Trends of antimalarial marine natural products: progresses, challenges and opportunities.

Covering 1972 to 2021Malaria remains a significant public health problem in some regions of the world. The great efforts to control malaria have been severely compromised due to the widespread resistance of Plasmodium falciparum to nearly all frontline drugs. Pursuit of novel molecules from the sea will potentially result in new interventions against malaria, which are urgently needed to combat the increase of resistance. Focusing on the strategy of the "Blue Drug Bank", the molecules highlighted here can serve as an inspiration for future medicinal chemistry campaigns. This review covers the developments in the field of antimalarial marine lead compounds reported between 1972 and July 2021, and offers a comprehensive overview on their progresses and potentials. We selected 60 representative potential candidate molecules from 361 marine natural products, and highlighted their structure-activity relationships, molecular mechanisms of targets, and drug-like properties in order to assess their full potential to be developed. We summarized 107 clinically proven or potential antimalarial targets and their subcellular locations in the relevant target proteins, which linked the molecules to the target proteins at the subcellular level. Hence, it could be expected that natural products targeting different mechanisms may prove to be an effective strategy in antimalarial drug research and development in the future.

Semisynthesis and biological evaluation of (+)-sclerotiorin derivatives as antitumor agents for the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma is one of the most common primary hepatic malignancy. Herein, a series of semisynthesized derivatives (2-30) of the natural product (+)-sclerotiorin (1) was prepared and evaluated the cytotoxic activities against six cancer cell lines. Among them, 3 and 5 were the most effective compounds against human hepatocellular carcinoma Bel-7402 cell line with IC50 values of 1.45 and 1.15 µM, respectively. Molecular mechanism study showed that 5 disrupted the mitochondrial membrane potential and induced apoptosis in a caspase-dependent manner. In addition, 5 affected AKT and ERK signaling pathways and induced AKT and ERK proteins degradation through ubiquitin-proteasome system. Furthermore, 5 displayed significant in vivo anticancer effects in the xenograft models with decreasing the tumor mass by 52.5%. The safety evaluation was confirmed by acute toxicity subchronic toxicity tests, paraffin sections of mice organ and blood routine examination. Taken together, 5 can be developed as a potential therapeutic agent for hepatocellular carcinoma.

Tuning the Superhydrophobic Properties of Hierarchical Nano-microstructural Silica Biomorph Arrays Grown at Triphasic Interfaces.

The three-dimensional hierarchical morphology of surfaces greatly affects the wettability, absorption and microfabrication properties of their hybrid materials, however few scalable methods exist that controls simultaneously complex geometric shape and spatial scattered location and their physical properties tuned. Consequently, this report describes a synthetic strategy that enables the position of well-ordered biomorph nano-microstructures on hydrophobic surfaces to be precisely controlled. The hierarchical architecture can be accurately positioned on polydimethylsiloxane (PDMS) surfaces in an unprecedented level by leveraging a solid/liquid/gas triphase dynamic reaction diffusion system strategy. The effect of salt concentrations, pH, CO2 levels, temperature and substrate patterning on this self-assembly process has been investigated, enabling protocols to be devised that enables the hydrophobic properties of the hierarchically assembled multiscale microstructures to be tuned as required. This combined top-down/bottom-up approach can be used to produce composites with outstanding hydrophobicity properties, affording superhydrophobic materials that are capable of retaining water droplets on their surfaces, even when the material is inverted by 180°, with a wide range of potential applications in oil/water separation technology and for selective cell recognition in biological systems.

Recombinant adenovirus expressing a dendritic cell-targeted melanoma surface antigen for tumor-specific immunotherapy in melanoma mice model.

Viral vectors represent a potential strategy for the treatment of human malignant tumors. Currently, recombinant adenovirus vectors are commonly used as gene therapy vehicles, as it possesses a proven safety profile in normal human cells. The recombinant adenovirus system has an ability to highly express exogenous genes and increase the stability of the carrier, which is only transiently expressed in the host cell genome, without integrating. Malignant melanoma cells are produced by the skin, and melanocyte tumors that exhibit higher malignant degrees lead to earlier transfer and higher mortality. In the present study, a recombinant adenovirus (rAd) was generated to express Anti-programmed death-1 (rAd-Anti-PD-1) and used to investigate the efficacy in melanoma cells and tumors. The results demonstrated that B16-F10 cell growth was significantly inhibited and the apoptosis incidence rate was markedly promoted following rAd-PD-1 treatment. The present study demonstrated that the production of α and ß interferon was increased, which led to the induction of dendritic cell (DCs) maturation in rAd-anti-PD-1-treated mice. The present study indicated that rAd-anti-PD-1 exhibited the ability to generate more cluster of differentiation (CD)4+CD8+ T cells and induce a PD-1-specific cytotoxic T lymphocyte through DC-targeted surface antigens in mice. This resulted in a further enhanced recognition of melanoma cells due to DCs being targeted by the rAd-anti-PD-1-encoded PD-1. Notably, mice treated with the rAd-anti-PD-1-targeted PD-1 demonstrated an improved protection compared with tumor-bearing mice from the challenge group treated with a recombinant gutless adenovirus and Anti-PD-1. In conclusion, the present study demonstrated that targeting the melanoma surface antigens via the rAd-anti-PD-1-infected tumor cells enhanced the ability of recombinant adenovirus to induce a potent tumor-inhibitory effect and antigen-specific immune response.

MicroRNA-34a contributes to the protective effects of glucagon-like peptide-1 against lipotoxicity in INS-1 cells.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) reduces fatty acid-induced beta-cell lipotoxicity in diabetes; however, the explicit mechanisms underlying this process are not fully understood. This study was designed to investigate the involvement of microRNA, which regulates gene expression by the sequence-specific inhibition of mRNA transcription in the GLP-1 mediation of beta-cell function. METHODS: The cell viability and apoptosis were determined using an methyl thiazoleterazolium (MTT) assay and flow cytometry. The expression of genes involved in beta-cell function, including microRNA-34a and sirtuin 1, were investigated using real-time PCR. The underlying mechanisms of microRNA-34a were further explored using cell-transfection assays. RESULTS: A 24-hours incubation of INS-1 cells with palmitate significantly decreased cell viability, increased cell apoptosis and led to the activation of microRNA-34a and the suppression of sirtuin 1. A co-incubation with GLP-1 protected the cells against palmitate-induced toxicity in association with a reduction in palmitate-induced activation of microRNA-34a. Furthermore, palmitate-induced apoptosis was significantly increased in cells that were infected with microRNA-34a mimics and decreased in cells that were infected with microRNA-34a inhibitors. CONCLUSION: MicroRNA-34a is involved in the mechanism of GLP-1 on the modulation of beta-cell growth and survival.