糖尿病患者尿糖水平与尿白细胞干化学及尿液炎性细胞因子的相关性研究

目的:对糖尿病患者尿糖水平对尿液白细胞干化学法测定的影响及尿液中炎性细胞因子的变化进行分析研究,确定尿糖对尿白细胞干化学的影响与程度及其与尿液炎性细胞因子变化的相关性。方法:收集2014-12-2015-04尿液常规标本,用显微镜镜检筛选出尿液白细胞阳性的病例,根据尿糖结果分为尿糖阴性组(-)、阳性组(微量组±、1+组、2+组、3+组和4+组),分析这6组标本尿液干化学白细胞检测结果的差异,设计实验进行验证,同时检测各组的炎性细胞因子的变化,作相关性分析。结果:尿糖阴性组与阳性组的白细胞干化学检查结果存在显著差异(P<0.05),随着尿糖浓度升高到2+(28 mmol/L)及以上时,差异越显著(P<0.05);且随着尿糖浓度升高,干化学法白细胞检测的假阴性率越高(P<0.05),此时炎性细胞因子亦增高(P<0.05)。结论:尿糖浓度升高(28mmol/L及以上时)会对尿液白细胞干化学法检查结果产生明显影响,在临床检验工作中,对尿糖阳性(特别是尿糖28mmol/L及以上)的样本应及时显微镜复检,以确保尿液白细胞检测结果的准确性。

Mesenchymal stem cells： a new strategy for immunosuppression and tissue repair

Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immunosuppressive in vitro and in vivo. Our recent studies have shown that un-stimulated MSCs are indeed incapable of immunosuppression; they become potently immunosuppressive upon stimulation with the supernatant of activated lymphocytes, or with combinations of IFN-γ, with TNF-α, IL-1α or IL-1β. This observation revealed that under certain circumstances, inflammatory cytokines can actually become immunosuppressive. We showed that there is a species variation in the mechanisms of MSC-mediated immunosuppression： immunosuppression by cytokine-primed mouse MSCs is mediated by nitric oxide （NO）, whereas immunosuppression by cytokine-primed human MSCs is executed through indoleamine 2, 3-dioxygenase （IDO）. Additionally, upon stimulation with the inflammatory cytokines, both mouse and human MSCs secrete several leukocyte chemokines that apparently serve to attract immune cells into the proximity with MSCs, where NO or IDO is predicted to be most active. Therefore, immunosuppression by inflammatory cytokine-stimulated MSCs occurs via the concerted action of chemokines and immune-inhibitory NO or IDO produced by MSCs. Thus, our results provide novel information about the mechanisms of MSC-mediated immunosuppression and for better application of MSCs in treating tissue injuries induced by immune responses.

Role of the endothelium in inflammatory bowel diseases

Inflammatory bowel diseases(IBD) are a complex group of diseases involving alterations in mucosal immunity and gastrointestinal physiology during both initiation and progressive phases of the disease.At the core of these alterations are endothelial cells,whose continual adjustments in structure and function coordinate vascular supply,immune cell emigration,and regulation of the tissue environment.Expansion of the endothelium in IBD(angiogenesis),mediated by inflammatory growth factors,cytokines and chemokines,is a hallmark of active gut disease and is closely related to disease severity.The endothelium in newly formed or inflamed vessels differs from that in normal vessels in the production of and response to inflammatory cytokines,growth factors,and adhesion molecules,altering coagulant capacity,barrier function and blood cell recruitment in injury.This review examines the roles of the endothelium in the initiation and propagation of IBD pathology and distinctive features of the intestinal endothelium contributing to these conditions.

More stories on Th17 cells

For more than two decades, immunologists have been using the so-called Th1/Th2 paradigm to explain most of the phenomena related to adaptive immunity. The Thl/Th2 paradigm implied the existence of two different, mutu- ally regulated, CD4＋ T helper subsets： Thl cells, driving cell-mediated immune responses involved in tissue damage and fighting infection against intracellular parasites; and Th2 cells that mediate IgE production and are particu- larly involved in eosinophilic inflammation, allergy and clearance of helminthic infections. A third member of the T helper set, IL-17-producing CD4＋ T cells, now called Th17 cells, was recently described as a distinct lineage that does not share developmental pathways with either Thl or Th2 cells. The Th17 subset has been linked to autoimmune disorders, being able to produce IL-17, IL-17F and IL-21 among other inflammatory cytokines. Interestingly, it has been reported that there is not only a cross-regulation among Thl, Th2 and Th17 effector cells but there is also a di- chotomy in the generation of Th17 and T regulatory cells. Therefore, Treg and Th17 effector cells arise in a mutually exclusive fashion, depending on whether they are activated in the presence of TGF-β or TGF-β plus inflammatory cytokines such as IL-6. This review will address the discovery of the Th17 cells, and recent progress on their development and regulation.

Cinnamon extract suppresses experimental colitis through modulation of antigen-presenting cells

AIM:To investigate the anti-inflammatory effects of cinnamon extract and elucidate its mechanisms for targeting the function of antigen presenting cells.METHODS:Cinnamon extract was used to treat murine macrophage cell line(Raw 264.7),mouse primary antigen-presenting cells(APCs,MHCII+) and CD11c+dendritic cells to analyze the effects of cinnamon extract on APC function.The mechanisms of action of cinnamon extract on APCs were investigated by analyzing cytokine production,and expression of MHC antigens and co-stimulatory molecules by quantitative real-time PCR and flow cytometry.In addition,the effect of cinnamon extract on antigen presentation capacity and APC-dependent T-cell differentiation were analyzed by [H3]-thymidine incorporation and cytokine analysis,respectively.To confirm the anti-inflammatory effects of cinnamon extract in vivo,cinnamon or PBS was orally administered to mice for 20 d followed by induction of experimental colitis with 2,4,6 trinitrobenzenesulfonic acid.The protective effects of cinnamon extract against experimental colitis were measured by checking clinical symptoms,histological analysis and cytokine expression prof iles in inflamed tissue.RESULTS:Treatment with cinnamon extract inhibited maturation of MHCII+ APCs or CD11c+ dendritic cells(DCs) by suppressing expression of co-stimulatory molecules(B7.1,B7.2,ICOS-L),MHCII and cyclooxygenase(COX)-2.Cinnamon extract induced regulatory DCs(rDCs) that produce low levels of pro-inflammatory cytokines [interleukin(IL)-1β,IL-6,IL-12,interferon(IFN)-γ and tumor necrosis factor(TNF)-α] while expressing high levels of immunoregulatory cytokines(IL-10 and transforming growth factor-β).In addition,rDCs generated by cinnamon extract inhibited APC-dependent T-cell proliferation,and converted CD4+ T cells into IL-10high CD4+ T cells.Furthermore,oral administration of cinnamon extract inhibited development and progression of intestinal colitis by inhibiting expression of COX-2 and pro-inflammatory cytokines(IL-1β,IFN-γ and TNF-α),while enhancing IL-10 levels.CONCLUSION:Our study suggests the potential of cinnamon extract as an anti-inflammatory agent by targeting the generation of regulatory APCs and IL-10+ regulatory T cells.

Leptin treatment ameliorates acute lung injury in rats with cerulein-induced acute pancreatitis

AIM:To determine the effect of exogenous leptin on acute lung injury (ALI) in cerulein-induced acute pancreatitis (AP). METHODS:Forty-eight rats were randomly divided into 3 groups. AP was induced by intraperitoneal (i.p.) injection of cerulein (50 μg/kg) four times,at 1 h intervals. The rats received a single i.p. injection of 10 μg/kg leptin (leptin group) or 2 mL saline (AP group) after cerulein injections. In the sham group,animals were given a single i.p. injection of 2 mL saline. Experimental samples were collected for biochemical and histological evaluations at 24 h and 48 h after the induction of AP or saline administration. Blood samples were obtained for the determination of amylase,lipase,tumor necrosis factor (TNF)-a,interleukin (IL)-1β,macrophage inflammatory peptide (MIP)-2 and soluble intercellular adhesion molecule (sICAM)-1 levels,while pancreatic and lung tissues were removed for myeloperoxidase (MPO) activity,nitric oxide (NOx) level,CD40 expression and histological evaluation. RESULTS:Cerulein injection caused severe AP,confirmed by an increase in serum amylase and lipase levels,histopathological findings of severe AP,and pancreatic MPO activity,compared to the values obtained in the sham group. In the leptin group,serum levels of MIP-2,sICMA-1,TNF-a,and IL-1b,pancreatic MPO activity,CD40 expression in pancreas and lung tissues,and NOx level in the lung tissue were lower compared to those in the AP group. Histologically,pancreatic and lungdamage was less severe following leptin administration. CONCLUSION:Exogenous leptin attenuates inflammatory changes,and reduces pro-inflammatory cytokines,nitric oxide levels,and CD40 expression in ceruleininduced AP and may be protective in AP associated ALI.

Effects of penehyclidine hydrochloride in small intestinal damage caused by limb ischemia-reperfusion

AIM:To investigate the protective effect of penehyclidine hydrochloride post-conditioning in the damage to the barrier function of the small intestinal mucosa caused by limb ischemia-reperfusion(LIR) injury. METHODS:Male Wistar rats were randomly divided into three groups(36 rats each) :the sham-operation group(group S) ,lower limb ischemia-reperfusion group(group LIR) ,and penehyclidine hydrochloride postconditioning group(group PHC) .Each group was divided into subgroups(n=6 in each group) according to ischemic-reperfusion time,i.e.immediately 0 h(T1) ,1 h(T2) ,3 h(T3) ,6 h(T4) ,12 h(T5) ,and 24 h(T6) .Bilateral hind-limb ischemia was induced by rubber band application proximal to the level of the greater trochanter for 3 h.In group PHC,0.15 mg/kg of penehyclidine hydrochloride was injected into the tail vein immediately after 3 h of bilateral hind-limb ischemia.The designated rats were sacrificed at different time-points of reperfusion;diamine oxidase(DAO) ,superoxide dismutase(SOD) activity,myeloperoxidase(MPO) of small intestinal tissue,plasma endotoxin,DAO,tumor necrosis factor-α(TNF-α) ,and interleukin(IL) -10 in serum were detected in the rats. RESULTS:The pathological changes in the small intestine were observed under light microscope.The levels of MPO,endotoxin,serum DAO,and IL-10 at T1-T6,and TNF-αlevel at T1-T4 increased in groups LIR and PHC(P<0.05) compared with those in group S,but tissue DAO and SOD activity at T1-T6 decreased(P<0.05) .In group PHC,the tissue DAO and SOD activity at T2-T6,and IL-10 at T2-T5 increased to higher levels than those in group LIR(P<0.05) ;however,the levels of MPO,endotoxin,and DAO in the blood at T2-T6,and TNF-αat T2 and T4 decreased(P<0.05) . CONCLUSION:Penehyclidine hydrochloride post-conditioning may reduce the permeability of the small intestines after LIR.Its protection mechanisms may be related to inhibiting oxygen free radicals and inflammatory cytokines for organ damage.

Role of cytokines and chemokines in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) includes a variety of histological conditions (ranging from liver steatosis and steatohepatitis, to fibrosis and hepatocarcinoma) that are characterized by an increased fat content within the liver. The accumulation/deposition of fat within the liver is essential for diagnosis of NAFLD and might be associated with alterations in the hepatic and systemic inflammatory state. Although it is still unclear if each histological entity represents a different disease or rather steps of the same disease, inflammatory processes in NAFLD might influence its pathophysiology and prognosis. In particular, non-alcoholic steatohepatitis (the most inflamed condition in NAFLDs, which more frequently evolves towards chronic and serious liver diseases) is characterized by a marked activation of inflammatory cells and the upregulation of several soluble inflammatory mediators. Among several mediators, cytokines and chemokines might play a pivotal active role in NAFLD and are considered as potential therapeutic targets. In this review, we will update evidence from both basic research and clinical studies on the potential role of cytokines and chemokines in the pathophysiology of NAFLD.

Polymorphisms of some cytokines and chronic hepatitis B and C virus infection

AIM： To study the relationship between the polymorphisms in some cytokines and the outcome of hepatitis B virus （HBV） and hepatitis C virus （HCV） infection. METHODS： Samples were obtained from 203 patients infected with HBV and/or HCV while donating plasma in 1987, and 74 controls were obtained from a rural area of North China. Antibodies to HBV or HCV antigens were detected by enzyme-linked imrnunoassay. The presence of viral particles in the serum was determined by nested reverse-transcriptase polymerase chain reaction （PCR）. Hepatocellular injury, as revealed by alanine aminotransferase （ALT） and aspartate aminotransferase level, was detected by a Beckman LX-20 analyzer. DNA was extracted from blood cells. Then, the single nucleotide polymorphisms of IL-2-330, IFN-γ＋874, IL-10-1082/-592 and IL-4-589 were investigated by restriction fragment length polymorphism-PCR or sequence specific primer-PCR.RESULTS： Persistent infection with HBV, HCV, and HBV/HCV coinfection was associated with IL-2-330 TT genotype and T allele, IFN-γ＋874 AA genotype, and IL-10-1082 AA genotype. The clinical outcome of HBV and/or HCV infection was associated with IL-2-330 TT genotype and T allele, IFN-γ＋874 AA genotype, and IL-10-1082 AA genotype. IL-2-330 GG genotype frequency showed a negative correlation with clinical progression, IL-10-1082 AA genotype frequency showed a positive correlation and IL-10-1082 AG genotype frequency showed a negative correlation with clinical progression. HCV RNA positive expression was associated with IL-10-1082 AA genotype and the A allele frequency. Abnormal serum ALT level was associated with IL-10-592 AC genotype frequency and IL-4-589 CC genotype, CT genotype, and the C allele. CONCLUSION： These results suggest that polymorphisms in some cytokine genes influence persistent HBV and HCV infection, clinical outcome, HCV replication, and liver damage.

CD74 in antigen presentation,inflammation,and cancers of the gastrointestinal tract

CD74 is a protein whose initial role in antigen presentation was recognized two decades ago. Recent studies have revealed that it has additional functions as a receptor for macrophage migration inhibitory factor and as a receptor for an important human pathogen, Helicobacter pylori （H pylon）. The role of CD74 as a receptor is important because after binding of migration inhibitory factor or H pylori, NF-κB and Erkl/2 activation occurs, along with the induction of proinflammatory cytokine secretion. This review provides an up-to-date account of the functions of CD74 and how it might be involved in inflammation and cancer within the gastrointestinal tract.

TRAIL receptor mediates inflammatory cytokine release in an NF-κB-dependent manner

In the present article, we report that DR4 or DR5 overexpression dramatically activates the release of the inflammatory cytokines IL-8, TNF-α, CCL20, MIP-2 and MIP-1β in an NF-κB-dependent manner in 293T, MDA-MB-231 and HCT-116 cells. We showed that death receptor-mediated signals were extracellular domain-independent, whereas the effect of overexpression of the DR4 intracellular domain was much less potent. The TRADD-TRAF2-NIK- IKKα/β signaling cascade, which plays an essential role in TNF-induced NF-κB activation, was found to be involved in tumor necrosis factor-related apoptosis-inducing ligand （TRAIL） receptor-mediated signal transduction. The FADD-caspase signaling pathway, which has been reported to be mostly related to apoptosis, was identified as being essential for DR4 or DR5 overexpression-mediated NF-κB activation and cytokine secretion and crosstalks with the TRADD-TRAF2-NIK-IKKα/β signaling cascade. Furthermore, a DR5 agonistic antibody （AD5-10） triggered the inflammatory cytokine release. These data, together with previous reports, provide strong evidence that TRAIL and TRAIL receptors play an important role in inflammation.

Hepatitis C virus infection and health-related quality of life

Hepatitis C virus(HCV) hepatitis and other diseases related to HCV,such as cryoglobulinemia,lymphoma and renal failure,impair health-related quality of life(HRQoL).In addition,HCV per se might directly influence HRQoL via colonization of microglia in the brain or,indirectly,via the effect of systemic inflammatory cytokines which,in turn,can trigger brain interleukin production.The treatment of HCV-related disorders with interferon(IFN) has an effect on HRQoL.Initially,IFN causes a transient deterioration of HRQoL,due to the induction of depression and other side effects of treatment.Subsequently,the subjects who obtain a sustained virologic response experience an improvement in HRQoL.Only rarely does interferon treatment causes permanent detrimental effects on HRQoL,due to residual psychiatric or neurologic side effects.Liver transplantation is the only treatment for end-stage HCV-related liver disease.HRQoL generally improves massively a few months after transplantation,except in the case of serious complications of the transplant procedure.Furthermore,high levels of anxiety and neuroticism pre-transplant are associated with lower HRQoL one year after transplant.Additionally,six months after transplant,patients with HCV who experience virologic recurrence show significantly greater depression,anxiety,phobic anxiety,and paranoid ideation than anti-HCV-negative patients.In conclusion,optimal care for the overall well-being of patients with HCV infection requires adequate knowledge of their neurological and psychological status.

Ficolins and infectious diseases

Ficolins are serum complement lectins,with a structure similar to mannose-binding lectin （MBL） and lung surfactant protein （SP）-A and SP-D.Ficolins activate the lectin complement system and play important roles in host innate immunity.Ficolins are members of the collectin family of proteins,which act as pattern recognition receptors （PRRs）.They are soluble oligomeric defense proteins with lectin-like activity,and are able to recognize pathogen-associated molecular patterns （PAMPs）,which are carbohydrate molecules on the surface of pathogens,and of apoptotic,necrotic,and malignant cells.Upon binding to their specific PAMPs,ficolins may trigger activation of the immune system either （1） by initiating activation of complement via the lectin pathway,（2） by a primitive type of opsonophagocytosis,or （3） by stimulating secretion of the inflammatory cytokines interferon （IFN）-γ,interleukin （IL）-17,IL-6,and tumor necrosis factor （TNF）-α,and production of nitric oxide （NO）by macrophages,thus limiting the infection and concurrently orchestrating the subsequent adaptive immune response.Recently,a number of reports have shown that dysfunction or abnormal expression of ficolins may play crucial roles in viral and bacterial diseases and in inflammation.This review summarizes the reports on the roles of ficolins in the infectious diseases,and provides insight into ficolins as novel innate immune therapeutic options to treat these diseases.

Interferon-γ inhibits ghrelin expression and secretion via a somatostatin-mediated mechanism

AIM- To investigate if and how the proinflammatory cytokine interferon γ （IFNγ） affects ghrelin expression in mice. METHODS： The plasma concentration of ghrelin, and gastric ghrelin and somatostatin expression, were ex- amined in wild-type mice and mice infected with Helico- bacter pylori （H. pylorO. Furthermore, ghrelin expression was examined in two achlorhydric mouse models with varying degrees of gastritis due to bacterial overgrowth. To study the effect of IFNγ, alone, mice were given a subcutaneous infusion of IFNγ, for 7 d. Finally, the influ- ence of IFNγ, and somatostatin on the ghrelin promoter was characterized. RESULTS： H. py/ori infection was associated with a 50% reduction in ghrelin expression and plasma concentration. Suppression of ghrelin expression was in- versely correlated with gastric inflammation in achlorh- dyric mouse models. Subcutaneous infusion of IFNγ, suppressed fundic ghrelin mRNA expression and plasma ghrelin concentrations. Finally, we showed that the ghrelin promoter operates under the control of soma- tostatin but not under that of IFNγ. CONCLUSION： Gastric infection and inflammation is associated with increased IFNγ, expression and reduced ghrelin expression. IFNγ, does not directly control ghre- lin expression but inhibits it indirectly via somatostatin.

Lactobacillus crispatus M206119 exacerbates murine DSS-colitis by interfering with inflammatory responses

AIM： TO investigate the role of Lactobacillus crispatus （L. crispatus） strain China Center for Type Culture Col- lection （CCTCC） M206119 in intestinal inflammation.METHODS： Forty 8-wk-old Balb/c mice （20± 2 g） were divided into four groups of 10 mice each. Three groups that had received dextran sulfate sodium （DSS） were administered normal saline, sulfasalazine or CCTCC M206119 strain, and the fourth group received none of these. We assessed the severity of colitis using a disease activity index, measured the colon length and weight, collected stools and mesenteric lymph nodes for bacterial microflora analysis. One centimeter of the proximal colon, middle colon and distal colon were collected and fixed in 10% buffered formalin, dehydrated in ethanol, and embedded in paraffin. Interleukin （IL）- 1β, IL-6 and tumor necrosis factor （TNF）-α expression was detected using reverse transcription polymerase chain reaction. Protective factors zonula occludens （ZO）-1 and β-defensin 2 were detected by immunoblot-ting. The features of CCTCC M206119 strain were identified based on morphology, biochemical profile, and 16S RNA sequencing.RESULTS： DSS-colitis animals treated with CCTCC M206119 had markedly more severe disease, with greater weight loss, diarrhea, fecal bleeding, and shortened colon length. In addition, the CCTCC-M206119- treated group had comparatively higher histologi- cal scores and more neutrophil infiltration than the controls. Expression of protective factors ZO-1 and β-defensin 2 was downregulated due to destruction of the mucosal barrier after CCTCC M206119 strain treatment. An in vitro assay demonstrated that CCTCC M206119 strain increased the nuclear translocation of nuclear factor-κB in epithelial cells. Intestinal proinflam- matory or anti-inflammatory cytokine responses were evaluated. Proinflammatory colonic cytokine （IL-Iβ, IL-6 and TNF-α） levels were clearly increased in CCTCC- M206119-treated animals, whereas anti-inflammatory colonic cytokine （IL-10） level was lowered compared with saline or 5-aminosalicylic-acid-treated DSS-colitis mice. Next, CCTCC M206119 strain was characterized as 1. crispatus by microscopic morphology, biochemical tests and 16S rRNA gene level.CONCLUSION： Not all lactobacilli are beneficial for in- testinal inflammation, and L. crispatus CCTCC M206119 strain is involved in exacerbation of intestinal inflamma- tion in DSS-colitis mice.

Value of adipokines in predicting the severity of acute pancreatitis:Comprehensive review

AIM:To analyze the prognostic value of adipokines in predicting the course,complications and fatal outcome of acute pancreatitis(AP).METHODS:We performed the search of PubMed database and the systemic analysis of the literature for both experimental and human studies on prognostic value of adipokines in AP for period 2002-2012.Only the papers that described the use of adipokines for prediction of severity and/or complications of AP were selected for further analysis.Each article had to contain information about the levels of measured adipokines,diagnosis and verification of AP,to specify presence of pancreatic necrosis,organ dysfunction and/or mortality rates.From the very beginning,study was carried out adhering to the PRISMA checklist and flowchart for systemic reviews.To assess quality of all included human studies,the Quality Assessment of Diagnostic Accuracy Studies tool was used.Because of the high heterogeneity between the studies,it was decided to refrain from the statistical processing or meta-analysis of the available data.RESULTS:Nine human and three experimental studies were included into review.In experimental studies significant differences between leptin concentrations at 24 and 48 h in control,acute edematous and acute necrotizing pancreatitis groups were found(P = 0.027 and P < 0.001).In human studies significant differences between leptin and resitin concentrations in control and acute pancreatitis groups were found.1-3 d serum adiponectin threshold of 4.5 μg/mL correctly classified the severity of 81% of patients with AP.This threshold yielded a sensitivity of 70%,specificity 85%,positive predictive value 64%,negative predictive value88%(area under curve 0.75).Resistin and visfatin concentrations differ significantly between mild and severe acute pancreatitis groups,they correlate with severity of disease,need for interventions and outcome.Both adipokines are good markers for parapancreatic necrosis and the cut-off values of 11.9 ng/mL and 1.8 ng/mL respectively predict the high ranges of radiological scores.However,the review revealed that all nine human studies with adipokines are very different in terms of methodology and objectives,so it is difficult to generalize their results.It seems that concentrations of the leptin and resistin increases significantly in patients with acute pancreatitis compared with controls.Serum levels of adiponectin,visfatin and especially resitin(positive correlation with Acute Physiology and Chronic Health Evaluation Ⅱ,Ranson and C-reactive protein) are significantly different in mild acute pancreatitis and severe acute pancreatitis patients,so,they can serve as a markers for the disease severity prediction.Resistin and visfatin can also be used for pancreatic and parapancreatic necrosis prediction,interventions needs and possible,outcome.CONCLUSION:High levels of adipokines could allow for prediction of a severe disease course and outcome even in small pancreatic lesions on computed tomography scans.

Role of Smad7 in inflammatory bowel diseases

Crohn's disease and ulcerative colitis,the major forms of inflammatory bowel diseases(IBD) in man,are complex diseases in which genetic and environmental factors interact to promote an excessive mucosal immune response directed against normal components of the bacterial microflora.There is also evidence that the pathologic process is due to defects in counterregulatory mechanisms,such as those involving the immunosuppressive cytokine transforming growth factor(TGF)-1.Indeed,studies in human IBD tissues and murine models of colitis have documented a disruption of TGF-1 signalling marked by a block in the phosphorylation of Smad3,a signalling molecule associated with the activated TGF-receptor,due to up-regulation of Smad7,an intracellular inhibitor of Smad3 phosphorylation.Knock-down of Smad7 with a specific antisense oligonucleotide restores TGF-1/Smad3 signalling,thus resulting in a marked suppression of inflammatory cytokine production and attenuation of murine colitis.These findings together with the demonstration that Smad7 antisense oligonucleotide is not toxic when administered in mice have paved the way for the development of a Smad7 antisense oligonucleotidebased pharmaceutical compound that is now ready to enter the clinics.In this article we review the available data supporting the pathogenic role of Smad7 in IBD and discuss whether and how Smad7 antisense therapy could help dampen the ongoing inflammation in IBD.

Expression of mucosal addressin cell adhesion molecule 1 on vascular endothelium of gastric mucosa in patients with nodular gastritis

AIM:The interaction of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) with integrin α4β7 mediates lymphocyte recruitment into mucosa-associated lymphoid tissue (MALT).Nodular gastritis is characterized by a unique military pattern on endoscopy representing increased numbers of lymphoid follicles with germinal center,strongly associated with H pylori infection.The purpose of this study was to address the implication of the MAdCAM-1/integrin β7 pathway in NG. METHODS:We studied 17 patients with NG and H pylori infection and 19 H pylori-positive and 14 H pylori-negative controls.A biopsy sample was taken from the antrum and snap-frozen for immunohistochemical analysis of MAdCAM- 1 and integrin β7.In simultaneous viewing of serial sections, the percentage of MAdCAM-1-positive to von Willebrand factor-positive vessels was calculated.We also performed immunostaining with anti-CD20,CD4,CD8 and CD68 antibodies to determine the lymphocyte subsets co- expressing integrin β7. RESULTS:Vascular endothelial MAdCAM-1 expression was more enhanced in gastric mucosa with than without H pylori infection.Of note,the percentages of MAdCAM-1-positive vessels were significantly higher in the lamina propria of NG patients than in H pylori-positive controls.Strong expression of MAdCAM-1 was identified adjacent to lymphoid follicles and dense lymphoid aggregates.Integrin β7-expressing mononuclear cells,mainly composed of CD20 and CD4 lymphocytes,were associated with vessels lined with MAdCAM-1-expressing endothelium.CONCLUSION: Our results suggest that the MAdCAM一1/ integrin a4p7 homing system may participate in gastric inflammation in response to H py/o}i-infection and contributes to MALT formation, typically leading to the development of NG.

Adenosine:An immune modulator of inflammatory bowel diseases

Inflammatory bowel disease(IBD)is a common and lifelong disabling gastrointestinal disease.Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response.Adenosine is an important modulator of inflammation and its anti-inflammatory effects have been well established in humans as well as in animal models.High extracellular adenosine suppresses and resolves chronic inflammation in IBD models.High extracellular adenosine levels could be achieved by enhanced adenosine absorption and increased de novo synthesis.Increased adenosine concentration leads to activation of the A2a receptor on the cell surface of immune and epithelial cells that would be a potential therapeutic target for chronic intestinal inflammation. Adenosine is transported via concentrative nucleoside transporter and equilibrative nucleoside transporter transporters that are localized in apical and basolateral membranes of intestinal epithelial cells,respectively. Increased extracellular adenosine levels activate the A2a receptor,which would reduce cytokines responsible for chronic inflammation.

The roles of toll-like receptors in carcinogenesis and cancer immunotherapy

Toll-like receptors （TLRs） are probably the most important class of pattern-recognition receptors. Members of the TLR family play key roles in the both innate and adaptive immune responses. Recognition of pathogen-associated molecular patterns （PAMPs） by TLRs, either alone or in heterodimedzation with other TLR or non-TLR receptors, induces the production of signals that are responsible for the activation of genes important for an effective host defense, especially those of proinflammatory cytokines. Thus, TLRs are involved in the development of many pathological conditions including infectious diseases, tissue damage, and cancer especially. In this review, the contribution of TLRs to tumorgenesis is evaluated. We hope to provide new insight into the progression of cancer and more importantly into the potential for TLRs as targets of therapeutics.