Associations among the TREM-1 Pathway, Tau Hyperphosphorylation, Prolactin Expression, and Metformin in Diabetes Mice.

INTRODUCTION: Diabetes mellitus (DM) is a risk factor for Alzheimer's disease (AD). Increasing evidence indicates that the triggering receptor expressed on myeloid cells (TREM)-1 amplifies chronic inflammation, as well as the roles of prolactin (PRL) and metformin (MET) in tau hyperphosphorylation. However, the associations among TREM-1, tau hyperphosphorylation, PRL expression, and MET in DM remain unclear. METHODS: Streptozotocin was used to induce experimental DM in C57BL/6N mice. MET was orally administered at a dose of 400 mg/kg body weight for 6 weeks prior to hippocampal collection in DM mice. Various parameters pertaining to the TREM-1 pathway, tau hyperphosphorylation, PRL, and related factors were analyzed. RESULTS: Quantitative polymerase chain reaction and Western blot analysis demonstrated that the expression levels of TREM-1, DAP12, casp1, interleukin-1ß, Cox2, inducible nitric oxide synthase, pituitary transcriptional factor-1 (Pit-1), and PRL were significantly increased in the hippocampus of DM mice; the expression levels of these pro-inflammatory mediators, PRL receptor (PRLR) short or long (PRLR-S and PRLR-L), and PRL regulatory element-binding (Preb) protein in DM mice treated with MET (DM + MET) were significantly decreased compared with those in control (CON) mice. The levels of p-Tau and glycogen synthase kinase-3 in the DM group were significantly higher than those in the CON group and significantly lower than those in the DM + MET group. CONCLUSION: We confirmed the therapeutic potential of MET for both DM and neurodegeneration. Our findings shed new light on the effects of DM on the pathophysiology of AD via the TREM-1 pathway and PRL expression. Thus, an improved understanding of the TREM-1 pathway in hyperglycemic conditions, as well as PRL, Preb, Pit-1, PRLR-L, and PRLR-S gene expression in the liver, brain, and other sites, may help unravel the pathogenesis of insulin resistance and neurodegeneration.

Effects of Edible Insect Tenebrio molitor Larva Fermentation Extract as a Substitute Protein on Hepatosteatogenesis and Proteomic Changes in Obese Mice Induced by High-Fat Diet.

Mealworms (Tenebrio molitor larva) are an edible insect and a protein-rich food; however, research on mealworms as a substitute protein is insufficient. In this study, mealworm fermentation extract (TMP) was assessed as a replacement for soy protein (SP) in a control diet (CON) or a high-fat diet (HFD) of mice for 12 weeks. TMP substitution reduced body weight, body weight gain, body fat mass (perirenal and mesenteric), fat size, glucose intolerance, and insulin resistance compared to the HFD-SP group. TMP alleviated hepatic steatosis (lipid contents and lipid droplets) in high-fat-fed mice and down-regulated the PPARγ, CD36, and DGAT2 gene levels. Proteomic analysis showed that a HFD for 12 weeks up-regulated 20 proteins and down-regulated 17 proteins in mice fed SP. On the other hand, TMP reversed the protein profiles. TMP significantly down-regulated KHK, GLO1, ATP5H, SOD, and DDAH1 and up-regulated DLD, Mup1, CPS1, Ces3b, PDI, and HYOU1 compared to the HFD-SP group. These proteins are involved in the glucose, lipid, and amino acid metabolism, as well as in oxidative stress and endoplasmic reticulum stress. Thus, substituting SP for TMP helped improve HFD-induced obesity, steatosis, and insulin resistance in mice. These results suggest that TMP is a potential substitute for commonly used protein sources.

Protective Effects of Methoxsalen Supplementation on Chronic Alcohol-Induced Osteopenia and Steatosis in Rats.

Osteopenia or osteoporosis occurs frequently in alcoholics and patients with alcoholic fatty liver disease. Methoxsalen (MTS), 8-methoxypsoralen, improved osteoporosis in ovariectomized and diabetic mouse models; however, its effects on alcohol-induced osteopenia and steatosis have not been reported. This study examined the effects of MTS on alcohol-induced bone loss and steatosis. Rats in the alcohol groups were fed a Liber-DeCarli liquid diet containing 36% of its calories as alcohol. MTS was at 0.005% in their diet, while alendronate (positive control; 500 µg/kg BW/day) was administered orally for eight weeks. The pair-fed group received the same volume of isocaloric liquid diet containing dextrin-maltose instead of alcohol as the alcohol control group consumed the previous day. In the alcohol-fed rats, the MTS and alendronate increased the bone volume density, bone surface density and trabecular number, while the bone specific surface, trabecular separation and structure model index were decreased in the tibia. MTS down-regulated tibial tartrate-resistant acid phosphatase 5 (TRAP) expression compared to the alcohol control group. MTS or alendronate prevented chronic alcohol-induced hepatic lipid accumulation and the triglyceride level in the alcohol-fed rats by decreasing the lipogenic enzyme activities and increasing the fatty acid oxidation enzyme activities. MTS reduced significantly the serum levels of alcohol, TRAP and tumor necrosis factor-α compared to the alcohol control group. Overall, these results suggest that MTS is likely to be an alternative agent for alcoholic osteopenia and hepatosteatosis.

Methoxsalen and Bergapten Prevent Diabetes-Induced Osteoporosis by the Suppression of Osteoclastogenic Gene Expression in Mice.

This study evaluated whether bergapten and methoxsalen could prevent diabetes-induced osteoporosis and its underlying mechanism. For 10 weeks, bergapten or methoxsalen (0.02%, w/w) was applied to diabetic mice that were provided with a high-fat diet and streptozotocin. Bone mineral density (BMD) and microarchitecture quality were significantly reduced in the diabetic control group; however, both bergapten and methoxsalen reversed serum osteocalcin, bone-alkaline phosphatase and femur BMD. These coumarin derivatives significantly increased bone volume density and trabecular number, whereas they decreased the structure model index of femur tissue in diabetic mice. Conversely, tartrate-resistant acid phosphatase 5 (TRAP) staining revealed that these derivatives reduced osteoclast numbers and formation in diabetic bone tissue. Additionally, both bergapten and methoxsalen tended to downregulate the expression of osteoclast-related genes such as receptor activator of nuclear factor kappa-B ligand (RANKL), nuclear of activated T-cells, cytoplasmic 1 (NFATc1) and TRAP in diabetic femurs, with NFATc1 and TRAP expression showing significant reductions. Our data suggest that both bergapten and methoxsalen prevent diabetic osteoporosis by suppressing bone resorption.

Scopoletin Supplementation Ameliorates Steatosis and Inflammation in Diabetic Mice.

Scopoletin is a bioactive component in many edible plants and fruits. This study investigated the effects of scopoletin on hepatic steatosis and inflammation in a high-fat diet fed type 1 diabetic mice by comparison with metformin. Scopoletin (0.01%, w/w) or metformin (0.5%, w/w) was provided with a high-fat diet to streptozotocin-induced diabetic mice for 11 weeks. Both scopoletin and metformin lowered blood glucose and HbA1c , serum ALT, TNF-α and IL-6 levels, glucose intolerance, and hepatic lipid accumulation compared with the diabetic control group. Scopoletin or metformin down-regulated hepatic gene expression of triglyceride (Pparg, Plpp2, and Dgat2) and cholesterol (Hmgcr) synthesis as well as inflammation (Tlr4, Myd88, Nfkb1, Tnfa, and Il6), while it up-regulated Cyp7a1 gene. Hepatic PPARγ and DGAT2 protein levels were also down-regulated in scopoletin or metformin group compared with the control group. Scopoletin or metformin also inhibited hepatic fatty acid synthase and phosphatidate phosphohydrolase activities. These results suggest that scopoletin protects against diabetes-induced steatosis and inflammation by inhibiting lipid biosynthesis and TLR4-MyD88 pathways. Copyright © 2017 John Wiley & Sons, Ltd.

Anti-adipogenic and anti-diabetic effects of cis-3',4'-diisovalerylkhellactone isolated from Peucedanum japonicum Thunb leaves in vitro.

Peucedanum japonicum Thunb is a medicinal plant belonging to the family Umbelliferae. This study evaluated the anti-diabetic and anti-obesity effects of cis-3',4'-diisovalerylkhellactone (cDIVK) isolated from Peucedanum japonicum Thunb leaves. cDIVK (30 and 50µM) effectively inhibited adipocyte differentiation and fat accumulation, whereas it stimulated glucose uptake compared with the control in 3T3-L1 cells. cDIVK significantly increased AMPK activation and suppressed protein and mRNA expression of major adipogenic transcriptional factors such as C/EBPα, PPARγ and SREBP-1c in 3T3-L1 cells. In addition, cDIVK had potential α-glucosidase inhibitory activity. These results indicated that cDIVK may act as a natural dual therapeutic agent for diabetes and obesity.

Anti­osteoclastogenic effect of fermented mealworm extract by inhibiting RANKL­induced NFATc1 action.

Augmented osteoclast activity and differentiation can lead to destructive bone diseases, such as arthritis and osteoporosis. Therefore, modulating osteoclastogenesis and differentiation may serve to be a possible strategy for treating such diseases. Tenebrio molitor larvae, also known as mealworms, are considered a good source of protein with nutritional value, digestibility, flavor and functional properties, such as antioxidant, anti-diabetic and anti-obesity effects. However, the role of mealworms in osteoclastogenesis remains poorly understood. The present study therefore investigated the effects of fermented mealworm extract (FME) on receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclastogenesis in bone marrow-derived macrophages (BMMs) whilst also attempting to understand the underlying mechanism, if any. The cells treated with RANKL were used as the negative control. To prepare FME, defatted mealworm powder was fermented with a Saccharomyces cerevisiae strain, and then extracted with fermented alcohol. Cell viability of BMMs isolated from 5-week-old Institute of Cancer Research mice was measured using Cell Counting Kit-8 assay. Subsequently, the effects of FME on osteoclast differentiation were measured using tartrate-resistant acid phosphatase (TRAP) staining. In addition, expression of markers associated with osteoclast differentiation was assessed by reverse transcription-quantitative PCR. Expression of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) was assessed by western blotting. TRAP staining revealed that FME inhibited osteoclast differentiation in a dose-dependent manner (10-100 µg/ml) without causing cytotoxicity. Specifically, the formation of osteoclasts appear to have been suppressed by FME as indicated by the reduction in the number of TRAP-positive multinucleated cells observed. Furthermore, FME treatment significantly decreased the mRNA expression of c-Fos, whilst also significantly decreasing the expression of NFATc1 on both protein and mRNA levels. c-Fos and NFATc1 are transcription factors that can regulate osteoclast differentiation. FME treatment also reduced the expression of genes associated with osteoclast differentiation and function, including dendritic cell-specific transmembrane protein, osteoclast associated Ig-like receptor, Cathepsin K and TRAP, compared with that in the control group. Subsequently, FME was found to effectively suppress RANKL-induced osteoclast differentiation compared with that by the non-fermented mealworm extract. These findings suggest that FME may confer anti-osteoclastogenic effects, providing insights into its potential application in treatment of osteoporosis.

"Nulichal" Barley Extract Suppresses Nitric Oxide and Pro-Inflammatory Cytokine Production by Lipopolysaccharides in RAW264.7 Macrophage Cell Line.

The cultivar "Nulichal," a type of naked waxy barley (Hordeum vulgare L.), was developed by the National Institute of Crop Science, Rural Development Administration, Korea, in 2010. In this study, we investigated the anti-inflammatory and antioxidant properties of the "Nulichal" ethanol extract (NRE) using various assays. The NRE exhibited a total phenolic content of 7.55±0.30 mg gallic acid equivalent/g and a flavonoid content of 1.74±0.08 mg rutin equivalent/g. Cell viability assays showed no toxicity of NRE on RAW264.7 macrophage cells up to concentrations of 500 µg/mL. The NRE (300 and 500 µg/mL) significantly reduced nitric oxide (NO) production induced by lipopolysaccharides (LPS). It also down-regulated the mRNA expression and protein levels of inducible NO synthase and cyclooxygenase-2 in a dose-dependent manner. Moreover, the NRE treatment significantly decreased the levels of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, and their mRNA expression compared to LPS treatment alone. The NRE demonstrated strong free radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals in a dose-dependent manner. The ferric reducing antioxidant power assay also showed increased antioxidant activity with increasing NRE concentrations. These findings suggest that the NRE can be used as a functional food with anti-inflammatory and antioxidant properties.

Korean naked waxy barley (saechalssal) extract reduces blood glucose in diabetic mice by modulating the PI3K-Akt-GSK3ß pathway.

Saechalssal barley is Korea's representative naked waxy barley. This study investigated the anti-diabetic effect of the extract derived from saechalssal and its mechanism. The prethanol extract of saechalssal (SPE) showed greater α-glucosidase inhibitory activity in vitro and a more significant lowering of the postprandial blood glucose levels in normal mice compared to its water extract (SWE). When mice with type 2 diabetes (T2DM) induced by a high-fat diet and streptozotocin were fed SPE (200 mg/kg/day) for six weeks, the fasting blood glucose and serum free fatty acid levels were significantly lower than those of the control group. SPE significantly elevated the hepatic glycogen accumulation with increasing glycogen synthesis-related gene (GYS2 and UGP2) levels compared to the control group. SPE stimulated the expression of the hepatic glycolysis-related genes (GK, PFK1, and PK) and suppressed the gluconeogenesis-related genes (G6Pase, FBP1, and PEPCK). SPE up-regulated the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt), whereas it down-regulated the phosphorylation of glycogen synthase kinase 3 beta (GSK3ß) compared to the control. The major flavonoids of SPE were naringin, prunin, and catechin, while its phenolic acids were ferulic acid and vanillic acid. These phytochemical compounds may contribute to the anti-hyperglycemic effects of SPE in diabetes. Overall, these results suggest that SPE has potential anti-diabetic activity through the regulating the PI3K/Akt/GSK3ß pathway.

Anti-Inflammatory and Antioxidant in Vitro Activities of Magnoliae Flos Ethanol Extract.

This study evaluated Magnoliea Flos ethanol extract (MFE) as a potential natural anti-inflammatory and antioxidant in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and in vitro antioxidant assays. MFE (10, 30, and 50 µg/mL) dose-dependently inhibited LSP-induced nitric oxide production, which is mediated by down-regulating gene and protein expression of inducible nitric oxide synthase and cyclooxygenase-2. MFE also down-regulated both gene and protein expression of nuclear factor-kappa B and its downstream genes, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), compared with vehicle-treated cells. As a result, MFE treatment of LPS-stimulated macrophages significantly suppressed release of pro-inflammatory cytokines, such as TNF-α and IL-6. The antioxidant in vitro test revealed 2,2-diphenyl-1-picrylhydrazyl and 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging activities of MFE (0.25∼5 mg/mL) of 16.62% to 75.17% and 38.54% to 92.91%, respectively. The ferric reducing antioxidant ability of MFE was 0.54 mM to 2.14 mM. Overall, MFE exhibited antioxidant activity and an effective anti-inflammatory response in LPS-stimulated macrophages, which is potentially valuable for application as a natural functional material.

Defatted Tenebrio molitor Larva Fermentation Extract Modifies Steatosis, Inflammation and Intestinal Microflora in Chronic Alcohol-Fed Rats.

This study examined the effects of defatted mealworm fermentation extract (MWF) on alcoholic liver injury in rats. The rats were fed either a Lieber-DeCarli control (Con) or alcohol liquid diet (EtOH). The alcohol-fed rats were administered MWF (50, 100, or 200 mg/kg/day) and silymarin (200 mg/kg/day) orally for eight weeks. MWF prevented alcohol-induced hepatocellular damage by decreasing their serum aspartate transaminase, alanine transaminase, and gamma-glutamyl transpeptidase levels significantly compared to the EtOH group. MWF effectively reduced the relative hepatic weight, lipid contents, and fat deposition, along with the down-regulation of transcriptional factors and genes involved in lipogenesis compared to the EtOH group. It also enhanced the antioxidant defense system by elevating the glutathione level and glutathione reductase activity. MWF attenuated the alcohol-induced inflammatory response by down-regulating hepatic inflammation-associated proteins expression, such as phosphorylated-inhibitor of nuclear factor-kappa B-alpha and tumor necrosis factor-alpha, in chronic alcohol-fed rats. Furthermore, sequencing analysis in the colonic microbiota showed that MWF tended to increase Lactobacillus johnsonii reduced by chronic alcohol consumption. These findings suggest that MWF can attenuate alcoholic liver injury by regulating the lipogenic and inflammatory pathway and antioxidant defense system, as well as by partially altering the microbial composition.

Heshouwu (Polygonum multiflorum Thunb.) Extract Attenuates Bone Loss in Diabetic Mice.

This study investigated the effects and mechanism of Heshouwu (Polygonum multiflorum Thunb.) water extract (HSW) on diabetes-related bone loss in mice. HSW was orally administered (300 mg/kg body weight) to high-fat diet and streptozotocin-induced diabetic mice for 10 weeks. HSW significantly alleviated mouse body weight loss and hyperglycemia compared with the control group, and elevated serum levels of insulin, osteocalcin, and bone-alkaline phosphatase. HSW supplementation also significantly increased the bone volume/tissue volume ratio and trabecular thickness and number, and decreased the bone surface/bone volume ratio and trabecular structure model index in the femur and tibia. Moreover, HSW significantly increased femoral bone mineral density. In addition, HSW down-regulated osteoclastogenic genes, such as nuclear factor of activated T-cells, cytoplasmic 1 and tartrate-resistant acid phosphatase 5 (TRAP), in both the femur and tibia tissue, and reduced serum TRAP level compare to those of control mice. These results indicate that HSW might relieve diabetes-related bone disorders through regulating osteoclast-related genes, suggesting HSW may be used as a preventive agent for diabetes-induced bone loss.

Heshouwu (Polygonum multiflorum Thunb.) ethanol extract suppresses pre-adipocytes differentiation in 3T3-L1 cells and adiposity in obese mice.

This study investigated whether Heshouwu (Polygonum multiflorum Thunb.) root ethanol extract (PME) has anti-obesity activity using 3T3-L1 cells and high-fat diet (HFD)-induced obese mice. Treatment with PME (5 and 10 µg/mL) dose-dependently suppressed 3T3-L1 pre-adipocyte differentiation to adipocytes and cellular triglyceride contents. In addition, PME inhibited mRNA and protein expression of adipogenic transcription factors such as CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ), which led to down-regulation of fatty acid synthase gene expression. After feeding mice PME (0.05%) with HFD for 12 weeks, their visceral fat mass, size and body weight were significantly reduced compared with the HFD group. Furthermore, PME supplementation significantly up-regulated the PPARα, CPT1, CPT2, UCP1 and HSL mRNA levels compared with the HFD group, whereas it down-regulated expression of the PPARγ and DGAT2 genes. Finally, HFD increased serum leptin, insulin, glucose and insulin and glucose levels; however, PME reversed these changes. These results demonstrated that PME might relieve obesity that occurs via inhibition of adipogenesis and lipogenesis as well as through lipolysis and fatty acid oxidation in 3T3-L1 cells and HFD-induced obese mice.

Young leaves of reed (Phragmites communis) suppress melanogenesis and oxidative stress in B16F10 melanoma cells.

This study investigated the effects young leaves of reed (Phragmites communis) water extract (YLR) on melanogenesis and oxidative stress using B16F10 cells. YLR decreased the intracellular melanin content, protein expression and enzyme activity of tyrosinase in a dose-dependent manner. YLR significantly decreased the gene and protein expression of melanogeneis-related proteins, such as microphthalmia-associated transcription factor (MITF), and tyrosinase-related protein-1 and -2. In addition, YLR up-regulated the melanogenesis inhibitory proteins, extracellular signal-regulated kinase (ERK) and protein kinase B (AKT), while it dose-dependently down-regulated p38 and cAMP response element-binding protein (CREB). Moreover, YLR significantly reduced H2O2-induced reactive oxygen species levels in B16F10 cells and showed antioxidant activity based on DPPH and ABTS free radical scavenging activity and SOD-like activity. These results suggest that YLR have anti-melanogensis properties that function through regulation of the CREB/MITF/tyrosinase pathway in B16F10 cells and antioxidant activity. Overall, these findings indicate that YLR has the potential for use in treatment of skin disorders and skin-whitening.

Anti-steatotic and anti-inflammatory effects of Hovenia dulcis Thunb. extracts in chronic alcohol-fed rats.

The anti-steatotic and anti-inflammatory effects of fruit water extract (FW) and seed ethanol extract (SE) of Hovenia dulcis Thunb. in chronic alcohol-fed rats were investigated. Rats were fed a liquid diet containing 36% calories from alcohol and orally administered FW or SE (300 and 500mg/kg/day). Both FW and SE reduced hepatic lipid contents and droplets, serum lipid concentration and inflammatory markers (hs-CRP, TNF-α and IL-6) levels compared with the alcohol control group. Alcohol led to significant decreases in the hepatic fatty acid oxidative gene (Ppargc1a, Cpt1a and Acsl1) levels, while it significantly increased the Myd88 and Tnfa gene levels. However, FW or SE supplementation significantly up-regulated gene expression of Ppargc1a, Ppara, Cpt1a and Acsl1, and down-regulated gene expression of Myd88, Tnfa and Crp compared with the alcohol control group. FW or SE supplementation also significantly decreased hepatic activities of fatty acid synthase and phosphatidate phosphohydrolase in chronic alcohol-fed rats. Plasma alcohol and acetaldehyde levels, hepatic enzyme activity and protein expression of CYP2E1 were lowered by FW or SE supplementation. These results indicate that both FW and SE play an important role in improvement of alcoholic hepatic steatosis and inflammation via regulation of lipid and inflammation metabolism.

Methoxsalen supplementation attenuates bone loss and inflammatory response in ovariectomized mice.

Methoxsalen (MTS) is a natural bioactive compound found in a variety of plants that has many known biofunctions; however, its effects on osteoporosis and related mechanisms are not clear. This study examined whether MTS exhibited preventive effects against postmenopausal osteoporosis. Female C3H/HeN mice were divided into four groups: Sham, ovariectomy (OVX), OVX with MTS (0.02% in diet), and OVX with estradiol (0.03 µg/day, s.c). After 6 weeks, MTS supplementation significantly increased femur bone mineral density and bone surface along with bone surface/total volume. MTS significantly elevated the levels of serum formation markers (estradiol, osteocalcin and bone-alkaline phosphatase) such as estradiol in OVX mice. Tartrate resistant acid phosphatase staining revealed that MTS suppressed osteoclast numbers and formation in femur tissues compared with the OVX group. Supplementation of MTS slightly up-regulated osteoblastogenesis-related genes (Runx-2, osterix, osteocalcin, and Alp) expression, whereas it significantly down-regulated inflammatory genes (Nfκb and Il6) expression in femur tissue compared with the OVX group. These results indicate that MTS supplementation effectively prevented OVX-induced osteoporosis via enhancement of bone formation and suppression of inflammatory response in OVX mice. Our study provides valid scientific information regarding the development and application of MTS as a food ingredient, a food supplement or an alternative agent for preventing postmenopausal osteoporosis.

Anti-Obesity Property of Lichen Thamnolia vermicularis Extract in 3T3-L1 Cells and Diet-Induced Obese Mice.

Thamnolia vermicularis (TV) is an edible lichen that is prevalent in the alpine zone of East Asia. This study evaluated the feasibility of using TV acetone extracts as a functional food based on experiments using cell line and obese mice. The cellular triglyceride levels and Oil red O staining of 3T3-L1 cells indicated that TV extracts (5 and 10 µg/mL) dose-dependently suppressed adipocyte differentiation and lipid accumulation compared with the control. The TV extract (0.4%, w/w) in a high-fat diet (HFD) was supplemented to C57BL/6N mice for 12 weeks, and TV extract supplement significantly reduced visceral fat mass and body weight compared with HFD feeding alone. The TV extract also induced significant decreases in serum and hepatic lipids, whereas it increased the serum high-density lipoproteins-cholesterol/total cholesterol ratio and fecal lipids levels. Moreover, the TV extract led to significantly lower homeostasis model assessment of insulin resistance in diet-induced obese mice. Taken together, these results suggest that the TV extract may have anti-obesity effects, including lipid-lowering, and it is a natural resource with the potential for use in obesity management.

Esculetin prevents non-alcoholic fatty liver in diabetic mice fed high-fat diet.

This study investigated the effects and mechanism of esculetin (6,7-dihydroxycoumarin) on non-alcoholic fatty liver in diabetic mice fed high-fat diet (HFD). The diabetic mice model was induced by injection of streptozotocin, after which they were fed HFD diet with or without esculetin for 11 weeks. Non-diabetic mice were provided a normal diet. Diabetes induced hepatic hypertrophy, lipid accumulation and droplets; however, esculetin reversed these changes. Esculetin treatment in diabetic mice fed HFD significantly down-regulated expression of lipid synthesis genes (Fasn, Dgat2 and Plpp2) and inflammation genes (Tlr4, Myd88, Nfkb, Tnfα and Il6). Moreover, the activities of hepatic lipid synthesis enzymes (fatty acid synthase and phosphatidate phosphohydrolase) and gluconeogenesis enzyme (glucose-6-phosphatase) in the esculetin group were decreased compared with the diabetic group. In addition, esculetin significantly reduced blood HbA1c, serum cytokines (TNF-α and IL-6) and chemokine (MCP-1) levels compared with the diabetic group without changing the insulin content in serum and the pancreas. Hepatic SOD activity was lower and lipid peroxidation level was higher in the diabetic group than in the normal group; however, esculetin attenuates these differences. Overall, these results demonstrated that esculetin supplementation could protect against development of non-alcoholic fatty liver in diabetes via regulation of lipids, glucose and inflammation.

Anti-steatotic and anti-inflammatory roles of syringic acid in high-fat diet-induced obese mice.

This study examined the effects of syringic acid (SA) on obese diet-induced hepatic dysfunction. Mice were fed high-fat diet (HFD) with or without SA (0.05%, wt/wt) for 16 weeks. SA reduced the body weight, visceral fat mass, serum levels of leptin, TNFα, IFNγ, IL-6 and MCP-1, insulin resistance, hepatic lipid content, droplets and early fibrosis, whereas it elevated the circulation of adiponectin. SA down-regulated lipogenic genes (Cidea, Pparγ, Srebp-1c, Srebp-2, Hmgcr, Fasn) and inflammatory genes (Tlr4, Myd88, NF-κB, Tnfα, Il6), whereas it up-regulated fatty acid oxidation genes (Pparα, Acsl, Cpt1, Cpt2) in the liver. SA also decreased hepatic lipogenic enzyme activities and elevated fatty acid oxidation enzyme activities relative to the HFD group. These findings suggested that dietary SA possesses anti-obesity, anti-inflammatory and anti-steatotic effects via the regulation of lipid metabolic and inflammatory genes. SA is likely to be a new natural therapeutic agent for obesity or non-alcoholic liver disease.

Anti-inflammatory and antioxidant effects of umbelliferone in chronic alcohol-fed rats.

BACKGROUND/OBJECTIVES: Inflammation is associated with various types of acute and chronic alcohol liver diseases. In this study, we examined whether umbelliferone (7-hydroxycoumarin, UF) ameliorates chronic alcohol-induced liver damage by modulating inflammatory response and the antioxidant system. METHODS: Rats were fed a Liber-Decarli liquid diet containing 5% alcohol with or without UF (0.05 g/L) for 8 weeks, while normal rats received an isocaloric carbohydrate liquid diet. RESULTS: Chronic alcohol intake significantly increased serum tumor necrosis factor-α (TNF-α) and interleukin 6 levels and decreased interleukin 10 level; however, UF supplementation reversed the cytokines related to liver damage. UF significantly suppressed hepatic lipopolysaccharide binding protein, toll-like receptor 4 (TLR4), nuclear factor kappa B, and TNF-α gene expression increases in response to chronic alcohol intake. Masson's trichrome staining revealed that UF improved mild hepatic fibrosis caused by alcohol, and UF also significantly increased the mRNA expressions and activities of superoxide dismutase and catalase in liver, and thus, decreased lipid peroxide and mitochondrial hydrogen peroxide levels. CONCLUSIONS: The findings of this study indicate that UF protects against alcohol-induced liver damage by inhibiting the TLR4 signaling pathway and activating the antioxidant system.