Anti-cancer studies using NTU 568 fermented extra
In our study, the traditional variation method was used to select the monascus strain Monascus purpureus NTU 568. Its fermentation extract and purified secondary metabolites showed good anti-cancer abilities, which were represented by direct inhibition of tumor formation (induction of cancer cell death, inhibition of cancer cell metastasis, suppression of new blood vessel development), indirect inhibition of tumor formation (through the suppression of chronic inflammation), and assistance in radio therapy.
The most significant difference between cancer cells and normal cells is the unstable genetic expression of the cancer cells and the appearance of uncontrollable reproduction, to the point of forming tumors. By using lung cancer-bearing mice, it was shown that eating NTU 568 fermented extra could suppress the formation of tumors, the metastasis of cancer cells, and tumor angiogenesis. These effects were associated with the secondary metabolites of red mold fermented extract, monakolin K and ankaflavin. It was also shown that the growth of colon cancer cells implanted in the chorioallantoic membrane of chicken embryos, as well as angiogenesis, was effectively suppressed by monascus extract. From red mold fermented rice and red mold fermented dioscorea, the study team also purified 32 pigment derivatives that had suppressive effects on cell growth in laryngeal cancer, colorectal cancer, and breast cancer. Some pigment derivatives were shown to have selectivity, with good suppressive effects on cancer cells while not affecting the growth of normal cells.
The cause of approximately 30% of cancers is chronic inflammation. Free radicals such as nitric oxide released by leukocytes and macrophages for the defense against foreign antigens can equally damage normal tissues and cells and may eventually lead to the formation of malignant tumors. In our study, the anti-cancer effects of NTU 568 fermented extra were evaluated using induced oral squamous cell tumors in hamsters as the experiment model, in which inflammatory damage was induced in the buccal cavity of the animals by the application of 7,12-dimethylbenz(a)anthracene (DMBA). The results showed that NTU 568 fermented extra could slow down the formation of oral tumors by suppressing various kinds of inflammatory reactions, including the production of nitric oxide, pro-inflammatory cytokines, and the pro-inflammatory enzymes. The main active component in the extract was monascin.
Cobalt-60 radiation is currently an effective medical tool to kill cancer cells. However, it also produces a number of side effects, including inducing inflammation and reducing food intake. In this study an animal experiment model of radiotherapy was developed using mouse melanoma. It was shown that feeding with the alcohol extract from red mold dioscorea increased the food intake of tumor-bearing mice, as well as significantly reducing the elevation of radiation-induced cytokines, including the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6, and the fibrogenic cytokine TGF-β.
Ankaflavin v.s immune modulation
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. We found yellow pigment ankaflavin, 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, ankaflavin 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, ankaflavin 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 ankaflavin treatment. Importantly, the inhibitory effect of ankaflavin on adhesion molecule production and immune cell infiltration was abolished by Nrf-2 small interfering RNA. We clearly illustrated that ankaflavin 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.
Monascin v.s diabetes
We investigated the improvement of monascin on insulin resistance and the mechanism of monascin for blood glucose regulation. We found monascin plays as a peroxisome proliferator activated receptor-γ (PPARγ) agonist to activate PPARγ, thereby attenuating insulin resistance in C2C12 cells induced by tumor necrosis factor-α (TNF-α) and FL83B hepatocytes induced by methylglyoxal (MG). In addition, monascin activates nclear factor-erythroid 2 related factor -2 (Nrf2) to inhibit activation of receptor for advanced glycationend products (RAGE), lowering oxidative stress and pro-inflammatory cytokine production in THP-1 monocytes. On the other hand, Wistar rats were administered with MG for 28 days to induce diabetes, and the oral glucose tolerance test (OGTT) was carried out before MG induction. Results indicated that the suppression of blood glucose elevation by monascin treatment was greater than rosiglitazone (PPARγ agonist), and this activity was not depended in insulin secretion, suggesting that monascin was able to promote glucose uptake in the absence of insulin. MG induction significantly resulted in hyperglycemia and hyperinsulinmia in Wistar rats, but monascin effectively inhibited inflammation and hyperglycemia caused by MG comparing to rosiglitazone treatment. We also found that monascin increased glyoxalase expression to metabolize MG via activating Nrf2, resulting in an attenuation of advanced glycationend products (AGEs) generation, but rosiglitazone treatment did not exert this effect in MG-induced rats. As a result of monascin significantly down-regulated blood glucose than rosiglitazone, hence, this study investigated the effect of monascin on liver. Result demonstrated that monascin elevated AMP protein kinase (AMPK) phosphorylation to improve glucose uptake of hepatic cells, and this result was confirmed in FL83B hepatocytes. However, the anti-diabetic effects of monascin were attenuated by GW9662 (PPARγ antagonist) or PPARγ siRNA treatment in vitro and in vivo. It suggested that improvements of monascin for hyperglycemia depended in PPARγ activation thereat monascin have potentials for development of anti-diabetic agent.
