Programmed cell death (PCD) is decisive in eliminating affected cells in human cancers, whereas there are increasing cases of cancer-related death due to side effects of modern treatment methods. There is an urge for new methods of growth inhibition and elimination of cancer cells with a lower cytotoxicity to normal cells. Irregularity along PCD pathways plays a crucial role in cancer cell carcinogenesis. Apoptosis is a distinct cell death mechanism occurring in multicellular organisms and also called type one programmed cell death. Autophagy and paraptosis are non-apoptotic PCD occurring in multicellular organisms. Natural compounds are the fundament of pharmacological treatments, and flavonoids are natural polyphenolic compounds which are unique due to their diverse chemical structures and various biological active mechanisms like anticancer, anti-inflammatory, antioxidative and much more. This gives an increasing number of studies indicating that some flavonoids from medicinal plants could be promising candidates for new natural anticancer drugs, which attract high interests of academic researchers and advanced users. An understanding of the underlying mechanism of PCD induced by flavonoids in cancer cells is important as it plays a pivotal role in the pathogenesis of many diseases. This systematic review is to report flavonoids and their derivatives as new anticancer candidates to stimulate PCD with a different mechanism based on the pharmacological evidence.

In this study, the anti-inflammatory activities of the extracts of different parts of Hovenia dulcis such as leaves, stems, and roots were investigated. Among them, the roots extract (RE) showed the most potent suppressive effect against pro-inflammatory mediators in LPS-stimulated mouse macrophage cells. RE induced dose-dependent reduction of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and concomitantly reduced the production of NO and PGE2. Additionally, pre-treatment with RE significantly suppressed the production of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, as well as mRNA levels. Moreover, phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear translocation of nuclear factor-kappa B (NF-kB) were also strongly attenuated by RE in RAW264.7 cell. Furthermore, RE induced HO-1 expression through nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and increase HO-1 activity in RAW264.7 macrophages. Therefore, these results indicate that RE strongly inhibits LPS-induced inflammatory responses by blocking NF-kB activation, inhibiting MAPKs phosphorylation, and enhancing HO-1 expression in macrophages, suggesting that RE of H. dulicis and a major component, 27-O-protocatechuoylbetulinic acid could be applied as a valuable natural anti-inflammatory material.