Flavonoids are highly diversified plant pigments that are present in a wide range of fruits, vegetables, nuts, and beverages. They are regularly consumed in the human diet and have various biological activities including anti-inflammatory, anti-cancer, and anti-viral properties. The flavonoids maybe one of the safest non-immunogenic drugs because they are small organic compounds which have been normally absorbed by the human body for long time. During the past decades, the patents on their health effects have inflated very much and the yearly number of the patents is on an increasing trend. This review summarizes the current patents on the health effects of various flavonoids, and suggests the possible expectation that a wide variety of diseases are successful treated with newly-developed specific flavonoids or their derivatives in the near future. In recent patents, specific flavonoids were described to function as anti-oxidants, enzyme inhibitors, hormones, or immune modulators. Moreover, the recent patents also tried to provide the molecular mechanism of the flavonoid compounds on treating or preventing various human diseases. Recent mechanistic studies in molecular level make it possible that specific flavonoids are identified to have a wide range of biological properties that can contribute to the beneficial effects on human health.

Lung cancer is one of the most common cancers in many countries and the leading cause of cancer deaths in the world accounting for 28% of all cancer death.1,2) The high mortality of this disease is due to the difficulty of early diagnosis and its high potential to invade locally and metastasize to distant organs. Therefore, there is need for novel diagnosis, treatment, and prevention, against lung cancer.As the functional compounds of the plants can serve as a starting point for the development of optimal derivatives, scientists are always searching for new medical herbs. Flavonoids are plant pigments which have been detected in all parts of plants and major functional components of many herbal preparations used in traditional medical protocols. [3][4][5][6] Fruits and vegetables, as well as popular beverages such as wine, tea, and coffee, are the main dietary sources of flavonoids. It has been reported that flavonoids show pharmacological effects such as antiviral, 7) antitumor, 8) antioxidant, 9,10) and anti-inflammatory activities. 11) They are low molecular weight polyphenolic compounds, which possess a basic 2-phenyl-benzo-gamma-pyrone structure harboring one or more hydroxyl groups. As the result of this basic chemical structure, one of the most obvious features of flavonoids is their ability to quench free radicals via the formation of resonance-stabilized phenoxyl radicals.12) Recently, They have attracted much attention because of their broad pharmacological activities, in particular antioxidant activities, and anti-tumorigenic activities. 13,14) Flavonoids exert protective effects, which appear to be related to specific structural characteristics.15) Recently, several studies have reported that the differential effects of flavonoids are attributable to substituted functional groups. 16,17) We also suggested that the OH group of the -5 or carbon-7 of the C6C3C6 skeleton is the key determinant of the anti-oxidant and anti-apoptotic activities associated with flavonoids.18,19) Therefore, investigations into the structurally related activities of flavonoids are important in terms of our understanding of their differential activities. The association between flavonoid intake and reduced disease risk was originally believed to be the consequence of the anti-oxidant effects of these compounds and recent evidence appears to indicate that flavonoids and their metabolites exert other intracellular effects, including the direct modulation of cell signaling pathways, including the MAPK( Mitogen activated protein kinase) cascade. [20][21][22][23] In this study, we describe the apoptotic cell death of human lung epithelial carcinoma A549 cells as the result of treatment with synthetic naringenin derivates, including 7-Obenzyl naringenin (KUF-1), 7-O-(m-metoxybenzyl) naringenin (KUF-2), 7-O-(2-naphtylmethyl) naringenin (KUF-5), 7-O-benzoxycarbonylmethyl naringenin (KUF-6), 7-O-(MeO-L-Leu-D-Pro-carbonylmethyl) naringenin (KUF-7), and 7-O-(MeO-Gly-D-Pro-carbonylmethyl) naringenin (KUF-8) (Fig. 1). The synthetic naring...

Flavonoids are micronutrients that are widely detected in foods of plant origin and have been ascribed pharmacological properties. Several biological functions of flavonoids have been thus far identified, whereas there currently exists a lack of evidence to support the relationship between the structure-activity relationship and apoptosis-inducing activity. In an attempt to determine the importance of the OH group or substitution of the 5- or 7-carbon in the diphenylpropane skeleton of flavonoids, we selected 14 different flavonoids with different structures, particularly with regard to the 5- or 7-carbon, and found that naringenin treatment caused a slight decrease in the cell viability of the human colorectal carcinoma RKO cells. Next, in order to characterize the effects of specific substitutions of the 7-carbon of naringenin on apoptosis-regulatory activities, and in an attempt to develop anti-proliferative flavonoid derivatives that would be more effective against colon cancer, we originally synthesized several modified naringenin derivatives (MNDs) including 7-O-benzyl naringenin (KUF-1) and 7-O-(m-metoxybenzyl) naringenin (KUF-2). Treatment with KUF-1 or KUF-2 resulted in significant apoptosis-inducing effects concomitant with losses in mitochondrial membrane potential, caspase activation, intracellular ROS production, and sustained ERK activation. Our data show that KUF-1 or KUF-2 regulate the apoptosis of RKO cells via intracellular ROS production coupled with the concomitant activation of the ERK signaling pathway, thereby implying that hydroxylation or substitution at C7 is critical for the apoptosis-inducing activity of flavonoids.

The availability of autologous adult stem cells is one of the essential prerequisites for human stem cell therapy. Urine-derived stem cells (USCs) are considered as desirable cell sources for cell therapy because donor-specific USCs are easily and non-invasively obtained from urine. Efficient isolation, expansion, and differentiation methods of USCs are necessary to increase their availability. Here, we developed a method for efficient isolation and expansion of USCs using Matrigel, and the rho-associated protein kinase (ROCK) inhibitor, Y-27632. The prepared USCs showed significantly enhanced migration, colony forming capacity, and differentiation into osteogenic or chondrogenic lineage. The USCs were successfully reprogramed into induced pluripotent stem cells (USC-iPSCs) and further differentiated into kidney organoid and hematopoietic progenitor cells (HPCs). Using flavonoid molecules, the isolation efficiency of USCs and the production of HPCs from the USC-iPSCs was increased. Taken together, we present an improved isolation method of USCs utilizing Matrigel, a ROCK inhibitor and flavonoids, and enhanced differentiation of USC-iPSC to HPC by flavonoids. These novel findings could significantly enhance the use of USCs and USC-iPSCs for stem cell research and further application in regenerative stem cell-based therapies.

Hepatocellular carcinoma (HCC) is a leading cause of cancerrelated death worldwide, and it is thus critical to identify novel molecular biomarkers of HCC prognosis and elucidate the molecular mechanisms underlying HCC progression. Here, we show that G-protein-coupled receptor 50 (GPR50) in HCC is overexpressed and that GPR50 knockdown may downregulate cancer cell progression through attenuation of the Notch signaling pathway. GPR50 knockdown was found to reduce HCC progression by inactivating Notch signaling in a ligand-independent manner through a disintegrin and metalloproteinase metallopeptidase domain 17 (ADAM17), a proteolytic enzyme that cleaves the Notch receptor, which was corroborated by GPR50 overexpression in hepatocytes. GPR50 silencing also downregulated transcription and translation of ADAM17 through the AKT/specificity protein-1 (SP1) signaling axis. Notably, GPR50 was found to directly interact with ADAM17. Overall, we demonstrate a novel GPR50mediated regulation of the ADAM17-Notch signaling pathway, which can provide insights into HCC progression and prognosis and development of Notch-based HCC treatment strategies.

Cancer stem cells (CSCs) are a subpopulation of cancer that can self-renew and differentiate into large tumor masses. Evidence accumulated to date shows that CSCs affect tumor proliferation, recurrence, and resistance to chemotherapy. Recent studies have shown that, like stem cells, CSCs maintain cells with self-renewal capacity by means of asymmetric division and promote cell proliferation by means of symmetric division. This cell division is regulated by fate determinants, such as the NUMB protein, which recently has also been confirmed as a tumor suppressor. Loss of NUMB expression leads to uncontrolled proliferation and amplification of the CSC pool, which promotes the Notch signaling pathway and reduces the expression of the p53 protein. NUMB genes are alternatively spliced to produce six functionally distinct isoforms. An interesting recent discovery is that the protein NUMB isoform produced by alternative splicing of NUMB plays an important role in promoting carcinogenesis. In this review, we summarize the known functions of NUMB and NUMB isoforms related to the proliferation and generation of CSCs.

Efficient maintenance of the undifferentiated status of human pluripotent stem cells (hiPSCs) is crucial for producing cells with improved proliferation, survival and differentiation, which can be successfully used for stem cell research and therapy. Here, we generated iPSCs from healthy donor peripheral blood mononuclear cells (PBMCs) and analyzed the proliferation and differentiation capacities of the generated iPSCs using single cell NGS-based 24-chromosome aneuploidy screening and RNA sequencing. In addition, we screened various natural compounds for molecules that could enhance the proliferation and differentiation potential of hiPSCs. Among the tested compounds, 3,2′-dihydroxyflavone (3,2′-DHF) significantly increased cell proliferation and expression of naïve stemness markers and decreased the dissociation-induced apoptosis of hiPSCs. Of note, 3,2′-DHF-treated hiPSCs showed upregulation of intracellular glutathione (GSH) and an increase in the percentage of GSH-high cells in an analysis with a FreSHtracer system. Interestingly, culture of the 3,2′-DHF-treated hiPSCs in differentiation media enhanced their mesodermal differentiation and differentiation into CD34+ CD45+ hematopoietic progenitor cells (HPC) and natural killer cells (NK) cells. Taken together, our results demonstrate that the natural compound 3,2′-DHF can improve the proliferation and differentiation capacities of hiPSCs and increase the efficiency of HPC and NK cell production from hiPSCs.

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