3��,4��-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling

Background and purpose:

We investigated the effects of a synthetic flavonol, 3′,4′-dihydroxyflavonol (DiOHF) on the expression of monocyte chemoattractant protein-1 (MCP-1) in rat vascular smooth muscle cells.

Experimental approach:

MCP-1 expression was assessed by quantitative real-time PCR and protein phosphorylation by immunoprecipitation and Western blots.

Key results:

DiOHF (1–30 µmol·L⁻¹) concentration-dependently reduced MCP-1 expression in both quiescent cells and cells stimulated with platelet-derived growth factor (PDGF) or interleukin 1-β. The effect of DiOHF was associated with a suppression of focal adhesion kinase (FAK)-mediated signalling. In vitro kinase assays demonstrated that DiOHF is a potent inhibitor of FAK kinase activity (EC₅₀= 2.4 µmol·L⁻¹). Expression of FAK-related non-kinase reduced basal MCP-1 expression, but not that induced by PDGF or interleukin 1-β. DiOHF also inhibited autophosphorylation of PDGF receptors. The PDGF receptor inhibitor AG-1296 potently suppressed basal and PDGF-induced MCP-1 expression. Inhibition of extracellular signal-regulated kinase activation by DiOHF, either directly or indirectly, may also be involved in its effects on MCP-1 expression. DiOHF had no inhibitory effect on either p38 or nuclear factor-κB activation. Moreover, DiOHF inhibited smooth muscle cell spreading (a FAK-mediated response) and proliferation.

Conclusions and implications:

This is the first report on a flavonoid compound (DiOHF) that is a potent FAK inhibitor. DiOHF also inhibits PDGF receptor autophosphorylation. These effects underlie the inhibitory action of DiOHF on MCP-1 expression in smooth muscle cells. Our results suggest that DiOHF might be a useful tool for dissection of the (patho)physiological roles of FAK signalling.British Journal of Pharmacology (2009) 157, 597–606; doi:10.1111/j.1476-5381.2009.00199.x; published online 9 April 2009     

注射用双黄连与几种抗生素联合体外抑菌活性的研究

目的：探讨注射用双黄连与抗生素联合使用的临床意义。方法：参考中国药典抗生素微生物检定法，测定注射用双黄连与头孢拉定等６种抗生素配伍使用后对金葡菌及克雷白氏肺炎杆菌的抑菌圈直径的变化。结果：注射用双黄连与氨苄青霉素、普鲁卡因青霉素、头孢唑啉钠及红霉素配伍后对金葡萄的体外抑菌效果明显增强；与头孢拉定、头孢唑啉钠及普鲁卡因青霉素配伍后对克氏肺炎杆菌的体外抑菌效果有不同程度的增强。结论：对于不同的细菌感染     

Human fibroblast tissue factor is inhibited by lipoprotein-associated coagulation inhibitor and placental anticoagulant protein but not by apolipoprotein A-II

Studies of proteins that inhibit tissue factor activity have generally been conducted using either an extracted tissue homogenate ("thromboplastin") or tissue factor protein reconstituted into phospholipid vesicles rather than with tissue factor expressed in cell membranes (its physiological environment). In the present study, a human fibroblast cell strain was used to evaluate the effects of lipoprotein associated coagulation inhibitor (LACI), placental anticoagulant protein (PAP), and apolipoprotein A-II (apo A-II) on human tissue factor in cell membranes. LACI was tested from 7.8 to 500 pmol/L on fibroblasts cultured at cell densities ranging from 3,500 to 9,925 cells/well, and caused a progressive inhibition of tissue factor activity. PAP was tested from 3.9 nmol/L to 1 mumol/L at cell densities ranging from 4,500 to 15,400 cells/well and caused up to 83% inhibition of tissue factor activity. Inhibition by these proteins appeared to be influenced by cell density as well as whether the cells were intact or disrupted. Apo A-II, up to 1 mumol/L, did not inhibit the tissue factor activity of intact or disrupted fibroblasts at any cell density examined even though it did inhibit the activity of tissue factor in phospholipid vesicles. Of these inhibitors of tissue factor-dependent activation of factor X, LACI was the most effective in suppressing the generation of factor Xa activity. The effects obtained with apo A-II are clearly dependent on the nature of the tissue factor preparation with which it is tested. The disparity between the inhibitory effect of apo A-II on the activity of tissue factor reconstituted into lipid vesicles and the absence of effect on the activity of tissue factor remaining in cell membranes serves to reemphasize the necessity of reexamining results obtained with model systems using as nearly physiological reagents as possible.     

Morphological analysis of degeneration and regeneration of syncytiotrophoblast in first trimester placental villi during organ culture

We have recently shown using dansyl-L-lysine exclusion studies that the release of human chorionic gonadotrophin (HCG) in conjunction with L- lactate dehydrogenase (LDH) from first trimester villi during organ culture is symptomatic of syncytiotrophoblast degeneration. The purpose of this study was to examine chorionic villi at the ultrastructural level in order to determine events occurring during organ culture. The tissue was sampled after 0, 24, 48 and 120 h in culture and processed for electron microscopy. In addition to confirming the previously recorded syncytial degeneration, the electron micrographs showed clearly the generation of a new syncytiotrophoblast layer. The new layer, derived from differentiating cytotrophoblast cells, was largely formed by 48 h and was maintained for at least 120 h in culture. This study demonstrates a model which provides an opportunity to study the differentiation of cytotrophoblast cells whilst they retain their anatomical relationships within the villous structure.      

Basic isoferritin and hypercalcaemia in renal cell carcinoma

A 63-year-old man with iron loss anaemia and hypercalcaemia was found to have a renal cell carcinoma. Despite the iron-deficient blood and bone marrow picture, the serum ferritin concentration was markedly raised. This was mainly due to a “basic isoferritin”. The serum parathormone concentration was normal. The serum ferritin and calcium concentrations returned to normal after the tumour was removed. We propose that the renal cell carcinoma cells in this patient secreted the basic isoferritin as well as humoral factor(s) responsible for hypercalcaemia.     

PGD9 Outcomes and Cost-Benefit of Inhaled Corticosteroid Therapy Introduction in Medicaid-Enrolled Asthmatic Children

OBJECTIVE: The purpose of this study was to assess the clinical and economic impact of the introduction of inhaled corticosteroid therapy for asthma in a cohort of children 12 years and younger who were North Carolina Medicaid enrollees.
METHODS: The North Carolina Medicaid claims database was used to retrieve clinical and economic variables for the purpose of this study. The case group, which was comprised of 84 children who started corticosteroid inhaler therapy between March 1994 and March 1995, was followed up for 1 year before and 1 year after the start of the therapy. The control group was comprised of 72 children with similar severity of asthma who remained on any other therapy other than corticosteroids for a continuous 2-year period. Paired t-tests were used to compare differences, and multiple regression analysis was used to adjust for potential confounders.
RESULTS: There was a 58% reduction in hospital visits, and a 19% reduction in physician visits in the case group after initiation of inhaled corticosteroids. In the control group, an increase of 34% in the number of outpatient visits occurred in the second year. All the decreases and increases were statistically significant. Children with regular patterns of inhaled corticosteroid refills were found to be significantly lower costing for Medicaid. However, after adjusting for potential confounders, no significant change in health care costs per asthmatic child occurred as a result of the introduction of inhaled corticosteroid therapy.
CONCLUSION: Overall, the study found that introduction of inhaled corticosteroids in a cohort of asthmatic children enrolled in Medicaid was beneficial to Medicaid because it brought about dramatic decreases in health care utilization without additionally increasing costs.     

鼓槌石斛化学成分的研究

自中药鼓槌石斛(Dendrobium chrysotoxum Lindl.)茎中分离到5个化合物,经光谱(UV,IR,MS,¹HNMR,DIFNOE和¹³CNMR)分析,分别鉴定为β-谷甾醇(I)、鼓槌菲(chrysotoxene,II)、毛兰素(erianin,III)、毛兰菲(confusarin,IV)和鼓槌联苄(chrysotobibenzyl,V)。II是新化合物,V是新天然产物。     

刺蒺藜果中一种新桂皮酰胺类成分的分离和鉴定

从刺蒺藜(Tribulus terrestris L)果实中分得两个化合物,经理化常数测定和光谱(UV,IR,¹HNMR,¹³CNMR,¹H-¹³CCOSY和MS)解析。化合物I鉴定为N-对羟基苯乙酮基-3-甲氧基-4-羟基取代桂皮酰胺,为一新化合物,命名为蒺藜酰胺(terrestriamide)。化合物II为8-甲基氢化茚酮-1,首次从该植物中获得。