Pivotal role of PGE2 and IL-10 in the cross-regulation of dendritic cell-derived inflammatory mediators

Exposure to pathogens induces antigen-presenting cells （APC） such as macrophages and dendritic cells （DC） to produce various endogenous mediators, including arachidonic acid （AA）-derived eicosanoids, cytokines, and nitric oxide （NO）. Many secreted products of activated APC can act by themselves in an autocrine manner and modulate their function. Moreover, the cross-interaction between endogenous bioactive molecules regulates the function of professional APC with important consequences for their ability to activate and sustain immune and inflammatory responses, and to regulate immune homeostasis. Although neglected for many years when compared to their role in cardiovascular homeostasis, cancer and inflammation, the importance of eicosanoids in immunology is becoming more defined. The role of prostaglandin （PG） E2 （PGE2）, one of the best known and most well studied eicosanoids, is of particular interest. It modulates the activities of professional DC by acting on their differentiation, maturation and their ability to secrete cytokines. Uniquely among haematopoietic cytokines, interleukin-10 （IL-10） is a pleiotropic molecule that displays both immunostimulatory and immunoregulatory activities. IL-10 has attached much attention because of its anti-inflammatory properties. It modulates expression of cytokines, soluble mediators and cell surface molecules by cells of myeloid origin, particularly macrophages and DC. We previously reported that PGE2 is a potent inducer of IL-10 in bone marrow-derived DC （BM-DC）, and PGE2-induced IL-10 is a key regulator of the BM-DC pro-inflammatory phenotype. BM-DC may be considered as an important model to study complex interactions between endogenous mediators, and autocrine IL-10 plays a pivotal role in the crossregulation of AA-derived lipid mediators, cytokines, and NO, with critical effects on immune and inflammatory responses.     

Immune mechanisms and immunotherapy in sepsis：where do we stand？

Sepsis and septic shock have continued to produce significant morbidity and mortality, in recent times, in acutely injured patients as well as patients in the intensive care units despite advances in antibiotic therapy and in the cardi ovascular and pulmonary support for these patients. This emphasizes the need to gain a better understanding of the fundamental mechanisms of the pathogenesis of sepsis syndrome in the critically ill or injured patients. The present knowled ge of the mechanisms of septic pathogenesis clearly indicates involvement of mod ulations in the functions of the cells of body's immune defense system, namely, monocytes/macrophages, polymorphonuclear leukocytes, and lymphocytes. Most of su ch knowledge has been derived from laboratory experiments in animal models of se ptic injury, or from studies of immune-system cells, in vitro. Clinical stud ies have also supported the role of immune perturbations. Yet, to date, very few the rapeutic approaches are available to effectively counter the sepsis-related immu ne disturbances. Functional modulations in the immune system cells, in the injured/septic hos ts, can exert not only adaptive/beneficial effects but also profoundly adverse effects on the non-immune-system cells such as endothelial, epithelial, neurona l, endocrine, neuro-endocrine, smooth muscle, skeletal muscle, and cardiac muscl e cells. The primary functional modulation in the immune-system cells after inju ry or with critical illness is activation of such cells via molecules from pat hogens, for example, lipopolysaccharide from gram negative organisms, lipoteic hoic acid/peptidoglycan from gram positive organisms, or zymosan from fungi. Suc h pathogenic molecules activate monocytes and tissue macrophages to result in th e expression and release of cytokine mediators (TNFα, IL-1, IL-6, IL-8, and IL- 10), as well as certain lipid mediators (PGE2, LTB4, PAF). While these media tors could play a host-defense role in support of the host via containment/destr uctio n of the pathogens, they could also exert detrimental effects in the host and co ntribute to host morbidity and mortality. Some of these mediators (TNFα, IL-1, IL-6, IL-8, LTB4, PAF) have been shown to be “pro-inflammatory”,and to potenti al ly exert a harmful effect on non-immune cell systems such as endothelial cells, epithelial cells, and muscle cells. Among the pro-inflammatory mediators, TNFα a nd IL-1 could play major harmful roles, and thus contribute to the injured host morbidity and mortality. Mediators, IL-10 and PGE2 have been shown to be “an ti-inflammatory” and to potentially contribute to a dreadful state of immuno-s uppression in the injured hosts, which can also lead to morbidity and mortality. Whi ch is worse, a harmful pro-inflammatory phase or harmful immuno-suppression ? Or Which occurs first, a harmful pro-inflammatory condition or a harmful immuno-su ppression? These are questions which can not be definitively answered for the g eneral population of critically ill/injured patients. It is reasonable to assum e that the answers to these question would vary from one patient subset to anot her patient subset. Thus, whether to treat the patient with a putative anti-pro- inflammatory agent or with a putative anti-anti-inflammatory agent remai ns unresolved for the general sepsis patient population. Paradoxically, TNFα, IL-1, and other pro-inflammatory mediators under certa in circumstances may serve as natural “blockers” of immuno-suppression or “pr omoters” of immune stimulation. This may be true in the case of some of the se ptic patients. Understandably, these patients should not be treated with anti-pro-inf lammatory agents. On the other hand, the anti-inflammatory mediators such as PGE 2, IL-10, and certain other naturally occurring antagonists of TNFα and IL-10 a ctions (TNFα, and IL-1 receptor antagonists) could not only be producing a cert ai n level of immune-suppression but also serving as important feed back controller of the pro-inflammatory mediators. Thus some of the naturally occurring anti-I nflammatory agents could indeed serve as adaptive/beneficial “anti-pro-inflamma tory”, therapeutic agents in certain subset of sepsis patients. Although there is little doubt that effective therapeutic control of the sep sis syndrome could be achieved via appropriate modulation of the cells of the I mmune system, at the present time we do not have an immune therapeutic regimen w hich can singly be efficacious for the general population of patients with the s eptic complication. This implies that before an effective treatment of sepsis p atients, the patients must be identified, by some diagnostic procedure, as to wh ether they need an anti-pro-inflammatory therapy or an anti-anti-inflammatory th erapy. Thus, although immuno-therapy of sepsis remains promising, its efficacy a waits further investigative work particularly through clinical studies in sepsis patients.     

Roles and relevance of mast cells in infection and vaccination

In addition to their well-established role in allergy mast cells have been described as contributing to functional regulation of both innate and adaptive immune responses in host defense.Mast cells are of hematopoietic origin but typically complete their differentiation in tissues where they express immune regulatory functions by releasing diverse mediators and cytokines.Mast cells are abundant at mucosal tissues which are portals of entry for common infectious agents in addition to allergens.Here,we review the current understanding of the participation of mast cells in defense against infection.We also discuss possibilities of exploiting mast cell activation to provide adequate adjuvant activity that is needed in high-quality vaccination against infectious diseases.     

Immunoglobulin expression and its biological significance in cancer cells

It is generally believed that the expression of a gene is restricted ＂within the right place and at the right time＂. This principle has long been considered applicable as well to the expression of immunoglobulin （Ig） lymphocytes of B cell lineage. However, increasing evidence has shown Ig ＂paradoxically＂ expressed in malignant tumors of epithelial origin. We reviewed the recent progress in the study of cancer-derived Ig, and also discussed its mechanisms and possible functions, trying to arouse interest and attention to those working in the field of immunology and oncology.     

Expression of the Apoptosis Inhibitor Survivin and its correlation with Thymidine Kinase and Axillary Lymph Node Metastasis in Breast Cancer

1 Introduction Many molecular factors have been demonstrated to interfere with cellular proliferation and programmed cell death. One of these factors is a recently discovered member of the "inhibitor of apoptosis protein(IAP)" called survivin. Survivin is abundantly expressed in most solid and hematologic malignancies, but undetectable in normal adult tissues. Interference with survivin function induces pleiotropic cell-division defects and apoptosis. Cytosolic thymidine kinase (TK) is a marker for proliferating cells and TK is one of several key enzymes involved in DNAmetabolism that phosphorylates thymidine to thymidine mono-phosphate. This study was aimed to detect the expression of suvivin and TK in breast cancer, and to explore a possible relationship between survivin expression and axillary lymph node metastasis.     

CO-EXPRESSION OF WIND-UP IN BOTH DORSAL HORN WDR UNIT AND FLEXOR SIGLE MOTOR UNIT INDUCED BY CUTANEOUS ELECTRICAL STIMULI IN HALOTHANE-ANESTHETIZED RATS

<正> Aim: The present project is to seek the possible electrical stimulation parameter by which wind-up of withdrawal reflex of rats and set up a appropriate animal model for recording the withdrawal reflex of wind-up phenomenon. Meanwhile, a parallel comparison will be made between the recording of withdrawal reflex and dorsal horn (DH) neuron responses in order to investigate the possible correlation associated with sensory and motor interaction of pain information via simultaneous recording. On the other hand, another comparison study     

内毒素诱导p38MAPK信号转导作用的研究进展

The diseases caused by endotoxin have seriously affected human health. Previous studies have shown that p38 MAPK pathway is involved in the intracellular signal transduction induced by lipopolysaccharide (LPS), which plays an important role in the activation of inflammation-related cells to release inflammation mediator. Recently there have been some progresses in the isoforms distribution, substrate, molecular mechanism of regulating the release of inflammatory mediators, cellular specific activation and levels of p38 MAPK.     

组胺在肿瘤免疫中的双向调节作用

Histamine is one of the important mediators of many diseases such as hypersensitivity,gastric ulcer, and inflammation. It regulates the local immune response in tumor tissues by multiple mechanisms with ambivalent and double - faced effects, which have been uncovered partially by thorough molecular immunological analyses. Histamine has differential effects on the growth of tumor cell depending on selective reaction with its receptors, and on the secretion of variety of cytokines from local activated immune cells in a reciprocal manner by shifting TH1/TH2 polarization towards predominance of TH2. In this review, we summarized recent data suggesting that endogenous histamine should be an important correlated factor involved in bidirectional regulation both to tumor tissue and to infiltrating immune cells．     

Lipopolysaccharide Could Be Internalized into Human Peripheral Blood Mononuclear Cells and Elicit TNF-α Release,but not via the Pathway of Toll-Like Receptor 4 on the Cell Surface

Lipopolysaccharide(LPS),the principal component of the outer membrane of Gram-negative bacteria,stimulatesvarious cell types to release numerous proinflammatory mediators such as TNF-α,IL-6 and IL-12,which maydamage cells and lead to organ injury,even sepsis and septic shock.Toll-like receptor 4(TLR4) has beenidentified as the receptor involved in the recognition of LPS,but the role of LPS uptake in activating signaltransduction remains controversial.In the present study,TNF-α was used as a marker of macrophages/monocytes activated by LPS,and CQ was used as an inhibitor of endosome mature in order to definitude whatstage of the signal transduction elicited by LPS was interrupted.We found that there indeed existedinternalization of LPS and internalization partially participated in LPS signaling since CQ inhibited cytokinerelease,and decreased accumulation of FITC-LPS in hPBMCs.In contrast,anti-hTLR4 antibody coulddecrease cytokine release,but had no inhibition on accumulation of FITC-LPS.This result revealed thatinhibition of cytokine release was related to reduction of FITC-LPS accumulation in the cells.But TLR4 on thecell surface couldn't participate in internalization of LPS.Thus,LPS signaling and internalization couldn't beviewed as mutually independent processes.Cellular & Molecular Immunology.2004;1(5):373-377.     

Peptidome analysis of human intrauterine adhesion tissues and the identification of antifibrotic peptide

Intrauterine adhesion(IUA) is a common clinical endometrial disease,which can severely damage the fertility and quality of life in women.This study aims to find the differentially expressed endogenous peptides and their possible roles in IUA.Liquid chromatography-mass spectrometry was used to identify the peptidomic profiling of IUA tissues,and the differentially expressed peptides were screened out.Using real-time quantitative PCR,Western blotting,and immunocytochemistry staining,the function o...     

How Much Do We Know about Atopic Asthma： Where Are We Now？

Asthma is a common disease in the worldwide and it affects over 3.5 million adults and children in the UK. Asthma is a chronic disease characterized by airway hyperresponsiveness, airway inflammation, airway remodelling and reversible airway obstruction. Inflammatory cells, cytokines, chemokines, adhesion molecules, and mediators are involved in pathogenesis of asthma. Chronic airway inflammation and remodelling are the major characters in asthma, which result in decreased pulmonary function. The precise processes are far understood at moment. Although corticosteroid therapy plus other exiting drugs （bronchodilators and oral leukotriene receptor antagonists） influences many different inflammatory and structural cell types and continues to be as the ＂gold standard＂ of therapy in asthma, many thousands have chronic, severe diseases and suffer daily symptoms which make their lives a misery. There remains a clear need for novel approaches to therapy, which will be informed by a clearer understanding of disease pathogenesis, particularly in the target organ where airway inflammation and remodelling, the hallmarks of asthma occur. Cellular ＆ Molecular Immunology.     

Chemo/Dietary prevention of cancer：perspectives in China

Cancer is a major disease worldwide and different approaches are needed for its prevention.Previous laboratory and clinical studies suggest that cancer can be prevented by chemicals,including those from the diet.Furthermore,epidemiological studies have suggested that deficiencies in certain nutrients can increase the risk of some cancers.In this article on chemo/dietary prevention,examples will be given to illustrate the effectiveness of chemopreventive agents in the prevention of breast,colon and prostate cancers in high-risk populations and the possible side effects of these agents.The potential usefulness of dietary approaches in cancer prevention and the reasons for some of the failed trials will be discussed.Lessons learned from these studies can be used to design more relevant research projects and develop effective measures for cancer prevention in the future.The development of effective chemopreventive agents,the use of nutrient supplements in deficient or carcinogen-exposed populations,and the importance of cohort studies will be discussed in the context of the current socioeconomic situation in China.More discussions are needed on how we can influence society to pay more attention to cancer prevention research and measures.     

A review: Systematic research approach on toxicity model of liver and kidney in laboratory animals

Therapeutic experiments are commonly performed on laboratory animals to investigate the possible mechanism(s) of action of toxic agents as well as drugs or substances under consideration. The use of toxins in laboratory animal models, including rats, is intended to cause toxicity. This study aimed to investigate different models of hepatotoxicity and nephrotoxicity in laboratory animals to help researchers advance their research goals. The current narrative review used databases such as Medline,...     

Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19

Background:Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019(Covid-19)on the basis of in vitro activity and data from uncontrolled studies and small,randomized trials.Methods:In this randomized,controlled,open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19,we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care.The primary outcome was 28-day mortality.     

Immunomodulatory Effects of Esculetin （6,7-Dihydroxycoumarin） on Murine Lymphocytes and Peritoneal Macrophages

Coumarins belong to a diverse group of naturally occurring non-nutrient phytochemicals known as benzo-α- pyrones. In this study, esculetin, a 6,7-dihydroxy derivative of coumarin with pleiotropic biological activities, was found to have no significant cytotoxic effect on normal murine macrophages, but it could increase the in vivo migration of the thioglycollate-elicited macrophages in a dose-dependent manner. Moreover, esculetin significantly increased the endocytic activity, and augmented the nitric oxide production and iNOS gene expression in LPS-treated macrophages. In addition, in vivo administration of esculetin into mice was shown to increase the mitogenesis of splenic lymphocytes towards Con A and LPS stimulations, and induced the LAK activity of splenic lymphocytes. Collectively, our results indicate that esculetin could exert immunomodulatory effects on murine macrophages and lymphocytes, both in vitro and in vivo, and this might be one of the possible mechanisms by which coumarins can exert their chemopreventive and anti-tumor activities in vivo. Cellular ＆ Molecular Immunology. 2005;2（3）： 181-188.     

牙周炎与p38丝裂原活化蛋白激酶通路的研究与进展

BACKGROUND: A series of inflammatory signal pathways are activated accompanied by increasing expressions of inflammatory factors after periodontal tissues being stimulated by exogenous substances like bacterium. Inflammation is closely related to periodontal tissue repair and regeneration. OBJECTIVE: To illustrate the correlation of immune response of periodontitis and periodontitis-related inflammatory cytokines to p38 mitogen activated protein kinase (p38MAPK) pathway, and to provide a new idea and method for the treatment of periodontitis in the future. METHODS: The related literatures of periodontitis and p38MAPK pathway published from January 1990 to January 2016 were retrieved from the databases of CBM, CNKI, SWIC and PubMed. The research and progress of periodontal tissue repair and regeneration after periodontitis were analyzed. RESULTS AND CONCLUSION:Totally 36 literatures were enrolled finally. Inflammation-regulated and inflammation-associated signaling pathways as well as subsequent expression of inflammatory mediators can partly control the excessive disease-induced inflammation and immune responses of the host, among which p38MAPK signaling pathway may be involved in the occurrence and development of periodontitis. More studies, however, are needed to validate these findings. The regulation of p38MAPK signaling pathway is still of great significance in the treatment of periodontal disease, and we hope to provide a new insight and basis for clinical diagnosis and treatment of periodontitis. 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

Analysis of the Mechanical Behavior of Bovine Hoof Horn Using Digital Image Correlation

INTRODUCTION Reducing the incidence and severity of lameness in dairy cattle would reduce pain and suffering,and the corresponding economic consequences. According to the Annual Report of the Animal WelfareFoundation of the British Veterinary Association "...if it were possible to substantially reduce the inci-dence of lameness, this single initiative would benefit more animals than any other (initiative)"〔1〕. Interms of economic impact, lameness cost US dairy farmers over $400 milli…     

Mutational screening of affected cardiac tissues and peripheral blood cells identified novel somatic mutations in GATA4 in patients with ventricular septal defect

The aim of this study was to examine how somatic mutations of the GATA4 gene contributed to the genesis of ventricular septal defect (VSD). The coding and intron-exon boundary regions of GATA4 were sequenced of DNA samples from peripheral blood cells and cardiac tissues of twenty surgically treated probands with VSD. Seven novel heterozygous variants were detected in cardiac tissues from VSD patients, but they were not detected in the peripheral blood cells of VSD patients or in 500 healthy control samples. We replicated 14 single nucleotide polymorphisms (SNPs) reported in NCBI. Bioinformatics analysis was performed to analyze the possible mechanism by which mutations were linked to VSD. Among those variants, c. 1004C>A (p.S335X) occurred in the highly conserved domain of GATA4 and generated a termination codon, which led to the production of truncated GATA4. The seven novel heterozygous GATA4 mutations were only identified in cardiac tissues with VSD, suggesting that they are of somatic origin. A higher mutation rate in cardiac tissues than in peripheral blood cells implies that the genetic contribution to VSD may have been underestimated.