Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to faci...Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.展开更多
Syrosingopine is an anti-hypertensive drug and can cause high intracellular lactate levels and end-product inhibition of lactate dehydrogenase by inhibiting the lactate transporters MCT1 and MCT4.Previous studies have...Syrosingopine is an anti-hypertensive drug and can cause high intracellular lactate levels and end-product inhibition of lactate dehydrogenase by inhibiting the lactate transporters MCT1 and MCT4.Previous studies have shown that syrosingopine plays an essential role in the process of glycolytic blockade,ATP depletion,and cell death in cancer due to high intracellular levels of lactate.展开更多
Background:Chronic endometritis(CE)is an important pathological factor contributing to female infertility and recurrent pregnancy loss.Although antibiotics are the primary clinical treatment for CE,they do not effecti...Background:Chronic endometritis(CE)is an important pathological factor contributing to female infertility and recurrent pregnancy loss.Although antibiotics are the primary clinical treatment for CE,they do not effectively improve pregnancy outcomes.Wen Yang Hua Zhuo(WYHZ)is a clinically employed classical formula known for its effects in warming yang,tonifying the spleen and kidneys,and resolving dampness.However,its underlying mechanisms remain unclear.This study aimed to elucidate how WYHZ modulates the immunometabolic microenvironment at the maternal-fetal interface in CE by targeting the MCT/HIF-1α/LDHA pathway to promote embryo implantation.Methods:In vivo,the model of CE was established by intrauterine injection of lipopolysaccharide(LPS)(1 mg/mL)into female C57/BL mice,followed by WYHZ treatment for 3 weeks to evaluate its effects on embryo implantation.Mechanistic studies were further conducted using the MCT-1 inhibitor AZD3965 and adeno-associated virus-mediated HIF-1αknockdown.In vitro,an in vitro CE model consisting of M1 macrophages and Ishikawa,as well as an in vitro embryo implantation model mediated by JAR cells,were constructed using Transwell,and the therapeutic mechanisms of WYHZ was validated using AZD3965 and lentiviral sh HIF-1αintervention.Metabolic enzyme activity assays,protein antibody microarrays,immunofluorescence,Western blotting,Seahorse analysis,and ELISA were employed.Results:WYHZ improved the immune-inflammatory microenvironment at the maternal-fetal interface by reducing pro-inflammatory cytokines and increasing anti-inflammatory factors.In parallel,WYHZ reprogrammed endometrial metabolism by enhancing glycolysis and suppressing mitochondrial oxidative phosphorylation,thereby improving endometrial receptivity and embryo implantation.Mechanistically,WYHZ activated the MCT/HIF-1α/LDHA pathway in endometrial epithelial cells,alleviating inflammatory stress and restoring receptivity.Both AZD3965 intervention and HIF-1αknockdown impaired endometrial receptivity and implantation,effects that were reversed by WYHZ.Conclusion:WYHZ modulates the immunometabolic microenvironment of the endometrium in the context of CE by targeting the activation of the MCT/HIF-1α/LDHA pathway,which improves endometrial receptivity and promotes embryo implantation.展开更多
基金This work was financially supported by the Natural Science Foundation of Guangxi Province(Nos.2018JJB140325,2018JJB140377)Guangxi Scientific and Technology Base and Talents of Project(Nos.2018AD19035)+2 种基金Talents Project for Cultivating High-level Talent Teams in the Qi Huang Project of Guangxi University of Chinese Medicine(2018002)the specific subject of the dominant discipline construction of Chinese Pharmacy of Guangxi University of Chinese Medicine,Guang Xi Key Laboratory of Translational Medicine for Treating High-incidence Infectious Diseases with Integrative Medicine and School research projects(no.B170021,2018MS003)Scientific Research Projects of Guangxi University of Chinese Medicine(B170021,2018MS003).
文摘Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.
基金supported in part by research grants from the National Natural Science Foundation of China(No.82102696 to JMF)and the National Institutes of Health(USA)(No.CA226303 to T.-C.He)supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund.
文摘Syrosingopine is an anti-hypertensive drug and can cause high intracellular lactate levels and end-product inhibition of lactate dehydrogenase by inhibiting the lactate transporters MCT1 and MCT4.Previous studies have shown that syrosingopine plays an essential role in the process of glycolytic blockade,ATP depletion,and cell death in cancer due to high intracellular levels of lactate.
基金supported by the National Natural Science Foundation of China(grant number:82205172,82274570).
文摘Background:Chronic endometritis(CE)is an important pathological factor contributing to female infertility and recurrent pregnancy loss.Although antibiotics are the primary clinical treatment for CE,they do not effectively improve pregnancy outcomes.Wen Yang Hua Zhuo(WYHZ)is a clinically employed classical formula known for its effects in warming yang,tonifying the spleen and kidneys,and resolving dampness.However,its underlying mechanisms remain unclear.This study aimed to elucidate how WYHZ modulates the immunometabolic microenvironment at the maternal-fetal interface in CE by targeting the MCT/HIF-1α/LDHA pathway to promote embryo implantation.Methods:In vivo,the model of CE was established by intrauterine injection of lipopolysaccharide(LPS)(1 mg/mL)into female C57/BL mice,followed by WYHZ treatment for 3 weeks to evaluate its effects on embryo implantation.Mechanistic studies were further conducted using the MCT-1 inhibitor AZD3965 and adeno-associated virus-mediated HIF-1αknockdown.In vitro,an in vitro CE model consisting of M1 macrophages and Ishikawa,as well as an in vitro embryo implantation model mediated by JAR cells,were constructed using Transwell,and the therapeutic mechanisms of WYHZ was validated using AZD3965 and lentiviral sh HIF-1αintervention.Metabolic enzyme activity assays,protein antibody microarrays,immunofluorescence,Western blotting,Seahorse analysis,and ELISA were employed.Results:WYHZ improved the immune-inflammatory microenvironment at the maternal-fetal interface by reducing pro-inflammatory cytokines and increasing anti-inflammatory factors.In parallel,WYHZ reprogrammed endometrial metabolism by enhancing glycolysis and suppressing mitochondrial oxidative phosphorylation,thereby improving endometrial receptivity and embryo implantation.Mechanistically,WYHZ activated the MCT/HIF-1α/LDHA pathway in endometrial epithelial cells,alleviating inflammatory stress and restoring receptivity.Both AZD3965 intervention and HIF-1αknockdown impaired endometrial receptivity and implantation,effects that were reversed by WYHZ.Conclusion:WYHZ modulates the immunometabolic microenvironment of the endometrium in the context of CE by targeting the activation of the MCT/HIF-1α/LDHA pathway,which improves endometrial receptivity and promotes embryo implantation.
