High-density lipoprotein cholesterol is associated with lowered cognitive recovery among acute ischemic stroke patients with mild cognitive impairment.

High-density lipoprotein (HDL) has been documented to be related to mild cognitive impairment (MCI) and dementia occurrence; however, the underlying basis behind this association remains unclear. We aimed to elucidate this basis by examining the association between HDL levels and cognitive improvements after 6 months, among acute ischemic stroke (AIS) patients with MCI. Five hundred fifty-eight AIS and MCI patients from the NICE study were enrolled, and divided into four groups, according to their baseline HDL quartiles; median HDL was 1.12 mmol/L (interquartile range 0.96-1.34 mmol/L). The primary outcome examined was the extent of cognitive improvement, defined as ΔMoCA (Montreal Cognitive Assessment) ≥ 2, while the secondary outcome was cognitive deterioration, defined as ΔADAS-cog (Alzheimer's Disease Assessment Scale-Cognitive Subscale) ≥ 4 or ΔMMSE (Mini-Mental State Examination) ≤ - 3, at 6-months post-AIS. We found that 314 (56.27%), 49 (8.78%), and 31 (5.56%) patients had ΔMoCA ≥ 2, ΔADAS-cog ≥ 4, and ΔMMSE ≤ - 3, respectively. Furthermore, cognitive improvement negatively correlated to HDL levels, with the lowest being present among patients in quartiles 4 (Q4; adjusted OR = 0.44, 95% CI 0.25-0.78, P = 0.0050) and Q3 (OR = 0.38, CI 0.23-0.65, P = 0.0004), compared to Q2 (OR = 0.57, CI 0.34-0.96, P = 0.0331). Q2 patients also had positive correlations with ΔADAS-cog ≥ 4 (OR = 5.18, CI 1.55-17.29, P = 0.0074). However, no association between HDL and ΔMMSE ≤ - 3 was observed, nor with LDL and any cognitive changes. Additionally, restricted cubic spline analysis found a nonlinear relationship between HDL and cognitive improvements. All these findings suggested that low plasma HDL was positively associated with improved cognitive functioning among AIS patients with MCI after 6 months.

Morphometric similarity network alterations in COVID-19 survivors correlate with behavioral features and transcriptional signatures.

OBJECTIVES: 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. MATERIALS & METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Case report: Levodopa-responsive parkinsonism with akinetic mutism after ventriculo-peritoneal shunt.

Background: 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. Case presentation: 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. Conclusion: 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.

Therapeutic effects of dental pulp stem cells on vascular dementia in rat models.

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.

Therapeutic potential of dental pulp stem cell transplantation in a rat model of Alzheimer's disease.

Dental pulp stem cells are dental pulp-derived mesenchymal stem cells that originate from the neural crest. They exhibit greater potential for the treatment of nervous system diseases than other types of stem cells because of their neurogenic differentiation capability and their ability to secrete multiple neurotrophic factors. Few studies have reported Alzheimer's disease treatment using dental pulp stem cells. Rat models of Alzheimer's disease were established by injecting amyloid-ß1-42 into the hippocampus. Fourteen days later, 5 × 106 dental pulp stem cells were injected into the hippocampus. Immunohistochemistry and western blot assays showed that dental pulp stem cell transplantation increased the expression of neuron-related doublecortin, NeuN, and neurofilament 200 in the hippocampus, while the expression of amyloid-ß was decreased. Moreover, cognitive and behavioral abilities were improved. These findings indicate that dental pulp stem cell transplantation in rats can improve cognitive function by regulating the secretion of neuron-related proteins, which indicates a potential therapeutic effect for Alzheimer's disease. This study was approved by the Animal Ethics Committee of Harbin Medical University, China (approval No. KY2017-132) on February 21, 2017.

Tanshinone IIA promotes the differentiation of bone marrow mesenchymal stem cells into neuronal-like cells in a spinal cord injury model.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Tanshinone IIA treatment enhances the therapeutic effects of BMSC transplant on SCI, likely by promoting the differentiation of neuronal cells.

Pep-1 peptide-functionalized liposome to enhance the anticancer efficacy of cilengitide in glioma treatment.

In this study, we have established an effective and novel nanocarrier system for the effective treatment of glioma. We have established the glioma tissue penetrating nanocarrier system by conjugating Pep-1 as a targeting ligand on the liposome surface to enhance the anticancer efficacy of cilengitide (CGL). The particles were nanosized and exhibited a controlled release of drug in both the pH conditions. The cellular uptake assay showed that conjugation of Pep-1 on the liposome surface remarkably increased the cellular uptake. The uptake of CGT-loaded Pep-1 peptide-conjugated liposome (PeCNL) increased to 89.8% compared to 47.5% for CNL indicating the efficient internalization of the nanocarriers. Consistently, PeCNL exhibited a significantly higher cytotoxic effect in cancer cells compared to that of non-targeted CGT-loaded liposome (CNL). PeCNL exhibited a higher apoptosis of cancer cells (∼35%) compared to that of CNL. Most importantly, PeCNL exhibited a significantly superior anticancer effect with tumor volume as low as ∼350mm3 indicating the superior anticancer potential of targeted formulations. Similarly, PeCNL showed the lowest staining for Ki67 indicating that the targeted NP has the maximum effect in controlling the proliferation of cancer cells. Taken together, Pep-1 conjugated liposome could exhibit better antitumor efficacy when applied to IL-13R2 receptor overexpressed specific brain glioma.

p68 RNA helicase promotes glioma cell proliferation in vitro and in vivo via direct regulation of NF-κB transcription factor p50.

The DEAD-box RNA helicase p68 plays a very important role in early organ development and maturation. However, the role of p68 in glioma is unclear. In this study, we showed that p68 protein levels were significantly elevated in high-grade gliomas compared to low-grade gliomas and normal adjacent brain tissues. Importantly, the expression of p68 was significantly associated with poorer overall survival and enhanced resistance to treatment with radiotherapy plus temozolomide for glioma patients. Ectopic expression of p68 enhanced glioma cell proliferation both in vitro and in vivo. In contrast, knockdown of endogenous p68 prevented glioma cell proliferation. Using a tandem affinity purification assay, we found a new p68-binding protein, nuclear factor (NF)-κB p50. We found that p68 bound with the N-terminal of NF-κB p50, and the mutant of p68 lacking the p50-interaction domain failed to stimulate glioma cell proliferation and tumor growth. Moreover, p68 induced NF-κB p50 accumulation in the nucleus through release of NF-κB p50 from IκBα and increased NF-κB p50 target luciferase transcription activity. Knockdown of NF-κB p50 rescued the phenotypes induced by p68 both in vitro and in vivo. We concluded that p68 induces glioma tumor growth through binding with NF-κB p50, regulating NF-κB p50 nucleus accumulation and transcription activity.

[1, 25-dihydroxyvitamin D3 promotes the apoptosis of inflammatory cells in acute experimental autoimmune encephalomyelitis: experiment with rats].

OBJECTIVE: 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)]. METHODS: 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. RESULTS: 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. CONCLUSION: 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.