Toll-like receptors (TLRs) are a well-known family of pattern recognition receptors that play an important role in a host immune system. TLR triggering leads to the induction of pro-inflammatory cytokines and chemokines, driving the activation of both innate and adaptive immunity. Recently, an increasing number studies have shown the link between TLRs and cancer. Among them, the toll-like receptor 4 (TLR4) signaling pathway is associated with inflammatory response and cancer progression. Dietary phytochemicals are potential modulators of immunological status with various pharmacological properties including anti-cancer, anti-oxidant and anti-inflammatory. Curcumin, 6-gingerol, 6-shogaol, 1-dehydro-10-gingerdione, epigallocatechin gallate (EGCG), luteolin, quercetin, resveratrol, caffeic acid phenethyl ester, xanthohumol, genistein, berberine, and sulforaphane can inhibit TLR4 activation. The aim of the present review is to describe the role of the TLR4 signaling pathway between inflammatory response and cancer progression. We further introduce bioactive phytochemicals with potential anti-inflammation and chemoprevention by inhibiting TLR activation.

are equal contributions to this paper.Abstract: Tyrosinase is known to be the first two and rate-limiting enzyme in the synthesis of melanin pigments responsible for colouring skin, hair and eyes. Tyrosinase inhibition is one major strategy used to treat hyperpigmentation. In human skin melanocytes, the cellular tyrosinase inhibition was examined by the conversion of L-tyrosine and oxidation of L-DOPA to dopaquinone. We evaluated the skin pigmentation inhibitor effects with both in vitro and in vivo systems to find skinwhitening agents without cytotoxic concerns. First, linderanolide B and subamolide A were isolated from the stems of Cinnamomum subavenium and exhibited mushroom tyrosinase inhibition. Then, these two herbal compounds were proved to have good pigmentation inhibitory abilities at low doses and demonstrated free cytotoxicities to normal human skin cells and zebrafish system. With molecular docking, in a virtual model of human tyrosinase, linderanolide B and subamolide A displayed meta lcoordinating interactions with Cu 2+ ions. The results obtained from biological assays showed that linderanolide B and subamolide A possessed anti-tyrosinase properties, which exhibited potential for application in medical cosmetology.

This study is the first to investigate the anticancer effect of isoobtusilactone A (IOA) in two human breast cancer cell lines, MCF-7 and MDA-MB-231. IOA exhibited effective cell growth inhibition by inducing cancer cells to undergo G 2 -M phase arrest and apoptosis. Further investigation revealed that IOA's inhibition of cell growth was also evident in a nude mice model. Cell cycle blockade was associated with increased levels of p21 and reduced amounts of cyclin B1, cyclin A, cdc2, and cdc25C. IOA also enhanced the levels of inactivated phosphorylated cdc2 and cdc25C. IOA triggered the mitochondrial apoptotic pathway, as indicated by a change in Bax/ Bcl-2 ratios, resulting in mitochondrial membrane potential loss, cytochrome c release, and caspase-9 activation. We also found that the generation of reactive oxygen species (ROS) is a critical mediator in IOA-induced cell growth inhibition. Enhancement of ROS by IOA activated apoptosis signalregulating kinase 1 (ASK1) resulted in the increased activation of c-Jun NH 2 -terminal kinase and p38. Antioxidants EUK8 and N-acetyl cystenine significantly decreased apoptosis by inhibiting the ASK1 dephosphorylation at Ser 967 and subsequently increased the interaction of ASK1 with thioredoxin or 14-3-3 proteins. Moreover, blocking ASK1 by small interfering RNA inhibition completely suppressed IOA-induced apoptosis. Taken together, these results imply a critical role for ROS and ASK1 in IOA's anticancer activity. [Cancer Res 2007;67(15):7406-20]

The natural compound sinularin, isolated from marine soft corals, is antiproliferative against several cancers, but its possible selective killing effect has rarely been investigated. This study investigates the selective killing potential and mechanisms of sinularin-treated breast cancer cells. In 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium, inner salt (MTS) assay, sinularin dose-responsively decreased the cell viability of two breast cancer (SKBR3 and MDA-MB-231) cells, but showed less effect on breast normal (M10) cells after a 24 h treatment. According to 7-aminoactinomycin D (7AAD) flow cytometry, sinularin dose-responsively induced the G2/M cycle arrest of SKBR3 cells. Sinularin dose-responsively induced apoptosis on SKBR3 cells in terms of a flow cytometry-based annexin V/7AAD assay and pancaspase activity, as well as Western blotting for cleaved forms of poly(ADP-ribose) polymerase (PARP), caspases 3, 8, and 9. These caspases and PARP activations were suppressed by N-acetylcysteine (NAC) pretreatment. Moreover, sinularin dose-responsively induced oxidative stress and DNA damage according to flow cytometry analyses of reactive oxygen species (ROS), mitochondrial membrane potential (MitoMP), mitochondrial superoxide, and 8-oxo-2′-deoxyguanosine (8-oxodG)). In conclusion, sinularin induces selective killing, G2/M arrest, apoptosis, and oxidative DNA damage of breast cancer cells.

Mahlavu cells, poorly differentiated and p53 mutants of a human hepatoma subline, are known to be highly refractory to a number of chemotherapeutic agents and radiotherapy due to their high expressions of multidrug resistance gene-1 (MDR-1) and Bcl-2 proteins. Thus, it is desirable to search for an alternative strategy for effective eradication of this type of cancer cells. We present evidence here for the first time that 6-shogaol (6-SG), an alkanone isolated from the rhizomes of ginger, can effectively induce apoptotic cell death of Mahlavu cells via an oxidative stress-mediated caspase-dependent mechanism. The cascade of events in 6-SG-induced apoptosis of these cells involved an initial overproduction of reactive oxygen species (ROS) followed by a severe depletion of intracellular glutathione (GSH) contents. Both events consequently entailed a significant drop in mitochondrial transmembrane potential (DeltaPsim), which ultimately activated the activities of caspases 3/7 resulting in the DNA fragmentation. Interestingly, we also found that N-acetylcysteine (NAC), an antioxidant and a precursor of GSH biosynthesis, could offer a near complete protection of apoptotic cell death exerted by 6-SG. Similarly, exogenously added GSH could also provide protection with an equal efficacy. However, it was paradoxical that both Boc-Asp(OMe)-fmk (a broad caspases inhibitor) and cyclosporin A (an mitochondrial permeability transition opening inhibitor) could only partially protect these cells from 6-SG-induced apoptosis. Taking these data into consideration, it is obvious that GSH depletion is the major contributing factor in arbitrating 6-SG-induced apoptosis of Mahlavu cells. In conclusion, we provide here a novel modality that can help to eradicate a p53 mutant of human hepatoma cells by using a natural consistent isolated form of ginger. These data also provide evidence to reaffirm the notion that consumption of certain foodstuffs can be beneficial to health because some of the constituents contained in them may be anticarcinogenic.