Search

Tissue transglutaminase (TG2) plays an important role in pulmonary arterial hypertension (PAH). Previous research indicate that TG2 and protein serotonylation catalyzed by TG2 are upregulated in PAH. Serotonin transporter inhibitor fluoxetine ameliorates PAH via inhibition of protein serotonylation. It is still unknown whether PAH is inhibited through direct inhibition of TG2. Therefore, the present study aimed to investigate the effects of TG2 inhibitor cystamine on monocrotalineinduced PAH in rats. Rats were treated with monocrotaline (60 mg x [kg.sup.-1], i.p.) in combination with or without cystamine (20, 40 mg x [kg.sup.-1] x [day.sup.-1], p.o.). The results showed that compared with monocrotaline alone, combination of monocrotaline with cystamine (40 mg x [kg.sup.-1] x [day.sup.-1], p.o.) relieved right ventricle hypertrophy, inhibited pulmonary arteriolar remodeling, and down-regulated protein expression of TG2, phosphorylated protein kinase B (Akt), and extracellular regulated protein kinase (ERK) at day 21 However, except for TG2 expression, these changes were not significantly inhibited by cystamine at day 35. In addition, cystamine dose-dependently enhanced the survival rate of rats injected with monocrotaline at day 35. The findings suggest that cystamine slows but not reverses monocrotaline-induced PAH in rats, which was largely associated with the inhibition of TG2 protein expression and Akt and ERK activation. Key words: Akt, cystamine, ERK, monocrotaline, pulmonary arterial hypertension, serotonin, transglutaminase. Resume : La transglutaminase tissulaire (TG2) joue un role important dans l'hypertension pulmonaire (HP). Les recherches anterieures montrent que la TG2 et la serotonylation des proteines catalysee par la TG2 sont regulees a la hausse dans l'HP. La fluoxetine, un inhibiteur du transporteur de la serotonine, permet d'attenuer l'HP par l'intermediaire de l'inhibition de la serotonylation des proteines. Mais on ne sait toujours pas si l'HP est inhibee par l'intermediaire d'une inhibition directe de la TG2. Par consequent, les presents travaux visaient a etudier les effets de la cystamine, un inhibiteur de la TG2, sur l'HP provoquee par la monocrotaline chez le rat. Nous avons administre aux rats de la monocrotaline (60 mg x [kg.sup.-1], i.p.) seule ou en association avec de la cystamine (20, 40 mg x [kg.sup.-1] x [jour.sup.-1], p.o.). Les resultats ont montre qu'au jour 21, comparativement a la monocrotaline seule, la monocrotaline en association avec la cystamine (40 mg x [kg.sup.-1] x [jour.sup.-1], p.o.) permettait d'attenuer l'hypertrophie ventriculaire droite, d'inhiber le remodelage des arterioles pulmonaires ainsi que de reguler a la baisse l'expression proteique de la TG2, de la proteine kinase B phosphorylee (Akt) et de la proteine kinase regulee dans le compartiment extracellulaire (ERK). Cependant, a l'exception de l'expression de la TG2, ces variations n'etaient pas inhibees de facon notable par la cystamine au jour 35. De plus, la cystamine entrainait une augmentation proportionnelle a la dose du taux de survie au jour 35 chez les rats auxquels etait injectee de la monocrotaline. Les resultats laissent entendre que la cystamine entrainerait chez le rat un ralentissement de l'evolution de l'HP (mais sans son inversion), ce qui serait largement associe avec l'inhibition de l'expression proteique de la TG2 ainsi que de l'activation de l'Akt et de l'ERK. [Traduit par la Redaction] Mots-cles: Akt, cystamine, ERK, monocrotaline, hypertension pulmonaire, serotonine, transglutaminase., Introduction Pulmonary arterial hypertension (PAH) is characterized by an increase in mean pulmonary artery pressure, due to pulmonary vascular remodelling that leads to an imbalance between excessive vasoconstrictors and low [...]

Early detection of high-risk population for osteoporosis is the key to preventing this disease. Methodology: In this cross-sectional study a continuous sample of 270 women and 89 men (age: 20–90 years) was divided into four groups by age (≤ 55 or > 55 years) and sex. Participants completed the IOF test. Low-, medium-, and high-risk grades were defined by an OSTA index of greater than -1, -1 to -4, and less than -4, respectively. Results: Most participants were categorized in the low-risk group (240 people, 66.9%), followed by the medium-risk (102 people, 28.4%) and high-risk groups (17 people, 4.7%). Compared to women, men in both age groups had significantly higher OSTA index and greater numbers of positive answers on the IOF test. 64.3% individuals were susceptible to osteoporosis risk (≥1 positive answers on the IOF test). Multiple regression analysis demonstrated that family history of fragility fracture (OR: 0.503, 95% CI: 0.26–0.97), height loss exceeding 3 cm (OR: 2.51, 95% CI: 1.55–4.05), and earlier menopause (OR: 0.434, 95% CI: 0.19–0.97) were associated with higher risk grades. Conclusions: Combined use of the OSTA and IOF test is a simple and effective method for assessing the risk of osteoporosis.

Activation of the small GTPase Ras homolog gene family member A (RhoA) and Rho-associated kinase (ROCK) are important in the pathogenesis of pulmonary arterial hypertension (PAH). Selective serotonin reuptake inhibitors inhibit activation of RhoA and ROCK in vitro, and ameliorate PAH and pulmonary arterial remodeling in vivo. However, little is known about whether the RhoA-ROCK signalling pathway is involved in the treatment of PAH with fluoxetine in vivo. The aim of the present study was to investigate the involvement of the RhoA-ROCK signalling pathway in the protective effect of the selective serotonin reuptake inhibitor fluoxetine against monocrotaline (MCT)-induced pulmonary arterial remodeling. MCT was applied to establish PAH in male Wistar rats. Fluoxetine was administered by gastric gavage once a day for 21 d. The results showed that MCT induced pulmonary arterial remodeling, raised the serotonylation and membrane translocation of RhoA in the lungs, and increased serotonin transporter (5-HTT), RhoA, and ROCK2 expression, and extracellular signal-regulated kinase (ERK) and Akt phosphorylation in the pulmonary arteries and the lungs. Fluoxetine markedly inhibited these MCT-induced changes. The findings suggest that fluoxetine inhibits MCT-induced pulmonary arterial remodeling in rats by inhibition of the RhoA-ROCK and Akt signalling pathways. Key words: RhoA, Rho kinase, monocrotaline, serotonin transporter, fluoxetine, pulmonary arterial remodeling, Akt. L'activation de la proteine RhoA, une petite GTPase membre de la famille des homologues de Ras, et de ROCK, une kinase associee a ROCK, est importante a la pathogenese de l'hypertension arterielle pulmonaire (HAP). Les inhibiteurs selectifs de recapture de la serotonine peuvent inhiber l'activation de RhoA et ROCK in vitro et ameliorer l'HAP et le remodelage arteriel pulmonaire in vivo. Cependant, on ignore si la voie de signalisation RhoA-ROCK est impliquee dans le traitement de l'HAP in vivo par la fluoxetine. Le but de cette etude etait d'examiner l'implication de la voie de signalisation RhoA-ROCK dans l'effet protecteur exerce par la fluoxetine, un inhibiteur selectif de recapture de la serotonine, sur le remodelage arteriel pulmonaire induit par la monocrotaline (MCT). La MCT a ete donnee a des rats males Wistar afin d' etablir un etat d' HAP. La fluoxetine a ete administree par gavage gastrique une fois par jour pendant 21 jours. Les resultats ont revele que la MCT induisait un remodelage arteriel pulmonaire, accroissait la serotonylation et la translocation membranaire de RhoA dans les poumons et augmentait l' expression du 5-HTT, de RhoA et de ROCK ainsi que la phosphorylation de ERK et Akt dans les arteres pulmonaires et les poumons. La fluoxetine inhibait fortement ces changements induits par la MCT. Ces resultats suggerent que la fluoxetine a inhibe le remodelage arteriel pulmonaire induit par la MCT chez les rats et que ce phenomene impliquait l'inhibition des voies de signalisation RhoA-ROCK et Akt. Mots-cles : RhoA, Rho kinase, monocrotaline, transporteur de serotonine, fluoxetine, remodelage pulmonaire arteriel, Akt. [Traduit par la Redaction], Introduction Pulmonary arterial hypertension (PAH) is characterized by a sustained and progressive increase in pulmonary arterial pressure with pathologic changes involving vasoconstriction, vascular remodeling, and inflammation, which may lead to [...]

The 2-azaspiro(5.5)undecane system characterized by a tunable amide position was synthesized from ester complex (1) which was first reduced to alcohol complex (2). An 80% yield of phthalimido complex (3) was obtained by Mitsunobu reaction from 2 and phthalimide. Addition of triphenylmethylium perchlorate to 3 resulted to a regiospecific hydride abstraction which yielded dienylium salt. This underwent regio and stereoselective addition with trimethylsilyl cyanide at the more substituted terminus and opposite the Fe(CO)3 group, respectively, to afford the intermediate complex.

The present study was performed to investigate the effects of 4-chloro-DL-phenylalanine (PCPA), a tryptophan hydroxylase (Tph) inhibitor (TphI), on pulmonary vascular remodeling and lung inflammation in monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats. Animal models of PAH were established using Sprague-Dawley (SD) rats by a single intraperitoneal injection of MCT (60 mg/kg). PCPA (50 or 100 mg/kg/day) was administered to the rats with PAH. On day 22, hemodynamic measurements and morphological observations of the lung tissues were performed. The levels of Tph-1 and serotonin transporter (SERT) in the lungs were analyzed by immunohistochemistry and western blot analysis. The expression of matrix metalloproteinase (MMP)-2 and MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 and inflammatory cytokines were assayed by western blot analysis. The activity of MMP-2 and MMP-9 was evaluated by gelatin zymography (GZ). MCT markedly promoted PAH, increased the right ventricular hypertrophy index, pulmonary vascular remodeling, lung inflammation and mortality, which was associated with the increased expression of Tph-1, SERT, MMP-2/-9, TIMP-1/-2 and inflammatory cytokines. PCPA markedly attenuated MCT-induced pulmonary vascular remodeling and lung inflammation, inhibited the expression of Tph-1 and SERT and suppressed the expression of MMP-2/-9, TIMP-1/-2, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1). These findings suggest that the amelioration of MCT-induced pulmonary vascular remodeling and lung inflammation by PCPA is associated with the downregulation of Tph-1, SERT, MMP/TIMP and inflammatory cytokine expression in rats.