• Microbiology and Biotechnology Letters
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• v.40 no.3
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• pp.180-185
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• 2012

Type 2 Diabetes Mellitus, a chronic metabolic disorder which results from a high blood glucose level, is one of the most prevalent and costly diseases of our time. Considering increasing rates of obesity and the aging population in Korea, the number of diabetic patients is likely to rise rapidly in the future. There are five conventional diabetic drugs which work through different mechanisms; sulfonylureas, biguanide, meglitinide, alpha-glucosidase inhibitors, and thiazolidinedione. Although they all have antidiabetic effects, some side effects such as hypoglycemia, weight gain and gastrointestinal intolerance are associated with them. Incretin based therapies, utilizing glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which have a lower risk of adverse side effects, have recently been introduced. At present PPAR-targeting drugs are being actively developed. In this research review, particular emphasis has been placed on the current trends and possible biological targets for the new generation of antidiabetic drugs.

• Journal of Life Science
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• v.32 no.6
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• pp.476-481
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• 2022

Ubiquitin signaling regulates virtually all aspects of eukaryotic biology and dynamic processes in which protein substrates are modified by ubiquitin. To regulate these processes, deubiquitinating enzymes (DUBs) cleave ubiquitin or ubiquitin-like proteins from these substrates. DUBs have been implicated in the pathogenesis of cancer, leading to the development of increasing numbers of small-molecule DUB inhibitors. On the other hand, recent studies have focused on the function of DUBs in metabolic diseases such as obesity, diabetes, and fatty liver diseases. DUBs play a positive or negative role in the progression and development of metabolic diseases. Their involvement in cell pathology and regulation of major transcription factors in metabolic syndrome has been examined in vitro and in animal and human biopsies. UCH, USP7, and USP19 were linked to adipocyte differentiation, body weight gain, and insulin resistance in genetic or diet-induced obesity. CYLD, USP4, and USP18 were found to be closely associated with fatty liver diseases. In addition, these liver diseases were accompanied by body weight change in certain cases. Collectively, in this review, we discuss the current understanding of DUBs in metabolic diseases with a particular focus on obesity. We also provide basic knowledge and regulatory mechanisms of DUBs and suggest these enzymes as therapeutic targets for metabolic diseases.

• BMB Reports
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• v.45 no.3
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• pp.141-146
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• 2012

Protein tyrosine phosphatase 1B (PTP1B) is important in the regulation of metabolic diseases and has emerged as a promising signaling target. Previously, we reported the PTP1B inhibitory activity of Rheum undulatum (RU). In the present study, we investigated the metabolic regulatory effects of RU in a high-fat diet (HFD) model. RU treatment significantly blocked body weight gain, which was accompanied by a reduction of feed efficiency. In addition, it led to a reduction of liver weight mediated by overexpression of PPAR${\alpha}$ and CPT1 in the liver, and an increase in the expression of adiponectin, aP2, and UCP3 in adipose tissue responsible for the reduction of total and LDL-cholesterol levels. Chrysophanol and physcion from RU significantly inhibited PTP1B activity and strongly enhanced insulin sensitivity. Altogether, our findings strongly suggest that 2 compounds are novel PTP1B inhibitors and might be considered as anti-obesity agents that are effective for suppressing body weight gain and improving lipid homeostasis.

• Biomolecules & Therapeutics
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• v.24 no.6
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• pp.589-594
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• 2016

Insulin is a peptide hormone of the endocrine pancreas and exerts a wide variety of physiological actions in insulin sensitive tissues, such as regulation of glucose homeostasis, cell growth, differentiation, learning and memory. However, the role of insulin in osteoblast cells remains to be fully characterized. In this study, we demonstrated that the insulin (100 nM) has the ability to stimulate the phosphorylation of protein kinase B (Akt/PKB) and extracellular signal-regulated kinase (ERK) and the levels of inhibin-${\beta}E$ in the osteoblast-like UMR-106 cells. This insulin-stimulated activities were abolished by the PI3K and MEK1 inhibitors LY294002 and PD98059, respectively. This is the first report proving that insulin is a potential candidate that enables the actions of inhibin-${\beta}E$ subunit of the TGF-${\beta}$ family. The current investigation provides a foundation for the realization of insulin as a potential stimulator in survival signaling pathways in osteoblast-like UMR-106 cells.

• Childhood Kidney Diseases
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• v.25 no.1
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• pp.35-39
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• 2021

Bartter syndrome is an autosomal recessive hypokalemic salt-losing tubulopathy, and classic Bartter syndrome is associated with mutations in the CLCNKB gene. While chronic hypokalemia is known to induce renal cyst formation in different renal diseases, renal cyst formation in Bartter syndrome is rarely reported. Russian six-year-old identical male twins were referred to our hospital for the evaluation of renal cysts, which were incidentally detected on abdominal sonography due to diarrhea. Both twins had shown symptoms of polydipsia, polyuria, and nocturia since they were one year olds. Vital signs including blood pressure were normal in both twins. Renal sonography revealed nephromegaly, increased echogenicity of renal cortex, and various sized multiple cysts in both kidneys for both twins. Laboratory findings included hyponatremia, hypokalemia, hypochloremia, and metabolic alkalosis. Bartter syndrome with renal cysts were suspected. Genetic analysis for both twins confirmed a homozygous c.1614delC deletion on exon 15 of the CLCNKB gene, which was confirmed as a previously unreported variant to the best of our knowledge. They were managed with potassium chloride, nonsteroidal anti-inflammatory drugs, and angiotensin-converting-enzyme inhibitors. Metabolic alkalosis, hypokalemia, hypochloremia, and polyuria partially improved during the short course of treatment. This is the first report of a homozygous mutation in the CLCNKB gene in an identical twin, presenting with renal cysts.

• Korean Journal of Pharmacognosy
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• v.34 no.2 s.133
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• pp.156-160
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• 2003

$NF-{\kappa}B$ (nuclear factor-kappa B) plays a particularly central role in epidermal biology. It has been established that ultraviolet radiation (UVR) is one of the mechanisms to induce the activation of $NF-{\kappa}B$ in human skin. We previously demonstrated that melanogenic inhibitors may act through the inhibition of $NF-{\kappa}B$ activation in keratinocytes. In order to find another type of melanogenic inhibitors of $NF-{\kappa}B$ activation, various kinds of the extracts from crude drugs $(30\;{\mu}g/ml)$ were preincubated with transfectant HaCaT cells for 3 hrs and then UVR $(60\;mj/cm^2)$ was irradiated. UVR-exposed cells were incubated for another 6 hrs to measure the $NF-{\kappa}B$ activity. $NF-{\kappa}B$ activation was measured with the secreatory alkaline phosphates (SEAP) reporter gene assay using a fluorescence detection method. Among natural products, Lycium chinense, Acanthopanax senticosus, Angelica koreana, Kalopanax pictus and Asparagus cochinchinensis were the most potent inhibitors of $NF-{\kappa}B$ activation by UVR. These observations suggest that some crude drugs might act partially through the modulation of the synthesis of melanotrophic factors to decrease melanogenesis in keratinocytes.

• Journal of the Korea Convergence Society
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• v.13 no.1
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• pp.161-166
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• 2022

HIF-2α is a transcription factor activated mainly in hypoxic condition known to play crucial roles in a wide variety of pathophysiological events including cancer, metabolic syndrome, arthritis etc. In this context, a number of N'-aryl isonicotinolyhydrazides, in which known pharmacophores are included, have been selected from commercial chemical library and tested for the inhibitory activities targeting HIF-2α in cultured HTB94 cell. HRE-luciferase and HIF-2α were introduced into the cell by transfection and adenoviri infection, respectively and the reporter gene assay discovered the potency of 2-hydroxy-1-naphthyl structure. Accordingly, the scaffold has been adjusted based on this structure and subjected to anti-HIF-2α activity test, identifying 2 compounds as HIF-2α inhibitors. The activities were confirmed by false positive test. This study has been performed via the convergence of biology and chemistry and the results may be useful for discovering novel inhibitors and HIF-2α biology studies, and contribute to the development of therapeutic agents.

• Animal Bioscience
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• v.37 no.4
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• pp.631-639
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• 2024

Objective: This study evaluates goat sperm motility in response to metabolic substrates and various inhibitors, aiming to assess the relative contribution of glycolysis and mitochondrial oxidation for sperm movement and adenosine triphosphate (ATP) production. Methods: In the present study, two main metabolic substrates; 0 to 0.5 mM glucose and 0 to 30 mM pyruvate were used to evaluate their contribution to sperm movements of goats. Using a 3-chloro-1,2-propanediol (3-MCPD), a specific inhibitor for glycolysis, and carbonyl cyanide 3-chlorophenylhydrazone as an inhibitor for oxidative phosphorylation, cellular mechanisms into ATP-generating pathways in relation to sperm movements and ATP production were observed. Data were analysed using one-way analysis of variance for multiple comparisons. Results: Sperm motility analysis showed that either glucose or pyruvate supported sperm movement during 0 to 30 min incubation. However, the supporting effects were abolished by the addition of a glycolysis inhibitor or mitochondrial uncoupler, concomitant with a significant decrease in ATP production. Although oxidative phosphorylation produces larger ATP concentrations than those from glycolysis, sperm progressivity in relation to these two metabolic pathways is comparable. Conclusion: Based on the present study, we suggest that goat sperm use glucose and pyruvate to generate cellular energy through glycolysis and mitochondrial respiration pathways to maintain sperm movement.

• Journal of Korean Biological Nursing Science
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• v.14 no.2
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• pp.129-138
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• 2012

Purpose: Cachexia is a complex metabolic syndrome associated with wasting of skeletal muscle which contributes to nearly one-third of all cancer deaths. Cachexia lowers the frequency of response to chemotherapy and radiation and ultimately can impact survival as well as quality of life during treatment. NF-kappa B is one of the most important molecular mediators of cachexia. In this study, therefore, possible candidates for inhibitors of NF-kappa B were searched. Methods: Amino acids that regulate cellular redox potential by adjusting the level of NAD/NADH ratio, such as aspartate, pyruvate, and isocitrate were selected. Results: Pyruvate effectively inhibited luciferase activity in TNF-stimulated 293T cells transfect with an NF-kB dependent luciferase reporter vector. Pyruvate also showed protective effect on muscle atrophy of differentiated C2C12 myocyte induced by TNF/IFN. Conclusion: We might be able to develop the nutritional management strategy for cancer cachexia patients with pyruvate supplementation.

• CELLMED
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• v.4 no.3
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• pp.17.1-17.8
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• 2014

Herbal remedies are commonly used by patients worldwide. Because these herbal preparations share the same metabolic and transport proteins with prescribed medicines, the potential for a drug-herb interaction is substantial and is an issue of significant concern. This review paper summarizes drug-herb interactions involving inhibition or induction of cytochrome P450 enzymes, drug transporters as well as modulation of drug pharmacodynamics. An increasing number of in vitro and animal studies, case reports and clinical trials evaluating such interactions have been reported, and implications of these studies are discussed in this review. The most commonly implicated drugs in the interaction include anticoagulants, antiplatelets, immunosuppressants, anti-neoplastics, protease inhibitors, and some antidepressants. Pharmacokinetic and/or pharmacodynamic interactions of five commonly used herbal remedies (danshen, garlic, Ginkgo biloba, ginseng, and St John's wort) with these drugs are presented, with focus of discussion being the potentials for interaction, their mechanisms and clinical implications. There is a necessity for adequate pharmacovigilance to be carried out in minimizing unanticipated but often preventable drug-herb interactions.