Gut microbiota dysbiosis contributes toα-synuclein-related pathology associated with C/EBPβ/AEP signaling activation in a mouse model of Parkinson’s disease

Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease,whether it plays a causal role in motor dysfunction,and the mechanism underlying this potential effect,remain unknown.CCAAT/enhancer binding proteinβ/asparagine endopeptidase(C/EBPβ/AEP)signaling,activated by bacterial endotoxin,can promoteα-synuclein transcription,thereby contributing to Parkinson’s disease pathology.In this study,we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling,α-synuclein-related pathology,and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation.We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier,as well as activation of the C/EBP/AEP pathway,α-synuclein aggregation,and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits.However,treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics.Importantly,we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits,intestinal inflammation,and endotoxemia.Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits,intestinal inflammation,endotoxemia,and intestinal barrier impairment.These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits,C/EBPβ/AEP signaling activation,andα-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s disease.Additionally,our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson’s disease.

Common susceptibility variants of KDR and IGF-1R are associated with poststroke depression in the Chinese population

Background Depression,one of the most frequent complications after stroke,increases the disease’s burden and physical disability.Poststroke depression(PSD)is a multifactorial disease with genetic,environmental and biological factors involved in its occurrence.Genetic studies on PSD to date have mainly focused on the monoamine system and brain-derived neurotrophic factors.However,understanding is still limited about the influence of the single nucleotide polymorphism(SNP)of other neurotrophic factors on PSD.Aims The present study aimed to investigate the relationship between seven vascular endothelial growth factor(VEGF)family gene variants that occur with PSD.Methods A multicentre candidate gene study from five hospitals in Jiangsu Province from June 2013 to December 2014 involved 121 patients with PSD and 131 patients with non-PSD.Demographic characteristics and neuropsychological assessments were collected.Theχ^(2)test was used to evaluate categorical variables,while the independent t-test was applied to continuous variables.SNPs in seven genes(VEGFA,VEGFB,KDR,FLT-1,IGF-1,IGF-1R and PlGF)were genotyped.Single-marker association for PSD was analysed byχ^(2)tests and logistic regression using SPSS and PLINK software.Results Patients with PSD included more women and those with lower education levels,lower body mass indexes,lower Mini-Mental State Examination scores,and higher scores on the 17-item Hamilton Depression Rating Scale than non-PSD patients.Ninety-two SNPs with seven genes were genotyped and passed quality control.The rs7692791 CC genotypes,the C allele of KDR and the rs9282715 T allele of IGF-1R increased the risk for PSD(χ^(2)=7.881,p=0.019;χ^(2)=4.259,p=0.039;χ^(2)=4.222,p=0.040,respectively).In addition,the SNP rs7692791 of KDR was significantly associated with PSD by the logistic regression of an additive model(p=0.015,OR=9.584,95%CI:1.549 to 59.31).Conclusions Patients with rs7692791 C allele carriers or the CC genotype of KDR and the rs9282715 T allele of IGF-1R may have PSD susceptibility.Findings such as these may help clinicians to identify the high-risk population for PSD earlier and,thus,enable them to provide more timely interventions.

Ginkgo biloba leaf extract improves the cognitive abilities of rats with D-galactose induced dementia

Standardized Ginkgo biloba leaf extract has been used in clinical trials for its beneficial effects on brain func- tions, particularly in dementia. Substantial experimental evidences indicated that Ginkgo biloba leaf extract （EGB） protected neuronal cells from a variety of insults. We investigated the effect of EGB on cognitive ability and protein kinase B （PKB） activity in hippocampal neuronal cells of dementia model rats. Rats received an intra- peritoneal injection of D-galactose to induce dementia. Forty-eight Spraque-Dawley rats were randomly divided into six groups, including the control group, D-galactose group （Gal）, low-dose EGB group （EGB-L）, mid-dose EGB group （EGB-M）, high-dose EGB group （EGB-H） and treatment group. The EGB-L, EGB-M and EGB-H groups were administered with EGB and D-galactose simultaneously. Y-maze, cresyl violet staining, TUNEL assays and immunohistochemistry staining were performed to detect learning and memory abilities, morpho- logical changes in the hippocampus, neuronal apoptosis and the expressing level of phospho-PKB, respectively. Rats in the Gal group showed decreased abilities of learning and memory, and hippocampal pyramidal cell layer was damaged, while EGB administration improved learning and memory abilities. The Gal group exhibited many stained, condensed nuclei and micronuclei, either isolated or within the cytoplasm of cells （39.5 ± 1.4）. Apoptotic cells decreased in the groups of EGB-L （35.9±0.9）, EGB-M （16.8± 1.0） and EGB-H （10.1±0.8）, and there were statistical significances compared with the Gal group. Immunoreactivity of phospho-PKB was localized diffusely throughout the cytosol of cells in all groups, while the immunoreactivity of the Gal group was weak. EGB signifi- cantly attenuated learning and memory impairment in a dose-dependent manner, while it could decrease the nmber of TUNEL-positive cells, and increase the activity of PKB. Our results demonstrated that EGB attenuated memory impairment and cell apoptosis in galactose-induced dementia model rats by activating PKB.

Association of plasminogen activator inhibitor-1 4G/5G promoter polymorphism with recurrent cerebral infarction in China’s North Jiangsu Province

BACKGROUND： Many international studies have shown that plasminogen activator inhibitor-1 （PAl-l） 4G/5G promoter polymorphism does not increase the risk for cerebral infarction. OBJECTIVE： Using PCR methodology and agarose electrophoresis to detect PAI-1 4G/5G promoter polymorphism in patients with recurrent cerebral infarction in the North Jiangsu Province of China, and to compare results with healthy subjects and patients with first-occurrence cerebral infarction in the same region. DESIGN, TIME AND SETTING： Non-randomized, concurrent, control trial. A total of 122 cerebral infarction patients were admitted to Xuzhou Medical College Hospital＇s Department of Neurology and Xuzhou Central Hospital＇s Department of Neurology between July 2003 and August 2006. PARTICIPANTS： The patients consisted of 63 males and 59 females, aged （62 ± 10） years. They were divided into first-occurrence （n = 58） and recurrence （n = 64） groups. In addition, 50 healthy subjects that underwent physical examination in the outpatient department, including 26 males and 24 females, aged （60 ±12） years, were selected as controls. METHODS AND MAIN OUTCOME MEASURES： PAl-1 4G/5G promoter polymorphism was detected and analyzed using PCR methodology and agarose electrophoresis. RESULTS： Significant differences were determined in terms of genotypic frequency and allele frequency of PAI-1 4G/5G promoter polymorphism, in patients with first-occurrence or recurrent cerebral infarction, when compared with healthy subjects （P 〈 0.05）. There was, however, no significant difference between the first-occurrence and recurrence groups （P 〉 0.05）. CONCLUSION： PAl- 1 4G/5G promoter polymorphism is genetic risk factor for cerebral infarction in China. However, it may be associated with recurrence of cerebral infarction in patients from the North Jiangsu Province of China.

Clinical Efficacy and Safety of Joint Butylphthalide and Human Albumin Treatment of PTCI

Objective:To observe the clinical efficacy and safety of butylphthalide joint human albumin in the treatment of the progress of type in acute cerebral infarction(PTCI).Methods:120 patients with PTCI in Department of Neurology of Shuyang People's Hospital were used to observe the efficacy.These patients were all treated by routine medicine including anti-platelet,statins,edaravone,ginkgo leaf extract and dipyridamole after admission.According to whether used butylphthalide and(or)human albumin in the treatment of PTCI,the patients were divided into A group 30 cases,B group 45 cases,and C group 45 cases.Patients of group C were given conventional treatment.Group B were given conventional treatment and human albumin injection(5 g,ivgtt,qd,3 days in a course);Group A were treated with butylphthalide(first,with butylphthalide and sodium chloride injection 100 ml,ivgtt,for 7 d,then with butylphthalide soft capsules 0.2 g,tid,for 21 d),human albumin(5 g,ivgtt,qd,for 3 d)and routine medicine.The change of NIHSS score,Barthel Index,and mRS of three groups respectively during progress,1 week,2 weeks and 90 days after progress were observed and analyzed.Results:NIHSS score,Barthel Index,and mRS of group A,group B and group C all showed no statistically significant(all p>0.05)on 1 week after treatment;NIHSS score and mRS of group A were both lower than group B and group C on 2 weeks and 90 days after treatment,and both of them showed statistically significant(p<0.05);Barthel Index of group A was higher than group B and group C on 90 days after treatment,it showed statistically significant(p<0.05);The total effective rate of group A(96.7%)>group B(88.9%)>group C(77.8%),showed statistically significant(p<0.05).Conclusions:Butylphthalide joint human albumin treatment of PTCI has good therapeutic effect and safety,it is useful to clinical promotion and further research.

Study on Related Factors of Aspirin Resistance in Acute Ischemic Stroke

Objective:To study the related factors of aspirin resistance(AR)in acute ischemic stroke.Methods:A total of 138 patients with acute ischemic stroke treated in hospital affiliated to Xuzhou medical university from August 2016 to August 2018 were the study subjects,examine his medical data from the past.They were divided into the AR group(40 cases)and the non-AR group(98 cases)according to whether AR appears.Gender,disease history,biochemical indicators and etc.were compared between the two groups.The independent risk factors of AR were investigated using univariate analysis and logistic regression analysis.Results:40 cases of AR occurred in 138 patients,with an incidence rate of 28.99%.Diabetes,platelet count(PLT),microRNA-19a(m iR-19a)expression,smoking,high-sensitivity C-reactive protein(hs-CRP),Low-density lipoprotein cholesterol(LDL-C),fibrinogen(FIB)and age difference between the AR group and non-AR group was statistically significant(P<0.05).Gender,hypertension,uric acid(UA),high-density lipoprotein cholesterol(HDL-C),triglycerides(TG),homocysteine(Hcy),total cholesterol(TC),and alanine aminotransferase(ALT)between the two groups were not significantly different(P>0.05).Logistic regression analysis showed that the independent risk factors for AR in acute ischemic stroke were diabetes(OR=2.773,95%CI:1.102~5.065,P=0.025),miR-19a(OR=3.021,95%CI:1.322~6.545,P=0.021),hs-CRP(OR=2.719,95%CI:1.301~5.022,P=0.028)and smoking(OR=1.983,95%CI:1.114~3.887,P=0.040).Conclusion:The incidence of AR is higher in acute ischemic stroke.Risk factors include diabetes,miR-19a expression,hs-CRP,smoking,etc.Clinical intervention measures can be taken to reduce the risk of AR and improve acute ischemic stroke prognosis.

Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease

Background:Parkinson’s disease(PD)is a neurodegenerative disease characterized by intraneuronal Lewy Body(LB)aggregates composed of misfolded alpha-synuclein(α-syn).The spread of misfoldedα-syn follows a typical pattern:starting in the olfactory bulb(OB)and the gut,this pathology is followed by the progressive invasion of misfoldedα-syn to the posterior part of the brain.It is unknown whether the administration of human mutant alpha-synuclein(hm-α-syn,a human mutation which occurs in familial PD)into the OB of rats would trigger similarα-syn propagation and subsequently cause pathological changes in broader brain fields associated to PD and establish an animal model of prodromal PD.Methods:hm-α-syn was overexpressed in the OB of rats with an AAV injection.Then motor and non-motor symptoms of the SD rats were tested in different behavioral tasks following the AAV injection.In follow-up studies,pathological mechanisms ofα-syn spread were explored at the histological,biochemical and micro-structure levels.Results:The experimental results indicated that hm-α-syn was overexpressed in the OB 3 weeks after the AAV injection.1)overexpression of the Hm-α-syn in the OB by the AAV injection could transfer to wider adjacent fields beyond the monosynaptic scope.2)The number of tyrosine hydroxylase positive cells body and fibers was decreased in the substantia nigra(SN)12 weeks after AAV injection.This was consistent with decreased levels of the DA neurotransmitter.Importantly,behavioral dysfunctions were found that included olfactory impairment after 3 weeks,motor ability impairment and decreased muscular coordination on a rotarod 6 weeks after the AAV injection.3)The morphological level studies found that the Golgi staining revealed the number of neuronal branches and synapses in the OB,prefrontal cortex(PFC),hippocampus(Hip)and striatum caudate putamen(CPU)were decreased.4)phosphorylatedα-syn,at Ser-129(pSer129),was found to be increased in hm-α-syn injected animals in comparison to controls that overexpressed GFP alone,which was also found in the most of LB stained by the thioflavine S(ThS)in the SN field.5)A marker of autophagy(LC3B)was increased in serval fields,which was colacolizated with a marker of apoptosis in the SN field.Conclusions:These results demonstrate that expression of exogenous mutantα-syn in the OB induces pathological changes in the sensitive brain fields by transferring pathogenicα-syn to adjacent fields.This method may be useful for establishing an animal model of prodromal PD.

Retraction Note: Alpha-synuclein overexpression in the olfactory bulb initiates prodromal symptoms and pathology of Parkinson’s disease

Retraction Note:Translational Neurodegeneration(2018)7:25 https://doi.org/10.1186/s40035-018-0128-6 The Editor-in-Chief has retracted this article.After pub-lication,concerns were raised regarding image overlap across various panels in Fig.8.The authors have stated that incorrect images were used,but have been unable to provide the full raw data.Additionally,the authors could not justify the anesthetic protocol used for rat stereotaxic surgery.The Editor-in-Chief therefore no longer has con-fidence in the presented data and ethics of this article.Author Haichen Niu has stated on behalf of all co-authors that they agree to this retraction.