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The present study is designed to investigate the anti-oral cancer properties of Solanum nigrum on oral squamous cell carcinoma. S. nigrum is a Chinese herb used for suppression of various cancers. However, the inhibition of S. nigrum on oral cancer is unclear. Therefore, human oral squamous cancer cells (SCC)-4 were used to evaluate the effect of aqueous extracts of S. nigrum (AESN) on cancer cell proliferation, cell cycle, mitochondrial function and apoptosis. The SCC-4 cells were treated by AESN to evaluate the inhibition of cell proliferation and mitochondrial function in vitro. Our results suggested that AESN markedly increased reactive oxygen species production. AESN also promoted caspase-9 and caspase-3 activation and subsequent triggering of the mitochondrial apoptotic pathway. The inhibition of glucose uptake was alleviated mediated by a dose-dependent manner in SCC-4 cells with AESN treatment for 24 h, resulting in mitochondrial fission. These results suggested that AESN has potential to be used as a functional food in adjuvant chemotherapy for treating human oral cancer by suppression of mitochondrial function., Graphical abstract Image 1

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.

The anti-obesity activity of Lactobacillus paracasei subsp. paracasei NTU 101 and Lactobacillus plantarum NTU 102 and their soy milk fermented products (SM101 and SM102) were investigated. Results indicated that the inhibition of 3T3-L1 differentiation and the accumulation of free fatty acids markedly increased in rats treated with SM101 and SM102. Moreover, the up-regulation and down-regulation of lipolysis and heparin-releasable lipoprotein lipase, respectively, were observed in the 3T3-L1 adipocytes of the SM101 and SM101 groups, and these effects of SM101 and SM102 were greater than unfermented soy milk (USM). We also found that SM101 and SM102 both improved obesity in Wistar rats fed with a high-fat diet (HFD) and that this improvement was stronger than that observed for USM. The level of serum leptin in HFD-induced rats was significantly elevated by the 5-week administration of SM101 and SM102 (106–1010 CFU/mL per rat per day); however, this activity was not promoted by USM. The anti-obesity activity of SM101 and SM102 may result from the increased daidzein and genistein levels that were observed during the fermentation by L. paracasei subsp. paracasei NTU 101 and L. plantarum NTU 102.

The effects of ankaflavin (AK) on adipokines level and insulin sensitivity were investigated. Mice were fed with high-fat diet (HFD) and AK to evaluate hyperglycemia and hyperlipidemia. Additionally, mature differentiated 3T3-L1 adipocytes were treated with AK or monascin (MS) to determine insulin signaling. Results showed that AK down-regulated serum and hepatic triacylglyceride (TG) and total cholesterol (TC) levels in mice, ameliorating hyperglycemia and hyperinsulinemia symptoms elicited by the HFD. AK elevated serum adiponectin levels in HFD-induced mice and mature 3T3-L1 adipocytes. The effect of AK on insulin sensitivity and adipokines secretion were abolished by peroxisome proliferator activated receptor-γ PPAR-γ antagonist GW9662. Moreover, we made the novel discovery that AK markedly promoted insulin receptor and Akt phosphorylation, and increased glucose uptake in mature 3T3-L1 adipocytes to a greater extent than did MS. Taken together, AK attenuated insulin resistance in HFD-induced mice and promoted insulin sensitivity in 3T3-L1 adipocytes through PPAR-γ activation.

The role of inflammation-induced oxidative stress in the pathogenesis and progression of chronic inflammatory airways diseases has received increasing attention in recent years. Nuclear factor-erythroid 2 related factor 2 (Nrf-2) is the primary transcription factor that regulates the expression of antioxidant and detoxifying enzymes. In this study, yellow pigment ankaflavin (AK), derived from Monascus-fermented products, elevated nuclear Nrf-2 protein translocation in both the A549 lung cell line and the lungs of ovalbumin (OVA)-challenged mice. Furthermore, AK increased the mRNA expression of antioxidant enzymes regulated by Nrf-2, leading to a reduction in allergen-driven airway inflammation, mucus cell hyperplasia, and eosinophilia in OVA-challenged mice. Additionally, AK prevented T-cell infiltration and Th2 cytokines including interleukin (IL)-4, IL-5, and IL-13 generation in bronchial alveolar lavage fluid. The adhesion molecules ICAM-1, VCAM-1, and eotaxin were substantially reduced by AK treatment. Importantly, the inhibitory effect of AK on adhesion molecule production and immune cell infiltration was abolished by Nrf-2 small interfering RNA. This is the first study to illustrate that AK acts as a novel Nrf-2 activator for modulating the oxidative stress pathway to improve the lung injury and ameliorate the development of airway inflammation.

Chronic inflammation in muscle tissue causes insulin resistance and type-2 diabetes. Peroxisome proliferator-activated receptor (PPAR) ligands are reported to activate the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, including pioglitazone, which belong to the thiazolidinedione (TZD). Monascin (MS), a Monascus metabolite, has been reported to exert anti-inflammatory activity in our recent study. Therefore, the alleviating mechanism of MS on tumor necrosis factor-α (TNF-α; 20 ng/mL) induced insulin resistance in C2C12 cells was investigated in this study. Results showed that MS increased the uptake of 2-[ N -(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy- d -glucose (2-NBDG) in C2C12 myotubes. This result was associated with both PPAR-γ activity and PI3K/Akt pathway caused by MS inhibited p -JNK activity and prevented PPAR-γ phosphorylation. Moreover, we found that MS may act a PPAR-γ agonist to improve insulin sensitivity, and this issue was further confirmed by PPAR-γ antagonist (GW9662). Briefly, MS as pioglitazone, stabilized PPAR-γ structure and diminished PPAR-γ phosphorylation thereby improving insulin resistance.

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 E2 (PGE2) overexpression in hamster buccal pouches in the DMBA treatment group and increased p53, serum tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) 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.