1,721,094 research outputs found
The role of small extracellular vesicles in cerebral and myocardial ischemia-Molecular signals, treatment targets, and future clinical translation
No full textThe heart and the brain mutually interact with each other, forming a functional axis that is disturbed under conditions of ischemia. Stem cell-derived extracellular vesicles (EVs) show great potential for the treatment of ischemic stroke and myocardial infarction. Due to heart-brain interactions, therapeutic actions of EVs in the brain and the heart cannot be regarded in an isolated way. Effects in each of the two organs reciprocally influence the outcome of the other. Stem cell-derived EVs modulate a large number of signaling pathways in both tissues. Upon ischemia, EVs prevent delayed injury, promote angiogenesis, enhance parenchymal remodeling, and enable functional tissue recovery. The therapeutic effects greatly depend on EV cargos, among which are noncoding RNAs like microRNAs (miRNAs) and proteins, which modulate cell signaling in a differential way that not always corresponds to each other in the two tissues. Interestingly, the same miRNA or protein localized in EVs can modulate different signaling pathways in the ischemic heart and brain, which may have diverse consequences for disease outcomes. Paying careful attention to unveiling these underlying mechanisms may provide new insights into tissue remodeling processes and identify targets for ischemic stroke and myocardial infarction therapies. Some of these mechanisms are discussed in this concise review, and consequences for the clinical translation of EVs are presented
Extracellular Vesicles as Diagnostic Tool in Transient Ischemic Attack and Ischemic Stroke
No full textTargeting epigenetic modifiers to reprogramme macrophages in non-resolving inflammation-driven atherosclerosis
No full textEpigenomic and epigenetic research has been providing several new insights into a variety of diseases caused by non-resolving inflammation, including cardiovascular diseases. Atherosclerosis (AS) has long been recognized as a chronic inflammatory disease of the arterial walls, characterized by local persistent and stepwise accelerating inflammation without resolution, also known as uncontrolled inflammation. The pathogenesis of AS is driven primarily by highly plastic macrophages via their polarization to pro- or anti-inflammatory phenotypes as well as other novel subtypes recently identified by single-cell sequencing. Although emerging evidence has indicated the key role of the epigenetic machinery in the regulation of macrophage plasticity, the investigation of epigenetic alterations and modifiers in AS and related inflammation is still in its infancy. An increasing number of the epigenetic modifiers (e.g. TET2, DNMT3A, HDAC3, HDAC9, JMJD3, KDM4A) have been identified in epigenetic remodelling of macrophages through DNA methylation or histone modifications (e.g. methylation, acetylation, and recently lactylation) in inflammation. These or many unexplored modifiers function to determine or switch the direction of macrophage polarization via transcriptional reprogramming of gene expression and intracellular metabolic rewiring upon microenvironmental cues, thereby representing a promising target for anti-inflammatory therapy in AS. Here, we review up-to-date findings involving the epigenetic regulation of macrophages to shed light on the mechanism of uncontrolled inflammation during AS onset and progression. We also discuss current challenges for developing an effective and safe anti-AS therapy that targets the epigenetic modifiers and propose a potential anti-inflammatory strategy that repolarizes macrophages from pro- to anti-inflammatory phenotypes
Animal models of ischemic stroke and their impact on drug discovery
No full textIntroduction: Representing the leading cause of long-term disability, ischemic stroke urgently needs further research and drug development. This review summarizes current animal models of ischemic stroke that can be used for drug discovery.
Areas covered: Several reproducible models of permanent and transient focal cerebral ischemia have been established in a variety of animal species including rats and mice, in which a brain-supplying artery, often the middle cerebral artery, is occluded by mechanical devices including sutures, clips and hooks, pharmacological agents or delivery of blot clots. The authors review existing literature about these models, outlining their utility for evaluating acute and post-acute stroke treatments. Since stroke is an age-related disease that strongly affects humans with vascular risk factors and co-morbidities, the authors give focus to strategies replicating risk factors in ischemic stroke models. Furthermore, the authors present models of spontaneous stroke.
Expert opinion: It is important that animal models mimic clinical conditions in a reliable and clinically relevant way, so here, they should replicate the pathophysiology of human stroke, stroke-associated risk factors and doses, times and modes of drug treatment. We propose that risk factor models should more widely be used in early drug discovery, if possible already during the identification of treatment targets.No Full Tex
Opportunities and Limitations of Vascular Risk Factor Models in Studying Plasticity-Promoting and Restorative Ischemic Stroke Therapies
No full textMajor efforts are currently made promoting neuronal plasticity and brain remodeling in the postacute stroke phase. Experimental studies evaluating new stroke therapies are mostly performed in rodents, which compared to humans exhibit a short lifespan. These studies widely employ young, otherwise healthy, rodents that lack the vascular risk factors and comorbidities of stroke patients. These risk factors compromise postischemic neurological recovery and brain plasticity and in several contexts reduce the brain responsiveness to recovery-inducing plasticity-promoting treatments. By examining risk factor models, which have hitherto been used for studying experimentally induced ischemic stroke, this review outlines the possibilities and limitations of risk factor models in the evaluation of plasticity-promoting and restorative stroke treatments
Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3 beta inhibition-independent pathways
Full text linkWOS: 000394660400015PubMed ID: 27126323Lithium promotes acute poststroke neuronal survival, which includes mechanisms that are not limited to GSK3 inhibition. However, whether lithium induces long-term neuroprotection and enhanced brain remodeling is unclear. Therefore, mice were exposed to transient middle cerebral artery occlusion and lithium (1mg/kg bolus followed by 2mg/kg/day over up to 7 days) was intraperitoneally administered starting 0-9h after reperfusion onset. Delivery of lithium no later than 6h reduced infarct volume on day 2 and decreased brain edema, leukocyte infiltration, and microglial activation, as shown by histochemistry and flow cytometry. Lithium-induced neuroprotection persisted throughout the observation period of 56 days and was associated with enhanced neurological recovery. Poststroke angioneurogenesis and axonal plasticity were also enhanced by lithium. On the molecular level, lithium increased miR-124 expression, reduced RE1-silencing transcription factor abundance, and decreased protein deubiquitination in cultivated cortical neurons exposed to oxygen-glucose deprivation and in brains of mice exposed to cerebral ischemia. Notably, this effect was not mimicked by pharmacological GSK3 inhibition. This study for the first time provides efficacy data for lithium in the postacute ischemic phase, reporting a novel mechanism of action, i.e. increased miR-124 expression facilitating REST degradation by which lithium promotes postischemic neuroplasticity and angiogenesis.German Research Council ( DFG) [HE3173/2-2, HE3173/3-1]; TUBITAK [2221]The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The present study was supported by the German Research Council (DFG; # HE3173/2-2 and # HE3173/3-1 to DMH) and TUBITAK (# 2221 to TRD)
Immunological and non-immunological effects of stem cell-derived extracellular vesicles on the ischaemic brain
No full textFollowing the implementation of thrombolysis and endovascular recanalization strategies, stroke therapy has profoundly changed in recent years. In spite of these advancements, a considerable proportion of stroke patients still exhibit functional impairment in the long run, increasing the need for adjuvant therapies that promote neurological recovery. Stem cell therapies have initially attracted great interest in the stroke field, since there were hopes that transplanted cells may allow for the replacement of lost cells. After the recognition that transplanted cells integrate poorly into existing neural networks and that they induce brain remodelling in a paracrine way by secreting a heterogeneous group of nanovesicles, these extracellular vesicles (EVs) have been identified as key players that mediate restorative effects of stem and progenitor cells in ischaemic brain tissue. We herein review restorative effects of EVs in stroke models and discuss immunological and non-immunological mechanisms that may underlie recovery of function
Assessing self-administration of medication: video-based evaluation of patient performance in the ABLYMED study
No full textBackground: Older adults often face challenges in medication management due to multimorbidity and complex medication regimens, which frequently go unreported. Unrecognized problems, however, may lead to a loss of drug efficacy and harmful side effects. This study aimed to quantify the prevalence of such problems by applying a novel video-based assessment procedure in a sample of elderly patients.Methods: In this study, 67 elderly in-patients (≥70 years old and regularly taking ≥5 different drugs autonomously) from the ABLYMED study participated in a placebo-based assessment of medication management with five different dosage forms in an instructed manner while being filmed. Patient performance was quantified by the median value of two raters who evaluated each step of medication administration, which were summed to sum scores for each dosage form and an overall impression for each dosage form with a standardized and previously validated rating scheme.Results: The median (Q1;Q3) sum score for tablets was 7.0 (5.0;8.0) with a theoretical range between 4.0 and 17.0, for eye-drops 2.0 (1.0;2.0) with a theoretical range between 1.0 and 5.0, for oral drops 4.0 (3.0;6.0) with a theoretical range between 3.0 and 12.0, for pens 7.0 (5.0;9.0) with a theoretical range between 4.0 and 17.0 and for patches 5.0 (4.0;7.0) with a theoretical range between 3.0 and 15.0. The most difficult step of medication administration was peeling off the protective liner of a patch: 30% had severe difficulties or it was not possible, 21% had moderate difficulties and 49% had mild or no difficulties.Discussion: In a sample of patients with autonomous medication management, our novel assessment procedure identified a substantial fraction of patients with handling problems for each dosage form. This suggests that patients´ medication management problems should be assessed regularly in clinical routine and tackled by patient-individual training or modification of the prescribed drug regimens to achieve effective drug therapy in the elderly
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