Can ecological niche models be used to accurately predict the distribution of invasive insects? A case study of Hyphantria cunea in China.

In recent decades, ecological niche models (ENMs) have been widely used to predict suitable habitats for species. However, for invasive organisms, the prediction accuracy is unclear. In this study, we employed the most widely used maximum entropy (MaxEnt) model and ensemble model (EM) Biomod2 and verified the practical effectiveness of the ENM in predicting the distribution areas of invasive insects based on the true occurrence of Hyphantria cunea in China. The results showed that when only limited data of invasive areas were used, the two ENMs could not effectively predict the distribution of suitable habitats of H. cunea, although the use of global data can greatly improve the prediction accuracy of ENMs. When analyzing the same data, Biomod2's prediction accuracy was significantly better than that of MaxEnt. For long-term predictions, the area of suitable habitat predicted by the ENMs was much greater than the occurrence area; for short-term predictions, the accuracy of the predicted area was significantly improved. Under the current conditions, the area of suitable habitat for H. cunea in China is 118 × 104 km2, of which 59.32% is moderately or highly suitable habitat. Future climate change could significantly increase the suitable habitat area of H. cunea in China, and the predicted area of suitable habitats in all climate scenarios exceeded 355 × 104 km2, accounting for 36.98% of the total land area in China. This study demonstrates the use of ENMs to study invasive insects and provides a reference for the management of H. cunea in China.

Identification of a novel GLUT1 inhibitor with in vitro and in vivo anti-tumor activity.

Glucose transporter (GLUT) is a group of membrane proteins which transport extracellular glucoses into cytoplasm, amongst GLUT1 is widely up-regulated in tumor cells. However, no FDA approved GLUT drug has been developed. In this study, we synthesized and identified a novel GLUT1 inhibitor (SMI277) based on in vitro assays and in vivo experiments. Compared with a known GLUT1 inhibitor, SMI277 showed stronger inhibitory activity to glucose uptake, and the inhibition was increased by 40 %. Lactate secretions were decreased by SMI277 in a dose dependent manner. SMI277 was able to inhibit cell proliferations and induce apoptosis of tumor cells. Compared to that of the control group, the tumor growth in mouse model with the administration of 10 mg/kg SMI277 was significantly alleviated and the tumor size was reduced by 58 % on day 21 after inoculation. Interestingly, SMI277 could negatively regulate the expression of GLUT1 protein. Ex vivo experiments showed that SMI277 was capable to enhance CD8+ T cell response. Residues Q283, F379 and E380 were identified as contact residues for GLUT1/SMI277 interactions by mutagenesis based binding affinity measurement. In conclusion, SMI277 appeared to be a good lead compound for drug development with specific GLUT1+ cancer treatment.

Identification of Novel CD39 Inhibitors Based on Virtual Screening and Enzymatic Assays.

The accumulation of adenosine in the tumor microenvironment mediates immunosuppression and promotes tumor growth and proliferation. Intervention of the adenosine pathway is an important direction of antitumor immunity research. CD39 is an important ecto-nucleotidases for adenosine generation, therefore targeting the CD39-adenosine pathway is an emerging immune checkpoint for anticancer treatment. However, currently no CD39 inhibitor has been approved by the U.S. Food and Drug Administration. The development of CD39 drugs is urgent for clinical application. In this study, we combined homology modeling, virtual screening, and in vitro enzymatic activity to characterize the structural features of the CD39 protein and identify a triazinoindole-based compound as a CD39 inhibitor. The identified inhibitor and one of its analogues could effectively prevent the enzymatic activity of CD39 with IC50 values of 27.42 ± 5.52 and 79.24 ± 12.21 µM, respectively. At the same time, the inhibitor significantly inhibited the adenosine monophosphate production in colorectal cancer cell lines (HT29 and MC38) and thereafter prevented cell proliferation. Molecular docking studies, mutagenesis, and microscale thermophoresis indicated that residues such as R85 could be the main contributor in binding triazinoindole compounds. The binding mode can potentially be utilized for hit-to-lead optimization, and the identified inhibitor can be further tested for its anticancer activity in vivo or may serve as a chemical agent to study CD39-related functions.

Discovery of bilirubin as novel P2X7R antagonist with anti-tumor activity.

As a unique ligand gated ion channel in the P2-receptor family, P2X7R is highly expressed in various tumors. The activated P2X7R facilitates tumor growth and metastasis. Hypoxia, inflammation and necrosis in the tumor microenvironment (TME) cause a large amount of adenosine triphosphate (ATP) accumulated in the TME. High concentration of ATP can abnormally activate P2X7R, which induces pore formation and further facilitates the Ca2+ ion influx and non-specific substance intake. Therefore, inhibition of P2X7R activation can be applied as a potential anti-tumor therapy strategy. However, there is currently no FDA approved drugs for this target for anti-tumor treatment. In this study, we identified bilirubin as novel P2X7R antagonist by using structure based virtual screening combined with cell based assays. Molecular docking studies indicated that bilirubin probably interacted with P2X7R by forming hydrogen-π interactions with residues V173, E174 and K311. The compound bilirubin inhibited the P2X7R gated EB intake by cancer cells. Meanwhile, bilirubin was capable to inhibit the cell proliferation and migration of P2X7R expressed HT29 cells. The phosphorylation of mTOR, STAT3 and GSK3ß were significantly decreased when bilirubin was present. Finally, in vivo experiment exhibited the anti-tumor effect of bilirubin in the MC38 bearing mice model, but did not show tissue damage in different organs. In conclusion, bilirubin was identified as a novel P2X7R antagonist and it may have potential for anti-cancer treatment, although various functions of the molecule should be considered.