The fruits of Swietenia macrophylla King have been processed commercially to a variety of health foods and healthcare products and exhibited antidiabetic, antiinflammatory, antimutagenicity, antitumor activity, and so on. This study was aimed to examine the glucose consumption in human hepatoma HepG2 cells and the expression of PPARγ of limonoids isolated from the fruits of S. macrophylla.The phytochemical investigation of the fruits led to the isolation of ten limonoids which structures were elucidated by spectroscopic analysis as swietenine (1), khayasin T (2), 6-deoxyswietenine (3), 3-O-tigloylswietenolide (4), swietenolide (5), 3,6-O,O-diacetylswietenolide (6), 7-deacetoxy-7-oxogedunin (7), fissinolide (8), proceranolide (9), 7-deacetoxy-7α-hydroxygedunin (10), and compound 10 was isolated from this plant for the first time. The glucose consumption assay revealed that compounds 1, 2, 3, 5, and 9 could promote glucose consumption significantly in normal hyperglycemia-induced HepG2 cells, furthermore, compounds 1, 5, and 9 had a better effect on promoting glucose consumption in insulin-resistant HepG2 cells. In addition, compounds 1 and 5 could dramatically enhance the expression of PPARγ protein in insulin-resistant HepG2 cells according to the western blotting analysis result.How to cite this article: Duan J-Y, Wang Y-J, Chen W, et al.Limonoids isolated from fruits of Swietenia macrophylla king enhance glucose consumption in insulin-resistant HepG2 cells via activating PPARγ.

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Oxidative stress is an important factor that causes pancreatic β‐cell dysfunction leading to the development and aggravation of diabetes. Swietenine (Stn) and swietenolide (Std) were isolated from the fruits of Swietenia macrophylla King and had the potential effects on treatment and prevention of diabetes. The aim of this study is to investigate the effects of Stn and Std on insulin secretion and apoptosis in H2O2 induced insulinoma cell line (INS‐1) cells. In the present study, INS‐1 cells were treated with 300 μM H2O2 for 4 h to establish the oxidative damage model. Cell apoptosis, insulin secretion, reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels, and Caspase‐3 enzyme activity were measured via corresponding methods. Finally, pancreatic duodenal home box factor‐1 (PDX‐1), B cell lymphoma‐2 (Bcl‐2), and Bax protein expression were detected by western blot. Experimental results showed that Stn and Std could significantly improve the INS‐1 cell viability, increase the secretion of insulin and reduce the ROS level in H2O2 induced INS‐1 cells. Furthermore, the SOD and GSH levels increased, and the MDA levels decreased compared with the model group after Stn and Std treatment. In addition, after treated with Stn and Std, cell apoptosis was improved, and the activity of Caspase 3 was also significantly inhibited. Meanwhile, Western blot results showed that Stn and Std could up‐regulate the expression of PDX‐1 protein, and affect the cell apoptosis pathway by up‐regulating the expression of Bcl‐2 protein and down‐regulating the expression of Bax protein. In conclusion, Stn and Std can signifcantly improve the insulin secretion function, protect oxidative stress injury, and reduce apoptosis in H2O2 induced INS‐1 cells, which provides a research basis for Stn and Std to be new drug candidates for the treatment and prevention of diabetes.

Hypericum patulum has been used as a folk medicine for its varied therapeutic effects including antifungal, wound‐healing, spasmolytic, stimulant, hypotensive activities. The water decoction is drank as tea could treat cold, infantile malnutrition. The present study aims to isolate the constituents of the plant and investigate their effects on the glucose consumption in insulin‐resistant HepG2 cells, furthermore, lipid metabolism in oleic acid (OA)‐treated HepG2 cells was also studied. The phytochemical investigation of the plant led to the isolation of eleven compounds, and their structures were identified by spectroscopic analysis as n‐dotriacontanol (1), shikimic acid (2), 1‐O‐caffeoylquinic acid methyl ester (3), 5‐O‐caffeoylquinic acid methyl ester (4), 5‐O‐coumaroylquinic acid methyl ester (5), 5‐O‐caffeoylquinic acid butyl ester (6), quercetin‐3‐O‐α‐L‐rhamnoside (7), quercetin (8), quercetin‐3‐O‐(4״‐methoxy)‐α‐L‐rahmnopyranosyl (9), hyperoside (10), and rutin (11). The results revealed that compounds 7, 9, and 10 could enhance glucose consumption significantly in hyperglycemia induced HepG2 cells and insulin‐resistant HepG2 cells. In addition, the western blotting analysis result exhibited that compounds 7, 9, and 10 in high concentration (5 μM, H) group could dramatically upregulate the expression of PPARγ protein, and even the effect of them had no significant difference compared with that of rosiglitazone. Furthermore, compounds 9 and 10 in middle concentration (2.5 μM, M) group and H group could dramatically promote triglyceride metabolism and decrease TG content in OA‐treated HepG2 cells, and even in H group, reactive oxygen species (ROS) level were significantly decreased compared with model group. Practical applications Hypericum patulum is a well‐known plant of the genera Hypericum for its varied preventive and therapeutic potential activities. To study the chemical constituents and their effects on glucose and lipid metabolism in vitro, we detected glucose consumption in insulin‐resistant HepG2 cells, triglyceride content and reactive oxygen species level in OA‐treated HepG2 cells. In addition, PPARγ protein was also detected by western blotting analysis in the study. Compounds 1, 2, 3, 5, 6, 9, 10, and 11 were isolated from the plant for the first time. Quercetin‐3‐O‐(4"‐methoxy)‐α‐L‐rahmnopyranosyl (9) and hyperoside (10) had potential therapeutic benefit against glucose and lipid metabolic disease. Therefore, this study might have certain guiding significance for further research and development of H. patulum.

Swietenia macrophylla King, belongs to the Meliaceae family, is a valuable medicinal plant and its fruits have been processed commercially to a variety of health foods. The seeds have long been known for their ethnomedicinal significance against these diseases. Swietenine (Swi) was isolated from S. macrophylla and could ameliorate inflammation and oxidative stress. In this study, HepG2 cells induced by H2O2 were used to construct oxidative stress model in vitro. The aim of this study was to investigate the protective effect of Swi on H2O2 induced oxidative injury in HepG2 cells and its molecular mechanism, and to explore the effect of Swi on liver injury in db/db mice and its possible mechanism. The results showed that Swi significantly inhibited HepG2 cells viability and reduced oxidative damage in a dose‐dependent manner as evidenced by a range of biochemical analysis and immunoblotting study. Moreover, it induced the protein and mRNA expression of HO‐1 together with its upstream mediator Nrf2 and activated the phosphorylation of AKT in HepG2 cells. LY294002, a PI3K/AKT inhibitor, significantly suppressed the Nrf2 nuclear translocation and HO‐1 expression in H2O2 induced HepG2 cells treated with Swi. In addition, RNA interference with Nrf2 significantly reduced the expression level of Nrf2 and HO‐1 in the nucleus. Swi has a significant protective effect on cell damage in H2O2 induced HepG2 cells by increasing the antioxidant capacity which is achieved through the AKT/Nrf2/HO‐1 pathway. Additionally, in vivo, Swi could protect the liver of type 2 diabetic mice by improving lipid deposition in liver tissue and inhibiting oxidative stress. These findings indicated that Swi can be a promising dietary agent to improve type 2 diabetes.