Azalomycin F<sub>5a</sub>, a 36-membered macrocyclic lactone isolated from several streptomyces strains, presented remarkable anti-methicillin-resistant Staphylococcus aureus (MRSA) activities. To improve ...Azalomycin F<sub>5a</sub>, a 36-membered macrocyclic lactone isolated from several streptomyces strains, presented remarkable anti-methicillin-resistant Staphylococcus aureus (MRSA) activities. To improve its anti-MRSA potential and to evaluate the probability of MRSA resistant to it before development, the anti-MRSA activities of azalomycin F<sub>5a</sub> in combination with vitamin K<sub>3</sub> were first evaluated using checkerboard assay. Then the minimal concentration inhibiting colony formation by 99% (MIC<sub>99</sub>) and mutant prevention concentration (MPC) of azalomycin F<sub>5a</sub> alone and in combination with vitamin K<sub>3</sub> against MRSA were determined using agar plates with linear antimicrobial concentration decrease. The fractional inhibitory concentration indexes (FICIs) of 0.25 - 0.50 showed the synergistic activity of azalomycin F<sub>5a</sub> in combination with vitamin K<sub>3</sub>. The mutant selection windows (MSWs, MIC<sub>99</sub>-MPC) of azalomycin F<sub>5a</sub> alone against MRSA tested were 2.07 - 6.40 μg/mL, and the MPCs of azalomycin F<sub>5a</sub> in combination with vitamin K<sub>3</sub> against MRSA tested were 1.60 - 3.20 μg/mL. These indicated that the MPCs of azalomycin F<sub>5a</sub> in combination could drop down to below its MIC<sub>99</sub> alone. According to the hypothesis of MSW, the narrower MSWs of azalomycin F<sub>5a </sub>alone, even closed MSWs in combination with vitamin K<sub>3</sub>, together with their synergistic anti-MRSA activities, indicated that azalomycin F<sub>5a </sub>had a good potential to develop as a new antimicrobial agent.展开更多
The expression of cytosolic phospholipase A2 (cPLA2) expression is up-regulated in animal model of ALS and in patients with familial amyotrophic lateral sclerosis (fALS). Inhibition of cyclooxygenase 2 (COX2), which i...The expression of cytosolic phospholipase A2 (cPLA2) expression is up-regulated in animal model of ALS and in patients with familial amyotrophic lateral sclerosis (fALS). Inhibition of cyclooxygenase 2 (COX2), which is a downstream enzyme of cPLA2, ameliorates the impairment of motor function in the ALS model mice. Therefore, the arachidonic acid cascade, including the cPLA2-COX2 pathway, is an important therapeutic target of ALS. The current study was designed to investigate the potential of AK106-001616, an inhibitor of cPLA2, in protection of motor neuron cell death induced by mutant superoxide dismutase (SOD1<sup>G93A</sup>). AK106-001616 (1 - 10 μM) protected NSC34 cells (mouse motor neuron like cells) against SOD1<sup>G93A</sup>-induced motor neuron cell death. Furthermore, aspirin, an inhibitor of COX1/2, reduced the SOD1<sup>G93A</sup>-induced motor neuron cell death at a concentration that inhibited COX2. Celecoxib, a selective COX2 inhibitor, also reduced the SOD1<sup>G93A</sup>-induced motor neuron cell death. These results suggest that the arachidonic acid cascade is important for SOD1<sup>G93A</sup>-induced motor neuron cell death and AK106-001616 has a potent neuroprotective effect against it. AK106-001616 may be a useful therapeutic agent against SOD1<sup>G93A</sup>-induced ALS.展开更多
文摘Azalomycin F<sub>5a</sub>, a 36-membered macrocyclic lactone isolated from several streptomyces strains, presented remarkable anti-methicillin-resistant Staphylococcus aureus (MRSA) activities. To improve its anti-MRSA potential and to evaluate the probability of MRSA resistant to it before development, the anti-MRSA activities of azalomycin F<sub>5a</sub> in combination with vitamin K<sub>3</sub> were first evaluated using checkerboard assay. Then the minimal concentration inhibiting colony formation by 99% (MIC<sub>99</sub>) and mutant prevention concentration (MPC) of azalomycin F<sub>5a</sub> alone and in combination with vitamin K<sub>3</sub> against MRSA were determined using agar plates with linear antimicrobial concentration decrease. The fractional inhibitory concentration indexes (FICIs) of 0.25 - 0.50 showed the synergistic activity of azalomycin F<sub>5a</sub> in combination with vitamin K<sub>3</sub>. The mutant selection windows (MSWs, MIC<sub>99</sub>-MPC) of azalomycin F<sub>5a</sub> alone against MRSA tested were 2.07 - 6.40 μg/mL, and the MPCs of azalomycin F<sub>5a</sub> in combination with vitamin K<sub>3</sub> against MRSA tested were 1.60 - 3.20 μg/mL. These indicated that the MPCs of azalomycin F<sub>5a</sub> in combination could drop down to below its MIC<sub>99</sub> alone. According to the hypothesis of MSW, the narrower MSWs of azalomycin F<sub>5a </sub>alone, even closed MSWs in combination with vitamin K<sub>3</sub>, together with their synergistic anti-MRSA activities, indicated that azalomycin F<sub>5a </sub>had a good potential to develop as a new antimicrobial agent.
文摘The expression of cytosolic phospholipase A2 (cPLA2) expression is up-regulated in animal model of ALS and in patients with familial amyotrophic lateral sclerosis (fALS). Inhibition of cyclooxygenase 2 (COX2), which is a downstream enzyme of cPLA2, ameliorates the impairment of motor function in the ALS model mice. Therefore, the arachidonic acid cascade, including the cPLA2-COX2 pathway, is an important therapeutic target of ALS. The current study was designed to investigate the potential of AK106-001616, an inhibitor of cPLA2, in protection of motor neuron cell death induced by mutant superoxide dismutase (SOD1<sup>G93A</sup>). AK106-001616 (1 - 10 μM) protected NSC34 cells (mouse motor neuron like cells) against SOD1<sup>G93A</sup>-induced motor neuron cell death. Furthermore, aspirin, an inhibitor of COX1/2, reduced the SOD1<sup>G93A</sup>-induced motor neuron cell death at a concentration that inhibited COX2. Celecoxib, a selective COX2 inhibitor, also reduced the SOD1<sup>G93A</sup>-induced motor neuron cell death. These results suggest that the arachidonic acid cascade is important for SOD1<sup>G93A</sup>-induced motor neuron cell death and AK106-001616 has a potent neuroprotective effect against it. AK106-001616 may be a useful therapeutic agent against SOD1<sup>G93A</sup>-induced ALS.
