l-Tryptophan Induces a Marine-Derived Fusarium sp. to Produce Indole Alkaloids with Activity against the Zika Virus.

The effects of l-tryptophan supplementation on secondary metabolite production in the marine-derived fungus Fusarium sp. L1 were investigated by culturing the fungus in GPY medium with and without the amino acid. HPLC analysis of the products showed distinct metabolite profiles between the two cultures. The 1H NMR spectrum of the EtOAc extract of the culture supplemented with l-tryptophan displayed a series of characteristic aromatic proton signals (δH 6.50-8.50) and NH signals (δH 10.50-11.50) that were not observed in those from cultures not supplemented with l-tryptophan. Subsequently, 23 distinct indole alkaloids, including six new compounds, fusaindoterpenes A and B (1 and 2), fusariumindoles A-C (3-5), and (±)-isoalternatine A (6), together with 17 known compounds, were obtained from this culture. Fusaindoterpene A (1) contains a 6/9/6/6/5 heterocyclic system. Their chemical structures were determined by analysis of HRMS, NMR spectroscopy, optical rotation calculation, ECD calculation, and single-crystal X-ray diffraction data. Compounds 2, 9, and 15 displayed inhibitory activity against the Zika virus (ZIKV) in a standard plaque assay with EC50 values of 7.5, 4.2, and 5.0 µM, respectively, while not showing significant cell cytotoxicity against the A549 adenocarcinomic human alveolar basal epithelial cell line.

A Marine Alkaloid, Ascomylactam A, Suppresses Lung Tumorigenesis via Inducing Cell Cycle G1/S Arrest through ROS/Akt/Rb Pathway.

Ascomylactam A was reported for the first time as a new 13-membered-ring macrocyclic alkaloid in 2019 from the mangrove endophytic fungus Didymella sp. CYSK-4 from the South China Sea. The aim of our study was to delineate the effects of ascomylactam A (AsA) on lung cancer cells and explore the antitumor molecular mechanisms underlying of AsA. In vitro, AsA markedly inhibited the cell proliferation with half-maximal inhibitory concentration (IC50) values from 4 to 8 µM on six lung cancer cell lines, respectively. In vivo, AsA suppressed the tumor growth of A549, NCI-H460 and NCI-H1975 xenografts significantly in mice. Furthermore, by analyses of the soft agar colony formation, 5-ethynyl-20-deoxyuridine (EdU) assay, reactive oxygen species (ROS) imaging, flow cytometry and Western blotting, AsA demonstrated the ability to induce cell cycle arrest in G1 and G1/S phases by increasing ROS generation and decreasing of Akt activity. Conversely, ROS inhibitors and overexpression of Akt could decrease cell growth inhibition and cell cycle arrest induced by AsA. Therefore, we believe that AsA blocks the cell cycle via an ROS-dependent Akt/Cyclin D1/Rb signaling pathway, which consequently leads to the observed antitumor effect both in vitro and in vivo. Our results suggest a novel leading compound for antitumor drug development.

Secondary Metabolites from the Marine-Derived Fungus Dichotomomyces sp. L-8 and Their Cytotoxic Activity.

Bioassay-guided isolation of the secondary metabolites from the fungus Dichotomomyces sp. L-8 associated with the soft coral Lobophytum crassum led to the discovery of two new compounds, dichotones A and B (1 and 2), together with four known compounds including dichotocejpin C (3), bis-N-norgliovictin (4), bassiatin (5) and (3R,6R)-bassiatin (6). The structures of these compounds were determined by 1D, 2D NMR and mass spectrometry. (3R,6R)-bassiatin (6) displayed significant cytotoxic activities against the human breast cancer cell line MDA-MB-435 and the human lung cancer cell line Calu3 with IC50 values of 7.34 ± 0.20 and 14.54 ± 0.01 µM, respectively, while bassiatin (5), the diastereomer of compound 6, was not cytotoxic.

Acrolein induces Alzheimer's disease-like pathologies in vitro and in vivo.

The pathologic mechanisms of Alzheimer's disease (AD) have not been fully uncovered. Acrolein, a ubiquitous dietary pollutant and by-product of oxidative stress, can induce cytotoxicity in neurons, which might play an important role in the etiology of AD. Here, we examined the effects of Acrolein on the AD pathologies in vitro and in vivo. We found Acrolein induced HT22 cells death in concentration- and time-dependent manners. Interestingly, Acrolein increased proteins' levels of amyloid precursor protein (APP), ß-secretase (BACE-1) and the amyloid ß-peptide transporter receptor for advanced glycation end products, and decreased A-disintegrin and metalloprotease (ADAM) 10 levels. In vivo, chronic oral exposure to Acrolein (2.5 mg/kg/day by intragastric gavage for 8 weeks) induced mild cognitive declination and pyknosis/atrophy of hippocampal neurons. The activity of superoxide dismutase was down-regulated while the level of malondialdehyde was up-regulated in rat brain. Moreover, Acrolein resulted in activation of astrocytes, up-regulation of BACE-1 in cortex and down-regulation of ADAM-10 in hippocampus and cortex. Taken together, our findings suggest that exposure to Acrolein induces AD-like pathology in vitro and in vivo. Scavenging Acrolein might be beneficial for the therapy of AD.

Off-line analysis of single-unit neuronal discharge in the globus pallidus region in Parkinson's disease.

BACKGROUND: The accuracy of microelectrode-guided localization can make the operation safe and effective, but only experienced neurosurgeons are capable of performing this operation. A good index to identify neuronal discharges between globus pallidus interna and globus pallidus externa is needed. The aim of this research was to establish a good and practical electrophysiologic index to distinguish neuronal discharge in the interior globus pallidus from neuronal discharge in the exterior globus pallidus region of the brain in Parkinson's disease. The effect of neurons having an atypical discharge on successful surgical localization was also quantitatively evaluated. METHODS: The study included 30 patients with primary Parkinson's disease who underwent pallidotomy between September 2000 and October 2002. During each pallidotomy, the neuronal discharges in the pallidum and its vicinity were recorded. The recorded spikes were used to calculate the frequency, burst index, pause index, and pause ratio of the single-unit discharge. The interior and exterior globus pallidus regions were compared in terms of frequency, burst index, pause index, and pause ratio. The sensitivity, specificity, false-negative ratio, false-positive ratio, and accuracy of those indices were then evaluated. RESULTS: The values of frequency, burst index, pause index, and pause ratio in the interior globus pallidus were (96 +/- 43) Hz, 2.31 +/- 1.81, 0.05 +/- 0.05, and 0.27 +/- 0.28, respectively, and in the exterior globus pallidus were (59 +/- 27) Hz, 0.88 +/- 0.63, 0.20 +/- 0.14, and 1.54 +/- 1.17, respectively. Use of the four indices to distinguish the two neuron types produced a sensitivity of 0.84, 0.78, 0.77, and 0.93 with a specificity of 0.64, 0.79, 0.88, and 0.87, respectively. The false-positive ratio was 0.36, 0.21, 0.12, and 0.13 and the false-negative ratio was 0.16, 0.22, 0.23, and 0.07 while the accuracy was 0.72, 0.79, 0.80, and 0.90, respectively. CONCLUSIONS: Pause ratio is a relatively reliable index to distinguish neuronal discharges between the interior and exterior globus pallidus regions in Parkinson's disease. The effect of neurons with atypical discharge on the successful surgical localization would be reduced to 10% when the pause ratio is used as the index.