Some eight years ago it was found that certain smooth muscle relaxants exert their effect by opening a specific K+ channel resulting in cell membrane hyperpolarization. The use of K+channel openers (cromakalim, pinacidil and RP-52891) and compounds which antagonize their actions (glibenclamide, phentolamine and alinidine) has enabled a great deal of research to be performed into the role of this K+ channel, not only in smooth muscle, but also in cardiac and skeletal muscle as well as neural and endocrine organ function. Much of the attention has centred on the smooth muscle relaxant actions of the K+ channel openers, since they have potential therapeutic use in disorders involving smooth muscle over-reactivity such as hypertension and asthma. More recently the cardiac actions of the K+ channel openers have become the focus of interest. Although there appear to be good theoretical reasons why K+ channel openers may be of use in some arrhythmias and in ischaemic heart disease there are major hurdles to overcome. In particular, given that the effect of these compounds on vascular smooth muscle occurs at a concentration 20- to 100-fold lower than that required to produce cardiac effects, it is likely their therapeutic usefulness will be limited until a breakthrough in cardiac/vascular selectivity is made. There is also growing interest in endogenous K+ channel openers and the physiological role of the K+ channel which they open. Opening of K+ channels, either spontaneously or by endogenous regulators, could possibly be an important hypotensive mechanism both under normal conditions and in a number of pathological conditions. Research into these areas will need to continue if the true therapeutic potential of K+ channel openers and their antagonists are to be realized. 相似文献
We studied cerebrospinal fluid Beta2-microglobulin (CSF B2-m) in 197 patients with a variety of neurological diseases to evaluate the usefulness of B2-m in the detection of meningeal dissemination of malignancy. In the control group we found a relationship between CSF log B2-m and age (P < 10−4). Age standardized reference values were established as 0.65–2.2 mg/l. The results show that CSF B2-m was elevated in leptomeningeal metastases from solid and haematological tumors. We observed slight elevations of CSF B2-m in epidural and parenchym metastases from solid tumors. Our study shows that B2-m in CSF is a sensitive marker for meningeal metastases especially from hemopoietic tumors. 相似文献
The prognostic role of tumor‐infiltrating tryptase+ mast cells in human solid tumors remains controversial. Herein, we conducted a meta‐analysis including 28 published studies with 4224 patients identified from PubMed and EBSCO to assess the prognostic impact of tumor‐infiltrating tryptase+ mast cells in human solid tumors. We found that tryptase+ mast cell infiltration significantly decreased overall survival (OS) and disease‐free survival (DFS) in all types of solid tumors. In stratified analyses, tryptase+ mast cell infiltration was significantly associated with worse OS in non‐small cell lung cancer, hepatocellular carcinoma and 5‐year survival in colorectal cancer. And these cells were inversely associated with DFS in hepatocellular and colorectal cancer. In addition, high density of intratumoral tryptase+ mast cells significantly correlated with lymph node metastasis of solid tumor. In conclusion, Tryptase+ mast cell infiltration leads to an unfavorable clinical outcome in solid tumors, implicating that it is a valuable biomarker for prognostic prediction for human solid malignances and targeting it may have a potential for effective treatment. 相似文献
IntroductionCD4+ T cells are essential for inducing optimal CD8+ T cell and antibody-producing B cell responses and maintaining their long-term immunological memory. Therefore, CD4+ T cells are a critical component in HIV vaccine development. Due to enormous viral gene variation and significant human host genetic diversity, HIV vaccines may need to be custom-made for different countries.MethodsPreviously, we designed a CD4+ T cell vaccine based on Chinese HIV isolates and HLA-DR alleles using bioinformatics tools and predicted that 20 epitopes could cover 98.1% of the Chinese population. In vivo testing of the poly-epitope antigen in mice only activated specific T cells for some epitopes. To elucidate the mechanism of the observed differential immunogenicity, we examined poly-epitope antigen processing and presentation using in vitro and in vivo analytical methods.ResultsEnzymatic digestion indicated that all 20 epitopes comprising the poly-epitope antigen could be liberated, but MHC II binding assays showed that neither binding affinity nor dissociation rate was associated with the magnitude of T cell immune responses elicited by each peptide epitope in vaccinated mice. Mass spectrometry analysis of MHC II-bound peptides suggested that the abundance of endogenously processed peptides bound to MHC II molecules was significantly associated with the relative immunodominance of these epitopes.ConclusionThese results provide a new rationale for improving the design and testing of poly-epitope vaccines for HIV and other diseases. 相似文献
BackgroundPsoriasis is a chronic inflammatory disease characterized by demarcated, raised, and scaling skin lesions. It often serves as a model for immune-mediated disorders. Gene expression profiling of affected skin has allowed insights into psoriasis pathogenesis. However, the mechanisms leading to specific mRNA expression alterations in psoriasis are barely understood.ObjectivesTo perform integrated microRNA-mRNA expression studies of non-lesional, peri-lesional, and lesional skin from psoriasis patients.MethodsCutaneous microRNA and mRNA expression profiles of 14 patients using Nanostring nCounter-technology and RNA sequencing as well as in vitro keratinocyte stimulation and qPCR studies.ResultsOnly 3.5 % of microRNAs manifested a robust gradual expression trend from non-lesional to paired lesional skin, with 61 % being upregulated and 39 % being downregulated. Relevance of these microRNA regulations was supported by their inverse association with 57 % of the mRNA species found to be regulated during psoriatic lesion development. Many of the involved mRNAs were downregulated and functionally related to keratinocyte metabolism, barrier function, and neuronal signaling, and were already regulated in peri-lesional skin. An integrated correlation analysis revealed a robust interaction for 134 microRNAs/mRNAs pairs. In vitro keratinocyte studies of selected microRNAs/mRNAs revealed regulations of all analyzed microRNAs in a psoriasis-like manner by IL-17A/TNF-α (e.g. hsa-miR-23a-3p), IFN-γ (e.g. hsa-miR-106a-5p/miR-17-5p), or IL-24 (e.g. hsa-miR-203a-3p). Moreover, most of their predicted target mRNAs (e.g. ID4, EPHB2) were respectively altered by the same cytokines.ConclusionOur study suggests that, during development of psoriatic lesions, defined aspects of psoriasis pathogenesis are regulated by the action of microRNAs. 相似文献