• BMB Reports
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• v.56 no.4
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• pp.246-251
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• 2023

Obesity increases the risk of mortality and morbidity because it results in hypertension, heart disease, and type 2 diabetes. Therefore, there is an urgent need for pharmacotherapeutic drugs to treat obesity. We performed a screening assay using natural products with anti-adipogenic properties in 3T3-L1 cells and determined that tschimganidine, a terpenoid from the Umbelliferae family, inhibited adipogenesis. To evaluate the anti-obesity effects of tschimganidine in vivo. Mice were fed either a normal chow diet (NFD) or a high-fat chow diet (HFD) with or without tschimganidine for 12 weeks. Treatment with tschimganidine decreased lipid accumulation and adipogenesis, accompanied by reduced expression of adipogenesis and lipid accumulation-related factors. Tschimganidine significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and decreased that of AKT. Depletion of AMPK relieved the reduction in lipid accumulation resulting from tschimganidine treatment. Moreover, tschimganidine administration drastically reduced the weight and size of both gonadal white adipose tissue (WAT) and blood glucose levels in high-fat diet-induced obese mice. We suggest that tschimganidine is a potent anti-obesity agent, which impedes adipogenesis and improves glucose homeostasis. Tschimganidine can then be evaluated for clinical application as a therapeutic agent.

• Herbal Formula Science
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• v.31 no.4
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• pp.231-243
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• 2023

Objectives : Jasminum officinale L. var. grandiflorum is used as a traditional or folk remedy in China to treat arthritis, hepatitis, duodenitis, conjunctivitis, gastritis, and diarrhea. In this study, we aimed to study the hepatocyte protective activity and molecular mechanism of Jasminum officinale L. var. grandiflorum aqueous extract (JGW) using HepG2 hepatocyte cell lines. Methods : HepG2 cells were pretreated with diverse concentrations of JGW, and then the cells were exposed to tert-butyl hydroperoxide (tBHP) for inducing oxidative stress. Hydrogen peroxide (H₂O₂) production, glutathione (GSH) concentration, mitochondrial membrane potential (MMP) and cell viability were measured to investigate hepato-protective effects of JGW. Phosphorylation of AMP-activated protein kinases (AMPK), acetyl coenzyme A carboxylase (ACC) and effects of compound C on cell viability were examined to observe the role of AMPK on JGW-mediated cytoprotection. Results : Pretreatment with JGW (10-300 ㎍/mL) significantly suppressed cytotoxicity induced by tBHP in a concentration dependent manner and reduced the expression of cleaved PARP and cleaved caspase-3 proteins related to apoptosis in HepG2 cells. In addition, pretreatment with JGW significantly prevented the increase in H₂O₂ production, GSH depletion, and lower MMP induced by tBHP. Treatment with JGW (30 minutes of incubation and concentrations of 100 and 300 ㎍/mL) increased the phosphorylation of AMPK and ACC and treatment with compound C, a chemical inhibitor of AMPK, inhibited the cytoprotective effect of JGW. Conclusions : Our results demonstrated that JGW may protect hepatocytes from oxidative stress via activation of AMPK.

• BMB Reports
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• v.45 no.9
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• pp.489-495
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• 2012

Ischemia is a blockage of blood supply due to an embolism or a hemorrhage in a blood vessel. When an organ cannot receive oxygenated blood and can therefore no longer replenish its blood supply due to ischemia, stresses, such as the disruption of blood glucose homeostasis, hypoglycemia and hypoxia, activate the AMPK complex. LKB1 and $CaMKK{\beta}$ are essential activators of the AMPK signaling pathway. AMPK triggers proangiogenic effects through the eNOS protein in tissues with ischemic conditions, where cells are vulnerable to apoptosis, autophagy and necrosis. The AMPK complex acts to restore blood glucose levels and ATP levels back to homeostasis. This review will discuss AMPK, as well as its key activators (LKB1 and $CaMKK{\beta}$), as a central energy regulator and evaluate the upstream and downstream regulating pathways of AMPK. We will also discuss how we can control this important enzyme in ischemic conditions to prevent harmful effects in patients with vascular damage.

• The Korean Journal of Physiology and Pharmacology
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• v.21 no.3
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• pp.279-286
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• 2017

The root bark extract of Aralia taibaiensis is used traditionally for the treatment of diabetes mellitus in China. The total saponin extracted from Aralia Taibaiensis (sAT) has effective combined antihyperglycemic and hypolipidemic activities in experimental type 2 diabetic rats. However, the active compounds have not yet been fully investigated. In the present study, we examined effects of twelve triterpenoid saponins on AMP-activated protein kinase (AMPK) activation, and found that compound 28-O-${\beta}$-D-glucopyranosyl ester (AT12) significantly increased phosphorylation of AMPK and Acetyl-CoA carboxylase (ACC). AT12 effectively decreased blood glucose, triglyceride (TG), free fatty acid (FFA) and low density lipoprotein-cholesterol (LDL-C) levels in the rat model of type 2 diabetes mellitus (T2DM). The mechanism by which AT12 activated AMPK was subsequently investigated. Intracellular ATP level and oxygen consumption were significantly reduced by AT12 treatment. The findings suggested AT12 was a novel AMPK activator, and could be useful for the treatment of metabolic diseases.

• Journal of Physiology & Pathology in Korean Medicine
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• v.27 no.6
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• pp.764-770
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• 2013

Stevia rebaudiana is a traditional herb used as a sweetener in Brazil and Paraguay as well as Korea and China. This study investigated the efficacy of Stevia rebaudiana methanol extract (SRE) to protect cells against the mitochondrial dysfunction and apoptosis in hepatocyte. To determine the effects of SRE on oxidative stress, we used the human derived hepatocyte cell line, HepG2 cell. Treatment of arachidonic acid (AA)+iron in HepG2 cells synergistically amplified cytotoxicity, as indicated by the excess reactive oxygen species (ROS) and mitochondrial permeability transition by fluorescence activated cell sorter (FACS) and immunoblot analysis. Treatment with SRE protected hepatocytes from AA+iron-induced cellular toxicity, as shown by alterations in the protein levels related with cell viability such as procaspase-3. SRE also prevented the mitochondrial dysfunction induced by AA+iron, and showed anti-oxidant effects as inhibition of $H_2O_2$ production and GSH depletion. Moreover, we measured the effects of SRE on AMP-activated protein kinase (AMPK), a key regulator in determining cell survival or death. Acetyl-CoA Carboxylase (ACC), a direct downstream target of AMPK. SRE increased phosphorylation of ACC, and prevented the inhibition of ACC phosphorylation by AA+iron. These results indicated that SRE has the ability to protect cells against AA+iron-induced $H_2O_2$ production and mitochondrial impairment, which may be mediated with AMPK-ACC pathway.

• Journal of Physiology & Pathology in Korean Medicine
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• v.28 no.1
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• pp.59-62
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• 2014

Glucose uptake plays a pivotal role in maintaining whole body glucose homeostasis in adipocytes and skeletal muscles. In the present study we have shown that Fructus Piperis Longi Extracts (FPLE) can stimulate glucose uptake in OP9 adipocytes. The increasing effects of FPLE on glucose uptake were inhibited by compound C pretreatment, which means that the glucose uptake effects by FPLE were carried out by AMP-activated protein kinase (AMPK) activation. Further studies revealed that FPLE stimulated glucose transport occurs through a mechanism involving extracellular signal-regulated kinase (ERK1/2) activation.

• The Korea Journal of Herbology
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• v.37 no.2
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• pp.1-11
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• 2022

Objectives : Although the anti-obesity effect of Schizandrae Fructus water extract has been demonstrated, its underlying mechanism is still unclear. Therefore, we aimed to evaluate the anti-obesity effect of Schizandrae Fructus water extract through the p-AMP-activated protein kinase (p-AMPK), sirtuin1 (Sirt1), and peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) signaling in 60% high-fat diet (HFD)-induced obese mouse model. Methods : Male C57BL/6 mice were divided into four groups. The Normal group was fed a normal diet and the obese groups were fed 60% HFD. Except for the Control group, the GG group was supplemented with 0.5% Garcinia gummigutta and the SCW group was supplemented with 0.5% Schizandrae Fructus water extract. After 6 weeks, obesity-related biomarkers in serum were measured and the expressions of protein for lipid-related factors in liver tissue were analyzed by western blot. Results : Treatment with SCW significantly down-regulated body weight compared to the Control group. SCW down-regulated levels of triglyceride and total cholesterol in serum and significantly increased p-AMPK, Sirt1, and PGC-1α in liver tissue. In addition, the expressions of fatty acid oxidation-related proteins such as peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase 1A (CPT-1A), uncoupling protein 1 (UCP1), and uncoupling protein 3 (UCP3) were significantly up-regulated. However, fatty acid synthesis-related proteins including sterol regulatory element-binding protein-1 (SREBP-1), phospho-Acetyl-CoA Carboxylase (p-ACC), and fatty acid synthase (FAS) were significantly down-regulated. Conclusions : Taken together, SCW treatment showed anti-obesity effect by regulating both fatty acid oxidation-related and fatty acid synthesis-related proteins through AMPK/Sirt1/PGC-1α signaling in 60% HFD-induced obese mice.

• Molecular & Cellular Toxicology
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• v.5 no.4
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• pp.298-303
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• 2009

(-)-Epigallocatechin-3-gallate (EGCG), a major flavonoid in green tea has multiple health benefits including chemoprevention, anti-inflammatory, anti-diabetic, and anti-obesity effects. In connection with these effects, EGCG can be a candidate to help the treatment of metabolic diseases. Metformin is a widely used anti-diabetic drug regulating cellular energy homeostasis via AMP-activated protein kinase (AMPK) activation. Therefore, the combination of metformin with EGCG may have additive or synergistic effects on treatment of type 2 diabetes. Nevertheless, there is no report for the pharmacokinetic and/or pharmacodynamic interaction of EGCG with metformin. Here, we evaluated the pharmacokinetic and pharmacodynamic interaction between metformin and EGCG in rats. Pharmacokinetics parameters of metformin were measured after oral administration of metformin in rats pre-treated with EGCG (10 mg/kg) or saline for 7 days. The results showed that there is no significant difference in pharmacokinetic parameters between saline control and EGCG-treated group. In addition, the hepatic AMPK activation by metformin in EGCG-treated rats was also similar to the control. The lack of additive effects of EGCG on AMPK activation or intracellular uptake of metformin was also evaluated in cells in the presence or absence of EGCG. Treatment of HepG2 cells with EGCG inhibited the metformin-induced AMPK activation. Combined results suggested that EGCG has no effect on the pharmacokinetics of metformin but may contribute to metformin action.

• Journal of Korean Medicine Rehabilitation
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• v.28 no.3
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• pp.13-25
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• 2018

Objectives We investigated anti-obesity effects of essential oils extracted from Cnidii Rhizoma (CR) in immature adipocytes to magnify it's clinical therapeutic usage. Methods Essential oil of CR was extracted with ethyl acetate or petroleum ether and through steam distillation, respectively. Oil red-O staining for monitoring its inhibition effect on adipogenesis and differentiation in murine 3T3-L1 adipocytes and 3-(4,5-methylthiazol-2-yl)-2,5-diphenyletetra zolium bromide (MTT) assay for cell safety were done. Also phospho-adenosine monophosphate (AMP)-activted protein kinase (P-AMPK), AMP-activated protein kinase, phospho-acetyl-CoA carboxylase (P-ACC), acetyl-CoA carboxylase, peroxisome proliferator-activated receptor-${\alpha}$ (PPAR-${\alpha}$), peroxisome proliferator-activated receptor-${\gamma}$ (PPAR-${\gamma}$) and CCAAT/enhancer binding protein ${\alpha}$ (C/EBP-${\alpha}$) expressions as obesity-related factors were measured by western blot analysis. Results Protein expressions of P-AMPK, P-ACC and PPAR-${\alpha}$ were increased in essential oils-treated adipocytes compared to those of control group, respectively. Furthermore, protein expressions of PPAR-${\gamma}$ and C/EBP-${\alpha}$ were decreased in essential oils-treated adipocytes compared to those of control group, respectively. Conclusions These results demonstrate that essential oils of CR inhibit adipogenesis and differentiation. Also they promote the oxidation of fatty acids in adipocytes. Thus, results suggest that essential oils of CR could be used as a valuable material for anti-obesity therapeutics via control of lipid metabolism.

• The Korea Journal of Herbology
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• v.36 no.6
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• pp.39-46
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• 2021

Objectives : AMP-activated protein kinase (AMPK) is a key metabolic regulator that reduces lipogenesis. AMPK is mainly activated via phosphorylation of liver kinase B (LKB) 1 under energy stress. Here, we highlighted the anti-obesity effect and underlying mechanism of Coix lacryma-jobi var. mayuen Stapf sprout water extract (CSW) sprout extract in connection with the LKB1/AMPK signaling pathway. Methods : C57BL/6 mice (20~25 g) fed HFD to induce obesity and at the same time administered CSW 100 mg/kg (CSWL; (CSWL; CSW low concentration) or CSW 200 mg/kg (CSWH; CSW high concentration) or Garcinia extract (Garcinia) 200 mg/kg orally for 6 weeks. Body weight and food intake were measured at the same time each day. After 6 weeks of CSW administration, liver tissue and serum were obtained through an autopsy. After the end of the experiment, biochemical analysis (triglycerides (TG), total cholesterol (TC), HDL-cholesterol, and LDL-cholesterol) was performed on the serum. And then, protein levels related to TG and TC synthesis were measured through western blot analysis in liver tissue. Results : As a result, serum TG, TC, and LDL-cholesterol levels were significantly increased in the control group and significantly decreased in the CSW administration group. On the other hand, the HDL-cholesterol level was increased in the CSW-administered group. And as a result of Western blot analysis, CSW significantly increased the phosphorylation of LKB1 & AMPK, and remarkably decreased the expression of factors related to TG and TC synthesis. Conclusions : Our findings suggest that CSW influences the TG and TC synthesis to positively affect HFD-induced obesity in C57BL/6 mice.