Wogonin induces cell cycle arrest and erythroid differentiation in imatinib-resistant K562 cells and primary CML cells
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// Hao Yang 1,* , Hui Hui 1,* , Qian Wang 1 , Hui Li 1 , Kai Zhao 1 , Yuxin Zhou 1 , Yu Zhu 3 , Xiaotang Wang 2 , Qidong You 1 , Qinglong Guo 1 and Na Lu 1 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, People’s Republic of China 2 Department of Chemistry and Biochemistry, Florida International University, Miami, FL, USA 3 Department of Hematology, The First Affiliated Hospital of Nanjing Medical University; Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu Province, People’s Republic of China * These authors contributed equally to this work Correspondence: Qing-Long Guo, email: // Na Lu, email: // Keywords : wogonin; CML; GATA-1; differentiation; cell cycle Received : May 15, 2014 Accepted : August 09, 2014 Published : August 10, 2014 Abstract Wogonin, a flavonoid derived from Scutellaria baicalensis Georgi, has been demonstrated to be highly effective in treating hematologic malignancies. In this study, we investigated the anticancer effects of wogonin on K562 cells, K562 imatinib-resistant cells, and primary patient-derived CML cells. Wogonin up-regulated transcription factor GATA-1 and enhanced binding between GATA-1 and FOG-1, thereby increasing expression of erythroid-differentiation genes. Wogonin also up-regulated the expression of p21 and induced cell cycle arrest. Studies employing benzidine staining and analyses of cell surface markers glycophorin A (GPA) and CD71 indicated that wogonin promoted differentiation of K562, imatinib-resistant K562, and primary patient-derived CML cells. Wogonin also enhanced binding between GATA-1 and MEK, resulting in inhibition of the growth of CML cells. Additionally, in vivo studies showed that wogonin decreased the number of CML cells and prolonged survival of NOD/SCID mice injected with K562 and imatinib-resistant K562 cells. These data suggested that wogonin induces cycle arrest and erythroid differentiation in vitro and inhibits proliferation in vivo .Keywords:
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Of 266 Chinese crude drugs, the hot water extract from the root of Scutellaria baicalensis showed potent mouse liver sialidase inhibitory activity; in addition, wogonin, wogonin glucuronide, baicalein, and baicalin were identified as the inhibitors. These flavonoids showed almost the same inhibitory activity when 50-125 micrograms/ml doses of the samples were used for the assay, while wogonin and baicalein showed a more potent activity than wogonin glucuronide and baicalin at the lower concentration (10 micrograms/ml). However, these flavonoids, except wogonin, showed negligible inhibitory activity against Arthrobacter ureafaciens sialidase. These results indicated that S. baicalensis extract contains the sialidase inhibitors which are specific to mouse liver sialidase.
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High-performance liquid chromatographic procedure was established for the quantitative method of flavonoids in Scutellaria root ("Huangqin", the root of Scutellaria baicalensis GEORGI). Eleven flavonoids, baicalein (I), baicalin (II), baicalein 7-O-glucoside (III), oroxylin A (IV), oroxylin A 7-O-glucuronide (V), wogonin (VI), wogonin 7-O-glucuronide (VII), chrysin (VIII), skullcapflavone II (IX), 5, 7, 2', 6'-tetrahydroxyflavanone (X) and dihydrooroxylin A (XI), were separated by the combined use of both operating conditions of 1 and 2 shown in Fig. 2 and 3, respectively. This method is considered to be useful for the chemical evaluation of commercially available Scutellaria root.
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Wogonin, a flavonoid isolated from Scutellaria baicalensis, has attracted increasing scientific attention in recent years because of its potent anti-tumor activity. Its role during viral infection has largely been unexplored. Wogonin treatment effectively suppressed both influenza A and B virus replication in Madin-Darby Canine Kidney (MDCK) cells and human lung epithelial (A549) cells. In contrast, wogonin treatment following influenza A virus infection led to up-regulation of interferon (IFN)-induced antiviral signaling. Additionally, influenza A virus infection in A549 cells induced 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and activation in a time-dependent manner and wogonin treatment led to the suppression of AMPK phosphorylation. Furthermore, the treatment with AMPK-specific inhibitor (compound C; CC) attenuated influenza A virus replication. These data suggest that wogonin possesses a potent anti-influenza activity mediated by regulation of AMPK activation, suggesting that wogonin has the potential to be developed as an anti-influenza drug.
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Objective: To study the change rule of dynamic accumulation of biennial Scutellaria baicalensis growth and development and active component in Chengde regions.Method: Took samples once every fifteen days from 1 May to 15 October 2008 and recorded the phenophase.Using high performance liquid chromatographic method to measure the content of baicalin,baicalein and wogonin,and using ultraviolet spectrophotometry to measure its flavonoids content.Result: The general growth rule of aerial parts of biennial S.baicalensis in Chengde regions was slow-fast-slow.Which was in vegetative growth two times.The general growth rule of root was fast-slow-fast,which had highest drying rate on 55.31%.The changes of content of baicalin and flavonoids were similar,which the highest content was at middle May,and the data were 17.61% and 42.92%.The changes of content of baicalein and wogonin were similar,which the highest content was at at June,and the data were 2.63% and 0.49%.Conclusion: The highest content of baicalin and flavonoids in biennial S.baicalensis which was grown in Chengde regions was at middle May.The highest content of wogonin and flavonoids was at June.The highest drying rate was in early and middle October.
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The growing interest in skin lightening has recently renewed attention on the esthetic applications of Chinese herbal medicine. Although Scutellaria baicalensis Georgi is used for antipyretic and antiinflammatory purposes, its whitening effect remains unclear. This study reports three major findings: (1) S. baicalensis has a potent inhibitory effect on melanogenesis; (2) wogonin and its glycoside are the active components of S. baicalensis; and (3) O-methylated flavones from S. baicalensis, such as wogonin, inhibit intracellular melanosome transport. Using a melanin quantification assay, we showed that S. baicalensis potently inhibits melanogenesis in B16F10 cells. Componential analyses revealed that the main components of S. baicalensis are baicalin, wogonoside, baicalein, wogonin, and oroxylin A. Among these five flavones, wogonin and wogonoside consistently inhibited melanogenesis in both B16F10 melanoma cells and primary melanocytes. Wogonin exhibited the strongest inhibition of melanin production and markedly lightened the color of skin equivalents. We identified microphthalmia-associated transcription factor and tyrosinase-related proteins as potential targets of wogonin- and wogonoside-induced melanogenesis suppression. In culture, we found that the melanosomes in wogonin-treated B16F10 cells were localized to the perinuclear region. Immunoblotting analyses revealed that wogonin significantly reduced in melanophilin protein, which is required for actin-based melanosome transport. Other actin-based melanosome transport-related molecules, i.e., Rab27A and myosin Va, were not affected by wogonin. Cotreatment with MG132 blocked the wogonin-induced decrease in melanophilin, suggesting that wogonin promotes the proteolytic degradation of melanophilin via the calpain/proteasomal pathway. We determined that the structural specificities of the mono-O-methyl group in the flavone A-ring and the aglycone form were responsible for reducing melanosome transport. Furthermore, wogonin and two wogonin analogs, mono-O-methyl flavones, strongly suppressed melanosome transport. Our findings suggest the applicability of S. baicalensis in the esthetic field. Thus, we propose a novel pharmacologic approach for the treatment of hyperpigmentation.
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By using an HBV-producing cell line (MS-G2) in vitro culture system, we found that wogonin isolated from Scutellaria baicalensis can suppress HBV surface antigen production (P < 0.001) without evidence of cytotoxicity. By assaying the endogenous HBV DNA polymerase activity, we found that both the relaxed circular and the linear forms of HBV DNA are significantly reduced in the wogonin-treated group. Wogonin deserves to be further evaluated for the treatment of human HBV infection.
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Scutellaria baicalensis Georgi (SB) is the medicinal plants mainly used in traditional Chinese medicine. It has been used for the treatment of various chronic inflammatory syndromes including respiratory disease, fever and gastric ulcer in traditional Eastern medicine and its major components; baicalin, baicalein and wogonin; were reported to have various biological effects. The aim of this study was to isolate the neuroprotective flavones from the root of S. baicalensis (SB) by bioactivity-guided fractionation of S. baicalensis methanol extract (SBME). Neuroprotective effect of isolated flavones, namely was studied on global ischemic model in rat by 4-VO. SBME was fractionated with different solvent and resulting fractions were administered at a dose of 25 mg/kg to the rat and potent neuroprotective fractions were sub-fractionated. At a dose of 10 mg/kg, isolated compounds, wogonin, and baicalein inhibited the hippocampal neuronal cell death by 78.6% and 81.0% respectively. Our study suggested that SB and its isolated flavones have potential neuroprotective effect and these findings may be one of the alternative therapies for the management of stroke and other neurodegenerative diseases. DOI: http://dx.doi.org/10.3126/jnpa.v27i1.12144 Journal of Nepal Pharmaceutical Association 2014 Vol.XXVII: 1-8
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Scutellaria baicalensis Georgi has been used for the treatment of chronic inflammatory syndromes including respiratory disease, fever and gastric ulcer in traditional Eastern medicine and its major components; baicalin, baicalein and wogonin; were reported to have various biological effects. In this study, we compared the neuroprotective effect of four isolated flavones form the root of S. baicalensis on global ischemic model in rat by 4-vessel occlusion method. S. baicalensis methanol extract was administered at a dose of 100mg/kg whereas four flavones namely, wogonin, baicalein, wogonoside and baicalin were orally administered at a dose of 10mg/kg. The viable pyramidal neurons were counted in the CA1 portion of hippocampus approximately +3.3, 3.5 and 3.7mm caudal to the bregma. At a dose of 10mg/kg, isolated compounds, wogonin, baicalein, wogonoside and baicalin inhibited the hippocampal neuronal cell death by 78.6%, 91.0%, 81.0% and 41.0% respectively whereas S. baicalensis methanol extract inhibited the neuronal cell death by 92% (p<0.001). There was no significant difference in the neuroprotective effect of wogonin, wogonoside and baicalein with that of S. baicalensis methanol extract. Our study suggested that S. baicalensis and its isolated flavones have potential neuroprotective effect and these findings may be one of the alternative therapies for the management of stroke.
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