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Lee C.-L.,National Taitung University | Kuo T.-F.U.,National Taiwan University | Wu C.-L.,Sunway Biotechnology Company Ltd | Wang J.-J.,Fooyin University | Pan T.-M.,National Taiwan University
Journal of Agricultural and Food Chemistry | Year: 2010

Amyloid beta (Aβ) peptide is closely related to the onset of Alzheimer's disease (AD). A high-cholesterol or high-energy diet was demonstrated to stimulate Aβ formation and deposition in the amyloid precursor protein (APP) pathway and, oppositely, downregulate the secretion of the neuroprotective soluble APP α-fragment (sAPPα). Wonascus-fermented red mold rice (RMR) Including multiple cholesterol-lowering agents, antioxidants, and anti-inflammatory agents has been proven to ameliorate Aβ40 infusion-Induced memory deficit in our previous study. In this study, the ethanol extract of RMR (RE) and natural RMR were respectively tested for their effect on the mediation of the proteolytic process of APP in cholesterol-treated human neuroblastoma IMR32 cell, as well as their effect on memory and learning ability and the expression of AD risk factors in intracerebroventricular Aβ40-infused hyperlipidemic rats. In the results, RE suppressed cholesterolraised -secretase activity and further resulted in the increase of sAPPα secretion in the IMR32 cell. In the animal test, RMR potently reversed the memory deficit in the water maze and passive avoidance tasks. RMR administration could prevent against Aβ40 infusion plus the great damage caused by a high energy diet in hippocampus and cortex involved in the raise of thiobarbituric acid reactive substances and reactive oxygen species. The neuroprotection provided by RMR downregulates Aβ40 formation and deposition by suppressing the cholesterol-raised β-secretase activity and apollpoprotein E expression, as well as mediates the proteolytic process of APP toward neuroprotective sAPPα secretion in hippocampus. ©2010 American Chemical Society.


Lee C.-L.,National Taitung University | Kung Y.-H.,National Taitung University | Wu C.-L.,Sunway Biotechnology Company Ltd | Hsu Y.-W.,National Taiwan University | Pan T.-M.,National Taiwan University
Journal of Agricultural and Food Chemistry | Year: 2010

Monascus-fermented red mold dioscorea (RMD) has been proven to possess greater hypolipidemic effect than red mold rice (RMR) even though they include equal levels of cholesterol-lowering agent monacolin K. However, higher concentrations of yellow pigments (monascin and ankaflavin) were found in RMD than in RMR. In this study, purified monascin and ankaflavin were administered to hyperlipidemic hamsters for 8 weeks, respectively, to test whether these two compounds were novel hypolipidemic ingredients. In the statistical results, monascin and ankaflavin showed significant effect on lowering cholesterol, triglyceride, and low-density lipoprotein cholesterol levels in serum, as well as aorta lipid plaque ( p < 0.05). Importantly, monascin and ankaflavin, unlike monacolin K, were able to perform up-regulation rather than down-regulation on high-density lipoprotein cholesterol(HDL-C) levels in serum. This finding not only explained why RMD showed greater hypolipidemic and HDL-C-raising effect than RMR but also proved that monascin and ankaflavin would act as novel and potent hypolipidemic ingredients. ©2010 American Chemical Societ.


Lee B.-H.,National Taiwan University of Science and Technology | Hsu W.-H.,National Taiwan University of Science and Technology | Hsu Y.-W.,Sunway Biotechnology Company Ltd | Pan T.-M.,National Taiwan University of Science and Technology
Journal of Functional Foods | Year: 2013

The effects of dimerumic acid (DMA) on apoptosis prevention and insulin production in the glucose metabolite methylglyoxal (MG)-treated pancreatic RINm5F cells were evaluated. MG was found to induce apoptotic signal molecules mediated by oxidative stress in RINm5F cells, including caspase-3 and caspas-9, resulting in cell death and decreasing insulin production. In addition, DMA elevated insulin synthesis via up-regulating mammalian homologue of avian MafA/L-Maf (Maf-A) and pancreatic-duodenal homeobox-1 (PDX-1) and inhibited MG-mediated CCAAT/enhancer binding proteins-β (C/EBPβ) expression, which is a negative regulator for insulin production. Nuclear factor-erythroid2-related factor 2 (Nrf2) is essential for antioxidant responsive element (ARE)-mediated induction. Results indicated that nuclear translocation of Nrf2 was promoted by DMA in MG-treated RINm5F cells to increase heme oxygenase-1 (HO-1) and glutamate-cysteine ligase (GCL) expressions. We confirmed that DMA protected PDX-1, Maf-A, and insulin production against MG-induced oxidative stress mediating by Nrf2 in Nrf2-knockdown RINm5F cells. These results suggest that DMA exerts antioxidative ability to attenuate MG-induced pancreatic cell damage and elevates insulin level to improve diabetes. © 2013 Elsevier Ltd.


Lee C.-L.,National Taitung University | Hung Y.-P.,National Taitung University | Hsu Y.-W.,SunWay Biotechnology Company Ltd | Pan T.-M.,National Taiwan University of Science and Technology
Journal of Agricultural and Food Chemistry | Year: 2013

Monacolin K has long been considered a major effective component in the hypolipidemic functions of Monascus. Monacolin K also serves as a well-known hypolipidemic medication, but its side effect myopathy is a concern. Monascin and ankaflavin, the yellow pigments produced by Monascus species, have been proven to possess hypolipidemic functions; however, no studies have compared the hypolipidemic effects of monascin, ankaflavin, and monacolin K under the same dosages. In this study, the equal dosages of monascin, ankaflavin, and monacolin K were oral administrated to hamsters fed a high cholesterol diet for 6 weeks. Comparison of the displayed hypolipidemic and anti-atherosclerosis effects was performed, in addition to an investigation into the inducement of side effect. The results indicated that monascin and ankaflavin were similar to monacolin K in significantly reducing total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels in serum and lipid plaque (p < 0.05) in the heart aorta. In addition, ankaflavin achieved the effects of serum TC and TG reduction, with no significant difference as compared to those effects of monacolin K (p > 0.05). However, as compared to monacolin K, ankaflavin possessed more significant effects on the prevention of fatty liver and lipid plaque accumulation in heart aorta. More importantly, monascin significantly enhanced high-density lipoprotein cholesterol (HDL-C) concentrations, while monacolin K displayed the opposite effect. Regarding the side effect, monacolin K also raised elevated creatinine phosphokinase (CPK) activity, which was highly correlated with rhabdomyolysis development, while monascin and ankaflavin did not induce such a side effect. In conclusion, MS and AK had the potential to be developed as hypolipidemic agents without rhabdomyolysis development. © 2012 American Chemical Society.


Lee B.-H.,National Taiwan University of Science and Technology | Hsu W.-H.,National Taiwan University of Science and Technology | Huang T.,National Taiwan University of Science and Technology | Chang Y.-Y.,National Taiwan University of Science and Technology | And 2 more authors.
Journal of Agricultural and Food Chemistry | Year: 2013

Hyperglycemia is associated with advanced glycation end products (AGEs). This study was designed to evaluate the inhibitory effects of monascin on receptor for advanced glycation end product (RAGE) signal and THP-1 monocyte inflammation after treatment with S100b, a specific ligand of RAGE. Monascin inhibited cytokine production by S100b-treated THP-1 monocytes via up-regulation of nuclear factor-erythroid 2-related factor-2 (Nrf2) and alleviated p47phox translocation to the membrane. Methylglyoxal (MG, 600 mg/kg bw) was used to induce diabetes in Wistar rats. Inhibitions of RAGE and p47phox by monascin were confirmed by peripheral blood mononuclear cells (PBMCs) of MG-induced rats. Silymarin (SM) was used as a positive control group. It was found that monascin promoted heme oxygenase-1 (HO-1) expression mediated by Nrf2. Suppressions of AGEs, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-β) in serum of MG-induced rats were attenuated in the monascin administration group treated with retinoic acid (RA). RA treatment resulted in Nrf2 inactivation by increasing RA receptor-α (RARα) activity, suggesting that RA acts as an inhibitor of Nrf2. The results showed that monascin exerted anti-inflammatory and antioxidative effects mediated by Nrf2 to prevent the development of diseases such as type 2 diabetes caused by inflammation. © 2013 American Chemical Society.


Hsu W.-H.,National Taiwan University of Science and Technology | Chen T.-H.,National Taiwan University of Science and Technology | Lee B.-H.,National Taiwan University of Science and Technology | Hsu Y.-W.,SunWay Biotechnology Company Ltd | Pan T.-M.,National Taiwan University of Science and Technology
Food and Chemical Toxicology | Year: 2014

Yellow pigments monascin (MS) and ankaflavin (AK) are secondary metabolites derived from Monascus-fermented products. The hypolipidemic and anti-inflammatory effects of MS and AK indicate that they have potential on preventing or curing nonalcoholic fatty liver disease (NAFLD). Oleic acid (OA) and high-fat diet were used to induce steatosis in FL83B hepatocytes and NAFLD in mice, respectively. We found that both MS and AK prevented fatty acid accumulation in hepatocytes by inhibiting fatty acid uptake, lipogenesis, and promoting fatty acid beta-oxidation mediated by activating peroxisome proliferator-activated receptor (PPAR)-α and AMP-activated kinase (AMPK). Furthermore, MS and AK significantly attenuated high-fat diet-induced elevation of total cholesterol (TC), triaceylglycerol (TG), free fatty acid (FFA), and low density lipoprotein-cholesterol (LDL-C) in plasma. MS and AK promoted AMPK phosphorylation, suppressed the steatosis-related mRNA expression and inflammatory cytokines secretion, as well as upregulated farnesoid X receptor (FXR), peroxisome proliferator-activated receptor gamma co-activator (PGC)-1α, and PPARα expression to induce fatty acid oxidation in the liver of mice. We provided evidence that MS and AK act as PPARα agonists to upregulate AMPK activity and attenuate NAFLD. MS and AK may be supplied in food supplements or developed as functional foods to reduce the risk of diabetes and obesity. © 2013 Elsevier Ltd.


Hsu W.-H.,National Taiwan University of Science and Technology | Lee B.-H.,National Taiwan University of Science and Technology | Li C.-H.,National Taiwan University of Science and Technology | Hsu Y.-W.,SunWay Biotechnology Company | Pan T.-M.,National Taiwan University of Science and Technology
Journal of Agricultural and Food Chemistry | Year: 2013

Abnormal cellular accumulation of the dicarbonyl metabolite methylglyoxal (MG) results in cell damage, inflammation, and oxidative stress. It is also associated with increased protein linkage to form advanced glycation end products (AGEs) or induce DNA strand breaks. The association between peroxisome proliferator-activated receptor-γ (PPARγ) and nuclear factor-erythroid 2-related factor 2 (Nrf2) is unclear. This study investigated Nrf2 activator protection against PPARγ phosphorylation and degradation to maintain pancreatic function. MG was used at a noncytotoxic concentration (200 μM) to induce protein kinase C (PKC) and PPARγ phosphorylation in pancreatic RINm5F cells. For in vivo studies, MG (60 mg/kg bw) was intraperitoneally (IP) injected into Balb/C mice for 28 d to induce pancreas damage, at which point we investigated the effect of monascin protection (PPARγ and Nrf2 activator), rosiglitazone (PPARγ activator), allyl isothiocyanate (AITC; Nrf2 activator), or N-acetylcysteine (NAC) on pancreatic function. The in vitro and in vivo results indicated that MG leads to marked PPARγ phosphorylation (serine 82); this effect led to reduction in pancreatic and duodenal homeobox-1 (PDX-1), glucokinase (GCK), and insulin expression. However, monascin and rosiglitazone may protect PPARγ degradation by elevating PDX-1, GCK, and as a result, insulin expression. Monascin and AITC can attenuate PKC activation to suppress PPARγ phosphorylation caused by oxidative stress through the Nrf2 pathway. Similarly, the N-acetylcysteine (NAC) antioxidant also improved oxidative stress and pancreatic function. This study examined whether MG caused impairment of PDX-1, GCK, and insulin through PPARγ phosphorylation and degradation. MG and AGE accumulation improved on Nrf2 activation, thereby protecting against pancreas damage. Taken together, PPARγ activation maintained pancreatic PDX-1, GCK, and insulin expression levels to regulate blood glucose levels. © 2013 American Chemical Society.


Hsu W.-H.,National Taiwan University of Science and Technology | Lee B.-H.,National Taiwan University of Science and Technology | Hsu Y.-W.,SunWay Biotechnology Company Ltd | Pan T.-M.,National Taiwan University of Science and Technology
Journal of Agricultural and Food Chemistry | Year: 2013

Advanced glycation end products (AGEs) signaling through its receptors (RAGE) results in an increase in reactive oxygen species (ROS) and is thought to contribute to hepatic fibrosis via hyperglycemia. Carboxymethyllysine (CML) is a key AGE, with highly reactive dicarbonyl metabolites. We investigated the inhibitory effect of Monascus-fermented metabolite monascin and rosiglitazone on CML-induced RAGE signaling in hepatic stellate cells (HSCs) and its resulting antihepatic fibrosis activity. We found that monascin and rosiglitazone upregulated peroxisome proliferator-activated receptor-γ (PPAR-γ) to attenuate α-smooth muscle actin (SMA) and ROS generation in CML-treated HSCs in a RAGE activation-independent pathway. Therefore, monascin may delay or inhibit the progression of liver fibrosis through the activation of PPAR-γ and might prove to be a major antifibrotic mechanism to prevent liver disease. © 2013 American Chemical Society.


Lee C.-L.,National Taitung University | Wen J.-Y.,National Taitung University | Hsu Y.-W.,SunWay Biotechnology Company Ltd | Pan T.-M.,National Taiwan University of Science and Technology
Journal of Agricultural and Food Chemistry | Year: 2013

Monascus-fermented monascin and ankaflavin are found to strongly inhibit differentiation and lipogenesis and stimulate lipolysis effects in a 3T3-L1 preadipocyte model, but the in vivo regulation mechanism is unclear. This study uses obese rats caused by a high-fat diet to examine the effects of daily monascin and ankaflavin feeding (8 weeks) on antiobesity effects and modulation of differentiation, lipogenesis, and lipid absorption. The results show that monascin and ankaflavin had a significant antiobesity effect, which should result from the modulation of monascin and ankaflavin on the inhibition of differentiation by inhibiting CCAT/enhancer-binding protein β (C/EBPβ) expression (36.4% and 48.3%) and its downstream peroxisome proliferator- activated receptor γ (PPARγ) (55.6% and 64.5%) and CCAT/enhancer-binding protein α (C/EBPα) expressions (25.2% and 33.2%) and the inhibition of lipogenesis by increasing lipase activity (14.0% and 10.7%) and decreasing heparin releasable lipoprotein lipase (HR-LPL) activity (34.8% and 30.5%). Furthermore, monascin and ankaflavin are the first agents found to suppress Niemann-Pick C1 Like 1 (NPC1L1) protein expression (73.6% and 26.1%) associated with small intestine tissue lipid absorption. Importantly, monascin and ankaflavin are not like monacolin K, which increases creatine phosphokinase (CPK) activity, known as a rhabdomyolysis indicator. © 2013 American Chemical Society.


Chuang C.-Y.,National Taiwan University of Science and Technology | Shi Y.-C.,National Taiwan University of Science and Technology | You H.-P.,Sunway Biotechnology Company Ltd | Lo Y.-H.,National Taiwan University of Science and Technology | Pan T.-M.,National Taiwan University of Science and Technology
Journal of Agricultural and Food Chemistry | Year: 2011

γ-Aminobutyric acid (GABA) has several well-known physiological functions including antihypertension and antidepression. In this research, we focus on the antidepressant effects of oral administration of GABA-rich Monascus-fermented product in depression animal model (forced swimming test, FST) by Sprague-Dawley rats, and try to find its possible mechanism in the brain monoamine system. GABA and the Monascus-fermented product (MFP) significantly decreased the duration of immobility time in a short-term test. In a long-term test, the antidepressant-like effect of MFP was better than that of GABA at the same dosage (2.6 mg/kg), and the efficacy of MFP was similar to that of fluoxetine. Moreover, GABA might recover the level of monoamines norepinephrine, dopamine (DA), and 5-hydroxytryptamine (5-HT) in hippocampus and normalize the turnover ratio of 5-HT and DA in hippocampus and amygdala. In addition to the functions of GABA, the MFP has more potential in decreasing the turnover ratio of DA in the frontal cortex and striatum to improve depressive symptoms. © 2011 American Chemical Society.

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