Environmental pollution is one of the major problems for human health. Toxic heavy metals are normally present as soil constituents or can also be spread out in the environment by human activity and agricultural techn...Environmental pollution is one of the major problems for human health. Toxic heavy metals are normally present as soil constituents or can also be spread out in the environment by human activity and agricultural techniques. Soil contamination by heavy metals as cadmium, highlights two main aspects： on one side they interfere with the life cycle of plants and therefore reduce crop yields, and on the other hand, once adsorbed and accumulated into the plant tissues, they enter the food chain poisoning animals and humans. Considering this point of view, understanding the mechanism by which plants handle heavy metal exposure, in particular cadmium stress, is a primary goal of plant-biotechnology research or plant breeders whose aim is to create plants that are able to recover high amounts of heavy metals, which can be used for phytoremediation, or identify crop varieties that do not accumulate toxic metal in grains or fruits. In this review we focus on the main symptoms of cadmium toxicity both on root apparatus and shoots. We elucidate the mechanisms that plants activate to prevent absorption or to detoxify toxic metal ions, such as synthesis of phytochelatins, metallothioneins and enzymes involved in stress response. Finally we consider new plant-biotechnology applications that can be applied for phytoremediation.展开更多
Nitrogen （N） is an essential macronutrient that affects plant growth and development. N is an important component of chlorophyll, amino acids, nucleic acids, and secondary metabolites. Nitrate is one of the most abu...Nitrogen （N） is an essential macronutrient that affects plant growth and development. N is an important component of chlorophyll, amino acids, nucleic acids, and secondary metabolites. Nitrate is one of the most abundant N sources in the soil. Because nitrate and other N nutrients are often limiting, plants have developed sophisticated mechanisms to ensure adequate supply of nutrients in a variable environment. Nitrate is absorbed in the root and mobilized to other organs by nitrate transporters. Nitrate sensing activates signaling pathways that impinge upon molecular, metabolic, physiological, and developmental responses locally and at the whole plant level. With the advent of genomics technologies and genetic tools, important advances in our understanding of nitrate and other N nutrient responses have been achieved in the past decade. Furthermore, techniques that take advantage of natural polymor- phisms present in divergent individuals from a single species have been essential in uncovering new components. However, there are still gaps in our understanding of how nitrate signaling affects biolog- ical processes in plants. Moreover, we still lack an integrated view of how all the regulatory factors iden- tified interact or crosstalk to orchestrate the myriad N responses plants typically exhibit. In this review, we provide an updated overview of mechanisms by which nitrate is sensed and transported throughout the plant. We discuss signaling components and how nitrate sensing crosstalks with hormonal pathways for developmental responses locally and globally in the plant. Understanding how nitrate impacts on plant metabolism, physiology, and growth and development in plants is key to improving crops for sustainable agriculture.展开更多
It is widely known that branched chain amino acids（BCAA） are not only elementary components for building muscle tissue but also participate in increasing protein synthesis in animals and humans. BCAA（isoleucine, le...It is widely known that branched chain amino acids（BCAA） are not only elementary components for building muscle tissue but also participate in increasing protein synthesis in animals and humans. BCAA（isoleucine, leucine and valine） regulate many key signaling pathways, the most classic of which is the activation of the m TOR signaling pathway. This signaling pathway connects many diverse physiological and metabolic roles. Recent years have witnessed many striking developments in determining the novel functions of BCAA including：（1） Insufficient or excessive levels of BCAA in the diet enhances lipolysis.（2） BCAA, especially isoleucine, play a major role in enhancing glucose consumption and utilization by up-regulating intestinal and muscular glucose transporters.（3）Supplementation of leucine in the diet enhances meat quality in finishing pigs.（4） BCAA are beneficial for mammary health, milk quality and embryo growth.（5） BCAA enhance intestinal development, intestinal amino acid transportation and mucin production.（6） BCAA participate in up-regulating innate and adaptive immune responses.In addition, abnormally elevated BCAA levels in the blood（decreased BCAA catabolism） are a good biomarker for the early detection of obesity, diabetes and other metabolic diseases. This review will provide some insights into these novel metabolic and physiological functions of BCAA.展开更多
Intrahepatic cholestasis of pregnancy （ICP） is the most common pregnancy-related liver disorder. Maternal effects of ICP are mild; however, there is a clear association between ICP and higher frequency of fetal dist...Intrahepatic cholestasis of pregnancy （ICP） is the most common pregnancy-related liver disorder. Maternal effects of ICP are mild; however, there is a clear association between ICP and higher frequency of fetal distress, preterm delivery, and sudden intrauterine fetal death. The cause of ICP remains elusive, but there is evidence that mutations in genes encoding hepatobiliary transport proteins can predispose for the development of ICP. Recent data suggest that ursodeoxycholic acid is currently the most effective pharmacologic treatment, whereas obstetric management is still debated. Clinical trials are required to identify the most suitable monitoring modalities that can specifically predict poor perinatal outcome. This article aims to review current achievements and unsolved problems of ICR展开更多
Vascular plants contain two gene families that encode monosaccharide transporter proteins. The classical monosaccharide transporter（-like） gene superfamily is large and functionally diverse, while the recently ident...Vascular plants contain two gene families that encode monosaccharide transporter proteins. The classical monosaccharide transporter（-like） gene superfamily is large and functionally diverse, while the recently identified SWEET transporter family is smaller and, thus far, only found to transport glucose. These transporters play essential roles at many levels, ranging from organelles to the whole plant. Many family members are essential for cellular homeostasis and reproductive success. Although most transporters do not directly participate in long-distance transport, their indirect roles greatly impact carbon allocation and transport flux to the heterotrophic tissues of the plant. Functional characterization of some members from both gene families has revealed their diverse roles in carbohydrate partitioning, phloem function, resource allocation, plant defense, and sugar signaling. This review highlights the broad impacts and implications of monosaccharide transport by describing some of the functional roles of the monosaccharide transporter（-like） superfamily and the SWEET transporter family.展开更多
Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATPbinding ...Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATPbinding cassette(ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.展开更多
Salinity is a global challenge to agricultural production. Understanding Na^+ sensing and transport in plants under salt stress will be of benefit for breeding robustly salt-tolerant crop species. In this review, firs...Salinity is a global challenge to agricultural production. Understanding Na^+ sensing and transport in plants under salt stress will be of benefit for breeding robustly salt-tolerant crop species. In this review, first, possible salt stress sensor candidates and the root meristem zone as a tissue harboring salt stress-sensing components are proposed. Then,the importance of Na^+ exclusion and vacuolar Na^+ sequestration in plant overall salt tolerance is highlighted. Other Na^+ regulation processes, including xylem Na^+ loading and unloading, phloem Na^+ recirculation, and Na^+ secretion, are discussed and summarized.Along with a summary of Na^+ transporters and channels, the molecular regulation of Na^+ transporters and channels in response to salt stress is discussed. Finally, some largely neglected issues in plant salt stress tolerance, including Na^+ concentration in cytosol and the role of Na^+ as a nutrient, are reviewed and discussed.展开更多
Background The persistence of sleep disordered breathing （SDB） symptoms after tonsil and/or adenoid （T＆A） surgery are common in children with obstructive sleep apnea （OSA）. We tested the hypothesis that disturb...Background The persistence of sleep disordered breathing （SDB） symptoms after tonsil and/or adenoid （T＆A） surgery are common in children with obstructive sleep apnea （OSA）. We tested the hypothesis that disturbances of glucose transporters （GLUTs） in intraabdominal adipose tissue caused by chronic intermittent hypoxia （CIH） from the pedo-period could facilitate the appearance of periphery insulin resistance in Sprague-Dawley （SD） rats. We tested the hypothesis that the changes of GLUTs in adipose tissue may be one of the reasons for persistent SDB among clinical OSA children after T＆A surgery. Methods Thirty 21-day-old SD rats were randomly divided into a CIH group, a chronic continuous hypoxia （CCH） group and a normal oxygen group （control group） and exposed for 40 days. The changes of weight, fasting blood glucose and fasting blood insulin levels were measured. Hyperinsulinemic-euglycemic clamp techniques were used to measure insulin resistance in each animal. Real-time quantitative PCR and Western blotting were used to measure GLUT mRNA and proteins in intraabdominal adipose tissue. Additional intraabdomial white adipose tissue （WAT） was also processed into paraffin sections and directly observed for GLUTs1-4 expression. Results When compared with control group, CIH increased blood fasting insulin levels, （245.07±53.89） pg/ml vs. （168.63±38.70） pg/ml, P=-0.038, and decreased the mean glucose infusion rate （GIR）, （7.25±1.29） mg·kg^-1·min^-1 vs. （13.34±1.54） mg·kg^-1·min^-1, P 〈0.001. GLUT-4 mRNA and protein expression was significantly reduced after CIH compared with CCH or normal oxygen rats, 0.002±0.002 vs. 0.039±0.009, P 〈0.001; 0.642±0.073 vs. 1.000±0.103, P=0.035. Conclusions CIH in young rats could induce insulin resistance via adverse effects on glycometabolism. These findings emphasize the importance of early detection and treatment of insulin insensitivity in obese childhood OSA.展开更多
The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeos...The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size,and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor(FXR)and the G-protein-coupled bile acid receptor(TGR5).展开更多
The kidney is a vital organ for the elimination of therapeutic drugs and their metabolites.Renal drug transporters,which are primarily located in the renal proximal tubules,play an important role in tubular secretion ...The kidney is a vital organ for the elimination of therapeutic drugs and their metabolites.Renal drug transporters,which are primarily located in the renal proximal tubules,play an important role in tubular secretion and reabsorption of drug molecules in the kidney.Tubular secretion is characterized by high clearance capacities,broad substrate specificities,and distinct charge selectivity for organic cations and anions.In the past two decades,substantial progress has been made in understanding the roles of transporters in drug disposition,efficacy,toxicity and drug–drug interactions(DDIs).In the kidney,several transporters are involved in renal handling of organic cation(OC) and organic anion(OA) drugs.These transporters are increasingly recognized as the target for clinically significant DDIs.This review focuses on the functional characteristics of major human renal drug transporters and their involvement in clinically significant DDIs.展开更多
K＋ uptake in the high-affinity range of concentrations and its components have been widely studied. In Arabidposis thaliana, the AtHAK5 transporter and the AtAKT1 channel have been shown to be the main transport prot...K＋ uptake in the high-affinity range of concentrations and its components have been widely studied. In Arabidposis thaliana, the AtHAK5 transporter and the AtAKT1 channel have been shown to be the main transport proteins involved in this process. Here, we study the role of these two systems under two important stress conditions： low K＋ supply or the presence of salinity. T-DNA insertion lines disrupting AtHAK5 and A tAKT1 are employed for long-term experi- ments that allow physiological characterization of the mutant lines. We found that AtHAK5 is required for K＋ absorption necessary to sustain plant growth at low K＋ in the absence as well as in the presence of salinity. Salinity greatly reduced AtHAK5 transcript levels and promoted AtAKTl-mediated K＋ efflux, resulting in an important impairment of K＋ nutrition. Although having a limited capacity, AtHAK5 plays a major role for K＋ acquisition from low K＋ concentrations in the presence of salinity.展开更多
Terrestrial plants have two to four times more ATP-binding cassette （ABC） transporter genes than other organisms, including their ancestral microalgae. Recent studies found that plants harboring mutations in these t...Terrestrial plants have two to four times more ATP-binding cassette （ABC） transporter genes than other organisms, including their ancestral microalgae. Recent studies found that plants harboring mutations in these transporters exhibit dramatic phenotypes, many of which are related to developmental processes and functions necessary for life on dry land. These results suggest that ABC transporters multiplied during evolution and assumed novel functions that allowed plants to adapt to terrestrial environmental conditions. Examining the literature on plant ABC transporters from this viewpoint led us to propose that diverse ABC transporters enabled many unique and essential aspects of a terrestrial plant＇s lifestyle, by transporting various compounds across specific membranes of the plant.展开更多
Cancer is the second leading cause of death in the US.Current major treatments for cancer management include surgery,cytotoxic chemotherapy,targeted therapy,radiation therapy,endocrine therapy and immunotherapy.Despit...Cancer is the second leading cause of death in the US.Current major treatments for cancer management include surgery,cytotoxic chemotherapy,targeted therapy,radiation therapy,endocrine therapy and immunotherapy.Despite the endeavors and achievements made in treating cancers during the past decades,resistance to classical chemotherapeutic agents and/or novel targeted drugs continues to be a major problem in cancer therapies.Drug resistance,either existing before treatment(intrinsic)or generated after therapy(acquired),is responsible for most relapses of cancer,one of the major causes of death of the disease.Heterogeneity among patients and tumors,and the versatility of cancer to circumvent therapies make drug resistance more challenging to deal with.Better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment and achieve better outcomes.In this review,intrinsic and acquired resistance will be discussed.In addition,new discoveries in mechanisms of drug resistance will be reviewed.Particularly,we will highlight roles of ATP in drug resistance by discussing recent findings of exceptionally high levels of intratumoral extracellular ATP as well as intracellular ATP internalized from extracellular environment.The complexity of drug resistance development suggests that combinational and personalized therapies,which should take ATP into consideration,might provide better strategies and improved efficacy for fighting drug resistance in cancer.展开更多
Pharmacokinetics(PK)is the study of the absorption,distribution,metabolism,and excretion(ADME)processes of a drug.Understanding PK properties is essential for drug development and precision medication.In this review w...Pharmacokinetics(PK)is the study of the absorption,distribution,metabolism,and excretion(ADME)processes of a drug.Understanding PK properties is essential for drug development and precision medication.In this review we provided an overview of recent research on PK with focus on the following aspects:(1)an update on drug-metabolizing enzymes and transporters in the determination of PK,as well as advances in xenobiotic receptors and noncoding RNAs(ncRNAs)in the modulation of PK,providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy;(2)current status and trends in assessing drug-drug interactions,especially interactions between drugs and herbs,between drugs and therapeutic biologies,and microbiota-mediated interactions:(3)advances in understanding the effects of diseases on PK,particularly changes in metabolizing enzymes and transporters with disease progression;(4)trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies:(5)emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes,especially non-P450s.Existing challenges and perspectives on future directions are discussed,and may stimulate the development of new research models,technologies,and strategies towards the development of better drugs and improved clinical practice.展开更多
Pleiotropic drug resistance （PDR） transporters belonging to the ABCG subfamily of ATP-binding cassette （ABC） transporters are identified only in fungi and plants. Members of this family are expressed in plants in ...Pleiotropic drug resistance （PDR） transporters belonging to the ABCG subfamily of ATP-binding cassette （ABC） transporters are identified only in fungi and plants. Members of this family are expressed in plants in response to various biotic and abiotic stresses and transport a diverse array of moleculesacross membranes, Although their detailed transport mechanism is largely unknown, they play important roles in detoxification processes, preventing water loss, transport of phytohormones, and secondary metabolites. This review provides insights into transport mechanisms of plant PDR transporters, their expression profiles, and multitude functions in plants.展开更多
文摘Environmental pollution is one of the major problems for human health. Toxic heavy metals are normally present as soil constituents or can also be spread out in the environment by human activity and agricultural techniques. Soil contamination by heavy metals as cadmium, highlights two main aspects： on one side they interfere with the life cycle of plants and therefore reduce crop yields, and on the other hand, once adsorbed and accumulated into the plant tissues, they enter the food chain poisoning animals and humans. Considering this point of view, understanding the mechanism by which plants handle heavy metal exposure, in particular cadmium stress, is a primary goal of plant-biotechnology research or plant breeders whose aim is to create plants that are able to recover high amounts of heavy metals, which can be used for phytoremediation, or identify crop varieties that do not accumulate toxic metal in grains or fruits. In this review we focus on the main symptoms of cadmium toxicity both on root apparatus and shoots. We elucidate the mechanisms that plants activate to prevent absorption or to detoxify toxic metal ions, such as synthesis of phytochelatins, metallothioneins and enzymes involved in stress response. Finally we consider new plant-biotechnology applications that can be applied for phytoremediation.
文摘Nitrogen （N） is an essential macronutrient that affects plant growth and development. N is an important component of chlorophyll, amino acids, nucleic acids, and secondary metabolites. Nitrate is one of the most abundant N sources in the soil. Because nitrate and other N nutrients are often limiting, plants have developed sophisticated mechanisms to ensure adequate supply of nutrients in a variable environment. Nitrate is absorbed in the root and mobilized to other organs by nitrate transporters. Nitrate sensing activates signaling pathways that impinge upon molecular, metabolic, physiological, and developmental responses locally and at the whole plant level. With the advent of genomics technologies and genetic tools, important advances in our understanding of nitrate and other N nutrient responses have been achieved in the past decade. Furthermore, techniques that take advantage of natural polymor- phisms present in divergent individuals from a single species have been essential in uncovering new components. However, there are still gaps in our understanding of how nitrate signaling affects biolog- ical processes in plants. Moreover, we still lack an integrated view of how all the regulatory factors iden- tified interact or crosstalk to orchestrate the myriad N responses plants typically exhibit. In this review, we provide an updated overview of mechanisms by which nitrate is sensed and transported throughout the plant. We discuss signaling components and how nitrate sensing crosstalks with hormonal pathways for developmental responses locally and globally in the plant. Understanding how nitrate impacts on plant metabolism, physiology, and growth and development in plants is key to improving crops for sustainable agriculture.
基金supported by the National Key Basic Research Program(S.Y.Q.,Grant Number 2012CB124704)
文摘It is widely known that branched chain amino acids（BCAA） are not only elementary components for building muscle tissue but also participate in increasing protein synthesis in animals and humans. BCAA（isoleucine, leucine and valine） regulate many key signaling pathways, the most classic of which is the activation of the m TOR signaling pathway. This signaling pathway connects many diverse physiological and metabolic roles. Recent years have witnessed many striking developments in determining the novel functions of BCAA including：（1） Insufficient or excessive levels of BCAA in the diet enhances lipolysis.（2） BCAA, especially isoleucine, play a major role in enhancing glucose consumption and utilization by up-regulating intestinal and muscular glucose transporters.（3）Supplementation of leucine in the diet enhances meat quality in finishing pigs.（4） BCAA are beneficial for mammary health, milk quality and embryo growth.（5） BCAA enhance intestinal development, intestinal amino acid transportation and mucin production.（6） BCAA participate in up-regulating innate and adaptive immune responses.In addition, abnormally elevated BCAA levels in the blood（decreased BCAA catabolism） are a good biomarker for the early detection of obesity, diabetes and other metabolic diseases. This review will provide some insights into these novel metabolic and physiological functions of BCAA.
文摘Intrahepatic cholestasis of pregnancy （ICP） is the most common pregnancy-related liver disorder. Maternal effects of ICP are mild; however, there is a clear association between ICP and higher frequency of fetal distress, preterm delivery, and sudden intrauterine fetal death. The cause of ICP remains elusive, but there is evidence that mutations in genes encoding hepatobiliary transport proteins can predispose for the development of ICP. Recent data suggest that ursodeoxycholic acid is currently the most effective pharmacologic treatment, whereas obstetric management is still debated. Clinical trials are required to identify the most suitable monitoring modalities that can specifically predict poor perinatal outcome. This article aims to review current achievements and unsolved problems of ICR
文摘Vascular plants contain two gene families that encode monosaccharide transporter proteins. The classical monosaccharide transporter（-like） gene superfamily is large and functionally diverse, while the recently identified SWEET transporter family is smaller and, thus far, only found to transport glucose. These transporters play essential roles at many levels, ranging from organelles to the whole plant. Many family members are essential for cellular homeostasis and reproductive success. Although most transporters do not directly participate in long-distance transport, their indirect roles greatly impact carbon allocation and transport flux to the heterotrophic tissues of the plant. Functional characterization of some members from both gene families has revealed their diverse roles in carbohydrate partitioning, phloem function, resource allocation, plant defense, and sugar signaling. This review highlights the broad impacts and implications of monosaccharide transport by describing some of the functional roles of the monosaccharide transporter（-like） superfamily and the SWEET transporter family.
文摘Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATPbinding cassette(ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.
基金supported by a Ph.D. scholarship provided by University of Tasmania (185466S9A),Australiathe Open Fund of State Key Laboratory of Tea Plant Biology Utilization at Anhui Agricultural University (SKLTOF20170112)
文摘Salinity is a global challenge to agricultural production. Understanding Na^+ sensing and transport in plants under salt stress will be of benefit for breeding robustly salt-tolerant crop species. In this review, first, possible salt stress sensor candidates and the root meristem zone as a tissue harboring salt stress-sensing components are proposed. Then,the importance of Na^+ exclusion and vacuolar Na^+ sequestration in plant overall salt tolerance is highlighted. Other Na^+ regulation processes, including xylem Na^+ loading and unloading, phloem Na^+ recirculation, and Na^+ secretion, are discussed and summarized.Along with a summary of Na^+ transporters and channels, the molecular regulation of Na^+ transporters and channels in response to salt stress is discussed. Finally, some largely neglected issues in plant salt stress tolerance, including Na^+ concentration in cytosol and the role of Na^+ as a nutrient, are reviewed and discussed.
文摘Background The persistence of sleep disordered breathing （SDB） symptoms after tonsil and/or adenoid （T＆A） surgery are common in children with obstructive sleep apnea （OSA）. We tested the hypothesis that disturbances of glucose transporters （GLUTs） in intraabdominal adipose tissue caused by chronic intermittent hypoxia （CIH） from the pedo-period could facilitate the appearance of periphery insulin resistance in Sprague-Dawley （SD） rats. We tested the hypothesis that the changes of GLUTs in adipose tissue may be one of the reasons for persistent SDB among clinical OSA children after T＆A surgery. Methods Thirty 21-day-old SD rats were randomly divided into a CIH group, a chronic continuous hypoxia （CCH） group and a normal oxygen group （control group） and exposed for 40 days. The changes of weight, fasting blood glucose and fasting blood insulin levels were measured. Hyperinsulinemic-euglycemic clamp techniques were used to measure insulin resistance in each animal. Real-time quantitative PCR and Western blotting were used to measure GLUT mRNA and proteins in intraabdominal adipose tissue. Additional intraabdomial white adipose tissue （WAT） was also processed into paraffin sections and directly observed for GLUTs1-4 expression. Results When compared with control group, CIH increased blood fasting insulin levels, （245.07±53.89） pg/ml vs. （168.63±38.70） pg/ml, P=-0.038, and decreased the mean glucose infusion rate （GIR）, （7.25±1.29） mg·kg^-1·min^-1 vs. （13.34±1.54） mg·kg^-1·min^-1, P 〈0.001. GLUT-4 mRNA and protein expression was significantly reduced after CIH compared with CCH or normal oxygen rats, 0.002±0.002 vs. 0.039±0.009, P 〈0.001; 0.642±0.073 vs. 1.000±0.103, P=0.035. Conclusions CIH in young rats could induce insulin resistance via adverse effects on glycometabolism. These findings emphasize the importance of early detection and treatment of insulin insensitivity in obese childhood OSA.
基金supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIH,No.R01DK047987)supported by a Research Supplement to Promote Diversity in Health Related Research from the NIH
文摘The classical functions of bile acids include acting as detergents to facilitate the digestion and absorption of nutrients in the gut. In addition, bile acids also act as signaling molecules to regulate glucose homeostasis, lipid metabolism and energy expenditure. The signaling potential of bile acids in compartments such as the systemic circulation is regulated in part by an efficient enterohepatic circulation that functions to conserve and channel the pool of bile acids within the intestinal and hepatobiliary compartments. Changes in hepatobiliary and intestinal bile acid transport can alter the composition, size,and distribution of the bile acid pool. These alterations in turn can have significant effects on bile acid signaling and their downstream metabolic targets. This review discusses recent advances in our understanding of the inter-relationship between the enterohepatic cycling of bile acids and the metabolic consequences of signaling via bile acid-activated receptors, such as farnesoid X nuclear receptor(FXR)and the G-protein-coupled bile acid receptor(TGR5).
基金supported by the U.S. National Institutes of Health National Institute of General Medical Sciences (Grant R01 GM066233)the National Center for Advancing Translational Sciences (Grant TL1 TR000422)
文摘The kidney is a vital organ for the elimination of therapeutic drugs and their metabolites.Renal drug transporters,which are primarily located in the renal proximal tubules,play an important role in tubular secretion and reabsorption of drug molecules in the kidney.Tubular secretion is characterized by high clearance capacities,broad substrate specificities,and distinct charge selectivity for organic cations and anions.In the past two decades,substantial progress has been made in understanding the roles of transporters in drug disposition,efficacy,toxicity and drug–drug interactions(DDIs).In the kidney,several transporters are involved in renal handling of organic cation(OC) and organic anion(OA) drugs.These transporters are increasingly recognized as the target for clinically significant DDIs.This review focuses on the functional characteristics of major human renal drug transporters and their involvement in clinically significant DDIs.
文摘K＋ uptake in the high-affinity range of concentrations and its components have been widely studied. In Arabidposis thaliana, the AtHAK5 transporter and the AtAKT1 channel have been shown to be the main transport proteins involved in this process. Here, we study the role of these two systems under two important stress conditions： low K＋ supply or the presence of salinity. T-DNA insertion lines disrupting AtHAK5 and A tAKT1 are employed for long-term experi- ments that allow physiological characterization of the mutant lines. We found that AtHAK5 is required for K＋ absorption necessary to sustain plant growth at low K＋ in the absence as well as in the presence of salinity. Salinity greatly reduced AtHAK5 transcript levels and promoted AtAKTl-mediated K＋ efflux, resulting in an important impairment of K＋ nutrition. Although having a limited capacity, AtHAK5 plays a major role for K＋ acquisition from low K＋ concentrations in the presence of salinity.
文摘Terrestrial plants have two to four times more ATP-binding cassette （ABC） transporter genes than other organisms, including their ancestral microalgae. Recent studies found that plants harboring mutations in these transporters exhibit dramatic phenotypes, many of which are related to developmental processes and functions necessary for life on dry land. These results suggest that ABC transporters multiplied during evolution and assumed novel functions that allowed plants to adapt to terrestrial environmental conditions. Examining the literature on plant ABC transporters from this viewpoint led us to propose that diverse ABC transporters enabled many unique and essential aspects of a terrestrial plant＇s lifestyle, by transporting various compounds across specific membranes of the plant.
文摘Cancer is the second leading cause of death in the US.Current major treatments for cancer management include surgery,cytotoxic chemotherapy,targeted therapy,radiation therapy,endocrine therapy and immunotherapy.Despite the endeavors and achievements made in treating cancers during the past decades,resistance to classical chemotherapeutic agents and/or novel targeted drugs continues to be a major problem in cancer therapies.Drug resistance,either existing before treatment(intrinsic)or generated after therapy(acquired),is responsible for most relapses of cancer,one of the major causes of death of the disease.Heterogeneity among patients and tumors,and the versatility of cancer to circumvent therapies make drug resistance more challenging to deal with.Better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment and achieve better outcomes.In this review,intrinsic and acquired resistance will be discussed.In addition,new discoveries in mechanisms of drug resistance will be reviewed.Particularly,we will highlight roles of ATP in drug resistance by discussing recent findings of exceptionally high levels of intratumoral extracellular ATP as well as intracellular ATP internalized from extracellular environment.The complexity of drug resistance development suggests that combinational and personalized therapies,which should take ATP into consideration,might provide better strategies and improved efficacy for fighting drug resistance in cancer.
基金supported by National Natural Science Foundation of China(grants:81573489,81522047,81730103,81320108027,81660618,and 81773808)the National Key Research and Development Program(grant:2017YFE0109900 and 2017YFC0909303,China)+5 种基金the 111 project(grant:B16047,China)the Key Laboratory Foundation of Guangdong Province(grant:2017B030314030,China)Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China)National Engineering and Technology Research Center for New drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004,China)Natural Science Foundation of Guangdong(grant:2017A030311018 and 2015A030313124,China)National Institutes of Health(grants No.R01CA225958 and R01GM113888 to Ai-Ming Yu,USA).
文摘Pharmacokinetics(PK)is the study of the absorption,distribution,metabolism,and excretion(ADME)processes of a drug.Understanding PK properties is essential for drug development and precision medication.In this review we provided an overview of recent research on PK with focus on the following aspects:(1)an update on drug-metabolizing enzymes and transporters in the determination of PK,as well as advances in xenobiotic receptors and noncoding RNAs(ncRNAs)in the modulation of PK,providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy;(2)current status and trends in assessing drug-drug interactions,especially interactions between drugs and herbs,between drugs and therapeutic biologies,and microbiota-mediated interactions:(3)advances in understanding the effects of diseases on PK,particularly changes in metabolizing enzymes and transporters with disease progression;(4)trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies:(5)emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes,especially non-P450s.Existing challenges and perspectives on future directions are discussed,and may stimulate the development of new research models,technologies,and strategies towards the development of better drugs and improved clinical practice.
基金supported by the National Natural Science Foundation of China (30470189, 81071821, 81101655)the Fundamental Research for the Central University of China (721500011)the key Project of Hunan Provincial Natural Science Foundation of China (13JJ2016)
文摘Pleiotropic drug resistance （PDR） transporters belonging to the ABCG subfamily of ATP-binding cassette （ABC） transporters are identified only in fungi and plants. Members of this family are expressed in plants in response to various biotic and abiotic stresses and transport a diverse array of moleculesacross membranes, Although their detailed transport mechanism is largely unknown, they play important roles in detoxification processes, preventing water loss, transport of phytohormones, and secondary metabolites. This review provides insights into transport mechanisms of plant PDR transporters, their expression profiles, and multitude functions in plants.
