• Asian-Australasian Journal of Animal Sciences
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• v.20 no.7
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• pp.1156-1168
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• 2007

The somatotropic (GH-IGF-I) axis consists of many hormonal and nutritional factors that control GH release from the somatotrophs in the anterior pituitary. The GH-releasing substances are GHRH and GHS (GHRP or ghrelin), while the GH release-inhibiting substances are somatostatin (SRIF), insulin-like growth factor-I (IGF-I), leptin and glucocorticoids. However, there is evidence showing that nutrition is involved in the control of the somatotropic axis. In addition, weaning is a drastic event for neonates because their alimentary and endocrine circumstances are changed due to the switch, even if gradual, from a liquid milk diet to one composed of such solids as hay and grains. The biological role of ghrelin is one of the hormonal factors that have been focused on ever since ghrelin was discovered at the end of the last century. A 27-amino acid peptide that is mainly synthesized and released from the abomasum epithelium, ghrelin has not been fully evaluated in relation to the somatotropic axis of the ruminant. It has also proven difficult even to investigate the cellular mechanisms of ghrelin action, because this hormone exerts animal-species-dependent actions via a complex set of intracellular signaling pathways. This is also the case for the action of leptin. Another substance, IGF-I, shows a partial inhibitory action on GH secretion in the ruminant. The effect of nutrition is also different among animal species. This is evident by the fact that undernutrition suppresses the circulating GH levels in rodents, but increases it in ruminants and humans. Recently, weaning has been shown to change the postprandial GH responses in ruminants; milk feeding increases, but hay and concentrate feeding suppress, the postprandial circulating GH levels. Even if the postprandial GH level is increased, the ghrelin level is decreased by milk feeding. Macronutrients also possess stimulatory and inhibitory actions on GH secretion in vivo and in vitro. These findings indicate the complexity of the control mechanisms of the somatotropic axis. In the present review, we summarize recent findings on the factors controlling the axis of the ruminant.

• Journal of Dairy Science and Biotechnology
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• v.34 no.1
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• pp.1-7
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• 2016

Colostrum, a nutrient-rich fluid produced by female mammals after giving birth, is the specific initial diet of mammalian neonates. Colostrum is important for the nutrition, growth, and development of newborn infants and contributes to the immunologic defense of neonates. It contains immunoglobulins, antimicrobial peptides, such as lactoferrin and lactoperoxidase, and other bioactive molecules, including growth factors, such as IGF (insulin-like growth factor), EGF (epithermal growth factor), $TGF-{\beta}$ (transforming growth factor), and FGF (fibroblast growth factor). Bovine colostrum is a rich source of growth factors, which play a central role in wound healing. The biological activities of colostrum emphasize the relevance of the synergistic activity of growth factors to stimulate keratinocyte proliferation and migration, which are essential for tissue repair. Colostrum increases the expression of early differentiation markers, such as keratin 1 and 10 and involucrin, and late differentiation markers, including loricrin and filaggrin. Additionally, colostrum increases granulation tissue volume in the dermis, suggesting that it has a beneficial effect on wound healing. The therapeutic use of colostrum or individual peptides present in colostrum has a positive and curative influence on various gastrointestinal diseases.

• Journal of Ginseng Research
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• v.42 no.4
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• pp.436-446
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• 2018

Background: The potential therapeutic values of Korean Red Ginseng extract (KRGE) in autoimmune disorders of nervous system have not been fully investigated. Methods: We used an acute experimental autoimmune encephalomyelitis animal model of multiple sclerosis and determined the effects and mechanism of KRGE on spinal myelination. Results: Pretreatment with KRGE (100 mg/kg, orally) for 10 days before immunization with myelin basic protein $(MBP)_{68-82}$ peptide exerted a protective effect against demyelination in the spinal cord, with inhibited recruitment and activation of immune cells including microglia, decreased mRNA expression of detrimental inflammatory mediators (interleukin-6, interferon-${\gamma}$, and cyclooxygenase-2), but increased mRNA expression of protective inflammatory mediators (insulin-like growth factor ${\beta}1$, transforming growth factor ${\beta}$, and vascular endothelial growth factor-1). These results were associated with significant downregulation of p38 mitogen-activated protein kinase and nuclear factor-${\kappa}B$ signaling pathways in microglia/macrophages, T cells, and astrocytes. Conclusion: Our findings suggest that KRGE alleviates spinal demyelination in acute experimental autoimmune encephalomyelitis through inhibiting the activation of the p38 mitogen-activated protein kinase/nuclear factor-${\kappa}B$ signaling pathway. Therefore, KRGE might be used as a new therapeutic for autoimmune disorders such as multiple sclerosis, although further investigation is needed.

• Journal of Life Science
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• v.18 no.7
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• pp.931-939
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• 2008

The purpose of this study was to determine the effect of energy supplement on responses of plasma insulin-like growth factor (IGF)-1 and IGF binding proteins (IGFBPs) to growth hormone-releasing peptide-2 (GHRP-2) administration in normal protein-fed wethers, and to observe the effect of GHRP-2 treatment on hepatic growth hormone (GH) receptor in well-fed wethers. Plasma IGF-1 and 39-42 kDa IGFBP-3 during the HENP (CP, crude protein 0.34 and TDN, total digestible nutrients 1.83 kg/day DM, dry matter intake) treatment period were higher than in the LENP (CP 0.32 kg and TDN 0.87 kg/day DM intake) period (P<0.05). The response of GH was stimulated by GHRP-2 ($12.5\;{\mu}g/kg$ body weight/day) administration during both of the feed treatment periods (P<0.05). The area under curve (AUC) increment and average concentration of GH (0-180 min) with GHRP-2 administration was higher during HENP treatment than LENP treatment (P<0.01). During the HENP treatment period from day 1 to day 7 of twice daily GHRP-2 treatment, the plasma IGF-1 increment was increased on days 2, 6 and 7 of GHRP-2 administration (P<0.05). On the basis of ligand blotting, the proportions of plasma 39-43 kDa IGFBP-3 during the HENP treatment period only showed a significant difference on days 6 and 7 with GHRP-2 administration. No significant difference in the specific binding of $^{125}I-labeled$ oGH to hepatic membranes was detected between the saline and GHRP-2 treatments of the HENP-fed wethers. These results suggest that the nutritional balance between energy and protein may affect the endogenous GH / IGF-1 axis as well as plasma IGFBP-3 levels.

• Experimental and Molecular Medicine
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• v.50 no.12
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• pp.2.1-2.12
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• 2018

Glucagon-like peptide-1 (GLP-1) has a broad spectrum of biological activity by regulating metabolic processes via both the direct activation of the class B family of G protein-coupled receptors and indirect nonreceptor-mediated pathways. GLP-1 receptor (GLP-1R) agonists have significant therapeutic effects on non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in animal models. However, clinical studies indicated that GLP-1 treatment had little effect on hepatic steatosis in some NAFLD patients, suggesting that GLP-1 resistance may occur in these patients. It is well-known that the gut metabolite sodium butyrate (NaB) could promote GLP-1 secretion from intestinal L cells. However, it is unclear whether NaB improves hepatic GLP-1 responsiveness in NAFLD. In the current study, we showed that the serum GLP-1 levels of NAFLD patients were similar to those of normal controls, but hepatic GLP-1R expression was significantly downregulated in NAFLD patients. Similarly, in the NAFLD mouse model, mice fed with a high-fat diet showed reduced hepatic GLP-1R expression, which was reversed by NaB treatment and accompanied by markedly alleviated liver steatosis. In addition, NaB treatment also upregulated the hepatic p-AMPK/p-ACC and insulin receptor/insulin receptor substrate-1 expression levels. Furthermore, NaB-enhanced GLP-1R expression in HepG2 cells by inhibiting histone deacetylase-2 independent of GPR43/GPR109a. These results indicate that NaB is able to prevent the progression of NAFL to NASH via promoting hepatic GLP-1R expression. NaB is a GLP-1 sensitizer and represents a potential therapeutic adjuvant to prevent NAFL progression to NASH.

• Clinical and Experimental Reproductive Medicine
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• v.23 no.3
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• pp.247-268
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• 1996

It has been known for a long time that gonadotropins and steroid hormones play a pivotal role in a series of reproductive biological phenomena including the maturation of ovarian follicles and oocytes, ovulation and implantation, maintenance of pregnancy and fetal growth & development, parturition and mammary development and lactation. Recent investigations, however, have elucidated that in addition to these classic hormones, multiple growth factors also are involved in these phenomena. Most growth factors in reproductive organs mediate the actions of gonadotropins and steroid hormones or synergize with them in an autocrine/paracrine manner. The insulin-like growth factor(IGF) system, which is one of the most actively investigated areas lately in the reproductive organs, has been found to have important roles in a wide gamut of reproductive phenomena. In the present communication, published literature pertaining to the intrauterine IGF system will be reviewed preceded by general information of the IGF system. The IGF family comprises of IGF-I & IGF-II ligands, two types of IGF receptors and six classes of IGF-binding proteins(IGFBPs) that are known to date. IGF-I and IGF-II peptides, which are structurally homologous to proinsulin, possess the insulin-like activity including the stimulatory effect of glucose and amino acid transport. Besides, IGFs as mitogens stimulate cell division, and also play a role in cellular differentiation and functions in a variety of cell lines. IGFs are expressed mainly in the liver and messenchymal cells, and act on almost all types of tissues in an autocrine/paracrine as well as endocrine mode. There are two types of IGF receptors. Type I IGF receptors, which are tyrosine kinase receptors having high-affinity for IGF-I and IGF-II, mediate almost all the IGF actions that are described above. Type II IGF receptors or IGF-II/mannose-6-phosphate receptors have two distinct binding sites; the IGF-II binding site exhibits a high affinity only for IGF-II. The principal role of the type II IGF receptor is to destroy IGF-II by targeting the ligand to the lysosome. IGFs in biological fluids are mostly bound to IGFBP. IGFBPs, in general, are IGF storage/carrier proteins or modulators of IGF actions; however, as for distinct roles for individual IGFBPs, only limited information is available. IGFBPs inhibit IGF actions under most in vitro situations, seemingly because affinities of IGFBPs for IGFs are greater than those of IGF receptors. How IGF is released from IGFBP to reach IGF receptors is not known; however, various IGFBP protease activities that are present in blood and interstitial fluids are believed to play an important role in the process of IGF release from the IGFBP. According to latest reports, there is evidence that under certain in vitro circumstances, IGFBP-1, -3, -5 have their own biological activities independent of the IGF. This may add another dimension of complexity of the already complicated IGF system. Messenger ribonucleic acids and proteins of the IGF family members are expressed in the uterine tissue and conceptus of the primates, rodents and farm animals to play important roles in growth and development of the uterus and fetus. Expression of the uterine IGF system is regulated by gonadal hormones and local regulatory substances with temporal and spatial specificities. Locally expressed IGFs and IGFBPs act on the uterine tissue in an autocrine/paracrine manner, or are secreted into the uterine lumen to participate in conceptus growth and development. Conceptus also expresses the IGF system beginning from the peri-implantation period. When an IGF family member is expressed in the conceptus, however, is determined by the presence or absence of maternally inherited mRNAs, genetic programming of the conceptus itself and an interaction with the maternal tissue. The site of IGF action also follows temporal (physiological status) and spatial specificities. These facts that expression of the IGF system is temporally and spatially regulated support indirectly a hypothesis that IGFs play a role in conceptus growth and development. Uterine and conceptus-derived IGFs stimulate cell division and differentiation, glucose and amino acid transport, general protein synthesis and the biosynthesis of mammotropic hormones including placental lactogen and prolactin, and also play a role in steroidogenesis. The suggested role for IGFs in conceptus growth and development has been proven by the result of IGF-I, IGF-II or IGF receptor gene disruption(targeting) of murine embryos by the homologous recombination technique. Mice carrying a null mutation for IGF-I and/or IGF-II or type I IGF receptor undergo delayed prenatal and postnatal growth and development with 30-60% normal weights at birth. Moreover, mice lacking the type I IGF receptor or IGF-I plus IGF-II die soon after birth. Intrauterine IGFBPs generally are believed to sequester IGF ligands within the uterus or to play a role of negative regulators of IGF actions by inhibiting IGF binding to cognate receptors. However, when it is taken into account that IGFBP-1 is expressed and secreted in primate uteri in amounts assessedly far exceeding those of local IGFs and that IGFBP-1 is one of the major secretory proteins of the primate decidua, the possibility that this IGFBP may have its own biological activity independent of IGF cannot be excluded. Evidently, elucidating the exact role of each IGFBP is an essential step into understanding the whole IGF system. As such, further research in this area is awaited with a lot of anticipation and attention.

• Food Science and Preservation
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• v.22 no.1
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• pp.134-144
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• 2015

The anti-diabetic effects of Allium tuberosum Rottler extracts (ATE) and ATE fermented with lactic acid bacteria in db/db mice were evaluated. The electron donating activity of ATE fermented with Lactobacillus plantarum, and Lactobacillus casei, respectively, increased compared to that of ATE, but the superoxide radical scavenging activity of the ATE incubated with L. plantarum decreased. The superoxide radical scavenging activity of the ATE fermented with both L. plantarum and L. casei was similar to that of the ATE. Therefore, fermented ATE (FATE) was prepared for in vivo testing by incubating it with both L. plantarum and L. casei. The db/db mice were divided into six groups: normal (non-diabetic mice), diabetic control (DM), and four experimental groups administered 200 or 400 mg/kg/day ATE (ATE200 and ATE400) and 200 or 400 mg/kg/day FATE (FATE200 and FATE400). Weight gain was significantly inhibited in the FATE200 group compared with that in the other db/db mice groups (p<0.05). The areas under the curve of the ATE400 and FATE400 groups were significantly smaller than that of the DM group in the glucose tolerance evaluation. The serum glucagon-like peptide-1 levels in the ATE400 and FATE400 groups increased. These results indicate that administering ATE and FATE may be effective against anti-hyperglycemia by regulating insulin resistance. In particular, FATE may be beneficial for controlling obesity in type 2 diabetes.

• Proceedings of the Korean Nutrition Society Conference
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• 1995.11b
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• pp.11-34
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• 1995

Growth hormone (GH) plays a key role in regulating postnatal growth and can stimulate growth of animals by acting directly on specific receptors on the plasma membrane of tissues or indirectly through stimulating insulin-like growth factor (IGF)-I synthesis and secretion by the liver and other tissues. IGF-I and IGF-Ⅱ are polypeptides with structural similarity with proinsulin that stimulate cell proliferation by endocrine, paracrine and autocrine mechanisms. The initial event in the metabolic action of IGFs on target cells appears to be their binding to specific receptors on the plasma membrane. Current evidence indicates that the mitogenic actions of both IGFs are mediated primarily by binding to the type I IGF receptors, and that IGF action is also mediated by interactions with IGF-binding proteins (IGFBPs). Six distinct IGFBPs have been identified that are characterized by cell-specific interaction, transcriptional and post-translational regulation by many different effectors, and the ability to either potentiate or inhibit IGF actions. Nutritional deficiencies can have their devastating consequence during growth. Although IGF-I is the major mediator of GH's action on somatic growth, nutritional status of an organism is a critical regulator of IGF-I and IGFBPs. Various nutrient deficiencies result in decreased serum IGF-I levels and altered IGFBP levels, but the blood levels of GH are generally unchanged or elevated in malnutrition. Effects of protein, energy, vitamin C and D, and zinc on serum IGF and IGFBP levels and tissue mRNA levels were reviewed in the text. Multiple factors are involved in the regulation of intestinal epithelial cell growth and differentiation. Among these factors the nutritional status of individuals is the most important. The intestinal epithelium is an important site for mitogenic action of the IGFs in vivo, with exogenous IGF-I stimulating mucosal hyperplasia. Therefore, the IGF system appears to provide and important mechanism linking nutrition and the proliferation of intestinal epithelial cells. In order to study the detailed mechanisms by which intestinal mucosa is regulated, we have utilized IEC-6 cells, an intestinal epithelial cell line and Caco-2 cells, a human colon adenocarcinoma cell line. Like intestinal crypt cells analyzed in vivo or freshly isolated intestinal epithelial cells, IEC-6 cells and Caco-2 cells possess abundant quatities of both type Ⅰ and type Ⅱ IGF receptors. Exogenous IGFs stimulate, whereas addition of IGFBP-2 inhibits IEC-6 cell proliferation. To investigate whether endogenously secreted IGFBP-2 inhibit proliferation, IEC-6 cells were transfected with a full-length rat IGFBP-2 cDNA anti-sense expression construct. IEC-6 cells transfected with anti-sense IGFBP-2 protein in medium. These cells grew at a rate faster than the control cells indicating that endogenous IGFBP-2 inhibits proliferation of IEC-6 cells, probably by sequestering IGFs. IEC-6 cells express many characteristics of enterocyte, but do not undergo differentiation. On the other hand, Caco-2 cells undergo a spontaneous enterocyte differentiation. On the other hand, Caco-2 cells undergo a spontaneous enterocyte differentiation after reaching confluency. We have demonstrated that Caco-2 cells produce IGF-Ⅱ, IGFBP-2, IGFBP-3, and an as yet unidentified 31,000 Mr IGFBP, and that both mRNA and peptide secretion of IGFBP-2 and IGFBP-3 increased, but IGFBP-4 mRNA and protein secretion decreased after the cells reached confluency. These changes occurred in parallel to and were coincident with differentiation of the cells, as measured by expression of sucrase-isomaltase. In addition, Caco-2 cell clones forced to overexpress IGFBP-4 by transfection with a rat IGFBP-4 cDNA construct exhibited a significantly slower growth rate under serum-free conditions and had increased expression of sucrase-isomaltase compared with vector control cells. These results indicate that IGFBP-4 inhibits proliferation and stimulates differentiation of Caco-2 cells, probably by inhibiting the mitogenic actions of IGFs.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2008.04a
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• pp.5-20
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• 2008

GLP-1-based drugs (GLP-1 analogues and DPP IV inhibitors) and incretin mimetics are currently one of the most exciting classes of agents for type II diabetes. GLP-1, a gut peptide, is an incretin that potentiates glucose-dependent insulin release from the pancreas, slows GI-transit and stimulates the proliferation of beta-cells. DPP IV inhibitors act like incretins by inhibiting DPP IV which inactivates GLP-1. LC15-0133 is a competitive, reversible DPP IV inhibitor ($IC_{50}$ = 24 nM, Ki=0.247 nM) with excellent selectivity over other critical human proteases such as DPP II, DPP 8, elastase, trypsin. and urokinase. LC15-0133 showed long half-life and good bioavailability in rats and dogs. Inhibition of plasma DPP IV activity by LC15-0133 was kept more than 50% 24 hours after oral dosing in rats and dogs at 0.1 mg/kg and 0.02 mg/kg, respectively. The Minimum effective doses of LC15-0133 were 0.01 mg/kg for lowering blood glucose excursion during oral glucose tolerance test and 0.1 mg/kg for increasing glucose-induced GLP-1 response in C57BL/6 mice. Repeat oral administration of LC15-0133 for 1 month delayed the progression to diabetes and reduced HbA1c levels in a dose-dependent manner in Zucker Diabetic Fatty rats. In conclusion, LC15-0133 is a novel, potent, selective and orally active DPP IV inhibitor and showed an excellent blood glucose lowering effects in various animal models.

• Korean journal of applied entomology
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• v.54 no.4
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• pp.359-367
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• 2015

Physiological plasticity of insects can be closely related with their epigenetic change. This hypothesis was tested using a polyphagous lepidopteran insect, Spodoptera exigua, by assessing the effects of different diets on development and DNA methylation. Three different diets (Welsh onion (WO), Chinese cabbage (CC), artificial diet (AD)) were assessed by feeding a cohort of larvae from neonate to last instar. There were significant differences in larval developmental rate, pupal weight and adult emergence according to diet treatments. AD-fed larvae exhibited the fastest developmental rate along with the highest pupal weight and adult emergence. Among natural hosts, WO was more favorable for development of S. exigua than CC. Total hemolymph proteins and sugars in the last instar larvae were varied among different diets. Gene expression of an insulin-like peptide (SeILP1) presumably associated with development was also varied among diets. Cytosine methylation of genomic DNA was assessed using a monoclonal antibody. Genomic DNA of S. exigua larvae was methylated. DNA methylation was apparently varied among different diet-fed larvae. The facts that a cohort of S. exigua was differentiated in developmental rate and cytosine methylation by different diets suggest that epigenetic factor(s) may play a crucial role in the physiological plasticity.