Although substance P (SP), a potent proinflammatory peptide, is involved in inflammation and immune responses, the effect of SP on the expression of macrophage inflammatory protein 3alpha[MIP-3alpha, chemokine C-C ligand 20 (CCL20)] in periodontal ligament (PDL) cells is unknown. Equally enigmatic is the link between SP, the stress protein heme oxygenase-1 (HO-1), and CCL20 production. We investigated whether SP induces the release of chemokine CCL20 from immortalized PDL (IPDL) cells, and further clarify SP-mediated pathways. We also examined the relationship between HO-1 and CCL20 by treating PDL cells with SP. Incubating IPDL cells with SP increased expression of CCL20 mRNA and CCL20 protein in a dose-time-dependent manner. Highly selective p38 and extracellular-regulated kinase 1/2 (ERK1/2) inhibitors abrogated SP-induced expression of CCL20 in IPDL cells. SP is also responsible for initiating phosphorylation of IkappaB, degradation of IkappaB and activation of nuclear factor (NF)-kappaB. SP induced expression of HO-1 in both a concentration- and time-dependent manner, and CCL20 reflected similar patterns. The inductive effects of SP on HO-1 and CCL20 were enhanced by HO-1 inducer hemin and the membrane-permeable guanosine 3',5'-monophosphate (cGMP) analogue 8-bromo-cGMP. Conversely, this pathway was inhibited by the HO-1 inhibitor zinc protoporphyrin IX (ZnPP IX) and the selective inhibitor of guanylate cyclase, 1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one (ODQ). We report herein the pathway that connects SP along with other modulators of neuroimmunoregulation to the induction of HO-1 and the inflammatory mediator macrophage inflammatory protein (MIP)-3alpha/CCL20 in IPDL cells, which play an important role in the development of periodontitis or inflammation during orthodontic tooth movement. 相似文献
The health effects of green tea are associated with catechins: (?)-epigallocatechin-3-O-gallate (EGCG), (?)-epigallocatechin, (?)-epicatechin-3-O-gallate, and (?)-epicatechin. An understanding of compound absorption, distribution, metabolism, excretion, and toxicity characteristics is essential for explaining its biological activities. Herein, absorption, distribution, metabolism, excretion, and toxicity properties of in vivo detected metabolites of green tea catechins (GTCs) have been analyzed in silico. The influence of metabolic transformations on absorption, distribution, metabolism, and excretion profiles of GTCs corresponds to the effects of size, charge, and lipophilicity, as already observed for other small molecules. Mutagenic, carcinogenic, or liver toxic effects were predicted only for a few metabolites. Similar to galloylated GTCs EGCG and (--)-epicatechin-3-O-gallate, the sulfo-conjugates were predicted to bind at the warfarin binding site. The low free plasma concentration of these derivatives may be consequential to their serum albumin binding. The activity cliff detected for methylated conjugates of EGCG indicates that GTCs' pro-oxidative activity in bound state comes primarily from free hydroxyl groups of the pyrogallol ring B. 相似文献
The vitamin D‐deficient model, established in the C57BL/6 mouse after 8 weeks of feeding vitamin D‐deficient diets in the absence or presence of added calcium, was found associated with elevated levels of plasma parathyroid hormone (PTH) and plasma and liver cholesterol, and a reduction in cholesterol 7α‐hydroxylase (Cyp7a1, rate‐limiting enzyme for cholesterol metabolism) and renal Oat3 mRNA/protein expression levels. However, there was no change in plasma calcium and phosphate levels. Appraisal of the liver revealed an up‐regulation of mRNA expressions of the small heterodimer partner (Shp) and attenuation of Cyp7a1, which contributed to hypercholesterolemia in vitamin D‐deficiency. When vitamin D‐sufficient or D‐deficient mice were further rendered hypercholesterolemic with 3 weeks of feeding the respective, high fat/high cholesterol (HF/HC) diets, treatment with 1α,25‐dihydroxyvitamin D3 [1,25(OH)2D3], active vitamin D receptor (VDR) ligand, or vitamin D (cholecalciferol) to HF/HC vitamin D‐deficient mice lowered the cholesterol back to baseline levels. Cholecalciferol treatment partially restored renal Oat3 mRNA/protein expression back to that of vitamin D‐sufficient mice. When the protein expression of protein kinase C (PKC), a known, negative regulator of Oat3, was examined in murine kidney, no difference in PKC expression was observed for any of the diets with/without 1,25(OH)2D3/cholecalciferol treatment, inferring that VDR regulation of renal Oat3 did not involve PKC in mice. As expected, plasma calcium levels were not elevated by cholecalciferol treatment of vitamin D‐deficient mice, while 1,25(OH)2D3 treatment led to hypercalcemia. In conclusion, vitamin D‐deficiency resulted in down‐regulation of liver Cyp7a1 and renal Oat3, conditions that are alleviated upon replenishment of cholecalciferol. 相似文献
Gastric cancer accounts for a sizeable proportion of global cancer mortality with high morbidity and poor prognosis. Kinesin superfamily proteins (KIFs) are microtubule‐dependent motor proteins that function as oncogenes in cancer cells, it has been discovered in recent years. Kinesin family member 2a (KIF2A), a member of the KIFs, has received attention for its role in carcinogenesis and its prognostic value in several human cancers such as breast cancer, colorectal cancer, and squamous cell carcinoma. However, the role of KIF2A in human gastric cancer remains unknown. In this study we aimed to explore the expression and biological functions of KIF2A in human gastric cancer cells, as well as to reveal its potential action mechanism. First, we found that KIF2A was markedly increased in gastric cancer cells (MKN‐28, MKN‐45, NCI‐N87 and SGC‐7901) compared to normal gastric mucosa epithelial cells (GES‐1). Then KIF2A was successfully silenced in MKN‐45 and SGC‐7901 cells to facilitate further research into its function. We discovered that KIF2A silencing can significantly inhibit the growth and invasion of MKN‐45 and SGC‐7901 cells in a time‐independent manner, accompanying a decreased expression of Membrane type 1‐matrix metalloproteinase (MT1‐MMP). When MT1‐MMP was reintroduced into MKN‐45 and SGC‐7901 cells in the KIF2A‐siRNA group, only invasion inhibition effects on MKN‐45 and SGC‐7901 cells induced by KIF2A silencing can be reversed. In conclusion, our study reveals that down‐regulation of KIF2A can inhibit gastric cancer cell invasion by suppressing MT1‐MMP. 相似文献
酸敏感离子通道(acid-sensing ion channels,ASICs)是在外周和中枢神经系统中广泛表达的质子门控的阳离子通道,ASIC1a作为其重要的组成部分在许多生理和病理过程中起重要作用。作为细胞外质子的关键受体,ASIC1a参与涉及组织酸中毒的多种病理生理过程,如疼痛、炎症、癫痫发作、多发性硬化等。自身免疫疾病是机体在应对自身抗原发生免疫反应时,过度活化的T、B细胞导致机体多组织器官受损的慢性炎症性疾病。近年来研究发现,ASIC1a在多种自身免疫性疾病发生中发挥着重要作用,该文就ASIC1a的生物学特征作简要综述,重点探讨ASIC1a在自身免疫性疾病发病机制中的研究进展。 相似文献
Introduction: While chemotherapy still remains a cornerstone of oncologic therapy, immunotherapy with monoclonal antibodies has steadily improved the treatment strategy for several hematologic malignancies. New treatment options need to be developed for relapsed and refractory non-Hodgkin lymphoma (NHL) patients. Currently, novel agents targeting specific molecules on the surface of lymphoma cells, such as anti-CD37 antibodies, are under considerable investigation. Here we report on anti-CD37 targeting for the treatment of patients with B-cell NHL.
Areas covered: CD37 seems to be the perfect therapeutic target in patients with NHL. The CD37 antigen is abundantly expressed in B-cells, but is absent on normal stem cells and plasma cells. It is hoped that anti-CD37 monoclonal antibodies will increase the efficacy and reduce toxicity in patients with both newly diagnosed and relapsed and refractory disease. Recent clinical trials have shown promising outcomes for these agents, administered both as monotherapy and in combination with standard chemotherapeutics.
Expert opinion: The development of new therapeutic options might help to avoid cytotoxic chemotherapy entirely in some clinical settings. This article presents the latest state of the art on the new treatment strategies in NHL patients. It also discusses recently approved agents and available clinical trial data. 相似文献