Dual-target inhibitors based on COX-2: a review from medicinal chemistry perspectives

suppl data and figure</p

Distribution of thifluzamide, fenoxanil and tebuconazole in rice paddy and dietary risk assessment

<div><p>Distribution behaviors of thifluzamide, fenoxanil, and tebuconazole applied to rice were investigated in South China. Analysis was by a modified QuEChERS method with gas chromatography (thifluzamide and fenoxanil) and liquid chromatography mass spectrometry (tebuconazole). Thifluzamide and tebuconazole partitioned mainly into the soil, with half-lives in the paddy soil of 12–14 and 5.3–7.8 days, respectively. Fenoxanil partitioned mainly into the rice plants, with half-lives of 3.3–4.4 days. The half-lives of thifluzamide, fenoxanil, and tebuconazole in paddy water were 0.17–0.89, 1.8–3.0, and 1.6–4.0 days, respectively. The residues in rice grains at the pre-harvest interval of 14 days were all below the established maximum limit values. The dietary risks assessed as hazard quotients at the pre-harvest interval were less than 1.</p></div

Effects of mutations on the channel sensitivity to DDT.

(A) Representative traces from AaNav1-1, V1016G, V1016I, T1520I, F1534C, T1520I+F1534C and V1016I+F1534C channels after incubation with DDT (100 μM). (B) Percentages of channel inactivation inhibited by DDT (100 μM). The number of oocytes for each mutant was more than 8. Error bars indicate mean ± s.e. The asterisks indicate significant differences in sensitivity of mutants versus wildtype to DDT as determined by using one-way ANOVA with Scheffé's post hoc analysis (p post hoc analysis (p < 0.05).</p

Sequential selection of kdr mutations for pyrethroid resistance in <i>Ae</i>. <i>aegypti</i>.

Darker background colors indicate higher levels of resistance. V1016 and T1520I are selected in mosquitoes carrying F1534C. F1534C (and probably V1016I) emerged under the DDT pressure prior to usage of pyrethroids. T1520I was selected under pressure of Type I pyrethroids.</p

Effects of mutations V1016I and F1534C on the channel sensitivity to permethrin (PMT) and deltamethrin (DMT).

(A) Representative tail currents induced by 1.0 μM PMT. (B) Representative tail currents induced by 1.0 μM DMT. (C) Dose-response curves of the channels modification by PMT. (D) Dose-response curves of the channels modification by DMT. The dose-response curve was fitting with Hill equation. Statistical significance was determined by using one-way ANOVA with Scheffé's post hoc analysis, and significant values were set at p < 0.05. The number of oocytes for each mutant construct was more than 6.</p

Voltage dependence of slow inactivation of AaNa_v1-1 and mutant sodium channels.

Voltage dependence of slow inactivation of AaNav1-1 and mutant sodium channels.</p

DataSheet_1_Qi-Li-Qiang-Xin Alleviates Isoproterenol-Induced Myocardial Injury by Inhibiting Excessive Autophagy via Activating AKT/mTOR Pathway.docx

Background: Apoptosis and autophagy are two important patterns of cell death in the process of heart failure. Qi-Li-Qiang-Xin (QLQX), a traditional Chinese medicine, has been frequently used in the treatment of chronic heart failure (CHF) in China. However, the potential effect of QLQX on autophagy has not been reported. In this study, we aimed to investigate whether QLQX alleviated isoproterenol (ISO)-induced myocardial injury through regulating autophagy.Methods: The rapid identification of chemical ingredients of QLQX was performed by UPLC-Q-TOF-MS, and the contents of major constituents in QLQX were also measured by UPLC-Q-TOF-MS. ISO was used to induce myocardial injury in H9c2 cardiomyocytes and SD rats. In vivo, cardiac function was evaluated by echocardiography and cardiac structure was observed by HE and Masson staining. Expressions of Bcl-2, Bax, LC3, P62, AKT, p-AKT, mTOR, and p-mTOR were detected by western blotting. In vitro, H9c2 cells were pretreated with QLQX for 3 h before ISO (80 µM, 48h) addressed. Cell viability, LDH and CK-MB release, apoptosis ratio, and the level of autophagy were measured. Western blotting was also performed to detected related protein expressions.Result:In vivo, treatment by QLQX significantly improved cardiac function and alleviated ISO-induced myocardial structural damage. In addition, QLQX markedly decreased apoptosis and inhibited autophagic activity, accompanied by activating the AKT/mTOR pathway. In vitro, the increased cell apoptosis induced by ISO was paralleling with the gradually increasing level of autophagy. Furthermore, 3-MA, an autophagic inhibitor, could block ISO-induced autophagy in H9c2 cells. Our results suggested that both QLQX and 3-MA treatment could decrease cell death induced by ISO, implying that QLQX protected against ISO-induced myocardial injury possibly by inhibiting excessive autophagy-mediated cell death. In addition, blockage of AKT signaling by an AKT inhibitor, capivasertib, could reduce the effect of QLQX on inhibiting ISO-induced apoptosis and autophagy-mediated cell death.Conclusion: QLQX could alleviate ISO-induced myocardial injury by inhibiting apoptosis and excessive autophagy-mediated cell death via activating the AKT/mTOR pathway.</p

Voltage dependence of activation and fast inactivation of AaNa_v1-1 and mutant sodium channels.

Voltage dependence of activation and fast inactivation of AaNav1-1 and mutant sodium channels.</p

Effects of mutations T1520I and F1534C on the channel sensitivity to pyrethroids.

(A) Channel modification by 1.0 μM PMT. (B) Channel modification by 1.0 μM DMT. (C) Channel modification by 1.0 μM cypermethrin, cyfluthrin, NRDC 157 and bifenthrin. The number of oocytes for each mutant was > 6. The asterisks indicate significant differences from the AaNav1-1 channel as determined by using the one way ANOVA with Scheffé's post hoc analysis (p post hoc analysis (p < 0.05).</p

Molecular evidence of sequential evolution of DDT- and pyrethroid-resistant sodium channel in <i>Aedes aegypti</i> - Fig 6

(A) Sequence alignment of sodium channel segments involved in the proposed mechanism by which mutation T1520/3i(-1)I allosterically induces small changes in the PyR1 site geometry. Highlighted are residues (except position 2i18), which are shown in panels B and C. Residue numbers in NavPaS and EeNav1.4 are sequential numbers in the PDB files of the cryo-EM structures where some segments are lacking. (B) and (C), Cryo-EM structures of eukaryotic sodium channels NavPaS (B) and EeNav1.4 (C). The pore-module helices in repeats I, II, III, and IV are magenta, yellow, green and gray, respectively. Side chains in positions 2i18 and 3i13, which correspond to AaNav1-1 residues 1016 and 1534, are space-filled. In both channels, these residues are in the II/III repeat interface that harbors the pyrethroid receptor site PyR1. Threonine T3(i-1) in the extracellular loop of NavPaS, which correspond to T1520/3(i-1) in AaNav1-1, is close to the N-terminus of IIIS6 and in AaNav1-1 it cannot directly interact with PyR1-bound pyrethroids.</p