Identification of histone deacetylase inhibitors as neutrophil recruitment modulators in zebrafish using a chemical library screen.

Tissue injury-induced neutrophil recruitment is a prerequisite for the initiation and amplification of inflammatory responses. Although multiple proteases and enzymes involved in post-translational modification (PTM) of proteins regulate leukocyte recruitment, an unbiased functional screen of enzymes regulating inflammatory leukocyte recruitment has yet to be undertaken. Here, using a zebrafish tail fin amputation (TFA) model to screen a chemical library consisting of 295 compounds that target proteases and PTM enzymes, we identified multiple histone deacetylase (HDAC) inhibitors that modulate inflammatory neutrophil recruitment. AR-42, a pan-HDAC inhibitor, was shown to inhibit neutrophil recruitment in three different zebrafish sterile tissue injury models: a TFA model, a copper-induced neuromast damage and mechanical otic vesicle injury (MOVI) model, and a sterile murine peritonitis model. RNA sequencing analysis of AR-42-treated fish embryos revealed downregulation of neutrophil-associated cytokines/chemokines, and exogenous supplementation with recombinant human IL-1ß and CXCL8 partially restored the defective neutrophil recruitment in AR-42-treated MOVI model fish embryos. We thus demonstrate that AR-42 non-cell-autonomously modulates neutrophil recruitment by suppressing transcriptional expression of cytokines/chemokines, thereby identifying AR-42 as a promising anti-inflammatory drug for treating sterile tissue injury-associated diseases.

Diversity of Fungal Endophytes in American Ginseng Seeds.

Seeds play a critical role in the production of American ginseng. Seeds are also one of the most important media for the long-distant dissemination and the crucial way for pathogen survival. Figuring out the pathogens carried by seeds is the basis for effective management of seedborne diseases. In this paper, we tested the fungi carried by the seeds of American ginseng from the main production areas of China using incubation and highly throughput sequencing methods. The seed-carried rates of fungi in Liuba, Fusong, Rongcheng, and Wendeng were 100, 93.8, 75.2, and 45.7%, respectively. Sixty-seven fungal species, which belonged to 28 genera, were isolated from the seeds. Eleven pathogens were identified from the seed samples. Among the pathogens, Fusarium spp. were found in all of the seed samples. The relative abundance of Fusarium spp. in the kernel was higher than that in the shell. Alpha index showed that the fungal diversity between seed shell and kernel differed significantly. Nonmetric multidimensional scaling analysis revealed that the samples from different provinces and between seed shell and kernel were distinctly separated. The inhibition rates of four fungicides to seed-carried fungi of American ginseng were 71.83% for Tebuconazole SC, 46.67% for Azoxystrobin SC, 46.08% for Fludioxonil WP, and 11.11% for Phenamacril SC. Fludioxonil, a conventional seed treatment agent, showed a low inhibitory effect on seed-carried fungi of American ginseng.

4-Aminoquinoline melanin-concentrating hormone 1-receptor (MCH1R) antagonists.

Structure-activity relationships of a 4-aminoquinoline MCH1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4-, and 6-positions of the original HTS hit. Improvements to the original screening lead included lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl, and hydrocinnamyl carboxamides at the 6-position. Modifications of the 4-amino group were not well tolerated.