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1.
Eur J Immunol ; 44(8): 2468-77, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24777913

ABSTRACT

Basophils have been shown to contribute to anaphylaxis through either an IgE-FcεRI-dependent pathway or an IgG-FcγR pathway. However, it remains largely unclear whether basophils can be activated to promote anaphylaxis via a non-FcR pathway as well. The glycolipid receptor ASGM1 (Asialoganglioside gangliotetraosylceramide), which has an exposed GalNAcß1-4Gal moiety and serves as a receptor for pathogen associated molecular patterns such as flagellin, was recently found to be expressed on basophils. Here, we demonstrate that stimulation of basophils with anti-ASGM1 antibodies promotes platelet-activating factor (PAF) secretion in vitro and in vivo. Moreover, we found that ASGM1 stimulation triggers basophil- and PAF-dependent anaphylactic shock in pertussis toxin (PTX)-pretreated mice. Thus, ASGM1 has a crucial role in basophil activation and basophil-mediated anaphylaxis-like shock in mice, especially when the vascular permeability is increased by PTX treatment. Our findings describe a novel anaphylaxis-associated pathway that is antigen-, antibody-, and FcR-independent.


Subject(s)
Anaphylaxis/immunology , Basophils/immunology , Platelet Activating Factor/immunology , Receptors, Cell Surface/immunology , Anaphylaxis/blood , Animals , Antibodies/immunology , Antigens/immunology , Capillary Permeability/immunology , Cells, Cultured , Female , Immunoglobulin E/blood , Mice , Mice, Inbred C57BL
2.
J Orthop Surg Res ; 9: 136, 2014 Dec 31.
Article in English | MEDLINE | ID: mdl-25551285

ABSTRACT

PURPOSE: This study is to develop a new suturing technique for flexor tendon repair by modifying the extant Tsuge repair techniques and to use biomechanical analysis to compare the new method with four established repair techniques and evaluate its clinical efficacy in the repair of 47 flexor tendons in 22 patients. METHODS: The biomechanical analysis relied on 50 flexor digitorum profundus tendons harvested from fresh cadavers. The tendons were randomly divided into five groups, transected, and repaired by use of a 1. double-loop suture, 2. double modified locking Kessler, 3. four-strand Savage, 4. modified six-strand Savage, and 5. the new technique. The tensile force and breaking force of all repaired tendons were measured by static loading trials. For clinical application, 22 patients with acute flexor tendon injuries were treated with the new modified Tsuge suture and follow-up for more than 12 months. RESULTS: While differences in the tensile force and breaking force in the modified Tsuge sutures and modified six-strand Savage sutures were not statistically significant, static loading trials showed the tensile force, in the form of a 2-mm gap formation, and the breaking force of the new modified Tsuge sutures were, statistically, both higher than the ones characteristic of double-loop sutures, double modified locking Kessler, and four-strand Savage sutures. After 12 months, restored functions were observed in all the patients during the postoperative 12 months. Total active motion (TAM) score demonstrated that more than 90% fingers were estimated as excellent or good. CONCLUSION: The new modified Tsuge sutures described here have evident higher tensile and breaking forces compared to other four-strand core suture techniques, suggesting, in turn, that this new technique is a good alternative for flexor tendon repairs in clinical applications.


Subject(s)
Suture Techniques , Tendon Injuries/surgery , Tendons/surgery , Aged , Biomechanical Phenomena , Cadaver , Female , Follow-Up Studies , Humans , In Vitro Techniques , Male , Middle Aged , Sutures , Tensile Strength
3.
Article in English | WPRIM (Western Pacific) | ID: wpr-636619

ABSTRACT

Alveolar epithelial type II (AT II) cells are essential for lung development and remodeling, as they are precursors for type I cells and also produce other non-repair cells (fibroblasts). Progenitor cells are believed to possess capability of multi-potent transdifferentiation, which is closely related to the niche, suggesting the importance of establishment of a lung progenitor cell niche model. We hypothesized that pulmonary surfactant-associated protein A (SPA) suicide gene system would cause AT II cell to kill itself through apoptosis and leave its niche. In vitro, the recombinant adeno-associated virus vectors-SPA-thymidine kinase (rAAV-SPA-TK) system was established to get targeted apoptotic AT II cells. The apoptosis of AT II cells was detected by using MTT. The results showed that cloned SPA gene promoter had specific transcriptional activity in SPA high expression cells, and SPA high expression cells (H441) transfected with TK gene had higher sensitivity to ganciclovir (GCV) than SPA low expression cells (A549). In vivo, increased apoptosis of AT II cells induced by GCV in rAAV-SPA-TK system was observed by TUNEL. Finally, the successful packaging and application of rAAV-SPA-TK system provide experimental basis to get specific lung progenitor cell (AT II) niche in vitro and in vivo.

4.
Article in English | WPRIM (Western Pacific) | ID: wpr-351075

ABSTRACT

Alveolar epithelial type II (AT II) cells are essential for lung development and remodeling, as they are precursors for type I cells and also produce other non-repair cells (fibroblasts). Progenitor cells are believed to possess capability of multi-potent transdifferentiation, which is closely related to the niche, suggesting the importance of establishment of a lung progenitor cell niche model. We hypothesized that pulmonary surfactant-associated protein A (SPA) suicide gene system would cause AT II cell to kill itself through apoptosis and leave its niche. In vitro, the recombinant adeno-associated virus vectors-SPA-thymidine kinase (rAAV-SPA-TK) system was established to get targeted apoptotic AT II cells. The apoptosis of AT II cells was detected by using MTT. The results showed that cloned SPA gene promoter had specific transcriptional activity in SPA high expression cells, and SPA high expression cells (H441) transfected with TK gene had higher sensitivity to ganciclovir (GCV) than SPA low expression cells (A549). In vivo, increased apoptosis of AT II cells induced by GCV in rAAV-SPA-TK system was observed by TUNEL. Finally, the successful packaging and application of rAAV-SPA-TK system provide experimental basis to get specific lung progenitor cell (AT II) niche in vitro and in vivo.


Subject(s)
Humans , Antiviral Agents , Pharmacology , Apoptosis , Cell Line, Tumor , Cell Survival , Cells, Cultured , Dependovirus , Genetics , Dose-Response Relationship, Drug , Electrophoresis, Polyacrylamide Gel , Epithelial Cells , Cell Biology , Metabolism , Ganciclovir , Pharmacology , Gene Expression Regulation, Neoplastic , Genes, Transgenic, Suicide , Genetics , Genetic Vectors , Genetics , In Situ Nick-End Labeling , Luciferases , Genetics , Metabolism , Promoter Regions, Genetic , Genetics , Pulmonary Alveoli , Cell Biology , Metabolism , Pulmonary Surfactant-Associated Protein A , Genetics , Metabolism , Thymidine Kinase , Genetics , Metabolism
5.
Clin Immunol ; 149(3): 411-20, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24211715

ABSTRACT

Hashimoto's thyroiditis (HT) has long been epidemiologically associated with excess iodine levels. However, the underlying immunological mechanisms still remain largely unexplored. Th17 cells are commonly recognized as playing vital roles in various autoimmune diseases. Here we show that intra-thyroid infiltrating Th17 cells and serum IL-17 levels were significantly increased in HT patients. However, the concentration of serum IL-17 was inversely correlated with patients' residual thyroid function while the heterogeneously expressed thyroid IL-17 was directly correlated with local fibrosis. Administration of moderate high levels of iodine was found to facilitate the polarization of murine splenic naïve T cells into Th17 cells, whereas extreme high levels of iodine favored Th1 polarization and inhibited Treg development. These findings suggest that both Th1 and Th17 cells may be involved in the pathogenesis of HT and high levels of iodine may play a critical role in this process by modulating T cell differentiation.


Subject(s)
Hashimoto Disease/pathology , Interleukin-17/immunology , Th1 Cells/pathology , Th17 Cells/pathology , Thyroid Gland/pathology , Adult , Aged , Animals , Case-Control Studies , Cell Differentiation/drug effects , Cell Movement/drug effects , Female , Fibrosis , Hashimoto Disease/blood , Hashimoto Disease/immunology , Humans , Interleukin-17/biosynthesis , Interleukin-17/blood , Iodine/pharmacology , Male , Mice , Middle Aged , Organ Specificity , Spleen/immunology , Spleen/metabolism , Spleen/pathology , Th1 Cells/immunology , Th1 Cells/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Thyroid Gland/immunology , Thyroid Gland/metabolism
6.
Nat Commun ; 4: 2508, 2013.
Article in English | MEDLINE | ID: mdl-24149070

ABSTRACT

Gluconeogenesis is a fundamental feature of hepatocytes. Whether this gluconeogenic activity is also present in malignant hepatocytes remains unexplored. A better understanding of this biological process may lead to novel therapeutic strategies. Here we show that gluconeogenesis is not present in mouse or human malignant hepatocytes. We find that two critical enzymes 11ß-HSD1 and 11ß-HSD2 that regulate glucocorticoid activities are expressed inversely in malignant hepatocytes, resulting in the inactivation of endogenous glucocorticoids and the loss of gluconeogenesis. In patients' hepatocarcinoma, the expression of 11ß-HSD1 and 11ß-HSD2 is closely linked to prognosis and survival. Dexamethasone, an active form of synthesized glucocorticoids, is capable of restoring gluconeogenesis in malignant cells by bypassing the abnormal regulation of 11ß-HSD enzymes, leading to therapeutic efficacy against hepatocarcinoma. These findings clarify the molecular basis of malignant hepatocyte loss of gluconeogenesis and suggest new therapeutic strategies.


Subject(s)
Carcinoma, Hepatocellular/genetics , Dexamethasone/pharmacology , Glucocorticoids/pharmacology , Gluconeogenesis/drug effects , Glycolysis/drug effects , Liver Neoplasms/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 2/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , Animals , Base Sequence , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Female , Gene Expression Regulation, Neoplastic , Hepatocytes/drug effects , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Mice , Mice, Inbred BALB C , Molecular Sequence Data , Neoplasms, Experimental , Primary Cell Culture , Prognosis , Signal Transduction , Survival Analysis
7.
J Immunol ; 191(6): 3453-61, 2013 Sep 15.
Article in English | MEDLINE | ID: mdl-23956429

ABSTRACT

Mechanisms by which tumor cells metastasize to distant organs still remain enigmatic. Immune cells have been assumed to be the root of metastasis by their fusing with tumor cells. This fusion theory, although interpreting tumor metastasis analogically and intriguingly, is arguable to date. We show in this study an alternative explanation by immune cell-derived microparticles (MPs). Upon stimulation by PMA or tumor cell-derived supernatants, immune cells released membrane-based MPs, which were taken up by H22 tumor cells, leading to tumor cell migration in vitro and metastasis in vivo. The underlying molecular basis was involved in integrin α(M)ß2 (CD11b/CD18), which could be effectively relayed from stimulated innate immune cells to MPs, then to tumor cells. Blocking either CD11b or CD18 led to significant decreases in MP-mediated tumor cell metastasis. This MP-mediated transfer of immune phenotype to tumor cells might also occur in vivo. These findings suggest that tumor cells may usurp innate immune cell phenotypes via MP pathway for their metastasis, providing new insight into tumor metastatic mechanism.


Subject(s)
Carcinoma, Hepatocellular/pathology , Cell-Derived Microparticles/metabolism , Immunity, Innate , Liver Neoplasms/pathology , Macrophage-1 Antigen/metabolism , Neoplasm Invasiveness/pathology , Animals , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Cell-Derived Microparticles/immunology , Disease Models, Animal , Flow Cytometry , Immunity, Innate/immunology , Liver Neoplasms/immunology , Liver Neoplasms/metabolism , Mice , Mice, Inbred BALB C , Microscopy, Confocal , Microscopy, Electron, Transmission
8.
J Immunol ; 190(12): 6051-8, 2013 Jun 15.
Article in English | MEDLINE | ID: mdl-23677469

ABSTRACT

Despite various suspected causes, ranging from endocrine and genetic to infectious and immunological aspects, the molecular mechanisms of miscarriage still remain enigmatic. This work provides evidence that downregulation of 11ß-hydroxysteroid dehydrogenase (HSD) type 2, the key enzyme inactivating glucocorticoid activities, insults the pregnant inflammatory milieu by inhibiting the biosynthesis of lipoxin A4 (LXA4), a metabolite of arachidonic acid, leading to an early loss of the pregnancy. Both LXA4 and its biosynthetic enzymes were found to be decreased in women with spontaneous miscarriages and in the murine miscarriage model. Replenishing LXA4 reversed LPS-induced miscarriages in mouse models, whereas blocking LXA4 signaling resulted in miscarriages in the pregnant mice. The protective effect of LXA4 might be explained by LXA4's role in regulating uterine and placental inflammatory factors and mast cells. The underlying molecular mechanism involved miscarriage-inducing infections or stresses that downregulate the expression of 11ß-HSD2, but not 11ß-HSD1, resulting in increases in glucocorticoid activity and decreases in LXA4. Together, these findings suggest that the stress/glucocorticoid/LXA4 axis might be a common pathway through which miscarriages occur.


Subject(s)
11-beta-Hydroxysteroid Dehydrogenases/metabolism , Abortion, Spontaneous/physiopathology , Glucocorticoids/metabolism , Lipoxins/metabolism , Stress, Physiological/physiology , Animals , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunohistochemistry , Mice , Mice, Inbred BALB C , Pregnancy , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction
9.
Nat Commun ; 3: 1282, 2012.
Article in English | MEDLINE | ID: mdl-23250412

ABSTRACT

Cellular microparticles are vesicular plasma membrane fragments with a diameter of 100-1,000 nanometres that are shed by cells in response to various physiological and artificial stimuli. Here we demonstrate that tumour cell-derived microparticles can be used as vectors to deliver chemotherapeutic drugs. We show that tumour cells incubated with chemotherapeutic drugs package these drugs into microparticles, which can be collected and used to effectively kill tumour cells in murine tumour models without typical side effects. We describe several mechanisms involved in this process, including uptake of drug-containing microparticles by tumour cells, synthesis of additional drug-packaging microparticles by these cells that contribute to the cytotoxic effect and the inhibition of drug efflux from tumour cells. This study highlights a novel drug delivery strategy with potential clinical application.


Subject(s)
Antineoplastic Agents/administration & dosage , Cell-Derived Microparticles/metabolism , Drug Carriers/metabolism , Neoplasms/drug therapy , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Membrane/metabolism , Cisplatin/administration & dosage , Cisplatin/therapeutic use , Female , Liver Neoplasms/drug therapy , Methotrexate/administration & dosage , Methotrexate/therapeutic use , Mice , Mice, Inbred BALB C , Mice, SCID , Neoplasms, Experimental , Ovarian Neoplasms/drug therapy
10.
Antioxid Redox Signal ; 15(4): 1043-83, 2011 Aug 15.
Article in English | MEDLINE | ID: mdl-21294649

ABSTRACT

Lipid rafts, the sphingolipid and cholesterol-enriched membrane microdomains, are able to form different membrane macrodomains or platforms upon stimulations, including redox signaling platforms, which serve as a critical signaling mechanism to mediate or regulate cellular activities or functions. In particular, this raft platform formation provides an important driving force for the assembling of NADPH oxidase subunits and the recruitment of other related receptors, effectors, and regulatory components, resulting, in turn, in the activation of NADPH oxidase and downstream redox regulation of cell functions. This comprehensive review attempts to summarize all basic and advanced information about the formation, regulation, and functions of lipid raft redox signaling platforms as well as their physiological and pathophysiological relevance. Several molecular mechanisms involving the formation of lipid raft redox signaling platforms and the related therapeutic strategies targeting them are discussed. It is hoped that all information and thoughts included in this review could provide more comprehensive insights into the understanding of lipid raft redox signaling, in particular, of their molecular mechanisms, spatial-temporal regulations, and physiological, pathophysiological relevances to human health and diseases.


Subject(s)
Disease , Health , Membrane Microdomains/metabolism , NADPH Oxidases/metabolism , Ceramides/metabolism , Cholesterol/metabolism , Humans , Membrane Microdomains/chemistry , Metabolic Networks and Pathways/physiology , NADPH Oxidases/chemistry , Oxidation-Reduction , Signal Transduction/physiology
11.
Cancer Metastasis Rev ; 30(2): 177-84, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21267769

ABSTRACT

Mast cells are of paramount importance to allergies, pathogen immune responses during infections, and angiogenesis, as well as innate and adaptive immune regulations. Beyond all these roles, mast cells are now more and more being recognized as modulators of tumor microenvironment. Notwithstanding mounting evidences of mast cell accumulation in tumors, their exact role in tumor microenvironment is still incompletely understood. In this review, we discuss the significant role of mast cells in the remodeling of tumor microenvironment by either releasing various factors after activation or interacting with other cells within tumor and, as a result, the possible role of mast cell in cancer invasion and metastasis. We also discuss recent findings that mast cells actively release microparticles, which account for the transfer of membrane-type receptor signal and regulatory molecules such as microRNAs to tumor cells and immune cells. These findings on mast cells provide further insights into the complexity of tumor microenvironment remodeling.


Subject(s)
Mast Cells/immunology , Neoplasms/immunology , Signal Transduction/immunology , Tumor Microenvironment/immunology , Animals , Cytokines/immunology , Cytokines/metabolism , Humans , Mast Cells/metabolism , Mast Cells/pathology , Models, Immunological , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasms/metabolism , Neoplasms/pathology
12.
Med Hypotheses ; 76(2): 293-5, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21075541

ABSTRACT

Natural killer (NK) cells play critical roles in defense against tumors and viral infections. They exert their cytotoxic functions through the secretion of granules containing cytotoxic molecules, such as perforin and granzymes. These cytotoxic molecules are stored within dual-functional organelles, known as secretory lysosomes. Target cell recognition induces the formation of an "immunological synapse", between the NK cell and its target, into which cytotoxic granules release their contents. However the post-exocytosis regulation of the process is still largely unknown. Recent research and the data accumulated therefrom lead to new hypotheses that suggest that, not unlike synaptic vesicle recycling in neuronal terminals, NK cells also recycle not just their secretory lysosome membranes but their correlated cytotoxic molecules (perforin and granzymes). The newly endocytosed vesicles are used to replenish the "reserve pool" of vesicles for continued NK cell serial killings. These hypotheses, if proved to be correct, will significantly improve our understanding of NK cell cytotoxicity mechanisms and might even suggest new NK cell-based therapies that rely on NK serial killing abilities for overcoming tumors.


Subject(s)
Killer Cells, Natural/cytology , Antigen-Presenting Cells/cytology , Cytoplasm/metabolism , Endocytosis , Endosomes/metabolism , Exocytosis , Granzymes/chemistry , Humans , Immune System , Immunological Synapses , Lysosomes/metabolism , Models, Biological , Models, Theoretical , Perforin/chemistry , T-Lymphocytes/cytology
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