Inhibiting Jak2 Ameliorates Pulmonary Hypertension: Fulfilling the Promise of Precision Medicine.
Ontology highlight
ABSTRACT:
SUBMITTER: Leopold JA
PROVIDER: S-EPMC7780993 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Background: The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated. Methods: The PAH model was established by a single intraperitoneal injection of monocrotaline (MCT, 50 mg/kg) in adult male Sprague-Dawley rats. Donepezil was administered via intraperitoneal injection daily after 1 week of MCT administration. At the end of the study, PAH status was confirmed by echocardiography and hemodynamic measurement. Testing for acetylcholinesterase activity and cholinergic receptor expression was used to evaluate parasympathetic activity. Indicators of pulmonary arterial remodeling and right ventricular (RV) dysfunction were assayed. The proliferative and apoptotic ability of pulmonary arterial smooth muscle cells (PASMCs), inflammatory reaction, macrophage infiltration in the lung, and activation of bone marrow-derived macrophages (BMDMs) were also tested. PASMCs from the MCT-treated rats were co-cultured with the supernatant of BMDMs treated with donepezil, and then, the proliferation and apoptosis of PASMCs were evaluated. Results: Donepezil treatment effectively enhanced parasympathetic activity. Furthermore, it markedly reduced mean pulmonary arterial pressure and RV systolic pressure in the MCT-treated rats, as well as reversed pulmonary arterial remodeling and RV dysfunction. Donepezil also reduced the proliferation and promoted the apoptosis of PASMCs in the MCT-treated rats. In addition, it suppressed the inflammatory response and macrophage activation in both lung tissue and BMDMs in the model rats. More importantly, donepezil reduced the proliferation and promoted the apoptosis of PASMCs by suppressing M2-macrophage activation. Conclusion: Donepezil could prevent pulmonary vascular and RV remodeling, thereby reversing PAH progression. Moreover, enhancement of the parasympathetic activity could reduce the proliferation and promote the apoptosis of PASMCs in PAH by suppressing M2-macrophage activation.
| S-EPMC8005547 | biostudies-literature
Project description:BackgroundStudies of the genetic basis of drug response could help clarify mechanisms of drug action/metabolism, and facilitate development of genotype-based predictive tests of efficacy or toxicity (pharmacogenetics).ObjectivesWe conducted a systematic review and field synopsis of pharmacogenetic studies to quantify the scope and quality of available evidence in this field in order to inform future research.Data sourcesOriginal research articles were identified in Medline, reference lists from 24 meta-analyses/systematic reviews/review articles and U.S. Food and Drug Administration website of approved pharmacogenetic tests. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTION CRITERIA: We included any study in which either intended or adverse response to drug therapy was examined in relation to genetic variation in the germline or cancer cells in humans.Study appraisal and synthesis methodsStudy characteristics and data reported in abstracts were recorded. We further analysed full text from a random 10% subset of articles spanning the different subclasses of study.ResultsFrom 102,264 Medline hits and 1,641 articles from other sources, we identified 1,668 primary research articles (1987 to 2007, inclusive). A high proportion of remaining articles were reviews/commentaries (ratio of reviews to primary research approximately 25 ratio 1). The majority of studies (81.8%) were set in Europe and North America focussing on cancer, cardiovascular disease and neurology/psychiatry. There was predominantly a candidate gene approach using common alleles, which despite small sample sizes (median 93 [IQR 40-222]) with no trend to an increase over time, generated a high proportion (74.5%) of nominally significant (p<0.05) reported associations suggesting the possibility of significance-chasing bias. Despite 136 examples of gene/drug interventions being the subject of >or=4 studies, only 31 meta-analyses were identified. The majority (69.4%) of end-points were continuous and likely surrogate rather than hard (binary) clinical end-points.Conclusions and implications of key findingsThe high expectation but limited translation of pharmacogenetic research thus far may be explained by the preponderance of reviews over primary research, small sample sizes, a mainly candidate gene approach, surrogate markers, an excess of nominally positive to truly positive associations and paucity of meta-analyses. Recommendations based on these findings should inform future study design to help realise the goal of personalised medicines. SYSTEMATIC REVIEW REGISTRATION NUMBER: Not Registered.
| S-EPMC2778625 | biostudies-literature
Project description:Background and objective: Abnormal activation of Janus kinase 2 (JAK2) promotes the pathogenesis and progress of inflammatory bowel disease (IBD) by stimulating the cytokine traffic. Based on docking studies, arbutin, a natural product extracted from a traditional medicinal plant bearberry, was found to bind to JAK2. The study aimed to investigate the effects and mechanisms of regulating JAK2 by arbutin on colitis in mice. Methods: A mice colitis model was established to mimic human IBD. The mice freely drank water containing dextran sulfate sodium. Inflammation in epithelial (IEC6) and immune (RAW264.7) cells was analyzed following treatment with lipopolysaccharides (LPS). Results: Colitis symptoms, including body weight loss, increased disease activity index, and increased colon weight/length ratio, were significantly alleviated by arbutin. Mediators of colonic pro-inflammatory cytokines as well as apoptosis markers in colitis were suppressed by the glycoside. High expression of phosphorylated JAK2 in colitis was significantly reversed by arbutin. The effects of arbutin treatment on colitis were considerably inhibited by the JAK2 inhibitor AG490. LPS-induced inflammatory responses were also suppressed by arbutin, which was notably inhibited by the JAK2 inhibitor AG490. Conclusion: The findings obtained herein suggest the protective role of arbutin and provide novel insights into alternative colitis treatments, which involve inhibition of the JAK2 signaling pathway.
| S-EPMC8477021 | biostudies-literature
Project description:Integrated sequencing strategies have provided a broader understanding of the genomic landscape and molecular classifications of multiple cancer types and have identified various therapeutic opportunities across cancer subsets. Despite pivotal advances in the characterization of genomic alterations in glioblastoma, targeted agents have shown minimal efficacy in clinical trials to date, and patient survival remains poor. In this review, we highlight potential reasons why targeting single alterations has yielded limited clinical efficacy in glioblastoma, focusing on issues of tumor heterogeneity and pharmacokinetic failure. We outline strategies to address these challenges in applying precision medicine to glioblastoma and the rationale for applying targeted combination therapy approaches that match genomic alterations with compounds accessible to the central nervous system.
| S-EPMC4490873 | biostudies-literature
Project description:The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.
| S-EPMC7021559 | biostudies-literature
Project description: Not available
| S-EPMC7397766 | biostudies-literature
Project description:Chronic lung diseases contribute significantly to the morbidity and mortality of the population. There are few effective treatments for many chronic lung diseases, and even fewer therapies that can arrest or reverse the progress of the disease.In this review, we present the current state of regenerative therapies for the treatment of chronic lung diseases. We focus on endothelial progenitor cells, mesenchymal stem cells, and endogenous lung stem/progenitor cells; summarize the work to date in models of lung diseases for each of these therapies; and consider their potential benefits and risks as viable therapies for patients with lung diseases.Cell-based regenerative therapies for lung diseases offer great promise, with preclinical studies suggesting that the next decade should provide the evidence necessary for their ultimate application to our therapeutic armamentarium.
| S-EPMC3513384 | biostudies-literature
Project description:Management of patients with interstitial lung disease (ILD) requires accurate classification. However, this process relies on subjective interpretation of nonspecific and overlapping clinical features that could hamper clinical care. The development and implementation of objective biomarkers reflective of specific disease states could facilitate precision-based approaches based on patient-level biology to improve the health of ILD patients. Omics-based studies allow for the seemingly unbiased and highly efficient screening of candidate biomarkers and offer unprecedented opportunities for discovery. This review outlines representative major omics-based discoveries in a well-studied condition, idiopathic pulmonary fibrosis, to develop a roadmap to personalized medicine in ILD.
| S-EPMC8168687 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous, unpredictable and ultimately lethal chronic lung disease. Over the last decade, two anti-fibrotic agents have been shown to slow disease progression, however, both drugs are administered uniformly with minimal consideration of disease severity and inter-individual molecular, genetic, and genomic differences. Advances in biological understanding of disease endotyping and the emergence of precision medicine have shown that "a one-size-fits-all approach" to the management of chronic lung diseases is no longer appropriate. While precision medicine approaches have revolutionized the management of other diseases such as lung cancer and asthma, the implementation of precision medicine in IPF clinical practice remains an unmet need despite several reports demonstrating a large number of diagnostic, prognostic and theragnostic biomarker candidates in IPF. This review article aims to summarize our current knowledge of precision medicine in IPF and highlight barriers to translate these research findings into clinical practice.
| S-EPMC10469771 | biostudies-literature
Project description: Not available
| S-EPMC5233857 | biostudies-literature