急性脑梗塞患者血浆肿瘤坏死因子-α含量的变化

目的动态观察急性脑梗塞患者血浆肿瘤坏死因子-α(TNF-α)含量的变化及血浆肿瘤坏死因子与梗塞灶面积、部位的关系。方法采用双抗体夹心(EILAS)法测定了68例脑梗塞患者及46例正常对照组TNF-α含量。结果急性脑梗塞患者TNF-α含量显著高于正常组。病后3天TNF-α含量最高,恢复期TNF-α含量显著下降,但仍显著高于正常对照组,且TNF-α含量与梗塞灶面积和部位均无明显相关性。结论TNF-α是神经—内分泌—免疫调节系统中的关键介质。TNF-α参与了脑梗塞患者炎症/免疫反应发生发展过程。

Helicobacter pylori infection and endocrine disorders:Is there a link?

Helicobacter pylori(H pylori) infection is a leading world-wide infectious disease as it affects more than half of the world population and causes chronic gastritis,peptic ulcer disease and gastric malignancies.The infection elicits a chronic cellular inflammatory response in the gastric mucosa.However,the effects of this local inflammation may not be confi ned solely to the digestive tract but may spread to involve extraintestinal tissues and/or organs.Indeed,H pylori infection has been epidemiologically linked to extra-digestive conditions and diseases.In this context,it has been speculated that H pylori infection may be responsible for various endocrine disorders,such as autoimmune thyroid diseases,diabetes mellitus,dyslipidemia,obesity,osteoporosis and primary hyperparathyroidism.This is a review of the relationship between H pylori infection and these endocrine disorders.

T cell immune response is correlated with fibrosis and inflammatory activity in hepatitis B cirrhotics

AIM： TO explore the relationship among interferon-γ （IFN-γ） activity, fibrogenesis, T cell immune responses and hepatic inflammatory activity. METHODS： Peripheral blood samples from a total of 43 hepatitis B cirrhotic patients （LC） and 19 healthy controls （NC） were collected to measure their serum levels of IFN-γ, interleukin-2 （IL-2）, soluble interleukin-2 receptor （sIL-2R）, interleukin-10 （IL-10） and three serological markers of fibrosis including hyaluronic acid （HA）, procollagen type III peptide （PIIIP）, and type iV collagen were measured using a double antibody sandwich ELISA. Also, serum total bilirubin （TB） and alanine aminotransferase （ALT） were measured by routine measures. RESULTS： The concentrations of serological markers of fibrosis in patients with active cirrhosis （ALC） were significantly higher than those in stationary liver cirrhosis （SLC） or NC groups. The levels of serological markers in HBeAg-positive patients were significantly higher than those in HBeAg-negative patients. In SLC and ALC patients, a negative linear correlation was found between IFN-γ levels and the serological markers of fibrosis. IFN-γ and IL-2 levels in the ALC group were significantly higher than those in the SLC and NC groups, but the statistical difference was not significant between the latter two. In contrast, IL-10 levels in the SLC group were significantly higher than that in the NC group, but no significant difference was found between SLC and ALC groups. The sIL-2R level was elevated gradually in all these groups, and the differences were significant. Positive linear correlations were seen between IFN-γ activity and ALT levels （r = 0.339, P 〈 0.05）, and IL-2 activity and TB levels （r = 0.517, P 〈 0.05）. sIL-2R expression was positively correlated with both ALT and TB levels （r = 0.324, 0.455, P 〈 0.05）, whereas there was no statistically significant correlation between IL-10 expression and serum ALT and TB levels （r = -0.102, -0.093, P 〉 0.05）. Finally, there was a positive correlation between IFN-γ and IL-2 levels. CONCLUSION： T cell immune responses are correlated with fibrosis and hepatic inflammatory activity and may play an important role in liver cirrhosis.

Fenofibrate for patients with asymptomatic primary biliary cirrhosis

AIM:Primary biliary cirrhosis (PBC) is a chronic, cholestatic disease of autoimmune etiology,the histology of which shows a destruction of the intrahepatic bile duct and portal inflammation. Ursodeoxycholic acid (UDCA) is now used as a first-line drug for asymptomatic PBC (aPBC) because it is reported that UDCA decreases mortality and prolongs the time of liver transplantation.However, only 20-30% of patients respond fully to UDCA.Recently,lipoprotein-lowering agents have been found to be effective for PBC.The aim of this study was to examine the safety and efficacy of fenofibrate, a member of the fibrate class of hypolipidemic and anti-inflammatory agent via peroxysome proliferatory-activated receptor α,in patients with aPBC.METHODS:Fenofibrate was administered for twelve weeks in nine patients with aPBC who failed to respond to UDCA.UDCA was used along with fenofibrate during the study.The data from aPBC patients were analyzed to assess the biochemical effect of fenofibrate during the study.RESULTS: The serum levels of alkaline phosphatase (ALP)(285±114.8IU/L) and immunoglobulin M (IgM) (255.8±85.9mg/dl) significantly decreased to 186.9±76.2IU/L and 192.9±67.5mg/dL respectively, after fenofibrate treatment in patients with aPBC (P<0.05). Moreover,the titer of antimitochondrial antibody (AMA) also decreased in 4 of 9 patients with aPBC. No adverse reactions were observed in any patients.CONCLUSION:Fenofibrate appears to be significantly effective in treating patients with aPBC who respond incompletely to UDCA alone.Although the mechanism of fenofibrate on aPBC has not yet been fully clarified,combination therapy using fenofibrate and UDCA might be related to the anti-immunological effects, such as the suppression of AMA production as well as its antiinflammatory effect.

Invasive front of colorectal cancer:Dynamic interface of pro-/anti-tumor factors

Tumor-host interaction at the invasive front of colorectal cancer represents a critical interface encompassing a dynamic process of de-differentiation of colorectal carci-noma cells known as epithelial mesenchymal transition (EMT). EMT can be identified histologically by the presence of "tumor budding" ,a feature which can be highly specific for tumors showing an inf iltrating tumor growth pattern. Importantly,tumor budding and tumor border configuration have generated considerable interest as additional prognostic factors and are also recognized as such by the International Union Against Cancer. Evidence seems to suggest that the presence of tumor budding or an infiltrating growth pattern is inversely correlated with the presence of immune and inflammatory responses at the invasive tumor front. In fact,several tumor-associated antigens such as CD3,CD4,CD8,CD20,Granzyme B,FOXP3 and other immunological or inflammatory cell types have been identified as poten-tially prognostic in patients with this disease. Evidence seems to suggest that the balance between protumor (including budding and inf iltrating growth pattern) and anti-tumor (immune response or certain inflammatory cell types) factors at the invasive front of colorectal cancer may be decisive in determining tumor progression and the clinical outcome of patients with colorectal cancer. On one hand,the inf iltrating tumor border configuration and tumor budding promote progression and dissemination of tumor cells by penetrating the vascular and lymphatic vessels. On the other,the host attempts to fend off this attack by mounting an immune response to protect vascular and lymphatic channels from invasion by tumor buds. Whereas standard pathology reporting of breast and prostate cancer involves additional prognostic features,such as the BRE and Gleason scores,the ratio of pro-and anti-tumor factors could be a promising approach for the future development of a prognostic score for patients with colorectal cancer which could complement tumor node metastasis staging to improve the clinical management of patients with this disease.

Linarin ameliorates innate inflammatory response in an experimental dry eye model via modulation of the NLRP3 inflammasome

Objective To investigate the effect and mechanism of linarin(LA) in an experimental dry eye model.Methods LA or vehicle was applied in two dry eye models: an in vitro hyperosmotic stress model and an in vivo desiccating stress(DS) murine model. The viability of human corneal epithelial cells(HCECs) was measured using a cell counting kit(CCK-8).Tear secretion was assessed using the phenol red cotton test. The tear break-up time(TBUT) was recorded using 0.1% liquid fluorescein sodium. Corneal epithelial permeability was evaluated through Oregon green dextran(OGD) staining.Conjunctival goblet cells were counted using periodic acid-Schiff(PAS) staining. Terminal deoxynucleotidyl transfer d UTP nickend labeling(TUNEL) staining was used to quantify apoptotic cells in both models. The expression of Ki-67 was measured in HCECs in the cell model while that of matrix metalloproteinase(MMP)-3 and-9 was measured in the murine model through immunofluorescence staining. Real-time quantitative PCR(RTqPCR) was performed to assess the expression of MMP-3 and MMP-9 in the corneal epithelium and NLRP3, ASC, Caspase-1,interleukin(IL)-1β, IL-18, and tumor necrosis factor(TNF)-α in the conjunctiva. The protein expression levels of NLRP3, ASC,Caspase-1, IL-1β, and IL-18 in the conjunctiva were assessed via Western blot.Results In the in vitro model, treatment of HCECs with LA showed no toxicity, increased proliferation, and reduced apoptosis. In the murine model, compared to the control, LA significantly increased tear production and TBUT, improved OGD staining, and increased the number of goblet cells. Topical treatment of LA to mice provided decreased expression of MMP-3, MMP-9, TNF-α, and apoptotic corneal epithelium. Topical administration of LA also suppressed the NLRP3 inflammasome in the dry eye disease(DED) murine model by decreasing the expression of NLRP3, ASC, Caspase-1, IL-1β, and IL-18 in the conjunctiva.Conclusion Our findings support the safety and efficacy of LA in the treatment of DED. LA alleviated corneal epithelial damage and suppressed NLRP3 inflammasome-mediated immunity in the conjunctiva in a murine model of DED.

Network Biological Modeling:A Novel Approach to Interpret the Traditional Chinese Medicine Theory of Exterior-Interior Correlation Between the Lung and Large Intestine

Objective To study the common pathogenesis of pneumonia and colitis using modern biological network analysis tools,and to explore the theory that the lung and large intestine are exteriorly and interiorly related.Methods The relevant target genes(hereinafter,“targets”)of pneumonia and colitis were separately queried on the GeneCards database.The main targets of the two diseases were then screened out according to their correlation scores and intersected to obtain those common to the two diseases.Metascape was used to analyze the main and common targets identified,and the Database for Annotation,Visualization and Integrated Discovery(DAVID)was used to enrich and analyze the common targets.Cytoscape 3.7.2 software was used to build the network diagram.Results In total,54 targets,such as TNF,IL-10,IL-6,IL-2,IL-4,TLR4,TLR2,CXCL8,IL-17A and IFNG,etc.,are common to pneumonia and colitis,which are mainly enriched in these processes such as cytokine–cytokine receptor interaction,the Tcell receptor signaling pathway,the Toll-like receptor signaling pathway and the Jak-STAT signaling pathway.The Metascape modular analysis identified 11 modules for pneumonia,six modules for colitis,and two modules for the common targets.Conclusions Pneumonia and colitis have the same pathogenic targets and mechanisms of action and finally interact with each other through inflammatory reactions and immune responses.This provides a probable molecular mechanism that explains the theory that the lung and large intestine are exteriorly and interiorly related.

Crohn’s disease:Evidence for involvement of unregulated transcytosis in disease etio-pathogenesis

Crohn’s disease(CD)is a chronic inflammatory bowel disease.Research has identified genetic predisposition and environmental factors as key elements in the development of the disease.However,the precise mechanism that initiates immune activation remains undefined.One pathway for luminal antigenic molecules to enter the sterile lamina propria and activate an immune response is via transcytosis.Transcytosis,although tightly regulated by the cell,has the potential for transepithelial transport of bacteria and highly antigenic luminal molecules whose uncontrolled translocation into the lamina propria can be the source of immune activation.Viewed as a whole,the evidence suggests that unregulated intestinal epithelial transcytosis is involved in the inappropriate presentation of immunogenic luminal macromolecules to the intestinal lamina propria.Thus fulfilling the role of an early pre-morbid mechanism that can result in antigenic overload of the lamina propria and initiate an immune response culminating in chronic inflammation characteristic of this disease.It is the aim of this paper to present evidence implicating enterocyte transcytosis in the early etio-pathogenesis of CD.

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.

Trichosanthin functions as Th2-type adjuvant in induction of allergic airway inflammation

It is important to understand the pathogenesis of asthma induced by natural allergens, which could exclude the interference of artificial adjuvant and provide insights of natural immune response in the disease. In the present study, we show that Trichosanthin （TCS） could induce airway inflammation even without the help of alum. Furthermore, TCS appeared capable of replacing alum to promote OVA-specific airway inflammation. TCS induced accumulation of IL-4-producing eosinophils in peritoneum at an early stage and the adjuvant function of TCS was eliminated by blockage of IL-4 at this stage. Finally, the eosinophils triggered by TCS from WT mice, but not from IL-4- deficient mice were shown to function as adjuvant for the induction of OVA-specific Th2 responses. Our data indicate that TCS is not only an allergen, but also a Th2-typc adjuvant modulating the switching of immune responses to a Th2 pathway. This chain of events results from IL-4 production by eosinophils at an early stage of TCS-priming. In conclusion, TCS may be useful as a Th2 adjuvant, and innate immune cells, such as eosinophils, may be a good target to study the initiation of Th2 response.

Effects of recombinant sCR1 on the immune inflammatory reaction in acute spinal cord injury tissue of rats

Objective: To determine the effects of recombinant soluble complement receptor type I (sCR1) on the immune inflammatory reaction in acute spinal cord injury tissue of rats and its protective effects. Methods: SD rat models of acute spinal cord injury were prepared by modified Allen’s method. The motor function of the rat lower extremities in sCR1 group and normal saline (NS) group was evaluated by the tiltboard experiment at 12 h, 1 d, 3 d, 7 d, and 14 d. The neutrophil infiltration and C3c positive expression were observed. The myeloperoxidase activity was assessed in the injury tissue at 12 h, 1 d, 3 d, 7 d, and 14 d after injury in the two groups. Results: The motor function of rat in sCR1 group at 3 d, 7 d, and 14 d was obviously better than that in NS group (P< 0.01, P< 0.01, P< 0.01). C3c positive expression in sCR1 group at each time point after injury was obviously less than that in NS group (P< 0.01). The myeloperoxidase activity in sCR1 group at each time point after injury was obviously less than that in NS group (P< 0.01). Conclusions: Recombinant soluble complement receptor type I (sCR1) can lessen the immune inflammatory reaction in acute spinal cord injury tissue and relieve secondary spinal cord injury by inhibiting the activation of the complement system.

Harnessing the immune system for the treatment of breast cancer

Standard treatment options for breast cancer include surgery, chemotherapy, radiation, and targeted therapies, such as adjuvant hormonal therapy and monoclonal antibodies. Recently, the recognition that chronic inflammation in the tumor microenvironment promotes tumor growth and survival during different stages of breast cancer development has led to the development of novel immunotherapies. Several immunotherapeutic strategies have been studied both preclinically and clinically and already have been shown to enhance the efficacy of conven- tional treatment modalities. Therefore, therapies targeting the immune system may represent a promising next-generation approach for the treatment of breast cancers. This review will discuss recent findings that elucidate the roles of suppressive immune cells and proinflammatory cytokines and chemokines in the tumor-promoting microen- vironment, and the most current immunotherapeutic strategies in breast cancer.