Piperonyl-Tethered Rhodanine Derivatives Potently Inhibit Chitinolytic Enzymes of Ostrinia furnacalis.

Insect pest chitinases are potential target for developing new insect growth regulators. Piperine was found first to inhibit the insect chitinase (OfChi-h) from Ostrinia furnacalis (Asian corn borer) in this work, except for previously reported OfChtI. Novel piperonyl-tethered rhodanine derivatives 7a-j were rationally designed with piperine as lead and synthesized by introducing a unique rhodanine moiety into the piperine scaffold based on the similar binding cavity of OfChtI and OfChi-h. Compared to piperine, compounds 7a-j showed approximately 100- to 400-fold or 110- to 210-fold higher inhibitory capacity against two chitinases, respectively. Molecular mechanism studies indicated that π interactions are crucial for improving inhibitory activity against two chitinases due to the introduction of the conjugated rhodanine ring. Moreover, compounds 7a-c could dramatically inhibit the growth and development of O. furnacalis larvae by in vivo activity evaluation. This study provides novel piperonyl-tethered rhodanine derivatives inhibiting dual chitinases as insect growth regulator candidates.

[Increased level of Th17 cells in peripheral blood correlates with the development of hepatocellular carcinoma].

OBJECTIVE: To investigate the potential correlation between the level of Th17 cells in peripheral blood and the development of human hepatocellular carcinoma (HCC). METHODS: Th17 cells in the blood samples from 61 HCC patients and 38 healthy controls were assessed by flow cytometry (FCM). The mRNA expression levels of IL-17, IL-23p19 and RORc in peripheral blood mononuclear cells (PBMC) were detected by quantitative real-time PCR. The potential correlation of increased Th17 cells in blood with the clinical characteristics of the 61 patients, including gender, age, preoperative AFP concentration, tumor diameter, portal vein tumor thrombus (PVTT), metastasis and TNM stages was analyzed. Statistical analysis was performed using the software GraphPad Prizm 5.0. RESULTS: The number of Th17 cells in 61 HCC patients was significantly higher than that in the normal controls (4.67% ± 0.79% vs 3.25% ± 0.68%, P < 0.0001). The same tendency was also found in the mRNA levels of IL-17, IL-23p19 and RORc in PBMC (P < 0.05). The increased level of Th17 cells in HCC patients showed a positive correlation with the tumor size, PVTT, metastasis and TNM stages (P < 0.05 for each group). The level of Th17 cells in HCC patients was increased along with the increasing TNM stages I to stage IV: 4.05% ± 0.82%, 4.32% ± 0.67%, 4.94% ± 0.70%, and 5.22% ± 0.87%, respectively, where the level of Th17 cells in patients with advanced stage of HCC (III-IV) was significantly higher than that in early stage (I-II, P = 0.0008). CONCLUSION: The increased of level of Th17 cells in peripheral blood of HCC is significantly correlated with the tumor size, PVTT, metastasis and TNM stage, indicating that the Th17 cells might participate in promoting invasion and progression of HCC directly or indirectly by secreting characteristic cytokines.

Cardiac troponin I autoantibody induces myocardial dysfunction by PTEN signaling activation.

BACKGROUND: The objective of the current study was to study the molecular mechanism(s) underlying cardiac troponin I autoantibody (cTnIAAb) binding to cardiomyocyte and resultant myocardial damage/dysfunction. METHODS: cTnIAAb was purified from serum of 10 acute myocardial infarction (AMI) patients with left ventricular remodeling. Recombinant human cTnI was used to generate three mouse-derived monoclonal anti-cTnI antibodies (cTnImAb1, cTnImAb2, and cTnImAb3). The target proteins in cardiac myocyte membrane bound to cTnImAb and effect of cTnIAAb and cTnImAb on apoptosis and myocardial function were determined. FINDINGS: We found that cTnIAAb/cTnImAb1 directly bound to the cardiomyocyte membraneα-Enolase (ENO1) and triggered cell apoptosis via increased expression of ENO1 and Bax, decreased expression of Bcl2, subsequently activating Caspase8, Caspase 3, phosphatase and tensin homolog (PTEN) while inhibiting Akt activity. This cTnIAAb-ENO1-PTEN-Akt signaling axis contributed to increased myocardial apoptosis, myocardial collagen deposition, and impaired systolic dysfunction. INTERPRETATION: Results obtained in this study indicate that cTnIAAb is involved in the process of ventricular remodeling after myocardial injury. FUND: The National Natural Science Foundation of China (Grant#: 81260026).