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Three new bufadienolides with a Δ14,15 double bond, named bufogarlides A-C (1-3), together with three known analogs (4-6), were isolated from the skins of Bufo bufo gargarizans. Their structures were identified by analyses of spectroscopic data (1 D and 2 D NMR, HR-ESIMS), and comparison with the literature data. All the isolates were evaluated for their cytotoxic activities against ovarian carcinoma cell lines A2780 and SKOV3. Among them, compound 5 showed the highest potential for the growth inhibition of cancerous cells A2780 and SKOV3 with the IC50 values of 21.09 and 67.08 nM, respectively.

The conserved p38/PMK-1 pathway that is an evolutionarily conserved module used by mammals and nematodes in immune response against bacterial infections. Brevilin A (BA), a sesquiterpene lactone compound of Centipeda minima has been shown to exhibit activities such as anti-tumor, anti-bacterial and anti-protozoal. However, whether the Brevilin A influences the immune response and the underlying molecular mechanisms remain obscure. We find that 10 μM Brevilin A increases resistance to not only the Gram-negative pathogens Pseudomonas aeruginosa and Salmonella enterica but also the Gram-positive pathogens Enterococcusfaecalis and Staphylococcus aureus. Meanwhile, Brevilin A enhances the resistance to pathogens by reducing the bacterial burden in the intestine. Through the genetic screening in C. elegans, we find that Brevilin A promotes innate immunity via p38 MAPK pathway. Furthermore, Brevilin A activates the p38/PMK-1 in the intestine for innate immune response. In addition, we also find that Brevilin A increases the resistance of oxidative stress and extends lifespan through p38 MAPK pathway. Our work suggests that Brevilin A may be a viable candidate for the treatment of infectious diseases.

Metformin, as the first-line oral drug for type 2 diabetes, has proven benefits against aging, cancer and cardiovascular diseases. But the influence of metformin to the immune response and its molecular mechanisms remain obscure. Metformin increases resistance to not only the Gram-negative pathogens Pseudomonas aeruginosa and Salmonella enterica but also the Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus. Meanwhile, metformin protects the animals from the infection by enhancing the tolerance to the pathogen infection rather than by reducing the bacterial burden. Through the screening of classical immune pathways in C. elegans, we find metformin enhances innate immunity through p38 MAPK pathway. Furthermore, activated p38/PMK-1 by metformin acts on the intestine for innate immune response. In addition, metformin-treated mice have increased resistance to P. aeruginosa PA14 infection and significantly increased the levels of active PMK-1. Therefore, promoted p38/PMK-1-mediated innate immunity by metformin is conserved from worms to mammals. Our work provides a conserved mechanism by which metformin enhances immune response and boosts its therapeutic application in the treatment of pathogen infection.

Metformin, a widely prescribed first-line drug for the treatment of type II diabetes mellitus, has been shown to extend lifespan and delay the onset of age-related diseases. The precisely mechanisms by which these effects are realized remain elusive. We find that metformin exposure is restricted to adults, which is sufficient to extend lifespan. However, limiting metformin exposure to the larvae has no significant effect on Caenorhabditis elegans longevity. Here, we show that after metformin treatment, the level of S-adenosylmethionine (SAM) is reduced in adults but not in the larvae. Potential mechanisms by which reduced SAM might increase lifespan include altering the histone methylation. However, the molecular connections between metformin, SAM limitation, methyltransferases, and healthspan-associated phenotypes are unclear. Through genetic screening of C. elegans, we find that metformin promotes the healthspan through an H3K4 methyltransferase/demethylase complex to downregulate the targets, including mTOR and S6 kinase. Thus, our studies provide molecular links between meformin, SAM limitation, histone methylation, and healthspan and elucidate the mode action of metformin-regulated healthspan extension will boost its therapeutic application in the treatment of human aging and age-related diseases.

Background Hepatocellular carcinoma (HCC) is the most aggressive and frequently diagnosed malignancy of the liver. Despite aggressive therapy, life expectancy of many patients in these cases is extended by only a few months. Hepatocellular carcinoma (HCC) has a particularly poor prognosis and would greatly benefit from more effective therapies. Methods The CCK-8 assay and colony formation assays were used to test the cell proliferation and viability. The effects of combination Biochanin A and SB590885 on apoptosis and cell cycle arrest of HCC cells were analysed by flow cytometry. The expression of ERK MAPK and PI3K/AKT/mTOR signalling as well as apoptosis and cell cycle-related proteins in HCC cells were tested by western blotting. The HCC cell xenograft model was established to test the tumor proliferation. Serum and plasma were tested for liver and kidney safety markers (ALP, ALT, AST, total bilirubin, creatinine, urea nitrogen) by using SpectraMax i3X. Results The combination of natural product Biochanin A with the BRAF inhibitor SB590885 synergistically suppressed proliferation, and promoted cell cycle arrest and apoptosis in vitro. Furthermore, we demonstrated that the combination of Biochanin A and SB590885 led to increased impairment of proliferation and HCC tumour inhibition through disrupting of the ERK MAPK and the PI3K/AKT pathways in vitro. The volumes tumors and the weights of tumours were significantly reduced by the combination treatment compared to the control or single treatments in vivo. In addition, we found that there was no significant hepatorenal toxicity with the drug combination, as indicated by the hepatorenal toxicity test. Conclusion The results identify an effective combination therapy for the most aggressive form of HCC and provide the possibility of therapeutic improvement for patients with advanced HCC.

Let $$1< c < \frac{59}{44},\, c\ne \frac{4}{3}$$ . In this paper it is proved that for any sufficiently large real N, for almost all real $$T\in (N,2N]$$ (in the sense of Lebesgue measure), the inequality $$|p_1^{c} + p_2^{c} - T|< T^{-\frac{9}{10c}(\frac{59}{44}-c)}$$ is solvable in primes $$p_1, p_2$$ . This result constitutes an improvement upon that of Kumchev and Laporta.

Two new 19-hydroxy bufadienolides, named bufohydrolide A (1) and bufohydrolide B (2), and four known analogs (3-6) were isolated from the aqueous extracts of the skins of Bufo melanosticus. Their structures were established by spectral data analyses, such as UV, IR, 1 D/2D NMR and mass spectra. Compounds 1-6 were evaluated for their cytotoxic activity against SMMC-7721, HT-29 and A549 cells. Noteworthily, all six isolates exhibited various levels of anti-proliferative activities with IC50 values ranging from 0.02 ± 0.0002 to 25 ± 0.5 μM.

Resin AB-8 was screened from seven resins with different polarity and particle size because of its better decoloration and deproteinization efficiency to polysaccharide from the root of Actinidia valvata (AvPs), and then the optimized parameter conditions were applied by the single-factor experiments and were shown as follows: a concentration of crude polysaccharide of 3 mg/mL, an adsorption time of 40 min, an initial pH of 7.0, a flow rate of 1.5 BV/h. In addition, the results of HPGPC, FT-IR, PMP-HPLC-DAD, 1H NMR and Congo red test showed that the sugar chain, structural group, monosaccharide composition and triple-helix conformation structure of AvPs were not broken during resin AB-8 treatment. Moreover, AvPs could keep the stability of biological activity after the resin AB-8 treatment, and revealed an obviously antioxidant and anticancer activities in vitro as well. This research suggests that this method is promising for the deproteinization and decolorization of AvPs which could be explored as a potential antioxidant or anticancer agent for use in functional food or medicine.

Summary: The longevity of an organism is influenced by both genetic and environmental factors. With respect to genetic factors, a significant effort is being made to identify pharmacological agents that extend lifespan by targeting pathways with a defined role in the aging process. Sanguinarine (San) is a benzophenanthridine alkaloid that exerts a broad spectrum of properties. In this study, we utilized Caenorhabditis elegans to examine the mechanisms by which sanguinarine influences aging and innate immunity. We find that 0.2 μM sanguinarine extends healthspan in C. elegans. We further show that sanguinarine generates reactive oxygen species (ROS), which is followed by the activation of PMK-1/SKN-1pathway to extend healthspan. Intriguingly, sanguinarine increases resistance to pathogens by reducing the bacterial burden in the intestine. In addition, we also find that sanguinarine enhances innate immunity through PMK-1/SKN-1 pathway. Our data suggest that sanguinarine may be a viable candidate for the treatment of age-related disorders.

Tyrosinase inhibitors could effectively limit the activity of tyrosinase in melanocytes to reduce the excessive synthesis and deposition of melanin. However, low skin permeability and lacking in targeting greatly restricted their application. Herein, ZnO quantum dots were synthesized by gel-sol method and grafted with BQ-788, which have been employed as transdermal and targeting carrier to delivery ellagic acid to melanocytes. Ellagic acid loaded ZnO quantum dots with the size distribution of around 9 nm could targetedly bind to melanocytes and enter the melanocytes by endocytosis within 1 h. The ellagic acid release behavior was controlled by the decreasing of pH via the rapid dissolution of ZnO. When the concentration of BQ-788/EA@ZnO was 12.5 μg/mL, the inhibition rate on tyrosinase activity and melanin deposition were up to 44.23 ± 4.97% and 37.50 ± 5.23%, respectively. In view of their good biocompatibility, they were of great potential in clinically external application for tyrosinase inhibition.

Let [Formula: see text] denote the integral part of the real number [Formula: see text]. In this paper, it is proved that for [Formula: see text], the Diophantine equation [Formula: see text] is solvable in prime variables [Formula: see text] for sufficiently large integer [Formula: see text].

Three new bufadienolides, (2β,5β,14β)-2,5,14-trihydroxy-bufa-20,22-dienolide (1), (3α,16β)-3,16-dihydroxy-bufa-14,20,22-trienolide (2) and (3β,5β,16α)-3,5,16-trihydroxy-bufa-14,20,22-trienolide (3), together with three known analogs (4-6), were isolated from the aqueous extracts of the skins of Bufo melanosticus. Their structures were determined by spectroscopic studies, including HR-ESIMS and NMR data analyse. In the preliminary assay, all the above mentioned compounds showed cytotoxic activity against the carcinoma cell lines Bel-7402, HO-8910 and HCT-116, with IC50 values ranging from 0.01 to 24.07 μM, consistent with the practical application of toad skin and cinobufacini (Hua Chan Su).

Let 1 0 such that for each real numberN>N(c) the inequality\(|p_1^c + p_2^c + p_3^c - N|< N^{ - \tfrac{1}{c}(\tfrac{{11}}{{10}} - c)} \log ^{c_1 } N\) is solvable in prime numbersp 1,p 2,p 3, wherec 1 is some absolute positive constant.

Gastric cancer (GC) is one of the most common malignancies as well as the third leading cause for cancer-related death. Molecular basis of GC are essential and critical for its therapeutic treatment, but still remain poorly understood. T-cell intracellular antigen-1 (TIA1) extensively involves in cancer progression, whereas its role and regulation mechanism in GC have not been revealed. In the present study, we found that TIA-1 protein level was down-regulated in GC tissues and TIA1 inhibited proliferation and promoted apoptosis of GC cells. Then, we used bioinformatics to predict miR-487a as the upstream regulator of TIA1 and we also observed an inverse correlation between miR-487a level and TIA-1 protein level in GC tissues. Next, we demonstrated that miR-487a directly targeted TIA1 via binding to its 3′-untranslated region. Furthermore, we investigated the role of miR-487a-TIA1 pathway in the growth of GC cells both in vitro and in vivo. The repression of TIA-1 by miR-487a promoted cell proliferation and suppressed cell apoptosis in vitro, and the knockdown of miR-487a had the opposite effects. Finally, we demonstrated that miR-487a promoted the development of gastric tumor growth in xenograft mice by targeting TIA-1. These effects could be partially reversed by restoring the expression of TIA-1. Overall, our results reveal that TIA1 is a tumor suppressor gene and is directly regulated by miR-487a in GC, which may offer new therapeutic targets for GC treatment.

Two new 19-hydroxy bufadienolides, named bufohydrolide A (

Additional file 1: Table S1. Synergistic indexes of combination treatment with Biochanin A and SB590885 in Bel-7402 and Sk-Hep1 hepatocellular carcinoma cell lines. Table S2. Clinical and biological analyses. Table S3. The STR test results of SK-Hep-1 cells. Table S4. The STR test results of Bel‑7402 cells.

The prognosis of patients with advanced hepatocellular carcinoma (HCC) remains obscure. From a clinical point of view, the ERK MAPK pathway and the PI3K/AKT pathway are activated in the majority of liver cancer. In addition, long term used to single agent treatment of HCC, frequently results in reverse activation of the ERK MAPK pathway or the PI3K/AKT pathway, leading to drug resistance. Thus, it is important to research the mechanism of combination agents that could suppress different pathways to treat HCC. Here, we found that combination natural product magnolin with BRAF inhibitor SB590885 synergistically suppressed the proliferation, promoted cell cycle arrest and apoptosis in hepatocellular carcinoma cells Bel-7402 and SK-Hep1. Furthermore, we demonstrated that the magnolin and the SB590885 combination led to increased impaired proliferation via inhibition of the ERK MAPK pathway and the PI3K/AKT pathway. These findings highlight the important role of agent combination and provided the approaches of therapeutic improvement for patients with advanced HCC.

Ensemble Empirical Mode Decomposition (EEMD) has been widely used due to the more advanced processing of mode mixing than Empirical Mode Decomposition (EMD). However, EEMD still suffers mode mixing in the vibration analysis of rotating machinery. It proposes Extremum Feature Preserving Ensemble Empirical Mode Decomposition (EFPEEMD) for the feature extraction of rotor systems in rotating machinery. In the method, a fluctuant variation (FV) index is developed to quantitatively recognize the amplitude of added noise on the basis of the empirical rules in EEMD. The results of a misalignment vibration signal of a rotor system and an inner race defect signal of a rolling bearing show that, the primary vibration modes can be extracted rapidly and independently based on the elimination of the non-stationary and non-linear interference. Moreover, the fluctuant variation index removes the originally manual and empirical steps, thus enhancing the accuracy and automation of EEMD on the basis of preserving the extreme information.

In this study, aioxidant and anticancer activities of the extracts were evaluated from various habitats of Selaginella doederleinii. The evaluation on antioxidative capacity revealed that the extracts were the highest from Guizhou province using DPPH radical scavenging, ABTS radical scavenging, ferric reducing and FRAP methods, while those of the extracts from Sichuan province were the lowest from different habitats. The evaluation on antitumous effect showed that the extracts from Guizhou province were the highest against A549 cell line and 7721 cell line, while those of the extracts from Sichuan province were the lowest in different habitats. Results obtained revealed that the extracts of S. doederleinii were found to be potentially as a readily valuable bioactive source of natural products. Ethyl acetate extraction of S. doederleinii exhibited as the most potent fraction will be further in-depth study.

The genome sequence, genetic characterization and nblA gene function of Microcystis aeruginosa myovirus isolated from Lake Dianchi in China (MaMV-DC) have been analysed. The genome DNA is 169 223 bp long, with 170 predicted protein-coding genes (001L–170L) and a tRNA gene. About one-sixth of these genes have homologues in the host cyanobacteria M. aeruginosa. The genome carries a gene homologous to host nblA, which encodes a protein involved in the degradation of cyanobacterial phycobilisome. Its expression during MaMV-DC infection was confirmed by reverse transcriptase PCR and Western blot detection and abundant expression was companied by the significant decline of phycocyanin content and massive release of progeny MaMV-DC. In addition, expressing MaMV-DC nblA reduced the phycocyanin peak and the phycocyanin to chlorophyll ratio in model cyanobacteria. These results confirm that horizontal gene transfer events have occurred between cyanobacterial host and cyanomyovirus and suggest that MaMV-DC carrying host-derived genes (such as 005L, that codes for NblA) is responsible for more efficient expression of cyanophage genes and release of progeny cyanophage. This study provides novel insight into the horizontal gene transfer in cyanophage and the interactions between cyanophage and their host.

We report the results of the preliminary isolation of two virus-like particles (VLPs) that are infectious to freshwater cyanobacteria from Lake Donghu,the largest urban lake in China,located in Wuhan City,Hubei Province. By light and transmission electron microscopy,we observed VLPs causing lytic infections in freshwater bloom-forming cyanobacteria,and we detected their infections by exposing the VLPs to 12 cyanobacterial strains,including Microcystis aeruginosa HAB1801 and Anabaena spiroides HAB1211. They were termed ‘Anabaena spiroides geminivirus-like (AsGV-L)' particles and ‘Microcystis aeruginosa corticovirus-like (MaCV-L)' particles,based on their ultrastructural morphological characteristics and host specificities.

The MaMV-DC cyanophage, which infects the bloom-forming cyanobacterium Microcystis aeruginosa , was isolated from Lake Dianchi, Kunming, China. Twenty-one cyanobacterial strains were used to detect the host range of MaMV-DC. Microcystic aeruginosa FACHB-524 and plaque purification were used to isolate individual cyanophages, and culturing MaMV-DC with cyanobacteria allowed us to prepare purified cyanophages for further analysis. Electron microscopy demonstrated that the negatively stained viral particles are tadpole-shaped with an icosahedral head approximately 70 nm in diameter and a contractile tail approximately 160 nm in length. Using one-step growth experiments, the latent period and burst size of MaMV-DC were estimated to be 24 -48 hours and approximately 80 infectious units per cell, respectively. Restriction endonuclease digestion and agarose gel electrophoresis were performed using purified MaMV-DC genomic DNA, and the genome size was estimated to be approximately 160 kb. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed four major structural proteins. These results support the growi ng interest in using freshwater cyanophages to control bloom-forming cyanobacterium.