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1.  MiR-132 Suppresses the Migration and Invasion of Lung Cancer Cells via Targeting the EMT Regulator ZEB2 
PLoS ONE  2014;9(3):e91827.
MicroRNAs (miRNAs) are small, non-coding RNAs which can function as oncogenes or tumor suppressor genes in human cancers. Emerging evidence reveals that deregulation of miRNAs contributes to the human non-small cell lung cancer (NSCLC). In the present study, we demonstrated that the expression levels of miR-132 were dramatically decreased in examined NSCLC cell lines and clinical NSCLC tissue samples. Then, we found that introduction of miR-132 significantly suppressed the migration and invasion of lung cancer cells in vitro, suggesting that miR-132 may be a novel tumor suppressor. Further studies indicated that the EMT-related transcription factor ZEB2 was one direct target genes of miR-132, evidenced by the direct binding of miR-132 with the 3′ untranslated region (3′ UTR) of ZEB2. Further, miR-132 could decrease the expression of ZEB2 at the levels of mRNA and protein. Notably, the EMT marker E-cadherin or vimentin, a downstream of ZEB2, was also down-regulated or up-regulated upon miR-132 treatment. Additionally, over-expressing or silencing ZEB2 was able to elevate or inhibit the migration and invasion of lung cancer cells, parallel to the effect of miR-132 on the lung cancer cells. Meanwhile, knockdown of ZEB2 reversed the enhanced migration and invasion mediated by anti-miR-132. These results indicate that miR-132 suppresses the migration and invasion of NSCLC cells through targeting ZEB2 involving the EMT process. Thus, our finding provides new insight into the mechanism of NSCLC progression. Therapeutically, miR-132 may serve as a potential target in the treatment of human lung cancer.
doi:10.1371/journal.pone.0091827
PMCID: PMC3953608  PMID: 24626466
2.  Synchronous evolution of an odor biosynthesis pathway and behavioral response 
Current biology : CB  2012;23(1):11-20.
SUMMARY
Background
Rodents use olfactory cues for species-specific behaviors. For example, mice emit odors to attract mates of the same species but not competitors of closely related species. This implies rapid evolution of olfactory signaling, although odors and chemosensory receptors involved are unknown.
Results
Here, we identify a mouse chemosignal, trimethylamine, and its olfactory receptor, trace amine-associated receptor 5 (TAAR5), to be involved in species-specific social communication. Abundant (>1,000-fold increased) and sex-dependent trimethylamine production arose de novo along the Mus lineage after divergence from Mus caroli. The two-step trimethylamine biosynthesis pathway involves synergy between commensal microflora and a sex-dependent liver enzyme, flavin-containing monooxygenase 3 (FMO3), which oxidizes trimethylamine. One key evolutionary alteration in this pathway is the recent acquisition in Mus of male-specific Fmo3 gene repression. Coincident with its evolving biosynthesis, trimethylamine evokes species-specific behaviors, attracting mice but repelling rats. Attraction to trimethylamine is abolished in TAAR5 knockout mice, and furthermore, attraction to mouse scent is impaired by enzymatic depletion of trimethylamine or TAAR5 knockout.
Conclusions
TAAR5 is an evolutionarily conserved olfactory receptor required for a species-specific behavior. Synchronized changes in odor biosynthesis pathways and odor-evoked behaviors could ensure species-appropriate social interactions.
doi:10.1016/j.cub.2012.10.047
PMCID: PMC3543494  PMID: 23177478
3.  The Suppressive Role and Aberrent Promoter Methylation of BTG3 in the Progression of Hepatocellular Carcinoma 
PLoS ONE  2013;8(10):e77473.
Background
BTG3 (B-cell translocation gene 3) has been identified as a tumor suppressor and hypermethylation contributes to its down-regulation in some tumors, but its role in hepatocellular carcinoma (HCC) remain unknown. This study aimed to detect the expression and methylation status of BTG3 in HCC cell lines or tissues, and determine its function in HCC progression.
Methodology
The expression of BTG3 was detected in HCC cell lines and HCC tissue by real-time RT-PCR, Western blot or immunohistochemistry. The promoter methylation status of BTG3 was measured by using methylation-specific PCR in HCC cell lines. A series of assays were performed to evaluate the effect of BTG3 on proliferation, invasion and cell cycle transition in vitro.
Results
BTG3 expression was lower in HCC cell lines than in hepatocyte cell line LO2 (P<0.05). BTG3 was also down-regulated in HCC tissues. Its expression was positively correlated with differentiation and distant metastasis (P<0.05). Patients with lower BTG3 expression had shorter overall survival time (P=0.029). DNA methylation directed repression of BTG3 mRNA expression in HCC cell lines. BTG3 suppressed proliferation, invasion and induces G1/S cycle arrest of HCC cells in vitro.
Conclusion
Down-regulation of BTG3 due to the promoter hypermethylation is closely associated with proliferation, invasion and cell cycle arrest of HCC cells. It may be a novel prognostic biomarker for HCC patients.
doi:10.1371/journal.pone.0077473
PMCID: PMC3798399  PMID: 24147003
4.  Roles of Adrenergic α1 and Dopamine D1 and D2 Receptors in the Mediation of the Desynchronization Effects of Modafinil in a Mouse EEG Synchronization Model 
PLoS ONE  2013;8(10):e76102.
Background
Synchronized electroencephalogram (EEG) activity is observed in pathological stages of cognitive impairment and epilepsy. Modafinil, known to increase the release of catecholamines, is a potent wake-promoting agent, and has shown some abilities to desynchronize EEG,but its receptor mechanisms by which modafinil induces desynchoronization remain to be elucidated. Here we used a pharmacological EEG synchronization model to investigate the involvement of adrenergic α1 receptors (R, α1R) and dopamine (DA) D1 and D2 receptors (D1Rs and D2Rs) on modafinil-induced desynchronization in mice.
Methodology/Principal Findings
Mice were treated with cholinergic receptor antagonist scopolamine and monoamine depletor reserpine to produce experimental EEG synchronization characterized by continuous large-amplitude synchronized activity, with prominent increased delta and decreased theta, alpha, and beta power density. The results showed that modafinil produced an EEG desynchronization in the model. This was characterized by a general decrease in amplitude of all the frequency bands between 0 and 20 Hz, a prominent reduction in delta power density, and an increase in theta power density. Adrenergic α1R antagonist terazosin (1 mg/kg, i.p.) completely antagonized the EEG desynchronization effects of modafinil at 90 mg/kg. However, DA D1R and D2R blockers partially attenuated the effects of modafinil. The modafinil-induced decrease in the amplitudes of the delta, theta, alpha, and beta waves and in delta power density were completely abolished by pretreatment with a combination of the D1R antagonist SCH 23390 (30 µg/kg) and the D2R antagonist raclopride (2 mg/kg, i.p.).
Conclusions/Significance
These results suggest that modafinil-mediated desynchronization may be attributed to the activation of adrenergic α1R, and dopaminergic D1R and D2R in a model of EEG synchronization.
doi:10.1371/journal.pone.0076102
PMCID: PMC3792106  PMID: 24116090
5.  The top cited articles on glioma stem cells in Web of Science☆ 
Neural Regeneration Research  2013;8(15):1431-1438.
Background:
Glioma is the most common intracranial tumor and has a poor patient prognosis. The presence of brain tumor stem cells was gradually being understood and recognized, which might be beneficial for the treatment of glioma.
Objective:
To use bibliometric indexes to track study focuses on glioma stem cell, and to investigate the relationships among geographic origin, impact factors, and highly cited articles indexed in Web of Science.
Methods:
A list of citation classics for glioma stem cells was generated by searching the database of Web of Science-Expanded using the terms “glioma stem cell” or “glioma, stem cell” or “brain tumor stem cell”. The top 63 cited research articles which were cited more than 100 times were retrieved by reading the abstract or full text if needed. Each eligible article was reviewed for basic information on subject categories, country of origin, journals, authors, and source of journals. Inclusive criteria: (1) articles in the field of glioma stem cells which was cited more than 100 times; (2) fundamental research on humans or animals, clinical trials and case reports; (3) research article; (4) year of publication: 1899–2012; and (5) citation database: Science Citation Index-Expanded. Exclusive criteria: (1) articles needing to be manually searched or accessed only by telephone; (2) unpublished articles; and (3) reviews, conference proceedings, as well as corrected papers.
Results:
Of 2 040 articles published, the 63 top-cited articles were published between 1992 and 2010. The number of citations ranged from 100 to 1 754, with a mean of 280 citations per article. These citation classics came from nineteen countries, of which 46 articles came from the United States. Duke University and University of California, San Francisco led the list of classics with seven papers each. The 63 top-cited articles were published in 28 journals, predominantly Cancer Research and Cancer Cell, followed by Cell Stem Cell and Nature.
Conclusion:
Our bibliometric analysis provides a historical perspective on the progress of glioma stem cell research. Articles originating from outstanding institutions of the United States and published in high-impact journals are most likely to be cited.
doi:10.3969/j.issn.1673-5374.2013.15.011
PMCID: PMC4107765  PMID: 25206439
Neural regeneration; reviews; brain glioma; stem cells; glioma stem cells; cancer stem cells; literature analysis; Web of Science; bibliometrics; citation; neuroregeneration
6.  Repair of damaged intestinal mucosa in a mouse model of sepsis 
BACKGROUND:
The intestine is not only the main target attacked by sepsis but also the vital organ which mediated sepsis. The recovery of the damaged intestinal barrier structure and function is related to the occurrence and outcome of multiple organ dysfunction syndrome (MODS). How to protect and reduce the damage of the intestinal mucosa and how to promote the reconstruction of the intestinal mucosa have been the important topics in sepsis for many years. This study aimed to investigate the influential factors of intestinal mucosal reconstruction after intestinal epithelial injury in vivo in a mouse model of sepsis.
METHODS:
Mice were subjected to cecal ligation and puncture (CLP) for induction of sepsis to assess intestinal mucosal damage, epithelial cell apoptosis, and transformed number of goblet cells, and to detect the concentration of TNF-α, IL-1 and TGF-β1 and TFF3 (trefoil factor 3) expression in the small intestinal mucosa. All above were performed by HE staining, western blot, ELISA and immunohistochemistry respectively. The experimental animals were divided into a sepsis group and a sham-operation group. The animals with sepsis were separately killed at 6 (7 animals), 24 (7 animals) and 48 hours (7 animals) after CLP.
RESULTS:
Injured intestinal mucosa was observed in the 3 groups under a light microscope, in which damage scores in the 24-hour and 48-hour groups were higher than in the 6-hour group and no difference was found between the two groups. Moreover, less of goblet cells or other epithelial cells adjacent to the injured surface migrated into the wound to cover the denuded area. The number of goblet cells was substantially decreased in the three CLP groups compared with the sham-operation group. Protein levels of IL-1 and TNF-α were significantly increased by 3–4 fold at all time points when compared with the sham-operation group, and cleaved caspase-3 by 4 fold. Although TFF3 expression was modestly increased for 6 hours after the onset of CLP, it appeared to decline at 24 hours and 48 hours as shown by Western blot. A similar tendency was observed upon TGF-β1, i.e. the protein level was not elevated at 24 hours and 48 hours, but increased modestly at 6 hours.
CONCLUSIONS:
Sepsis from CLP shows less restitution on the surface of injured intestinal mucosa. There is evidence that both constant inflammatory reaction and epithelial cell apoptosis may affect mucosal reestablishment of the intestine at the onset of sepsis. Mucosa after severe sepsis showed the state of high inflammation, and declined goblet cell function and mucosal reconstruction, which affected the repair of damaged intestinal barrier. Constant inflammatory reaction, and declined goblet cell function and mucosal reconstruction ability may affect the reestablishment of intestinal mucosa at the onset of sepsis.
doi:10.5847/wjem.j.issn.1920-8642.2013.03.012
PMCID: PMC4129853  PMID: 25215123
Sepsis; Cecal ligation and puncture; Intestinal mucosa; Restitution; Goblet cells; Intestinal trefoil factor 3; Transforming growth factor β1; Cysteine-containing aspartate-specific proteases
7.  p300 exerts an epigenetic role in chronic neuropathic pain through its acetyltransferase activity in rats following chronic constriction injury (CCI) 
Molecular Pain  2012;8:84.
Background
Neuropathic pain is detrimental to human health; however, its pathogenesis still remains largely unknown. Overexpression of pain-associated genes and increased nociceptive somato-sensitivity are well observed in neuropathic pain. The importance of epigenetic mechanisms in regulating the expression of pro- or anti-nociceptive genes has been revealed by studies recently, and we hypothesize that the transcriptional coactivator and the histone acetyltransferase E1A binding protein p300 (p300), as a part of the epigenetic mechanisms of gene regulation, may be involved in the pathogenesis of neuropathic pain induced by chronic constriction injury (CCI). To test this hypothesis, two different approaches were used in this study: (I) down-regulating p300 with specific small hairpin RNA (shRNA) and (II) chemical inhibition of p300 acetyltransferase activity by a small molecule inhibitor, C646.
Results
Using the CCI rat model, we found that the p300 expression was increased in the lumbar spinal cord on day 14 after CCI. The treatment with intrathecal p300 shRNA reversed CCI-induced mechanical allodynia and thermal hyperalgesia, and suppressed the expression of cyclooxygenase-2 (COX-2), a neuropathic pain-associated factor. Furthermore, C646, an inhibitor of p300 acetyltransferase, also attenuated mechanical allodynia and thermal hyperalgesia, accompanied by a suppressed COX-2 expression, in the spinal cord.
Conclusions
The results suggest that, through its acetyltransferase activity in the spinal cord after CCI, p300 epigenetically plays an important role in neuropathic pain. Inhibiting p300, using interfering RNA or C646, may be a promising approach to the development of new neuropathic pain therapies.
doi:10.1186/1744-8069-8-84
PMCID: PMC3558366  PMID: 23176208
Neuropathic pain; p300; COX-2; Acetyltransferase activity; CCI
8.  A Novel Knowledge-Driven Systems Biology Approach for Phenotype Prediction upon Genetic Intervention 
Deciphering the biological networks underlying complex phenotypic traits, e.g., human disease is undoubtedly crucial to understand the underlying molecular mechanisms and to develop effective therapeutics. Due to the network complexity and the relatively small number of available experiments, data-driven modeling is a great challenge for deducing the functions of genes/ proteins in the network and in phenotype formation. We propose a novel knowledge-driven systems biology method that utilizes qualitative knowledge to construct a Dynamic Bayesian network (DBN) to represent the biological network underlying a specific phenotype. Edges in this network depict physical interactions between genes and/or proteins. A qualitative knowledge model first translates typical molecular interactions into constraints when resolving the DBN structure and parameters. Therefore, the uncertainty of the network is restricted to a subset of models which are consistent with the qualitative knowledge. All models satisfying the constraints are considered as candidates for the underlying network. These consistent models are used to perform quantitative inference. By in silico inference, we can predict phenotypic traits upon genetic interventions and perturbing in the network. We applied our method to analyze the puzzling mechanism of breast cancer cell proliferation network and we accurately predicted cancer cell growth rate upon manipulating (anti)cancerous marker genes/proteins.
doi:10.1109/TCBB.2011.18
PMCID: PMC3211072  PMID: 21282866
Dynamic Bayesian network; genetic network; phenotype prediction; genetic intervention; systems biology; breast cancer; cell proliferation
9.  Clinical evaluation of two multifocal intraocular lens implantation patterns 
AIM
To evaluate the visual outcomes and patient satisfaction of two multifocal intraocular lens implantation patterns, with the decision between the two patterns being guided by the patients' choice of visual zones that best suited their lifestyle, or lifestyle zones.
METHODS
This is a prospective non-randomized comparative study. The lifestyle zones of 32 consecutive age-related cataract patients (64 eyes) were investigated individually to guide the surgical decision between two multifocal intraocular lens implantation patterns. The first group (MIX) received a combined implantation of a ReZoom NXG1 lens in the dominant eye and a Tecnis ZM900 lens in the other eye. The second group (MATCH) received bilateral ReZoom NXG1 lenses. One year postoperatively, the patients were assessed for binocular uncorrected visual acuity, reading visual acuity, reading speed and depth of focus under different luminance and were surveyed for visual disturbances, satisfaction and complete spectacle independence.
RESULTS
According to the determination of lifestyle zones, 18 and 14 patients were included in the MIX and MATCH groups, respectively. One year postoperatively, each of the patients exhibited positive visual outcomes and lifestyle satisfaction, although there were still some differences between the two groups. Generally, patients in the MATCH group had better distance visual acuity than those in the MIX group. In contrast, patients in the MIX group had better near visual acuity, better reading acuity and better reading speed than those in the MATCH group. Between the two groups, there was no clear difference in intermediate visual acuity, and the depths of focus between the two groups were approximately equal. The results of the mean NEI-RQL-42 questionnaire score, overall satisfaction, and complete spectacle independence did not differ between the two groups.
CONCLUSION
Different multifocal intraocular lenses implantation patterns can have differing advantages and disadvantages; however, the best results with respect to visual outcome and patient satisfaction can be achieved by taking individual lifestyle zones into account.
doi:10.3980/j.issn.2222-3959.2012.01.16
PMCID: PMC3340833  PMID: 22553760
intraocular lens; visual outcomes; patient satisfaction
10.  Systematic Search for Recipes to Generate Induced Pluripotent Stem Cells 
PLoS Computational Biology  2011;7(12):e1002300.
Generation of induced pluripotent stem cells (iPSCs) opens a new avenue in regenerative medicine. One of the major hurdles for therapeutic applications is to improve the efficiency of generating iPSCs and also to avoid the tumorigenicity, which requires searching for new reprogramming recipes. We present a systems biology approach to efficiently evaluate a large number of possible recipes and find those that are most effective at generating iPSCs. We not only recovered several experimentally confirmed recipes but we also suggested new ones that may improve reprogramming efficiency and quality. In addition, our approach allows one to estimate the cell-state landscape, monitor the progress of reprogramming, identify important regulatory transition states, and ultimately understand the mechanisms of iPSC generation.
Author Summary
Converting somatic cells back to the stem cell state (called induced pluripotent stem cells or iPSCs) exemplifies the recent advancement of cellular reprogramming that holds great promise for developing regenerative medicine. Generation of iPSCs is often achieved by overexpressing three to four genes in somatic cells that are critical for regulating pluripotency. Developing optimal reprogramming recipe is a non-trivial task that requires significant effort. We present here a computational method that can facilitate discovery of effective recipes to generate iPSCs with high efficiency and better quality. In addition, our approach provides a new way to estimate the landscape in the cell-state space and monitor the trajectory of cellular reprogramming from a differentiated cell to an iPS cell. This work provides not only practical recipes for iPSC generation but also theoretical understanding of the reprogramming process.
doi:10.1371/journal.pcbi.1002300
PMCID: PMC3245295  PMID: 22215993
11.  A TRPA1-dependent mechanism for the pungent sensation of weak acids 
The Journal of General Physiology  2011;137(6):493-505.
Acetic acid produces an irritating sensation that can be attributed to activation of nociceptors within the trigeminal ganglion that innervate the nasal or oral cavities. These sensory neurons sense a diverse array of noxious agents in the environment, allowing animals to actively avoid tissue damage. Although receptor mechanisms have been identified for many noxious chemicals, the mechanisms by which animals detect weak acids, such as acetic acid, are less well understood. Weak acids are only partially dissociated at neutral pH and, as such, some can cross the cell membrane, acidifying the cell cytosol. The nociceptor ion channel TRPA1 is activated by CO2, through gating of the channel by intracellular protons, making it a candidate to more generally mediate sensory responses to weak acids. To test this possibility, we measured responses to weak acids from heterologously expressed TRPA1 channels and trigeminal neurons with patch clamp recording and Ca2+ microfluorometry. Our results show that heterologously expressed TRPA1 currents can be induced by a series of weak organic acids, including acetic, propionic, formic, and lactic acid, but not by strong acids. Notably, the degree of channel activation was predicted by the degree of intracellular acidification produced by each acid, suggesting that intracellular protons are the proximate stimulus that gates the channel. Responses to weak acids produced a Ca2+-independent inactivation that precluded further activation by weak acids or reactive chemicals, whereas preactivation by reactive electrophiles sensitized TRPA1 channels to weak acids. Importantly, responses of trigeminal neurons to weak acids were highly overrepresented in the subpopulation of TRPA1-expressing neurons and were severely reduced in neurons from TRPA1 knockout mice. We conclude that TRPA1 is a general sensor for weak acids that produce intracellular acidification and suggest that it functions within the pain pathway to mediate sensitivity to cellular acidosis.
doi:10.1085/jgp.201110615
PMCID: PMC3105510  PMID: 21576376
12.  TRPA1 is a Component of the Nociceptive Response to CO2 (CO2 Sensing by TRPA1) 
In humans, high concentrations of CO2, as found in carbonated beverages, evoke a mixture of sensations that include a stinging or pungent quality. The stinging sensation is thought to originate with the activation of nociceptors which innervate the respiratory, nasal and oral epithelia. The molecular basis for this sensation is unknown. Here we show that CO2 specifically activates a subpopulation of trigeminal neurons that express TRPA1, a mustard oil and cinnamaldehyde-sensitive channel, and that these responses are dependent on a functional TRPA1 gene. TRPA1 is sufficient to mediate responses to CO2 as TRPA1 channels expressed in HEK-293 cells, but not TRPV1 channels were activated by bath applied CO2. CO2 can diffuse into cells and produce intracellular acidification, which could gate TRPA1 channels. Consistent with this mechanism, TRPA1 channels in excised patches were activated in a dose-dependent manner by intracellular protons. We conclude that TRPA1, by sensing intracellular acidification, constitutes an important component of the nociceptive response to CO2.
doi:10.1523/JNEUROSCI.2715-10.2010
PMCID: PMC2993877  PMID: 20881114
CO2; nociceptors; trigeminal; pain; TRP channel; proton
13.  A Requirement for CDK6 in Thymocyte Development and Tumorigenesis 
Cancer research  2009;69(3):810-818.
CDK6 promotes cell cycle progression and is over-expressed in human lymphoid malignancies. To determine the role of CDK6 in development and tumorigenesis, we generated and analyzed knockout mice. Cdk6-deficient mice show pronounced thymic atrophy due to reduced proliferative fractions and concomitant transitional blocks in the double negative (DN) stages. Using the OP9-DL1 system to deliver temporally controlled, Notch-receptor dependent signaling, we show that CDK6 is required for Notch-dependent survival, proliferation and differentiation. Furthermore, CDK6-deficient mice were resistant to lymphomagenesis induced by active AKT, a downstream target of Notch signaling. These results demonstrate a critical requirement for CDK6 in Notch/AKT-dependent T cell development and tumorigenesis and strongly support CDK6 as a specific therapeutic target in human lymphoid malignancies.
doi:10.1158/0008-5472.CAN-08-2473
PMCID: PMC2636510  PMID: 19155308
CDK6; thymocytes; thymus; development; tumorigenesis
14.  Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1 
Neural Development  2008;3:15.
Background
β-Amyloid precursor protein (APP) has been reported to play a role in the outgrowth of neurites from cultured neurons. Both cell-surface APP and its soluble, ectodomain cleavage product (APPs-α) have been implicated in regulating the length and branching of neurites in a variety of assays, but the mechanism by which APP performs this function is not understood.
Results
Here, we report that APP is required for proper neurite outgrowth in a cell autonomous manner, both in vitro and in vivo. Neurons that lack APP undergo elongation of their longest neurite. Deletion of APLP1 or APLP2, homologues of APP, likewise stimulates neurite lengthening. Intriguingly, wild-type neurons exposed to APPs-α, the principal cleavage product of APP, also undergo neurite elongation. However, APPs-α is unable to stimulate neurite elongation in the absence of cellular APP expression. The outgrowth-enhancing effects of both APPs-α and the deletion of APP are inhibited by blocking antibodies to Integrin β1 (Itgβ1). Moreover, full length APP interacts biochemically with Itgβ1, and APPs-α can interfere with this binding.
Conclusion
Our findings indicate that APPs-α regulates the function of APP in neurite outgrowth via the novel mechanism of competing with the binding of APP to Itgβ1.
doi:10.1186/1749-8104-3-15
PMCID: PMC2442059  PMID: 18573216
15.  Functional and morphological changes of the gut barrier during the restitution process after hemorrhagic shock 
AIM: To investigate the functional, morphological changes of the gut barrier during the restitution process after hemorrhagic shock, and the regional differences of the large intestine and small intestine in response to ischemia/reperfusion injury.
METHODS: Forty-seven Sprague-Dawley rats with body weight of 250-300 g were divided into two groups: control group (sham shock n = 5) and experimental group (n = 42). Experimental group was further divided into six groups (n = 7 each) according to different time points after the hemorrhagic shock, including 0th h group, 1st h group, 3rd h group, 6th h group, 12th h group and 24th h group. All the rats were gavaged with 2 mL of suspension of lactulose (L) (100 mg/2 mL) and mannitol (M) (50 mg/each) at the beginning and then an experimental rat model of hemorrhagic shock was set up. The specimens from jejunum, ileum and colon tissues and the blood samples from the portal vein were taken at 0, 1, 3, 6, 12 and 24 h after shock resuscitation, respectively. The morphological changes of the intestinal mucosa, including the histology of intestinal mucosa, the thickness of mucosa, the height of villi, the index of mucosal damage and the numbers of goblet cells, were determined by light microscope and/or electron microscope. The concentrations of the bacterial endotoxin lipopolysaccharides (LPS) from the portal vein blood, which reflected the gut barrier function, were examined by using Limulus test. At the same time point, to evaluate intestinal permeability, all urine was collected and the concentrations of the metabolically inactive markers such as L and M in urine were measured by using GC-9A gas chromatographic instrument.
RESULTS: After the hemorrhagic shock, the mucosal epithelial injury was obvious in small intestine even at the 0th h, and it became more serious at the 1st and the 3rd h. The tissue restitution was also found after 3 h, though the injury was still serious. Most of the injured mucosal restitution was established after 6 h and completed in 24 h. Two distinct models of cell death-apoptosis and necrosis-were involved in the destruction of rat intestinal epithelial cells. The number of goblet cells on intestinal mucosa was reduced significantly from 0 to 24 h (the number from 243±13 to 157±9 for ileum, 310±19 to 248±18 for colon; r = -0.910 and -0.437 respectively, all P<0.001), which was the same with the large intestine, but the grade of injury was lighter with the values of mucosal damage index in 3 h for jejunum, ileum, and colon being 2.8, 2.6, 1.2, respectively. The mucosal thickness and the height of villi in jejunum and ileum diminished in 1 h (the average height decreased from 309±24 to 204±23 µm and 271±31 to 231±28 µm, r = -0.758 and -0.659, all P<0.001; the thickness from 547±23 to 418±28 µm and 483±45 to 364±35 µm, r = -0.898 and -0.829, all P<0.001), but there was no statistical difference in the colon (F = 0.296, P = 0.934). Compared with control group, the urine L/M ratio and the blood LPS concentration in the experimental groups raised significantly, reaching the peak in 3-6 h (L/M: control vs 3 h vs 6 h was 0.029±0.09 vs 0.063±0.012 vs 0.078±0.021, r = -0.786, P<0.001; LPS: control vs 3 h vs 6 h was 0.09±0.021 vs 0.063±0.012 vs 0.25±0.023, r = -0.623, P<0.001), and it kept increasing in 24 h.
CONCLUSION: The gut barrier of the rats was seriously damaged at the early phase of ischemic reperfusion injury after hemorrhagic shock, which included the injury and atrophy in intestinal mucosa and the increasing of intestinal permeability. Simultaneously, the intestinal mucosa also showed its great repairing potentiality, such as the improvement of the intestinal permeability and the recovery of the morphology at different phases after ischemic reperfusion injury. The restitution of gut barrier function was obviously slower than that of the morphology and there was no direct correlation between them. Compared with the small intestine, the large intestine had stronger potentiality against injury. The reduction of the amount of intestinal goblet cells by injury did not influence the ability of intestinal mucosal restitution at a certain extent and it appeared to be intimately involved in the restitution of the epithelium.
doi:10.3748/wjg.v11.i35.5485
PMCID: PMC4320358  PMID: 16222741
Gut barrier; Hemorrhagic shock; Restitution

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