Therapeutic Effect of a Synthetic RORα/γ Agonist in an Animal Model of Autism.
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ABSTRACT:
SUBMITTER: Wang Y
PROVIDER: S-EPMC4759619 | biostudies-other | 2016 Feb
REPOSITORIES: biostudies-other
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Project description:The motor and nonmotor symptoms of Parkinson's disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate β sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated β sheet aggregate (β23), and prevented β23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII's neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation.
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Project description:BackgroundPersistent fibroblast activation initiated by transforming growth factor β (TGF-β) is a fundamental event in the pathogenesis of systemic sclerosis, and its pharmacological inhibition represents a potential therapeutic strategy. The nuclear receptor, peroxisome proliferator-activated receptor γ (PPAR-γ), exerts potent fibrotic activity. The synthetic oleanane triterpenoid, 2-cyano-3,12-dioxo-olean-1,9-dien-28-oic acid (CDDO), is a PPAR-γ agonist with potential effects on TGF-β signalling and dermal fibrosis.ObjectiveTo examine the modulation of fibrogenesis by CDDO in explanted fibroblasts, skin organ cultures and murine models of scleroderma.Material and methodsThe effects of CDDO on experimental fibrosis induced by bleomycin injection or by overexpression of constitutively active type I TGF-β receptor (TgfbR1ca) were evaluated. Modulation of fibrotic gene expression was examined in human skin organ cultures. To delineate the mechanisms underlying the antifibrotic effects of CDDO, explanted skin fibroblasts cultured in two-dimensional monolayers or in three-dimensional full-thickness human skin equivalents were studied.ResultsCDDO significantly ameliorated dermal fibrosis in two complementary mouse models of scleroderma, as well as in human skin organ cultures and in three-dimensional human skin equivalents. In two-dimensional monolayer cultures of explanted normal fibroblasts, CDDO abrogated fibrogenic responses induced by TGF-β. These CDDO effects occurred via disruption of Smad-dependent transcription and were associated with inhibition of Akt activation. In scleroderma fibroblasts, CDDO attenuated the elevated synthesis of collagen. Remarkably, the in vitro antifibrotic effects of CDDO were independent of PPAR-γ.ConclusionsThe PPAR-γ agonist triterpenoid CDDO attenuates fibrogenesis by antagonistically targeting canonical TGF-β/Smad and Akt signalling in a PPAR-γ-independent manner. These findings identify this synthetic triterpenoid as a potential new therapy for the control of fibrosis.
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Project description:Insulin resistance and hepatic lipid accumulation constitute the metabolic underpinning of nonalcoholic steatohepatitis (NASH). We tested the hypothesis that saroglitazar, a PPAR α/γ agonist would improve NASH in the diet-induced animal model of NAFLD. Mice received chow diet and normal water (CDNW) or high fat western diet and ad lib sugar water (WDSW). After 12 weeks, WDSW fed mice were randomized to receive (1) WDSW alone, (2) WDSW + vehicle, (3) WDSW + pioglitazone or (4) WDSW + saroglitazar for an additional 12 weeks. Compared to mice on WDSW and vehicle controls, mice receiving WDSW + saroglitazar had lower weight, lower HOMA-IR, triglycerides, total cholesterol, and ALT. Saroglitazar improved steatosis, lobular inflammation, hepatocellular ballooning and fibrosis stage. NASH resolved in all mice receiving saroglitazar. These effects were at par with or superior to pioglitazone. Molecular analyses confirmed target engagement and reduced oxidative stress, unfolded protein response and fibrogenic signaling. Transcriptomic analysis further confirmed increased PPAR-target expression and an anti-inflammatory effect with saroglitazar. Lipidomic analyses demonstrated that saroglitazar also reduced triglycerides, diglycerides, sphingomyelins and ceramides. These preclinical data provide a strong rationale for developing saroglitazar for the treatment of NASH in humans.
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Project description:BackgroundIn the post-genomic era, multi-faceted research on complex disorders such as autism has generated diverse types of molecular information related to its pathogenesis. The rapid accumulation of putative candidate genes/loci for Autism Spectrum Disorders (ASD) and ASD-related animal models poses a major challenge for systematic analysis of their content. We previously created the Autism Database (AutDB) to provide a publicly available web portal for ongoing collection, manual annotation, and visualization of genes linked to ASD. Here, we describe the design, development, and integration of a new module within AutDB for ongoing collection and comprehensive cataloguing of ASD-related animal models.DescriptionAs with the original AutDB, all data is extracted from published, peer-reviewed scientific literature. Animal models are annotated with a new standardized vocabulary of phenotypic terms developed by our researchers which is designed to reflect the diverse clinical manifestations of ASD. The new Animal Model module is seamlessly integrated to AutDB for dissemination of diverse information related to ASD. Animal model entries within the new module are linked to corresponding candidate genes in the original "Human Gene" module of the resource, thereby allowing for cross-modal navigation between gene models and human gene studies. Although the current release of the Animal Model module is restricted to mouse models, it was designed with an expandable framework which can easily incorporate additional species and non-genetic etiological models of autism in the future.ConclusionsImportantly, this modular ASD database provides a platform from which data mining, bioinformatics, and/or computational biology strategies may be adopted to develop predictive disease models that may offer further insights into the molecular underpinnings of this disorder. It also serves as a general model for disease-driven databases curating phenotypic characteristics of corresponding animal models.
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Project description:BackgroundAutism spectrum disorders (ASD) is a common disease and the incidence has been rising constantly. Acupuncture is one of the most widely used complementary and alternative medicine therapies. Despite studies had been done on the effectiveness of acupuncture on ASD children, how factors such as chronological age and the onset pattern influence the effectiveness of the therapy remains unclear. The aim of this retrospective study is to know how symptomatology of ASD alters upon the introduction of scalp acupuncture and how do age and onset type affect the effectiveness of the therapy.MethodsASD children aged 2-11 years old were invited to join the study. In the course of the investigation, they received a total of 30 sessions of scalp acupuncture therapy. They were then evaluated to compare the performance on various aspects before and after the treatment. The influence on the therapeutic effect by factors including chorological age and onset pattern were further taken into consideration and analyzed. In addition, investigation on the relationship between allergies and onset pattern of ASD was performed by statistically analyzing the received epidemiologic data from the participants.Results68 children with ASD participated in the study. It is found that the significant effective rate of scalp acupuncture on ASD is 97%. Scalp acupuncture can improve verbal communication problems the most while noise sensitivity improves the least. The therapeutic effectiveness decreases with increasing age and children with natal autism benefit more from acupuncture than those with regressive autism. In the latter part of the study, we observe a positive correlation between the family history of allergy and onset pattern.ConclusionScalp acupuncture is an effective treatment for alleviating the symptomatology of ASD. The therapeutic effectiveness is expected to be higher for those patients with natal or early onset of the disorder, and at a younger age when they receive the therapy. The study result helps to formulate an ideal regimen for ASD patients and allow therapists and parents to make appropriate expectation towards the therapeutic outcome of acupuncture. Early intervention of scalp acupuncture therapy recommended. The relationship between the family history of allergic disorder and the onset type of ASD hints that the etiologies of natal and regressive ASD are discrete. It shows a great significance in differentiating the onset pattern in carrying out clinical assessments or researches on ASD patients.Trial registration This retrospective study was approved by the Committee on the Use of Human and Animal Subjects in Teaching and Research, Hong Kong Baptist University on 4th Aug 2017. The retrospectively registered number is HASC/Student/17-18/0115.
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