• Interdisciplinary Bio Central
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• v.4 no.2
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• pp.3.1-3.7
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• 2012

Epidermal growth factor receptor (EGFR) is a member of the ErbB family (ErbB1-4) of receptor tyrosine kinases (RTKs). EGFR controls numerous physiological functions, including cell proliferation, migration, differentiation and survival. Importantly, aberrant signaling by EGFR has been linked to human cancers in which EGFR and its various ligands are frequently overexpressed or mutated. EGFR coordinates activation of multiple downstream factors and is subject of various regulatory processes as it mediates biology of the cell it resides in. Therefore, many studies have been devoted to understanding EGFR biology and targeting the protein for the goal of controlling tumor in clinical settings. Endocytic regulation of EGFR offers a promising area for targeting EGFR activity. Upon ligand binding, the activated receptor undergoes endocytosis and becomes degraded in lysosome, thereby terminating the signal. En route to lysosome, the receptor becomes engaged in activating various signaling pathways including PI-3K, MAPK and Src, and endocytosis may offer both spatial and temporal regulation of downstream target activation. Therefore, endocytosis is an important regulator of EGFR signaling, and increasing emphasis is being placed on endocytosis in terms of cancer treatment and understanding of the disease. In this review, EGFR signaling pathway and its intricate regulation by endocytosis will be discussed.

• BMB Reports
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• v.49 no.8
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• pp.405-413
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• 2016

Tau proteins, which stabilize the structure and regulate the dynamics of microtubules, also play important roles in axonal transport and signal transduction. Tau proteins are missorted, aggregated, and found as tau inclusions under many pathological conditions associated with neurodegenerative disorders, which are collectively known as tauopathies. In the adult human brain, tau protein can be expressed in six isoforms due to alternative splicing. The aberrant splicing of tau pre-mRNA has been consistently identified in a variety of tauopathies but is not restricted to these types of disorders as it is also present in patients with non-tau proteinopathies and RNAopathies. Tau mis-splicing results in isoform-specific impairments in normal physiological function and enhanced recruitment of excessive tau isoforms into the pathological process. A variety of factors are involved in the complex set of mechanisms underlying tau mis-splicing, but variation in the cis-element, methylation of the MAPT gene, genetic polymorphisms, the quantity and activity of spliceosomal proteins, and the patency of other RNA-binding proteins, are related to aberrant splicing. Currently, there is a lack of appropriate therapeutic strategies aimed at correcting the tau mis-splicing process in patients with neurodegenerative disorders. Thus, a more comprehensive understanding of the relationship between tau mis-splicing and neurodegenerative disorders will aid in the development of efficient therapeutic strategies for patients with a tauopathy or other, related neurodegenerative disorders.

• Journal of Physiology & Pathology in Korean Medicine
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• v.26 no.3
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• pp.281-286
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• 2012

The present study was designed to investigate the effect of Rehmannia glutinosa on phosphorylation of extracellular signal-regulated kinase(ERK) and cAMP response element-binding protein(CREB) in the acute cocaine-treated rats. Rats orally received vehicle or extract of Rehmannia glutinosa 1 h prior to saline (1 ml/kg, i.p.) or cocaine hydrochloride (20 mg/kg, i.p.) treatment. Rats were sacrificed 15 min after a single intraperitoneal injection of saline or cocaine. Rehmannia glutinosa at dose of 50 mg/kg significantly decreased phosphorylation of ERK, CREB and Elk-1 in the nucleus accumbens and striatum of the cocaine-treated rat brain by immunocytochemistry. These results suggest that Rehmannia glutinosa may contribute to the effects of cocaine on gene expression and on behaviors.

• Journal of Physiology & Pathology in Korean Medicine
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• v.23 no.2
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• pp.452-456
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• 2009

The purpose of this study was to investigate the anti-inflammatory effects and cellular mechanism of piperine on murine peritoneal macrophages. To evaluate the effects of piperine, we examined the production of nitric oxide (NO), interleukin (IL)-10 and IL-12. To investigate inhibitory mechanism of piperine, we examined the MAPKs and Ik-Ba in murine peritoneal macrophages, Piperine itself does not have any cytotoxic effect and reduced lipopolysaccharid (LPS), Poly(I:C), CpG-ODN -induced production of NO, IL-10 and IL-12 in peritoneal macrophages. Piperine inhibited the activation of extracelluar signal-regulated kinase (ERK 1/2) and c-Jun NH2-terminal kinase (JNK 1/2) not the activation of p38 and the degradation of inhibitory kappa B a (Ik-Ba) in the LPS-stimulated murine peritoneal macrophages.ln conclusion, Piperine down-regulated LPS-induced production of NO, IL-10 and IL-12, which could provide a clinical basis for anti-inflammatory properties of piperine.

• 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.

• Molecular & Cellular Toxicology
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• v.5 no.4
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• pp.283-290
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• 2009

Differential gene expression profiling was performed in the hepatic tissue of marine medaka fish (Oryzias javanicus) after exposure to benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH), by heterologous hybridization using a medaka cDNA microarray. Thirty-eight differentially expressed candidate genes, of which 23 were induced and 15 repressed (P<0.01), were identified and found to be associated with cell cycle, development, endocrine/reproduction, immune, metabolism, nucleic acid/protein binding, signal transduction, or non-categorized. The presumptive physiological changes induced by BaP exposure were identified after considering the biological function of each gene candidate. The results obtained in this study will allow future studies to assess the molecular mechanisms of BaP toxicity and the development of a systems biology approach to the stress biology of organic chemicals.

• Journal of Physiology & Pathology in Korean Medicine
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• v.26 no.4
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• pp.437-440
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• 2012

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that Cryptotanshione(CT), a tanshinone from oriental traditional medicinal herb Danshen (Salvia miltiorrhiza Bunge), had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells. CT inhibited the protein expression of hypoxia-inducible factor-1alpha (HIF-$1{\alpha}$) under hypoxic condition. Consistently, CT blocked hypoxia-induced phosphorylation and nuclear accumulation of STAT3. In addition, CT reduced cellular of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Of note, chromatin immunoprecipitation (ChiP) assay revealed that CT inhibited binding of STAT3 to VEGF promoter. Taken together, our results suggest that CT has anti-angiogenic activity by disturbing the binding STAT3 to the VEGF promoter in PC-3 cells.

• Journal of Physiology & Pathology in Korean Medicine
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• v.31 no.3
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• pp.167-172
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• 2017

In this study, we investigated the effect of Puerariae Radix ethanol extracts (EPR). The effect of the EPR on proliferation of human hair dermal papilla cells(HHDPCs) by MTT assay and observed Expression of mechanisms that regulate cell proliferation extracellular signal-regulated kinase(ERK) and Akt by western blot. The results showed EPR increased the proliferation of HHDPCs and up-regulation phosphorylation of ERK and Akt. ERK and Akt increased by EPR inhibited phosphorylation by PD98059 (ERK inhibitor) and LY294002 (Akt inhibitor), and cell proliferation was also inhibited. These results suggested EPR increases the proliferation of HHDPCs through phosphorylation of ERK and Akt, and therefore is a beneficial effect for the alopecia treatment.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2000.04a
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• pp.6-7
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• 2000

Recently, free radicals such as active oxygen species, nitric oxide, etc are believed to be one of the key substances in physiological and pathological, toxicological phenomena, and oxidative damages, and all organism have defencing system against such as free radicals. Formation and extinction of free radicals may be regulated through bio-redox system, in which various enzymes and compounds should be involved in very complicated manner. Thus, direct and non-invasive measurement of in vivo free radical reactions with living animals must be essential to understand the role of free radicals in pathophysiological phenomena. Electron spin resonance spectroscopy (ESR) is very selective and sensitive technique to detect free radicals, but a conventional ESR spectrometer has large detect in application to living animals, since high frequent microwave is absorbed with water, resulting in generation of high fever in living body. In order to estimate in vivo free radical reactions in living whole animals, we develop in vivo ESR-CT technique using nitroxide radicals as spin probes. Nitroxide radicals and their reduced forms, hydroxylamines, are known to interact with various redox systems. We found that! ! the signal decay due to reduction of nitroxyl radicals is influenced by aging, inspired oxygen concentration, ischemia-referfusion injury, radiation, etc. In the present paper, I will introduce in vivo ESR technique and my laboratory recent results concerning non-invasive evaluation of free radical reactions in living mice.

• Plant Biotechnology Reports
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• v.5 no.1
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• pp.19-25
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• 2011

Tocopherols belong to the plant-derived poly phenolic compounds known for antioxidant functions in plants and animals. Activation of mitogen-activated protein kinases (MAPK) is a common reaction of plant cells in defense-related signal transduction pathways. We report a novel non-antioxidant function of ${\alpha}$-tocopherol in higher plants linking the physiological role of tocopherol with stress signalling pathways. Pre-incubation of a low concentration of $50{\mu}M$ ${\alpha}$-tocopherol negatively interferes with MAPK activation in elicitor-treated tobacco BY2 suspension culture cells and wounded tobacco leaves, whereas pre-incubated BY2 cells with ${\alpha}$-tocopherol phosphate did not show the inhibitory effect on stimuli-induced MAPK activation. The decreased MAPK activity was neither due to a direct inhibitory effect of ${\alpha}$-tocopherol nor due to the induction of an inhibitory or inactivating activity directly affecting MAPK activity. The data support that the target of ${\alpha}$-tocopherol negatively regulates an upstream component of the signaling pathways that leads to stress dependent MAPK activation.