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The outer membrane composed predominantly of lipopolysaccharide (LPS) is an essential biological barrier for most Gram-negative (G-) bacteria. Lipopolysaccharide transport protein (Lpt) complex LptDE is responsible for the critical final stage of LPS transport and outer membrane assembly. The structure and function of LptDE are highly conserved in most G- bacteria but absent in mammalian cells, and thus LptDE complex is regarded as an attractive antibacterial target. In recent 10 years, the deciphering of the three-dimensional structure of LptDE protein facilities the drug discovery based on such "non-enzyme" proteins. Murepavadin, a peptidomimetic compound, was reported to be the first compound able to target LptD, enlightening a new class of antibacterial molecules with novel mechanisms of action. This article is devoted to summarize the molecular characteristics, structure-function of LptDE protein complex and review the development of murepavadin and related peptidomimetic compounds, in order to provide references for relevant researches.
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Objective:To evaluate the role of activation of vesicular glutamate transporter 2 (VGLUT2) neurons in vagal nodose ganglion in dexmedetomidine-caused bradycardia in mice.Methods:Ninety-six SPF healthy male VGLUT2-cre mice, aged 10 weeks, weighing 20-25 g, were divided into 6 groups ( n=16 each) by the random number table method: normal saline control group (NS group), dexmedetomidine group (Dex group), viral control + chemogenetic control + dexmedetomidine group (eGFP-NS+ Dex group), viral transfection + chemogenetic control + dexmedetomidine group (hM4Di-NS+ Dex group), viral control + chemogenetic inhibition + dexmedetomidine group (eGFP-CNO+ Dex group) and viral transfection + chemogenetic inhibition + dexmedetomidine group (hM4Di-CNO+ Dex group). Dexmedetomidine 100 μg/kg was intraperitoneally injected in Dex group. The equal volume of normal saline was intraperitoneally injected in NS group. AAV2/9-hSyn-DIO-hM4Di-eGFP was injected in the right nodose ganglion in hM4Di-NS+ Dex group and hM4Di-CNO+ Dex group, and AAV2/9-hSyn-DIO-eGFP was injected in the right nodose ganglion in eGFP-NS+ Dex group and eGFP-CNO+ Dex group, allowing the virus expression for 21 days. On the 22nd day after virus injection, clozapine-n-oxide (CNO) 5 mg/kg was intraperitoneally injected in hM4Di-CNO+ Dex group and eGFP-CNO+ Dex group, the equal volume of normal saline was intraperitoneally injected in hM4Di-NS+ Dex group and eGFP-NS+ Dex group, 1 h later the efficacy of CNO reached the peak, and then dexmedetomidine 100 μg/kg was intraperitoneally injected. The respiratory rate, heart rate, SpO 2 and discharge frequency of the right vagal nodose ganglion were synchronously measured by multi-channel electrophysiology in vivo. The expression of phosphorylated extracellular signal-regulated kinase (pERK) and VGLUT2 and co-expression of pERK and VGLUT2 in the right vagal nodose ganglion were detected by immunofluorescence assay. Results:Compared with NS group, the percentage of heart rate variation and neuron firing frequency after administration were significantly increased, and pERK expression was up-regulated in the other five groups ( P<0.05). Compared with Dex group, the percentage of heart rate variation and neuron firing frequency after administration were significantly decreased, and pERK expression was down-regulated in hM4Di-CNO+ Dex group, and no significant change was found in the parameters mentioned above in hM4Di-NS+ Dex group, eGFP-NS+ Dex group and eGFP-CNO+ Dex group ( P>0.05). Compared with hM4Di-CNO+ Dex group, the percentage of heart rate variation and neuron firing frequency after administration were significantly increased, and pERK expression was up-regulated in eGFP-CNO+ Dex group ( P<0.05). There was no significant difference in the percentage of respiratory variation and SpO 2 among the six groups ( P>0.05). The expression of VGLUT2-positive neurons was abundant in nodose ganglia, and the co-expression rate of pERK and VGLUT2 was nearly 90%. The co-expression rate of pERK and VGLUT2 decreased to about 30% after inhibition of VGLUT2 neurons in ganglion. Conclusions:The mechanism by which dexmedetomidine causes bradycardia is associated with activation of VGLUT2 neurons in vagal nodose ganglia in mice.
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In recent years, with the deepening of tumor biology research, people have a newer and more comprehensive understanding of complex tumor metabolism reprogramming. The glucose transport protein-1(GLUT-1) is a glucose transporter widely expressed in the cell membranes of various tissues and represents unusual overexpression in the plasma membrane of virous cancer cell. GLUT-1 can transport man-nose, galactose, glucosamine and ascorbic acid (AA). GLUT-1 is overexpressed in different degrees on the plasma membrane of different tumor cells. Overexpressed GLUT-1 will make tumor cells take in more glucose to reprogram the metabolic mode of cells, and at the same time, it influences the change of tumor microenvironment. And the regulation of GLUT-1 in tumors has been the focus of attention in recent years, and the upstream regulators that have been reported mainly include phosphatase and tension homolog deleted on chromosome ten (PTEN) and hypoxia inducible factor (HIF). GLUT-1 also plays an important role in tumorigenesis and development by influencing the p53 and cellular tumorigenic gene (c-Myc) pathways. The review introduces structure and function of GLUT-1, the effects of transporting different substrates in tumor metabolic reprogramming, the regulation of GLUT-1, and the current treatment of GLUT-1. Meanwhile, the review discusses mechanisms and development of the role of GLUT-1 in cancer metabolism reprogramming, and points out the existing problems to provide reference for the research of metabolism reprogramming and targeted therapy of malignant tumors.
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Abstract Background: Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular impairment, increasing the rates of atherosclerotic and non-atherosclerotic events. Additionally, adverse kidney events are directly linked with T2DM and cardiovascular diseases. In this context, the sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated both cardioprotective and renoprotective effects in patients with or without T2DM. Therefore, the present meta-analysis aims to evaluate cardiovascular outcomes involving SGLT2i as monotherapy or other add-on antidiabetic agents (ADA) in patients with or without T2DM. Objetive: The present meta-analysis aims to evaluate cardiovascular outcomes involving SGLT2i as monotherapy or add-on other ADA in patients with or without T2DM. Methods: The entrance criteria to SGLT2i studies were: describing any data regarding cardiovascular effects; enrolling more than 1,000 participants; being approved by either the FDA or the EU, and having available access to the supplementary data. The trial had to exhibit at least one of the following results: major adverse cardiovascular events (MACE), cardiovascular death or hospitalization for heart failure, cardiovascular death, hospitalization for heart failure, renal or cardiovascular adverse events, or non-cardiovascular death. The significance level of 0.05 was adopted in the statistical analysis. Results: Nine trials with a total of 76,285 participants were included in the meta-analysis. SGLT2i reduced MACE (RR 0.75, 95% CI [0.55-1.01]), cardiovascular death or hospitalization for heart failure (RR 0.72, 95% CI [0.55-0.93]), cardiovascular death (RR 0.66, 95% CI [0.48-0.91]), hospitalization for heart failure (RR 0.58, 95% CI [0.46-0.73]), renal or cardiovascular adverse events (RR 0.55, 95% CI [0.39-0.78]), and non-cardiovascular death (RR 0.88, 95% CI [0.60-1.00]). Conclusions: Conjunction overall data suggests that these drugs can minimize the risk of cardiovascular events, thus decreasing mortality in patients, regardless of the presence of T2DM.
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Humans , Cardiotonic Agents , Cardiovascular Diseases/mortality , Cardiovascular Diseases/drug therapy , Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Reproducibility of Results , Outcome Assessment, Health Care , Sodium-Glucose Transporter 2 , Hospitalization , Kidney Diseases/drug therapyABSTRACT
Glutamine plays a significant role in metabolism of protein and energy in cells. However, glutamine must be transported into cells to be utilized via the specific vector on cell membrane. The most important transporter is the Na ∗ dependent glutamine vector alanine-serine-cysteine transporter 2 (ASCT2). The regulation of ASCT2 biological function is closely related to human health. The ASCT2 is not only broadly expressed in normal tissues and organs but increases its expression in cancer to fulfill the augmented glutamine demand. Interactions with proteins and post-translational modifications regulate ASCT2 stability and transport activity. Two asparagine residues, namely N163 and N212, are the sites of glycosylation that have responsibility for the definitive localization into the plasma membrane. However, it has little effect on the intrinsic transport function of ASCT2. This review summarizes the regulation of biological function of ASCT2 and its significance in the treatment of disease.
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The dietary fats are composed primarily of triacylglycerols and some amount of phospholipids and cholesterol. Being hydrophobic in nature, these are insoluble in water, and hence cannot be transported in the blood plasma per se; to enable these lipids to be transported by the blood stream to various peripheral tissues, nature has devised the technique of making these soluble by binding them to proteins. These proteins involved in lipid transport are known as apolipoproteins, and the protein-lipid particle is known as lipoprotein. Thus, lipoproteins can be considered to be the primary transportmechanism to carry lipids from the alimentary tract to various parts of the body. Lipoproteins have gained prominence in medical field over the past few decades because of their role in the aetio-pathogenesis of cardiovascular diseases, principally atherosclerosis which is the cause of coronary artery disease and myocardial infarction. The various types and sub-types of lipoproteins have been found to have differing and even opposing roles in the development of arterial diseases. An understanding of the differing populations of lipoproteins, the associated proteins and other enzymes, and the myriad variety of inter-actions among themselves and with body cells is vital to our understanding the pathways involved in the development of cardio-vascular disordersand in determining the precise steps where pharmacological interventions can be introduced
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Objective To observe the effect of spinal cord stimulation on expression of spinal GLT-1 and GLAST in rats with diabetic neuropatbic pain.Methods Forty-eight healthy male SD rats,only 2 months old,weighting 250-300 g,using the random number table method,were divided into four groups (n=12):the control group (group C),diabetes neuralgia group (group D),false stimulation group (group N)and spinal cord stimulation group (group S).The model of diabetes was induced by the pedtoneal injec-tion of streptozocin (STZ),electrodes were placed into the epidural space 1 9 days after injection of STZ in groups N and S,in addition,group S was performed 26-28 days after injection of STZ.Mechanical contrac-tion leg threshold (MWT)were determined one day before STZ injection,2 d,7 d,14 d and 28 d after STZ injection.The rats were sacrificed,the lumbar spinal cord tissue were obtained for determination of GLT-1 and GLAST expression in spinal cord tissues on 28 d after measurement of MWT.Results Compared with group C,MWT was decreased 14 d and 28 d after STZ injection,and expression levels of GLT-1 and GLAST mRNA were increased on 14 d and 28 d (P<0.05);Compared with before STZ injection,MWT of group D,group N and group S was decreased on 14 d and 28 d (P<0.05);Compared with group D, MWT was increased,and expression levels of GLT-1 and GLAST mRNA were increased in group S on 28 d after STZ injection (P<0.05 ).Conclusion The mechanism of spinal cord stimulation reducing rats diabetes neuralgia may be related to elevating the expression of GLT-1 and GLAST.
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Objective To investigate the regulation of insulin VGLUT2 gene expression in pancreatic β cells and its exactly mechanism.Methods The rat pancreatic β cell line RIN-5F was treated by different insulin concentrations and different siRNA.The changes of VGLUT2 mRNA and protein expression levels were detected by adopting real-time qPCR and Western blot.Results In-sulin with a concentration of 100,200 nmol/L significantly inhibited the expressions of VGLUT2 mRNA and protein in RIN-5RF cells(P<0.05),moreover the inhibiting effect was most significant at 100 nmol/L.After 100 nmol/L insulin treatment,the expres-sions of VGLUT2 mRNA and protein at 12,18,24 h were significantly inhibited compared with that at 0 h(P<0.05).Compared with the Blank group,Lip2000 group and Control-siRNA group,after interfering RIN-5F by using IR-siRNA,IRS1-siRNA and IRS2-siRNA,the inhibition situation of VGLUT2 mRNA and protein expressions by 100 nmol/L insulin in each group was signifi-cantly recovered(P<0.05).Conclusion Insulin at low concentration could inhibit VGLUT 2 gene expression in rat pancreatic β cell line RIN-5F.
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Smad3 is a major transporter in the transforming growth factor β (TGF-β) signaling pathway.It is in charge of the transfer of TGF-β signal from the surface of the cell membrane into the nucleus.The TGF-β signal can be bound to the target gene in the nucleus and regulate its expression.Abnormalities in Smad3 expression level and functional status will lead to abnormal signal transduction,involving cell growth,proliferation,development,differentiation,migration,apoptosis and other basic life activities.This review focused on the differential expression of Smad3 in hepatocellular carcinoma (HCC)and the adjacent tissue.The character of Smad3 in HCC is outlined in three parts:Smad3 upstream signaling source,Smad3 self-assembly maturation and Smad3 downstream effects,which may provide a summary and reference for the follow-up study on Smad3.
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Objective To study the expression of sex hormone-binding globulin(SHBG),insulin signaling pathway and glucose transporter in placenta of pregnant women with gestational diabetes mellitus(GDM),and to explore its role in the pathogenesis of GDM. Methods A total of 10 full-term and non-obese(BMI0.05). Results of linear correlation analysis showed that there were positive correlations between SHBG mRNA and IRS-2 mRNA(P<0.05),SHBG mRNA and PI3K p85α mRNA(P<0.05),and SHBG mRNA and GLUT-4 mRNA(P<0.05). There was also a remarkable positive correlation between IRS-2 mRNA and GLUT-4 mRNA(P<0.01). There existed negative correlations between IRS-1 mRNA and PI3K p85α mRNA(P<0.05),and IRS-1 mRNA and GLUT-3 mRNA(P<0.05). There existed a remarkable positive correlation between IRS-2 mRNA and GLUT-1 mRNA(P<0.01). Conclusion The defective receptors of insulin signaling pathway are present in GDM placental tissue. Decreased expression of SHBG may be involved in the regulation insulin signaling ,leading to a concomitant decrease expression of relevant insulin signaling components in placental tissue ,implying insulin resistance and developing GDM finally.
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Objective Recent studies have shown that inflammatory cytokines are involved in the occurrence and development of diabetes mellitus .The article aimed to investigate the effects of anti-inflammatory drug--diacerein on hepatic PPAR-γand GLUT-2 protein expression and its role in the regulation of glucose and lipid metabolism in rats with type 2 diabetes mellitus ( T2DM) . Methods 55 male SD rats were randomly divided into 4 groups:normal control group (n=10), T2DM group (n=15), pioglitazone intervention group(n=15), and diacerein treatment group(n=15) .Rats in normal control group were fed with normal diet , the other 3 groups were fed with high fat diet .At the end of 8th experi-ment week, rats in 3 groups fed with high fat diet were treated with intraperitoneal injection of 30mg/kg streptozotocin ( STZ) solution, while rats in normal control group were injected with the same volume of sterile sodium citrate solution .At the end of 10th week, OGTT modeling rats were screened .Rats in pioglitazone intervention group were treated with 10 mg/kg pioglitazone by intragastric administra-tion, rats in diacerein group was treated with 50mg/kg diacerein by intragastric administration , and rats in normal control group and T2DM group were given the same volume of normal saline .The intervention lasted 4 weeks.At the end of 8th, 10th and 14th week, the blood examination of glycolipid , FINS, IL-1βand liver function indexes was done on fasting rats .Fourteenth weeks later , after getting blood samples , all rats were sacrificed and liver tissues were isolated .Western blot was applied in the detection of PPAR γand immu-nohistochemistry was applied to detect GLUT-2 protein in livers. Results At the end of 8th week, the FBG level in pioglitazone in-tervention group increased compared with normal control group ( P0 .05) show-ing higher levels compared with T 2DM group ( P<0.01).At 14th weekend, the GLUT-2 expression levels in normal control group (0.209±0.023), pioglitazone intervention group (0.226±0.017) and diacerein treatment group (0.232±0.012) were higher than that of T2DM group (0.173±0.009,P<0.01);and the GLUT-2 expression levels in pioglitazone intervention group and diacerein treatment group were higher than that of normal control group (P<0.05).The expression level of liver PPAR-γwas in positive correlation with those of GLUT-2 protein, HDL-C, FINS, ISI ( r=0.815, 0.780, 0.747, P<0.01) and in negative correlation with those of FBG , HbA1c, TC, TG, AST, ALT, IL-1β(r=-0.465,-5.716,-0.615,-0.675,-0.617,-0.521,-4.827, P<0.05). Conclusion Diacerein can enhance liver PPAR-γand GLUT-2 expression levels and reduce the levels of IL-1β, HbA1c and blood lipid, thus im-prove insulin resistance in T 2DM rats.
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Objective To explore the diagnosis value of serum cystatin C (Cys C),neutrophil gelatinase-associated lipocalin (NGAL) and urinary interleukin-18 (IL-18) levels in critically cases from pediatric Intensive Care Units (ICU).Methods 114 cases from June 2015 to January 2017 in Xidian Group Hospital were enrolled in the study.According to whether cases secondary to AKI,they were divided into AKI group (64 cases) and non-AKI group (50 cases).At same time 50 healthy cases were selected as the control group.The Serum creatinine (Scr),urinary nitrogen (BUN),Cys C,NGAL and urinary IL-18 levels were measured in each subject.The relationship between the indexes of AKI group was analyzed by Pearson analysis.The value of serum Cys-C,NGAL and urinary IL-18 in the diagnosis of AKI was analyzed by receiver operating characteristic (ROC) curve.Results Serum Cys-C,NGAL and urinary IL-18 levels of the AKI group were higher than that of the non-AKI group and the control group,the difference had statistical significance (t=3.137～28.642,t1 =7.653～33.672,all P＜0.05).The levels of serum Cys-C and NGAL were positively correlated with Scr levels (Beta=0.273,0.514,all P＜0.05).The urinary IL-18 levels were negatively correlated with serum albumin (Alb) (Beta =-0.342,P＜0.05).The area under the ROC carve (AUC) of serum Cys-C,NGAL and urinary IL-18 was 0.872 (95％ CI:0.831～0.936),0.823 (95％ CI:0.641～0.925) and 0.714 (95％CI:0.598～0.833).Conclusion The levels of serum Cys-C and NGAL were elevated earlier than Scr,and it can be used as reliable indicators of early diagnosis of early cases AKI in ICU.
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Bile acids participated in regulation of many physiological functions in the human body. Transporters in liver and intestinal play an important role in maintaining the enterohepatic circulation and bile acid homeostasis. With the rapid development of molecular biology in recent years, there has been great progress toward cloning and identifying the individual bile acid transporters and explaining their complex regulation. Bile acid transporters were regulated by various factors including bile acids, nuclear receptors, transcription factors, hormones, etc., which influence their protein expression, cell location and transport activities. This article reviews the research progress of bile acid transporters for the purpose of providing references for the mechanism research of bile acid transporter related disorders and drug development.
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The body is exposed to various organic anions,so it is the best way to remove the toxic substances in the body quickly and effectively.Cross epithelial active transport mediated by organic anion transporter is the rate limiting process.Renal secretion and re-absorption of a variety of endogenous and exogenous organic anions are occurred in the proximal tubular epithelial cells of the organic anion transporter family.The expression of organic anion transporter-1 (OAT1) in proximal tubular epithelial cells plays an important role in the introduction of organic anion into the renal tubular epithelial cells.This article reviewed the renal expression,the substrate and the polymorphism of the organic anion transport protein OAT1,the renal toxicity of adefovir dipivoxil,the interaction between organic anion transporters and drug,and the influence of the renal toxicity on the renal toxicity of adefovir dipivoxil.
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Lesinurad (RDEA 594), discovered by Ardea Biosciences, is a new drug used for the treatment of gout. RDEA594 could increase the excretion of uric acid to reduce uric acid levels by inhibiting the uric acid salt transport protein 1 (URAT1). In this essay, we summarize synthetic methods of lesinurad reported in recent years, evaluate and analyze them briefly, aiming to lay a foundation for lesinurad synthesis process to achieve industrialization.
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Objective To study the expression of copper transport protein 1 in the inner ear of rat and the changes of CTR1 expression after those round window niche copper sulfate and cisplatin infusion .Methods 24 male wistar rats were randomly divided into 4 groups :Group I as the normal control group (nontreatment group);Group II as the round window niche cisplatin infusion group(0 .5 mg/ml);Group III as the round window niche cisplatin infusion group (1 mg/ml);group IV as the round window niche copper sulfate infusion (0 .02 mg/kg) .The CTR1 protein was detected by the immunohistochemical (IHC) otaining and Western-blot ,and the CTR1mRNA expres‐sion levels were detected by RT -PCR .Results The expression of CTR1 protein was observed in the cytoplasm and cell membrane of Corti organ cells ,spiral ganglion cells and stria vascularis in all groups .The average optical densi‐ties of CTR1 protein was a downward trend .The expression of CTR1 protein was observed in four different groups . The optical density analysis of CTR1 showed that the optical densities were 0 .532 ± 0 .031 ,0 .394 ± 0 .024 ,0 .234 ± 0 .030 and 0 .191 ± 0 .015 ,respectively .There was a downward trend ,and there were statistically differences among the groups (P<0 .05) .The CTR1 mRNA was observed in all groups .The optical density analysis of CTR1 mRNAshowed that the optical densities were 0 .508 ± 0 .035 ,0 .391 ± 0 .022 ,0 .240 ± 0 .02 and 0 .186 ± 0 .021 ,respective‐ly .It had a downward trend and were statistically differences among the groups (P<0 .05) .Conclusion The CTR1 protein was abundantly expressed in Corti organ ,spiral ganglion cells and stria vascularis of the cochlea .The round window cisplatin and copper sulfate infusion can change the expression of CTR1 proteins in inner ear .
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Objective: To investigate the expression of intraflagellar transport 20 (IFT20) protein in lung cancer tissues and its effect on the proliferation of lung cancer A549 cells. Methods: The expressions of IFT20 protein in 20 specimens of lung cancer tissues and 4 specimens of normal lung tissues were detected by immunohistochemistry. After the small interfering RNA (siRNA) targeting IFT20 gene was transfected into A549 cells, the expression level of IFT20 mRNA was detected by real-time fluorescence-based quantitative-PCR, the proliferation of A549 cells was determined by MTT assay, the number and length of cilia were observed by immunofluorescence staining, and the proteins expressions in A549 cells were measured by protein chip detection. Results: The expression of IFT20 protein was weakly positive in lung cancer tissues and moderately positive in normal lung tissues. The expression level of IFT20 mRNA in lung cancer A549 cells after transfection with IFT20-targeted siRNA was lower than those in the negative control cells (A549 cells were transfected with control siRNA) and the blank control cells (A549 cells with no transfection) (P < 0.05). The proliferation of A549 cells after transfection with IFT20-targeted siRNA was accelerated (P < 0.05), the expression level of IFT20 protein was down-regulated, the number of cilia was reduced, the length of cilia was shorterned, or the cilia was disappeared (all P < 0.05). The expression levels of X-linked inhibitor of apoptosis protein (XIAP), survivin, high temperature requirment A (HTRA), heat shock protein (Hsp) 27, Hsp70 and second mitochondria-derived activator of caspase (SMAC) were up-regulated (all P < 0.05). Conclusion: The IFT20 protein is lowly expressed in lung cancer tissues. After the inhibition of IFT20 expression, the cilia become less and shorter, which promotes the proliferation of lung cancer A549 cells.
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OBJECTIVE: To elucidate the mechanism of the active chemical substance of Radix Polygoni Multiflori which is an important Yunyao with lipid-lowering activity, 2, 3, 5, 4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), for regulating lipid metabolism, thus making a foundation for further studies of Radix Polygoni Multiflori.
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Objective: Aiming at the target point of sodium-glucose transport protein (SGLT) inhibitors, to screen and estimate the hypoglycemic effects of novel glycoside derivatives by urine glucose testing methods. Methods: SD rats were ig administered with eight novel glycoside derivatives (30 mg/kg); The urine of rats was collected and the content of glucose was measured by hexokinase method in various periods. Also, the blood samples were obtained from tail vain of rats, the blood glucose was measured using blood glucose meter, and the glucose tolerance test of the active compounds was carried out. Results: In novel glycoside derivatives, N-glycoside TY702-1N and S-glycoside TY702-1S had less hypoglycemic effect, C-glycoside TY702-4C had more obvious effect of excreting glucose, and it has a dose-dependent manner in blood glucose and urine gluose. Conclusion: TY702-4C is a lead compound with good prospect in the research and development of new drug with more efficient and better pharmacokinetic characteristics.
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Visceral hypersensitivity plays an important role in motor and sensory abnormalities associated with irritable bowel syndrome, but the underlying mechanisms are not fully understood. The present study was designed to evaluate the expression of the 5-HT4 receptor and the serotonin transporter (SERT) as well as their roles in chronic visceral hypersensitivity using a rat model. Neonatal male Sprague-Dawley rats received intracolonic injections of 0.5% acetic acid (0.3-0.5 mL at different times) between postnatal days 8 and 21 to establish an animal model of visceral hypersensitivity. On day 43, the threshold intensity for a visually identifiable contraction of the abdominal wall and body arching were recorded during rectal distention. Histological evaluation and the myeloperoxidase activity assay were performed to determine the severity of inflammation. The 5-HT4 receptor and SERT expression of the ascending colon were monitored using immunohistochemistry and Western blot analyses; the plasma 5-HT levels were measured using an ELISA method. As expected, transient colonic irritation at the neonatal stage led to visceral hypersensitivity, but no mucosal inflammation was later detected during adulthood. Using this model, we found reduced SERT expression (0.298 ± 0.038 vs 0.634 ± 0.200, P < 0.05) and increased 5-HT4 receptor expression (0.308 ± 0.017 vs 0.298 ± 0.021, P < 0.05). Treatment with fluoxetine (10 mg·kg-1·day-1, days 36-42), tegaserod (1 mg·kg-1·day-1, day 43), or the combination of both, reduced visceral hypersensitivity and plasma 5-HT levels. Fluoxetine treatment increased 5-HT4 receptor expression (0.322 ± 0.020 vs 0.308 ± 0.017, P < 0.01) but not SERT expression (0.219 ± 0.039 vs 0.298 ± 0.038, P = 0.654). These results indicate that both the 5-HT4 receptor and SERT play a role in the pathogenesis of visceral hypersensitivity, and its mechanism may be involved in the local 5-HT level.