Abstract Hypoxic preconditioning of stem cells and neural progenitor cells has been tested for promoting cell survival after transplantation. The present investigation examined the hypothesis that ...hypoxic preconditioning of bone marrow mesenchymal stem cells (BMSCs) could not only enhance their survival but also reinforce regenerative properties of these cells. BMSCs from eGFP engineered rats or pre-labeled with BrdU were pre-treated with normoxia (20% O2 , N-BMSCs) or sub-lethal hypoxia (0.5% O2 . H-BMSCs). The hypoxia exposure up-regulated HIF-1α and trophic/growth factors in BMSCs, including brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF) and its receptor FIK-1, erythropoietin (EPO) and its receptor EPOR, stromal derived factor-1 (SDF-1) and its CXC chemokine receptor 4 (CXCR4). Meanwhile, many pro-inflammatory cytokines/chemokines were down-regulated in H-BMSCs. N-BMSCs or H-BMSCs were intravenously injected into adult rats 24 h after 90-min middle cerebral artery occlusion. Comparing to N-BMSCs, transplantation of H-BMSCs showed greater effect of suppressing microglia activity in the brain. Significantly more NeuN-positive and Glut1-positive cells were seen in the ischemic core and peri-infarct regions of the animals received H-BMSC transplantation than that received N-BMSCs. Some NeuN-positive and Glut-1-positive cells showed eGFP or BrdU immunoflourescent reactivity, suggesting differentiation from exogenous BMSCs into neuronal and vascular endothelial cells. In Rotarod test performed 15 days after stroke, animals received H-BMSCs showed better locomotion recovery compared with stroke control and N-BMSC groups. We suggest that hypoxic preconditioning of transplanted cells is an effective means of promoting their regenerative capability and therapeutic potential for the treatment of ischemic stroke.
Objectives This study explored the novel strategy of hypoxic preconditioning of bone marrow mesenchymal stem cells before transplantation into the infarcted heart to promote their survival and ...therapeutic potential of mesenchymal stem cell transplantation after myocardial ischemia. Methods Mesenchymal stem cells from green fluorescent protein transgenic mice were cultured under normoxic or hypoxic (0.5% oxygen for 24 hours) conditions. Expression of growth factors and anti-apoptotic genes were examined by immunoblot. Normoxic or hypoxic stem cells were intramyocardially injected into the peri-infarct region of rats 30 minutes after permanent myocaridal infarction. Death of mesenchymal stem cells was assessed in vitro and in vivo after transplantation. Angiogenesis, infarct size, and heart function were measured 6 weeks after transplantation. Results Hypoxic preconditioning increased expression of pro-survival and pro-angiogenic factors including hypoxia-inducible factor 1, angiopoietin-1, vascular endothelial growth factor and its receptor, Flk-1, erythropoietin, Bcl-2, and Bcl-xL. Cell death of hypoxic stem cells and caspase-3 activation in these cells were significantly lower compared with that in normoxic stem cells both in vitro and in vivo. Transplantation of hypoxic versus normoxic mesenchymal stem cells after myocardial infarctiion resulted in an increase in angiogenesis, as well as enhanced morphologic and functional benefits of stem cell therapy. Conclusions Hypoxic preconditioning enhances the capacity of mesenchymal stem cells to repair infarcted myocardium, attributable to reduced cell death and apoptosis of implanted cells, increased angiogenesis/vascularization, and paracrine effects.
Abstract
Honey stimulates cellular secretion of cytokines, which has been attributed to activation of lipopolysaccharide (LPS)-dependent and LPS-independent pathways. The objective of this study was ...to identify whether LPS is present in Australian honey samples at levels that can stimulate interleukin-6 (IL-6) secretion by fibroblasts and whether it can transduce cell signalling by activating toll-like receptor 4 (TLR4). IL-6 was measured in culture media of fibroblasts exposed to honey for 24 h. LPS was detected in a 0.125 mg/mL solution of grey ironbark honey (0.61 ± 0.05 ng/g honey). TLR4 signalling was observed in RAW264.7 macrophages that were exposed to honey and this was prevented by preincubating the honey with the LPS-neutralising agent, polymyxin B. Australian
Eucalyptus
,
Leptospermum
and
Cyathode
honeys stimulated IL-6 secretion in cultured human dermal fibroblasts. To examine whether the response was dependent on floral source, fibroblasts were exposed to four different samples of grey ironbark honey obtained from Queensland and New South Wales, Australia. The magnitude of the cytokine response to these honeys was highly varied. We conclude that Australian honeys contain endotoxin at levels that can stimulate IL-6 secretion by fibroblasts and that signalling in macrophages involves TLR4 activation. The IL-6 secretory response was independent of floral source.
•Low dose NAC with hypothermia decreases infarct volumes in female neonatal HI rats.•NAC decreases ICAM, MMP-9, CXCL-1 expression in female rats after severe HI.•Long-term NAC treatment may be ...necessary for functional improvement in both sexes.
Approximately half of moderate to severely hypoxic-ischemic (HI) newborns do not respond to hypothermia, the only proven neuroprotective treatment. N-acetylcysteine (NAC), an antioxidant and glutathione precursor, shows promise for neuroprotection in combination with hypothermia, mitigating post-HI neuroinflammation due to oxidative stress. As mechanisms of HI injury and cell death differ in males and females, sex differences must be considered in translational research of neuroprotection. We assessed the potential toxicity and efficacy of NAC in combination with hypothermia, in male and female neonatal rats after severe HI injury. NAC 50mg/kg/d administered 1h after initiation of hypothermia significantly decreased iNOS expression and caspase 3 activation in the injured hemisphere versus hypothermia alone. However, only females treated with hypothermia +NAC 50mg/kg showed improvement in short-term infarct volumes compared with saline treated animals. Hypothermia alone had no effect in this severe model. When NAC was continued for 6 weeks, significant improvement in long-term neuromotor outcomes over hypothermia treatment alone was observed, controlling for sex. Antioxidants may provide insufficient neuroprotection after HI for neonatal males in the short term, while long-term therapy may benefit both sexes.
Background
Fetal ventriculomegaly is a source of apprehension for expectant parents and may present prognostic uncertainty for physicians. Accurate prenatal counseling requires knowledge of its cause ...and associated findings as the differential diagnosis is broad. We have observed an association between ventriculomegaly and incomplete hippocampal inversion.
Objective
To determine whether ventricular size is related to incomplete hippocampal inversion.
Materials and methods
We retrospectively evaluated pre- and postnatal brain MRIs in normal subjects (mean GA, 31 weeks; mean postnatal age, 27 days) and patients with isolated ventriculomegaly (mean GA, 31 weeks; mean postnatal age, 68 days) at a single academic medical center. Lateral ventricular diameter, multiple qualitative and quantitative markers of hippocampal inversion, and evidence of intraventricular hemorrhage were documented.
Results
Incomplete hippocampal inversion and ventricular size were associated in both normal subjects (
n
=51) and patients with ventriculomegaly (
n
=32) (
P
<0.05). Severe ventriculomegaly was significantly associated with adverse clinical outcome in postnatal (
P
=0.02) but not prenatal (
P
=0.43) groups. In all additional cases of isolated ventriculomegaly, clinical outcome was normal over the time of assessment (mean 1±1.9 years; range 0.01 to 10 years).
Conclusion
Lateral ventricular atrial diameter and incomplete hippocampal inversion are associated. Less hippocampal inversion correlates with larger atria. For every 1-mm increase in fetal ventricular size, the odds of incomplete hippocampal inversion occurring increases by a factor of 1.6 in normal controls and 1.4 in patients with ventriculomegaly.
Graphical Abstract
This study aims to provide a comprehensive description of the phenotypic and genotypic spectrum of SNAP25 developmental and epileptic encephalopathy (SNAP25-DEE) by reviewing newly identified and ...previously reported individuals.
Individuals harboring heterozygous missense or loss-of-function variants in SNAP25 were assembled through collaboration with international colleagues, matchmaking platforms, and literature review. For each individual, detailed phenotyping, classification, and structural modeling of the identified variant were performed.
The cohort comprises 23 individuals with pathogenic or likely pathogenic de novo variants in SNAP25. Intellectual disability and early-onset epilepsy were identified as the core symptoms of SNAP25-DEE, with recurrent findings of movement disorders, cerebral visual impairment, and brain atrophy. Structural modeling for all variants predicted possible functional defects concerning SNAP25 or impaired interaction with other components of the SNARE complex.
We provide a comprehensive description of SNAP25-DEE with intellectual disability and early-onset epilepsy mostly occurring before the age of two years. These core symptoms and additional recurrent phenotypes show an overlap to genes encoding other components or associated proteins of the SNARE complex such as STX1B, STXBP1, or VAMP2. Thus, these findings advance the concept of a group of neurodevelopmental disorders that may be termed “SNAREopathies.”
To evaluate the Specific Test of Early Infant Motor Performance (STEP), a rapid screening test of preterm infants at risk for developmental delay.
We prospectively studied 23 preterm infants' ...performance on the STEP and the Test of Infant Motor Performance (TIMP) at term and 3 months, and on the Bayley-III at 12 months. We investigated the psychometric qualities of the STEP and determined STEP cutoff scores for low and high-performing infants.
STEP scores at term and 3 months strongly correlate with 12-month Bayley-III gross motor and cognitive scaled scores, while TIMP scores did not. The STEP showed excellent reliability and required 6-10 min to administer.
STEP is a short, easy to administer, early developmental assessment with unique scoring that emphasizes qualitative and quantitative aspects of muscle tone in movements and predicts 12-month Bayley gross motor and cognitive scaled scores.
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