Novel combination of Olesoxime/Resveratrol-encapsulated exosomes to improve cognitive function by targeting amyloid ß-induced Alzheimer's disease: investigation on in vitro and in vivo model.

Alzheimer's disease (AD) is a fatal neurological illness that worsens with time. Preventing the aggregate formation of amyloid beta protein is a promising approach to treat Alzheimer's disease. This article describes an amiable procedure for the synthesis of Olesoxime-Resveratrol (OLX-RSV) encapsulated in exosomes. By suppressing Aß1-42 aggregation and crossing the blood-brain barrier also known as BBB after intravenous treatment without resulting in any discernible damage, the nanocomposite demonstrated good biocompatibility. A variety of characterization technique including particle size, TEM, and in vitro drug release experiments, were used to characterize the exosomes. Human Neuroblastoma (SHSY5Y) cells were used to test the cytotoxicity and viability of cells of the formulation using the Cell Counting Kit-8 assay. The prepared OLX-RSV-loaded exosomes were tested for their ability to suppress Aß1-42 in SHSY5Y Cells by analyzing the amyloid samples using CD spectra. The effects of apoptosis on Human neuroblastoma cells were studied using cytofluorometry. The parameters of SOD, caspase-3 and the ability to scavenge reactive oxygen species (ROS) were also evaluated. The behavioral outcomes of Morris water maze test demonstrated that OLX-RSV-loaded exosomes significantly enhanced the APP/PS1 mice's capacity to learn and remember spatial cues. Therefore, we hypothesized that OLX-RSV-loaded exosomes could be a useful and efficient method in the treatment of AD.

The value of postcontrast delayed 3D fluid-attenuated inversion recovery MRI in the diagnosis of unilateral peripheral vestibular dysfunction.

Background: Clinically, unilateral peripheral vestibular dysfunction (UPVD) with dizziness or vertigo as the chief complaint is quite common. This study aimed to investigate the correlations between 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging (3D-FLAIR MRI) findings and cochleovestibular function test results in patients with UPVD and to explore the possible etiologies of UPVD. Methods: This retrospective study enrolled 76 patients with UPVD. Endolymphatic hydrops (EH) and perilymphatic enhancement (PE) in the vestibule and cochlea on 3D-FLAIR images, their correlations with the parameters of the cochleovestibular function test and vascular risk factors, and the immunological findings of patients with EH and PE were assessed. Results: Of the included patients, 48.7% showed positive MRI findings (the presence of EH and PE on 1 side). The pure-tone average (PTA) was higher in patients with cochlear PE than in those with vestibular (P=0.014) and cochlear EH (P=0.02). The canal paresis (CP) value was also higher in patients with vestibular PE than in those with vestibular (P=0.002) and cochlear EH (P=0.003). Video head impulse test (vHIT) gains were lower in patients with vestibular and cochlear PE than in those with vestibular and cochlear EH (P<0.001). A positive correlation was observed between the degree of vestibular and cochlear EH and PTA (both P values <0.001). PTA and CP with a cutoff value of 32 dB and 46.5%, respectively, yielded high sensitivity and specificity in determining positive MRI findings (P<0.001 and P=0.029, respectively). The prevalence of vascular risk factors was significantly higher in patients with PE than in those with EH (P=0.033). Conclusions: (I) Nearly half of the patients UPVD exhibited abnormal MRI findings. Cutoff values for PTA and CP of 32 dB and 46.5%, respectively, indicated that patients were more likely to have abnormal imaging findings. (II) The severity of EH was positively correlated with hearing impairment. (III) Patients with PE showed severe hearing impairment and vestibular dysfunction, which was presumed to be associated with vascular damage.

Oxymatrine-mediated prevention of amyloid ß-peptide-induced apoptosis on Alzheimer's model PC12 cells: in vitro cell culture studies and in vivo cognitive assessment in rats.

Alzheimer's disease (AD) is a major neurological disease affecting elderly individuals worldwide. Existing drugs only reduce the symptoms of the disease without addressing the underlying causes. Commonly, Aß25-35 peptide aggregation is the main reason for AD development. Recently, the discovery of multiple protein-targeting molecules has provided a new strategy for treating AD. This study demonstrates the neuroprotective potential of oxymatrine against multiple mechanisms, such as acetylcholinesterase, mitochondrial damage, and ß-amyloid-induced cell toxicity. The in vitro cell culture studies showed that oxymatrine possesses significant potential to inhibit acetylcholine esterase and promotes antioxidant, antiapoptotic effects while preventing Aß25-35 peptide aggregation in PC12 cells. Furthermore, oxymatrine protects PC12 cells against Aß25-35-induced cytotoxicity and down-regulates the reactive oxygen species generation. The in vivo acute toxicological studies confirm the safety of oxymatrine without causing organ damage or death in animals. Overall, this study provided evidence that oxymatrine is an efficient neuroprotective agent, with a potential to be a multifunctional drug for Alzheimer's disease treatment. These findings present a reliable and synergistic approach for treating AD.

Moxibustion exhibits therapeutic effects on spinal cord injury via modulating microbiota dysbiosis and macrophage polarization.

In this study, we aimed to study the effect of moxibustion (MOX) on microbiota dysbiosis and macrophage polarization, so as to unveil the mechanism underlying the therapeutic effect of MOX in the management of spinal cord injury (SCI). SCI animal models were established to study the effect of MOX. Accordingly, it was found that MOX treatment significantly suppressed the Ace index and Shannon index in the SCI group. Moreover, the reduced relative levels of Lactobacillales and Bifidobacteriales and the elevated relative level of Clostridiales in the SCI animals were mitigated by the treatment of MOX. The body weight, food intake, energy expenditure (EE) index and respiratory quotient (RQ) index of SCI mice were all evidently decreased, but the levels of interleukin (IL)-17, interferon (IFN)-γ, monocyte chemoattractant protein-1 (MCP-1) and IL-1ß were increased in the SCI group. Moreover, MOX treatment significantly mitigated the dysregulation of above factors in SCI mice. Accordingly, we found that the Basso Mouse Scale (BMS) score was negatively correlated with the level of Clostridiales while positively correlated with the level of Lactobacillales. The apoptotic index and caspase-3 level were both evidently increased in the SCI group, while the SCI+MOX group showed reduced levels of apoptotic index and caspase-3. Therefore, it can be concluded that the treatment with MOX can promote microbiota dysbiosis and macrophage polarization, thus alleviating spinal cord injury by down-regulating the expression of inflammatory cytokines.

Clinical characteristics of patients with dizziness/vertigo showing a dissociation between caloric and video head impulse test results.

OBJECTIVE: To explore the clinical characteristics of patients with dizziness/vertigo who showed a dissociation between the results of the caloric test and video head impulse test (vHIT). METHODS: A total of 327 patients who complained of dizziness/vertigo were continuously included. All patients underwent both the horizontal vHIT (h-vHIT) and caloric tests. Of the 327 patients, 69 patients showed a dissociation between the results of the two tests, 4 patients were excluded because the interval between the two tests exceeded 7 days. Finally, 65 patients were included in the analysis. RESULTS: Among the 65 patients, 55 (84.6%) patients showed a positive caloric test (+) with a negative h-vHIT (-), and 10 (15.4%) patients showed a negative caloric test (-) with a positive h-vHIT (+). Peripheral and central lesions were identified in 50 (90.9%) and 5 (9.1%) patients, respectively, in the caloric test (+)/h-vHIT (-) group; and central lesions were found in 6 (60%) patients in caloric test (-)/h-vHIT (+) group. The etiologies were unilateral peripheral vestibular dysfunction (n = 25), Meniere's disease (MD, n = 10), sudden hearing loss with vertigo (SHLV, n = 7), benign paroxysmal positional vertigo (n = 5), vestibular neuritis (n = 2), autoimmune inner ear disease (n = 1), vestibular migraine (VM, n = 3), multiple sclerosis (n = 1), and multiple system atrophy (n = 1) in the caloric test (+)/h-vHIT (-) group, which were SHLV (n = 3), MD (n = 1), VM (n = 1), episodic ataxia type 2 (n = 1), cerebellopontine angle tumor (N = 1), Parkinson's disease (n = 1), Persistent postural perceptual dizziness (n = 1), and posterior circulation ischemia (n = 1) in the caloric test (-)/h-vHIT (+) group. CONCLUSION: Dissociation between the results of caloric test and h-vHIT is not uncommon. A positive caloric test with a negative h-vHIT occurred more frequently, and these patients mostly had peripheral vestibular lesions; while a negative caloric test with a positive h-vHIT was unusual, these patients had both peripheral and central lesions.

Fingolimod protects against cerebral ischemia reperfusion injury in rats by reducing inflammatory cytokines and inhibiting the activation of p38 MAPK and NF-κB signaling pathways.

Fingolimod (FTY720) is a sphingosine 1-phosphate (S1P) receptor agonist. Here, to understand biological activity of FTY720 pretreatment and post-treatment on cerebral ischemia reperfusion injury (CIRI), rat transient middle cerebral artery occlusion/reperfusion (tMCAO/R) model was generated. Neurological deficit scoring was assessed after tMCAO/R. Four groups were established including sham-operated control group, operated group, and two FTY720-treated groups. Neuron damage was observed by Nissl staining. Gene expression was measured using qPCR and western blot analysis. Tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) levels were evaluated by enzyme-linked immunosorbent assay (ELISA). We uncovered that neurological score in two FTY720-treated groups was significantly lower than that in the operated group. FTY720 pretreatment or posttreatment groups had a significantly increased number of Nissl bodies in cerebral cortex as compared with the operated group, indicating that FTY720 administration reduced neuronal damage. Besides, FTY720 posttreatment improved memory impairment induced by tMCAO/R. In addition, IL-1ß, IL-6, and TNF-α levels in the cerebral cortex and hippocampus of two FTY720-treated groups were significantly decreased in comparison to the operated group, showing that FTY720 could reduce the release of inflammatory cytokines in brain tissue. Furthermore, phosphorylation of p38MAPK and NF-κB pathway-related molecules in ischemic brain tissues of FTY720 group were markedly down-regulated compared to the operated group. Together, FTY720 pretreatment or posttreatment improved the neurological deficit of middle cerebral ischemia/reperfusion rat model and reduced neuronal damage by decreasing the levels of inflammatory cytokines and attenuating the phosphorylation levels of p38MAPK and NF-κB pathway-associated molecules. FTY720 exhibits neuroprotective effects against ischemic reperfusion injury in rats.

Cerebellar fastigial nucleus is involved in post-stroke depression through direct cerebellar-hypothalamic GABAergic and glutamatergic projections.

The present study aimed to investigate whether the cerebellar fastigial nucleus (FN) is involved in post-stroke depression (PSD), and to observe the effect of direct cerebellar-hypothalamic γ-aminobutyric acid (GABA)ergic and glutamatergic projections on PSD, in order to understand the mechanisms underlying the cerebellar modulation of mood and emotion. Healthy Sprague-Dawley rats were randomly divided into five groups: Sham-operated, Stroke, PSD, FN lesion, and decussation of superior cerebellar peduncle (XSCP) lesion groups. Sham surgery was performed in animals of the Sham group (n=6). The rats in the other four groups (n=6 for each group) underwent middle cerebral artery occlusion. The rats were examined twice a week in an open field test. In addition, the expression of cytokines in hippocampal tissues, and the content of glutamate and GABA in the lateral hypothalamic area (LHA) were measured. The results showed that scores corresponding to the behavioral signs of depression were decreased in the PSD, FN lesion and XSCP lesion groups. In addition, the mRNA levels of tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß in the hippocampus of the PSD, FN lesion and XSCP lesion groups were significantly increased. The GABA and glutamate content in the LHA were also decreased significantly in the PSD, FN lesion and XSCP lesion groups. Taken together, the findings of the present study indicated that the cerebellar FN may be involved in PSD through the direct cerebellar-hypothalamic glutamatergic and GABAergic projections.

Administration of resveratrol improved Parkinson's disease-like phenotype by suppressing apoptosis of neurons via modulating the MALAT1/miR-129/SNCA signaling pathway.

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) has been implicated in the pathogenesis of Parkinson's disease (PD). In addition, resveratrol was shown to regulate the expression of MALAT1. Therefore, the objective of this study was to clarify the role of resveratrol in PD. During the study, luciferase assays were conducted to determine the effect of resveratrol on the transcription efficiency of MALAT1 promoter as well as the regulatory relationships among MALAT1, miR-129, and SNCA. In addition, real-time PCR, Western blot analysis, MTT and flow cytometry analyses were conducted to investigate the mechanism of resveratrol in PD. Furthermore, a PD mouse model was established to study the role of resveratrol in vivo. It was found that resveratrol increased the number of TH+ cells and the expression of miR-129, while decreasing the expression of MALAT1 and SNCA. In addition, MALAT1 inhibited the expression of miR-129, a negative regulator of SNCA, thus increasing the expression of SNCA. A further mechanistic study revealed that resveratrol inhibited MALAT1 expression by blocking the transcription of the MALAT1 promoter. Finally, MPTP treatment could decrease cell proliferation and increase cell apoptosis, while resveratrol could partly offset the effect of MPTP. In summary, the therapeutic effect of resveratrol in the treatment of PD can be attributed to its ability to modulate the MALAT1/miR-129/SNCA signaling pathway.

ELECTROACUPUNCTURE AT THE WANGU ACUPOINT SUPPRESSES EXPRESSION OF INFLAMMATORY CYTOKINES IN THE HIPPOCAMPUS OF RATS WITH VASCULAR DEMENTIA.

BACKGROUND: Vascular dementia (VD) is the most frequent psychiatric complication of stroke, and is often difficult to treat. Incidence rate of vascular cognition impairment is still 70% after stroke in one year (Sui R et al.2011). Stroke patients with VD suffer from a higher mortality rate and have worse functional outcomes and quality of life. However, despite the extensive literatures on this topic, there is no agreement on the causal mechanisms and effective therapy for VD. The objective of this study is to examine if electroacupuncture at the Wangu acupoint (GB 12), whose position is similar to the cerebellar fastigial nucleus, could reduce inflammatory cytokines in the hippocampus of rats with vascular dementia (VD). MATERIALS AND METHODS: The 54 healthy, male, Sprague-Dawley (SD) rats, 9 months old, and of clean grade (300-450) g, were randomly divided into three groups: sham surgery group, VD group and electro-acupuncture group. The ethology scores of VD rats were evaluated and the mRNA expressions of inflammatory cytokines (TNF-α, IL-6 and IL-1ß) in the hippocampus were assessed and the hippocampal tissues were observed by hematoxylin-eosin staining. RESULTS: Compared with the VD group, in the electroacupuncture group, the rats' learning ability improved significantly and the mRNA expression of TNF-α, IL-6 and IL-1ß decreased. Simultaneously, the damage extent of nerve cells in the hippocampal tissues decreased, with their morphology recovered to nearly normal. CONCLUSIONS: Electro-acupuncture at the Wangu acupoint can decrease the levels of inflammatory cytokines in the hippocampus, reduce the damage extent of nerve cells in the hippocampus, and thus provide a new neuroprotective method in VD.

Effect of SNP polymorphisms of EDN1, EDNRA, and EDNRB gene on ischemic stroke.

The objective of this study is to investigate the association between SNP polymorphisms of endothelin-1 (EDN1) and endothelin receptor (EDNRA and EDNRB) gene and ischemic stroke (IS) in the Chinese Han population in northern. A case-control study was introduced. We genotyped eight SNPs (rs1800541, rs2070699, and rs5370 in EDN1 gene; rs1801708, rs5333, and rs5335 in EDNRA gene; and rs3818416 and rs5351 in EDNRB gene) and calculated their polymorphic distribution in control group, IS group, and the IS subgroups. In male population, EDN1 gene rs2070699 G allele increased the incidence risk to 1.78 times (P = 0.009; OR 1.78; 95 % CI 1.15-2.75) and the risk of morbidity of rs5370 T allele carrying increased to 1.49 times (P = 0.048; OR 1.49; 95 % CI 1.00-2.21). EDNRA gene mutation rs5335 homozygous CC morbidity risk was significantly lower (P = 0.016; OR 0.52; 95 % CI 0.31-0.88). In the female population, the mutant homozygous AA cancer risk was significantly higher than G allele carriers (P = 0.019; OR 2.65; 95 % CI 1.18-6.00) on EDNRA gene rs1801708. In EDN1 gene, T allele of rs5370 and G allele of rs2070699 may be IS incidence risk factors in Northern Han male population. A allele of rs1801708 in EDNRA gene can increase the risk of IS in Northern Han women population.

Association of nNOS gene polymorphism with ischemic stroke in Han Chinese of North China.

Nitric oxide (NO) is an important messenger molecule and effector molecule. This study aimed to investigate the relation of neuronal nitric oxide synthase (nNOS) gene polymorphism with ischemic stroke in Han Chinese of North China. This was a case-control study. A total of 413 patients with ischemic stroke were recruited from Han Chinese of North China. There were 201 males and 212 females. In addition, 477 healthy subjects served as controls including 224 males and 253 females. Multiplex SNaPshot was employed to detect nNOS gene polymorphism (rs2293050, rs2139733, rs7308402, and rs1483757). Results showed that the rs1483757, rs2139733, and rs2293050 genotypes and allele frequencies were comparable between patients and controls. However, ischemic stroke patients had significantly reduced AG genotype and A allele frequency when compared with controls (P = 0.037, P = 0.041). After adjusting confounding factors (gender, age, smoking, history of drinking, hypertension, and diabetes), AG genotype and A allele were still related to ischemic stroke (OR = 0.572, 95% CI: 0.335-0.978, P = 0.041; OR = 0.611, 95% C: 0.378-0.985, and P = 0.041) and both were found to be protective factors. Our results showed that rs7308402 gene polymorphism of nNOS is related to ischemic stroke in Han Chinese of North China.