Monocarboxylate transporters（MCTs）, which carry monocarboxylates such as lactate across biological membranes, have been associated with cerebral ischemia/reperfusion process. In this study, we studied the effect of ...Monocarboxylate transporters（MCTs）, which carry monocarboxylates such as lactate across biological membranes, have been associated with cerebral ischemia/reperfusion process. In this study, we studied the effect of ischemic preconditioning（IPC） on MCT4 immunoreactivity after 5 minutes of transient cerebral ischemia in the gerbil. Animals were randomly designated to four groups（sham-operated group, ischemia only group, IPC ＋ sham-operated group and IPC ＋ ischemia group）. A serious loss of neuron was found in the stratum pyramidale of the hippocampal CA1 region（CA1）, not CA2/3, of the ischemia-only group at 5 days post-ischemia; however, in the IPC ＋ ischemia groups, neurons in the stratum pyramidale of the CA1 were well protected. Weak MCT4 immunoreactivity was found in the stratum pyramidale of the CA1 in the sham-operated group. MCT4 immunoreactivity in the stratum pyramidale began to decrease at 2 days post-ischemia and was hardly detected at 5 days post-ischemia; at this time point, MCT4 immunoreactivity was newly expressed in astrocytes. In the IPC ＋ sham-operated group, MCT4 immunoreactivity in the stratum pyramidale of the CA1 was increased compared with the sham-operated group, and, in the IPC ＋ ischemia group, MCT4 immunoreactivity was also increased in the stratum pyramidale compared with the ischemia only group. Briefly, present findings show that IPC apparently protected CA1 pyramidal neurons and increased or maintained MCT4 expression in the stratum pyramidale of the CA1 after transient cerebral ischemia. Our findings suggest that MCT4 appears to play a significant role in the neuroprotective mechanism of IPC in the gerbil with transient cerebral ischemia.展开更多
Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs...Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs.However,potential application of MCT1 to facilitate the oral delivery is still unclear.Irregular oral absorption,poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil(5-FU).Herein,we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages.Interestingly,due to high MCT1 affinity and good gastrointestinal stability,5-FUoctanedioic acid monoester prodrug exhibited significant improvement in membrane permeability(13.1-fold)and oral bioavailability(4.1-fold)compared to 5-FU.More surprisingly,stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells,which provides an ideal foundation for the improvement of oral bioavailability.In summary,good gastrointestinal stability,high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs,and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.展开更多
Monocarboxylic acid transporter 1(MCT1)maintains axonal function by transferring lactic acid from oligodendrocytes to axons.Subarachnoid hemorrhage(SAH)induces white matter injury,but the involvement of MCT1 is unclea...Monocarboxylic acid transporter 1(MCT1)maintains axonal function by transferring lactic acid from oligodendrocytes to axons.Subarachnoid hemorrhage(SAH)induces white matter injury,but the involvement of MCT1 is unclear.In this study,the SAH model of adult male Sprague-Dawley rats was used to explore the role of MCT1 in white matter injury after SAH.At 48 h after SAH,oligodendrocyte MCT1 was significantly reduced,and the exogenous overexpression of MCT1 significantly improved white matter integrity and long-term cognitive function.Motor training after SAH significantly increased the number of ITPR2+SOX10+oligodendrocytes and upregulated the level of MCT1,which was positively correlated with the behavioral ability of rats.In addition,miR-29b and miR-124 levels were significantly increased in SAH rats compared with non-SAH rats.Further intervention experiments showed that miR-29b and miR-124 could negatively regulate the level of MCT1.This study confirmed that the loss of MCT1 may be one of the mechanisms of white matter damage after SAH and may be caused by the negative regulation of miR-29b and miR-124.MCT1 may be involved in the neurological improvement of rehabilitation training after SAH.展开更多
基金supported by a Priority Research Centers Program grant(NRF-2009-0093812)through the National Research Foundation of Korea funded by the Ministry of Science,ICT and Future Planningby 2014 Research Grant from Kangwon National University
文摘Monocarboxylate transporters（MCTs）, which carry monocarboxylates such as lactate across biological membranes, have been associated with cerebral ischemia/reperfusion process. In this study, we studied the effect of ischemic preconditioning（IPC） on MCT4 immunoreactivity after 5 minutes of transient cerebral ischemia in the gerbil. Animals were randomly designated to four groups（sham-operated group, ischemia only group, IPC ＋ sham-operated group and IPC ＋ ischemia group）. A serious loss of neuron was found in the stratum pyramidale of the hippocampal CA1 region（CA1）, not CA2/3, of the ischemia-only group at 5 days post-ischemia; however, in the IPC ＋ ischemia groups, neurons in the stratum pyramidale of the CA1 were well protected. Weak MCT4 immunoreactivity was found in the stratum pyramidale of the CA1 in the sham-operated group. MCT4 immunoreactivity in the stratum pyramidale began to decrease at 2 days post-ischemia and was hardly detected at 5 days post-ischemia; at this time point, MCT4 immunoreactivity was newly expressed in astrocytes. In the IPC ＋ sham-operated group, MCT4 immunoreactivity in the stratum pyramidale of the CA1 was increased compared with the sham-operated group, and, in the IPC ＋ ischemia group, MCT4 immunoreactivity was also increased in the stratum pyramidale compared with the ischemia only group. Briefly, present findings show that IPC apparently protected CA1 pyramidal neurons and increased or maintained MCT4 expression in the stratum pyramidale of the CA1 after transient cerebral ischemia. Our findings suggest that MCT4 appears to play a significant role in the neuroprotective mechanism of IPC in the gerbil with transient cerebral ischemia.
基金financially Supported by National Nature Sci-ence Foundation of China(No.81773656,U1608283,81573497)Liaoning Revitalization Talents Program,No XLYC1808017,Key projects of Technology bureau in Shenyang,No18400408Key projects of Liaoning Province Department of Education,No.2017LZD03
文摘Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs.However,potential application of MCT1 to facilitate the oral delivery is still unclear.Irregular oral absorption,poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil(5-FU).Herein,we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages.Interestingly,due to high MCT1 affinity and good gastrointestinal stability,5-FUoctanedioic acid monoester prodrug exhibited significant improvement in membrane permeability(13.1-fold)and oral bioavailability(4.1-fold)compared to 5-FU.More surprisingly,stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells,which provides an ideal foundation for the improvement of oral bioavailability.In summary,good gastrointestinal stability,high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs,and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.
基金supported by National Key R&D Program of China(Nos.2018YFC1312600 and 2018YFC1312601)National Natural Science Foundation of China(Nos.81830036,81771254,81771255,81873741,and 82071307)+4 种基金China Postdoctoral Science Foundation(No.2019M651954)Natural Science Foundation of Jiangsu Province(Nos.BK20180204 and 20211552)Suzhou Key Medical Centre(No.Szzx201501)Gusu Health Personnel Training Project(No.GSWS2019030)Grants from Suzhou Government(No.SYS2019045).
文摘Monocarboxylic acid transporter 1(MCT1)maintains axonal function by transferring lactic acid from oligodendrocytes to axons.Subarachnoid hemorrhage(SAH)induces white matter injury,but the involvement of MCT1 is unclear.In this study,the SAH model of adult male Sprague-Dawley rats was used to explore the role of MCT1 in white matter injury after SAH.At 48 h after SAH,oligodendrocyte MCT1 was significantly reduced,and the exogenous overexpression of MCT1 significantly improved white matter integrity and long-term cognitive function.Motor training after SAH significantly increased the number of ITPR2+SOX10+oligodendrocytes and upregulated the level of MCT1,which was positively correlated with the behavioral ability of rats.In addition,miR-29b and miR-124 levels were significantly increased in SAH rats compared with non-SAH rats.Further intervention experiments showed that miR-29b and miR-124 could negatively regulate the level of MCT1.This study confirmed that the loss of MCT1 may be one of the mechanisms of white matter damage after SAH and may be caused by the negative regulation of miR-29b and miR-124.MCT1 may be involved in the neurological improvement of rehabilitation training after SAH.
