Publications

Abstract Background Cancer is a primary public health problem worldwide today. Tetrandrine (Tet) and fangchinoline (Fan) are extracted from the traditional Chinese medicine Stephania tetrandra S., which are two types of bis-benzyl isoquinoline alkaloids with anti-tumor activity. However, Tet and Fan are not suitable for clinical application due to their high effective doses. Results Through chemical modification, 19 novel Tet and Fan derivatives were firstly proposed and synthesized in this work, and they were assessed for the cytotoxicity against six tumor cell lines (H520, H460, HepG-2, HeLa, A549, and MCF-7) and human bronchial epithelial cells (BEAS-2b) by the CCK-8 assay. Compared to the parent Fan, ten derivatives demonstrated better cytotoxic effects, and 4b exhibited the strongest inhibitory activity against A549 cells growth (IC 50 = 0.78 µM) and low toxicity against BEAS-2b cells (IC 50 = 17.22 µM). Encouragingly, the IC 50 value of compound 4b was 0.78 µM, demonstrating 3.53-fold, 10.22-fold and 12.13-fold more anticancer activity than HCPT, Tet and Fan, respectively. Subsequently, the anti-tumor mechanism of compound 4b was studied by hoechst 33258, flow cytometry, cell scratch, western blotting, and JC-1 staining. The results indicated compound 4b remarkably inhibited the cell migration by decreasing MMP-2 and MMP-9 expression and inhibited the proliferation of A549 cells by arresting the G2/M cell cycle. Meanwhile, compound 4b could also induce A549 cell apoptosis by promoting endogenous pathways of mitochondrial regulation. Subsequently, we simulated the drug stability of compound 4b in vivo , compound 4b showed a hydrolysis half-life of over 8 h in simulated gastric and intestinal fluids. In addition, in vivo experiments in nude mice presented that the growth of tumor tissues was markedly inhibited by the consumption of compound 4b in a dose-dependent manner, and the inhibition rate of the high-dose group (40 mg/kg) was greater than 50%. Regarding the anti-tumor mechanism of compound 4b , it was found that compound 4b could inhibit the mTOR/PI3K/AKT pathway in vivo . Furthermore, the binding mode of BCl-2 and Bax with compound 4b was investigated by performing a molecular docking study. Conclusions In summary, our present study unveiled the antitumor activities of 19 novel derivatives against the normal lung epithelial BESA-2b cells and six cancer cell lines in vitro . Furthermore, the following experiments illuminated that compound 4b could exert antitumor effects and induce apoptosis by regulating the PI3K/Akt/mTOR signaling pathway in vivo through triggering the mitochondria-mediated intrinsic pathways. This newly Fan derivative could exert antitumor effects in vivo and in vitro , which implied that compound 4b would be a prospective new anti-lung cancer drug for future development.

Nowadays, cancer is one of the deadliest diseases in the world, which has been estimated to cause 9.9 million deaths in 2020. Conventional treatments for cancer commonly involve mono-chemotherapy or a combination of radiotherapy and mono-chemotherapy. However, the negative side effects of these approaches have been extensively reported and have prompted the search of new therapeutic drugs. In this context, scientific community started to look for innovative sources of anticancer compounds in natural sources, including traditional plants. Currently, numerous studies have evaluated the anticancer properties of natural compounds derived from plants, both in vitro and in vivo. In pre-clinical stages, some promising compounds could be mentioned, such as the sulforaphane or different phenolic compounds. On the other hand, some phytochemicals obtained positive results in clinical stages and were further approved for cancer treatment, such as vinca alkaloids or the paclitaxel. Nevertheless, these compounds are not exempt of limitations, such as low solubility, restricted effect on their own, negative side-effects, etc. This review aims to compile the information about the current phytochemicals used for cancer treatment and also promising candidates, main action mechanisms and also reported limitations. In this sense, some strategies to face the limitations have been considered, such as nano-based formulations to improve solubility or chemical modification to reduce toxicity. In conclusion, although more research is still necessary to develop more efficient and safe phytochemical drugs, more of these compounds might be used in future cancer therapies.

Lotus is an edible and medicinal plant, and the extracts from its different parts exhibit various bioactivities. In the present study, the hot water–soluble polysaccharides from lotus seeds (LSPS) were evaluated for their cancer cell cytotoxicity, immunomodulatory and antitumor activities. LSPS showed significant inhibitory effects on the mouse gastric cancer MFC cells, human liver cancer HuH-7 cells and mouse hepatocarcinoma H22 cells. The animal studies showed that LSPS inhibited tumor growth in H22 tumor-bearing mice with the highest inhibition rate of 45.36%, which is comparable to that induced by cyclophosphamide (30 mg/kg) treatment (50.79%). The concentrations of white blood cells were significantly reduced in cyclophosphamide-treated groups (p < 0.01), while LSPS showed much fewer side effects according to the hematology analysis. LSPS improved the immune response in H22 tumor-bearing mice by enhancing the spleen and thymus indexes, and increasing the levels of serum cytokines including tumor necrosis factor-α and interleukin-2. Moreover, LSPS also showed in vivo antioxidant activity by increasing superoxide dismutase activity, thus reducing the malondialdehyde level in the liver tissue. These results suggested that LSPS can be used as an antitumor and immunomodulatory agent.

Nowadays, computing calculations are becoming more and more demanding due to the huge pool of resources available. This demand must be satisfied in terms of computational efficiency and resilience, which is compromised in distributed and heterogeneous platforms. Not only this, data obtained are often either reused by other researchers or recalculated. In this work, a set of tools to overcome the problem of creating and executing fault tolerant distributed applications on dynamic environments is presented. Such a set also ensures the reproducibility of the performed experiments providing a portable, unattended and resilient framework that encapsulates the infrastructure-dependent operations away from the application developers and users, allowing performing experiments based on Open Access data repositories. In this way, users can seamlessly search and lately access datasets that can be automatically retrieved as input data into a code already integrated in the proposed workflow. Such a search is based on metadata standards and relies on Persistent Identifiers (PID) to assign specific repositories. The applications profit from Distributed Toolbox, a framework devoted to the creation and execution of distributed applications and includes tools for unattended cluster and grid execution, where a total fault tolerance is provided. By decoupling the definition of the remote tasks from its execution and control, the development, execution and maintenance of distributed applications is significantly simplified with respect to previous solutions, increasing their robustness and allowing running them on different computational platforms with little effort. The integration with Open Access databases and employment of PIDs for long-lasting references ensures that the data related to the experiments will persist, closing a complete research circle of data access/processing/storage/dissemination of results.

Overdominance (heterozygote advantage) for fitness is a form of balancing selection which supports the maintenance of genetic polymorphisms in the populations. This mode of selection is expected to generate a conspicuous footprint on neutral genetic variation in genomic regions of restricted recombination, which contrasts with the signature generated by other types of natural selection. In particular, gene diversity is expected to be increased at neutral sites tightly linked to overdominant sites, as opposed to background selection and selective sweeps. We produced extensive whole-genome sequencing data to analyse genetic diversity across regions exhibiting varying recombination patterns in a Drosophila melanogaster population with known demographic history. The results were compared with simulation data in order to quantify the magnitude of the contribution of overdominant loci to genetic diversity which could be compatible with observations. We analysed sequencing data from 51 individual male flies sampled from a large population and estimated the average nucleotide diversity (π) in 100-kb consecutive windows across the main autosomal chromosomes. By using the available recombination map in the species, we evaluated the changes in π in relation with the levels of recombination across genomic regions. We then carried out computer simulations following the demographic history, the genomic architecture and the recombination map of the main autosomal chromosomes assuming models which include deleterious (background selection) and advantageous (selective sweeps) mutations, or models also including increasing rates of overdominant mutations. By comparing the results obtained from simulations and the observed data, we conclude that a parsimonious model of background selection and adaptation to captivity explains the observed patterns of neutral variation in the studied population better than the models including overdominance.

The 40-year journey of ginseng clinical trials has experienced emerging, boom, and stable or transitional stages. The global network of ginseng clinical trials has relevant regional distribution in Asia, North America and Europe. South Korea makes a great contribution to building up large research clusters and strong cooperation links. Universities are the key contributors to ginseng clinical trials. The development of ginseng products could be focused on the clinical trial in diseases with higher effectiveness or effect size, such as sexual function and cognitive & behavior and require rigorous investigations and evidence to evaluate safety. More attention should be paid to different effects from different preparations. We believe this review will provide new insights into the understanding of global ginseng clinical trials and identifies potential future perspectives for research and development of ginseng.