• Molecular & Cellular Toxicology
• /
• v.5 no.3
• /
• pp.222-229
• /
• 2009

Our previous finding that pre-initiation treatment of indole-3-carbinol (I3C) represents a chemopreventive effect in dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis has prompted us to test the global expression of genes at an early stage. Rats were continuously fed 300 ppm I3C in their diet at 6 weeks of age and were injected with DMBA at 7 weeks of age, and were sacrificed at 8 weeks of age. Global gene expression analysis using oligonucleotide microarrays was conducted to detect altered genes in DMBA- or DMBA plus I3C-treated mammary glands. Altered genes were identified by fold changes of 1.2 and by t-test (P<0.05) from the log ratios of the hybridization intensity of samples between control (Group 1) and DMBA (Group 2), and from those of samples between DMBA (Group 2) and DMBA plus I3C (Group 3). From these genes, we chose altered genes that were up- or down-regulated by DMBA treatment and recovered to the control level by I3C treatment. For early stage of carcinogenesis, I3C treatment induced the recovery to normal levels of several genes including cell cycle pathway (cyclin B2, cell division cycle 2 homolog A), MAP signaling pathway (fibroblast growth factor receptor 1, platelet derived growth factor receptor, beta polypeptide), and insulin signaling (protein phosphatase 1, regulatory (inhibitor) subunit 3B and flotillin 2), which were up-regulated by DMBA treatment. In addition, I3C treatment induced the recovery to normal levels of several genes including those of MAPK signaling (transforming growth factor, beta receptor 1 and protein phosphatase 3, catalytic subunit, beta isoform), which were down-regulated by DMBA treatment. These results suggest that the targeting of these genes presents a possible approach for chemoprevention in DMBA-induced mammary carcinogenesis.

• The Korean Journal of Physiology and Pharmacology
• /
• v.24 no.5
• /
• pp.395-402
• /
• 2020

This study has investigated the effect of a potent bioflavonoid, troxerutin, on diabetes-induced changes in pro-inflammatory mediators and expression of microRNA-146a and nuclear factor-kappa-B (NF-κB) signaling pathway in aortic tissue of type-I diabetic rats. Male Wistar rats were randomly divided into four groups (n = 6/each): healthy, healthy-troxerutin, diabetic, and diabetic-troxerutin. Diabetes was induced by streptozotocin injection (60 mg/kg; intraperitoneally) and lasted 10 weeks. Troxerutin (150 mg/kg/day) was administered orally for last month of experiment. Inflammatory cytokines IL-1β, IL-6, and TNF-α, as well as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM), cyclooxygenase-II (COX-II), and inducible-nitric oxide synthase (iNOS) were measured on aortic samples by enzyme-linked immunosorbent assay. Gene expressions for transcription factor NF-κB, interleukin-1 receptor-associated kinase-1 (IRAK-1), TNF receptor-associated factor-6 (TRAF-6), and microRNA-146a were determined using real-time polymerase chain reaction. Ten-week diabetes significantly increased mRNA levels of IRAK-1, TRAF-6, NF-κB, and protein levels of cytokines IL-1β, IL-6, TNF-α, adhesion molecules ICAM-1, VCAM, and iNOS, COX-II, and decreased expression of microRNA-146a as compared with healthy rats (p < 0.05 to p < 0.01). However, one month treatment of diabetic rats with troxerutin restored glucose and insulin levels, significantly decreased expression of inflammatory genes and pro-inflammatory mediators and increased microRNA level in comparison to diabetic group (p < 0.05 to p < 0.01). In healthy rats, troxerutin had significant reducing effect only on NF-κB, TNF-α and COX-II levels (p < 0.05). Beside slight improvement of hyperglycemia, troxerutin prevented the activation of NF-κB-dependent inflammatory signaling in the aorta of diabetic rats, and this response may be regulated by microRNA-146a.

• Journal of Ginseng Research
• /
• v.46 no.4
• /
• pp.526-535
• /
• 2022

Background: During the pathogenesis of tendinopathy, the chronic inflammation caused by the injury and apoptosis leads to the generation of scars. Ginsenoside Rg1 (Rg1) is extracted from ginseng and has anti-inflammatory effects. Rg1 is a unique phytoestrogen that can activate the estrogen response element. This research aimed to explore whether Rg1 can function in the process of tendon repair through the estrogen receptor. Methods: In this research, the effects of Rg1 were evaluated in tenocytes and in a rat model of Achilles tendinitis (AT). Protein levels were shown by western blotting. qRT-PCR was employed for evaluating mRNA levels. Cell proliferation was evaluated through EdU assay and cell migration was evaluated by transwell assay and scratch test assay. Results: Rg1 up-regulated the expression of matrix-related factors and function of tendon in AT rat model. Rg1 reduced early inflammatory response and apoptosis in the tendon tissue of AT rat model. Rg1 promoted tenocyte migration and proliferation. The effects of Rg1 on tenocytes were inhibited by ICI182780. Rg1 activates the insulin-like growth factor-I receptor (IGF1R) and MAPK signaling pathway. Conclusion: Rg1 promotes injured tendon healing in AT rat model through IGF1R and MAPK signaling pathway activation.

• The Journal of the Convergence on Culture Technology
• /
• v.4 no.1
• /
• pp.315-323
• /
• 2018

Rapid increase of diabetic population is a major health concern in Korea. In a trial to develop food components which can prevent and/or cure diabetes, we investigated the anti-diabetic activity of curcumin in high fat diet (HFD)-induced type 2 diabetes mellitus (T2DM) animal model. C57BL/6 mice were divided into three groups: normal diet (ND), high fat diet (HFD), and curcumin (CUR, HFD+0.02% curcumin). Mice were fed each diet for 16 weeks. CUR significantly reduced body weight gain, the levels of plasma glucose, insulin, total-cholesterol (T-C), and LDL-C, whereas increased HDL-C compared to those of HFD group. Notably, insulin signaling pathway was activated by CUR. This suggests that CUR improves obesity-associated T2DM by overcoming insulin resistance in part.

• Molecules and Cells
• /
• v.38 no.12
• /
• pp.1044-1053
• /
• 2015

This study first investigated the effects of corn gluten hydrolysate (CGH) (1.5 g/day) administration for 7 days on appetite-responsive genes in lean Sprague-Dawley (SD) rats. In a second set of experiments, the metabolic changes occurring at multiple time points over 8 weeks in response to CGH (35.33% wt/wt) were observed in high-fat (HF, 60% of energy as fat) diet-fed SD rats. In lean rats, the hypothalamus neuropeptide-Y and proopiomelanocortin mRNA levels of the CGH group were significantly changed in response to CGH administration. In the second part of the study, CGH treatment was found to reduce body weight and perirenal and epididymal fat weight. CGH also prevented an increase in food intake at 2 weeks and lowered plasma leptin and insulin levels in comparison with the HF group. This reduction in the plasma and hepatic lipid levels was followed by improved insulin resistance, and the beneficial metabolic effects of CGH were also partly related to increases in plasma adiponectin levels. The Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR), an index of insulin resistance, was markedly improved in the HF-CGH group compared with the HF group at 6 weeks. According to the microarray results, adipose tissue mRNA expression related to G-protein coupled receptor protein signaling pathway and sensory perception was significantly improved after 8 weeks of CGH administration. In conclusion, the present findings suggest that dietary CGH may be effective for improving hyperglycemia, dyslipidemia and insulin resistance in diet-induced obese rats as well as appetite control in lean rats.

• Journal of Ginseng Research
• /
• v.43 no.4
• /
• pp.527-538
• /
• 2019

Background: Ginsenoside Rg1 was shown to exert ligand-independent activation of estrogen receptor (ER) via mitogen-activated protein kinase-mediated pathway. Our study aimed to delineate the mechanisms by which Rg1 activates the rapid ER signaling pathways. Methods: ER-positive human breast cancer MCF-7 cells and ER-negative human embryonic kidney HEK293 cells were treated with Rg1 ($10^{-12}M$, $10^{-8}M$), $17{\beta}$-estradiol ($10^{-8}M$), or vehicle. Immunoprecipitation was conducted to investigate the interactions between signaling protein and ER in MCF-7 cells. To determine the roles of these signaling proteins in the actions of Rg1, small interfering RNA or their inhibitors were applied. Results: Rg1 rapidly induced $ER{\alpha}$ translocation to plasma membrane via caveolin-1 and the formation of signaling complex involving linker protein (Shc), insulin-like growth factor-I receptor, modulator of nongenomic activity of ER (MNAR), $ER{\alpha}$, and cellular nonreceptor tyrosine kinase (c-Src) in MCF-7 cells. The induction of extracellular signal-regulated protein kinase and mitogen-activated protein kinase kinase (MEK) phosphorylation in MCF-7 cells by Rg1 was suppressed by cotreatment with small interfering RNA against these signaling proteins. The stimulatory effects of Rg1 on MEK phosphorylation in these cells were suppressed by both PP2 (Src kinase inhibitor) and AG1478 [epidermal growth factor receptor (EGFR) inhibitor]. In addition, Rg1-induced estrogenic activities, EGFR and MEK phosphorylation in MCF-7 cells were abolished by cotreatment with G15 (G protein-coupled estrogen receptor-1 antagonist). The increase in intracellular cyclic AMP accumulation, but not Ca mobilization, in MCF-7 cells by Rg1 could be abolished by G15. Conclusion: Ginsenoside Rg1 exerted estrogenic actions by rapidly inducing the formation of ER containing signalosome in MCF-7 cells. Additionally, Rg1 could activate EGFR and c-Src ER-independently and exert estrogenic effects via rapid activation of membrane-associated ER and G protein-coupled estrogen receptor.

• Food Science and Preservation
• /
• v.22 no.6
• /
• pp.893-900
• /
• 2015

In this study, we evaluated the antidiabetic effect of a submerged culture of Ceriporia lacerata mycelium (CL01) on hematological indices, as well as protein and mRNA expression of the insulin-signaling pathway, in db/db mice. After CL01 was administrated for 4 weeks, blood glucose levels decreased consistently, and plasma insulin and c-peptide levels each decreased by roughly 55.8%, 40% of those in the negative control (p<0.05). With regard to HOMA-IR, an insulin resistance index, insulin resistance of the CL01-fed group improved over that of the negative control group by about 62% (p<0.05). In addition, we demonstrated that the protein expression levels of pIR, pAkt, pAMPK, and GLUT4 and the mRNA expression levels of Akt2, IRS1, and GLUT4 in the muscle cells of db/db mice increased in the CL01-fed group compared to the corresponding levels in the control group. These results demonstrate that CL01 affects glucose metabolism, upregulates protein and gene expression in the insulin-signaling pathway, and decreases blood glucose levels effectively by improving insulin sensitivity. More than 90% of those who suffer from type 2 diabetes are more likely to suffer from hyperinsulinemia, hypertension, obesity, and other comorbidities because of insulin resistance. Therefore, it is possible that CL01 intake could be used as a fundamental treatment for type 2 diabetes by lowering insulin resistance, and these results may prove be useful as basic evidence for further research into the mechanisms of a cure for type 2 diabetes.

• Journal of Life Science
• /
• v.22 no.10
• /
• pp.1428-1433
• /
• 2012

Longevity is an exciting but difficult subject to study because it is determined by complex processes that require the coordinated action of several genetic factors as well as physiological and environmental influences. Genetic approaches have been applied to animal models to identify the molecular mechanism responsible for longevity. Several experimental model organisms obtained over the last decades suggest that the complete deletion of a single gene by gene targeting has proven to be an invaluable tool for the discovery of the mechanisms underlying longevity. The first discovery of long-lived mutants came from Caenorhabditis elegans research, which identified the insulin/IGF-1 pathway as responsible for longevity in this worm. IGF-1 is a multifunctional polypeptide that has sequence similarity to insulin and is involved in normal growth and development of cells. Several factors in the IGF-1 system have since been studied by gene targeting in the control of longevity in lower species, including nematode and fruit fly. In addition, significant progress has been made using mice models to extend the lifespan by targeted mutations that interfere with growth hormone/IGF-1 and IGF-1 signaling cascades. A recent finding that IGF-1 is involved in aging in mice was achieved by using liver-specific knockout mutant mice, and this clearly demonstrated that the IGF-1 signal pathway can extend the lifespan in both invertebrates and vertebrate models. Although the underlying molecular mechanisms for the control of longevity are not fully understood, it is widely accepted that reduced IGF-1 signaling plays an important role in the control of aging and longevity. Several genes involved in the IGF-1 signaling system are reviewed in relation to longevity in genetically modified mice models.

• BMB Reports
• /
• v.54 no.6
• /
• pp.323-328
• /
• 2021

Periodontal diseases have been reported to have a multidirectional association with metabolic disorders. We sought to investigate the correlation between periodontitis and diabetes or fatty liver disease using HFD-fed obese mice inoculated with P. gingivalis. Body weight, alveolar bone loss, serological biochemistry, and glucose level were determined to evaluate the pathophysiology of periodontitis and diabetes. For the evaluation of fatty liver disease, hepatic nonalcoholic steatohepatitis (NASH) was assessed by scoring steatosis, inflammation, hepatocyte ballooning and the crucial signaling pathways involved in liver metabolism were analyzed. The C-reactive protein (CRP) level and NASH score in P. gingivalis-infected obese mice were significantly elevated. Particularly, the extensive lobular inflammation was observed in the liver of obese mice infected with P. gingivalis. Moreover, the expression of metabolic regulatory factors, including peroxisome proliferator-activated receptor γ (Pparγ) and the fatty acid transporter Cd36, was up-regulated in the liver of P. gingivalis-infected obese mice. However, inoculation of P. gingivalis had no significant influence on glucose homeostasis, insulin resistance, and hepatic mTOR/AMPK signaling. In conclusion, our results indicate that P. gingivalis can induce the progression of fatty liver disease in HFD-fed mice through the upregulation of CD36-PPARγ axis.

• Journal of Ginseng Research
• /
• v.48 no.1
• /
• pp.12-19
• /
• 2024

Skeletal muscle (SM) is the largest organ of the body and is largely responsible for the metabolism required to maintain body functions. Furthermore, the maintenance of SM is dependent on the activation of muscle satellite (stem) cells (MSCs) and the subsequent proliferation and fusion of differentiating myoblasts into mature myofibers (myogenesis). Natural compounds are being used as therapeutic options to promote SM regeneration during aging, muscle atrophy, sarcopenia, cachexia, or obesity. In particular, ginseng-derived compounds have been utilized in these contexts, though ginsenoside Rg1 is mostly used for SM mass management. These compounds primarily function by activating the Akt/mTOR signaling pathway, upregulating myogenin and MyoD to induce muscle hypertrophy, downregulating atrophic factors (atrogin1, muscle ring-finger protein-1, myostatin, and mitochondrial reactive oxygen species production), and suppressing the expressions of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cachexia. Ginsenoside compounds are also used for obesity management, and their anti-obesity effects are attributed to peroxisome proliferator activated receptor gamma (PPARγ) inhibition, AMPK activation, glucose transporter type 4 (GLUT4) translocation, and increased phosphorylations of insulin resistance (IR), insulin receptor substrate-1 (IRS-1), and Akt. This review was undertaken to provide an overview of the use of ginseng-related compounds for the management of SM-related disorders.