Cardiovascular Diseases of Developmental Origins: Preventive Aspects of Gut Microbiota-Targeted Therapy.

Cardiovascular diseases (CVDs) can originate from early life. Accumulating evidence suggests that gut microbiota in early life is linked to CVDs in later life. Gut microbiota-targeted therapy has gained significant importance in recent decades for its health-promoting role in the prevention (rather than just treatment) of CVDs. Thus far, available gut microbiota-based treatment modalities used as reprogramming interventions include probiotics, prebiotics, and postbiotics. The purpose of this review is, first, to highlight current studies that link dysbiotic gut microbiota to the developmental origins of CVD. This is followed by a summary of the connections between the gut microbiota and CVD behind cardiovascular programming, such as short chain fatty acids (SCFAs) and their receptors, trimethylamine-N-oxide (TMAO), uremic toxins, and aryl hydrocarbon receptor (AhR), and the renin-angiotensin system (RAS). This review also presents an overview of how gut microbiota-targeted reprogramming interventions can prevent the developmental origins of CVD from animal studies. Overall, this review reveals that recent advances in gut microbiota-targeted therapy might provide the answers to reduce the global burden of CVDs. Still, additional studies will be needed to put research findings into practice.

The Protection of Lactic Acid Bacteria Fermented-Mango Peel against Neuronal Damage Induced by Amyloid-Beta.

Mango peels are usually discarded as waste; however, they contain phytochemicals and could provide functional properties to food and promote human health. This study aimed to determine the optimal lactic acid bacteria for fermentation of mango peel and evaluate the effect of mango peel on neuronal protection in Neuron-2A cells against amyloid beta (Aß) treatment (50 µM). Mango peel can be fermented by different lactic acid bacteria species. Lactobacillus acidophilus (BCRC14079)-fermented mango peel produced the highest concentration of lactic acid bacteria (exceeding 108 CFU/mL). Mango peel and fermented mango peel extracts upregulated brain-derived neurotrophic factor (BDNF) expression for 1.74-fold in Neuron-2A cells. Furthermore, mango peel fermented products attenuated oxidative stress in Aß-treated neural cells by 27%. Extracts of L. acidophilus (BCRC14079)-fermented mango peel treatment decreased Aß accumulation and attenuated the increase of subG1 caused by Aß induction in Neuron-2A cells. In conclusion, L. acidophilus (BCRC14079)-fermented mango peel acts as a novel neuronal protective product by inhibiting oxidative stress and increasing BDNF expression in neural cells.

Resveratrol Butyrate Esters Inhibit Obesity Caused by Perinatal Exposure to Bisphenol A in Female Offspring Rats.

Resveratrol butyrate esters (RBE) are derivatives of resveratrol (RSV) and butyric acid and exhibit biological activity similar to that of RSV but with higher bioavailability. The aim of this study was designed as an animal experiment to explore the effects of RBE on the serum biochemistry, and fat deposits in the offspring rats exposed to bisphenol A (BPA), along with the growth and decline of gut microbiota. We constructed an animal model of perinatal Bisphenol A (BPA) exposure to observe the effects of RBE supplementation on obesity, blood lipids, and intestinal microbiota in female offspring rats. Perinatal exposure to BPA led to weight gain, lipid accumulation, high levels of blood lipids, and deterioration of intestinal microbiota in female offspring rats. RBE supplementation reduced the weight gain and lipid accumulation caused by BPA, optimised the levels of blood lipids, significantly reduced the Firmicutes/Bacteroidetes (F/B) ratio, and increased and decreased the abundance of S24-7 and Lactobacillus, respectively. The analysis of faecal short-chain fatty acid (SCFA) levels revealed that BPA exposure increased the faecal concentration of acetate, which could be reduced via RBE supplementation. However, the faecal concentrations of propionate and butyrate were not only significantly lower than that of acetate, but also did not significantly change in response to BPA exposure or RBE supplementation. Hence, RBE can suppress BPA-induced obesity in female offspring rats, and it demonstrates excellent modulatory activity on intestinal microbiota, with potential applications in perinatological research.

Polysaccharides obtained from mycelia of Cordyceps militaris attenuated doxorubicin-induced cytotoxic effects in chemotherapy.

OBJECTIVES: Fungus Cordyceps militaris has been used as a herbal tonic in traditional Chinese medicine, which could be surface liquid-cultured for mycelia production. To evaluate the potential of polysaccharides obtained from mycelia of Cordyceps militaris (PS-MCM) for attenuation of side-effects of chemotherapy. METHODS: Doxorubicin was used to induce cytotoxicity in THP-1 monocytes and EL-4 T cells, and the effects of PS-MCM on cell viability and cytokine production were detected on doxorubicin-treated THP-1 and EL-4 cells. RESULTS: PS-MCM reduced doxorubicin-induced cell death and promoted cell proliferation in THP-1 and EL-4 cells. Moreover, PS-MCM elevated the level of cytokines associated with immune-modulation of THP-1 and EL-4 cells. CONCLUSION: These findings indicate that PS-MCM has potential for development as a functional food to counteract side effects of chemotherapy.

Miracle Fruit (Synsepalum dulcificum) Exhibits as a Novel Anti-Hyperuricaemia Agent.

Miracle fruit (Synsepalum dulcificum) belongs to the Sapotaceae family. It can change flavors on taste buds, transforming acidic tastes to sweet. We evaluated various miracle fruit extracts, including water, butanol, ethyl acetate (EA), and hexane fractions, to determine its antioxidant effects. These extracts isolated from miracle fruit exerted potential for reduction of uric acid and inhibited xanthine oxidase activity in vitro and in monosodiumurate (MSU)-treated RAW264.7 macrophages. Moreover, we also found that the butanol extracts of miracle fruit attenuated oxonic acid potassium salt-induced hyperuricaemia in ICR mice by lowering serum uric acid levels and activating hepatic xanthine oxidase. These effects were equal to those of allopurinol, suggesting that the butanol extract of miracle fruit could be developed as a novel anti-hyperuricaemia agent or health food.

Monascus secondary metabolites monascin and ankaflavin inhibit activation of RBL-2H3 cells.

Monascus-fermented products have been used as dietary food and traditional medicine due to their beneficial effects on circulation and digestive systems in Asia for thousands of years. Besides, monascin and ankaflavin, secondary metabolites from Monascus-fermented products, have proven anti-inflammatory and immunomodulatory effects. In previous research, monascin and ankaflavin ameliorated ovalbumin-induced airway allergic reaction often used as a type I allergy asthma model. Additionally, mast cells play critical roles in type I allergy. Therefore, RBL-2H3 cells were used as the mast cell model to determine whether the improving effects on asthma of monascin and ankaflavin came from influencing mast cells. PMA and ionomycin are common activators of mast cells because they stimulate the main signaling molecules during mast cell activation. Forty micromolar monascin and ankaflavin inhibited PMA/ionomycin-induced mast cell degranulation and TNF-α secretion through suppressing the phosphorylation of PKC and MAPK family ERK, JNK, and p38. Consequently, monascin and ankaflavin affected the activation of mast cells and may have the potential to improve type I allergy.

Treatment of metabolic syndrome with ankaflavin, a secondary metabolite isolated from the edible fungus Monascus spp.

Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including anti-inflammatory pigments (such as monascin and ankaflavin [AK]), monacolins, and dimerumic acid. These secondary metabolites have anti-inflammatory, anti-oxidative, and anti-tumor activities. We found that AK positively regulates several transcription factors associated with the prevention of metabolic syndrome and other diseases, including peroxisome proliferator-activated receptor (PPAR)-gamma, PPAR-alpha, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). AK reduced hyperglycemia and enhanced pancreatic function via PPAR-gamma activation and increased lipid metabolism due to PPAR-alpha activation. The compound also exerted antioxidant effects via activation of Nrf2. These results suggest that AK belongs to the class of selective peroxisome proliferator-activated receptor modulators (SPPARMs), which are associated with a good safety profile when used in patients suffering from metabolic syndrome. Together with our studies to determine how AK production can be increased during Monascus fermentation, these data demonstrate the great potential of AK as a nutraceutical or therapeutic agent.

A novel PPARgamma agonist monascin's potential application in diabetes prevention.

Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products possess a number of functional secondary metabolites, including the anti-inflammatory pigments monascin and ankaflavin. Monascin has been shown to prevent or ameliorate several conditions, including hypercholesterolemia, hyperlipidemia, diabetes, and obesity. Recently, monascin has been shown to improve hyperglycemia, attenuate oxidative stress, inhibit insulin resistance, and suppress inflammatory cytokine production. In our recent study, we have found that monascin is a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. The PPARgamma agonist activity had been investigated and its exerted benefits are inhibition of inflammation in methylglyoxal (MG)-treated rats, prevention of pancreas impairment causing advanced glycation endproducts (AGEs), promotion of insulin expression in vivo and in vitro, and attenuated carboxymethyllysine (CML)-induced hepatic stellate cell (HSC) activation in the past several years. Moreover, our studies also demonstrated that monascin also activated nuclear factor-erythroid 2-related factor 2 (Nrf2) in pancreatic RIN-m5F cell line thereby invading methylglyoxal induced pancreas dysfunction. In this review, we focus on the chemo-preventive properties of monascin against metabolic syndrome through PPARgamma and Nrf2 pathways.

Graptopetalum paraguayense and resveratrol ameliorates carboxymethyllysine (CML)-induced pancreas dysfunction and hyperglycemia.

Hyperglycemia is associated with advanced glycation end products (AGEs). Recently, AGEs were found to cause pancreatic damage, oxidative stress, and hyperglycemia through the AGE receptor. Carboxymethyllysine (CML) is an AGE but whether it induces pancreatic dysfunction remains unclear. Graptopetalum paraguayense, a vegetable consumed in Taiwan, has been used in folk medicine and is an antioxidant that protects against liver damage. We investigated the protective properties of G. paraguayense 95% ethanol extracts (GPEs) against CML-induced pancreatic damage. The results indicated that resveratrol, GPE, and gallic acid (the active compound of GPE) increased insulin synthesis via upregulation of pancreatic peroxisome proliferator activated-receptor-γ (PPARγ) and pancreatic-duodenal homeobox-1 (PDX-1) but inhibited the expression of CML-mediated CCAAT/enhancer binding protein-ß (C/EBPß), a negative regulator of insulin production. Moreover, resveratrol and GPE also strongly activated nuclear factor-erythroid 2-related factor 2 (Nrf2) to attenuate oxidative stress and improve insulin sensitivity in the liver and muscle of CML-injected C57BL/6 mice and resulted in reduced blood glucose levels. Taken together, these findings suggested that GPE and gallic acid could potentially be used as a food supplement to protect against pancreatic damage and the development of diabetes.

Monascin improves diabetes and dyslipidemia by regulating PPARγ and inhibiting lipogenesis in fructose-rich diet-induced C57BL/6 mice.

Monascin (MS) is a yellow compound isolated from Monascus-fermented products that has pancreatic protective, anti-inflammatory, anti-oxidative, and hypolipidemic activity. We recently found that MS also acts as a peroxisome proliferator-activated receptor-gamma (PPARγ) agonist, thereby promoting insulin sensitivity in C2C12 cells. However, the attenuation of hyperglycemia by MS treatment in vivo remains uncertain. In the present study, both MS and pioglitazone significantly down-regulated blood glucose and hyperinsulinemia in fructose-rich diet (FRD)-induced C57BL/6 mice (8 weeks). In addition, inhibitions of inflammatory factor production, serum dyslipidemia, and hepatic fatty acid accumulation by MS and pioglitazone were attenuated by GW9662 (PPARγ antagonist). These results were mediated by MS-suppressing FRD-elevated lipogenic transcription factors, including sterol regulatory element-binding protein-1c (SREBP-1c), carbohydrate response element-binding protein (ChREBP), PPARγ coactivator-1α (PGC-1α), and PPARγ coactivator-1ß (PGC-1ß). Taken together, de novo lipogenesis results in hyperlipidemia and hyperglycemia by fructose induction thereby leading to diabetes development; we found that MS may inhibit lipogenesis in FRD-induced mice. These findings suggest that MS acts as an antidiabetic agent and thus may have therapeutic potential for prevention of diabetes.

Antioxidant and anti-inflammatory effects of pigeon pea (Cajanus cajan L.) extracts on hydrogen peroxide- and lipopolysaccharide-treated RAW264.7 macrophages.

Chronic inflammation has been linked to a wide range of progressive diseases, including cancer, neurological disease, metabolic disorder, and cardiovascular disease. Epidemiological studies have provided convincing evidence that natural dietary compounds, which humans consume as food, possess many biological activities, including chemopreventative activities against various chronic inflammatory diseases. Here, we investigated the effect of 50% ethanol extracts of pigeon pea, as well as its major component, cyanidin-3-monoglucoside, an anthocyanin, on DNA damage, the activity of antioxidant enzymes, and free radical scavenging capacity in hydrogen peroxide (H(2)O(2))-treated RAW264.7 macrophages. High-pressure liquid chromatography results indicated that 2 mg of the 50% ethanol extracts of pigeon pea contained 45 µg of cyanidin-3-monoglucoside. A comet assay indicated that 50% ethanol extracts of pigeon pea (2 mg mL(-1)) and of cyanidin-3-monoglucoside (10 µM) protected RAW264.7 cells from DNA damage induced by a 24 h H(2)O(2) treatment. These results can be attributed to the prevention of reduction in antioxidant enzyme activity and lipid peroxidation in H(2)O(2)-treated murine RAW264.7 macrophages by the 50% ethanol extracts of pigeon pea. Moreover, as there is an active interplay between oxidative stress and inflammation, we also evaluated the anti-inflammatory activity of the 50% ethanol extracts of pigeon pea and cyanidin-3-monoglucoside in lipopolysaccharide-treated RAW264.7 macrophages. We found that the 50% ethanol extracts of pigeon pea and of cyanidin-3-monoglucoside suppressed the production of inflammatory cytokines, including TNF-α, IL-1ß, and IL-6, in these macrophages. These results imply that pigeon pea could be developed as a functional food by the food industry, or could be utilized for the commercial production of anthocyanins as antioxidants.

Fagopyrum tataricum (buckwheat) improved high-glucose-induced insulin resistance in mouse hepatocytes and diabetes in fructose-rich diet-induced mice.

Fagopyrum tataricum (buckwheat) is used for the treatment of type 2 diabetes mellitus in Taiwan. This study was to evaluate the antihyperglycemic and anti-insulin resistance effects of 75% ethanol extracts of buckwheat (EEB) in FL83B hepatocytes by high-glucose (33 mM) induction and in C57BL/6 mice by fructose-rich diet (FRD; 60%) induction. The active compounds of EEB (100 µg/mL; 50 mg/kg bw), quercetin (6 µg/mL; 3 mg/kg bw), and rutin (23 µg/mL; 11.5 mg/kg bw) were also employed to treat FL83B hepatocytes and animal. Results indicated that EEB, rutin, and quercetin + rutin significantly improved 2-NBDG uptake via promoting Akt phosphorylation and preventing PPARγ degradation caused by high-glucose induction for 48 h in FL83B hepatocytes. We also found that EEB could elevate hepatic antioxidant enzymes activities to attenuate insulin resistance as well as its antioxidation caused by rutin and quercetin. Finally, EEB also inhibited increases in blood glucose and insulin levels of C57BL/6 mice induced by FRD.

Monascus purpureus-fermented products and oral cancer: a review.

Tobacco and alcohol consumption have been reported as major factors for the development of oral cancer. Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products have many functional secondary metabolites, including monacolin K, citrinin, ankaflavin, and monascin. In several recent studies performed in our laboratory, these secondary metabolites have shown anti-inflammatory, anti-oxidative, and anti-tumor activities. Many published studies have shown the efficacy of Monascus-fermented products in the prevention of numerous types of cancer. The current article discusses and provides evidence to support that Monascus-fermented metabolites may be developed as painting drugs for the mouth to prevent or cure oral carcinogenesis. This is a novel therapeutic approach focusing on tumor growth attenuation to improve patient survival and quality of life.

Red Mold Rice against Hepatic Inflammatory Damage in Zn-deficient Rats.

The protective effect of red mold rice (RMR) against liver injury in rats fed with a Zn-deficient diet for 12 weeks was investigated in this study. Rats were orally administered RMR (151 mg/kg body weight or 755 mg/kg body weight; 1 × dose or 5 × dose, respectively) with or without Zn once a day for 4 consecutive weeks. The severity of liver damage was evaluated by measuring the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in Zn-deficient rats. RMR significantly inhibited the elevation of serum ALT levels by Zn-deficient induction. Hepatic antioxidase activity was also significantly increased in the RMR + Zn group (RZ), thereby suppressing the productions of reactive oxygen species (ROS) and proinflammatory cytokines in the liver of Zn-deficient rats. These findings suggested that RMR exerted hepatoprotective effects against Zn deficiency-induced liver inflammation.

Immunomodulatory and antioxidant potential of Lactobacillus exopolysaccharides.

BACKGROUND: Immunomodulation by probiotic microorganisms has become a topic of increasing interest in food microbiology. Polysaccharides are broadly used in the food industry as gelling, thickening, stabilizing, or emulsifying agents. Some probiotics such as lactic acid bacteria also produce exopolysaccharides that stimulate macrophage production of cytokines. The aim of this study was to characterize the effects of exopolysaccharides of Lactobacillus paracasei subsp. paracasei NTU 101 (101EP) and Lactobacillus plantarum NTU 102 (102EP) exopolysaccharides on antioxidant activity and immunomodulation in vitro. RESULTS: The sugar composition (including arabinose, galactose, glucose, fructose, mannose, and maltose) of 101EP and 102EP was quantified by high-performance anion-exchange chromatography. Cytokine production (including IL-6, TNF-α, and IL-1ß) was induced by 101EP and 102EP in Raw 264.7 in a dose-dependent manner (5-500 µg mL(-1) ). 101EP and 102EP also demonstrated potential antioxidant properties (1,1-diphenyl-2-picrylhydrazyl radical scavenging activity, chelation of ferrous ions, inhibition of linoleic acid peroxidation, and reducing power) in vitro. CONCLUSION: 101EP and 102EP stimulate cell proliferation and may be useful as a mild immune modulator of macrophages.

Effects of red mold dioscorea on oral carcinogenesis in DMBA-induced hamster animal model.

Monascus-fermented products offer valuable therapeutic benefits and have been extensively used for centuries in East Asia. Dioscorea has been proved to have anti-cancer effect. The aim of this study is to investigate the anti-tumor ability of the ethanol extract of red mold dioscorea (RMDE) on 7,12-dimethyl-1,2-benz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. We induced oral squamous cell carcinoma (OSCC) in the buccal pouch of male Syrian golden hamsters by painting with 0.5% DMBA three times a week for 14 weeks. From 9 to 14 weeks, a dose of 50, 100, and 200 mg RMDE per kg body weight were painting with the hamsters for 6 weeks on days alternate to the DMBA application. The results demonstrated that RMDE decreased nitric oxide (NO), reactive oxygen species (ROS), and prostaglandin E(2) (PGE(2)) overexpression in hamster buccal pouches in the DMBA treatment group and increased p53, serum tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) to significantly stimulate caspase-8 and -3 activities, indicating that RMDE reduced oxidative damage causing by DMBA and induced apoptosis in oral cancer cells. Therefore, RMDE may have therapeutic potentials against OSCC.

Red mold dioscorea-induced G2/M arrest and apoptosis in human oral cancer cells.

BACKGROUND: Monascus-fermented products are among the most commonly used traditional food supplements. Dioscorea is known to exhibit anticancer properties. In this study the effects of the ethanol extract of red mold dioscorea (RMDE) on cell proliferation, cell cycle and apoptosis in human oral cancer cells were investigated. RESULTS: RMDE exercised growth inhibition on squamous cell carcinoma-25 (SCC-25) cells. RMDE-mediated G2/M phase arrest was associated with the down-regulation of NF-κB, resulting in the inhibition of cyclin B1 and CDK1 expression; this may be the mechanism by which RMDE inhibits cancer cells. Furthermore, the proapoptotic activity of RMDE was revealed by the Annexin V-FITC/PI double-staining assay. In addition, the proapoptotic effect of RMDE was evident by the inhibition of Bax expression in the mitochondria, resulting in the activation of caspase-9 and caspase-3 and subsequent triggering of the mitochondrial apoptotic pathway. RMDE also enhanced caspase-8 activity, indicating the involvement of the death receptor pathway in RMDE-mediated SCC-25 cell apoptosis. CONCLUSION: RMDE treatment inhibited the growth of SCC-25 cells by arresting cell cycle at the G2/M phase and induced apoptosis in a time- and dose-dependent manner. Therefore RMDE may be a good candidate for development as a dietary supplement against oral cancer.

Protection of Monascus-fermented dioscorea against DMBA-induced oral injury in hamster by anti-inflammatory and antioxidative potentials.

Monascus -fermented products offer valuable therapeutic benefits and have been extensively used in East Asia. This study investigated the prevention of oral tumor formation and antioxidative ability of the ethanol extracts from red mold dioscorea (RMDE) on 7,12-dimethyl-1,2-benz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. The HBP was painted with DMBA three times per week for 14 weeks, and animals were painted with celecoxib, RMDE (50, 100, and 200 mg/kg of bw), and ethanol extracts from dioscorea (200 mg/kg of bw) on days alternate to the DMBA application. The results demonstrated that RMDE attenuated tumor formation by elevating the antioxidase activity and suppressing the overproduction of reactive oxygen species, nitric oxide, prostaglandin E(2), and pro-inflammatory cytokines in the HBP caused by DMBA induction. These results indicated that RMDE exerted anti-inflammatory and antioxidative activity to prevent oral cancer. Therefore, the metabolite from Monascus fermentation may serve as a possible functional edible substance for the prevention of oral cancer.