• Nutrition Research and Practice
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• v.15 no.5
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• pp.591-603
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• 2021

BACKGROUND/OBJECTIVES: Unregulated inflammatory responses caused by hyperglycemia may induce diabetes complications. Hesperetin, a bioflavonoid, is a glycoside in citrus fruits and is known to have antioxidant and anticarcinogenic properties. However, the effect of inflammation on the diabetic environment has not been reported to date. In this study, we investigated the effect of hesperetin on proinflammatory cytokine secretion and its underlying mechanistic regulation in THP-1 macrophages with co-treatment LPS and hyperglycemic conditions. MATERIALS/METHODS: THP-1 cells differentiated by PMA (1 µM) were cultured for 48 h in the presence or absence of hesperetin under normoglycemic (5.5 mM/L glucose) or hyperglycemic (25 mM/L glucose) conditions and then treated with LPS (100 ng/mL) for 6 h before harvesting. Inflammation-related proteins and mRNA levels were evaluated by enzyme-linked immunosorbent assay, western blot, and quantitative polymerase chain reaction analyses. RESULTS: Hesperetin (0-100 µM, 48 h) treatment did not affect cell viability. The tumor necrosis factor-α and interleukin-6 levels increased in cells co-treated with LPS under hyperglycemic conditions compared to normoglycemic conditions, and these increases were decreased by hesperetin treatment. The TLR2/4 and MyD88 activity levels increased in cells co-treated with LPS under hyperglycemic conditions compared to normoglycemic conditions; however, hesperetin treatment inhibited the TLR2/4 and MyD88 activity increases. In addition, nuclear factor-κB (NF-κB) and Acetyl-NF-κB levels increased in response to treatment with LPS under hyperglycemic conditions compared to normoglycemic conditions, but those levels were decreased when treated with hesperetin. SIRT3 and SIRT6 expressions were increased by hesperetin treatment. CONCLUSIONS: Our results suggest that hesperetin may be a potential agent for suppressing inflammation in diabetes.

• Exercise Science
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• v.26 no.3
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• pp.223-228
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• 2017

PURPOSE: This study investigated the protective role of high-intensity interval training against acute liver injury induced by D-galactosamine (D-Gal)/lipopolysaccharide (LPS). METHODS: A total of 30 male BALB/c mice aged 5-week were randomly assigned to high-intensity, interval training group (EX, n=10) or control group in cage (Non-EX, n=20) for 10 weeks. Peritoneal injection of D-Gal (700 mg/kg body weight) and LPS ($10{\mu}g/kg$ body weight) was applied to induce acute liver injury, and liver tissue was harvested 6 hours after the injection. Hematoxylin and Eosin (H&E) staining was used for liver histology. Real-time PCR was used to quantify expression of pro-inflammatory and anti-inflammatory genes in the liver. RESULTS: The liver histology showed that D-Gal/LPS treatment resulted in hepatic damage and increased number of neutrophils in conjunction with upregulation of hepatic IL-6 and $TNF-{\alpha}$ mRNAs and downregulation of hepatic $PPAR{\alpha}$ and SIRT1 mRNAs. On the other hand, the 10-week interval training resulted in a significant improvement in cardiorespiratory fitness assessed as run time to exhaustion on a treadmill. In addition, the interval training attenuated the D-Gal/LPS-induced liver damage and increased number of neutrophil in conjunction with downregulation of hepatic IL-6 and $TNF-{\alpha}$ mRNAs and upregulation of hepatic $PPAR{\alpha}$ and SIRT1 mRNAs. CONCLUSIONS: This study suggests that high-intensity interval training suppresses the D-Gal and LPS-induced acute liver damage and inflammatory responses.

• Journal of Korean Medicine for Obesity Research
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• v.14 no.1
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• pp.13-23
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• 2014

Objectives: This study was performed to evaluate the effects of Metformin and Lonicerae Flos, Agrobacterium Rhizogenes, Coptidis Rhizoma, Atractylodis Rhizoma Alba, Houttuyniae Herba extracs combinations on hypoglycemia in RAW 264.7 cells. Methods: Expressions of Sirt1, p-adenosine monophosphate-activated kinase (p-AMPK), AMPK-alpha, peroxisome proliferator activated receptor (PPAR)-alpha, PPAR-gamma, X-box binding protein 1 (XBP-1), tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were analyzed by real time polymerase chain reaction and Western blotting analysis. Results: The level of gene expression of Sirt1, p-AMPK, AMPK-alpha, PPAR-alpha and XBP-1 in relation to that of beta-actin were increased or decreased significantly with the Metformin and Lonicerae Flos, Agrobacterium Rhizogenes extracts combination groups. The level of gene expression of TNF-alpha and IL-6 were increased significantly with the Metformin and Houttuyniae Herba, Coptidis Rhizoma extracts combination groups. Conclusions: Metformin and Lonicerae Flos, Agrobacterium Rhizogenes extracts combination groups showed synergistic hypoglycemic effects by increasing AMPK and PPAR gene expression in RAW 264.7 cells.

• Biomolecules & Therapeutics
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• v.31 no.6
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• pp.629-639
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• 2023

Cardiovascular diseases (CVDs) are the most common cardiovascular system disorders. Cellular senescence is a key mechanism associated with dysfunction of aged vascular endothelium. Hyaluronic acid and proteoglycan link protein 1 (HAPLN1) has been known to non-covalently link hyaluronic acid (HA) and proteoglycans (PGs), and forms and stabilizes HAPLN1-containing aggregates as a major component of extracellular matrix. Our previous study showed that serum levels of HAPLN1 decrease with aging. Here, we found that the HAPLN1 gene expression was reduced in senescent human umbilical vein endothelial cells (HUVECs). Moreover, a recombinant human HAPLN1 (rhHAPLN1) decreased the activity of senescence-associated β-gal and inhibited the production of senescence-associated secretory phenotypes, including IL-1β, CCL2, and IL-6. rhHAPLN1 also downregulated IL-17A levels, which is known to play a key role in vascular endothelial senescence. In addition, rhHAPLN1 protected senescent HUVECs from oxidative stress by reducing cellular reactive oxygen species levels, thus promoting the function and survival of HUVECs and leading to cellular proliferation, migration, and angiogenesis. We also found that rhHAPLN1 not only increases the sirtuin 1 (SIRT1) levels, but also reduces the cellular senescence markers levels, such as p53, p21, and p16. Taken together, our data indicate that rhHAPLN1 delays or inhibits the endothelial senescence induced by various aging factors, such as replicative, IL-17A, and oxidative stress-induced senescence, thus suggesting that rhHAPLN1 may be a promising therapeutic for CVD and atherosclerosis.

• Nutrition Research and Practice
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• v.10 no.4
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• pp.377-384
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• 2016

BACKGROUND/OBJECTIVES: Resveratrol, a natural polyphenol, has multiple functions in cellular responses including apoptosis, survival, and differentiation. It also participates in the regulation of inflammatory response and oxidative stress. MicroRNA-Let-7A (miR-Let7A), known as a tumor suppressor miRNA, was recently reported to play a crucial role in both inflammation and apoptosis. Therefore, we examined involvement of miR-Let7A in the modulation of inflammation and cell survival/apoptosis regulated by resveratrol. MATERIALS/METHODS: mRNA expression of pro-/anti-inflammatory cytokines and sirtuin 1 (SIRT1), and protein expression of apoptosis signal-regulating kinase 1 (ASK1), p-ASK1, and caspase-3 and cleaved caspase-3 were measured, and cell viability and Hoechst/PI staining for apoptosis were observed in Lipopolysaccharide (LPS)-stimulated human THP-1 macrophages with the treatment of resveratrol and/or miR-Let7A overexpression. RESULTS: Pre-treatment with resveratrol ($25-200{\mu}M$) resulted in significant recovery of the reduced cell viabilities under LPS-induced inflammatory condition and in markedly increased expression of miR-Let7A in non-stimulated or LPS-stimulated cells. Increased mRNA levels of tumor necrosis $factor-{\alpha}$ and interleukin (IL)-6 induced by LPS were significantly attenuated, and decreased levels of IL-10 and brain-derived neurotrophic factor were significantly restored by resveratrol and miR-Let7A overexpression, respectively, or in combination. Decreased expression of IL-4 mRNA by LPS stimulation was also significantly increased by miR-Let7A overexpression co-treated with resveratrol. In addition, decreased SIRT1 mRNA levels, and increased p-ASK1 levels and PI-positive cells by LPS stimulation were significantly restored by resveratrol and miR-Let7A overexpression, respectively, or in combination. CONCLUSIONS: miR-Let7A may be involved in the inflammatory response and cell survival/apoptosis modulated by resveratrol in human THP-1 macrophages.

• Korean Journal of Food Science and Technology
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• v.49 no.6
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• pp.685-692
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• 2017

Mitochondrial biogenesis-a process that leads to an increment in the number and density of mitochondria, improves physical performance and body health by enhancing exercise capacity. In the present study, we investigated the stimulatory effect of Ashitaba and red ginseng complex (ARC) on exercise capacity in L6 skeletal muscle cells and mice. In L6 skeletal muscle cells, ARC increased the mitochondrial contents and ATP production by activating AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-$1{\alpha}$) and up-regulating the mRNA expression of nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor A (TFAM). In the animal experiments, mice treated with ARC showed an increment in exercise capacity as compared with mice treated with Ashitaba extract or red ginseng extract alone. These studies indicate that ARC might serve as a potential natural candidate for enhancing exercise capacity by stimulation of mitochondrial biogenesis.

• The Korea Journal of Herbology
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• v.34 no.6
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• pp.79-89
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• 2019

Objective : This study investigated the anti-diabetic effects of DM1, a herbal mixture with Atractylodis Rhizoma, Anemarrhenae Rhizoma, and Cinnamomi Cortex in high fat diet (HFD)-induced diabetic mice and the mechanism in C2C12 mouse skeletal muscle cells. Methods : The C57B/6 mice were fed high fat for 12 weeks, and then administrated DM1 extract (500 mg/kg, p.o.) for 4 weeks. The changes of body weight, calorie and water intakes, fasting blood glucose levels and the serum levels of glucose, insulin, triglyceride, HDL-cholesterol, AST and ALT were measured in mice. The histological changes of liver and pancreas tissues were also observed by H&E stain. C2C12 myoblasts were differentiated into myotubes and then treated with DM1 extract (0.5, 1, and 2 mg/㎖) for 24 hr. The expression of myosin heavy chain (MHC), PGC1α, Sirt1 and NRF1, and the AMPK phosphorylation were determined in the myotubes by western blot, respectively. Results : The DM1 extract administration significantly decreased the calorie and water intakes, glucose, triglyceride, AST and ALT levels and increased insulin and HDL-cholesterol in HFD-induced diabetic mice. DM1 extract inhibited lipid accumulation in liver tissue and improved glucose tolerance. In C2C12 myotubes, DM1 treatment increased the expression of MHC, PGC1α, Sirt-1, NRF-1 and the AMPK phosphorylation. Conclusion : In our results indicate that DM1 can improve diabetic symptoms by decreasing the obesity, glucose tolerance and fatty liver in HFD-induced diabetic mice, and responsible mechanism is might be related with energy enhancement.

• Biomolecules & Therapeutics
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• v.28 no.6
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• pp.561-568
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• 2020

We examined the anticancer effects of a novel sirtuin inhibitor, MHY2256, on HCT116 human colorectal cancer cells to investigate its underlying molecular mechanisms. MHY2256 significantly suppressed the activity of sirtuin 1 and expression levels of sirtuin 1/2 and stimulated acetylation of forkhead box O1, which is a target protein of sirtuin 1. Treatment with MHY2256 inhibited the growth of the HCT116 (TP53 wild-type), HT-29 (TP53 mutant), and DLD-1 (TP53 mutant) human colorectal cancer cell lines. In addition, MHY2256 induced G0/G1 phase arrest of the cell cycle progression, which was accompanied by the reduction of cyclin D1 and cyclin E and the decrease of cyclin-dependent kinase 2, cyclin-dependent kinase 4, cyclin-dependent kinase 6, phosphorylated retinoblastoma protein, and E2F transcription factor 1. Apoptosis induction was shown by DNA fragmentation and increase in late apoptosis, which were detected using flow cytometric analysis. MHY2256 downregulated expression levels of procaspase-8, -9, and -3 and led to subsequent poly(ADP-ribose) polymerase cleavage. MHY2256-induced apoptosis was involved in the activation of caspase-8, -9, and -3 and was prevented by pretreatment with Z-VAD-FMK, a pan-caspase inhibitor. Furthermore, the autophagic effects of MHY2256 were observed as cytoplasmic vacuolation, green fluorescent protein-light-chain 3 punctate dots, accumulation of acidic vesicular organelles, and upregulated expression level of light-chain 3-II. Taken together, these results suggest that MHY2256 could be a potential novel sirtuin inhibitor for the chemoprevention or treatment of colorectal cancer or both.

• Journal of Life Science
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• v.29 no.8
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• pp.837-845
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• 2019

The purpose of this study was to analyze the effects of aerobic exercise and resveratrol supplementation on mitochondrial biogenesis in skeletal muscle of high-fat diet-induced obese mice. In this study, 4-wk-old C57BL/6 male mice were divided into four groups, with 10 animals in each group: a normal diet group (NC), high-fat diet group (HC), high-fat diet group with resveratrol supplementation (HRe), and high-fat diet GROUP with exercise (HE). Aerobic exercise was performed on a treadmill for 40~60 min/d at 10~14 m/min, 0% grade, 4 d/wk for 16 wk. Resveratrol (25 mg/kg bodyweight) was administrated once a day, 4 d/wk for 16 wk. There was a significance difference in COX-IV mRNA expression in the NC group versus that in the HC group (p<0.05). The expression of the SIRT-3, PGC-1a, and COX-IV mRNA genes in the HE group increased significantly as compared with the expression of these genes in the HC and HRe groups (p<0.05). These results indicated that high- fat diet-induced obesity did not affect mitochondria biogenesis gene expression in skeletal muscle. In contrast, aerobic exercise training increased the expression of mitochondria biogenesis gene expression in skeletal muscle in high-fat diet-induced obese mice. These findings suggested that aerobic exercise but not resveratrol supplementation had a positive effect on mitochondrial biogenesis in skeletal muscle in high-fat diet-induced obese mice.

• Journal of Korean Medicine for Obesity Research
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• v.22 no.2
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• pp.102-114
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• 2022

Objectives: We investigated the effects of Allii Fistulosi Bulbus (AFB) on high fat diet (HFD)-induced obesity in mice and the regulation of energy metabolism in muscle tissues of mice. Methods: The C57BL/6 mice (6 weeks, male) were fed a HFD for 8 weeks and then administrated with AFB extract at 500 mg/kg (p.o.) once daily for 4 weeks. The body weight (BW), muscle weight, calorie intake, fasting blood glucose (FBG) and serum glucose, insulin, and low-density lipoprotein-cholesterol (LDL-C) levels were measured in mice. It was also observed the histological changes of pancreas, liver, and fat tissues with hematoxylin and eosin staining. It was investigated the phosphorylation of insulin receptor substrate 1 (IRS-1), Ser/Thr kinase (AKT), and adenosine monophosphate-activated protein kinase (AMPK), and the expression of phosphoinositide 3-kinase, glucose transporter type 4 (GLUT4), and sirtuin1 (Sirt1) in gastrocnemius tissues by western blot, respectively. Results: The increases of BWs, calorie intakes and FBG levels in obesity mice were decreased significantly by the administration of AFB extract. The AFB extract administration was reduced significantly serum levels of glucose, insulin, and LDL-C in obesity mice. The AFB extract inhibited lipid accumulation in liver tissues, hyperplasia of pancreatic islets, and enlargement of fat tissues in obesity mice. The phosphorylation of IRS-1 and AKT was increased significantly in muscle tissues and AMPK phosphorylation and the GLUT4 and Sirt1 expression were decreased significantly in muscle tissues after the AFB administration. Conclusions: Our study indicates that AFB extract improves symptoms of obesity through regulation of energy regulating proteins in muscle tissues.