Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular se...Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily （TRPV1, TRPV3, and TRPV4）, and finally members of the melastatin group （TRPM2, TRPM3, and TRPMS）. Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory com- pounds targeting specific pain/itch-TRPs so that physio- logical protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1- modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accom- plished via simple dosing strategies, and also by incorpo- rating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.展开更多
Objective: The analgesic effect of Paeonia Lactiflora has been widely accepted in traditional Chinese medicine. But little is known about the potential mechanism. This study aims to elucidate the effective components ...Objective: The analgesic effect of Paeonia Lactiflora has been widely accepted in traditional Chinese medicine. But little is known about the potential mechanism. This study aims to elucidate the effective components and analgesic mechanism based on network pharmacology. Methods: TCMSP was screened to collect the possible active ingredients and their CAS and SMILES was searched in Pubchem and further be used for reverse molecular docking in Swiss Target Prediction database to obtain potential targets. Pain-related molecules were obtained from GeenCards database, and the predicted targets of Paeonia Lactiflora for pain treatment were selected by Wayne diagram. For mechanism analysis, the protein-protein interactions were constructed by String, the GO analysis and KEGG analysis were conducted in DAVID. Results: Through GO analysis and KEGG analysis, we found that the pain related signaling pathways mainly involved in serotonergic synapse, calcium signaling pathway, inflammatory mediator TRP channels. Using network-based systems biology and molecular docking analyses, we predicted that 11 active ingredients in Paeonia Lactiflora has the analgesic effects with 97 potential targets. PRKCA, CASP3, ALOX15, SLC6A4, PRKCG, ALOX5, PRKCB, ALOX12, EGFR, ADRB2, RYR3, RYR1, NOS2, PTAFR, PRKCQ, and PRKCD were involved in the analgesic effects of Paeonia Lactiflora. Conclusion: Paeonia Lactiflora may alleviate pain through inflammatory mediator regulation of TRP channels, Ca2+ signaling pathway and 5-HT receptor. PRKCA, PRKCB, PRKCD,PRKCQ, and PRKCG may be new targets for pain treatment.展开更多
To compare the efficacy and safety of two aminoglycoside antibiotics, etimicin and netilmicin, in the treatment of bacterial infections Methods A randomized, open label, controlled clinical trial was conducted for t...To compare the efficacy and safety of two aminoglycoside antibiotics, etimicin and netilmicin, in the treatment of bacterial infections Methods A randomized, open label, controlled clinical trial was conducted for the treatment of 65 patients hospitalized with respiratory tract infections, urinary tract infections, and skin and tissue infections Thirty four patients received etimicin and thirty one patients received netilmicin at a dose of 100?mg every 12 hours by intravenous infusion The duration of treatment was 7-10 days in both groups Results 47 patients were enrolled in the etimicin group; 35 patients were assessable for safety and 34 patients were assessable for efficacy, 46 patients were enrolled in the netilmicin group; 32 patients were assessable for safety and 31 patients were assessable for efficacy The results show that overall efficacy was 85 3% for the etimicin group and 83 9% for the netilmicin group, whereas bacterial clearance rates were 87 5% for the etimicin group and 89 7% for the netilmicin group The incidence of adverse reactions was 8 6% (3/35) and 9 4% (3/32), respectively Conclusion Etimicin and netilmicin were effective and safe for the treatment of respiratory tract infection, urinary tract infection, and skin and tissue infections The results show there was no statistically significant difference between the two groups ( P >0 05)展开更多
Tryptophan（Trp） residues in a pullulanase were modified by N-bromosuccinimide（NBS）. The results of the Spande method indicate that there are 18 Trp residues in the pullulanase and nine of them are located on the s...Tryptophan（Trp） residues in a pullulanase were modified by N-bromosuccinimide（NBS）. The results of the Spande method indicate that there are 18 Trp residues in the pullulanase and nine of them are located on the surface af the enzyme. Three of these Trp residues are nonessential residues which show the fastest reaction rate according to the Zou＇s plot. Two of the seven relative faster reacting residues are essential for the activity of the enzyme. The other eight are the slowest in the reaction rate or non-reactive residues for the reaction. The fluorescence and circular dichroism（CD） spectra of the pullulanase have been changed after the reaction with NBS. Potassium iodide（KI） and acrylamide also have remarkable influences on the fluorescence spectra of the pullulanase.展开更多
MYB34, MYB51, and MYB122 transcription factors are known as decisive regulators of indolic glucosinolate （IG） biosynthesis with a strong impact on expression of genes encoding CYP79B2 and CYP79B3 enzymes that redund...MYB34, MYB51, and MYB122 transcription factors are known as decisive regulators of indolic glucosinolate （IG） biosynthesis with a strong impact on expression of genes encoding CYP79B2 and CYP79B3 enzymes that redundantly convert tryptophan to indole-3-acetaldoxime （IAOx）. This intermediate represents a branching point for IG biosynthesis, and pathways leading to camalexin and indole-carboxylic acids （ICA）. Here we investigate how these MYBs affect the pathogen-triggered Trp metabolism. Our experiments indicated that these three MYBs affect not only IG production but also constitutive biosynthesis of other IAOx- derived metabolites. Strikingly, the PENETRATION 2 （PEN2）-dependent IG-metabolism products, which are absent in myb34/51/122 and pen2 mutants, were indispensable for full flg22-mediated induction of other IAOx-dedved compounds. However, germ induction and accumulation of ICAs and camalexin upon path- ogen infection was not compromised in myb34/51/122 plants, despite strongly reduced IG levels. Hence, in comparison with cyp79B2/B3, which lacks all IAOx-derived metabolites, we found myb34/51/122 an ideal tool to analyze IG contribution to resistance against the necrotrophic fungal pathogen Plectosphaerella cucumerina. The susceptibility of myb34/51/122 was similar to that of pen2, but much lower than susceptibility of cyp79B2/B3, indicating that MYB34/51/122 contribute to resistance toward P. cucumerina exclu- sively through IG biosynthesis, and that PEN2 is the main leaf myrosinase activating IGs in response to microbial pathogens.展开更多
基金supported by the National Institutes of Health,USA(DE018549,UL1TR001117,P30AR066527,and AR48182 to WL,AR48182-S1 to WL as co-investigatorF33DE024668 and K12DE022793 to YC)+1 种基金the US Department of Defense(W81XWH-13-1-0299 to WL)the Harrington Discovery Institute,Cleveland OH(to WL)
文摘Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily （TRPV1, TRPV3, and TRPV4）, and finally members of the melastatin group （TRPM2, TRPM3, and TRPMS）. Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory com- pounds targeting specific pain/itch-TRPs so that physio- logical protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1- modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accom- plished via simple dosing strategies, and also by incorpo- rating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.
基金the National Natural Science Foundation of China (Grant No. 81874404).
文摘Objective: The analgesic effect of Paeonia Lactiflora has been widely accepted in traditional Chinese medicine. But little is known about the potential mechanism. This study aims to elucidate the effective components and analgesic mechanism based on network pharmacology. Methods: TCMSP was screened to collect the possible active ingredients and their CAS and SMILES was searched in Pubchem and further be used for reverse molecular docking in Swiss Target Prediction database to obtain potential targets. Pain-related molecules were obtained from GeenCards database, and the predicted targets of Paeonia Lactiflora for pain treatment were selected by Wayne diagram. For mechanism analysis, the protein-protein interactions were constructed by String, the GO analysis and KEGG analysis were conducted in DAVID. Results: Through GO analysis and KEGG analysis, we found that the pain related signaling pathways mainly involved in serotonergic synapse, calcium signaling pathway, inflammatory mediator TRP channels. Using network-based systems biology and molecular docking analyses, we predicted that 11 active ingredients in Paeonia Lactiflora has the analgesic effects with 97 potential targets. PRKCA, CASP3, ALOX15, SLC6A4, PRKCG, ALOX5, PRKCB, ALOX12, EGFR, ADRB2, RYR3, RYR1, NOS2, PTAFR, PRKCQ, and PRKCD were involved in the analgesic effects of Paeonia Lactiflora. Conclusion: Paeonia Lactiflora may alleviate pain through inflammatory mediator regulation of TRP channels, Ca2+ signaling pathway and 5-HT receptor. PRKCA, PRKCB, PRKCD,PRKCQ, and PRKCG may be new targets for pain treatment.
文摘To compare the efficacy and safety of two aminoglycoside antibiotics, etimicin and netilmicin, in the treatment of bacterial infections Methods A randomized, open label, controlled clinical trial was conducted for the treatment of 65 patients hospitalized with respiratory tract infections, urinary tract infections, and skin and tissue infections Thirty four patients received etimicin and thirty one patients received netilmicin at a dose of 100?mg every 12 hours by intravenous infusion The duration of treatment was 7-10 days in both groups Results 47 patients were enrolled in the etimicin group; 35 patients were assessable for safety and 34 patients were assessable for efficacy, 46 patients were enrolled in the netilmicin group; 32 patients were assessable for safety and 31 patients were assessable for efficacy The results show that overall efficacy was 85 3% for the etimicin group and 83 9% for the netilmicin group, whereas bacterial clearance rates were 87 5% for the etimicin group and 89 7% for the netilmicin group The incidence of adverse reactions was 8 6% (3/35) and 9 4% (3/32), respectively Conclusion Etimicin and netilmicin were effective and safe for the treatment of respiratory tract infection, urinary tract infection, and skin and tissue infections The results show there was no statistically significant difference between the two groups ( P >0 05)
文摘Tryptophan（Trp） residues in a pullulanase were modified by N-bromosuccinimide（NBS）. The results of the Spande method indicate that there are 18 Trp residues in the pullulanase and nine of them are located on the surface af the enzyme. Three of these Trp residues are nonessential residues which show the fastest reaction rate according to the Zou＇s plot. Two of the seven relative faster reacting residues are essential for the activity of the enzyme. The other eight are the slowest in the reaction rate or non-reactive residues for the reaction. The fluorescence and circular dichroism（CD） spectra of the pullulanase have been changed after the reaction with NBS. Potassium iodide（KI） and acrylamide also have remarkable influences on the fluorescence spectra of the pullulanase.
文摘MYB34, MYB51, and MYB122 transcription factors are known as decisive regulators of indolic glucosinolate （IG） biosynthesis with a strong impact on expression of genes encoding CYP79B2 and CYP79B3 enzymes that redundantly convert tryptophan to indole-3-acetaldoxime （IAOx）. This intermediate represents a branching point for IG biosynthesis, and pathways leading to camalexin and indole-carboxylic acids （ICA）. Here we investigate how these MYBs affect the pathogen-triggered Trp metabolism. Our experiments indicated that these three MYBs affect not only IG production but also constitutive biosynthesis of other IAOx- derived metabolites. Strikingly, the PENETRATION 2 （PEN2）-dependent IG-metabolism products, which are absent in myb34/51/122 and pen2 mutants, were indispensable for full flg22-mediated induction of other IAOx-dedved compounds. However, germ induction and accumulation of ICAs and camalexin upon path- ogen infection was not compromised in myb34/51/122 plants, despite strongly reduced IG levels. Hence, in comparison with cyp79B2/B3, which lacks all IAOx-derived metabolites, we found myb34/51/122 an ideal tool to analyze IG contribution to resistance against the necrotrophic fungal pathogen Plectosphaerella cucumerina. The susceptibility of myb34/51/122 was similar to that of pen2, but much lower than susceptibility of cyp79B2/B3, indicating that MYB34/51/122 contribute to resistance toward P. cucumerina exclu- sively through IG biosynthesis, and that PEN2 is the main leaf myrosinase activating IGs in response to microbial pathogens.
