Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-ß-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding.

Metallo-ß-lactamases (MBLs) are zinc-dependent enzymes capable of hydrolyzing all bicyclic ß-lactam antibiotics, posing a great threat to public health. However, there are currently no clinically approved MBL inhibitors. Despite variations in their active sites, MBLs share a common catalytic mechanism with carbapenems, forming similar reaction species and hydrolysates. We here report the development of 2-aminothiazole-4-carboxylic acids (AtCs) as broad-spectrum MBL inhibitors by mimicking the anchor pharmacophore features of carbapenem hydrolysate binding. Several AtCs manifested potent activity against B1, B2, and B3 MBLs. Crystallographic analyses revealed a common binding mode of AtCs with B1, B2, and B3 MBLs, resembling binding observed in the MBL-carbapenem product complexes. AtCs restored Meropenem activity against MBL-producing isolates. In the murine sepsis model, AtCs exhibited favorable synergistic efficacy with Meropenem, along with acceptable pharmacokinetics and safety profiles. This work offers promising lead compounds and a structural basis for the development of potential drug candidates to combat MBL-mediated antimicrobial resistance.

Columbamine suppresses proliferation and invasion of melanoma cell A375 via HSP90-mediated STAT3 activation.

PURPOSE: The goal of this study is to explore the effects of columbamine in melanoma cells and the signaling pathway involved. METHODS: Human melanoma cell line A375 cells were used in this study. Cell proliferative ability was detected by MTT assay and clone formation assay. Cell migration and invasion were measured by wound healing assay and transwell assay, respectively. Protein expression was examined by Western blotting. RESULTS: Columbamine reduced cell proliferative ability and the number of clone spots in A375 cells. Western blotting results demonstrated that expression of cleaved caspase 3, an activated cell death protease, was upregulated by 20 and 50 µM of columbamine. Wound healing results showed that the scratch width was wider in cell treated with 20 and 50 µM of columbamine than that in cell treated with 0 and 10 µM of columbamine. Phosphorylation of STAT3 and expression of HSP90 was also repressed by columbamine in a concentration-dependent manner. Overexpression of HSP90 attenuated the inhibition of cell proliferation, migration and invasion induced by columbamine. CONCLUSION: Columbamine inhibited melanoma cell proliferation, migration, and invasion in A375 cells through inactivation of STAT3, which is mediated by HSP90.

Ovalbumin-modified nanoparticles increase the tumor accumulation by a tumor microenvironment-mediated "giant".

We designed a pH intelligently driven self-assembled nano-platform (GOx@ZIF-OVA). The nano-platform was composed of glucose oxidase (GOx), ovalbumin (OVA) and zeolitic imidazolate skeleton-8 (ZIF-8). The goal was to address the depth and cumulative limits of the drug at the tumor site. Firstly, OVA-modified GOx@ZIF could greatly increase tumor accumulation due to spontaneous self-assembly from 142.2 ± 9.1 to 705.5 ± 52.1 nm and the 5779.4 ± 598.3 nm giant at pH values of 7.4, 6.5, and 5.0, respectively. More importantly, the tumor-like sphere experiments demonstrated that the encapsulated GOx "vampires" can cut off the energy source of tumors and poisonous tumor cells without depth limitations. Furthermore, immunofluorescence assay and cytotoxicity assay tests in vivo proved that T cell infiltration could be significantly increased, triggering an effective anti-tumor immune response and inhibiting lung metastasis. Therefore, the experimental results demonstrated that the acid-smart-driven nano-platform has the potential to address the limitations of tumor depth and drug accumulation in solid tumors.

miR-34a-5p Inhibits Cell Proliferation, Migration and Invasion Through Targeting JAG1/Notch1 Pathway in HPV-Infected Human Epidermal Keratinocytes.

Condyloma acuminate (CA) is a communicable disease caused by human papillomavirus (HPV). This study aimed to study the targeting relationship between miR-34a-5p and Jagged 1 (JAG1), as well as its regulatory effect in HPV-infected cells. Human keratinocyte HaCaT cells were infected with HPV16E6, and CA tissues were collected. The expression level of miR-34a-5p and JAG1 were detected in CA tissues and HPV-HaCaT cells. Cell proliferation, migration and invasion were respectively measured using 3-(4, 5)-dimethylthiahiazo-(-z-y1)-3, 5-diphenytetrazoliumromide (MTT), cell wound healing and Transwell assay. The potential binding sites of miR-34a-5p and JAG1 were predicted by website TargetScan, and confirmed using dual luciferase reporter gene assay. The proteins of Notch1 pathway-related were assessed using western blotting. The results showed that miR-34a-5p expression was decreased, and JAG1 expression was increased in CA tissues and HPV-HaCaT cells. Cell proliferation, migration and invasion were decreased when miR-34a-5p over-expression and JAG1 knock-down in HPV-HaCaT cells. Furthermore, miR-34a-5p had a targeting effect on JAG1. The expression level of Notch1, NICD, Hes1 and Hey1 were increased when miR-34a-5p knock-down. miR-34a-5p could inhibit cell development, and regulate the activity of Notch1 pathway through targeting JAG1 expression in HPV-infected keratinocytes.