Anthocyanins Derived from Vitis coignetiae Pulliat Contributes Anti-Cancer Effects by Suppressing NF-κB Pathways in Hep3B Human Hepatocellular Carcinoma Cells and In Vivo.

We previously demonstrated that anthocyanins from the fruits of Vitis coignetiae Pulliat (AIMs) induced the apoptosis of hepatocellular carcinoma cells. However, many researchers argued that the concentrations of AIMs were too high for in vivo experiments. Therefore, we performed in vitro at lower concentrations and in vivo experiments for the anti-cancer effects of AIMs. AIMs inhibited the cell proliferation of Hep3B cells in a dose-dependent manner with a maximum concentration of 100 µg/mL. AIMs also inhibited the invasion and migration at 100 µg/mL concentration with or without the presence of TNF-α. To establish the relevance between the in vitro and in vivo results, we validated their effects in a Xenograft model of Hep3B human hepatocellular carcinoma cells. In the in vivo test, AIMs inhibited the tumorigenicity of Hep3B cells in the xenograft mouse model without showing any clinical signs of toxicity or any changes in the body weight of mice. AIMs inhibited the activation NF-κB and suppressed the NF-κB-regulated proteins, intra-tumoral microvessel density (IMVD) and the Ki67 activity of Hep3B xenograft tumors in athymic nude mice. In conclusion, this study indicates that AIMs have anti-cancer effects (inhibition of proliferation, invasion, and angiogenesis) on human hepatocellular carcinoma xenograft through the inhibition of NF-κB and its target protein.

Estrogen receptor α in T cells suppresses follicular helper T cell responses and prevents autoimmunity.

Estrogen receptor alpha (ERα) is a sex hormone nuclear receptor that regulates various physiological events, including the immune response. Although there have been some recent studies on ERα regarding subsets of T cells, such as Th1, Th2, Th17, and Treg cells, its role in follicular helper T (TFH) cells has not yet been elucidated. To determine whether ERα controls TFH response and antibody production, we generated T cell-specific ERα knockout (KO) mice by utilizing the CD4-Cre/ERα flox system (CD4-ERα KO) and then analyzed their phenotype. At approximately 1 year of age, CD4-ERα KO mice spontaneously showed mild autoimmunity with increased autoantibody production and CD4+CD44+CXCR5+Bcl-6+ TFH cells in the mesenteric lymph nodes and spleen. We next immunized 6-8-week-old CD4-ERα KO mice with sheep red blood cells (SRBCs), which resulted in an increased proportion of TFH cells and germinal center (GC) responses. In addition, 17ß-estradiol (E2) treatment decreased TFH responses in wild-type mice and suppressed the mRNA expression of Bcl-6 and IL-21. Finally, we confirmed that the production of high-affinity antigen-specific antibodies and isotype class switching induced by NP-conjugated ovalbumin immunization were elevated in CD4-ERα KO mice under sufficient estrogen conditions. These results collectively demonstrate that the female sex hormone receptor ERα inhibits the TFH cell response and GC reaction to control autoantibody production, which was related to estrogen signaling and autoimmunity.

Rotenoisin A is a novel anti-adipogenic compound.

The purpose of this study was to investigate the mechanisms underlying the inhibitory effects of rotenoisin A on adipogenesis in 3T3-L1 preadipocytes. 3T3-L1 cells were treated with rotenoisin A for 8 days after the induction of differentiation. Oil-red O staining showed that rotenoisin A significantly inhibited DMI-induced lipid accumulation and adipocyte differentiation. We found that rotenoisin A treatment of 3T3-L1 preadipocytes significantly reduced the mRNA and protein levels of the key adipocyte-specific transcription factors C/EBPß, C/EBPα, and PPARγ and markedly inhibited the expression of fatty acid-binding protein (aP2), fatty acid synthase (FAS), and lipoprotein lipase (LPL). Furthermore, we observed that rotenoisin A substantially increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target phosphorylated acetyl CoA carboxylase (ACC). However, co-treatment with Compound C, an AMPK inhibitor, reversed the rotenoisin A-induced inhibition of the expression of the adipogenic transcription factors C/EBPα and PPARγ and decreased the levels of phosphorylated AMPK in differentiated 3T3-L1 cells. These results demonstrated that the anti-adipogenesis mechanism involves the down-regulation of critical adipogenic transcription factors, including C/EBPß, C/EBPα, and PPARγ, through activation of the AMPK signaling pathway by rotenoisin A.

Korean Scutellaria baicalensis Georgi flavonoid extract induces mitochondrially mediated apoptosis in human gastric cancer AGS cells.

Korean Scutellaria baicalensis Georgi has been widely used in Korean folk medicines for its range of medicinal benefits, including its anticancer effect. The aim of the present study was to investigate the underlying molecular mechanism of action of a flavonoid extract from Korean Scutellaria baicalensis Georgi (FSB) on AGS human gastric cancer cells (gastric adenocarcinoma) in which FSB exhibits an anticancer effect. Treatment of AGS cells with FSB significantly inhibited cell viability in a concentration-dependent manner. Furthermore, FSB significantly increased the proportion of cells in sub-G1 phase, and Annexin V and Hoechst 33258 fluorescent staining confirmed the apoptotic cell death. Furthermore, western blotting results identified that treatment of AGS cells with FSB significantly downregulated the expression of caspase family members, namely procaspases 3 and 9, and poly(ADP-ribose) polymerase (PARP), and subsequently upregulated cleaved caspase 3 and cleaved PARP. It was observed that FSB treatment significantly decreased the mitochondrial membrane potential of AGS cells. In addition, the ratio of the mitochondrion-associated proteins B cell lymphoma 2-associated X protein and B cell lymphoma extra large was upregulated. The results of the present study provide novel insight into the underlying molecular mechanism of the anticancer effects of FSB on AGS human gastric cancer cells and indicate that FSB may be an alternative chemotherapeutic agent for the treatment of gastric cancer.

Sex-Based Selectivity of PPARγ Regulation in Th1, Th2, and Th17 Differentiation.

Peroxisome proliferator-activated receptor gamma (PPARγ) has recently been recognized to regulate adaptive immunity through Th17 differentiation, Treg functions, and TFH responses. However, its role in adaptive immunity and autoimmune disease is still not clear, possibly due to sexual differences. Here, we investigated in vitro treatment study with the PPARγ agonist pioglitazone to compare Th1, Th2, and Th17 differentiation in male and female mouse splenic T cells. Pioglitazone treatment significantly inhibited various effector T cell differentiations including Th1, Th2, and Th17 cells from female naïve T cells, but it selectively reduced IL-17 production in male Th17 differentiation. Interestingly, pioglitazone and estradiol (E2) co-treatment of T cells in males inhibited differentiation of Th1, Th2, and Th17 cells, suggesting a mechanism for the greater sensitivity of PPARγ to ligand treatment in the regulation of effector T cell differentiation in females. Collectively, these results demonstrate that PPARγ selectively inhibits Th17 differentiation only in male T cells and modulates Th1, Th2, and Th17 differentiation in female T cells based on different level of estrogen exposure. Accordingly, PPARγ could be an important immune regulator of sexual differences in adaptive immunity.

Flavonoids isolated from Citrus platymamma induced G2/M cell cycle arrest and apoptosis in A549 human lung cancer cells.

Citrus platymamma hort. ex Tanaka belongs to the Rutaceae family and is widely used in folk medicines in Korea due to its anti-proliferative, anti-cancer, anti-oxidant, anti-inflammatory and anti-diabetic activities. However, the molecular mechanism of its anti-cancer effect is not well understood. The present study was conducted to elucidate the anti-cancer effect and molecular mechanism of flavonoids from Citrus platymamma (FCP) on A549 cells. FCP displayed concentration-dependent inhibition on A549 cells proliferation. Further, flow cytometry revealed that FCP significantly increased the sub-G1 (apoptotic cell population) and G2/M phase population, and the total number of apoptotic cells, in a dose-dependent manner. Nuclear condensation and fragmentation were also observed upon staining with Hoechst 33342 in FCP-treated A549 cells. Immunoblotting demonstrated a dose-dependent downregulation of cyclin B1, cyclin-dependent kinase 1, cell division cycle 25c, pro-caspases -3, -6, -8 and -9, and poly (adenosine diphosphate-ribose) polymerase (PARP) in FCP-treated A549 cells. In addition, FCP induced caspase-3 activation and subsequent PARP cleavage, and increased the B-cell lymphoma (Bcl)-2-associated X protein/Bcl-extra large ratio in A549 cells. These findings suggest that FCP induced G2/M arrest and apoptosis of A549 cells. The present study provides evidence that FCP may be useful in the treatment of human lung cancer.

Gender-specific differences in PPARγ regulation of follicular helper T cell responses with estrogen.

Peroxisome proliferator-activated receptor gamma (PPARγ), a master regulator of adipocyte differentiation, has recently been connected with effector T cells, though its role is still not clear. Here, we investigated the roles of PPARγ in follicular helper T (TFH) cell responses regarding gender specificity. NP-OVA immunization in female but not male CD4-PPARγ(KO) mice induced higher proportions of TFH cells and germinal center (GC) B cells following immunization than were seen in wild type mice. Treatment with the PPARγ agonist pioglitazone significantly reduced TFH cell responses in female mice while pioglitazone and estradiol (E2) co-treatment ameliorated TFH cells and GC responses in male mice. E2 treatment significantly enhanced PPARγ expression in male T cells, while T cell activation in the estrus but not in the diestrus stage of the menstrual cycle of females was inhibited by pioglitazone, suggesting that an estrogen-sufficient environment is important for PPARγ-mediated T cell regulation. These results demonstrate gender-based differences in sensitivities of PPARγ in TFH responses. These findings suggest that appropriate function of PPARγ is required in the regulation of female GC responses and that therapeutic strategies for autoimmune diseases using PPARγ agonists need to be tailored accordingly.

Flavonoids of Korean Citrus aurantium L. Induce Apoptosis via Intrinsic Pathway in Human Hepatoblastoma HepG2 Cells.

Korean Citrus aurantium L. has long been used as a medicinal herb for its anti-inflammatory, antioxidant, and anticancer properties. The present study investigates the anticancer role of flavonoids extracted from C. aurantium on human hepatoblastoma cell, HepG2. The Citrus flavonoids inhibit the proliferation of HepG2 cells in a dose-dependent manner. This result was consistent with the in vivo xenograft results. Apoptosis was detected by cell morphology, cell cycle analysis, and immunoblot. Flavonoids decreased the level of pAkt and other downstream targets of phosphoinositide-3-kinase/Akt pathway - P-4EBP1 and P-p70S6K. The expressions of cleaved caspase 3, Bax, and Bak were increased, while those of Bcl-2 and Bcl-xL were decreased with an increase in the expression of Bax/Bcl-xL ratio in treated cells. Loss of mitochondrial membrane potential was also observed in flavonoid-treated HepG2 cells. It was also observed that the P-p38 protein level was increased both dose and time dependently in flavonoid-treated cells. Collectively, these results suggest that flavonoid extracted from Citrus inhibits HepG2 cell proliferation by inducing apoptosis via an intrinsic pathway. These findings suggest that flavonoids extracted from C. aurantium L. are potential chemotherapeutic agents against liver cancer.

Flavonoids isolated from Citrus platymamma induce mitochondrial-dependent apoptosis in AGS cells by modulation of the PI3K/AKT and MAPK pathways.

Citrus platymamma hort. ex Tanaka (Rutaceae family) has been widely used in Korean folk medicine for its wide range of medicinal benefits including an anticancer effect. In the present study, we aimed to investigate the molecular mechanism of the anticancer effects of flavonoids isolated from Citrus platymamma (FCP) on AGS cells. FCP treatment significantly inhibited AGS cell growth in a dose­dependent manner. Furthermore, FCP significantly increased the percentage of cells in the sub-G1 phase (apoptotic cell population), and apoptosis was confirmed by Annexin V double staining. Chromatin condensation and apoptotic bodies were also noted in the FCP-treated AGS cells. Moreover, immunoblotting results showed that FCP treatment significantly decreased the expression of procaspase-3, -6, -8 and -9, and PARP and increased cleaved caspase-3, cleaved PARP and the Bax/Bcl-xL ratio in a dose-dependent manner. In addition, the phosphorylation of AKT was significantly decreased, whereas extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) were significantly increased in the FCP-treated AGS cells. Taken together, the cell death of AGS cells in response to FCP was mitochondrial-dependent via modulation of the PI3K/AKT and MAPK pathways. These findings provide new insight for understanding the mechanism of the anticancer effects of FCP. Thus, FCP may be a potential chemotherapeutic agent for the treatment of gastric cancer.

Green Chemistry at the present in Korea.

OBJECTIVES: Despite the great contribution made by chemical substances to the development of modern civilization, their indiscriminate use has caused various kinds of damage to the global environment and human beings. Accordingly, the major developed countries and international society have tried to ensure the safe use of chemicals and a reduction in the use of hazardous chemicals through the establishment of the United Nations Environment Programme and various international agreements. In this reason, we tried to introduce about Green Chemistry progress at the present in worldwide and Korea. METHODS: We checked and analyzed relative journals, reports using keyword as like Green Chemistry, alternative chemicals, eco-friendly etc. and major country's government homepage search. RESULTS: Green Chemistry theory, which argues for the reduction or removal of harmfulness in chemicals throughout their entire life-cycle, has been spreading, and major developed countries, such as the US and Denmark, have developed and operate programs to provide reliable chemical information to help replace hazardous chemicals. Korea has also been conducting studies as like eco-innovation project. Through this project the "Alternative Chemical Search program," has been developed, distributed, and operated since 2011 to provide reliable information to small and medium-sized businesses that have difficulties collecting information to ensure conformity to international regulations. The program provides information that includes the regulations of major countries and Korea, information on 340 alternative chemicals, 70 application cases, and 1:1 consulting. CONCLUSIONS: The Alternative Chemical Search program is expected to contribute to the establishment of response systems for regulation of Korean small and medium-sized businesses, and it also will be used to provide basic data for Korean hazardous chemical regulation, together with the Act on the Registration and Evaluation, etc. of Chemical Substances and the Chemical Control act, making it possible to establish an infrastructure for Green Chemistry in Korea and to increase national competitiveness.

Naringin induces autophagy-mediated growth inhibition by downregulating the PI3K/Akt/mTOR cascade via activation of MAPK pathways in AGS cancer cells.

Naringin, one of the major bioflavonoid of Citrus, has been demonstrated as potential anticancer agent. However, the underlying anticancer mechanism still needs to be explored further. This study investigated the inhibitory effect of Naringin on human AGS cancer cells. AGS cell proliferation was inhibited by Naringin in a dose- and time-dependent manner. Naringin did not induce apoptotic cell death, determined by no DNA fragmentation and the reduced Bax/Bcl-xL ratio. Growth inhibitory role of Naringin was observed by western blot analysis demonstrating downregulation of PI3K/Akt/mTOR cascade with an upregulated p21CIPI/WAFI. Formation of cytoplasmic vacuoles and autophagosomes were observed in Naringin-treated AGS cells, further confirmed by the activation of autophagic proteins Beclin 1 and LC3B with a significant phosphorylation of mitogen activated protein kinases (MAPKs). Collectively, our observed results determined that anti-proliferative activity of Naringin in AGS cancer cells is due to suppression of PI3K/Akt/mTOR cascade via induction of autophagy with activated MAPKs. Thus, the present finding suggests that Naringin induced autophagy- mediated growth inhibition shows potential as an alternative therapeutic agent for human gastric carcinoma.

Tetraarsenic hexoxide demonstrates anticancer activity at least in part through suppression of NF-κB activity in SW620 human colon cancer cells.

Tetraarsenic hexoxide (As4O6) has been used in Korean traditional medicine for the treatment of cancer since the late 1980's, and arsenic trioxide (As2O3) is currently used as a chemotherapeutic agent. Previous studies suggest that the As4O6-induced cell death pathway is different from that of As2O3 and its mechanism of anticancer activity remains unclear. Nuclear factor (NF)-κB is a well-known transcription factor involved in cell proliferation, invasion and metastasis. Hence, in the present study, we investigated the effects of As4O6 on NF-κB activity and NF-κB-regulated gene expression in vitro and in vivo. The cytotoxicity assay revealed that As4O6 inhibited the growth of SW620 cells in a dose-dependent manner, and the half maximal inhibitory concentration (IC50) was ~1 µM after a 48 h treatment. As4O6 suppressed NF-κB activation and suppressed inhibitory κBα (IκBα) phosphorylation stimulated by tumor necrosis factor (TNF). As4O6 also suppressed downstream NF-κB-regulated proteins involved in cancer anti-apoptosis, proliferation, invasion and metastasis. In addition, As4O6 marginally suppressed tumor growth and the anti-NF-κB activity was confirmed using an in vivo xenograft mouse model in which animals were injected with SW620 cells. The present study provides evidence that As4O6 has anticancer properties through suppression of NF-κB activity and NF-κB-mediated cellular responses.

Changes in Glucose Metabolism in Vertical Sleeve Gastrectomy.

BACKGROUND: We evaluated metabolic changes after vertical sleeve gastrectomy (VSG) surgery in a rat model using proteomics and metabolomic profiling in liver and serum. METHODS: Rats were randomly divided into two groups: sham (n = 10) and VSG (n = 12). Food intake, body weight, blood glucose, insulin, and thyroid hormone levels were measured. Two-dimensional electrophoresis, nuclear resonance spectroscopy, mass spectroscopy, immunofluorescence, and immunoblot analyses were used to determine and validate changes in metabolites and proteins in liver tissue and serum samples. RESULTS: Food intake and body weight decreased after VSG group (p < 0.05 and p < 0.05, respectively). Random blood glucose (sham, 183.3 ± 5.6 mg/dL; VSG, 138.5 ± 3.7 mg/dL) decreased while random insulin (sham, 0.45 ± 0.16 µg/L; VSG, 1.05 ± 0.18 µg/L) increased after VSG (p < 0.05 and p < 0.01, respectively). We found that expressions of gluconeogenic enzymes (phosphoenolpyruvate carboxykinase-1 and glucose-6-phosphatase) and concentrations of pyruvate and malate decreased while lactate, NADH, NADPH, glucose, and AMP/ATP ratio increased after VSG. Thyroid hormones, triiodothyronine (T3) and free thyroxine (fT4), decreased after VSG. CONCLUSION: This study proves that VSG suppresses hepatic glucose production.

Functional polysaccharides from Grifola frondosa aqueous extract inhibit atopic dermatitis-like skin lesions in NC/Nga mice.

Grifola frondosa (GF), distributed widely in far east Asia including Korea, is popularly used as traditional medicines and health supplementary foods, especially for enhancing the immune functions of the body. To extend the application of GF polysaccharides (GFP) for atopic dermatitis (AD), we investigated the effects of GFP on the 2,4-dinitrochlorobenzene-induced AD-like skin lesion in NC/Nga mice. GFP treatment significantly reduced the dorsa skin dermatitis score and combination treatment with GFP, and dexamethasone has a synergistic effect in AD-like skin lesion by reduced Serum IgE, mast cells infiltration, and cytokines expression. These results indicate that GFP suppressed the AD-like skin lesions by controlling the Th-1/Th-2-type cytokines in NC/Nga mice. These findings strongly suggest that GFP can be useful for AD patients as a novel therapeutic agent and might be used for corticosteroids replacement or supplement agent.

Pramipexole protects dopaminergic neurons through paraplegin against 6-hydroxydopamine.

The neurotransmitter dopamine (DA) regulates various physiological and psychological functions, such as movement, motivation, behavior, and learning. DA exerts its function through DA receptors and a series of studies have reported the role of DAergic receptors in preventing DAergic neuronal degeneration. Here, we studied the DA receptor-mediated neuroprotective effect of the D2-like receptor agonists against 6-hydroxydopamine (6-OHDA)-induced DAergic neurodegeneration. D2-like receptor agonists were administered in the substantia nigra in vivo and to primary cultured neurons. Treatment of 6-OHDA decreased tyrosine hydroxylase (TH) and paraplegin (mitochondrial regulation protein) immunoreactivity, whereas pretreatment with quinpirole (a full D2-like receptor agonist) preserved TH and paraplegin reactivity. This led us to test which DA receptors were necessary for the neuroprotective effect and whether paraplegin can be regulated by D2 or D3 receptor agonists. Pretreatment with the D2 receptor selective agonist, sumanirole, did not preserve TH and paraplegin reactivity from 6-OHDA. However, the D3 receptor agonist, pramipexole, protected TH reactivity and restored paraplegin expression to the control level in the presence of 6-OHDA. Interestingly, pretreatment with the D3 receptor antagonist GR103691 reduced TH and paraplegin expression levels. These results suggest that the D3 receptor agonist may protect DA neurons from the effect of 6-OHDA through the modulation of the mitochondrial regulation protein paraplegin.

Proteome profiling of lipopolysaccharide induced L6 rat skeletal muscle cells response to flavonoids from Scutellaria baicalensis Georgi.

BACKGROUND: Scutellaria baicalensis Georgi is a commonly used medicinal herb in several Asian countries like Korea, China and Japan for thousands of years. It has been reported to have various medicinal properties such as anti-microbial, anti-inflammatory and anti-cancer effects. However, the anti-inflammatory mechanism of S. baicalensis G at proteome level has not yet been reported. Hence, we performed a proteome analysis to study differentially expressed proteins and its anti-inflammatory role in lipopolysaccharide (LPS) stimulated L6 skeletal muscle cells response to flavonoids isolated from S. baicalensis G. METHODS: For that, 150 µg of proteins from the L6 cells of the control (Vehicle only), LPS treated and flavonoid treated groups were separated using 18 cm, pH 4-7 IPG strips in the first dimension and resolved by 12% linear gradient SDS-polyacrylamide gel electrophoresis (SDS-PAGE). The silver stained gels were analyzed by using progenesis SameSpots software and twenty six differentially expressed protein spots (≥ 2 fold, p < 0.05) were selected for matrix assisted laser desorption ionization- time of flight mass spectroscopy/mass spectrometry (MALDI-TOF/MS) analysis. Also, the expression of COX-2, iNOS and Annexin A2 proteins were analyzed by western blot. RESULTS: Totally, 12 differentially expressed proteins were successfully identified by MALDI-TOF/MS and database searching, that's involved in inflammatory responses such vimentin, T-box transcription factor TBX3, annexin A1, annexin A2 and annexin A5. In addition, flavonoids inhibited the expression of COX-2, iNOS and Annexin A2 proteins in LPS-stimulated L6 skeletal muscle cells. CONCLUSIONS: The findings revealed that the flavonoids from S. baicalensis G. directly protect the LPS stimulated inflammation process in L6 cells and, would be helpful to study further the muscle cell inflammatory mechanism. This is the first proteome study provide the anti-inflammatory mechanism of flavonoids from S. baicalensis G. in LPS stimulated L6 skeletal muscle cells.

Morin, a flavonoid from Moraceae, suppresses growth and invasion of the highly metastatic breast cancer cell line MDA-MB­231 partly through suppression of the Akt pathway.

Morin, a flavonoid found in figs and other Moraceae, displays a variety of biological actions, such as anti-oxidant, anti-inflammatory and anti-carcinogenic. However, the anticancer effects of morin and in particular its anti-metastatic effects are not well known. Therefore, in the present study, we investigated the anticancer effects of morin on highly metastatic human breast cancer cells. Our results showed that morin significantly inhibited the colony forming ability of highly metastatic MDA-MB­231 breast cancer cells from low doses (50 µM) without cytotoxicity. In addition, morin changed MDA-MB­231 cell morphology from mesenchymal shape to epithelial shape and inhibited the invasion of MDA-MB­231 cells in a dose-dependent manner. Morin decreased matrix metalloproteinase-9 (MMP-9) secretion and expression of the mesenchymal marker N-cadherin of MDA-MB­231 cells, suggesting that morin might suppress the EMT process. Furthermore, morin significantly decreased the phosphorylation of Akt, and inhibition of the Akt pathway significantly reduced MDA-MB­231 invasion. In an in vivo xenograft mouse model, morin suppressed MDA-MB­231 cancer cell progression. Taken together, our findings suggest that morin exhibits an inhibitory effect on the cancer progression and EMT process of highly metastatic breast cancer cells at least in part through inhibiting Akt activation. This study provides evidence that morin may have anticancer effects against metastatic breast cancer.

hesperidin induces paraptosis like cell death in hepatoblastoma, HepG2 Cells: involvement of ERK1/2 MAPK [corrected].

Hesperidin, a natural flavonoid abundantly present in Citrus is known for its anti-cancer, anti-oxidant and anti-inflammatory properties. In this study we examined the effect of hesperidin on HepG2 cells. HepG2 cells treated with various concentration of hesperidin undergo a distinct type of programed cell death. Cytoplasmic vacuolization, mitochondria and endoplasmic reticulum swelling and uncondensed chromatin were observed in hesperidin treated cells. DNA electrophoresis show lack of DNA fragmentation and western blot analysis demonstrates lack of caspase activation and PARP cleavage. It was observed that hesperidin induced cell death is nonautophagic and also activate mitogen activated protein kinase ERK1/2. Taken together, the data indicate that hesperidin induces paraptosis like cell death in HepG2 cells with the activation of ERK1/2. Thus our finding suggests that hesperidin inducing paraptosis may offer an alternative tool in human liver carcinoma therapy.

Korean Scutellaria baicalensis Georgi methanol extracts inhibits metastasis via the Forkhead Box M1 activity in hepatocellular carcinoma cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis Georgi, commonly known as skullcaps, and it has been widely used as traditional therapeutic herb in several eastern Asia including Korea, China and Japan because of its remarkable anti-inflammatory and anti-cancer effects. Our study focuses on the anti-metastatic effects of Scutellaria baicalensis Georgi in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Methanol extract of Scutellaria baicalensis Georgi was examined for identification of its composition by HPLC-MS/MS. The extract was evaluated for the anti-metastasis activity using HepG2 hepatocellular carcinoma cells via immunoblotting and RT-PCR. For mechanical study, specific Forkhead Box M1 (FOXM1) vector was transfected to HepG2 cells. RESULTS: Scutellaria baicalensis Georgi potentially inhibited proliferation of HepG2 cells dose dependently. Scutellaria baicalensis Georgi decreased metastasis through the regulation of matrix metalloproteinase 2 (MMP-2) and FOXM1 activities at the transcription and translation levels. CONCLUSIONS: The results of the present study suggest that Scutellaria baicalensis Georgi could be a potent chemotherapeutic agent against HCC. Its clinical use guarantee for further study and individual flavonoids from Scutellaria baicalensis Georgi should also be investigated.