BACKGROUND The expression of amino acid transporters is known to vary during acute pancreatitis(AP)except for LAT1(slc7a5),the expression of which remains stable.LAT1 supports cell growth by importing leucine and ther...BACKGROUND The expression of amino acid transporters is known to vary during acute pancreatitis(AP)except for LAT1(slc7a5),the expression of which remains stable.LAT1 supports cell growth by importing leucine and thereby stimulates mammalian target of rapamycin(mTOR)activity,a phenomenon often observed in cancer cells.The mechanisms by which LAT1 influences physiological and pathophysiological processes and affects disease progression in the pancreas are not yet known.AIM To evaluate the role of LAT1 in the development of and recovery from AP.METHODS AP was induced with caerulein(cae)injections in female and male mice expressing LAT1 or after its knockout(LAT1 Cre/LoxP).The development of the initial AP injury and its recovery were followed for seven days after cae injections by daily measuring body weight,assessing microscopical tissue architecture,mRNA and protein expression,protein synthesis,and enzyme activity levels,as well as by testing the recruitment of immune cells by FACS and ELISA.RESULTS The initial injury,evaluated by measurements of plasma amylase,lipase,and trypsin activity,as well as the gene expression of dedifferentiation markers,did not differ between the groups.However,early metabolic adaptations that support regeneration at later stages were blunted in LAT1 knockout mice.Especially in females,we observed less mTOR reactivation and dysfunctional autophagy.The later regeneration phase was clearly delayed in female LAT1 knockout mice,which did not regain normal expression of the pancreas-specific differentiation markers recombining binding protein suppressor of hairless-like protein(rbpjl)and basic helixloop-helix family member A15(mist1).Amylase mRNA and protein levels remained lower,and,strikingly,female LAT1 knockout mice presented signs of fibrosis lasting until day seven.In contrast,pancreas morphology had returned to normal in wild-type littermates.CONCLUSION LAT1 supports the regeneration of acinar cells after AP.Female mice lacking LAT1 exhibited more pronounced alterations than male mice,indicating a sexual dimorphism of amino acid metabolism.展开更多
Glioma is the most common primary craniocerebral tumor caused by the cancerous growth of glial cells in the brain and spinal cord.Currently,standard treatment is the surgical resection followed by concurrent radiation...Glioma is the most common primary craniocerebral tumor caused by the cancerous growth of glial cells in the brain and spinal cord.Currently,standard treatment is the surgical resection followed by concurrent radiation and chemotherapy.However,the blood-brain barrier(BBB)prevents most antitumor drugs from entering the brain and reduces their efficacy,especially in lowgrade glioma.Since L-type amino acid transporter 1(LAT1)is highly expressed in glioma cells and mediates drug transport across the BBB,it is a promising target for drug delivery and treatment of glioma.Temozolomide(TMZ)is the first-line treatment for glioma,however,patients often exhibit drug resistance at advanced stage.A multikinase inhibitor and inducer of ferroptosis,sorafenib can improve the therapeutic effects of TMZ.Therefore,to optimize the glioma treatment and cross the BBB,we designed LAT1-targeting nanoparticles co-loaded with TMZ and sorafenib.Our results from both in vitro and in vivo studies confirmed that LAT1-targeting nanoparticles significantly increased the cellular uptake,cytotoxicity,accumulation at tumor site,and the anti-tumor efficacy compared to the non-target nanoparticles.Therefore,LAT1 can be used as a potential target for braintargeted drug delivery,and sorafenib-induced ferroptosis can aid the anti-glioma efficacy of TMZ.展开更多
基金Swiss National Science Foundation,Grant No.31_166430/1(to Verrey F)。
文摘BACKGROUND The expression of amino acid transporters is known to vary during acute pancreatitis(AP)except for LAT1(slc7a5),the expression of which remains stable.LAT1 supports cell growth by importing leucine and thereby stimulates mammalian target of rapamycin(mTOR)activity,a phenomenon often observed in cancer cells.The mechanisms by which LAT1 influences physiological and pathophysiological processes and affects disease progression in the pancreas are not yet known.AIM To evaluate the role of LAT1 in the development of and recovery from AP.METHODS AP was induced with caerulein(cae)injections in female and male mice expressing LAT1 or after its knockout(LAT1 Cre/LoxP).The development of the initial AP injury and its recovery were followed for seven days after cae injections by daily measuring body weight,assessing microscopical tissue architecture,mRNA and protein expression,protein synthesis,and enzyme activity levels,as well as by testing the recruitment of immune cells by FACS and ELISA.RESULTS The initial injury,evaluated by measurements of plasma amylase,lipase,and trypsin activity,as well as the gene expression of dedifferentiation markers,did not differ between the groups.However,early metabolic adaptations that support regeneration at later stages were blunted in LAT1 knockout mice.Especially in females,we observed less mTOR reactivation and dysfunctional autophagy.The later regeneration phase was clearly delayed in female LAT1 knockout mice,which did not regain normal expression of the pancreas-specific differentiation markers recombining binding protein suppressor of hairless-like protein(rbpjl)and basic helixloop-helix family member A15(mist1).Amylase mRNA and protein levels remained lower,and,strikingly,female LAT1 knockout mice presented signs of fibrosis lasting until day seven.In contrast,pancreas morphology had returned to normal in wild-type littermates.CONCLUSION LAT1 supports the regeneration of acinar cells after AP.Female mice lacking LAT1 exhibited more pronounced alterations than male mice,indicating a sexual dimorphism of amino acid metabolism.
基金This work was supported by the National High Technology Research and Development Program of China(No.2019YFC0121000)the National Natural Science Foundation of China(Nos.32201127 and 82270113)Medical Scientific Research Foundation of Guangdong Province,China(No.A2021298).
文摘Glioma is the most common primary craniocerebral tumor caused by the cancerous growth of glial cells in the brain and spinal cord.Currently,standard treatment is the surgical resection followed by concurrent radiation and chemotherapy.However,the blood-brain barrier(BBB)prevents most antitumor drugs from entering the brain and reduces their efficacy,especially in lowgrade glioma.Since L-type amino acid transporter 1(LAT1)is highly expressed in glioma cells and mediates drug transport across the BBB,it is a promising target for drug delivery and treatment of glioma.Temozolomide(TMZ)is the first-line treatment for glioma,however,patients often exhibit drug resistance at advanced stage.A multikinase inhibitor and inducer of ferroptosis,sorafenib can improve the therapeutic effects of TMZ.Therefore,to optimize the glioma treatment and cross the BBB,we designed LAT1-targeting nanoparticles co-loaded with TMZ and sorafenib.Our results from both in vitro and in vivo studies confirmed that LAT1-targeting nanoparticles significantly increased the cellular uptake,cytotoxicity,accumulation at tumor site,and the anti-tumor efficacy compared to the non-target nanoparticles.Therefore,LAT1 can be used as a potential target for braintargeted drug delivery,and sorafenib-induced ferroptosis can aid the anti-glioma efficacy of TMZ.
