Novel shikonin derivatives suppress cell proliferation, migration and induce apoptosis in human triple-negative breast cancer cells via regulating PDK1/PDHC axis.

AIMS: PDK1 is one of the key enzymes in the glucose metabolism pathway, which is abnormally high expressed in breast cancer tissues and can promote tumor proliferation and metastasis. PDK1 and the PDHC/PDK axis are important targets for regulating glucose metabolism and anti-tumor activity. In this study, we evaluated the anti-tumor activities of a series of semi-synthesized shikonin (SK) derivatives against human breast cancer cells. MAIN METHODS: The anti-proliferation activity of SK derivatives against human breast cancer cell lines was tested by CCK-8 and EdU assay. Flow cytometry was utilized to evaluate cell apoptosis, reactive oxygen species and cell cycle distribution. Cell migration ability was determined by wound healing and trans-well assay. PDK1 targeting effect was confirmed by western bolting, molecular docking, bio-layer interferometry and PDK1 enzyme activity assay. Nude-mouse transplanted tumor model was used to evaluate their anti-tumor effect in vivo. KEY FINDINGS: Findings revealed that SK derivatives had good anti-proliferation ability against MDA-MB-231 cell. They induced cell apoptosis by regulating the mitochondrial apoptosis and death receptor pathway. They also inhibited cell migration by suppressing EMT progression. Molecular docking, PDK1 affinity and enzyme activity demonstrated their PDK1 targeting. In vivo antitumor experiment showed that E2 could significantly inhibit tumor growth with lower side-effect on mice than SK. SIGNIFICANCE: In conclusion, the novel SK derivatives E2 and E5 inhibited tumor glycolysis by targeting PDK1 and ultimately induced apoptosis. Our data demonstrated that E2 would be a good lead compound for the treatment of human TNBC as a novel PDK1 inhibitor.

Shikonin N-benzyl matrinic acid ester derivatives as novel telomerase inhibitors with potent activity against lung cancer cell lines.

In this study, a series of novel shikonin N-benzyl matrinic acid ester derivatives (PMMB-299-PMMB-310) were synthesized and tested for their ability to inhibit the proliferation of cancer cells. Compared with shikonin and matrine, some of the ester derivatives were found to exhibit better anti-proliferative activity against seven different cancer cell lines, with less cytotoxicity toward non-cancerous cells. The strongest anti-proliferative activity was exhibited by PMMB-302, which had an IC50 value of 2.71 µM against A549 cells. The compound caused cell cycle arrest in the G2/M phase and induced apoptosis. Effects on the expression of apoptosis-related molecules such as Bcl2, Bcl-XL, caspase-3, caspase-9 and FADD suggested that PMMB-302 has tumor suppressive roles in lung cancer cells. In addition, PMMB-302 inhibited expression of telomerase core proteins, dyskerin and NHP2, and telomerase reverse transcriptase RNA. Moreover, molecular docking of PMMB-302 was subsequently conducted to determine the probable binding mode with telomerase. Taken together, the results indicate that PMMB-302 acts as a tumor suppressor in lung cancer cells by negatively regulating telomerase expression.

Concentration level, distribution model, source analysis, and ecological risk assessment of polycyclic aromatic hydrocarbons in sediments from laizhou bay, China.

To master the distribution patterns and environmental risk of 16 USEPA preferential polycyclic aromatic hydrocarbons (PAHs) in surface sediments from Laizhou Bay, 20 samples were collected and investigated in this survey. The average PAH concentration in these sediments ranged from 268.97 ng/g to 895.37 ng/g with an average of 612.52 ng/g, thereby suggesting a relatively low PAH pollution in Laizhou Bay compared with other bays in the world. Tricyclic PAHs account for 79% of the total PAH content and were eventually identified as the most crucial component of these sediments. The PCA-MLR results identify fossil fuel combustion, biomass burning, and coke oven as the main sources of PAHs that account for 26.69%, 67.16%, and 6.15% of the total PAH concentration in the collected sediments, respectively. The effect range low/effect range median (ERL/ERM) reveal the low toxicity of PAHs in these sediments. However, the concentration of Fle at each survey site exceeds the ERL level. Meanwhile, the mean effects range-median quotient (M-ERM-Q) indicates the low level of ecological risk of PAHs in the surface sediments from Laizhou Bay. However, the contingency risk of Fle and Phe cannot be ruled out.

Risk assessment and source apportionment of PAHs in surface sediments from Caofeidian Long Island, China.

Sediment samples were collected from Caofeidian Long Island, China to investigate the contamination level and distribution pattern of 16 polycyclic aromatic hydrocarbons (PAHs). Source identification and risk assessment were also performed on these PAHs. The distribution patterns and source identification results indicated that the PAHs in the survey area originated from coal, biomass, and petroleum combustion as well as the combination of these three processes. Although the concentration of fluorene in the sediment exceeded the ERL level in some sampling sites, the effect range low-effect range median ratio implied a relatively low level of toxicity in these sediments. Meanwhile, the mean effects range-median quotient indicated that the 16 PAHs in sediments from Caofeidian Long Island pose a low ecological risk.

Evaluation of the diagnostic ratios of adamantanes for identifying seriously weathered spilled oils from simulated experiment and actual oil spills.

The composition and physical properties of spilled oil have great changes during the seriously weathering process. It brings great difficulties to the source identification of oil spill. So the stable and trustworthy diagnostic ratios (DRs) for accurate identification of severely weathered spilled oils are very important. The explosion of Sinopec pipeline happened on November 22, 2013 at Qingdao, China. Local beaches at Jiaozhou Bay were polluted by spilled oils. We have collected original spilled oil samples from an area free from human interference near the oil leakage point after the accident. Synchronized with actual beach weathering, laboratory experiments were conducted to simulate oil weathering for 360 days by using the collected original spilled oil samples. Based on t test and the repeatability limit method, 50 diagnostic ratios (DRs) of adamantanes were screened. Four DRs, namely 1,3-dimethyladamantane/total dimethyladamantane, 1-methyladamantane/(1-methyladamantane + 1,3-dimethyladamantane), dialkyl diamantane/total diamantane, and diamantane/(diamantane + dialkyl diamantane), have maintained remarkable stability during the simulated weathering experiments and field weathering process. These stable ratios can retain the characteristics of oil source during weathering. They are very beneficial to improve the accuracy of identifying the source of severely weathered oil and can be used as an effective supplement to existing index system for source identification.

Study on immobilization of marine oil-degrading bacteria by carrier of algae materials.

This study investigated the immobilizations with of bacteria two kinds of algal materials, Enteromorpha residue and kelp residue. The lipophilicity of them were compared by diesel absorption rates. The immobilization efficiency of Bacillus sp. E3 was measured to evaluate whether these carriers would satisfy the requirement for biodegradation of oil spills. The bacteria were immobilized through adsorption with the sterilized and non-sterilized carriers to compare the differences between the two treatments. Oil degradation rates were determined using gravimetric and GC-MS methods. Results showed the absorption rates of Enteromorpha residue and kelp residue for diesel were 411 and 273% respectively and remained approximately 105 and 120% after 2 h of erosion in simulated seawater system. After immobilized of Bacillus sp. E3, the oil degradation rates of them were higher than 65% after 21 days biodegradations. GC-MS analysis showed that two immobilizations degraded higher than 70% of the total alkane and the total PAHs, whereas the free bacteria degraded 63% of the total alkane and 66% the total PAHs. And the bacteria immobilized with the carriers degraded more HMW-alkanes and HMW-PAHs than the free bacteria. The bacteria immobilized by non-sterilized kelp residue showed a considerably higher degradation rate than that using sterilized kelp residue. A considerably higher cells absorption rate of immobilization was obtained when using kelp residue, and the preparation of immobilization was low cost and highly efficient. The experiments show the two algae materials, especially the kelp residue, present potential application in bioremediation of marine oil spills.

Microbial diversity and ecotoxicity of sediments 3 years after the Jiaozhou Bay oil spill.

In 2013, the "Qingdao oil pipeline explosion" released an estimated 2000 tons of oil into the environment. Sediment samples were collected from ten sites in Jiaozhou Bay and Shilaoren Beach to evaluate the influence of the spilled oil on the benthic environment 3 years after the oil spill accident. The compositions of oil, bacterial diversity and biotoxicity were examined in this study. The results showed that the concentration of total petroleum hydrocarbons (TPHs) peaked near the oil leak point and gradually decreased along the coastline, ranging from 21.5 to 133.2 µg/g. The distribution of polycyclic aromatic hydrocarbons (PAHs) was correlated with TPH, and naphthalenes were dominant in the 20 detected PAHs. The bacterial diversities in seriously polluted and slightly polluted sediments were completely different. As degrading bacteria, Alcanivorax and Lutibacter were the main genera at the oil-polluted sites. The analysis of biotoxicity by the luminescent bacteria method showed great differences among the polluted sites, the control site in Jiaozhou Bay, and the non-polluted site outside of Jiaozhou Bay. The biotoxicity also peaked at the site near the oil leak point. These results indicate that the oil spill that occurred 3 years ago still affects the environment and impacts the bacterial communities in the sediments.

Distribution characteristics, sources, and ecological risk assessment of polycyclic aromatic hydrocarbons in sediments from the Qinhuangdao coastal wetland, China.

Sixteen USEPA priority polycyclic aromatic hydrocarbons (PAHs) were analyzed by gas chromatography-mass spectrometry. Twenty-three samples were collected from the surface sediments of Qinhuangdao coastal wetlands in this survey. This research aimed to identify the PAHs contamination level, composition pattern, pollution sources, and assess the ecological risk of PAHs. The results showed that the sum of PAH concentrations ranged from 341.61ng/g to 4703.80ng/g (mean: 1367.80ng/g), which is higher than the reported values for different wetlands worldwide. Five- and four-ring PAHs (34.08% and 32.97% of Æ©16PAHs, severally) were predominant in the wetland sediment. The PAH source distribution in the surface sediments was determined using diagnostic ratio and PCA/MLR. Consequently, multiple PAH sources were found. Of the total PAHs, 70.01% was derived from vehicular emission, 25.73% from coke oven, and 4.26% from petroleum-based product spills. The effect range low/effect range median (ERL/ERM) values indicated a low toxicity risk level. However, the DBahA concentrations exceeded the ERL level, and even the ERM level, in some stations. The mean effects range-median quotient (M-ERM-Q) suggests a low ecological risk for the PAHs, but a medium risk for some stations in the coastal wetland sediments.