• Journal of Integrative Natural Science
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• v.8 no.1
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• pp.40-47
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• 2015

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that has recently emerged as a promising target in drug discovery. It is involved in multiple cellular processes and associated with the pathogenesis of several diseases. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis was performed on a series of GSK-3 inhibitors to understand the structural basis for inhibitory activity. Comparative molecular field analysis (CoMFA) method was used to derive 3D-QSAR models. A reliable CoMFA model was developed using ligand-based alignment scheme. The model produced statistically acceptable results with a cross-validated correlation coefficient ($q^2$) of 0.594 and a non-cross-validated correlation coefficient ($r^2$) of 0.943. Robustness of the model was checked by bootstrapping and progressive scrambling analysis. This study could assist in the design of novel compounds with enhanced GSK-3 inhibitory activity.

• BMB Reports
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• v.35 no.3
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• pp.283-290
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• 2002

The glycogen-associated protein phosphatase (PP1G/$R_{GL}$) may play a central role in the hormonal control of glycogen metabolism in the skeletal muscle. Here, we investigated the in vivo epinephrine effect of glycogen metabolism in the skeletal muscle of the wild-type and $R_{GL}$ knockout mice. The administration of epinephrine increased blood glucose levels from 200±20 to 325±20 mg/dl in both wild-type and knockout mice. Epinephrine decreased the glycogen synthase -/+ G6P ratio from 0.24±0.04 to 0.10±0.02 in the wild-type, and from 0.17±0.02 to 0.06±0.01 in the knockout mice. Conversely, the glycogen phosphorylase activity ratio increased from 0.21±0.04 to 0.65±0.07 and from 0.30±0.04 to 0.81±0.06 in the epinephrine trated wild-type and knockout mice respectively. The glycogen content of the knockout mice was substantially lower (27%) than that of both wild-type mice; and epinephrine decreased glycogen content in the wild-type and knockout mice. Also, in Western blot analysis there was no compensation of the other glycogen targeting components PTG/R5 and R6 in the knockout mice compared with the wild-type. Therefore, $R_{GL}$ is not required for the epinephrine stimulation of glycogen metabolism, and rather another phosphatase and/or regulatory subunit appears to be involved.

• The Korean Journal of Physiology and Pharmacology
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• v.26 no.1
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• pp.59-65
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• 2022

Phosphorylation levels of glycogen synthase kinase 3β (GSK3β) negatively correlated with psychomotor stimulant-induced locomotor activity. Locomotor sensitization induced by psychomotor stimulants was previously shown to selectively accompany the decrease of GSK3β phosphorylation in the nucleus accumbens (NAcc) core, suggesting that intact GSK3β activity in this region is necessary for psychomotor stimulants to produce locomotor sensitization. Similarly, GSK3β in the NAcc was also implicated in mediating the conditioned effects formed by the associations of psychomotor stimulants. However, it remains undetermined whether GSK3β plays a differential role in the two sub-regions (core and shell) of the NAcc in the expression of drug-conditioned behaviors. In the present study, we found that GSK3β phosphorylation was significantly lower in the NAcc shell obtained from rats expressing amphetamine (AMPH)-induced conditioned locomotor activity. Further, we demonstrated that these effects were normalized by treatment with lithium chloride, a GSK3β inhibitor. These results suggest that the behavior produced by AMPH itself and a conditioned behavior formed by associations with AMPH are differentially mediated by the two sub-regions of the NAcc.

• Journal of Yeungnam Medical Science
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• v.12 no.2
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• pp.319-330
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• 1995

The influence of normal late pregnancy on insulin action and insulin secretion was studied in the Sprague-Dawley female rats. On 20th day after mating, intravenous glucose tolerance test(IVGTT) was performed in non pregnant control and pregnant rats. As results of IVGTT, glucose disappearance rate was not significantly different in both groups, but secretory response of insulin was significantly(p<0.05) increased in pregnant rat. And the ratio of insulin/glucose was significantly higher in pregnant rats, which means existence of insulin resistance. These insulin resistance was overcomed by increased secretory response of pancreatic insulin. Insulinogenic index(${\Delta}$ insulin/glucose - 5 min) was highly significantly (r=0.62, p<0.01) correlated with progesterone concentration. Glycogen level and amounts of $^{14}C$-glucose incorporated into glycogen after IVGTT were significantly(p<0.05) decreased in the liver, but were not changed significantly in soleus. Glycogen synthase activity of soleus and liver was not differ significantly in the both groups. Insulin binding at varying concentrations of insulin to crude membrane of pregnant liver was not significantly different from control. In conclusions, although these pregnant rats were normal glucose tolerance due to increased secretory response of insulin, that was correlated with progesterone concentration, pregnant rat had insulin resistance. The mechanisms of insulin resistance were not related to defect of insulin binding phase and glycogen synthase, but suggest pre-receptor and/or postreceptor phase.

• Journal of Nutrition and Health
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• v.35 no.8
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• pp.825-833
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• 2002

The effects of dietary supplementation of Eleutherococcus senticosus, taurine and carnitine on maximal endurance exercise performance along with other related parameters were evaluated in rats that underwent aerobic exercise training for 6 weeks. Thirty-two male rats (4 weeks old) were randomly divided into 4 groups, and fed experimental diets and/or aerobic exercise trained according to the protocol: SC (sedentary control group), EC (exercise-trained control group), EE (exercise-trained Eleutherococcus senticosus-supplemented group), and EETC (exercise-trained Eleutherococcus senticosus, taurine and carnitine-supplemented group). The food efficiency ratio of EC rats was significantly lower than the value for SC rats (p < 0.01). Exercise-trained control animals (92 $\pm$ 8.8 min) could run significantly longer until exhausted on the treadmill than sedentary control rats (11 $\pm$ 0.8 min) (p < 0.001). Animals fed an Eleutherococcus senticosus-supplemented diet, and an Eleuthherococcus sonticosus, taurine and carnitine- supplemented diet while undergoing aerobic exercise training for 6 weeks exhibited, respectively, 8 and 5 minutes longer running performance until exhausted than the rats fed the control diet. The gastrocnemius muscle glycogen concentration of the rats, measured at 48 hours post maximal exercise performance test, was 43% higher in EC rats than the value for SC rats (p < 0.05), but was not different among EC, EE, and EETC rats. The mitochondrial citrate synthase activity of the soleus muscle was significantly higher in EC rats compared to the value for SC rats (p < 0.01), and showed a tendency to increase, without statistical significance, in EE or EETC rats compared to the value for EC rats. These results indicate that aerobic exercise training for 6 weeks significantly improved maximal exercise performance, muscle glycogen content along with citrate synthase activity, which are important in the energy metabolism of muscle under aerobic exercise. Dietary supplementation of Eleutherococcus senticosus in rats while undergoing aerobic exercise training improved maximal endurance exercise performance without significantly affecting muscle glycogen content and enzyme activities involved in energy metabolism during exercise. Taurine and carnitine supplementation failed to show an additive effect on maximal endurance exercise performance when consumed along with Eleutherococcus senticosus.

• Nutrition Research and Practice
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• v.11 no.3
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• pp.180-189
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• 2017

BACKGROUND/OBJECTIVES: Recent living condition improvements, changes in dietary habits, and reductions in physical activity are contributing to an increase in metabolic syndrome symptoms including diabetes and obesity. Through such societal developments, humankind is continuously exposed to metabolic diseases such as diabetes, and the number of the victims is increasing. This study investigated Cordyceps militaris water extract (CMW)-induced glucose uptake in HepG2 cells and the effect of CMW treatment on glucose metabolism. MATERIALS/METHODS: Colorimetric assay kits were used to determine the glucokinase (GK) and pyruvate dehydrogenase (PDH) activities, glucose uptake, and glycogen content. Either RT-PCR or western blot analysis was performed for quantitation of glucose transporter 2 (GLUT2), hepatocyte nuclear factor 1 alpha ($HNF-1{\alpha}$), phosphatidylinositol 3-kinase (PI3k), protein kinase B (Akt), phosphorylated AMP-activated protein kinase (pAMPK), phosphoenolpyruvate carboxykinase, GK, PDH, and glycogen synthase kinase 3 beta ($GSK-3{\beta}$) expression levels. The ${\alpha}-glucosidase$ inhibitory activities of acarbose and CMW were evaluated by absorbance measurement. RESULTS: CMW induced glucose uptake in HepG2 cells by increasing GLUT2 through $HNF-1{\alpha}$ expression stimulation. Glucose in the cells increased the CMW-induced phosphorylation of AMPK. In turn, glycolysis was stimulated, and glyconeogenesis was inhibited. Furthermore, by studying the mechanism of action of PI3k, Akt, and $GSK-3{\beta}$, and measuring glycogen content, the study confirmed that the glucose was stored in the liver as glycogen. Finally, CMW resulted in a higher level of ${\alpha}-glucosidase$ inhibitory activity than that from acarbose. CONCLUSION: CMW induced the uptake of glucose into HepG2 cells, as well, it induced metabolism of the absorbed glucose. It is concluded that CMW is a candidate or potential use in diabetes prevention and treatment.

• Korean Journal of Exercise Nutrition
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• v.24 no.2
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• pp.1-5
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• 2020

[Purpose] Lactate has several beneficial roles as an energy resource and in metabolism. However, studies on the effects of oral administration of lactate on fat metabolism and glycogen synthesis are limited. Therefore, the purpose of the present study was to investigate how oral administration of lactate affects fat metabolism and glycogen synthesis factors at specific times (0, 30, 60, 120 min) after intake. [Methods] Male Sprague Dawley (SD) rats (n = 24) were divided into four groups as follows: the control group (0 min) was sacrificed immediately after oral lactate administration; the test groups were administered lactate (2 g/kg) and sacrificed after 30, 60, and 120 min. Skeletal muscle and liver mRNA expression of GLUT4, FAT/CD36, PDH, CS, PC and GYS2 was assessed using reverse transcription-polymerase chain reaction. [Results] GLUT4 and FAT/CD36 expression was significantly increased in skeletal muscle 120 min after lactate administration. PDH expression in skeletal muscle was altered at 30 and 120 min after lactate consumption, but was not significantly different compared to the control. CS, PC and GYS2 expression in liver was increased 60 min after lactate administration. [Conclusion] Our results indicate that exogenous lactate administration increases GLUT4 and FAT/CD36 expression in the muscle as well as glycogen synthase factors (PC, GYS2) in the liver after 60 min. Therefore, lactate supplementation may increase fat utilization as well as induce positive effects on glycogen synthesis in athletes.

• Korean Journal of Food Science and Technology
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• v.33 no.5
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• pp.619-625
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• 2001

We determined whether the supplementation of Polygonatum Odoratum (Mill) Druce (POD) extract had a good effect on insulin resistance in peripheral tissues of 90% pancreatectomized (Px) and sham-operated (Sham) male Sprague Dawley rats. Px and Sham rats were divided into two groups; one group daily consumed 0.3 g of POD extracts per 1 ㎏ body weight for two months, and the other group had a placebo. All rats freely consumed a 40% fat diet. At the end of the experiment, a euglycemic hyperinsulinemic (EH) clamp was performed in a fasting, awake, and unstressed state to determine insulin resistance. At EH clamp, body weights were higher in Sham rats than Px rats, and serum glucose levels of baseline were affected by diabetic status and POD administration. Serum insulin concentrations were higher in Sham rats than Px rats, and POD administration decreased them in Sham rats compared to P. Glucose disposal rates in peripheral tissues increased with POD in both Px (n=10) and Sham (n=10) rats. But glycogen deposits in soleus muscle increased with POD administration in Px and Sham rats, and total glycogen synthase activity and fraction velocity were higher in POD groups. Triglyceride contents in quadriceps muscles decreased with POD in Px rats. In conclusions, POD improves insulin resistance by enhancing glucose utilization with increasing glycogen deposit and decreasing triglyceride contents in muscles.

• BMB Reports
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• v.48 no.5
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• pp.283-288
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• 2015

We found that resveratrol enhances interferon (IFN)-γ-induced tryptophanyl-tRNA-synthetase (TTS) expression in bone marrow-derived dendritic cells (BMDCs). Resveratrol-induced TTS expression is associated with glycogen synthase kinase-3β (GSK-3β) activity. In addition, we found that resveratrol regulates naive CD8⁺ T-cell polarization by modulating GSK-3β activity in IFN-γ-stimulated BMDCs, and that resveratol induces upregulation of TTS in CD8⁺ T-cells in the in vivo tumor environment. Taken together, resveratrol upregulates IFN-γ-induced TTS expression in a GSK-3β-dependent manner, and this TTS modulation is crucial for DC-mediated T-cell modulation. [BMB Reports 2015; 48(5): 283-288]

• The Korean Journal of Physiology and Pharmacology
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• v.15 no.2
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• pp.107-114
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• 2011

Neurofibrillary tangle (NFT) is a characteristic hallmark of Alzheimer's disease. GSK3β has been reported to play a major role in the NFT formation of tau. Dysfunction of autophagy might facilitate the aggregate formation of tau. The present study examined the role of GSK3${\beta}$-mediated phosphorylation of tau species on their autophagic degradation. We transfected wild type tau (T4), caspase-3-cleaved tau at Asp421 (T4C3), or pseudophosphorylated tau at Ser396/Ser404 (T4-2EC) in the presence of active or enzyme-inactive GSK3${\beta}$. Trehalose and 3-methyladenine (3-MA) were used to enhance or inhibit autophagic activity, respectively. All tau species showed increased accumulation with 3-MA treatment whereas reduced with trehalose, indicating that tau undergoes autophagic degradation. However, T4C3 and T4-2EC showed abundant formation of oligomers than T4. Active GSK3${\beta}$ in the presence of 3-MA resulted in significantly increased formation of insoluble tau aggregates. These results indicate that GSK3${\beta}$-mediated phosphorylation and compromised autophagic activity significantly contribute to tau aggregation.