Bioactivity of natural biflavonoids in metabolism-related disease and cancer therapies

Natural biflavonoids, such as amentoflavone, bilobetin, ginkgetin, isoginkgetin, taiwaniaflavone, morelloflavone, delicaflavone, hinokiflavone, and other derivatives (~ 40 biflavonoids), are isolated from Selaginella sp., Ginkgo biloba, Garcinia sp., and several other species of plants. They are able to exert therapeutic benefits by regulating several proteins/enzymes (PPAR-γ, CCAAT/enhancer-binding protein α [C/EBPα], STAT5, pancreatic lipase, PTP1B, fatty acid synthase, α-glucosidase [AG]) and insulin signaling pathways (via PI3K-AKT), which are linked to metabolism, cell growth, and cell survival mechanisms. Deregulated insulin signaling can cause complications of obesity and diabetes, which can lead to cognitive disorders such as Alzheimer's, Parkinson's, and dementia; therefore, the therapeutic benefits of these biflavones in these areas are highlighted. Since biflavonoids have shown potential to regulate metabolism, growth- and survival-related protein/enzymes, their relation to tumor growth and metastasis of cancer associated with angiogenesis are highlighted. The translational role of biflavones in cancer with respect to the inhibition of metabolism-related processes/pathways, enzymes, or proteins, such as STAT3/SHP-1/PTEN, kinesins, tissue kallikreins, aromatase, estrogen, protein modifiers, antioxidant, autophagy, and apoptosis induction mechanisms, are discussed. Finally, considering their observed bioactivity potential, oral bioavailability studies of biflavones and related clinical trials are outlined.