Discovery of a quinoline-containing compound JT21-25 as a potent and selective inhibitor of apoptosis signal-regulating kinase 1 (ASK1).

ASK1 kinase inhibition has become a promising strategy for treating inflammatory diseases, such as non-alcoholic steatohepatitis and multiple sclerosis. Here, we reported the discovery of a promising compound 9h (JT21-25) containing quinoline structures as a potent small molecule inhibitor of ASK1. The compound JT21-25 was selective against MAP3K kinases TAK1 (>1960.8-fold), and much higher than the selectivity of GS-4997 for TAK1 (312.3-fold). In addition, different concentrations of JT21-25 did not show significant toxicity in normal LO2 liver cells, and the cell survival rate was greater than 80 %. The Oil Red O staining experiment showed that at the 4 µM and 8 µM concentrations of JT21-25, only slight cytoplasmic fat droplets were observed in LO2 cells, and there was no significant fusion between fat droplets. In the biochemical analysis experiment, JT21-25 significantly reduced the content of CHOL, LDL, TG, ALT, and AST. In summary, these findings suggested that compound JT21-25 might be valuable for further investigation as a potential candidate in the treatment of associated diseases.

Exploring novel indazole derivatives as ASK1 inhibitors: Design, synthesis, biological evaluation and docking studies.

Apoptosis signal regulated kinase 1 (ASK1, MAP3K5) is a member of the mitogen activated protein kinase (MAPK) signaling pathway, involved in cell survival, differentiation, stress response, and apoptosis. ASK1 kinase inhibition has become a promising strategy for the treatment of Non-alcoholic steatohepatitis (NASH) disease. A series of novel ASK1 inhibitors with indazole scaffolds were designed and synthesized, and their ASK1 kinase activities were evaluated. The System Structure Activity Relationship (SAR) study discovered a promising compound 33c, which has a strong inhibitory effect on ASK1. Noteworthy observations included a discernible reduction in lipid droplets within LO2 cells stained with Oil Red O, coupled with a decrease in LDL, CHO, and TG content within the NASH model cell group. Mechanistic inquiries revealed that compound 33c could inhibit the protein expression levels of the upregulated ASK1-p38/JNK signaling pathway in TNF-α treated HGC-27 cells and regulate apoptotic proteins. In summary, these findings suggest that compound 33c may be valuable for further research as a potential candidate compound against NASH.

Membrane separation of antibiotics predicted with the back propagation neural network.

Antibiotics and antibiotic resistance genes (ARGs) have been frequently detected in the aquatic environment and are regarded as emerging pollutants. The prediction models for the removal effect of four target antibiotics by membrane separation technology were constructed based on back propagation neural network (BPNN) through training the input and output. The membrane separation tests of antibiotics showed that the removal effect of microfiltration on azithromycin and ciprofloxacin was better, basically above 80%. For sulfamethoxazole (SMZ) and tetracycline (TC), ultrafiltration and nanofiltration had better removal effects. There was a strong correlation between the concentrations of SMZ and TC in the permeate, and the R2 of the training and validation processes exceeded 0.9. The stronger the correlation between the input layer variables and the prediction target was, the better the prediction performances of the BPNN model than the nonlinear model and the unscented Kalman filter model were. These results showed that the established BPNN prediction model could better simulate the removal of target antibiotics by membrane separation technology. The model could be used to predict and explore the influence of external conditions on membrane separation technology and provide a certain basis for the application of the BPNN model in environmental protection.

Small-molecule inhibitors targeting apoptosis signal-regulated kinase 1.

Apoptosis signal regulated kinase 1 (ASK1, also known as MAP3K5) is a member of the mitogen activated protein kinase kinase kinase (MAP3K) family. Since its first isolation from a human macrophage library in 1996, its research has been ongoing for over 25 years. A large number of reports have revealed that ASK1, as a key activator of the p38 mitogen-activated protein kinase and c-Jun N-terminal kinase (JNK) signaling cascade, responds to various stressors, and its inhibitors have important potential value in the treatment of diseases such as inflammation, cancer, and the nervous system and so on. This review summarizes the recent development in this field, including the structure and signaling pathways of ASK1, with a particular focus on the structure-activity relationships, and the hit-to-lead optimization strategies.

Antibiotic fate in an artificial-constructed urban river planted with the algae Microcystis aeruginosa and emergent hydrophyte.

The behavior and removal of six antibiotics, that is, azithromycin, clarithromycin, sulfathiazole, sulfamethoxazole, ciprofloxacin, and tetracycline, in an artificial-controllable urban river (ACUR) were investigated. The ACUR was constructed to form five artificial eco-systems by planting three emergent hydrophytes and Microcystis aeruginosa: (1) Control; (2) MA: M. aeruginosa only; (3) MA-J-C: M. aeruginosa combined with Juncus effusus and Cyperus alternifolius; (4) MA-C-A: M. aeruginosa combined with C. alternifolius and Acorus calamus L.; (5) MA-A-J: M. aeruginosa combined with A. calamus L. and J. effusus. The MA-C-A system achieved the best removal of azithromycin and clarithromycin after 15-day test with the final concentrations 0.92 and 0.83 µg/L. The contents of ciprofloxacin and tetracycline in sediment were highest, up to 1453 and 1745 ng/g. The antibiotic plant bioaccumulation was higher in roots rather than the shoots (stem and leaves). No target antibiotics were detected in algae cells. The combination of hybrid hydrophytes had a certain effect on the removal of antibiotics, and thus selecting appropriate hydrophytes in urban rivers could greatly improve water quality. The overall removal of six antibiotics was greatly improved by the ACUR containing the hybrid hydrophytes and the algae, indicating a synergistic effect on antibiotic removal. PRACTITIONER POINTS: Controllable-mobile artificial eco-systems were developed with emergent hydrophytes and M. aeruginosa. The M. aeruginosa + Cyperus alternifolius + Acorus calamus L. system removed azithromycin and clarithromycin most at the end of tests. Emergent hydrophytes and M. aeruginosa have a synergistic effect on the removal of antibiotics. The combination of emergent hydrophytes did play an important role in the removal of antibiotics. The artificial eco-systems containing the hybrid hydrophytes and the algae could greatly improve the overall removal of antibiotics.