Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration

Background

The aim of the study was to assess the chronic effects of combined phosphodiesterase 3/4 inhibitor tolafentrine, administered by inhalation, during monocrotaline-induced pulmonary arterial hypertension (PAH) in rats.

Methods

CD rats were given a single subcutaneous injection of monocrotaline to induce PAH. Four weeks after, rats were subjected to inhalation of tolafentrine or sham nebulization in an unrestrained, whole body aerosol exposure system. In these animals (i) the acute pulmonary vasodilatory efficacy of inhaled tolafentrine (ii) the anti-remodeling effect of long-term inhalation of tolafentrine (iii) the effects of tolafentrine on the expression profile of 96 genes encoding cell adhesion and extracellular matrix regulation were examined. In addition, the inhibitory effect of tolafentrine on ex vivo isolated pulmonary artery SMC cell migration was also investigated.

Results

Monocrotaline injection provoked severe PAH (right ventricular systolic pressure increased from 25.9 ± 4.0 to 68.9 ± 3.2 after 4 weeks and 74.9 ± 5.1 mmHg after 6 weeks), cardiac output depression and right heart hypertrophy. The media thickness of the pulmonary arteries and the proportion of muscularization of small precapillary resistance vessels increased dramatically, and the migratory response of ex-vivo isolated pulmonary artery smooth muscle cells (PASMC) was increased. Micro-arrays and subsequent confirmation with real time PCR demonstrated upregulation of several extracellular matrix regulation and adhesion genes, such as matrixmetalloproteases (MMP) 2, 8, 9, 10, 11, 12, 20, Icam, Itgax, Plat and serpinb2. When chronically nebulized from day 28 to 42 (12 daily aerosol maneuvers), after full establishment of severe pulmonary hypertension, tolafentrine reversed about 60% of all hemodynamic abnormalities, right heart hypertrophy and monocrotaline-induced structural lung vascular changes, including the proportion of pulmonary artery muscularization. The upregulation of extracellular matrix regulation and adhesion genes was reduced by nearly 80% by inhalation of the tolafentrine. When assessed in vitro, tolafentrine blocked the enhanced PASMC migratory response.

Conclusion

In conclusion, we demonstrate for the first time that inhalation of combined PDE3/4 inhibitor reverses pulmonary hypertension fully developed in response to monocrotaline in rats. This "reverse-remodeling" effect includes structural changes in the lung vascular wall and key molecular pathways of matrix regulation, concomitant with 60% normalization of hemodynamics.     

Survivin as a Target for Anti-cancer Phytochemicals According to the Molecular Docking Analysis

International Journal of Peptide Research and Therapeutics - Survivin is a unique member of the inhibitor of apoptosis protein family. Research has approved Survivin’s ability to interact...     

Bioconversion of Hydrocortisone by Cyanobacterium Fischerella ambigua PTCC 1635

Summary The bioconversion of hydrocortisone by a locally isolated strain of cyanobacterium Fischerella ambigua PTCC 1635 was investigated. Fischerella ambigua had not been previously examined for this potential. The fermentation led to production of 11β,17α, 20β, 21-tetrahydroxypregn-4-en-3-one and 11β-hydroxyandrost-4-en-3,17-dione. The metabolites were isolated and purified by chromatographic methods and identified using instrumental analyses.     

Effect of some essential oils on mycelial growth of <Emphasis Type="Italic">Penicillium digitatum</Emphasis> Sacc.

The antifungal action of four essential oils of Foeniculum vulgare (fennel), Thymus vulgaris (thyme), Eugenia caryophyllata (Clove) and Salvia officinalis (sage) was tested in vitro against Penicillium digitatum Sacc. Direct contact and vapour phase were used to test the antifungal activity of these essential oils against P. digitatum that is responsible for green mould rot of citrus fruits. The vapour phase and direct contact of clove and thyme essential oils exhibited the strongest toxicity and totally inhibited the mycelial growth of the test fungus. Thyme and clove essential oils completely inhibited P. digitatum growth either when added into the medium 600 μl l⁻¹ or by their volatiles with 24 μl per 8 cm diameter Petri dish. In in vitro mycelial growth assay showed fungistatic and fungicidal activity by clove and thyme essential oils. Sage and fennel oils did not show any inhibitory activity on this fungus. Scanning electron microscopy (SEM) was done to study the mode of action of clove oil in P. digitatum and it was observed that treatment with the oil leads to large alterations in hyphal morphology.     

Positive correlation between vitamin D receptor gene TaqI variant and gastric cancer predisposition in a sample of Iranian population

Gastric cancer is the second cause of cancer-related mortality and the fourth most common cancers worldwide. Owing to the immune modulatory effect of vitamin D in the body, the role of vitamin D receptor gene in vitamin D regulation receives a great deal of research interest. The aim of the current study was to highlight the association between two variants of TaqI and FokI in the vitamin D receptor gene and gastric cancer predisposition in a sample of South Khorasan population. The present investigation consisted of 69 patients affected with gastric cancer and 100 healthy individuals. The genomic DNA was extracted by salting out the protocol from peripheral venous blood. Genotyping of TaqI and FokI variants were performed by PCR-RFLP method. Our findings manifested that TC genotype of TaqI polymorphism was statistically significant between the case and the control groups (p = 0.002). Moreover, the frequency of TC + CC genotypes was statistically significant between the two groups (p = 0.009). Furthermore, we could not find any meaningful association between FokI variant and the participant groups. The present results declared that, in our population, TC genotype of TaqI polymorphism has an association with gastric cancer susceptibility. In addition, more investigation with greater sample sizes is needed to confirm our results.     

Hemato-Immunological Responses and Disease Resistance in Siberian Sturgeon <Emphasis Type="Italic">Acipenser baerii</Emphasis> Fed on a Supplemented Diet of <Emphasis Type="Italic">Lactobacillus plantarum</Emphasis>

A feeding trial was conducted to investigate the effects of different levels of dietary Lactobacillus plantarum on hemato-immunological parameters and resistance against Streptococcus iniae infection in juvenile Siberian sturgeon Acipenser baerii. Fish (14.6 ± 2.3 g) were fed three experimental diets prepared by supplementing a basal diet with L. plantarum at different concentrations [1 × 10⁷, 1 × 10⁸ and 1 × 10⁹ colony-forming units (cfu) g^?1] and a control (non-supplemented basal) diet for 8 weeks. Innate immune responses (immunoglobulin (Ig), alternative complement activity (ACH50) and lysozyme activity) were significantly higher in fish fed the 1 × 10⁸ and 1 × 10⁹ cfu g^?1 L. plantarum diet compared to the other groups (P < 0.05). Furthermore, fish fed on various levels of L. plantarum significantly showed higher red blood cell (RBC), hemoglobin (Hb), white blood cell (WBC) and monocyte compared to those of the control group (P < 0.05). At the end of the feeding experiment, some fish were challenged with S. iniae to quantify the level of disease resistance. The mortality after S. iniae challenge was decreased in fish fed a probiotic. These results indicated that dietary supplementation of L. plantarum improved immune response and disease resistance of Siberian sturgeon juvenile.     

The Effects of Selenium Supplementation on Clinical Symptoms and Gene Expression Related to Inflammation and Vascular Endothelial Growth Factor in Infertile Women Candidate for In Vitro Fertilization

Biological Trace Element Research - This study was performed to determine the effects of selenium supplementation on clinical symptoms and gene expression related to inflammatory markers in...