Prevention of macrophage adhesion molecule-1 (Mac-1)-dependent neutrophil firm adhesion by taxifolin through impairment of protein kinase-dependent NADPH oxidase activation and antagonism of G protein-mediated calcium influx

Taxifolin has been reported to down-regulate the expression of intercellular adhesion molecule-1 (ICAM-1), a receptor-mediating firm adhesion with beta2 integrin (e.g., Mac-1) expressed on leukocytes. To evaluate whether taxifolin could modulate Mac-1-dependent firm adhesion by neutrophils, and the possible mechanism(s) underlying its anti-inflammatory action, its effects on N-formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol-12-myristate-13-acetate (PMA)-activated peripheral human neutrophils were studied. Pretreatment with taxifolin (1-100 microM) concentration-dependently diminished fMLP- or (PMA)-induced Mac-1-dependent firm adhesion and upexpression of surface Mac-1. Mobilisation of intracellular calcium and production of reactive oxygen species (ROS) signal the upexpression of Mac-1 and firm adhesion by neutrophils. Taxifolin impeded the calcium influx induced by fMLP (a receptor-mediated activator) or AlF(4)(-) (a G protein-mediated activator). Taxifolin also effectively inhibited the fMLP- or PMA-induced ROS production with 50% inhibitory concentration (IC(50)) less than 10microM, possibly through impairing the activation of NADPH oxidase, a major ROS-generating enzyme in neutrophils, by restricting the activation of p38 mitogen-activated protein kinase (p38 MAPK) and protein kinase C (PKC). In conclusion, we propose that impairment of ROS production by NADPH oxidase through interfering with p38 MAPK- and/or PKC-dependent signals, and antagonism of G protein-mediated calcium influx may account for the inhibition of Mac-1-dependent neutrophil firm adhesion that confers taxifolin the anti-inflammatory activity.     

2-(2-(dimethylaminomethyl)phenoxy)-5-iodophenylamine: an improved serotonin transporter imaging agent

Imaging serotonin transporters (SERT) is an emerging research tool potentially useful to cast light on the mechanisms of drug action as well as to monitor the treatment of depressed patients. We have prepared two new derivatives of 3, 2-(2-(dimethylaminomethyl)phenoxy)-5-iodophenylamine (4) and 2-(2-(dimethylaminomethyl)benzyl)-5-iodophenylamine (5) (K(i) for SERT = 0.37 and 48.6 nM, respectively). Both [(125)I]4 and [(125)I]5 displayed excellent brain uptakes in rats, and they showed a highest uptake in hypothalamus (between 60 and 240 min), a region populated with the highest density of SERT. The specific uptake of [(125)I]4 in the hypothalamus resulted in a target to nontarget ratio ([hypothalamus-cerebellum]/cerebellum) of 4.3 at 2 h. Autoradiography of rat brain sections (ex vivo at 2 h) of [(125)I]4 showed an excellent regional distribution pattern consistent with known SERT localization. These data suggest that [(123)I]4 may be useful for imaging SERT binding sites in the brain by single photon emission computed tomography (SPECT).     

Delivery systems for bone growth factors - the new players in skeletal regeneration

Given the challenge of an increasing elderly population, the ability to repair and regenerate traumatised or lost tissue is a major clinical and socio-economic need. Pivotal in this process will be the ability to deliver appropriate growth factors in the repair cascade in a temporal and tightly regulated sequence using appropriately designed matrices and release technologies within a tissue engineering strategy. This review outlines the current concepts and challenges in growth factor delivery for skeletal regeneration and the potential of novel delivery matrices and biotechnologies to influence the healthcare of an increasing ageing population.     

Dehydroepiandrosterone induces apoptosis of thymocyte through Fas/Fas-L pathway

Dehydroepiandrosterone (DHEA), the most plentiful steroid hormone, has been convincingly known to have many biological effects and diverse influence in various types of cells, tissues and organs. The effects of DHEA on the humoral and cellular immune response are widely tested, but it is unclear whether DHEA itself serves as an activator of immune function and the literature pertaining to the in vitro effects of DHEA remains contested. In the present paper, the effects of DHEA on the thymocytes in vitro were studied. The results showed that DHEA could enhance the expression of Fas and Fas-L and induce thymocyte apoptosis. This suggests that dehydroepiandrosterone may induce the apoptosis of thymocyte through Fas/Fas-L pathway.     

Functional interaction between tumor suppressor menin and activator of S-phase kinase

Multiple endocrine neoplasia type I (MEN1), a hereditary tumor syndrome, is characterized by the development of tumors in multiple endocrine organs. The gene mutated in MEN1 patients, Men1, encodes a tumor suppressor, menin. Overexpression of menin leads to inhibition of Ras-transformed cells. However, it is unclear whether menin is essential for repression of cell proliferation, and if it is, how it inhibits cell proliferation. Here, we show that targeted disruption of the Men1 gene leads to enhanced cell proliferation, whereas complementation of menin-null cells with menin reduces cell proliferation. Moreover, menin interacts with activator of S-phase kinase (ASK), a component of the Cdc7/ASK kinase complex that is crucial for cell proliferation, but does not appear to alter Cdc7 kinase activity in in vitro kinase assays. We identify the COOH terminus of menin as the domain that mediates the specific interaction with ASK. Notably, wild-type menin completely represses ASK-induced cell proliferation, although it does not obviously affect the steady-state cell cycle profile of ASK-infected cells. Interestingly, disease-related COOH-terminal menin mutants that do not interact with ASK completely fail to repress ASK-induced cell proliferation. Together, these findings demonstrate a functional link between menin and ASK in the regulation of cell proliferation.     

Anthocyanidins inhibit activator protein 1 activity and cell transformation: structure-activity relationship and molecular mechanisms

Anthocyanins are the chemical components that give the intensecolor to many fruits and vegetables, such as blueberries, redcabbages and purple sweet potatoes. Extensive studies have indicatedthat anthocyanins have strong antioxidant activities. To investigatethe mechanism of anthocyanidins as an anticancer food source,six kinds of anthocyanidins representing the aglycons of mostanthocyanins, were used to examine their effects on tumor promotionin mouse JB6 cells, a validated model for screening cancer chemopreventiveagents and elucidating the molecular mechanisms. Of the sixanthocyanins tested, only those with an ortho-dihydroxyphenylstructure on the B-ring suppressed 12-O-tetradecanoylphorbol-13-acetate(TPA)-induced cell transformation and activator protein-1 transactivation,suggesting that the ortho-dihydroxyphenyl may contribute tothe inhibitory action. Delphinidin, but not peonidin, blockedthe phosphorylation of protein kinases in the extracellularsignal-regulated protein kinase (ERK) pathway at early timesand the c-Jun N-terminal kinase (JNK) signaling pathway at latertimes. p38 kinase was not inhibited by delphinidin. Furthermore,two mitogen-activated protein kinase (MAPK) specific inhibitors(SP600125 for JNK and UO126 for ERK) could specifically blockthe activation of JNK and ERK and cell transformation. Thoseresults demonstrate that anthocyanidins contribute to the inhibitionof tumorigenesis by blocking activation of the MAPK pathway.These findings provide the first molecular basis for the anticarcinogenicaction of anthocyanidins.     

Echinocystic acid induces apoptosis in HL-60 cells through mitochondria-mediated death pathway

Echinocystic acid (EA) is a natural triterpone enriched in various herbs and used for medicinal purpose in many Asian countries. In the present study, we reported that EA can induce apoptosis in human promyelocytic leukemia cells (HL-60), as characterized by DNA fragmentation, poly (ADP) ribose polymerase cleavage. The efficacious induction of apoptosis was observed at 100 microM for 6 h. Further molecular analysis showed that EA induced the cleavage of Bid protein, the loss of mitochondrial membrane potential (DeltaPsim) cytochrome c release from mitochondria into cytosol, and activation of caspase-3, -8 and -9. However, EA did not generate reactive oxygen species (ROS), and antioxidants including N-acetyl cysteine and catalase could not block EA-induced apoptosis in the HL-60 cells. These data suggest that EA induces apoptosis in HL-60 cells through ROS-independent mitochondrial dysfunction pathway.     

Motilin in human milk and its elevated plasma concentration in lactating women

BACKGROUND AND AIMS: The aims of this study were to investigate whether: (i) lactating women had an elevated plasma level of motilin; (ii) there was a correlation between the plasma motilin level and the motilin level in breast milk in lactating women; and (iii) there was a difference in motilin levels between the colostrum and mature human milk in a controlled postprandial state. METHODS: Twenty control women and 18 lactating women were enrolled in this study. All samples were drawn in a controlled postprandial state. The concentration of motilin was measured using radioimmunoassay. RESULTS: The plasma motilin level in lactating women was 434 +/- 180 pmol/L on the fifth day after delivery and 450 +/- 204 pmol/L on the 42nd day after delivery (P > 0.05). Both of these values were significantly higher than those in the control women (231 +/- 48 pmol/L, P < 0.05). The motilin level in human milk in the controlled postprandial state was 161 +/- 56 pmol/L on the fifth day and 154 +/- 60 pmol/L on the 42nd day after parturition (P = 0.7). Although there was motilin in the breast milk and an elevated plasma level of motilin in the lactating women, there was no correlation in motilin level between the blood and the breast milk. CONCLUSIONS: Motilin is elevated in the blood of lactating women and human milk contains motilin. These elevated levels of motilin sustain for a period of at least 6 weeks. Further studies are necessary to assess whether motilin is involved in the development of gastrointestinal motility in the early stage of life in infancy.     

Epidemiology of chronic obstructive arterial disease of the lower limbs and diabetic patients at the University Hospital of Cotonou (Benin)

The aims of this study were to determine the prevalence of chronic obstructive arterial disease of the lower limbs and to identify the factors which contribute to its occurrence in a population of adult African francophone diabetics. This was a prospective study which included all consenting diabetics systematically over a 6 month period at the out patient clinic or during hospital admission. Patients with incomplete data were excluded. An ankle systolic pressure index of less than 0.9 was required for the diagnosis of obstructive arterial disease. Demographic parameters, the characteristics of the diabetes, the quality of blood sugar control, the presence of classical cardiovascular risk factors and the results of their treatment, the nature and distribution of the arterial lesions on ultrasonography were all studied. A univariate analysis and a multivariate analysis of their correspondences were undertaken to determine the correlation coefficients. The prevalence of arterial disease of the lower limbs in the 102 diabetics retained for the study (average age 53 years) was 33.3%. The arterial disease was distal in 47% of cases and diffuse in 26.5% of cases. The arterial wall was calcified in 19.6% of cases. In univariate analysis only age was correlated with arterial disease (p = 0.04), the duration of diabetes tended to be related (p = 0.07). In multi-factorial analysis of Correspondences with other factors, hypertension, hyperlipidaemia and multiple cardiovascular risk factors seemed to be correlated with arterial disease of the lower limbs. Therefore, arterial disease of the lower limbs is very common and an early complication of diabetic patients in Benin. Predisposing factors were age and, probably, duration of diabetes, hypertension, hyperlipidaemia and multiple cardiovascular risk factors.