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Apical sodium-dependent bile acid transporter （ASBT） is a key transporter responsible for intestinal reabsorption of bile acid and plays an important role in maintaining bile acid and cholesterol homeostasis， and its expression is regulated by various factors including transcription factors， nuclear receptors， and intestinal microflora. The abnormal expression and function of ASBT can lead to disorders in the metabolism of bile acid and cholesterol， causing a variety of hepatobiliary diseases. At present， ASBT has attracted wide attention as a therapeutic target. This article elaborates on the biological characteristics and expression regulation mechanism of ASBT and reviews the role of ASBT in hepatobiliary diseases， in order to provide a new direction for the treatment of related diseases.
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Sodium-dependent glucose transporter 2 inhibitors(SGLT2i)are a new class of glucose-lowering drugs, can reduce blood sugar by inhibiting the reabsorption of glucose at the proximal tubule and are widely used in clinical treatment of type 2 diabetes.SGLT2i can not only lower blood sugar, but also offer multiple cardiovascular benefits.Several large randomized controlled trials have confirmed the safety and efficacy of SGLT2i for heart failure with preserved ejection fraction(HFpEF). Herein, we present an overview on advances in SGLT2i for HFpEF.
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SGLT2 inhibitors currently have clear benefits in the treatment of heart failure whether combined with diabetes or not. Ventricular remodeling after myocardial infarction leads to the occurrence and development of heart failure, and eventually leads to death. There are relatively few studies on SGLT2 inhibitors in patients with myocardial infarction. The purpose of this article is to review the research progress of SGLT2 inhibitors application before and after myocardial infarction.
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ObjectiveTo explore the underlying mechanism of bran-fried Atractylodis Rhizoma （AR） in improving gastrointestinal function by comparing the effects of raw AR and bran-fried AR on the small intestine tissue structure and transport-related protein carriers in rats with spleen deficiency syndrome. MethodSeventy male SD rats were randomly divided into a normal group， a model group， high- and low-dose raw AR groups （10， 2.5 g·kg-1）， high- and low-dose bran-fried AR groups （10， 2.5 g·kg-1）， and a compound glutamine group （9 mg·kg-1）， with 10 rats in each group. Except for the normal group， the other six groups were subjected to the spleen deficiency model induced by the method of bitter and cold breaking stagnated Qi and abnormal hunger and fullness for 21 days. After modeling， each treatment group was given medication orally according to the corresponding doses every day for a total of 14 days， and the normal group and the model group were given an equal volume of normal saline orally. During the treatment period， the general survival status， macroscopic syndrome score， daily increase in body weight and food intake， and rectal temperature of the spleen deficiency rats were evaluated， and after the treatment， the rats were sacrificed. The pathological changes in the small intestine tissues of each group were observed by hematoxylin-eosin （HE） staining. The content of serum 5-hydroxytryptamine （5-HT） was detected by enzyme-linked immunosorbent assay （ELISA）， and the content of serum D-xylose， lactate， and amylase was detected by colorimetry. The levels of free fatty acid receptor 3 （FFA3） and peptide transporter 1 （PepT1） in small intestinal tissues were detected by the Bradford method， and the protein expression of sodium-dependent glucose transporter 1 （SGLT1） and glucose transporter 1 （GLUT1） in small intestinal tissue was detected by immunohistochemistry. Real-time fluorescence-based quantitative PCR was used to detect the mRNA expression of glucose transporter 2 （GLUT2）， sodium/hydrogen exchanger 3 （NHE3）， and 5-hydroxytryptamine receptor 4 （5-HT4R）. ResultCompared with the normal group， the model group exhibited symptoms of spleen deficiency， such as sluggishness， squint， reduced food intake， and lethargy at the end of modelling， damaged basic structure of the small intestinal mucosal epithelium and lamina propria， increased serum lactate and 5-HT content， and decreased serum amylase and D-xylose （P<0.01）. Compared with the model group， all treatment groups showed varying degrees of improvement， with the small intestinal microstructure repaired to different degrees. The daily weight gain， anal temperature， and macroscopic syndrome score of spleen deficiency improved to varying degrees （P<0.05， P<0.01）. The serum lactate and 5-HT content decreased to varying degrees， while the serum amylase and D-xylose content increased to varying degrees （P<0.05， P<0.01）. The PepT1 content in the small intestinal tissues increased， while the FFA3 content decreased to varying degrees. The protein expression of SGLT1 and GLUT1 increased， while the mRNA expression of GLUT2 and NHE3 increased to varying degrees. The mRNA expression of 5-HT4R decreased to varying degrees （P<0.05， P<0.01）. Compared with the high- and low-dose raw AR groups， the high- and low-dose bran-fried AR groups showed significant improvement in general conditions and histopathological improvement of the small intestinal tissues. The daily weight gain， anal temperature， and macroscopic syndrome score of spleen deficiency also improved （P<0.05， P<0.01）. The serum lactate and 5-HT content decreased， while the serum amylase and D-xylose content increased （P<0.05， P<0.01）. The PepT1 content in the small intestinal tissues increased， while the FFA3 content decreased. The protein expression of SGLT1 and GLUT1 increased， while the mRNA expression of GLUT2 and NHE3 increased. The mRNA expression of 5-HT4R decreased significantly （P<0.05， P<0.01）. ConclusionBran-fried AR can improve the spleen deficiency-related symptoms and histopathology of the small intestinal tissues in spleen deficiency model rats. Its mechanism may be related to the regulation of the expression of various transport-related protein carriers and the secretion of various digestive enzymes after stir-frying of AR， thus restoring the absorption and transport function of the small intestine.
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Cardiometabolic disease (CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids (BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses via diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs via targeting Farnesoid X receptor (FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis per se is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.
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Bile acids (BAs) are a major component of bile salt, which plays a vital role in the metabolism of lipids in humans. Ninety-five percent of bile acids are recycled by the enterohepatic circulation (EHC), and therefore EHC is essential for bile acid homeostasis. There are four transporters that mediate the transmembrane transport of bile acids, each of which plays an important role in the enterohepatic circulation. Gene defects in bile acid transporters can lead to disorders of the enterohepatic circulation, ultimately leading to clinical phenotypes such as metabolic diseases and even death. Bile transporter expression is altered in patients with various metabolic disease states, suggesting that disruption of bile acid transporters may be a pivotal pathological mechanism for the development of metabolism diseases. Thus, many drugs targeting bile acid transporters are being developed. We provide a concise overview of the progress of bile acid transporters research, discuss the relationship between different bile acid transporters and disease development, and summarize the current progress in drug development targeting bile acid transporters.
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Diabetes mellitus is a metabolic disease characterized by hyperglycemia. It is found that the incidence and mortality of abdominal aortic aneurysm (AAA) in diabetes mellitus patients are lower than that in non-diabetes mellitus patients. This review will present the protective role of diabetes mellitus and its treatment on the aortic disease process, aiming to provide more support for the clinical treatment of AAA.
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Bile acids (BAs) are amphipathic molecules important for metabolism of cholesterol, absorption of lipids and lipid soluble vitamins, bile flow, and regulation of gut microbiome. There are over 30 different BA species known to exist in humans and mice, which are endogenous modulators of at least 6 different membrane or nuclear receptors. This diversity of ligands and receptors play important roles in health and disease; however, the full functions of each individual BA
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ObjectiveTo investigate the feasibility of apical sodium-dependent bile salt transporter (ASBT) and asialoglycoprotein receptor (ASGPR) in the design of oral liver-targeting preparations for the treatment of hepatic alveolar echinococcosis (HAE) by measuring the expression of ASBT and ASGPR. MethodsA total of 18 male Sprague-Dawley rats were selected, among which 10 were used to establish a model of HAE (HAE group) and 8 were used as controls (normal group). Immunofluorescence assay, Western blotting, and quantitative real-time PCR were used to measure the expression distribution, protein expression level, and mRNA expression level of ASBT in the ileal tissue of HAE model rats and normal rats; the same methods were used to measure the expression level of ASGPR in the non-diseased liver tissue and the marginal zone of liver tissue lesion of HAE model rats and the liver tissue of normal rats. The t-test was used for comparison of normally distributed continuous data between two groups; a one-way analysis of variance was used for comparison between three groups, and the least significant difference t-test was used for comparison between two groups. ResultsThe results of immunofluorescence assay, Western blotting, and quantitative real-time PCR showed that compared with the normal group, the HAE group had significantly upregulated expression of ASBT in the ileal tissue (t=5309, 4.110, and 28.060, all P＜0.05) and a significantly higher expression level of ASGPR (the closer to the lesion, the higher the expression) (F=110666, 128.201, and 143.879, all P＜0.001). ConclusionASBT and ASGPR can be used as potential mediated receptors for oral liver-targeting preparations for HAE, which provides a theoretical basis for the design of oral liver-targeting preparations for the treatment of HAE.
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Orally administered drug entities have to survive the harsh gastrointestinal environment, penetrate the enteric epithelia and circumvent hepatic metabolism before reaching the systemic circulation. Whereas the gastrointestinal stability can be well maintained by taking proper measures, hepatic metabolism presents as a formidable barrier to drugs suffering from first-pass metabolism. The pharmaceutical academia and industries are seeking alternative pathways for drug transport to circumvent problems associated with the portal pathway. Intestinal lymphatic transport is emerging as a promising pathway to this end. In this review, we intend to provide an updated overview on the rationale, strategies, factors and applications involved in intestinal lymphatic transport. There are mainly two pathways for peroral lymphatic transport-the chylomicron and the microfold cell pathways. The underlying mechanisms are being unraveled gradually and nowadays witness increasing research input and applications.
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Proteins and peptides (PPs) have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy, but fewer side effects. Owing to the poor stability and limited permeability through gastrointestinal (GI) tract and epithelia, the therapeutic PPs are usually administered by parenteral route. Given the big demand for oral administration in clinical use, a variety of researches focused on developing new technologies to overcome GI barriers of PPs, such as enteric coating, enzyme inhibitors, permeation enhancers, nanoparticles, as well as intestinal microdevices. Some new technologies have been developed under clinical trials and even on the market. This review summarizes the history, the physiological barriers and the overcoming approaches, current clinical and preclinical technologies, and future prospects of oral delivery of PPs.
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Aim To investigate the effects of vitamin C (VC) on glycine receptor (GlyR) subtypes. Methods The HEK-293T cells were transfected with plasmids expressing different subtypes of GlyR. Then the cells were incubated with different concentrations of VC. The EC2 concentration of glycine-activated currents were recorded by patch clamp before or after incubation of VC. The effects of the sodium-dependent vitamin C transporter-type 2 ( SVCT2 ) inhibitor sulfinpyrazone on VC induced potentiation of GlyRs were also examined. The method of amino acid point mutation was used to explore the critical site for interaction between VC and GlyR. Results Ascorbic acid dose-dependently increased the currents mediated by GlyRal and GlyRa3, with a3 subunits being the most sensitive to VC. Ascorbic acid had no significant effect on the current mediated by the al subunit of GlyRs. Cell incubation with sulfinpyrazone did not affect the VC induced potentiation of GlyR function. The mutation of Ser296 at the third transmembrane domain of a3 GlyR significantly reduced the potentiation of VC on GlyR func-tion. Conclusions Ascorbic acid can enhance the function of GlyR al and a3 subunits, but not a2 sub- unit. Such enhancement is not likely to be an effect oc- curing inside cells. The Ser296 of GlyR plays a key role in the VC induced enhancement of GlyR function.
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Objective: To study the mechanism that TSG can reduce plasma glucose level by inhibiting sodium-dependent glucose cotransporters 2 (SGLT2) and α-glucosidase in vitro and in vivo. Methods: Molecular docking method was used to study the binding affinities of TSG and diabetes related targets. The structures of targets were taken from Protein Data Bank or references. 1-NBDG and PNPG were used as the substrates for the inhibition assays of TSG against SGLT2 and α-glucosidase respectively in vitro. The antihyperglycemic activity of TSG was operated by oral glucose tolerance test (OGTT) and urinary glucose excretion (UGE) test in rats. Results: TSG was identified as the inhibitors of SGLT2 with the docking score of -9.35 less than -9.79 of dapagliflozin as the positive control and α-glucosidase with the docking score of -5.44 compared to -5.58 of acarbose as the positive control. TSG showed the inhibitory rate of 21.6% at the dose of 10 μmol/L against SGLT2 and 32.5% at the dose of 100 μmol/L in vitro test. Compared with model group, the group of 120 mg/kg dose had significant difference (P < 0.05) but the overall effect was not as strong as dapagliflozin in OGTT and UGE test. The result of rat in vivo test showed that glucose inhibition rate of TSG (120 mg/kg) was (9.3 ± 1.0)%, urinary glucose content was (435.5 ± 84.0) mg/kg, which showed certain hypoglycemic effect. Conclusion: TSG exhibited antiglycemic activity through inhibiting SGLT2 and α-glucosidase, which was considered to be a new lead compound of dual target inhibitors.
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Sodium-dependent phosphate cotransporter is encoded by the solute carrier family 17 gene.The gene is located on chromosome 6 and is an important transporter of the organic anion as the substrate and is expressed in kidney and other tissues .Among them, the sodium-dependent phosphate transporter type 1, 3, and 4 have the func-tion of transferring uric acid , and abnormal function can lead to the decrease of uric acid excretion , which can cause hyperuricemia and even induce gout .
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Objective To study that puerarin can prevent the renal glucose reabsorbtion process and promote urinary glucose excretion by inhibiting sodium-dependent glucose cotransporters 2 (SGLT2) to reduce plasma glucose in diabetes rats.Methods Molecular docking was carried out on puerarin and the obtained SGLT2 complexes through homology modeling method with dapagliflozin as positive control.Chinese hamster ovary (CHO) cells stably expressing human SGLT2 and [14C]-MethylD-glucopyranoside ([14C]-AMG) as the substrate were used in vitro for the transport assays and IC50 for SGLT2.The antihyperglycemic activity ofpuerarin was operated by oral glucose tolerance test (OGTT) and urinary glucose excretion (UGE) test in rats.Results Puerarin was identified as the substrate of SGLT2 through molecular docking,but the overall effect was not as strong asdapagliflozin.In vitro experiments showed that puerarin can strongly inhibit hSGLT2,the maximum effect was about 84％ with the half inhibitory concentration (IC50) of 0.40 mol/L.OGTT results showed that glucose inhibition rates of puerarin 10,30,60 and 120 mg/kg doses were 5.1％,6.5％,16％,and 22％ respectively,in a dose-dependent manner.In the UGE experiment,the urine sugar increased with the increase of puerarin dose.Compared with model group,the 30,60,and 120 mg/kg dose groups had significant difference (P ＜ 0.05 and 0.01).Conclusion Puerarin exhibited antiglycemic activity through inhibiting SGLT2 and was considered to be a new lead compound of SGLT2 inhibitors.
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Bile acids play critical roles in the regulation of metabolism and absorption of lipids. The ileal apical sodium-dependent bile acid transporter (ASBT) located at the enterocyte brush border is responsible for the reuptake of bile acids and the maintenance of bile acid homeostasis. Recently, a number of investigations have been made concerning the regulation and control of ASBT and the relationship between ASBT and intestinal inflammation, tumorigenesis, diabetes mellitus and hyperlipemia, which suggests ASBT as a potential therapeutic target of these diseases. In this review, advances in the study of above-mentioned issues were summarized.
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Vitamin C is an essential micronutrient that affects immune responses. T cells are one of the main players in acquired immunity and have been reported to be influenced by in vivo vitamin C supplementation. Yet, the way by which T cells uptake vitamin C and what direct effects vitamin C exerts on the cells are not known. To elucidate, we isolated human peripheral blood T cells and analyzed the expression of sodium-dependent vitamin C transporters (SVCT). T cells were activated in vitro in the absence or presence of vitamin C, before or after activation. As results, human T cells expressed SVCT2, but not SVCT1, and the expression level increased following activation. Vitamin C added in the culture media generally did not affect T-cell behaviors following activation, such as proliferation, apoptosis, expression of CD25 and CD69, and interleukin 2 secretion, regardless whether it was added before or after activation. However, exceptionally, high concentration vitamin C, when it was added before activation, but not after activation, did exert toxic effects on cell activation with respect to the above-mentioned parameters. In conclusion, we showed the expression of SVCT2 in human T cells for the first time. Vitamin C exerted toxic effects, at least in vitro, when the concentration was high and when it was given before activation. These toxic effects are not thought to be via anti-oxidant effects of vitamin C.
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Humanos , Inmunidad Adaptativa , Antioxidantes , Apoptosis , Ácido Ascórbico , Medios de Cultivo , Técnicas In Vitro , Interleucina-2 , Micronutrientes , Transportadores de Sodio Acoplados a la Vitamina C , Linfocitos T , VitaminasRESUMEN
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).
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Bile acids play critical roles in the solubilization and absorption of lipids. The ileal apical sodium-dependent bile acid transporter( ASBT)located at the enterocyte brush border is responsible for the reuptake of bile acids and the maintenance of bile acid homeostasis. Recently,great success has been made in understanding the relationship between ASBT and intestinal inflammation,tumorigenesis,secretion,motility,sensation,gut microbiota,and gut-liver axis in addition to its expression regulation,which implicates ASBT as a contributor of some gastrointestinal diseases and a promising new therapeutic target for these diseases. In this review article,the advances in study on above-mentioned issues were summarized.
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Glucose and related hexoses are very important metabolic substrates. Their most important function is to provide quick fuel for most organisms in all three kingdoms because they are the first substrate for energy production in the form of ATP through glycolysis and the subsequent metabolic pathways. In this paper we review the current information about how glucose and related hexoses are transported across biological membranes to carry out their function either as a metabolic molecule or as energy store in marine invertebrate organisms. In these animals, there are two sugar transport systems that are mediated by the sodium/solute symporter family proteins (SGLT) and the major facilitative super-family proteins (GLUT). The most studied sugar transporters in marine invertebrates are involved with dietary sugar uptake, such as SGLT1, SGLT4, GLUT2 and GLUT5, however more studies need to be done to extend the knowledge about these and other sugar transporters involved in metabolic processes.