Synthesis, structure-activity relationships and preliminary mechanism study of N-benzylideneaniline derivatives as potential TLR2 inhibitors.

Toll-like receptor 2 (TLR2) can recognize pathogen-associated molecular patterns to defense against invading organisms and has been represents an attractive therapeutic target. Until today, none TLR2 small molecule antagonist have been developed in clinical trial. Herein, we designed and synthesized 50 N-benzylideneaniline compounds with the help of CADD. And subsequent in vitro studies leading to the optimized compound SMU-A0B13 with most potent inhibitory activity to TLR2 (IC50=18.21 ±â€¯0.87 µM). Preliminary mechanism studies indicated that this TLR2 inhibitor can work through the NF-κB signaling pathway with high specificity and low toxicity, and can also efficiently downregulate inflammatory cytokines, such as SEAP, TNF-α and NO in HEK-Blue hTLR2, human PBMC and Raw 264.7 cell lines. Additionally, the docking situation also indicate SMU-A0B13 can well bind to the TLR2-TIR (PDB: 1FYW) active domain, which probably explains the bioactivity.

Targeting pattern-recognition receptors to discover new small molecule immune modulators.

Pattern recognition receptors (PRRs) are key immune receptors of the innate immune system, which recognize the conserved pathogen-associated molecular patterns (PAMPs) of the invading pathogens. Compared to the adaptive immune receptors, PRRs have three distinguishing features, viz., universal expression, fast response and recognizing many kinds of microbes. Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), C-type lectin receptors (CLRs) and NOD-like receptors (NLRs) recognize viral nucleic acid/bacterial fragments and trigger anti-microbial innate immune responses. Upon recognition of their ligand species, PRRs recruit specific intracellular adaptor proteins to initiate signaling pathways culminating in the activation of nuclear factor-κB (NF-κB), mitogen-activated protein (MAP) kinases and interferon regulatory factors (IRFs) that control the transcription of genes encoding pro-inflammatory factors including type I interferon and other inflammatory cytokines, which are critical for eliminating the potential threat to the host. Here, we summarize the effects of small molecule regulators acting on signaling pathways initiated by TLR, RLR and NLR as well as their influence on innate and adaptive immune responses leading to therapy.

PCDD/Fs distribution characteristics and health risk assessment in fly ash discharged from MSWIs in China.

This study provided distribution and health risk information of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) in fly ash from 4 municipal solid waste incinerators (MSWIs) in four seasons from four sites, including Zhengzhou City in Henan Province, Chuzhou City in Anhui Province, Jilin City in Jilin Province and Zibo City in Shandong Province. The toxic equivalent concentration (I-TEQ) values of PCDD/Fs ranged from 0.0707 to 0.7742ng I-TEQ/g, and no identical sequence occurred during four seasons in different sampling sites. The stabilization process might efficiently reduce the content and toxicology of PCDD/Fs in fly ash. The value of PCDD/PCDF in fly ash ranged from 0.145 to 0.787 after solidification. The characteristic index (DCI) of 2,3,4,7,8-P5CDF was 0.803 with 6.6% under 95% probability for fly ash samples discharged from MSWIs. The 95th percentile carcinogenic risks (CRs) for onsite workers were lower than the threshold value (10-5), suggesting that the cancer risk levels of PCDD/Fs in fly ash for onsite workers were acceptable. The 95th percentile non-carcinogenic risks (non-CRs) for onsite workers were lower than 1, suggesting no obvious non-carcinogenic effect was developed for onsite workers. This paper provide an overview information on the distribution of PCDD/Fs in fly ash during four seasons, and it could be used as an important fingerprint to distinguish the fly ash sources. Thus, the research could provide basic information for fly ash management in environment.

Development of Antibacterial Drugs by Targeting Toll-Like Receptors.

The invading microbial pathogens are controlled by the rapid and effective innate immune responses sequentially formation of the long-lasting adaptive memories. Toll-like receptors (TLRs) play a vital role in innate and adaptive immune response by function as a bridge to modulate the immune response. Further, genetic studies in human or animals showed that regulation of TLR signaling contributes to the antibacterial efficacy, and developing novel reagent to modulate TLR related immune response becomes an interesting therapy method to against bacterial infections. Herein we review the recent developments of this area, focusing on the reagent of synthetic molecules, natural products and peptides (or proteins), as TLR-related antibacterial drugs.