Correlation study between motor rehabilitation level and psychological state in patients with limb movement disorders after stroke.

BACKGROUND: The psychological state of patients with post stroke limb movement disorders undergoes a series of changes that affect rehabilitation training and recovery of limb motor function. AIM: To determine the correlation between motor rehabilitation and the psychological state of patients with limb movement disorders after stroke. METHODS: Eighty patients with upper and lower limb dysfunction post stroke were retrospectively enrolled in our study. Based on Hospital Anxiety and Depression Scale (HADS) scores measured before rehabilitation, patients with HADS scores ≥ 8 were divided into the psychological group; otherwise, the patients were included in the normal group. Motor function and daily living abilities were compared between the normal and psychological groups. Correlations between the motor function and psychological status of patients, and between daily living ability and psychological status of patients were analyzed. RESULTS: After 1, 2, and 3 wk of rehabilitation, both the Fugl-Meyer assessment and Barthel index scores improved compared to their respective baseline scores (P < 0.05). A greater degree of improvement was observed in the normal group compared to the psychological group (P < 0.05). There was a negative correlation between negative emotions and limb rehabilitation (-0.592 ≤ r ≤ -0.233, P < 0.05), and between negative emotions and daily living ability (-0.395 ≤ r ≤ -0.199, P < 0.05). CONCLUSION: There is a strong correlation between motor rehabilitation and the psychological state of patients with post stroke limb movement disorders. The higher the negative emotions, the worse the rehabilitation effect.

Mechanism of Neural Regeneration Induced by Natural Product LY01 in the 5×FAD Mouse Model of Alzheimer's Disease.

Background: A sharp decline in neural regeneration in patients with Alzheimer's disease (AD) exacerbates the decline of cognition and memory. It is of great significance to screen for innovative drugs that promote endogenous neural regeneration. Cytisine N-methylene-(5,7,4'-trihydroxy)-isoflavone (LY01) is a new compound isolated from the Chinese herbal medicine Sophora alopecuroides with both isoflavone and alkaloid characteristic structures. Its pharmacological effects are worth studying. Objective: This study was designed to determine whether LY01 delays the cognitive and memory decline in the early stage of AD and whether this effect of LY01 is related to promoting neural regeneration. Methods: Eight-week-old 5×Familial Alzheimer's Disease (5×FAD) mice were used as disease models of early AD. Three doses of LY01 administered in two courses (2 and 5 weeks) of treatment were tested. Cognition, memory, and anxiety-like behaviors in mice were evaluated by the Morris water maze, fear conditioning, and open field experiments. Regeneration of neurons in the mouse hippocampus was observed using immunofluorescence staining. The effect of LY01 on cell regeneration was also demonstrated using a series of tests on primary cultured neurons, astrocytes, and neural stem cells (NSCs). In addition, flow cytometry and transcriptome sequencing were carried out to preliminarily explored the mechanisms. Results: We found that LY01 reduced the decline of cognition and memory in the early stage of 5×FAD mice. This effect was related to the proliferation of astrocytes, the proliferation and migration of NSCs, and increases in the number of new cells and neural precursor cells in the dentate gyrus area of 5×FAD mice. This phenomenon could be observed both in 2-week-old female and 5-week-old male LY01-treated 5×FAD mice. The neuronal regeneration induced by LY01 was related to the regulation of the extracellular matrix and associated receptors, and effects on the S phase of the cell cycle. Conclusion: LY01 increases the proliferation of NSCs and astrocytes and the number of neural precursor cells in the hippocampus, resulting in neural regeneration in 5×FAD mice by acting on the extracellular matrix and associated receptors and regulating the S phase of the cell cycle. This provides a new idea for the early intervention and treatment of AD.

Divergent syntheses of okaramines C, J, L, and S-U.

The total synthesis of six novel okaramines (C, J, L, and S-U) was accomplished with a precise synthesis scheme involving a few steps and a practical yield of 6.7%-23% was obtained. The significance of this study includes the design of a successful and convenient synthesis method for preparation of 3a-hydroxy-pyrrolo[2,3-b]-indole and C-7 prenylated l-tryptophan derivatives using a nucleophilic attack of cyclopropylazetoindoline and an aza-Claisen rearrangement of N-reverse-prenyl tryptophan, respectively.

The Effect of Estrogen Replacement Therapy on Alzheimer's Disease and Parkinson's Disease in Postmenopausal Women: A Meta-Analysis.

Background: Estrogen replacement therapy (ERT) is a common treatment method for menopausal syndrome; however, its therapeutic value for the treatment of neurological diseases is still unclear. Epidemiological studies were performed, and the effect of postmenopausal ERT on treating neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), was summarized through a meta-analysis. Methods: Twenty-one articles were selected using a systematic searching of the contents listed on PubMed and Web of Science before June 1, 2019. Epidemiological studies were extracted, and relevant research data were obtained from the original articles based on the predefined inclusion criteria and data screening principles. The Comprehensive Meta-Analysis Version 2 software was used to pool effective size, test heterogeneity, conduct meta-regression and subgroup analysis, and to calculate publication bias. Results: Our results showed that ERT significantly decreased the risk of onset and/or development of AD [odds ratio (OR): 0.672; 95% CI: 0.581-0.779; P < 0.001] and PD (OR: 0.470; 95% CI: 0.368-0.600; P < 0.001) compared with the control group. A subgroup and meta-regression analysis showed that study design and measure of effect were the source of heterogeneity. Age, sample size, hormone therapy ascertainment, duration of the treatment, or route of administration did not play a significant role in affecting the outcome of the meta-analysis. Conclusion: We presented evidence here to support the use of estrogen therapy for the treatment of AD and PD.

Blood and Cerebrospinal Fluid Autoantibody to Aß Levels in Patients with Alzheimer's Disease: a Meta-Analysis Study.

Autoantibodies to beta amyloid (Aß) have been suggested to be involved in the pathogenesis of Alzheimer's disease (AD). However, data from clinical studies were inconsistent on autoantibody to Aß levels in patients with AD. Therefore, we systematically searched the literature and performed meta-analysis to summarize the data of autoantibodies to Aß in AD patients. The systematic search from PubMed and Web of Science included thirty case-control studies with a total of 2901 individuals (1311 AD patients and 1590 healthy control subjects). Random-effect meta-analysis showed a significant increased endogenous IgG autoantibody to Aß levels in blood when compared with controls (Hedges' g = 0.337, 95% CI = 0.020 to 0.654, P = 0.03). In contrast, blood IgM autoantibody to Aß levels was significantly decreased in patients with AD relative to control subjects (Hedges' g = - 0.962, 95% CI = - 1.797 to - 0.126, P = 0.024). Furthermore, cerebrospinal fluid Aß levels were not significantly different between AD patients and control subjects (Hedges' g = - 0.446, 95% CI = - 2.357 to 1.464, P = 0.647). Subgroup analysis revealed that detection method contributed to the heterogeneity for studies measuring blood IgG autoantibody to Aß levels in AD patients. Meta-regression analyses suggested that sex is a confounder for the outcome of the meta-analysis. Taken together, the results of this meta-analysis clarified circulating autoantibodies to Aß levels in AD patients and suggested that endogenous IgG and IgM-class antibodies to Aß may play a role in the pathogenesis of AD.

Mallotus oblongifolius extracts ameliorate ischemic nerve damage by increasing endogenous neural stem cell proliferation through the Wnt/ß-catenin signaling pathway.

Mallotus oblongifolius (MO), an edible medicinal plant from Hainan in China, shows a wide range of bioactivities. The daily consumption of MO or its extracts has been observed to ameliorate ischemic nerve injury. However the mechanisms remain unclear. In this study, the effects of MO both in vitro and in vivo were investigated. The results indicated that MO improved the motor ability, neurosensory ability, balance and grasping ability of mice with ischemic injuries, induced by bilateral common carotid artery ligation (BCCAL). In addition, MO improved the morphology of neurons, resisted the loss of neurons, and enhanced the content of the nestin protein in the cerebral cortex and subgranular zone (SGZ) area. Furthermore, in the oxygen-glucose deprivation and reperfusion (OGD/R) treated cell model, MO could effectively activate the Wnt/ß-catenin signaling pathway and promote the proliferation of neural stem cells (NSCs) and increase the protein expression levels of ß-catenin and CyclinD1. Our results suggest that Mallotus oblongifolius may be used as nutraceuticals or functional foods to alleviate ischemic nerve damage and promote recovery from ischemic stroke.

Neuro-Protective Role of Metformin in Patients with Acute Stroke and Type 2 Diabetes Mellitus via AMPK/Mammalian Target of Rapamycin (mTOR) Signaling Pathway and Oxidative Stress.

BACKGROUND We investigated the effects of metformin on neurological function and oxidative stress in patients with type 2 diabetes mellitus with acute stroke. MATERIAL AND METHODS We randomly assigned 80 acute stroke patients to 2 groups: the metformin combined group and the insulin group. Each group had 40 patients and all were treated with standard stroke treatment. The indexes of nervous functional score and oxidative stress were measured before and 2 weeks after treatment. The primary fetal rat hippocampal neurons were gradually matured after 7 days of culture, and divided into the control group (Con), the oxygen-glucose deprivation model group (Mod), and the metformin group (Met). In the Met group, 10 mmol/L metformin was added, and the Con group and the Mod group received equal volumes of cell culture fluid. Cell viability, cell apoptosis rate, and the expression of Bax, Bcl-2, AMPK, pAMPK and mTOR were detected; MDA content and SOD activity were also detected. RESULTS Before treatment, there was no difference in the metrical indexes between the 2 groups. After treatment, the treatment group was better than the control group in neurological function scores and multiple oxidative stress-related indicators. The experimental results of primary fetal rat hippocampal neuronal cells suggest that this mechanism of improvement is closely related to the AMPK/mTOR signaling pathway. CONCLUSIONS Metformin can improve the neurological function and oxidative stress status of acute stroke patients with type 2 diabetes, and its mechanism may be related to the AMPK/mTOR signaling pathway and oxidative stress.

Genome-Wide, Integrative Analysis Implicates Exosome-Derived MicroRNA Dysregulation in Schizophrenia.

Genetic variants conferring risk for schizophrenia (SCZ) have been extensively studied, but the role of posttranscriptional mechanisms in SCZ is not well studied. Here we performed the first genome-wide microRNA (miRNA) expression profiling in serum-derived exosome from 49 first-episode, drug-free SCZ patients and 46 controls and identified miRNAs and co-regulated modules that were perturbed in SCZ. Putative targets of these SCZ-affected miRNAs were enriched strongly for genes that have been implicated in protein glycosylation and were also related to neurotransmitter receptor and dendrite (spine) development. We validated several differentially expressed blood exosomal miRNAs in 100 SCZ patients as compared with 100 controls by quantitative reverse transcription-polymerase chain reaction. The potential regulatory relationships between several SCZ-affected miRNAs and their putative target genes were also validated. These include hsa-miR-206, which is the most upregulated miRNA in the blood exosomes of SCZ patients and that previously reported to regulate brain-derived neurotrophic factor expression, which we showed reduced mRNA and protein levels in the blood of SCZ patients. In addition, we found 11 miRNAs in blood exosomes from the miRNA sequence data that can be used to classify samples from SCZ patients and control subjects with close to 90% accuracy in the training samples, and approximately 75% accuracy in the testing samples. Our findings support a role for exosomal miRNA dysregulation in SCZ pathophysiology and provide a rich data set and framework for future analyses of miRNAs in the disease, and our data also suggest that blood exosomal miRNAs are promising biomarkers for SCZ.

Concise Synthesis of Natural Phenylphenalenone Phytoalexins and a Regioisomer.

Concise total syntheses of the natural phytoalexins 2-hydroxy-8-(4-hydroxyphenyl)phenalen-1-one (1), 2-hydroxy-8-(3,4-dihydroxyphenyl)phenalen-1-one (2), and hydroxyanigorufone (4), together with regioisomer 3 are accomplished in 11 or 12 steps. The synthetic strategy features a Friedel-Crafts acylation to construct the 1H-phenalen-1-one tricyclic core followed by a Suzuki cross-coupling to obtain the target compounds.

Garcinol Upregulates GABAA and GAD65 Expression, Modulates BDNF-TrkB Pathway to Reduce Seizures in Pentylenetetrazole (PTZ)-Induced Epilepsy.

BACKGROUND Epilepsy is the most predominant neurological disorder characterized by recurrent seizures. Despite treatment with antiepileptic drugs, epilepsy still is a challenge to treat, due to the associated adverse effects of the drugs. Previous investigations have shown critical roles of BDNF-TrkB signalling and expression of glutamic acid decarboxylase 65 (GAD65) and GABAA in the brain during epilepsy. Thus, drugs that could modulate BDNF-TrkB signal and expression of GAD65 and GABAA could aid in therapy. Recent experimental data have focussed on plant-derived compounds in treatments. Garcinol (camboginol), is a polyisoprenylated benzophenone derived from the fruit of Garcinia indica. We investigated the effects of garcinol in pentylenetetrazole (PTZ)-induced epileptic models. MATERIAL AND METHODS Seizure scores were measured in epilepsy kindled mice. Neuronal degeneration and apoptosis were assessed by Nissl staining, TUNEL assay, and Fluoro-Jade B staining. Immunohistochemistry was performed to evaluate cleaved caspase-3 expressions. Expression of BDNF, TrkB, GABAA, GAD65, Bad, Bcl-2, Bcl-xL, and Bax were determined by western blots. RESULTS Significantly reduced seizure scores and mortality rates were observed with pretreatment with garcinol. Elevated expression of apoptotic proteins and caspase-3 in kindled mice were effectively downregulated by garcinol. Epileptogenic mice presented increased BDNF and TrkB with considerably decreased GABAA and GAD65 expression. Garcinol significantly enhanced GABAA and GAD65 while it suppressed BDNF and TrkB. Garcinol enhanced the performance of mice in Morris water maze tests. CONCLUSIONS Garcinol exerts neuroprotective effects via supressing apoptosis and modulating BDNF-TrkB signalling and GAD65/GABAA expressions and also enhanced cognition and memory of the mice.

MicroRNA-29a: A potential biomarker in the development of intracranial aneurysm.

AIM: To identify serum microRNA-29a (miR-29a) level in patients with intracranial aneurysm and its role in the development of intracranial aneurysm (IA). METHODS: Case group included 165 IA patients hospitalized in the department of neurosurgery between January 2010 and January 2012 while control group enrolled 220 healthy volunteers. Morning fasting blood samples were collected from peripheral vein. RT-PCR was used for miR-29a detection. Receiver Operating Characteristic (ROC) curve was drawn. Survival curves were drawn for survival analysis with Kaplan-Meier method and Long-rank test was conducted. MiR-29a expression Glasgow Prognosis Score (GOS) was used for prognosis scaling. Multivariate Cox proportional hazards regression analysis was performed for prognosis analysis. Results Cases had significantly higher miR-29a expressions than controls (P<0.05). ROC curve analysis indicated that miR-29a expression in IA had high effectiveness in IA diagnosis. Close associations were identified between miR-29a expression and rupture, Hunt-Hess level and surgical timing (all P<0.05). GOS strongly associated with history of hypertension, aneurysm location, rupture, Hunt-Hess level and miR-29a expression. Patients with low miR-29a expression had longer disease-free survival (DFS) and overall survival (OS) than those with high miR-29a expression (both P<0.05). MiR-29a expression, tumor aneurysm, rupture and Hunt-Hess were risk factors to the prognosis of IA (all P<0.05). CONCLUSION: MiR-29a may be closely related to IA development and therefore could be a useful predicator of IA prognosis, providing a new target for IA therapy.

[Inhibitory Effects of Sphingosine-1-phosphate Receptor-2 on Vascular Permeability in Mice].

OBJECTIVES: To determine the effect of sphingosine-1-phosphate receptor 2 (S1PR2) on vascular permeability in mice. METHODS: Acute lung injury models of mice were constructed with intra-tracheal administration of lipopolysaccharide (LPS) and compared with the controls with intra-tracheal administration of saline. The effect of S1PR2 on vascular permeability was observed by detecting leakage of Evans blue into lung tissues, pulmonary vascular leakage of fluorescein isothiocyanate (FITC)-dextran, and the wet/dry mass ratio of lungs. The effect of vascular endothelial growth factor (VEGF) on vascular endothelial permeability was detected by Miles analysis. RESULTS: LPS injections induced significant Evans blue leakage, FITC-dextran pulmonary vascular leakage and pulmonary edema, which appeared to be more serious in S1PR2-deleted mice compared with those in wild-type mice. LPS enhanced Evans blue leakage associated with VEGF in a dose-dependent way in both S1PR2-deleted mice and wild type mice. But the vascular permeability response in subcutaneous tissues induced by VEGF was higher in S1PR2-deleted mice than that in wild-type mice. CONCLUSIONS: S1PR2 is involved in endothelial cell barrier protections, which inhibits vascular permeability.

[Research progress in biological basis of cold and heat essence of Chinese medicine].

Cold-heat problem is one core of traditional Chinese medicine theory. This paper summarizes the experimental research related to the biological basis of cold-heat essence in cold-heat syndrome, cold-heat body constitution and cold-heat property of Chinese herbs. In view of the classical physiological and biochemical indices, gene expression, protein expression and metabolic differences, differences in cold-heat syndrome or cold-heat constitution are mainly based on neurotransmitter, thyroid function, sex hormone, cyclic nucleotide system, and energy metabolism relating to the corresponding gene and protein expression. Furthermore, this paper analyses the change of correlation indices that accompany with a dynamic development process of "constitution-syndrome-herbal intervention", implying that the research of biological basis of cold-heat essence has turned from single index to multiple indices, and from dispersion research to system research.

Inhibition of tumor angiogenesis by TTF1 from extract of herbal medicine.

AIM: To study the inhibition of tumor angiogenesis by 5,2,4´-trihydroxy-6,7,5´-trimethoxyflavone (TTF1) isolated from an extract of herbal medicine Sorbaria sorbifolia. METHODS: Angiogenic activity was assayed using the chick embryo chorioallantoic membrane (CAM) method. Microvessel density (MVD) was determined by staining tissue sections immunohistochemically for CD34 using the Weidner capillary counting method. The mRNA and protein levels of vascular endothelial growth factor (VEGF), vascular endothelialgrowth factor receptor 2 (VEGFR2, Flk-1/KDR), basic fibroblast growth factor (bFGF), cyclo-oxygenase (COX)-2 and hypoxia-inducible factor (HIF)-1α were detected by quantitative real-time polymerase chain reaction and Western blotting analysis. RESULTS: The TTF1 inhibition rates for CAM were 30.8%, 38.2% and 47.5% with treatment concentrations of 25, 50 and 100 µg/embryo × 5 d, respectively. The inhibitory rates for tumor size were 43.8%, 49.4% and 59.6% at TTF1 treatment concentrations of 5, 10, and 20 µmol/kg, respectively. The average MVD was 14.2, 11.2 and 8.5 at treatment concentrations of 5 µmol/kg, 10 µmol/kg and 20 µmol/kg TTF1, respectively. The mRNA and protein levels of VEGF, KDR, bFGF, COX-2 and HIF-1α in mice treated with TTF1 were significantly decreased. CONCLUSION: TTF1 can inhibit tumor angiogenesis, and the mechanism may be associated with the down-regulation of VEGF, KDR, bFGF, HIF-1α and COX-2.