Spinal cord injury (SCI) is one of the most severe central nervous system injuries. Currently, transplanting bone marrow mesenchymal stem cells (BMSCs) is considered a therapeutic option for SCI. Tanshinone IIA (TIIA) is one of the extracts obtained from Salvia miltiorrhiza Bunge, which has been shown to have some protective effects against SCI. The present research was aimed to explore whether TIIA would influence the fate of transplanted BMSCs in a rat model of SCI, especially with regard to their differentiation into neuronal cells. Bone marrow mesenchymal stem cells were obtained from immature rats and identified using flow cytometry. After SCI, 1.0 × 107 cells labeled with PKH67 were transfused into the injured spinal cord. TIIA was first injected into the tail vein (30 mg/kg) 1 h before surgery. From day 1 to day 7 post-SCI, TIIA was injected (20 mg/kg) per day at the same time. Recovery of locomotor function and histological regeneration of the spinal cord were compared among the groups, with the differentiation and distribution of BMSCs determined anatomically and biochemically by the expression of neural cell markers. Locomotor assessments showed that the rats in the BMSCs + TIIA group exhibited higher scores (19.33 ± 0.58) than those in the other groups (13.67 ± 1.53, 17.67 ± 0.58, 18.00 ± 1.73). The area of the cavity in the BMSCs + TIIA rats was smaller than that in the other groups (1.30 ± 0.56, 10.39 ± 1.59, 6.84 ± 1.18, 4.36 ± 0.69). Co-expression of glial fibrillary acid protein was observed in transplanted BMSCs, with a reduced rate in the BMSCs + TIIA group relative to that in the SCI group. In contrast, the expression levels of Nestin, neuron-specific nuclear protein (NeuN) and neurofilament protein 200 (NF200) were greatest in the transplanted cells in the BMSCs + TIIA group. Tanshinone IIA treatment enhances the therapeutic effects of BMSC transplant on SCI, likely by promoting the differentiation of neuronal cells.
Abstract Background: Focal cerebral ischemia is a common cerebrovascular disease with limited treatment options, and new treatments are therefore urgently needed. Hair follicle mesenchymal stem cells (HF-MSCs) are considered ideal cells for the treatment of neurological disorders. Insulin growth factor-1 (IGF-1) is an effective neuroprotective compound. Methods: In the present study, we used middle cerebral artery occlusion (MCAO) model to evaluate the therapeutic effects of HF-MSCs and IGF-1 in focal cerebral ischemia. After middle cerebral artery occlusion (MCAO), rats were randomly divided into six groups. HF-MSCs and IGF-1 were transplanted into rat models by tail vein injection. The fate of transplanted HF-MSCs in the rat brain was assessed using immunofluorescence, immunohistochemistry, Western blot analysis, and reverse transcription polymerase chain reaction (RT-PCR). Beam balance tests and neurological severity scores were used to assess neurological recovery. Results: HF-MSCs labeled with the green fluorescent dye PKH67 were found to colocalize with 4',6-diamidino-2-phenylindole (DAPI) and neural-specific markers. Rats in the HF-MSCs, IGF-1 and HF-MSCs + IGF-1 groups exhibited neural differentiation marker expression, with those in the HF-MSCs + IGF-1 group exhibiting the highest levels. Conclusions: These results suggest that the combined treatment of HF-MSCs and IGF-1 can enhance neurological recovery, representing a new therapeutic strategy for cerebral ischemia.
To explore the differences in the cortical morphometric similarity network (MSN) between COVID-19 survivors and healthy controls, and the correlation between these differences and behavioralfeatures and transcriptional signatures.39 COVID-19 survivors and 39 age-, sex- and education years-matched healthy controls (HCs) were included. All participants underwent MRI and behavioral assessments (PCL-17, GAD-7, PHQ-9). MSN analysis was used to compute COVID-19 survivors vs. HCs differences across brain regions. Correlation analysis was used to determine the associations between regional MSN differences and behavioral assessments, and determine the spatial similarities between regional MSN differences and risk genes transcriptional activity.COVID-19 survivors exhibited decreased regional MSN in insula, precuneus, transverse temporal, entorhinal, para-hippocampal, rostral middle frontal and supramarginal cortices, and increased regional MSN in pars triangularis, lateral orbitofrontal, superior frontal, superior parietal, postcentral, and inferior temporal cortices. Regional MSN value of lateral orbitofrontal cortex was positively associated with GAD-7 and PHQ-9 scores, and rostral middle frontal was negatively related to PHQ-9 scores. The analysis of spatial similarities showed that seven risk genes (MFGE8, MOB2, NUP62, PMPCA, SDSL, TMEM178B, and ZBTB11) were related to regional MSN values.The MSN differences were associated with behavioral and transcriptional signatures, early psychological counseling or intervention may be required to COVID-19 survivors. Our study provided a new insight into understanding the altered coordination of structure in COVID-19 and may offer a new endophenotype to further investigate the brain substrate.
Abnormal TDP-43 inclusions are a common pathologic finding in Alzheimer's disease (AD) but phenotypic differences of concurrent TDP-43 pathology are not well characterized. The goals of this study were to assess if TDP-43 pathology is associated with distinct clinical, pathologic and genetic features. TDP-43 pathology was assessed in nine brain regions of 199 pathologically confirmed cases of AD. Demographic, clinical and pathologic variables were compared between cases with and without TDP-43 pathology. Genotyping for AD-associated genes (CLU, BIN1, PICALM, EPHA1, CD33, CR1, CD2AP, ABCA7, MS4A4A/MS4A6A) was performed using an Illumina Human Omni1-Quad SNP array. Of all analyzed cases, 63% showed abnormal TDP-43 immunoreactivity in at least one brain region. In 33% of the positive cases, only the amygdala was affected; in 41% TDP-43 pathology extended into other regions of the mesial temporal lobe and in 26% additional diffuse neocortical involvement was present. No differences between TDP-43 positive and negative cases were found for brain weight, Braak stage, or NIA-RI criteria, but Lewy body pathology was significantly more common in TDP-43 positive (64%) compared to negative cases (46%; P<0.05). Demographically, no differences were seen in sex, education years and age of dementia onset. TDP-43 positive cases showed a trend towards higher age at death (81.4±6.3 vs 79.6±6.6 years; P =0.052) and had significantly longer dementia duration (11.0±4.5 vs 9.2±3.8 years; P<0.01). There was a trend towards a lower incidence of depression history in TDP-43 positive cases (10% vs 18%; P =0.15). Analysis of cardiovascular history revealed a significantly lower rate of hypertension in TDP-43 positive cases (13% vs 24%; P<0.05), but no differences for heart disease or diabetes. While most AD-associated genes showed no association with TDP-43 pathology, CD33 genotype conferred a slightly increased risk for TDP pathology in a recessive model (P<0.01). Inclusion of the amygdala in our analysis revealed a higher prevalence of TDP-43 pathology in AD than commonly described. TDP-43 pathology was associated with several phenotypic differences including higher prevalence of Lewy pathology, increased dementia duration and lower incidence of hypertension. Further studies are needed to determine the association between TDP pathology and depression.
To investigate the mechanism of rapid amelioration of the pathological changes in experimental allergic encephalomyelitis (EAE) by 1, 25-dihydroxyvitamin D(3) [1, 25-(OH)(2)D(3)].Forty Lewis rats were immunized with myelin basic protein in complete Freud's adjuvant so as to establish ESE animal models and then randomly divided into 4 equal groups: prevention group, fed with 1, 25-(OH)(2)D(3) since day 0 for 10 days, prevention-control group fed with peanut oil for 10 days, treatment group fed with 1, 25-(OH)(2)D(3) since the appearance of EAE symptoms (generally since day 10 or 11), and treatment-control group fed with peanut oil since the appearance of EAE symptoms. The clinical symptoms were scored since immunization till day 12 when the clinical symptoms reached the maximum level. The rats were sacrificed 13 days after sensitization with their brains and spinal cords taken out to undergo pathological examination, in situ TUNEL staining for detecting apoptotic cells, and semiquantitative immunohistochemical analysis to detect the inducible NO synthase (iNOS), FasL, and tumor growth factor (TGF)-beta 1, that might involve in the signal pathway of apoptosis. Peripheral blood samples were collected to isolate mononuclear cells (MNCs). The content of nitrite in the supernatant of MNC culture was evaluated.The scores of clinical symptoms and the pathological changes of both the prevention and treatment groups decreased conspicuously and were significantly lower than their respective control groups (both P < 0.01). In contrast, the apoptosis indexes of the 2 1, 25-(OH)(2)D(3) administration groups were significantly higher than those of the control groups (all P < 0.01). The TUNEL positive cell rates in the brain and spinal cord of the treatment and prevention groups were all significantly higher than those of their corresponding control groups (P < 0.05, P < 0.01). The numbers of iNOS positive cells in the treatment and prevention groups were both lower than those of their corresponding control groups, which was in accord with the improvement of clinical signs and tissue lesions. The levels of nitrite in the supernatant of MNC culture of the treatment and prevention groups were higher than those of their corresponding control groups, but not significantly.Administration of 1, 25-(OH)(2)D(3) rapidly ameliorates EAE symptoms by promoting the apoptosis of inflammatory cells. The elimination of infiltrating immune cells which reverses the pathological changes in central nervous system is associated with a favorable microenvironment provided by 1, 25-(OH)(2)D(3), such as decreasing of iNOS.
Parkinsonism and akinetic mutism (AM) following ventriculo-peritoneal shunt (VPS) without underdrainage used to be considered rare, but may be underdiagnosed in daily clinical practice. Although the pathophysiology is still unclear, in several case reports, the parkinsonism and AM after VPS shows responsiveness to dopaminergic treatment.We report a 19-year-old male that presented with severe parkinsonism and AM after VPS. Meanwhile, 18F-FDG-PET showed a cortical and subcortical hypometabolism. Fortunately, levodopa dramatically improved patient's symptoms and brain hypometabolism. This report provides support for the possibility that dopamine deficiency inhibits brain metabolism, and further elucidates the pathogenesis of parkinsonism and AM.This report highlights the presentation of a treatable parkinsonism and points out that Levodopa and/or dopamine agonist should be the first choice if the patients develop parkinson-like symptoms after VPS.
Dental pulp stem cells are a type of adult stem cells with strong proliferative ability and multi-differentiation potential. There are no studies on treatment of vascular dementia with dental pulp stem cells. In the present study, rat models of vascular dementia were established by two-vessel occlusion, and 30 days later, rats were injected with 2 × 107 dental pulp stem cells via the tail vein. At 70 days after vascular dementia induction, dental pulp stem cells had migrated to the brain tissue of rat vascular dementia models and differentiated into neuron-like cells. At the same time, doublecortin, neurofilament 200, and NeuN mRNA and protein expression levels in the brain tissue were increased, and glial fibrillary acidic protein mRNA and protein expression levels were decreased. Behavioral testing also revealed that dental pulp stem cell transplantation improved the cognitive function of rat vascular dementia models. These findings suggest that dental pulp stem cell transplantation is effective in treating vascular dementia possibly through a paracrine mechanism. The study was approved by the Animal Ethics Committee of Harbin Medical University (approval No. KY2017-132) in 2017.
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