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Insulin resistance contributes to several disorders including type 2 diabetes and cardiovascular diseases. Carpachromene is a natural active compound that inhibits α-glucosidase enzyme. The aim of the present study is to investigate the potential activity of carpachromene on glucose consumption, metabolism and insulin signalling in a HepG2 cells insulin resistant model. A HepG2 insulin resistant cell model (HepG2/IRM) was established. Cell viability assay of HepG2/IRM cells was performed after carpachromene/metformin treatment. Glucose concentration and glycogen content were determined. Western blot analysis of insulin receptor, IRS1, IRS2, PI3k, Akt, GSK3, FoxO1 proteins after carpachromene treatment was performed. Phosphoenolpyruvate carboxykinase (PEPCK) and hexokinase (HK) enzymes activity was also estimated. Viability of HepG2/IRM cells was over 90% after carpachromene treatment at concentrations 6.3, 10, and 20 µg/mL. Treatment of HepG2/IRM cells with carpachromene decreased glucose concentration in a concentration- and time-dependant manner. In addition, carpachromene increased glycogen content of HepG2/IRM cells. Moreover, carpachromene treatment of HepG2/IRM cells significantly increased the expression of phosphorylated/total ratios of IR, IRS1, PI3K, Akt, GSK3, and FoxO1 proteins. Furthermore, PEPCK enzyme activity was significantly decreased, and HK enzyme activity was significantly increased after carpachromene treatment. The present study examined, for the first time, the potential antidiabetic activity of carpachromene on a biochemical and molecular basis. It increased the expression ratio of insulin receptor and IRS1 which further phosphorylated/activated PI3K/Akt pathway and phosphorylated/inhibited GSK3 and FoxO1 proteins. Our findings revealed that carpachromene showed central molecular regulation of glucose metabolism and insulin signalling via IR/IRS1/ PI3K/Akt/GSK3/FoxO1 pathway.

Epidemiological studies have suggested that coffee consumption is associated with a decrease in the risk of developing obesity and diabetes; however, the detailed mechanisms underlying these effects of coffee consumption remain poorly understood. In this study, we examined the effects of chlorogenic acid on energy metabolism in vitro. Hepatocellular carcinoma G2 (HepG2) cells were cultured in a medium containing chlorogenic acid. Chlorogenic acid increased the activity of mitochondrial enzymes, including citrate synthase, isocitrate dehydrogenase, and malate dehydrogenase (MDH), which are involved in the tricarboxylic acid (TCA) cycle. Proteome analysis using the isobaric tags for the relative and absolute quantitation (iTRAQ) method revealed the upregulation of proteins involved in the glycolytic system, electron transport system, and ATP synthesis in mitochondria. Therefore, we propose a notable mechanism whereby chlorogenic acid enhances energy metabolism, including the TCA cycle, glycolytic system, electron transport, and ATP synthesis. This mechanism provides important insights into understanding the beneficial effects of coffee consumption.

Cyanidin-3-O-glucoside (C3G) is a natural anthocyanin abundant in fruits and vegetables that interacts and possibly modulates energy metabolism and oxidative stress. This study investigated the effect of C3G on gluconeogenesis and cancer cell senescence. C3G activates adenosine monophosphate-activated protein kinase (AMPK), a cellular energy sensor involved in metabolism and the aging process. C3G suppressed hepatic gluconeogenesis by reducing the expression of gluconeogenic genes through the phosphorylation inactivation of CRTC2 and HDAC5 coactivators via AMPK. C3G did not directly interact with AMPK but, instead, activated AMPK through the adiponectin receptor signaling pathway, as demonstrated through adiponectin receptor gene knockdown experiments. In addition, C3G increased cellular AMP levels in cultured hepatocytes, and the oral administration of C3G in mice elevated their plasma adiponectin concentrations. These effects collectively contribute to the activation of AMPK. In addition, C3G showed potent antioxidant activity and induced cellular senescence, and apoptosis in oxidative-stress induced senescence in hepatocarcinoma cells. C3G increased senescence-associated β-galactosidase expression, while increasing the expression levels of P16, P21 and P53, key markers of cellular senescence. These findings demonstrate that anthocyanin C3G achieves hypoglycemic effects via AMPK activation and the subsequent suppression of gluconeogenesis and exhibits anti-cancer activity through the induction of apoptosis and cellular senescence.

Supramolecular vesicles are a novel class of nanocarriers that have great potential in biomedicine. A multifunctional supramolecular vesicle (CAAP5G) based on the complex of CAAP5 and galactose derivative (G) assembled via host-guest interaction was constructed. Using Human embryonic kidney T (293T) cells as experimental models, the cytotoxic effects of CAAP5G was investigated to 0-50 µmol/L for 24 h. Notably, the CAAP5G vesicles revealed low-toxicity to 293T cells, it was critical to designing drug nano-carriers. Simultaneously, we have evaluated doxorubicin hydrochloride (DOX)-loaded CAAP5G vesicles anticancer efficiency, where DOX-loaded CAAP5G vesicles and free DOX incubated with Human hepatocellular carcinoma cancer cell (HpeG2 cells) and 293T cells for 24 h, 48 h, 72 h. It turned out that CAAP5G vesicles encapsulated anticancer drug (DOX) could decrease DOX side-effect on 293T cells and increase DOX anticancer efficiency. More importantly, the cysteamine as an adjuvant chemotherapy drug was released from CAAP5G vesicles in HepG2 cells where a higher GSH concentration exists. The adjuvant chemotherapy efficiency was evaluated, where free DOX and DOX-loaded CAAP5G vesicles incubated with DOX-resistance HepG2 cells (HepG2-ADR cells) for 24, 48, 72 h, respectively. The results revealed that the DOX encapsulated by CAAP5G vesicles could enhance the cytotoxicity of DOX and provide insights for designing advanced nano-carriers toward adjuvant chemotherapies.

This study aimed to investigate the effect of ethylacetate extract from (EET) on the proliferation and apoptosis of HepG2 and SMMC-7721 cells and determine the underlying mechanisms. HepG2 and SMMC-7721 cells were cultured in vitro until the exponential growth phase and then treated with different concentrations of EET for 24 h. We performed a colony forming assay to determine colony forming ability, CCK8 assay to detect cell proliferation, Annexin V-FITC/PI double staining to analyze cell apoptosis, and Western blot to measure the protein expression of Caspase-3, Bcl-2, and Bax. EET significantly inhibited the proliferation of HepG2 and SMMC-7721 cells in a concentration- and time-dependent manner ( <0.05). After treatment with 0, 50, 100, 150, 200, and 250 μg/mL EET for 24 h, HepG2 the proliferation rates were 100.00%±0.00%, 90.33%±1.76%, 67.67%±0.88%, 47.33%±0.88%, 37.00%±0.00%, and 30.33%±0.67%, respectively, and 100.00%±0.00%, 18.25%±1.05%, 19.99%±0.59%, 23.42%±0.46%, 29.70%±0.79%, and 29.8%±0.41% for SMMC-7721 cells, respectively. After treatment with 0, 50, 100, 150, 200, and 250 μg/mL EET for 24 h, the apoptotic rates were 11.08%±0.72%, 27.44%±0.51%, 32.92%±0.41%, 26.20%±0.47%, 22.92%±0.24%, and 55.60%±0.08%, for HepG2 cells, respectively, and 59.18%±0.17%, 41.24%±2.05%, 52.54%±0.39%, 50.54%±1.08%, and 57.44%±1.93% for SMMC-7721 cells, respectively. Compared with the treatment groups, the control group showed a significantly lower apoptotic rate (47.91%±1.09%, <0.05). EET at the different concentrations downregulated the protein expression of Caspase-3 in HepG2 cells and upregulated it in SMMC-7721 cells; it also downregulated the protein expression of Bcl-2 in HepG2 and SMMC-7721 cells and upregulated the protein expression of Bax in HepG2 and SMMC-7721 cells. These findings suggest that EET exerts antiproliferative and proapoptotic effects against HepG2 and SMMC-7721 cells mediated by downregulation or upregulation of Caspase-3 expression. Our study may help to develop EET for the pharmacological treatment of hepatoblastoma or hepatocellular carcinoma.

The present study evaluated the effects of Sophora flavescens Ait. root extract on the proliferation of human hepatoma cell line HepG2. HPLC-UV analysis showed that the highest matrine and oxymatrine contents were obtained in the chloroform extract, compared to ethanol extract and ethyl acetate extract. The morphological analysis revealed that the chloroform extract of Sophora flavescens Ait. (SFA-CHCl3 extract) induced alterations of HepG2 cell morphology, resulting in the shrinkage of cells, the formation of debris, and cell detachment. The proliferation of HepG2 cells was inhibited by SFA-CHCl3 extract treatment. Cell cycle analysis exhibited that the cell proportion of the G0/G1 phase of HepG2 cells with SFA-CHCl3 extract treatment was decreased, while the cell proportion of the G2/M phase was increased. Flow cytometry analysis indicated a dramatic increase in the apoptotic percentage of HepG2 cells over the time of SFA-CHCl3 extract treatment. The SFA-CHCl3 extract also caused morphological changes in HepG2 nuclear, including chromatin condensation and DNA fragmentation. SFA-CHCl3 extract treatment induced the bax up-regulation and the bcl-2 down-regulation in HepG2 cells. These results revealed that SFA-CHCl3 extract could be a potential apoptosis inducer in HepG2 cells.

Human-hepatoblastoma-derived cell line, HepG2, has been widely used in liver and liver cancer studies. HepG2 spheroids produced in a three-dimensional (3D) culture system provide a better biological model than cells cultured in a two-dimensional (2D) culture system. Since cells at the center of spheroids exhibit specific behaviors attributed to hypoxic conditions, a 3D cell culture system that allows the observation of such cells using conventional optical or fluorescence microscopes would be useful. In this study, HepG2 cells were cultured in “Cell Dome”, a micro-dome in which cells are enclosed in a cavity consisting of a hemispherical hydrogel shell. HepG2 cells formed hemispherical cell aggregates which filled the cavity of Cell Domes on 18 days of culture and the cells could continue to be cultured for 29 days. The cells at the center of hemispherical cell aggregates were observed using a fluorescence microscope. The cells grew in Cell Domes for 18 days exhibited higher Pi-class Glutathione S-Transferase enzymatic activity, hypoxia inducible factor-1α gene expression, and higher tolerance to mitomycin C than those cultured in 2D on tissue culture dishes (* p < 0.05). These results indicate that the center of the glass adhesive surface of hemispherical cell aggregates which is expected to have the similar environment as the center of the spheroids can be directly observed through glass plates. In conclusion, Cell Dome would be useful as an evaluation platform for organized HepG2 cells.

The aim of the present study was a comparative investigation of water and 70% ethanol extracts derived from yellow and red onion (Allium cepa L.) peels against diabetes and diabetic complications. The total phenolic contents (TPCs) and total flavonoid contents (TFCs) of each cultivar, measured to assess phytochemical characteristics, showed a direct correlation with the in vitro antioxidant effects. Among the two captives, the yellow onion peel extract showed higher antioxidant activity than red one. However, all extracts exhibited significant protein tyrosine phosphatase 1B (PTP1B) inhibitory activity (IC50; 0.30–0.86 μg/ml), showing water extracts more potent (IC50; approximately 0.3 μg/mL), than the 70% ethanol extracts (IC50; approximately 0.8 μg/ml). Similarly, in insulin‐resistant HepG2 cells, all extracts enhanced the glucose uptake and reduced the expression of PTP1B in a concentration‐dependent manner, water extract displaying better activity. Our results overall suggest that in vitro antioxidant and antidiabetic potentials vary among red and yellow cultivars and extracting solvents, which could therefore be a promising strategy to prevent diabetes and associated complications. The present study provides an insight into the bioactivity of waste onion peel toward diabetes and diabetic complications. Furthermore, the varying degree of TPC and TFC in different solvent extracts of two cultivars was compared and correlated with their potency. Overall result of the present study demonstrated onion peel as good food source to prevent diabetes and diabetic complications.

HepG2 cells are an inexpensive hepatocyte model that can be used for repeated experiments, but HepG2 cells do not express major cytochrome P450s (CYPs) and UDP glucuronosyltransferase family 1 member A1 (UGT1A1). In this study, we established CYP3A4–POR–UGT1A1–CYP1A2–CYP2C19–CYP2C9–CYP2D6 (CYPs–UGT1A1) knock-in (KI)-HepG2 cells using a PITCh system to evaluate whether they could be a new hepatocyte model for pharmaceutical studies. To evaluate whether CYPs–UGT1A1 KI-HepG2 cells express and function with CYPs and UGT1A1, gene expression levels of CYPs and UGT1A1 were analyzed by using real-time PCR, and metabolites of CYPs or UGT1A1 substrates were quantified by HPLC. The expression levels of CYPs and UGT1A1 in the CYPs–UGT1A1 KI-HepG2 cells were comparable to those in primary human hepatocytes (PHHs) cultured for 48 h. The CYPs and UGT1A1 activity levels in the CYPs–UGT1A1 KI-HepG2 cells were much higher than those in the wild-type (WT)-HepG2 cells. These results suggest that the CYPs–UGT1A1 KI-HepG2 cells expressed functional CYPs and UGT1A1. We also confirmed that the CYPs–UGT1A1 KI-HepG2 cells were more sensitive to drug-induced liver toxicity than the WT-HepG2 cells. CYPs–UGT1A1 KI-HepG2 cells could be used to predict drug metabolism and drug-induced liver toxicity, and they promise to be a helpful new hepatocyte model for drug discovery research.

Micro/nanocolloidal is confirmed as a self‐assembly structure in big eye tuna (Thunnus obesus) head soup, and lipids enriched with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the major component. In this study, the effect of big eye tuna head soup (BETHS) with different particle size micro/nanocolloidal on lipid accumulation was initially evaluated. The original soup and microfiltration soup (with or without ginger; OGS/OGSG and MFS/MFSG) were prepared firstly. A free fatty acid‐exposed (FFA‐exposed) HepG2 cell model was built using sodium oleic acid (OA) and sodium palmitic acid (PA) (2:1). The triglyceride (TG) and total cholesterol (TC) in the FFA‐exposed HepG2 cells were 8.6 ng/104 cells and 0.6 nM/104 cells, respectively, which were significantly different with control (p < .05). Both OGS and OGSG could significantly decline the TG deposition of FFA‐exposed HepG2 cells with 31% and 40% (p < .05), and in MFS and MFSG were 23% and 26% (p ≥ .05). Meanwhile, OGS inhibited the deposition of TG mainly in 18–24 hr, and OGSG mainly in 12–18 hr. All the BETHS samples showed no inhibition effect on TC deposition (p ≥ .05). This research might help to understand the improving activity of natural or traditional food products on metabolic syndrome. Big eye tuna head soup (BETHS) with 30% ginger had cytotoxicity on HepG2 cells. BETHS with larger micro/nano particles (MNPs) improved TG deposition (p < .05). Adding ginger promoted the TG deposition improvement of origin BETHS.