The small molecule raptinal can simultaneously induce apoptosis and inhibit PANX1 activity.

Discovery of new small molecules that can activate distinct programmed cell death pathway is of significant interest as a research tool and for the development of novel therapeutics for pathological conditions such as cancer and infectious diseases. The small molecule raptinal was discovered as a pro-apoptotic compound that can rapidly trigger apoptosis by promoting the release of cytochrome c from the mitochondria and subsequently activating the intrinsic apoptotic pathway. As raptinal is very effective at inducing apoptosis in a variety of different cell types in vitro and in vivo, it has been used in many studies investigating cell death as well as the clearance of dying cells. While examining raptinal as an apoptosis inducer, we unexpectedly identified that in addition to its pro-apoptotic activities, raptinal can also inhibit the activity of caspase-activated Pannexin 1 (PANX1), a ubiquitously expressed transmembrane channel that regulates many cell death-associated processes. By implementing numerous biochemical, cell biological and electrophysiological approaches, we discovered that raptinal can simultaneously induce apoptosis and inhibit PANX1 activity. Surprisingly, raptinal was found to inhibit cleavage-activated PANX1 via a mechanism distinct to other well-described PANX1 inhibitors such as carbenoxolone and trovafloxacin. Furthermore, raptinal also interfered with PANX1-regulated apoptotic processes including the release of the 'find-me' signal ATP, the formation of apoptotic cell-derived extracellular vesicles, as well as NLRP3 inflammasome activation. Taken together, these data identify raptinal as the first compound that can simultaneously induce apoptosis and inhibit PANX1 channels. This has broad implications for the use of raptinal in cell death studies as well as in the development new PANX1 inhibitors.

Synthesis and discovery of mitochondria-targeting oleanolic acid derivatives for potential PI3K inhibition.

Oleanolic acid and its derivatives have been widely reported for their antitumor activities. Recently, the introduction of a triphenylphosphonium cation moiety has been described to improve the selectivity and cytotoxicity of pentacyclic triterpenoids by targeting the mitochondria of human cancer cells. In this work, a series of novel mitochondria-targeting oleanolic acid derivatives were synthesized and their antitumor activities assessed. The majority of the compounds are more cytotoxicity to cancer cells than normal cells, especially for 6c with IC50 of 0.81 µM in A549 cells, which showed a slight increase compared to doxorubicin (0.97 µM). Mechanism studies demonstrated that 6c induced apoptosis of A549 cells in a dose-dependent manner, and reactive oxygen species production, mitochondrial membrane potential depolarization, and particularly pro-apoptotic proteins upregulated by western blotting experiment may be responsible for the results. Moreover, 6c arrested the cell cycle at G2/M phase and cell migration in A549 cells. Compound 6c had a comparable or somewhat improved activity to the positive control LY294002 in molecular docking studies and in vitro testing, demonstrating that the apoptosis mechanism may involve inhibition of the PI3K-Akt pathway. These results augur well for the use of 6c as a novel triphenylphosphonium-conjugated anticancer agent.

Reversing UVB-induced photoaging with Hibiscus sabdariffa calyx aqueous extract.

BACKGROUND: Hibiscus sabdariffa is commonly used in daily life and its extract is applied widely in food and cosmetics. However, it has not been evaluated for its anti-aging effects. RESULTS: Hibiscus sabdariffa calyx aqueous extract (HSCAE) has shown potential collagenase activity suppression effects, together with tyrosinase activity inhibition, and anti-oxidation as a free radical scavenger. The current investigation demonstrated that HSCAE was not cytotoxic in skin fibroblasts, and it significantly decreased ultraviolet B (UVB)-induced reactive oxygen species (ROS) on a flow cytometry assay. Moreover, HSCAE reduced matrix metalloproteinase (MMP) expression, increased tissue inhibition of metalloproteinase (TIMP)-1 level, and enhanced collagen content by inhibiting collagenase activity. It also blocked mRNA and protein expressions of melanin production pathway key factors, including the microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and dopachrome tautomerase-2 (TRP-2). CONCLUSION: These results demonstrated, for the first time, the potential of HSCAE as a natural antioxidant with the ability to maintain collagen production and to decrease melanin syntheses under UVB radiation, for anti-aging effects. © 2019 Society of Chemical Industry.

Stability of monacolin K and citrinin and biochemical characterization of red-koji vinegar during fermentation.

Red-koji vinegar is a Monascus -involved and acetic acid fermentation-derived traditional product, in which the presence of monacolin K and citrinin has attracted public attention. In this study, red-koji wine was prepared as the substrate and artificially supplemented with monacolin K and citrinin and subjected to vinegar fermentation with Acetobacter starter. After 30 days of fermentation, 43.0 and 98.1% of the initial supplements of monacolin K and citrinin were decreased, respectively. During fermentation, acetic acid contents increased, accompanied by decreases of ethanol and lactic acid contents and pH values. The contents of free amino acids increased while the contents of other organic acids, including fumaric acid, citric acid, succinic acid, and tartaric acid, changed limitedly. Besides, increased levels of total phenolics in accordance with increased antioxidative potency, α,α-diphenyl-ß-picrylhydrazyl scavenging, and xanthine oxidase inhibitory (XOI) activities were detected. It is of merit that most citrinin was eliminated and >50% of the monacolin K was retained; contents of free amino acids and total phenolics along with antioxidant and XOI activities of the red-koji vinegar were increased after fermentation.