Novel Natural Products from Extremophilic Fungi.

Extremophilic fungi have been found to develop unique defences to survive extremes of pressure, temperature, salinity, desiccation, and pH, leading to the biosynthesis of novel natural products with diverse biological activities. The present review focuses on new extremophilic fungal natural products published from 2005 to 2017, highlighting the chemical structures and their biological potential.

Flavans from Iris tenuifolia and their effects on ß-amyloid aggregation and neural stem cells proliferation in vitro.

Two new flavans (1, 2) and a new flavanone (3), together with three known compounds (4-6), were isolated from the roots of Iris tenuifolia. Their structures were elucidated by means of spectroscopic methods including 1D and 2D NMR techniques and mass spectrometry. Compounds 1, 4, and 6 were further confirmed by single-crystal X-ray diffraction analysis. Biological evaluation showed that compounds 1 and 4 were positive in inhibiting ß-amyloid (Aß) aggregation and promoting neural stem cells (NSCs) proliferation, respectively.

[Detoxication effect of water-soluble imprinted cross-linked chitosan on depleted uranium induced toxicity to renal cells].

To investigate whether a series of water-soluble cross-linked chitosan derivates synthesized in the guide of imprinting technology could be used as a uranium chelating agent to protect cells exposed to depleted uranium (DU), the imprinted chitosan derivates with high UO2(2+) chelating ability were screened, and cell model of human renal proximal tubule epithelium cells (HK-2) exposed to DU (500 micromol.L-1) was built, chitosan derivates (400 mg.L-1 ) was added to test group and diethylenetriaminepentaacetic acid (DTPA, 50 mg.L-1) was added to positive control group. The results showed that three Cu2+ imprinted chitosan derivates had higher uranium chelating ability (>49 microg.mg-1) than chitosan and non-imprinted chitosan derivates. Compared to the cells exposed to DU only, survival of cells in group added chitosan derivates rose up significantly (increased from 57.3% to 88.7%, and DTPA to 72.6%), and DU intracellular accumulation decreased, membrane damage and DNA damage also eased. Among the imprinted chitosan derivates, Cu2+ imprinted penta dialdehyde cross-linked carboxymethyl chitosan (Cu-P-CMC) was the best, and better than DTPA. From ultrastructure observation, the DU precipitates of test group added Cu-P-CMC were most grouped in a big hairy clusters in a string together outside cells. It is possible that the DU-chitosan derivates precipitates are too big to enter into cells, and from this way, the DU uptake by cells decreased so as to detoxication.

Rescue of cognitive deficits in APP/PS1 mice by accelerating the aggregation of ß-amyloid peptide.

BACKGROUND: Brain amyloid deposition is one of the main pathological characteristics of Alzheimer's disease (AD). Soluble oligomers formed during the process that causes ß-amyloid (Aß) to aggregate into plaques are considered to have major neurotoxicity. Currently, drug development for the treatment of Alzheimer's disease has encountered serious difficulties. Our newly proposed solution is to accelerate the aggregation of Aß to reduce the amount of cytotoxic Aß oligomers in brain tissue. This strategy differs from the existing strategy of reducing the total Aß content and the number of amyloid plaques. METHOD: In this study, we screened a small library and found that a flavonoid compound (ZGM1) promoted the aggregation of ß-amyloid (Aß). We further verified the binding of ZGM1 to Aß42 using a microscale thermophoresis (MST) assay. Subsequently, we used dot blotting (DB), transmission electron microscopy (TEM), and thioflavin T fluorescence (ThT) measurements to study the aggregation of Aß under the influence of ZGM1. By using cell experiments, we determined whether ZGM1 can inhibit the cytotoxicity of Aß. Finally, we studied the protective effects of ZGM1 on cognitive function in APPswe/PS1 mice via behavioral experiments and measured the number of plaques in the mouse brain by thioflavin staining. RESULTS: ZGM1 can bind with Aß directly and mediate a new Aß assembly process to form reticular aggregates and reduce the amount of Aß oligomers. Animal experiments showed that ZGM1 can significantly improve cognitive dysfunction and that Aß plaque deposition in the brain tissue of mice in the drug-administered group was significantly increased. CONCLUSION: Our research suggests that promoting Aß aggregation is a promising treatment method for AD and deserves further investigation.

Novel natural compounds from endophytic fungi with anticancer activity.

Plant endophytes are microorganisms that live in healthy plant tissues in part or all of their life history without causing obvious symptoms of infection in the host plants. Endophytes, a new type of microbial resource that can produce a variety of biological constituents, have great values for research and broad prospects for development. This article reviewed the research and development progress of endophytic fungi with cytotoxic activity between 2014 and 2017, including endophytic fungi sources, microbial taxonomy, compound classification and cytotoxic activity. The results showed that the 109 strains of endophytic fungi belong to 3 phyla, 7 classes and 50 genera. The secondary metabolites mainly contained alkaloids, terpenes, steroids, polyketides, quinones, isocoumarins, esters etc. The results of this study provide references for the development of new antitumor drugs and endophytes resources.

Apoptosis induced by one new podophyllotoxin glucoside in human carcinoma cells.

4-Demethyl-picropodophyllotoxin 7'-O-beta-D-glucopyranoside (4DPG), a new podophyllotoxin glucoside, was isolated from the rhizomes of Sinopodophyllum emodi (Wall.) Ying and showed cytotoxic effects in human carcinoma cells. Among the target cells (HeLa, A2 and SH-SY5Y), the cytotoxic effects of 4DPG showed dose- and time-dependency. Furthermore, the cervical carcinoma cell line, HeLa, was more sensitive to 4DPG. Flow cytometric analysis demonstrated the presence of apoptotic cells with low DNA content, a decrease of cell population at the G1 phase, and a concomitant increase of cell population at the G2/M phase. 4DPG also caused DNA fragmentation in HeLa cells. Treatment with 0.1 microM 4DPG increased p53 expression and Bax/Bcl-2 ratio in HeLa cells, as well as in A2 cells. These results suggested that 4DPG-induced apoptosis might be through a p53-dependent pathway.

Protective effects of ion-imprinted chitooligosaccharides as uranium-specific chelating agents against the cytotoxicity of depleted uranium in human kidney cells.

Occupational internal contamination with depleted uranium (DU) compounds can induce radiological and chemical toxicity, and an effective and specific uranium-chelating agent for clinical use is urgently needed. The purpose of this study was to investigate whether a series of synthesized water-soluble metal-ion-imprinted chitooligosaccharides can be used as uranium-specific chelating agents, because the chitooligosaccharides have excellent heavy metal ion chelation property and the ion-imprinting technology can improve the selective recognition of template ions. DU-poisoned human renal proximal tubule epithelium cells (human kidney 2 cells, HK-2) were used to assess the detoxification of these chitooligosaccharides. The DU-chelating capacity and selectivity of the chitooligosaccharides were determined by inductively coupled plasma-mass spectrometry (ICP-MS). Cell viability, cellular accumulation of DU, membrane damage, DNA damage, and morphological changes in the cellular ultrastructure were examined to assess the detoxification of these chitooligosaccharides. The results showed that the Cu²âº-imprinted chitooligosaccharides, especially the Cu²âº-imprinted glutaraldehyde-crosslinked carboxymethyl chitooligosaccharide (Cu-Glu-CMC), chelated DU effectively and specifically, and significantly reduced the loss of cell viability induced by DU and reduced cellular accumulation of DU in a dose-dependent manner, owing to their chelation of DU outside cells and their prevention of DU internalization. The ultrastructure observation clearly showed that Cu-Glu-CMC-chelated-DU precipitates, mostly outside cells, were grouped in significantly larger clusters, and they barely entered the cells by endocytosis or in any other way. Treatment with Cu-Glu-CMC also increased the activity of antioxidant enzymes, and reduced membrane damage and DNA damage induced by DU oxidant injury. Cu-Glu-CMC was more effective than the positive control drug, diethylenetriaminepentaacetic acid (DTPA), in protection of HK-2 cells against DU cytotoxicity, as a result of its chelation of UO2²âº to prevent the DU internalization and its antioxidant activity.

Cytotoxicity, apoptosis induction, and mitotic arrest by a novel podophyllotoxin glucoside, 4DPG, in tumor cells.

AIM: To define the in vitro cytotoxic activities of 4-demethyl-picropodophyllotoxin 7'-O-beta-D-glucopyranoside (4DPG), a new podophyllotoxin glucoside. METHODS: Antiproliferation activity was measured in several tumor cell lines by using the microculture tetrazolium MTT assays. Cell cycle distribution was analyzed using flow cytometry and mitosis index assays. Furthermore, transmission electron microscopy, TUNEL, DNA agarose electrophoresis, and activated caspase-3 were used to analyze the induction of apoptotic cell death. Moreover, intracellular changes in the cytoskeleton were detected using immunocytochemistry. RESULTS: 4DPG effectively inhibited the proliferation of cancer cells (HeLa, CNE, SH-SY5Y, and K562 cell lines). For the K562 cell line, the antiproliferation effect of 4DPG was much more potent than that of etoposide (IC50 value: 7.79 x 10(-9) mol/L for 4DPG vs 2.23 x 10(-5) mol/L for etoposide). Further, 4DPG blocked the cell cycle in the mitotic phase. The induction of apoptosis and elevated levels of activated caspase-3 were confirmed in cells treated with 4DPG. The microtubule skeleton of HeLa cells was disrupted immediately after treatment with 4DPG. CONCLUSION: The cytotoxicity of 4DPG is due to its inhibition of the microtubule assembly of cancer cells at a low concentration, thus inducing apoptosis. These properties qualify 4DPG to be a potential antitumor drug.