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
The gut microbiota plays a pivotal role in systemic metabolic processes and in particular functions,such as developing and preserving the skeletal muscle system.However,the interplay between gut microbiota/metabolites...The gut microbiota plays a pivotal role in systemic metabolic processes and in particular functions,such as developing and preserving the skeletal muscle system.However,the interplay between gut microbiota/metabolites and the regulation of satellite cell(SC)homeostasis,particularly during aging,remains elusive.We propose that gut microbiota and its metabolites modulate SC physiology and homeostasis throughout skeletal muscle development,regeneration,and aging process.Our investigation reveals that microbial dysbiosis manipulated by either antibiotic treatment or fecal microbiota transplantation from aged to adult mice,leads to the activation of SCs or a significant reduction in the total number.Furthermore,employing multi-omics(e.g.,RNA-seq,16S r RNA gene sequencing,and metabolomics)and bioinformatic analysis,we demonstrate that the reduced butyrate levels,alongside the gut microbial dysbiosis,could be the primary factor contributing to the reduction in the number of SCs and subsequent impairments during skeletal muscle aging.Meanwhile,butyrate supplementation can mitigate the antibiotics-induced SC activation irrespective of gut microbiota,potentially by inhibiting the proliferation and differentiation of SCs/myoblasts.The butyrate effect is likely facilitated through the monocarboxylate transporter 1(Mct1),a lactate transporter enriched on membranes of SCs and myoblasts.As a result,butyrate could serve as an alternative strategy to enhance SC homeostasis and function during skeletal muscle aging.Our findings shed light on the potential application of microbial metabolites in maintaining SC homeostasis and preventing skeletal muscle aging.展开更多
Background:Hypoxic microenvironment is immunosuppressive and protu-morigenic,and elevated lactate is an intermediary in the modulation of immune responses.However,as critical lactate transporters,the role of SLC16A1 a...Background:Hypoxic microenvironment is immunosuppressive and protu-morigenic,and elevated lactate is an intermediary in the modulation of immune responses.However,as critical lactate transporters,the role of SLC16A1 and SLC16A3 in immune infiltration and evasion of glioma is not fully elucidated.Methods:Gene expression in low‐and high‐grade glioma(LGG and GBM)was evaluated with TCGA database.The TISIDB,TIMER and CIBERSORT databases were utilized for the analysis of the correlation between SLC16A1 or SLC16A3 and immunocyte infiltration as well as immune checkpoints.Results:Compared with normal tissues,a significant increase of both SLC16A1 and SLC16A3 was found in LGG and GBM,and closely related to the poor prognosis only in LGG.Cancer SEA indicated that SLC16A1 was involved in hypoxia while SLC16A3 contributed to metastasis and inflamma-tion in glioma.The SLC16A3 expression was significantly correlated with neutrophil activation by GO analysis.TISCH showed the distribution of SLC16A1 on glioma cells and SLC16A3 on immune cells,which was correlated to tumor‐associated macrophages and neutrophils that are immunosuppressive.SLC16A1 and SLC16A3 were identified to tightly interacted with diverse immune checkpoints(especially PD1,PD‐L1,PD‐L2,Tim‐3)and immunosuppressive factors(TGF‐βand IL‐10)in glioma.Furthermore,SLC16A3 had a positive correlation to activation markers of tumor‐associated neutrophils and chemokines such as CCL2,CCL22,CXCR2,CXCR4 in LGG and CCL7,CCL20 CXCL8 in GBM,which could enhance infiltration of immunosuppressive cells to the tumor microenvironment.Conclusion:In general,our results suggest that SLC16A1 and SLC16A3 act as a bridge between tumor metabolism and immunity by promoting immuno-suppressive cell infiltration,which contributes to immune evasion and a worse prognosis in glioma.Targeting SLC16A1 and SLC16A3 may provide novel therapeutic strategy for immunotherapy in glioma.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 by the Guangdong Basic and Applied Basic Research Foundation(2020B1515020046)“GDAS”Project of Science and Technology Development(2021GDASYL20210102003,2018GDASCX-0102)+4 种基金the National Natural Science Foundation of China(82072436,32130099)Open Program of Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics(GPKLMMD-OP202102)Outstanding Youth Fund of Hunan Natural Science Foundation(2021JJ20045)the Outstanding Youth Fund of Hunan Natural Science Foundation(2021JJ20045)Youth Innovation Promotion Association of Chinese Academy of Sciences(2022370)。
文摘The gut microbiota plays a pivotal role in systemic metabolic processes and in particular functions,such as developing and preserving the skeletal muscle system.However,the interplay between gut microbiota/metabolites and the regulation of satellite cell(SC)homeostasis,particularly during aging,remains elusive.We propose that gut microbiota and its metabolites modulate SC physiology and homeostasis throughout skeletal muscle development,regeneration,and aging process.Our investigation reveals that microbial dysbiosis manipulated by either antibiotic treatment or fecal microbiota transplantation from aged to adult mice,leads to the activation of SCs or a significant reduction in the total number.Furthermore,employing multi-omics(e.g.,RNA-seq,16S r RNA gene sequencing,and metabolomics)and bioinformatic analysis,we demonstrate that the reduced butyrate levels,alongside the gut microbial dysbiosis,could be the primary factor contributing to the reduction in the number of SCs and subsequent impairments during skeletal muscle aging.Meanwhile,butyrate supplementation can mitigate the antibiotics-induced SC activation irrespective of gut microbiota,potentially by inhibiting the proliferation and differentiation of SCs/myoblasts.The butyrate effect is likely facilitated through the monocarboxylate transporter 1(Mct1),a lactate transporter enriched on membranes of SCs and myoblasts.As a result,butyrate could serve as an alternative strategy to enhance SC homeostasis and function during skeletal muscle aging.Our findings shed light on the potential application of microbial metabolites in maintaining SC homeostasis and preventing skeletal muscle aging.
基金Ningbo Health Branding Subject Fund,Grant/Award Number:PPXK2018‐04Zhejiang Medical and Health Science&Technology Project,Grant/Award Number:2020KY826National Natural Science Foundation of China,Grant/Award Number:81903144。
文摘Background:Hypoxic microenvironment is immunosuppressive and protu-morigenic,and elevated lactate is an intermediary in the modulation of immune responses.However,as critical lactate transporters,the role of SLC16A1 and SLC16A3 in immune infiltration and evasion of glioma is not fully elucidated.Methods:Gene expression in low‐and high‐grade glioma(LGG and GBM)was evaluated with TCGA database.The TISIDB,TIMER and CIBERSORT databases were utilized for the analysis of the correlation between SLC16A1 or SLC16A3 and immunocyte infiltration as well as immune checkpoints.Results:Compared with normal tissues,a significant increase of both SLC16A1 and SLC16A3 was found in LGG and GBM,and closely related to the poor prognosis only in LGG.Cancer SEA indicated that SLC16A1 was involved in hypoxia while SLC16A3 contributed to metastasis and inflamma-tion in glioma.The SLC16A3 expression was significantly correlated with neutrophil activation by GO analysis.TISCH showed the distribution of SLC16A1 on glioma cells and SLC16A3 on immune cells,which was correlated to tumor‐associated macrophages and neutrophils that are immunosuppressive.SLC16A1 and SLC16A3 were identified to tightly interacted with diverse immune checkpoints(especially PD1,PD‐L1,PD‐L2,Tim‐3)and immunosuppressive factors(TGF‐βand IL‐10)in glioma.Furthermore,SLC16A3 had a positive correlation to activation markers of tumor‐associated neutrophils and chemokines such as CCL2,CCL22,CXCR2,CXCR4 in LGG and CCL7,CCL20 CXCL8 in GBM,which could enhance infiltration of immunosuppressive cells to the tumor microenvironment.Conclusion:In general,our results suggest that SLC16A1 and SLC16A3 act as a bridge between tumor metabolism and immunity by promoting immuno-suppressive cell infiltration,which contributes to immune evasion and a worse prognosis in glioma.Targeting SLC16A1 and SLC16A3 may provide novel therapeutic strategy for immunotherapy in glioma.
