A growing body of evidence suggests that p300 histone acetyltransferase plays important roles in cancer cell differentiation and proliferation. Here, we employed structure-based hierarchical virtual screening method to identify novel lead compounds of p300 histone acetyltransferase. From a screening library containing approximate 100 000 diverse druglike compounds, 33 compounds were chosen for experimental testing and one compound, 4-acetyl-2-methyl-N-morpholino-3,4-dihydro-2H-benzo[b][1, 4]thiazine-7-sulfonamide (17), showed as micromolar inhibitor. Based on its predicted binding pose, we investigated its binding characteristics by designing two series of structural modifications. The obtained structure-activity relationship results are consistent with the predicted binding model. We expect that the identified novel p300 histone acetyltransferase inhibitors will serve as starting points for further development of more potent and specific histone acetyltransferase inhibitors.

AIM:To explore the molecular mecha-nism of Fuyangjing gel in the treatment of chronic eczema rats model based on janus protein kinase 1(JAK1)/signal transducer and activator of transcrip-tion 5(STAT5)signaling pathway.METHODS:Thirty-six SPF Wistar rats were randomly divided into nor-mal group,model group,Qingpeng ointment group,Fuyangjing gel low,medium and high dose groups.Except the normal group,the other groups of rats were treated with 2,4-dinitrochlorophenone solution to induce chronic eczema-like lesions on the back.After 3 weeks of modeling,Qingpeng ointment group and Fuyangjing gel low,medium and high dose groups were respectively treated with corresponding drugs.The model group was smeared with blank gel matrix once a day for 2 weeks,while the normal group was not treated.The severity and pathological changes of back le-sions in chronic eczema rats were observed.The ex-pression of phosphorylated protein tyrosine kinase 1(p-JAK1)and phosphorylated signal transduction and transcriptional activator 5(p-STAT5)in rat dor-sal skin was detected by Western blot.Detection of thymic stromallymphopietin(TSLP),JAK1,STAT5,in-terleukin-10(IL-10)and IL-17 mRNA expression lev-els in rat back skin by qRT-PCR;The levels of IL-4,IL-6,IL-10,IL-13 and IL-17 in serum of rats were deter-mined by enzyme-linked immunosorbent assay(ELI-SA).RESULTS:Compared with normal group,the se-rum levels of IL-4,IL-6,IL-13 and IL-17 in model group were significantly increased,while IL-10 lev-els were significantly decreased(P＜0.05).The ex-pression levels of p-JAK1,p-STAT5 protein and TSLP,JAK1,STAT5 and IL-17 mRNA in back lesions were significantly increased,while IL-10 mRNA levels were significantly decreased(P＜0.05).Compared with model group,serum levels of IL-4,IL-6,IL-13 and IL-17 in Qingpeng ointment group and Fuy-angjing gel low,medium and high dose groups were significantly decreased,while IL-10 levels were significantly increased(P＜0.05).The expres-sion levels of p-JAK1,p-STAT5 protein and TSLP,JAK1,STAT5 and IL-17 mRNA in back lesions were significantly decreased,while the mRNA levels of IL-10 were significantly increased(P＜0.05).The serum levels of IL-4,IL-6,IL-13 and IL-17 in Qingpeng oint-ment group were decreased,while IL-10 levels were increased(P＜0.05).The expression levels of p-JAK1,p-STAT5 protein and TSLP,JAK1,STAT5 and IL-17 mRNA in back lesions were decreased,while the mRNA levels of IL-10 were increased(P＜0.05).Com-pared with Qingpeng ointment group,there were no significant differences in serum levels of IL-4,IL-6,IL-10,IL-13 and IL-17 in Fuyangjing gel high-dose group(P＞0.05).There were no significant differenc-es in the expression levels of p-JAK1,p-STAT5 pro-tein and TSLP,JAK1,STAT5,IL-10 and IL-17 mRNA in back lesions(P＞0.05).CONCLUSION:Fuyangjing gel may play a role in the treatment of chronic eczema by regulating the expression of JAK1/STAT5 signal-ing pathway related inflammatory factors,proteins and genes.

ObjectiveTo explore the mechanism of Taohong Siwutang in regulating the levels of inflammatory mediators， cysteine-dependent aspartate-specific protease Caspase-14， and recombinant envoplakin （EVPL） in the mouse model of psoriasis. MethodForty-eight BALB/c mice were randomized into blank， model， methotrexate tablets（3.6×10^-4 g·kg^-1）， and low-， medium-， and high-dose Taohong Siwutang groups（7.14，14.28，28.56 g·kg^-1）. The mouse model of psoriasis-like skin lesion was induced by applying 5% imiquimod cream on the back of mice， and drug intervention was carried out at the same time. The psoriasis area and severity index （PASI） was scored by photographing. Hematoxylin-eosin staining was employed to observe the pathological changes of the skin， which was evaluated based on the Baker score. The levels of interleukin （IL）-2， IL-17， IL-22， and IL-23 in the peripheral blood of mice were measured by the enzyme-linked immunosorbent assay. Immunohistochemical staining was adopted to detect the positive expression of Caspase-14 and EVPL in mouse skin lesions. Western blot and real-time polymerase chain reaction were employed to determine the protein and mRNA levels， respectively， of IL-2， IL-17， IL-22， IL-23， Caspase-14， and EVPL in mouse skin lesions. ResultCompared with the blank group， the model group showed increased PASI score and Baker score， elevated levels of IL-2， IL-17， IL-22， and IL-23 in the peripheral blood， up-regulated mRNA and protein levels of IL-2， IL-17， IL-22 and IL-23， and down-regulated mRNA and protein levels and positive expression of Caspase-14 and EVPL in skin lesions （P<0.05）. Compared with the model group， drug interventions reduced the PASI score and Baker score， lowered the levels of IL-2， IL-17， IL-22， and IL-23 in the peripheral blood， down-regulated the mRNA and protein levels of IL-2， IL-17， IL-22， and IL-23， and up-regulated the mRNA and protein levels and positive expression of Caspase-14 and EVPL in skin lesions （P<0.05）. ConclusionTaohong Siwutang demonstrates good anti-inflammatory effect and skin barrier repair function in the treatment of psoriasis. It can significantly reduce the levels of inflammatory mediators in the peripheral blood and skin lesions and promote the expression of Caspase-14 and EVPL involved in skin barrier repair in the mouse model of psoriasis.