Mesenchymal stem cell-derived exosomes (MSC-Exo) have robust anti-inflammatory effects in the treatment of neurological diseases such as epilepsy, stroke, or traumatic brain injury. While astrocytes are thought to be mediators of these effects, their precise role remains poorly understood. To address this issue, we investigated the putative therapeutic effects and mechanism of MSC-Exo on inflammation-induced alterations in astrocytes.Methods: Lipopolysaccharide (LPS)-stimulated hippocampal astrocytes in primary culture were treated with MSC-Exo, which were also administered in pilocarpine-induced status epilepticus (SE) mice. Exosomal integration, reactive astrogliosis, inflammatory responses, calcium signaling, and mitochondrial membrane potentials (MMP) were monitored. To experimentally probe the molecular mechanism of MSC-Exo actions on the inflammation-induced astrocytic activation, we inhibited the nuclear factor erythroid-derived 2, like 2 (Nrf2, a key mediator in neuroinflammation and oxidative stress) by sgRNA (in vitro) or ML385 (Nrf2 inhibitor) in vivo.Results: MSC-Exo were incorporated into hippocampal astrocytes as well as attenuated reactive astrogliosis and inflammatory responses in vitro and in vivo. Also, MSC-Exo ameliorated LPS-induced aberrant calcium signaling and mitochondrial dysfunction in culture, and SE-induced learning and memory impairments in mice. Furthermore, the putative therapeutic effects of MSC-Exo on inflammation-induced astrocytic activation (e.g., reduced reactive astrogliosis, NF-κB deactivation) were weakened by Nrf2 inhibition.Conclusions: Our results show that MSC-Exo ameliorate inflammation-induced astrocyte alterations and that the Nrf2-NF-κB signaling pathway is involved in regulating astrocyte activation in mice. These data suggest the promising potential of MSC-Exo as a nanotherapeutic agent for the treatment of neurological diseases with hippocampal astrocyte alterations.
ObjectiveCoronary slow-flow phenomenon (CSFP) is an angiographic diagnosis characterised by a low rate of flow of contrast agent in the normal or near-normal epicardial coronary arteries. Many of the patients with CSFP may experience recurrent acute coronary syndromes. However, current clinical practice tends to underestimate the impact of CSFP due to the yet unknown effect on the cardiac function. This study was performed to evaluate left ventricular (LV) and right ventricular (RV) diastolic and systolic functions, using two-dimensional (2D) longitudinal strain and strain rate, in patients with CSFP, and to determine the relationships between the thrombolysis in myocardial infarction (TIMI) frame count (TFC) and LV and RV diastolic and systolic functions.MethodsSixty-three patients with CSFP and 45 age- and sex-matched controls without CSFP were enrolled in the study. Diagnosis of CSFP was made by TFC. LV and RV diastolic and systolic functions were assessed by 2D speckle-tracking echocardiography.ResultsLV peak early diastolic longitudinal strain rate (LSRe) was lower in patients with CSFP than in controls (P = 0.01). LV peak systolic longitudinal strain (LS) and LV peak systolic longitudinal strain rate (LSRs) were lower in patients with CSFP than in controls (P = 0.004 and P = 0.03, respectively). There was no difference in LV ejection fraction. RV peak early diastolic longitudinal strain rate (RSRe) was lower in patients with CSFP than in controls (P = 0.03). There were no differences in RV peak systolic longitudinal strain (RS), RV peak systolic longitudinal strain rate (RSRs), or RV fractional area change among the groups. The mean TFC correlated negatively with LSRe and RSRe in patients with CSFP (r = −0.26, P = 0.04 and r = −0.32, P = 0.01, respectively).ConclusionsLV diastolic and systolic functions were impaired in patients with CSFP. CSFP also affected RV diastolic function, but not RV systolic function.
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