52 research outputs found

    Towards Poisoning Fair Representations

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    Fair machine learning seeks to mitigate model prediction bias against certain demographic subgroups such as elder and female. Recently, fair representation learning (FRL) trained by deep neural networks has demonstrated superior performance, whereby representations containing no demographic information are inferred from the data and then used as the input to classification or other downstream tasks. Despite the development of FRL methods, their vulnerability under data poisoning attack, a popular protocol to benchmark model robustness under adversarial scenarios, is under-explored. Data poisoning attacks have been developed for classical fair machine learning methods which incorporate fairness constraints into shallow-model classifiers. Nonetheless, these attacks fall short in FRL due to notably different fairness goals and model architectures. This work proposes the first data poisoning framework attacking FRL. We induce the model to output unfair representations that contain as much demographic information as possible by injecting carefully crafted poisoning samples into the training data. This attack entails a prohibitive bilevel optimization, wherefore an effective approximated solution is proposed. A theoretical analysis on the needed number of poisoning samples is derived and sheds light on defending against the attack. Experiments on benchmark fairness datasets and state-of-the-art fair representation learning models demonstrate the superiority of our attack

    Design, synthesis and biological evaluation of quinoline-indole derivatives as anti-tubulin agents targeting the colchicine binding site

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    A series of novel isocombretastatin A-4 (isoCA-4) analogs were designed and synthesized by replacing 3,4,5-trimethoylphenyl and isovanillin of isoCA-4 with quinoline and indole moieties, respectively. The structure activity relationships (SARs) of these synthesized quinoline-indole derivatives have been intensively investigated. Two compounds 27c and 34b exhibited the most potent activities against five cancer cell lines with IC50 values ranging from 2 to 11ā€ÆnM, which were comparable to those of Combretastatin A-4 (CA-4, 1). Further mechanism investigations revealed that 34b effectively inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further cellular mechanism studies elucidated that 34b disrupted cell microtubule networks, arrested the cell cycle at G2/M phase, induced apoptosis and depolarized mitochondria of K562ā€Æcells. Moreover, 34b displayed potent anti-vascular activity in both wound healing and tube formation assays. Importantly, 27c and 34b significantly inhibited tumor growth in H22 xenograft models without apparent toxicity, suggesting that 27c and 34b deserve further research as potent antitumor agents for cancer therapy

    Discovery of Novel 4-Arylisochromenes as Anticancer Agents Inhibiting Tubulin Polymerization

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    XJP-L (8), a derivative of the natural product (Ā±)-7,8-dihydroxy-3-methylisochroman-4-one isolated from the peel of Musa sapien tum L., was found to exhibit weak inhibitory activity of tubulin polymerization (IC50 = 10.6 Ī¼M) in our previous studies. Thus, a series of 4-arylisochromene derivatives were prepared by incorporating the trimethoxyphenyl moiety into 8, among which compound (Ā±)-19b was identified as the most potent compound with IC50 values ranging from 10 to 25 nM against a panel of cancer cell lines. Further mechanism studies demonstrated that (Ā±)-19b disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis, and depolarized mitochondria of K562 cells. Moreover, (Ā±)-19b exhibited potent in vitro antivascular and in vivo antitumor activities. Notably, the R-configured enantiomer of (Ā±)-19b, which was prepared by chiral separation, was slightly more potent than (Ā±)-19b and was much more potent than the S-configured enantiomer in both antiproliferative and antitubulin assays. Our findings suggest that (Ā±)-19b deserves further research as a potential antitubulin agent for the treatment of cancers

    Design, synthesis, and biological evaluation of truncated deguelin derivatives as Hsp90 inhibitors

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    A series of novel B and C-rings truncated deguelin derivatives have been designed and synthesized in the present study as heat shock protein 90 (Hsp90) inhibitors. The synthesized compounds exhibited micromolar antiproliferative potency toward a panel of human cancer cell lines. Their structure-activity relationships (SARs) were investigated in a systematic manner. Compound 21c was identified to have high Hsp90 binding potency (60ā€ÆnM) and caused degradation of client proteins through ubiquitin proteasome system. Further biological studies showed that compound 21c induced a dose-dependent S and G2-phase cell cycle arrest on human breast cancer MCF-7ā€Æcells. Flow cytometry and Western blot analyses confirmed that compound 21c caused apoptosis of MCF-7ā€Æcells. In addition, compound 21c showed much potent inhibition on the migration and invasion of MCF-7ā€Æcells. Taken together, these results suggest that 21c might be a promising lead compound for further development of Hsp90 inhibitors

    Design, synthesis and biological evaluation of pyridine-chalcone derivatives as novel microtubule-destabilizing agents

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    Further optimization of the trimethoxyphenyl scaffold of parent chalcone compound (2a) by introducing a pyridine ring afforded a series of novel pyridine-chalcone derivatives as potential anti-tubulin agents. All the target compounds were evaluated for their antiproliferative activities. Among them, representative compound 16f exhibited the most potent activity with the IC50 values ranging from 0.023 to 0.045ā€ÆĪ¼M against a panel of cancer cell lines. Further mechanism study results demonstrated that compound 16f effectively inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Moreover, cellular mechanism studies disclosed that 16f caused G2/M phase arrest, induced cell apoptosis and disrupted the intracellular microtubule network. Also, 16f reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 16f significantly inhibited tumor growth in H22 xenograft models without apparent toxicity, which was stronger than the reference compound CA-4, indicating that it is worthy to investigate 16f as a potent microtubule-destabilizing agent for cancer therapy

    Design, synthesis and anticancer properties of isocombretapyridines as potent colchicine binding site inhibitors

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    A series of novel isocombretapyridines were designed and synthesized based on a lead compound isocombretastatin A-4 (isoCA-4) by replacing 3,4,5-trimethoxylphenyl with substituent pyridine nucleus. The MTT assay results showed that compound 20a possessed the most potent activities against all tested cell lines with IC50 values at nanomolar concentration ranges. Moreover, 20a inhibited tubulin polymerization at a micromolar level and also displayed potent anti-vascular activity in vitro. Further mechanistic studies were conducted to demonstrate that compound 20a could bind to the colchicine site of tubulin,and disrupte the cell microtubule networks, induce G2/M phase arrest, promote apoptosis and depolarize mitochondria of K562 cells in a dose-dependent manner. Notably, 20a exhibited more potent tumor growth inhibition activity with 68.7% tumor growth inhibition than that of isoCA-4 in H22 allograft mouse model without apparent toxicity. The present results suggested that compound 20a may serve as a promising potent microtubule-destabilizing agent candidate for the development of therapeutics to treat cancer

    THE PROTECTIVE EFFECTS OF CASSAVA ( MANIHOT ESCULENTA CRANTZ ) LEAF FLAVONOID EXTRACTS ON LIVER DAMAGE OF CARBON TETRACHLORIDE INJURED MICE

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    Background: Cassava leaf contains many kinds of flavonoids, most of flavonoids function as effective antioxidants in vivo. The protective effects of cassava (Manihot esculenta Crantz) leaf flavonoid extracts on liver damage were evaluated by carbon tetrachloride (CCl4)-induced injury in mice. Materials and methods: The protective effects of cassava leaf flavonoid extracts on liver damage were evaluated using CCl4-induced injury in mice. The mice were weighted to calculate sample quantity of mice. Bloods were taken to evaluate ALT and AST of serums. Livers were excised and weighted, and fixed for pathological observation. Prepared 10% liver tissue homogenate was used to evaluate MDA, SOD, GSH-PX levels. Results: Cassava leaf flavonoid extracts significantly decreased (p < 0.05) the relative liver weight when compared with the CCl4-treated group. The contents of ALT and AST in serum of experiment mice declined significantly when compared to those of the CCl4-treated group, but did not reach normal levels of control group. Pathological observation of livers showed that cassava leaf flavonoid extracts significantly ameliorated the CCl4-induced pathological changes. Conclusion These results provided biological evidence that cassava leaf flavonoid extracts indeed expressed potential efficacy of prohibiting liver injury in mice

    Design, synthesis and molecular modeling of isothiochromanone derivatives as acetylcholinesterase inhibitors

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    A series of novel isothio- and isoselenochromanone derivatives bearing N-benzyl pyridinium moiety were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Results: Most of the target compounds exhibited potent anti-AChE activities with IC50 values in nanomolar ranges. Among them, compound 15a exhibited the most potent anti-AChE activity (IC50 = 2.7 nM), moderate antioxidant activity and low neurotoxicity. Moreover, the kinetic and docking studies revealed that compound 15a was a mixed-type inhibitor, which bounds to peripheral anionic site and catalytic active site of AChE. Conclusion: Those results suggested that compound 15a might be a potential candidate for AD treatment

    HYL1 controls the miR156-mediated juvenile phase of vegetative growth

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    HYL1 is an important regulator of microRNA (miRNA) biogenesis. A loss-of-function mutation of HYL1 causes the reduced accumulation of some miRNAs but fails to display the miRNA-deficient phenotypes of these miRNAs. In Arabidopsis, miR156 mediates phase transition through repression of SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE (SPL) genes. However, it remains unknown whether, and if so how, HYL1 enables phase transition through miR156. This study showed that a loss-of-function mutation of the HYL1 gene caused defects in the timing of the juvenile phase. In the primary leaves of hyl1-2 mutants, abaxial trichomes were generated prematurely, the leaf blades elongated, and the blade base angles enlarged, as is observed for adult leaves. In hyl1-2 p35S::miR156a and hyl1-2 spl9-4 spl15-1 plants, increased accumulation of miR156a and repressed expression of the SPL genes were concomitant with a complete or partial rescue of the hyl1-2 phenotype in phase defects. In contrast, overexpression of the SPL9 gene in hyl1-2 mutants led to total disappearance of the juvenile phase. Moreover, HYL1 prevented the premature accumulation of adult-related transcripts in the primary leaves. Taken together, these results suggest that HYL1 controls the expression levels of miR156-targeted SPL genes and enables plants to undergo the juvenile phase, an important and critical step during plant development to ensure maximum growth and productivity
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