The Experts below are selected from a list of 93390 Experts worldwide ranked by ideXlab platform
Guiqing Liang - One of the best experts on this subject based on the ideXlab platform.
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Aldosterone synthase inhibition: cardiorenal protection in Animal Disease Models and translation of hormonal effects to human subjects.
Journal of Translational Medicine, 2014Co-Authors: Joël Ménard, Dean F Rigel, Catherine Watson, Arco Jeng, Michael Beil, Jing Liu, Wei Chen, Jennifer Leung-chu, Daniel Lasala, Guiqing LiangAbstract:BackgroundAldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. In vitro studies with recombinant human enzymes showed LCI699 to be a potent, reversible, competitive inhibitor of aldosterone synthase (K i¿=¿1.4¿±¿0.2 nmol/L in humans) with relative selectivity over 11ß-hydroxylase.MethodsHormonal effects of orally administered LCI699 were examined in rat and monkey in vivo Models of adrenocorticotropic hormone (ACTH) and angiotensin-II-stimulated aldosterone release, and were compared with the mineralocorticoid receptor antagonist eplerenone in a randomized, placebo-controlled study conducted in 99 healthy human subjects. The effects of LCI699 and eplerenone on cardiac and renal sequelae of aldosterone excess were investigated in a double-transgenic rat (dTGR) model overexpressing human renin and angiotensinogen.ResultsRat and monkey in vivo Models of stimulated aldosterone release predicted human dose¿ and exposure¿response relationships, but overestimated the selectivity of LCI699 in humans. In the dTGR model, LCI699 dose-dependently blocked increases in aldosterone, prevented development of cardiac and renal functional abnormalities independent of blood pressure changes, and prolonged survival. Eplerenone prolonged survival to a similar extent, but was less effective in preventing cardiac and renal damage. In healthy human subjects, LCI699 0.5 mg selectively reduced plasma and 24 h urinary aldosterone by 49¿±¿3% and 39¿±¿6% respectively (Day 1, mean¿±¿SEM; P¿
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aldosterone synthase inhibition cardiorenal protection in Animal Disease Models and translation of hormonal effects to human subjects
Journal of Translational Medicine, 2014Co-Authors: Joël Ménard, Dean F Rigel, Catherine Watson, Jing Liu, Wei Chen, Daniel Lasala, Arco Y Jeng, Michael E Beil, Jennifer Leungchu, Guiqing LiangAbstract:Background: Aldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. In vitro studies with recombinant human enzymes showed LCI699 to be a potent, reversible, competitive inhibitor of aldosterone synthase (Ki = 1.4 ± 0.2 nmol/L in humans) with relative selectivity over 11β-hydroxylase. Methods: Hormonal effects of orally administered LCI699 were examined in rat and monkey in vivo Models of adrenocorticotropic hormone (ACTH) and angiotensin-II-stimulated aldosterone release, and were compared with the mineralocorticoid receptor antagonist eplerenone in a randomized, placebo-controlled study conducted in 99 healthy human subjects. The effects of LCI699 and eplerenone on cardiac and renal sequelae of aldosterone excess were investigated in a double-transgenic rat (dTG rat) model overexpressing human renin and angiotensinogen. Results: Rat and monkey in vivo Models of stimulated aldosterone release predicted human dose– and exposure–response relationships, but overestimated the selectivity of LCI699 in humans. In the dTG rat model, LCI699 dose-dependently blocked increases in aldosterone, prevented development of cardiac and renal functional abnormalities independent of blood pressure changes, and prolonged survival. Eplerenone prolonged survival to a similar extent, but was less effective in preventing cardiac and renal damage. In healthy human subjects, LCI699 0.5 mg selectively reduced plasma and 24 h urinary aldosterone by 49 ± 3% and 39 ± 6% respectively (Day 1, mean ± SEM; P < 0.001 vs placebo), which was associated with natriuresis and an increase in plasma renin activity. Doses of LCI699 greater than 1 mg inhibited basal and ACTH-stimulated cortisol. Eplerenone 100 mg increased plasma and 24 h urinary aldosterone while stimulating natriuresis and increasing renin activity. In contrast to eplerenone, LCI699 increased the aldosterone precursor 11-deoxycorticosterone and urinary potassium excretion. Conclusions: These results provide new insights into the cardiac and renal effects of inhibiting aldosterone synthase in experimental Models and translation of the hormonal effects to humans. Selective inhibition of aldosterone synthase appears to be a promising approach to treat Diseases associated with aldosterone excess.
Steven W Dow - One of the best experts on this subject based on the ideXlab platform.
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concise review stem cell trials using companion Animal Disease Models
Stem Cells, 2016Co-Authors: Andrew M Hoffman, Steven W DowAbstract:Studies to evaluate the therapeutic potential of stem cells in humans would benefit from more realistic Animal Models. In veterinary medicine, companion Animals naturally develop many Diseases that resemble human conditions, therefore, representing a novel source of preclinical Models. To understand how companion Animal Disease Models are being studied for this purpose, we reviewed the literature between 2008 and 2015 for reports on stem cell therapies in dogs and cats, excluding laboratory Animals, induced Disease Models, cancer, and case reports. Disease Models included osteoarthritis, intervertebral disc degeneration, dilated cardiomyopathy, inflammatory bowel Diseases, Crohn's fistulas, meningoencephalomyelitis (multiple sclerosis-like), keratoconjunctivitis sicca (Sjogren's syndrome-like), atopic dermatitis, and chronic (end-stage) kidney Disease. Stem cells evaluated in these studies included mesenchymal stem-stromal cells (MSC, 17/19 trials), olfactory ensheathing cells (OEC, 1 trial), or neural lineage cells derived from bone marrow MSC (1 trial), and 16/19 studies were performed in dogs. The MSC studies (13/17) used adipose tissue-derived MSC from either allogeneic (8/13) or autologous (5/13) sources. The majority of studies were open label, uncontrolled studies. Endpoints and protocols were feasible, and the stem cell therapies were reportedly safe and elicited beneficial patient responses in all but two of the trials. In conclusion, companion Animals with naturally occurring Diseases analogous to human conditions can be recruited into clinical trials and provide realistic insight into feasibility, safety, and biologic activity of novel stem cell therapies. However, improvements in the rigor of manufacturing, study design, and regulatory compliance will be needed to better utilize these Models. Stem Cells 2016;34:1709-1729.
Lei Wei - One of the best experts on this subject based on the ideXlab platform.
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Rho kinase in the regulation of cell death and survival
Archivum Immunologiae et Therapiae Experimentalis, 2007Co-Authors: Jianjian Shi, Lei WeiAbstract:Rho kinase (ROCK) belongs to a family of serine/threonine kinases that are activated via interaction with Rho GTPases. ROCK is involved in a wide range of fundamental cellular functions, such as contraction, adhesion, migration, and proliferation. Recent studies have shown that ROCK plays an important role in the regulation of apoptosis in various cell types and Animal Disease Models. Two ROCK isoforms, ROCK1 and ROCK2, are assumed to be function redundant, this based largely on kinase construct overexpression and chemical inhibitors (Y27632 and fasudil) which inhibit both ROCK1 and ROCK2. Gene targeting and RNA interference approaches allow further dissection of distinct cellular, physiological, and patho-physiological functions of the two ROCK isoforms. This review, based on recent molecular, cellular, and Animal studies, focuses on the current understanding of ROCK signaling in the regulation of apoptosis and highlights new findings from recently generated ROCK-deficient mice.
Stefano Pluchino - One of the best experts on this subject based on the ideXlab platform.
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Neuro-immune interactions of neural stem cell transplants: from Animal Disease Models to human trials.
Experimental neurology, 2013Co-Authors: Elena Giusto, Matteo Donegà, Chiara Cossetti, Stefano PluchinoAbstract:Abstract Stem cell technology is a promising branch of regenerative medicine that is aimed at developing new approaches for the treatment of severely debilitating human Diseases, including those affecting the central nervous system (CNS). Despite the increasing understanding of the mechanisms governing their biology, the application of stem cell therapeutics remains challenging. The initial idea that stem cell transplants work in vivo via the replacement of endogenous cells lost or damaged owing to Disease has been challenged by accumulating evidence of their therapeutic plasticity. This new concept covers the remarkable immune regulatory and tissue trophic effects that transplanted stem cells exert at the level of the neural microenvironment to promote tissue healing via combination of immune modulatory and tissue protective actions, while retaining predominantly undifferentiated features. Among a number of promising candidate stem cell sources, neural stem/precursor cells (NPCs) are under extensive investigation with regard to their therapeutic plasticity after transplantation. The significant impact in vivo of experimental NPC therapies in Animal Models of inflammatory CNS Diseases has raised great expectations that these stem cells, or the manipulation of the mechanisms behind their therapeutic impact, could soon be translated to human studies. This review aims to provide an update on the most recent evidence of therapeutically-relevant neuro-immune interactions following NPC transplants in Animal Models of multiple sclerosis, cerebral stroke and traumas of the spinal cord, and consideration of the forthcoming challenges related to the early translation of some of these exciting experimental outcomes into clinical medicines.
Joël Ménard - One of the best experts on this subject based on the ideXlab platform.
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Aldosterone synthase inhibition: cardiorenal protection in Animal Disease Models and translation of hormonal effects to human subjects.
Journal of Translational Medicine, 2014Co-Authors: Joël Ménard, Dean F Rigel, Catherine Watson, Arco Jeng, Michael Beil, Jing Liu, Wei Chen, Jennifer Leung-chu, Daniel Lasala, Guiqing LiangAbstract:BackgroundAldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. In vitro studies with recombinant human enzymes showed LCI699 to be a potent, reversible, competitive inhibitor of aldosterone synthase (K i¿=¿1.4¿±¿0.2 nmol/L in humans) with relative selectivity over 11ß-hydroxylase.MethodsHormonal effects of orally administered LCI699 were examined in rat and monkey in vivo Models of adrenocorticotropic hormone (ACTH) and angiotensin-II-stimulated aldosterone release, and were compared with the mineralocorticoid receptor antagonist eplerenone in a randomized, placebo-controlled study conducted in 99 healthy human subjects. The effects of LCI699 and eplerenone on cardiac and renal sequelae of aldosterone excess were investigated in a double-transgenic rat (dTGR) model overexpressing human renin and angiotensinogen.ResultsRat and monkey in vivo Models of stimulated aldosterone release predicted human dose¿ and exposure¿response relationships, but overestimated the selectivity of LCI699 in humans. In the dTGR model, LCI699 dose-dependently blocked increases in aldosterone, prevented development of cardiac and renal functional abnormalities independent of blood pressure changes, and prolonged survival. Eplerenone prolonged survival to a similar extent, but was less effective in preventing cardiac and renal damage. In healthy human subjects, LCI699 0.5 mg selectively reduced plasma and 24 h urinary aldosterone by 49¿±¿3% and 39¿±¿6% respectively (Day 1, mean¿±¿SEM; P¿
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aldosterone synthase inhibition cardiorenal protection in Animal Disease Models and translation of hormonal effects to human subjects
Journal of Translational Medicine, 2014Co-Authors: Joël Ménard, Dean F Rigel, Catherine Watson, Jing Liu, Wei Chen, Daniel Lasala, Arco Y Jeng, Michael E Beil, Jennifer Leungchu, Guiqing LiangAbstract:Background: Aldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. In vitro studies with recombinant human enzymes showed LCI699 to be a potent, reversible, competitive inhibitor of aldosterone synthase (Ki = 1.4 ± 0.2 nmol/L in humans) with relative selectivity over 11β-hydroxylase. Methods: Hormonal effects of orally administered LCI699 were examined in rat and monkey in vivo Models of adrenocorticotropic hormone (ACTH) and angiotensin-II-stimulated aldosterone release, and were compared with the mineralocorticoid receptor antagonist eplerenone in a randomized, placebo-controlled study conducted in 99 healthy human subjects. The effects of LCI699 and eplerenone on cardiac and renal sequelae of aldosterone excess were investigated in a double-transgenic rat (dTG rat) model overexpressing human renin and angiotensinogen. Results: Rat and monkey in vivo Models of stimulated aldosterone release predicted human dose– and exposure–response relationships, but overestimated the selectivity of LCI699 in humans. In the dTG rat model, LCI699 dose-dependently blocked increases in aldosterone, prevented development of cardiac and renal functional abnormalities independent of blood pressure changes, and prolonged survival. Eplerenone prolonged survival to a similar extent, but was less effective in preventing cardiac and renal damage. In healthy human subjects, LCI699 0.5 mg selectively reduced plasma and 24 h urinary aldosterone by 49 ± 3% and 39 ± 6% respectively (Day 1, mean ± SEM; P < 0.001 vs placebo), which was associated with natriuresis and an increase in plasma renin activity. Doses of LCI699 greater than 1 mg inhibited basal and ACTH-stimulated cortisol. Eplerenone 100 mg increased plasma and 24 h urinary aldosterone while stimulating natriuresis and increasing renin activity. In contrast to eplerenone, LCI699 increased the aldosterone precursor 11-deoxycorticosterone and urinary potassium excretion. Conclusions: These results provide new insights into the cardiac and renal effects of inhibiting aldosterone synthase in experimental Models and translation of the hormonal effects to humans. Selective inhibition of aldosterone synthase appears to be a promising approach to treat Diseases associated with aldosterone excess.