxidative stress and the inflammatory response were consistent with those in mouse livers. This study indicated that shikonin attenuated APAP-induced acute liver injury via inhibiting oxidative stress and inflammatory responses in vivo and in vitro. These findings offer new insights into the potential therapy for APAP hepatotoxicity.
研究领域:
药理学
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毒理学
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肝病学
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICAL RESEARCH
·
2024
·
IF 2.8
Shaoyi Cao,Huaqiu Li,Xiaoyan Ye,Xinxing Xing,Yonghuan Xie,Xiangfeng Zeng,Hongjiao Liu,Xing Zhong,Xinyi Yang,Wenxiu Xing,Cairong Zhu,Xiaoping Wu
Background The T790M mutation in the epidermal growth factor receptor ( EGFR ) gene is the primary cause of resistance to EGFR-tyrosine kinase inhibitor (TKI) therapy in non-small cell lung cancer (NSCLC) patients. Previous research demonstrated that certain traditional Chinese medicine (TCM) monomers exhibit anti-tumor effects against various malignancies. This study aims to investigate the potentials of shikonin screened from a TCM monomer library containing 1060 monomers in killing EGFR -T790M drug-resistant NSCLC cells and elucidate the underlying mechanisms. Methods MTT method was used to screen for the TCM monomers with significant killing effects on H1975 cells carrying the EGFR -T790M mutation. The influences of the identified monomer shikonin on cell growth were determined by the colony formation assay. Annexin-V/PI staining and JC-1 staining were applied to detect the effects of shikonin on cell apoptosis. The influences of shikonin on cell membrane integrity were detected by lactate dehydrogenase (LDH) release assay. Reactive oxygen species (ROS) generation was analyzed using DCFH-DA as probe. The mechanisms of shikonin affecting the stability of cyclooxygenase-2 (COX-2) were evaluated by using specific inhibitors for protein degradation pathways. Western blotting was performed to assess the effects of the alteration of COX-2 expression or enzymatic activity on the related signal pathways as well as the apoptotic and pyroptotic markers. Results Shikonin was identified as a potent cytotoxic compound against EGFR -T790M-mutant NSCLC cells. Shikonin induced cell apoptosis and pyroptosis by triggering the activation of the caspase cascade and cleavage of poly (ADP-ribose) polymerase and gasdermin E by elevating intracellular ROS levels. Further investigations revealed that shikonin induced the degradation of COX-2 via the proteasome pathway, thereby decreasing COX-2 protein level and enzymatic activity and subsequently inhibiting the downstream PDK1/Akt and Erk1/2 signaling pathways through the induction of ROS production. Notably, COX-2 overexpression attenuated shikonin-induced apoptosis and pyroptosis, whereas COX-2 inhibition with celecoxib enhanced the cytotoxic effects of shikonin. Conclusions Combination treatment with shikonin and COX-2 inhibitor may be a suitable therapeutic strategy for EGFR -T790M-mutant NSCLC treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s40001-024-02187-7.
研究领域:
肿瘤学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF SOLID STATE ELECTROCHEMISTRY
·
2025
·
IF 2.6
Wang Rong,Zhu Liangqin,Wang Jianfei,Zeng Chenglong,Chen Ying,Wei Yan
A copper-coordinated poly-L-histidine/carboxylated multi-walled carbon nanotube (Cu-HIS/ f -MWCNTs) sensing interface was constructed using electropolymerization and self-assembly methods. The electrochemical response of shikonin (SHI) on this sensing interface was analyzed using cyclic voltammetry (CV) and chronoamperometry (CC). The results showed that the interface had a large effective surface area, and the imidazole groups on histidine exhibited good recognition and electrocatalytic oxidation of shikonin. At optimal conditions, the differential pulse voltammetry (DPV) peak current demonstrated a linear dependence on shikonin concentration within the range of 2 × 10 −4 to 10 µmol/L, achieving a detection limit of 0.07 nmol/L. The sensing interface demonstrated a broad detection range, along with excellent stability, selectivity, and reproducibility. It was successfully employed for the analysis of shikonin in real samples, yielding a spiked recovery rate from 98.4 to 104.8%.
研究领域:
分析化学
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生物医学工程
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材料科学
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产品关联
DOI
高影响因子
JOURNAL OF THE ELECTROCHEMICAL SOCIETY
·
2019
·Vol. 166
·期 6
·B388
·
IF 3.12
Jingdang Chai,Jie Zhang,Yangping Wen,Lie Zou,Xinxin Zhang,Xing Xin,Muhan Zhou,Jingkun Xu,Ge Zhang
An electrochemical sensor based on PEDOT:PSS-β-CD-SWCNT-COOH/GCE for highly sensitive analysis of shikonin (SHI) in PBS buffer solution was reported. PEDOT:PSS-β-CD-SWCNT-COOH composite was obtained by using poly(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS), β-Cyclodextrin (β-CD) and carboxylated single-walled carbon nanotube (SWCNT-COOH) to modify glassy carbon electrode (GCE) and characterized by scanning electron microscopy and electrochemical impedance spectroscopies. In optimized conditions, PEDOT:PSS-β-CD-SWCNT-COOH had a high sensitivity to SHI and it could detect SHI in linear ranges 6 nM to 30 μM with a low detection limit of 1.8 nM. And a series of experiments showed that the modified electrode exhibited good repeatability, reproducibility, and selectivity to electrochemical determination of SHI.
研究领域:
分析化学
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生物医学工程
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材料科学
✓ 已验证
DOI
高影响因子
CHINESE CHEMICAL LETTERS
·
2014
·
IF 1.178
Yan-Sha Gao,Li-Ping Wu,Kai-Xin Zhang,Jing-Kun Xu,Li-Min Lu,Xiao-Fei Zhu,Yao Wu
A simple and sensitive electroanalytical method for determination of shikonin, a widely used anti-tumoral agent, using β -cyclodextrin-functionalized multiwalled carbon nanotubes composite modified glassy carbon electrodes (MWCNTs/ β -CD/GCE) was presented. CDs are water-soluble and environmentally friendly and can improve the dispersibility of MWCNTs/ β -CD functional materials, which was confirmed by SEM. The electrochemical behaviors of shikonin on different electrodes were investigated by cyclic voltammetry (CV) and differential pulse voltammograms (DPVs). The results demonstrated that the redox peak currents of shikonin obtained at MWCNTs/ β -CD/GCE were much higher than those at the β -CD/GCE and MWCNTs/GCE, which can be attributed to the combination of the excellent electrocatalytic properties of MWCNTs and the molecular recognition ability of β -CD. At MWCNTs/ β -CD/GCE, the response current exhibits a linear range from 5.0 nmol/L to 10.0 μmol/L with a detection limit of 1.0 nmol/L (S/N = 3). As a practical application, the proposed method was applied to quantitatively determine shikoninin urine samples with satisfying results.
研究领域:
分析化学
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药理学
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材料科学
✓ 已验证
产品关联
DOI
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2017
·Vol. 175
·期 5
·840-854
·
IF 5.491
Yali Zhang,Tingting Xu,Zheer Pan,Xiangting Ge,Chuchu Sun,Chun Lu,Hongjin Chen,Zhongxiang Xiao,Bing Zhang,Yuanrong Dai,Guang Liang
Background and Purpose Acute lung injury (ALI) is a challenging clinical syndrome, which manifests as an acute inflammatory response. Myeloid differentiation protein 2 (MD2) has an important role in mediating LPS-induced inflammation. Currently, there are no effective molecular-based therapies for ALI or viable biomarkers for predicting the severity of disease. Recent preclinical studies have shown that shikonin, a natural naphthoquinone, prevents LPS-induced inflammation. However, little is known about the underlying mechanisms. Experimental Approach The binding affinity of shikonin to MD2 was analysed using computer docking, surface plasmon resonance analysis and elisa . In vitro , the anti-inflammatory effect and mechanism of shikonin were investigated through elisa , real-time quantitative reverse transcription PCR, Western blotting and immunoprecipitation assay. In vivo , lung injury was induced by intratracheal administration of LPS and assessed by changes in the histopathological and inflammatory markers. The underlying mechanisms were investigated by immunoprecipitation in lung tissue. Key Results Shikonin directly bound to MD2 and interfered with the activation of toll-like receptor 4 (TLR4) induced by LPS. In cultured macrophages, shikonin inhibited TLR4 signalling and pro-inflammatory cytokine production. These effects were produced through suppression of key signalling proteins including the NF-κB and the MAPK pathway. We also showed that shikonin inhibits MD2–TLR4 complex formation and reduces LPS-induced inflammatory responses in a mouse model of ALI. Conclusions and Implications Our studies have uncovered the mechanism underlying the biological activity of shikonin in ALI and suggest that the targeting of MD2 may prove to be beneficial as a treatment option for this condition.
研究领域:
药理学
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免疫学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Burn Care & Research
·
2025
·
IF 1.8
Deng Yuchen,Wen Chao,Wang Fang
BackgroundDespite the advancements of pharmacological treatments and gauze dressings in the field of skin wound healing, these methods present numerous limitations. Therefore, developing a multifunctional material capable of efficiently promoting skin wound healing is particularly crucial.MethodsCitric acid (CA)-modified chitosan (CS) loaded with Shikonin (SK) (CA-CS-SK) hydrogel was prepared via the freeze–thaw method. The physical properties of the hydrogel were profiled through FTIR, SEM, rotational rheometry, swelling experiment, degradation rate analysis, and drug release experiments. Furthermore, the biocompatibility of the hydrogel was comprehensively evaluated through hemolysis assay, CCK-8 cytotoxicity detection, and live/dead cell staining. Antimicrobial activity against E. coli and S. aureus of the hydrogel was gauged in vitro, and its therapeutic performance was ultimately validated in a mouse full-thickness wound model through H&E staining and ELISA.ResultsThe CA-CS-SK hydrogel exhibited appropriate rheological properties, swelling ratio, degradation rate, and drug release rate. It effectively suppressed the proliferation of E. coli and S. aureus, with superior inhibitory effects compared to CA-CS hydrogel and SK alone. Additionally, the hydrogel showed no significant toxicity to human dermal fibroblasts and did not cause erythrocyte rupture. Animal model experiments demonstrated that, compared to cotton gauze, CA-CS hydrogel, and SK, the CA-CS-SK hydrogel reduced levels of TNF-α and IL-6 at the wound site, alleviated the inflammatory response, and promoted wound healing.ConclusionThe CA-CS-SK hydrogel possesses high antibacterial activity, excellent biocompatibility, and efficient wound healing promotion capabilities, making it a highly promising material for skin wound treatment.
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PubMed
高影响因子
TOXICOLOGY LETTERS
·
2017
·
IF 3.858
Shuowen Tang,Ang Chen,Xiaojing Zhou,Li Zeng,Mingyao Liu,Xin Wang
Shikonin is a naphthoquinone pigment extracted from roots of Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae), and possesses various pharmaceutical activities, such as anti-inflammation and anti-cancer effects. In addition, shikonin as a natural red colorant for food garnishment and cosmetics ingredient is widely used in the world. However, the inhibition risk of shikonin on cytochrome P450 (CYP) remains unclear. The aim of this study was to investigate the potential inhibition of shikonin against CYP1A2, CYP2B1/6, CYP2C9/11, CYP2D1/6, CYP2E1 and CYP3A2/4 activities in human and rat liver microsomes through cocktail approach in vitro. The results demonstrated that shikonin exhibited no time-dependent inhibition of CYP activities. In human liver microsomes, shikonin was not only a mixed inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2D6 and CYP3A4, but also a competitive inhibitor of CYP2E1, with K i values no more than 7.72 μM. In rat liver microsomes, shikonin also exhibited the mixed inhibition on CYP1A2, CYP2B1, CYP2C11, CYP2D1, and the competitive inhibition on CYP2E1. Interestingly, shikonin presented an atypical kinetic inhibition of CYP3A2-mediated midazolam 1-hydroxylation in rats. In conclusion, the relatively low K i values of shikonin would have a high risk potential to cause the possible toxicity, especially drug-drug or food-drug interactions based on the potent inhibition of CYP enzymes.
研究领域:
药理学
·
毒理学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）