• Journal of Life Science
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• v.23 no.6
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• pp.736-742
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• 2013

Achyranthoside E dimethyl ester (AEDE) is an oleanolic acid glycoside from Achyranthes japonica. In this study, we investigated the effects of AEDE on nitric oxide (NO) production and underlying molecular mechanisms in lipopolysaccharide (LPS)-stimulated macrophages. AEDE inhibited LPS-induced NO secretion as well as inducible NO synthase (iNOS) expression, without affecting cell viability. Further study demonstrated that AEDE induced heme oxygenase-1 (HO-1) gene expression. In addition, the inhibitory effects of AEDE on iNOS expression were abrogated by small interfering RNA-mediated knock-down of HO-1. Moreover, AEDE induced nuclear translocation of nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates HO-1 expression. AEDE-induced expression of HO-1 was inhibited by inhibitors of phosphatidylinositol 3-kinase (PI-3K) and extracellular signal regulated kinase (ERK1/2). AEDE phosphorylated Akt and ERK1/2 as well. Therefore, these results suggest that AEDE suppresses the production of pro-inflammatory mediator such as NO by inducing HO-1 expression via PI-3K/Akt/ERK-Nrf2 signaling. These findings provide the scientific rationale for anti-inflammatory therapeutic use of AEDE.

• Journal of Microbiology and Biotechnology
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• v.33 no.12
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• pp.1635-1647
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• 2023

Muscle atrophy, which is defined as a decrease in muscle mass and strength, is caused by an imbalance between the anabolism and catabolism of muscle proteins. Thus, modulating the homeostasis between muscle protein synthesis and degradation represents an efficient treatment approach for this condition. In the present study, the protective effects against muscle atrophy of ethanol extracts of Morus alba L. (MA) and Angelica keiskei Koidz. (AK) leaves and their mixtures (MIX) were evaluated in vitro and in vivo. Our results showed that MIX increased 5-aminoimidazole-4-carboxamide ribonucleotide-induced C2C12 myotube thinning, and enhanced soleus and gastrocnemius muscle thickness compared to each extract alone in dexamethasone-induced muscle atrophy Sprague Dawley rats. In addition, although MA and AK substantially improved grip strength and histological changes for dexamethasone-induced muscle atrophy in vivo, the efficacy was superior in the MIX-treated group. Moreover, MIX further increased the expression levels of myogenic factors (MyoD and myogenin) and decreased the expression levels of E3 ubiquitin ligases (atrogin-1 and muscle-specific RING finger protein-1) in vitro and in vivo compared to the MA- and AK-alone treatment groups. Furthermore, MIX increased the levels of phosphorylated phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR) that were reduced by dexamethasone, and downregulated the expression of forkhead box O3 (FoxO3a) induced by dexamethasone. These results suggest that MIX has a protective effect against muscle atrophy by enhancing muscle protein anabolism through the activation of the PI3K/Akt/mTOR signaling pathway and attenuating catabolism through the inhibition of FoxO3a.

• Biomolecules & Therapeutics
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• v.31 no.4
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• pp.402-410
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• 2023

Long-term administration of levodopa (L-DOPA) to patients with Parkinson's disease (PD) commonly results in involuntary dyskinetic movements, as is known for L-DOPA-induced dyskinesia (LID). 5-Hydroxytryptophan (5-HTP) has recently been shown to alleviate LID; however, no biochemical alterations to aberrant excitatory conditions have been revealed yet. In the present study, we aimed to confirm its anti-dyskinetic effect and to discover the unknown molecular mechanisms of action of 5-HTP in LID. We made an LID-induced mouse model through chronic L-DOPA treatment to 6-hydroxydopamine-induced hemi-parkinsonian mice and then administered 5-HTP 60 mg/kg for 15 days orally to LID-induced mice. In addition, we performed behavioral tests and analyzed the histological alterations in the lesioned part of the striatum (ST). Our results showed that 5-HTP significantly suppressed all types of dyskinetic movements (axial, limb, orolingual and locomotive) and its effects were similar to those of amantadine, the only approved drug by Food and Drug Administration. Moreover, 5-HTP did not affect the efficacy of L-DOPA on PD motor manifestations. From a molecular perspective, 5-HTP treatment significantly decreased phosphorylated CREB and ΔFosB expression, commonly known as downstream factors, increased in LID conditions. Furthermore, we found that the effects of 5-HTP were not mediated by dopamine1 receptor (D1)/DARPP32/ERK signaling, but regulated by AKT/mTOR/S6K signaling, which showed different mechanisms with amantadine in the denervated ST. Taken together, 5-HTP alleviates LID by regulating the hyperactivated striatal AKT/mTOR/S6K and CREB/ΔFosB signaling.

• Fisheries and Aquatic Sciences
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• v.26 no.2
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• pp.133-144
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• 2023

Auranofin is a US Food and Drug Administration (FDA)-approved anti-arthritis medication that functions as a thioredoxin reductase inhibitor. Spermidine, a polyamine present in marine algae, can exert various physiological functions. Herein, we examined the synergistic anticancer activity of auranofin and spermidine in hepatocellular carcinoma (HCC). Combined treatment with auranofin and spermidine suppressed cell viability more efficiently than either treatment alone in HCC Hep3B cells. The isobologram plotted by calculating the half maximal inhibitory concentration (IC₅₀) values of each drug indicated that the two drugs exhibited a synergistic effect. Based on the analysis of annexin V and cell cycle distribution, auranofin and spermidine markedly induced apoptosis in Hep3B cells. Moreover, auranofin and spermidine increased mitochondria-mediated apoptosis by promoting mitochondrial membrane potential (Δψm) loss. Auranofin and spermidine significantly increased reactive oxygen species (ROS) production in Hep3B cells, and the blocking ROS suppressed apoptosis induced by spermidine and auranofin. In addition, auranofin and spermidine reduced the expression of phosphorylated phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt), and PI3K inhibitor accelerated auranofin- and spermidine-induced apoptosis. Using ROS scavenger and PI3K inhibitor, we revealed that ROS acts upstream of auranofin- and spermidine-induced apoptosis. Collectively, our study suggests that combination treatment with auranofin and spermidine could afford synergistic anticancer activity via ROS overproduction and reduced PI3K/Akt signaling pathway.

• Biomolecules & Therapeutics
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• v.26 no.4
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• pp.389-398
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• 2018

p-Cresol, found at high concentrations in the serum of chronic kidney failure patients, is known to cause cell senescence and other complications in different parts of the body. p-Cresol is thought to mediate cytotoxic effects through the induction of autophagy response. However, toxic effects of p-cresol on mesenchymal stem cells have not been elucidated. Thus, we aimed to investigate whether p-cresol induces senescence of mesenchymal stem cells, and whether melatonin can ameliorate abnormal autophagy response caused by p-cresol. We found that p-cresol concentration-dependently reduced proliferation of mesenchymal stem cells. Pretreatment with melatonin prevented pro-senescence effects of p-cresol on mesenchymal stem cells. We found that by inducing phosphorylation of Akt and activating the Akt signaling pathway, melatonin enhanced catalase activity and thereby inhibited the accumulation of reactive oxygen species induced by p-cresol in mesenchymal stem cells, ultimately preventing abnormal activation of autophagy. Furthermore, preincubation with melatonin counteracted other pro-senescence changes caused by p-cresol, such as the increase in total 5'-AMP-activated protein kinase expression and decrease in the level of phosphorylated mechanistic target of rapamycin. Ultimately, we discovered that melatonin restored the expression of senescence marker protein 30, which is normally suppressed because of the induction of the autophagy pathway in chronic kidney failure patients by p-cresol. Our findings suggest that stem cell senescence in patients with chronic kidney failure could be potentially rescued by the administration of melatonin, which grants this hormone a novel therapeutic role.

• 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.

• Microbiology and Biotechnology Letters
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• v.49 no.4
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• pp.543-551
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• 2021

Nocardiopsis species produce bioactive compounds, such as antimicrobial and anti-cancer agents and toxins. However, no reports have described their anti-inflammatory and anti-fibrotic effects during nasal polyp (NP) formation. In this study, we investigated whether marine-derived bacterial Nocardiopsis sp. 13G027 exerts anti-inflammatory and anti-fibrotic effects on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and transforming growth factor (TGF)-β1-induced NP-derived fibroblasts (NPDFs). Nitric oxide (NO) and prostaglandin E₂ (PGE₂) levels were analyzed. Extract from Nocardiopsis sp. 13G027 significantly inhibited the upregulation of NO and PGE₂ in LPS-activated RAW 264.7 macrophages. The expression of mitogen-activated protein kinases (MAPKs) and protein kinase B (Akt/PKB) in LPS-induced RAW 264.7 macrophages was evaluated; smooth muscle alpha-actin (α-SMA), collagen type I (Col-1), and fibronectin also phosphorylated small mothers against decapentaplegic (SMAD) 2 and 3 in TGF-β1-stimulated NPDFs. The Nocardiopsis sp. 13G027 extract suppressed the phosphorylation of MAPKs and Akt and the DNA-binding activity of activator protein 1 (AP-1). The expression of pro-fibrotic components such as α-SMA, Col-1, fibronectin, and SMAD2/3 was inhibited in TGF-β1-exposed NPDFs. These findings suggest that Nocardiopsis sp. 13G027 has the potential to treat inflammatory disorders, such as NP formation.

• Journal of Nutrition and Health
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• v.38 no.8
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• pp.656-662
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• 2005

Ginger (Zingiber of oficinale Roscoe, Zingiberaceae) is one of the most frequently and heavily consumed dietary condiments throughout the world. Besides its extensive use as a spice, the rhizome of ginger has also been used in traditional oriental herbal medicine for the management of symptoms such as common cold, digestive disorders, rheumatism, neurologia, colic, and motion-sickness. The oleoresin from rhizomes of ginger contains [6] -gingerol (1- [4'-hydroxy-3'-methoxyphenyl]-5-hydroxy-3-decanone) and its homologs as pungent ingredients that have been found to possess many interesting pharmacological and physiological activities, such as anti-inflammatory, analgesic, antipyretic, antiheatotoxic, and cardiotonic effects. However, the effect of [6]-gingerol on cell proliferation in breast cancer cell are not currently well known. Therefore, in this study, we examined effect of [6]-gingerol on protein and mRNA expression associated with cell proliferation in MDA-MB-231 human breast. cancer cell lines. We cultured MDA-MB-231 cells in presence of 0, 2.5, 5 and $10{\mu}M$ of [6] -gingerol. [6]-Gingerol inhibited breast cancer cell growth in a dose-depenent manner as determined by MTT assay. ErbB2 and ErbB3 protein and mRNA expression were decreased dose-dependently in cells treated with [6]-gingerol (p<0.05). In addition, phosphorylated Akt levels and total hぉ levels were markedly decreased in cells treated with $2.5{\mu}M$ [6]-gingerol (p<0.05). In conclusion, we have shown that [6]-gingerol inhibits cell proliferation through ErbB2 and ErbB3, reduction in MDA-MB-231 human breast cancer cell lines.

• Nutrition Research and Practice
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• v.10 no.5
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• pp.507-515
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• 2016

BACKGROUND/OBJECTIVES: This study was designed to investigate whether Gynura procumbens extract (GPE) can improve insulin sensitivity and suppress hepatic glucose production in an animal model of type 2 diabetes. MATERIALS/METHODS: C57BL/Ksj-db/db mice were divided into 3 groups, a regular diet (control), GPE, and rosiglitazone groups (0.005 g/100 g diet) and fed for 6 weeks. RESULTS: Mice supplemented with GPE showed significantly lower blood levels of glucose and glycosylated hemoglobin than diabetic control mice. Glucose and insulin tolerance test also showed the positive effect of GPE on increasing insulin sensitivity. The homeostatic index of insulin resistance was significantly lower in mice supplemented with GPE than in the diabetic control mice. In the skeletal muscle, the expression of phosphorylated AMP-activated protein kinase, pAkt substrate of 160 kDa, and PM-glucose transporter type 4 increased in mice supplemented with GPE when compared to that of the diabetic control mice. GPE also decreased the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in the liver. CONCLUSIONS: These findings demonstrate that GPE might improve insulin sensitivity and inhibit gluconeogenesis in the liver.

• Biomolecules & Therapeutics
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• v.23 no.2
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• pp.128-133
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• 2015

Although coffee is known to have antioxidant, anti-inflammatory, and antitumor properties, there have been few reports about the effect and mechanism of coffee compounds in colorectal cancer. Heat shock proteins (HSPs) are molecular chaperones that prevent cell death. Their expression is significantly elevated in many tumors and is accompanied by increased cell proliferation, metastasis and poor response to chemotherapy. In this study, we investigated the cytotoxicity of four bioactive compounds in coffee, namely, caffeine, caffeic acid, chlorogenic acid, and kahweol, in HT-29 human colon adenocarcinoma cells. Only kahweol showed significant cytotoxicity. Specifically, kahweol increased the expression of caspase-3, a pro-apoptotic factor, and decreased the expression of anti-apoptotic factors, such as Bcl-2 and phosphorylated Akt. In addition, kahweol significantly attenuated the expression of HSP70. Inhibition of HSP70 activity with triptolide increased kahweol-induced cytotoxicity. In contrast, overexpression of HSP70 significantly reduced kahweol-induced cell death. Taken together, these results demonstrate that kahweol inhibits colorectal tumor cell growth by promoting apoptosis and suppressing HSP70 expression.