• Preventive Nutrition and Food Science
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• v.22 no.1
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• pp.1-8
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• 2017

About 20 chemical elements are nutritionally essential for humans with defined molecular functions. Several essential and nonessential biometals are either functional nutrients with antidiabetic actions or can be diabetogenic. A key question remains whether changes in the metabolism of biometals and biominerals are a consequence of diabetes or are involved in its etiology. Exploration of the roles of zinc (Zn) in this regard is most revealing because 80 years of scientific discoveries link zinc and diabetes. In pancreatic ${\beta}$- and ${\alpha}$-cells, zinc has specific functions in the biochemistry of insulin and glucagon. When zinc ions are secreted during vesicular exocytosis, they have autocrine, paracrine, and endocrine roles. The membrane protein ZnT8 transports zinc ions into the insulin and glucagon granules. ZnT8 has a risk allele that predisposes the majority of humans to developing diabetes. In target tissues, increased availability of zinc enhances the insulin response by inhibiting protein tyrosine phosphatase 1B, which controls the phosphorylation state of the insulin receptor and hence downstream signalling. Inherited diseases of zinc metabolism, environmental exposures that interfere with the control of cellular zinc homeostasis, and nutritional or conditioned zinc deficiency influence the pathobiochemistry of diabetes. Accepting the view that zinc is one of the many factors in multiple gene-environment interactions that cause the functional demise of ${\beta}$-cells generates an immense potential for treating and perhaps preventing diabetes. Personalized nutrition, bioactive food, and pharmaceuticals targeting the control of cellular zinc in precision medicine are among the possible interventions.

• Natural Product Sciences
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• v.24 no.2
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• pp.99-102
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• 2018

This study investigated the effects of ombuoside, a flavonol glycoside, on dopamine biosynthesis in PC12 cells. Ombuoside at concentrations of 1, 5, and $10{\mu}M$ increased intracellular dopamine levels at 1 - 24 h. Ombuoside (1, 5, and $10{\mu}M$) also significantly increased the phosphorylation of tyrosine hydroxylase (TH) (Ser40) and cyclic AMP-response element binding protein (CREB) (Ser133) at 0.5 - 6 h. In addition, ombuoside (1, 5, and $10{\mu}M$) combined with L-DOPA (20, 100, and $200{\mu}M$) further increased intracellular dopamine levels for 24 h compared to L-DOPA alone. These results suggest that ombuoside regulates dopamine biosynthesis by modulating TH and CREB activation in PC12 cells.

• Archives of Pharmacal Research
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• v.21 no.2
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• pp.140-146
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• 1998

Hypoglycemic action of brazilin was found to be based on the improvement of peripheral glucose utility, and this action might be correlated with the insulin action pathway. In the present study we investigated the effect of brazilin on the insulin receptor autophosphorylation, protein kinase C (PKC), protein phosphatase and insulin receptor serine kinase in order to confirm whether the hypoglycemic mechanism is concerned with insulin action pathway. Brazilin was found to inhibit PKC and insulin receptor serine kinase, which are involved in the regulation of insulin signal pathway. But any significant effect was not shown on insulin receptor tyrosine kinase activity, autophosphorylation and phosphatase activity. These findings suggest that brazilin might enhance insulin receptor function by decreasing serine phosphorylation, which might mediate hypoglycemic effect of brazilin.

• BMB Reports
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• v.41 no.6
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• pp.479-484
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• 2008

In the present study, we demonstrate that ephrin-A5 is able to induce a transient increase of MAP kinase activity in PC12 cells. However, the effects of ephrin-A5 on the MAP kinase signaling pathway are about three-fold less than that of EGF. In addition, we demonstrate that EphA4 is the only Eph member expressed in PC12 cells, and that tyrosine phosphorylation induced by ephrin-A5 treatment is consistent with the magnitude and longevity of MAP kinase activation. Experiments using the Ras dominant negative mutant N17Ras reveal that Ras plays a pivotal role in ephrin-A5-induced MAP kinase activation in PC12 cells. Importantly, we found that the EphA4 receptor is rapidly internalized by endocytosis upon engagement of ephrin-A5, leading to a subsequent reduction in the MAP kinase activation. Together, these data suggest a novel regulatory mechanism of differential Ras-MAP kinase signaling kineticsexhibited by the forward signaling of EphA4 in PC12 cells.

• BMB Reports
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• v.50 no.3
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• pp.150-155
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• 2017

Non-small-cell lung cancer (NSCLC) is the third most common cancer that spreads to the bone, resulting in osteolytic lesions caused by hyperactivation of osteoclasts. Activating mutations in epidermal growth factor receptor-tyrosine kinase (EGF-TK) are frequently associated with NSCLC, and afatinib is a first-line therapeutic drug, irreversibly targeting EGF-TK. However, the effects of afatinib on osteoclast differentiation and activation as well as the underlying mechanism remain unclear. In this study, afatinib significantly suppressed receptor activator of nuclear factor ${\kappa}B$ (RANK) ligand (RANKL)-induced osteoclast formation in bone marrow macrophages (BMMs). Consistently, afatinib inhibited the expression of osteoclast marker genes, whereas, it upregulated the expression of negative modulator genes. The bone resorbing activity of osteoclasts was also abrogated by afatinib. In addition, afatinib significantly inhibited RANKL-mediated Akt/protein kinase B and c-Jun N-terminal kinase phosphorylation. These results suggest that afatinib substantially suppresses osteoclastogenesis by downregulating RANK signaling pathways, and thus may reduce osteolysis after bone metastasis.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1998.11a
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• pp.145-145
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• 1998

In the present study, we have demonstrated that taurine could stimulate the production of nitric oxide and the activity of ERK2 (extracellular signal regulated protein kinase or pp42 MAP kinase). Nitric oxide(NO), the product of inducible nitric oxide synthase(iNOS), is known to be implicated in the metabolism of bone. ERK cascade plays a key role in the gene expression of iNOS in osteoblastic cell. We investigated whether taurine (l-20mM) could stimulate ERK2 activity, nitric oxide production, and inducible nitric oxide synthase in osteoblast-like UMR-106 cells. Nitric oxide was measured spectophotometrically as nitrite and the activation of ERK2 and iNOS was studied using Western 145 blot analysis. Taurine increased the production of nitric oxide in a dose-dependent manner and the effect was reached to a maximum at 10 mM. The activation of iNOS were consistent with NO levels. The tyrosine phosphorylation of ERK2 was increased by taurine in a time-dependent manner. The these result suggest that taurine might stimulate the production of nitric oxide in osteoblast-like cells by the activation of ERK2 and could regulate the metabolism of bone via nitric oxide.

• Bulletin of the Korean Chemical Society
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• v.29 no.5
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• pp.1013-1017
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• 2008

Syndecan-3 is a cell-surface heparan sulfate proteoglycan, which performs a variety of functions during cell adhension process. It is also a coreceptor for growth factor, mediating cell-cell and cell-matrix interaction. Syndecan-3 contains a cytoplasmic domain potentially associated with the cytoskeleton. Syndecan-3 is specifically expressed in neuron cell and has related to neuron cell differentiation and development of actin filament in cell migration. Syndecans each have a unique, central, and variable (V) region in their cytoplasmic domains. And that region of syndecan-3 may modulate the interactions of the conserved C1 regions of the cytoplasmic domains by tyrosine phosphorylation. Cytoplasmic domain of syndecan-3 has been synthesized for NMR structural studies. The solution structure of syndecan-3 cytoplasmic domain has been determined by two-dimensional NMR spectroscopy and simulated-annealing calculation. The cytoplasmic domain of the syndecan proteins has a tendency to form a dimmer conformation with a central cavity, however, that of syndecan-3 demonstrated a monomer conformation with a flexible region near C-terminus. The structural information might add knowledge about the structure-function relationships among syndecan proteins.

• Animal cells and systems
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• v.7 no.3
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• pp.173-186
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• 2003

The transition metal cadmium is a serious occupational and environmental toxin. To inhibit cadmium-induced damage, cells respond by increasing the expression of genes that encode stress-responsive proteins. The metal-regulatory transcription factor 1 (MTF-1) is a key regulator of heavy-metal induced transcription of metallothionein-I and II and other genes in mammals and other metazoans. Transcriptional activation of genes by MTF-1 is mediated through binding to metal-responsive elements in the target gene promoters. Phosphorylation of MTF-1 plays a critical role in the cadmium-inducible transcriptional activation of metallothionein and other responses. Studies using inhibitors indicate that multiple kinases and signal transduction cascades, including those mediated by protein kinase C, tyrosine kinase and casein kinase II, are essential for cadmium-mediated transcriptional activation. In addition, calcium signaling is also involved in regulating metal-activated transcription. In several species, cadmium induces heat shock genes. Recently much progress has been made in elucidating the cellular machinery that regulates this metal-inducible gene expression. This review summarizes these recent advances in understanding the role of some known cadmium-responsive genes and the molecular mechanisms that activate metal-responsive transcription factor, MTF-1.

• Journal of Plant Biotechnology
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• v.45 no.4
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• pp.315-321
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• 2018

Molecular and functional characterization of proteins and their levels is of great interest in understanding the mechanism of diverse cellular processes. In this study, we report on the convenient Escherichia coli-based protein expression system that allows recombinant of soluble proteins expression and cytosolic domain of membrane-localised kinases, followed by the detection of autophosphorylation activity in protein kinases. This approach is applied to regulatory proteins of Arabidopsis thaliana, including 14-3-3, calmodulin, calcium-dependent protein kinase, TERMINAL FLOWER 1(TFL1), FLOWERING LOCUS T (FT), receptor-like cytoplasmic kinase and cytoplasmic domain of leucine-rich repeat-receptor like kinase proteins. Our Western blot analysis which uses phospho-specific antibodies showed that five putative LRR-RLKs and two putative RLCKs have autophosphorylation activity in vitro on threonine and/or tyrosine residue(s), suggesting their potential role in signal transduction pathways. Our findings were also discussed in the broader context of recombinant expression and biochemical analysis of soluble and membrane-localised receptor kinases in microbial systems.

• Development and Reproduction
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• v.25 no.1
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• pp.67-72
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• 2021

This study investigated the IGF-1 signal in specific tissues using Pacific oysters artificially matured via water temperature elevation. Pacific oysters were subjected to water temperature elevation from March to June, and 20 were randomly sampled each month. The condition index (CI) and tissue weight rate (TWR) were examined by measuring shell length, shell height, shell width, and soft tissue weight. The IGF-1 signal in tissues (adductor muscle, digestive glands, gills, labial palps, mantle edges, and gonads) was analyzed by sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. From April to June, the TWR of females and males increased from 19.1±2.9 to 21.0±3.6 and 18.2±2.0 to 19.2±2.5, respectively, while the CI remained the same. The IGF-1 signal in each tissue differed. IGF-1 was expressed in the adductor muscle, while tyrosine was expressed in all tissues. The phosphor (p)-ERK and p-AKT activities were high in the adductor muscle, mantle edge, and gonads. IGF-1 signaling affected the growth and maturity of the Pacific oysters examined.