Beta-Hydroxyisovalerylshikonin

The roots of Lithosperraum erythrorhizon Sieb. et Zucc.

Simultaneous Addition of Shikonin and Its Derivatives with Lipopolysaccharide Induces Rapid Macrophage Death.[Pubmed:27251498]

Biol Pharm Bull. 2016;39(6):969-76.

Macrophages play pivotal roles in inflammatory responses. Previous studies showed that various natural products exert antiinflammatory effects by regulating macrophage activation. Recent studies have shown that shikonin (SHK) and its derivatives (Beta-Hydroxyisovalerylshikonin, acetylshikonin, and isobutylshikonin), which are 1,4-naphthoquinone pigments extracted from the roots of Lithospermum erythrorhizon, have various pharmacological, including antiinflammatory and antitumor, effects. Even though there have been many studies on the antiinflammatory activities of SHK derivatives, only a few have described their direct effects on macrophages. We investigated the effects of SHK derivatives on lipopolysaccharide (LPS)-treated macrophages. Low doses of SHK derivatives induced significant macrophage cytotoxicity (mouse macrophage-like J774.1/JA-4 cells and mouse peritoneal macrophages) in the presence of LPS. SHK activated caspases-3 and -7, which led to DNA fragmentation, but this cytotoxicity was prevented through a pan-caspase inhibitor in LPS-treated JA-4 cells. Maximal cytotoxic effects were achieved when SHK was added immediately before LPS addition. These results indicate that SHK derivatives induce caspase-dependent apoptotic cell death of LPS-treated macrophages and suggest that SHK acts during an early stage of LPS signaling.

Anti-inflammatory effects of beta-hydroxyisovalerylshikonin in BV2 microglia are mediated through suppression of the PI3K/Akt/NF-kB pathway and activation of the Nrf2/HO-1 pathway.[Pubmed:24365262]

Food Chem Toxicol. 2014 Mar;65:82-9.

In the present study, we investigated whether Beta-Hydroxyisovalerylshikonin (beta-HIVS) affects the production of proinflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2) in BV2 microglial cells. Our data showed that beta-HIVS inhibited secretion of NO and PGE2 and downregulated expression of their main regulatory genes, inducible NO synthesis (iNOS) and cyclooxygenase-2 (COX-2). beta-HIVS also reduced the LPS-induced DNA-binding activity of nuclear factor-kappaB (NF-kappaB) by suppressing nuclear translocation of the NF-kappaB subunits and inhibiting the degradation and phosphorylation of IkappaBalpha. Furthermore, an NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), attenuated LPS-stimulated iNOS and COX-2 expression, suggesting that NF-kappaB inhibition is a main effector in the expression of iNOS and COX-2. We also found that LPS-induced NF-kappaB activation is regulated through inhibition of PI3K/Akt phosphorylation in response to beta-HIVS. Additionally, beta-HIVS caused the induction of heme oxygenase-1 (HO-1) via upregulation of nuclear factor-erythroid 2-related factor 2 (Nrf2), both of which are involved in the secretion of proinflammatory mediators such as NO and PGE2. Taken together, our data indicate that beta-HIVS diminishes the proinflammatory mediators NO and PGE2 and the expression of their regulatory genes, iNOS and COX-2, in LPS-stimulated BV2 microglial cells by inhibiting PI3K/Akt-dependent NF-kappaB activation and inducing Nrf2-mediated HO-1 expression.

In vitro and in vivo anticancer effects of Lithospermum erythrorhizon extract on B16F10 murine melanoma.[Pubmed:22995444]

J Ethnopharmacol. 2012 Nov 21;144(2):335-45.

ETHNOPHARMACOLOGICAL RELEVANCE: Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases including skin cancer. In this study, hexane extract from the roots of Lithospermum erythrorhizon (LEH) was chemically characterized and its anticancer activity was tested against the most aggressive form of skin cancer. MATERIALS AND METHODS: The in vitro anticancer studies viz. cell growth, cell cycle and apoptosis, and the expression of tumor regulating proteins were analyzed against B16F10 melanoma cells. In addition, C57BL/6 mice models were used to evaluate the in vivo anticancer potential of LEH. Mice were intraperitoneally injected with LEH at doses of 0.1 and 10mg/kg every 3 days. The tumor inhibition ratio was determined after 21 days of treatment and the histopathological analyses of the tumor tissues were compared. Further, LEH was purified and its active compounds were structurally elucidated and identified by NMR spectra and quantified by HPLC analyses. RESULTS: LEH effectively inhibits the growth of melanoma cells with an IC(50) of 2.73mug/ml. Cell cycle analysis revealed that LEH increased the percentage of cells in sub-G1 phase by dose dependent manner. LEH exhibited down regulation of anti-apoptotic Bcl-2 family proteins and up regulation of apoptotic Bax protein expression. Importantly, LEH induced cleavage of poly (ADP-ribose) polymerase (PARP) and activated the caspase cascade (caspase 3) with this cleavage mediating the apoptosis of B16F10 cells. LEH treatment at a dose of 10mg/kg for 21 days in experimental mice implanted with tumors resulted in significant reduction of the tumor growth (43%) and weight (36%). Histopathology analysis of LEH treated tumor tissues showed evidence of increased necrotic cells in a concentration dependent manner. Meanwhile, five naphthoquinone compounds [Shikonin (1); Deoxyshikonin (2); Beta-Hydroxyisovalerylshikonin (3); Acetylshikonin (4) and Isobutyrylshikonin (5)] were purified from LEH and responsible for its anticancer activity. CONCLUSION: LEH induced apoptosis in B16F10 cells by activation of caspase 3 and inducing sub-G1 cell cycle arrest. LEH exhibited both in vitro and in vivo anticancer activity. Shikonin derivatives in the LEH are responsible for the anticancer activity.

Anti-neoplastic effect of beta-hydroxyisovalerylshikonin on a human choriocarcinoma cell line.[Pubmed:21472272]

Mol Med Rep. 2010 May-Jun;3(3):515-8.

Beta-Hydroxyisovalerylshikonin (beta-HIVS), a compound isolated from the traditional asian medicinal herb Lithospermum radix, is an ATP non-competitive inhibitor of protein-tyrosine kinases such as v-Src and EGFR, and has been shown to induce apoptosis in several human tumor cell lines. We investigated the effect of beta-HIVS in the choriocarcinoma cell line, BeWo. BeWo cells were treated with various concentrations of beta-HIVS, and changes in cell growth, the cell cycle, apoptosis, and related parameters were examined. An MTT assay showed that BeWo cells were sensitive to the growth inhibitory effect of beta-HIVS. Cell cycle analysis indicated that exposure to beta-HIVS decreased the proportion of cells in the S phase and increased the proportion in the G0/G1 phases of the cell cycle. Induction of apoptosis was confirmed by Annexin V staining of externalized phosphatidylserine and by the loss of mitochondrial transmembrane potential. This induction occurred in conjunction with the altered expression of genes related to cell growth, malignant phenotype, and apoptosis. These results suggest that beta-HIVS may serve as a therapeutic agent for the treatment of choriocarcinoma.

AMPK and SREBP-1c mediate the anti-adipogenic effect of beta-hydroxyisovalerylshikonin.[Pubmed:26865314]

Int J Mol Med. 2016 Mar;37(3):816-24.

Beta-Hydroxyisovalerylshikonin (beta-HIVS), which is a natural naphthoquinone compound, is one of the main chemicals isolated from a therapeutic plant, Lithospermum erythrorhizon. In the present study, we demonstrated that beta-HIVS inhibited the adipogenesis of 3T3-L1 cells through AMP-activated protein kinase (AMPK)-mediated modulation of sterol regulatory element binding protein (SREBP)1c. The anti-adipogenic effect of beta-HIVS was accompanied by the increased phosphorylation of AMPK and precursor SREBP1c. In beta-HIVS-treated 3T3-L1 cells, AMPK was activated and phosphorylated precursor SREBP1c, preventing the cleavage of precursor SREBP1c to mature SREBP1c. Expression of the fat-forming enzymes, acetyl-CoA carboxylase (ACC)1, fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD)1, which are transcribed by mature SREBP1c, were downregulated, resulting in reduced intracellular fat accumulation. The anti-adipogenic effect of beta-HIVS was significantly attenuated by AMPK knockdown. Knockdown of AMPK using siRNA decreased the phosphorylation of precursor SREBP1c and increased the levels of mature SREBP. The levels of the fat-forming enzymes, ACC1, FAS and SCD1, as well as intracellular fat accumulation were also significantly increased by AMPK knockdown. These results suggest that beta-HIVS activated AMPK, which was followed by the downregulation of mature SREBP1c and fat-forming enzymes, leading to the inhibition of adipogenesis.

Antibacterial and cytotoxic activities of naphthoquinone pigments from Onosma visianii Clem.[Pubmed:28435429]

EXCLI J. 2017 Feb 16;16:73-88.

In this study, the antibacterial and cytotoxic activities of isolated compounds from the roots of Onosma visianii were investigated. By using different chromatographic techniques and appropriate spectroscopic methods, the seven naphthoquinones were described: deoxyshikonin ( 1 ), isobutyrylshikonin ( 2 ), alpha-methylbutyrylshikonin ( 3 ), acetylshikonin ( 4 ), Beta-Hydroxyisovalerylshikonin ( 5 ), 5,8-O-dimethyl isobutyrylshikonin ( 6 ) and 5,8-O-dimethyl deoxyshikonin ( 7 ). Among the tested compounds, 3 and 4 exhibited the highest antibacterial activities toward all tested bacterial species (MIC50 and MIC90 for gram positive bacteria: 6.40 mug/mL-12.79 mug/mL and 6.82 mug/mL-13.60 mug/mL, respectively; for gram negative bacteria: 4.27 mug/mL-8.53 mug/mL and 4.77 mug/mL-9.54 mug/mL, respectively). Also, naphthoquinones 3 and 4 exhibited strong cytotoxic activity against MDA-MB-231 cells (IC50 values 86.0 mug/mL and 80.2 mug/mL, respectively), while compounds 1 , 3 , 4 and 5 significantly decreased viability of HCT116 cells (IC50 values of 97.8 mug/mL, 15.2 mug/mL, 24.6 mug/mL and 30.9 mug/mL, respectively). Our results indicated that all tested naphthoquinone pigments are potential candidates for clinical uses as antibacterial and cytotoxic agents.

Beta-hydroxyisovalerylshikonin is a natural product isolated from Lithospermium radix, acts as a potent inhibitor of protein tyrosine kinases (PTK), with IC50s of 0.7μM and 1μM for EGFR and v-Src receptor, respectively. Beta-hydroxyisovalerylshikonin is effective against a wide variety of tumor cell lines, and most efficiently induces cell-death in NCI-H522 and DMS114 cells.

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