Analysis of Factors Associated with Hemorrhagic Transformation in Acute Cerebellar Infarction.

OBJECTIVES: Hemorrhagic transformation (HT) is a frequent and severe complication of ischemic stroke. This study aimed to evaluate the factors associated with the occurrence of HT in patients with acute cerebellar infarction. MATERIALS AND METHODS: A total of 190 patients, 141 male (74.2%) and 49 female (25.8%) with mean age 61.84 ± 12.16 years, who were admitted within 72 h of acute cerebellar infarction onset from January 2017 to March 2021 were retrospectively recruited. The multivariate logistic regression analysis was used to evaluate the independent influent factors for HT and receiver-operating characteristic (ROC) curve was applied to calculate the predictive value of those factors for HT in patients with acute cerebellar infarction. RESULTS: 37 out of 190 recruited patients (19.47%) had HT within 14 days after acute cerebellar infarction onset. The incidence rates of HT occurring within 3 days, 3-7 days and 7-14 days were 13.5%, 40.5% and 45.9%, respectively. Results of the multivariable logistic regression analysis indicated that atrial fibrillation (AF) (OR 6.196, 95% CI 1.357-28.302, P = 0.019), infarct diameter (OR 5.813, 95% CI 2.932-11.526, P < 0.001), white matter hyperintensity (WMH) (OR 2.44, 95% CI 1.134-5.252, P = 0.023) were independent risk factors for HT in acute cerebellar infarction, while lymphocyte count (OR 0.319, 95% CI 0.142-0.716, P = 0.006) showed an independently protective effect. CONCLUSIONS: Infarct diameter, AF and WMH are independent risk factors for HT in patients with acute cerebellar infarction, while the lymphocyte count is a protective factor.

Mild hyperhomocysteinemia induces blood-brain barrier dysfunction but not neuroinflammation in the cerebral cortex and hippocampus of wild-type mice.

This study explored the potential effects of mild hyperhomocysteinemia (HHcy) on the blood-brain barrier (BBB) and neuroinflammation. Seven-week-old male wild-type C57BL/6 mice were fed normal mouse chow (the control group) or a methionine-enriched diet (the HHcy group) for 14 weeks. Mice in the HHcy group exhibited a slight increase in serum Hcy levels (13.56 ± 0.61 µmol/L). Activation of the ERK signaling pathway, up-regulation of matrix metalloproteinase-9 (MMP-9), and degradation of tight junction proteins (occludin and claudin-5) were observed in both the cerebral cortex and hippocampus of mice with mild HHcy. However, microglia were not activated and the levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were not changed in either the cerebral cortex or hippocampus of mice with mild HHcy. Moreover, the signaling activity of STAT3 also did not differ significantly between the two groups. These findings demonstrate that the BBB is highly vulnerable to homocysteine insult. Even a slight increase in serum homocysteine levels up-regulates MMP-9 expression and disrupts the BBB integrity. Meanwhile, microglia activation or the STAT3 pathway might not contribute to the effects of mild HHcy on the brain.

Effects of MTHFR C677T and A1298C Polymorphisms on Migraine Susceptibility: A Meta-Analysis of 26 Studies.

BACKGROUND: Multiple studies have evaluated the associations between 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and migraine risk with conflicting results. Therefore, we conducted a meta-analysis on this theme. METHODS: We searched the electronic databases of PubMed, EmBase, ScienceDirect, and Cochrane Library for all relevant studies published until April 6, 2018. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) in allelic, dominant, recessive, homozygous, and heterozygous models were calculated using random effects model to assess the strength of associations. We also performed subgroup analyses stratified by ethnicity and migraine subtypes, respectively. RESULTS: Twenty-six studies (20 in Caucasians, 3 in Asians, 2 in Indians, and 1 in Pakistanis) with 10,228 migraineurs and 28,608 controls were included in this meta-analysis. In the overall population, the allele 677T and TT genotype were associated with an increased risk for total migraine and migraine with aura (MA) (total migraine: T vs C: OR = 1.19, 95%CI = 1.06-1.33, P = .004; TT vs CC: OR = 1.32, 95%CI = 1.07-1.64, P = .011; MA: T vs C: OR = 1.28, 95%CI = 1.09-1.51, P = .003; TT vs CC: OR = 1.51, 95%CI = 1.09-2.08, P = .012), but not for migraine without aura (MO). Subgroup analysis stratified by ethnicity revealed similar findings in Caucasians. In Asians, the association was detected only in recessive model in total migraine (TT vs CT + CC: OR = 1.80, 95%CI = 1.14-2.85, P = .012). Results in Indians did not suggest any association in either total migraine or its subtypes. Pooled results of 5 studies (4 in Caucasians and 1 in Indians) on A1298C polymorphism indicated a significant association between the CC genotype and migraine risk (CC vs AA: OR = 1.78, 95%CI = 1.03-3.07, P = .038), which only appeared for MO (CC vs AA: OR = 2.83, 95%CI = 1.30-6.16, P = .009). CONCLUSIONS: Our meta-analysis suggested that allele 677T in MTHFR C677T polymorphism might be a genetic risk factor for MA in Caucasians, and genotype 1298CC might contribute to MO susceptibility.

Association of CD1 and FcγR gene polymorphisms with Guillain-Barré syndrome susceptibility: a meta-analysis.

CD1 and immunoglobulin G Fc receptor (FcγR) genes have been proposed to be involved in the pathogenesis of Guillain-Barré syndrome (GBS). However, results of different studies are conflicting. This meta-analysis aimed to systematically examine the association between CD1 and FcγR gene polymorphisms and GBS. A comprehensive literature search through PubMed, EmBase, ScienceDirect, and Cochrane Library was performed to identify all eligible studies. The strength of association was assessed by pooled odds ratios (ORs) and corresponding 95% confidence intervals (95% CI) in allelic, dominant, recessive, homozygous and heterozygous genetic models. Four case-control studies about polymorphisms of exon 2 in CD1A and CD1E genes and GBS risk and five studies (six cohorts) about FcγR gene polymorphisms and GBS risk were included in this meta-analysis. The association between exon 2 of CD1E gene polymorphism and GBS was marginally significant in Caucasians in allelic model (OR = 1.193, 95% CI = 1.001-1.423, P = 0.049). FcγRIIA gene polymorphism was significantly associated with GBS risk in Caucasians under allelic model (OR = 1.553, 95% CI = 1.018-2.368, P = 0.041) and dominant model (OR = 1.320, 95% CI = 1.027-1.697, P = 0.030). However, no significant association was found between polymorphisms in exon 2 of CD1A, FcγRIIIA and FcγRIIIB genes and GBS susceptibility. This meta-analysis suggested that FcγRIIA gene polymorphism may contribute to GBS risk in Caucasians and revealed a certain trend toward significance in the association of exon 2 of CD1E gene with GBS in Caucasians. Further studies with larger sample size are required to validate these results.

Association of TLR9 polymorphisms with sporadic Parkinson's disease in Chinese Han population.

Previous studies have acknowledged that inflammatory reaction has implicated in Parkinson's disease (PD) pathogenesis nowadays. Toll-like receptors (TLRs), as key players in the inflammatory reaction, play a pivotal role in the PD pathogenesis and accumulating evidences have shown that TLRs are increased in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of PD. Therefore, the present study aimed to identify the role of the polymorphisms of rs187084 and rs352140 in TLR9 gene with PD. The genotypes were detected by polymerase chain reaction and restriction fragment length polymorphism analysis in 380 PD patients and 380 healthy matched individuals in Chinese Han population. For rs352140, our data revealed a significant difference in allele distribution in female PD group and its healthy matched control (P = 0.040). Moreover, rs352140 T allele carriers of female group were associated with a reduced risk of PD (TT + TC vs. CC, P = 0.018). However, no significant differences in genotype and allele distribution were found between the age and gender subgroups for rs187084. Therefore, our studies indicate that the rs352140 gene polymorphism may be associated with the susceptibility of female PD in Chinese Han population.

Effects of DeSUMOylated Spastin on AMPA Receptor Surface Delivery and Synaptic Function Are Enhanced by Phosphorylating at Ser210.

Surface trafficking of AMPA receptors (AMPARs) is one of the important mechanisms mediating synaptic plasticity which is essential for cognitive functions such as learning and memory. Spastin, as a novel binding partner for the AMPAR, has been reported to regulate AMPAR surface expression and synaptic function. Additionally, Spastin undergoes two posttranslational modifications, phosphorylation and SUMOylation, both of which are crucial for synaptic function. However, gaps exist in our knowledge of how Spastin phosphorylation cross-talks with its SUMOylation in the regulation of AMPAR surface expression and synaptic function. Here, we reported that deSUMOylation of Spastin at Lys427 increased the surface level of AMPAR GluA2 subunit, the amplitude and frequency of miniature excitatory synaptic currents (mEPSC), and facilitated the morphological maturation of dendritic spines in cultured hippocampal neurons. Further studies demonstrated that Spastin phosphorylation at Ser210 further increased the enhancement of GluA2 surface expression and synaptic function by deSUMOylated Spastin, while dephosphorylation had the opposite effect. Simultaneously, deSUMOylation at Lys427 significantly increased the promoting effect of Spastin phosphorylation on synaptic function. In conclusion, our study suggests that cooperative interactions between phosphorylated and deSUMOylated Spastin are novel pathways to enhance synaptic function.

Systemic sclerosis with cerebral infarction and severe stenosis of internal carotid artery and coronary artery: A case report.

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by microangiopathy, extensive fibrosis and autoantibody production. It is generally believed that microvascular disease is the hallmark of SSc. Macrovascular involvement is not initially considered as a feature of SSc, but its mortality is high, which should not be ignored. Up to the present, SSc patients with cerebral involvement and multiple macrovascular stenosis have been rarely described. We herein report a case of cerebral infarction and severe stenosis of the internal carotid artery and coronary artery associated with SSc.

Lipoprotein(a) and residual vascular risk in statin-treated patients with first acute ischemic stroke: A prospective cohort study.

Objectives: Statins either barely affect or increase lipoprotein(a) [Lp(a)] levels. This study aimed to explore the factors correlated to the change of Lp(a) levels as well as the relationship between Lp(a) and the recurrent vascular events in statin-treated patients with first acute ischemic stroke (AIS). Methods: Patients who were admitted to the hospital with first AIS from October 2018 to September 2020 were eligible for inclusion. Correlation between the change of Lp(a) levels and potential influencing factors was assessed by linear regression analysis. Cox proportional regression models were used to estimate the association between Lp(a) and recurrent vascular events including AIS, transient ischemic attack, myocardial infarction and coronary revascularization. Results: In total, 303 patients, 69.6% males with mean age 64.26 ± 11.38 years, completed the follow-up. During the follow-up period, Lp(a) levels increased in 50.5% of statin-treated patients and the mean percent change of Lp(a) levels were 14.48% (95% CI 6.35-22.61%). Creatinine (ß = 0.152, 95% CI 0.125-0.791, P = 0.007) and aspartate aminotransferase (AST) (ß = 0.160, 95% CI 0.175-0.949, P = 0.005) were positively associated with the percent change of Lp(a) levels. During a median follow-up of 26 months, 66 (21.8%) patients had a recurrent vascular event. The median time period between AIS onset and vascular events recurrence was 9.5 months (IQR 2.0-16.3 months). The on-statin Lp(a) level ≥70 mg/dL (HR 2.539, 95% CI 1.076-5.990, P = 0.033) and the change of Lp(a) levels (HR 1.003, 95% CI 1.000-1.005, P = 0.033) were associated with the recurrent vascular events in statin-treated patients with first AIS. Furthermore, the on-statin Lp(a) levels ≥70 mg/dL (HR 3.612, 95% CI 1.018-12.815, P = 0.047) increased the risk of recurrent vascular events in patients with low-density lipoprotein cholesterol (LDL-C) levels < 1.8 mmol/L. Conclusions: Lp(a) levels increased in half of statin-treated patients with first AIS. Creatinine and AST were positively associated with the percent change of Lp(a) levels. Lp(a) is a determinant of residual vascular risk and the change of Lp(a) is positively associated with the risk of recurrent vascular events in these patients.

Association between vitamin D receptor polymorphisms and susceptibility to Parkinson's disease: An updated meta-analysis.

The relationships between vitamin D receptor (VDR) gene polymorphisms, particularly ApaI, BsmI, FokI, and TaqI, and Parkinson's disease (PD) has received increasing attention in the research community. However, as the results yielded by this increased research have hitherto conflicted, we performed an updated meta-analysis of reports on the relationships between VDR polymorphisms and PD published before October 2019 that we collected from the PUBMED, EMBASE, EBSCO, China National Knowledge Infrastructure (CNKI), and Wanfang databases. The ten articles that met our screening criteria included 2782 patients and 3194 healthy controls. All the data that we received were analyzed with Stata 12.0 statistical software. The odds ratio (OR) and 95 % confidence intervals (CIs) were used to determine the relationship between VDR gene diversity and PD. While we did not find a significant correlation between the ApaI, BsmI, and TaqI polymorphisms and the risk of PD in any of the considered genetic models, we found a clear association between the FokI polymorphism and susceptibility to PD (C vs. T: OR = 1.246, 95 % CI: 1.101-1.411, P = 0; CC vs. TT: OR = 1.630, 95 % CI: 1.243-2.139, P = 0; CT vs. TT: OR = 1.382, 95 % CI: 1.059-1.804, P = 0.017; CC + CT vs. TT: OR = 1.491, 95 % CI: 1.159-1.919,P = 0.002; CC vs. CT + TT: OR = 1.261, 95 % CI: 1.062-1.496, P = 0.008). Our subgroup analysis performed according to ethnicity revealed that FokI increased the risk of PD in Asian populations (C vs. T: OR = 1.261, 95 % CI: 1.080-1.472, P = 0.003; CC vs. TT: OR = 1.664, 95 % CI: 1.189-2.330, P = 0.003; CT vs.TT: OR = 1.387, 95 % CI: 1.000-1.925, P = 0.05; CC + CT vs. TT: OR = 1.497, 95 % CI: 1.098-2.042, P = 0.011; CC vs. CT + TT: OR = 1.285, 95 % CI: 1.036-1.593, P = 0.022). Overall, the gene polymorphism of FokI only increases the risk of PD among Asian populations. Given the limited sample size of this study, the findings should be carefully explained.

Serum homocysteine level is an independent predictor for hemorrhagic transformation within 24 h of intravenous thrombolysis in acute ischemic stroke.

The study aimed to investigate the role of serum homocysteine in hemorrhagic transformation (HT) and symptomatic intracranial hemorrhage (sICH) within 24 h of intravenous (IV) recombinanttissueplasminogenactivator(rt-PA) in acute ischemic stroke (AIS) patients. 236 consecutive AIS patients (169 men, median 65 years old) who underwent to IV rt-PA within 4.5 h of symptom onset were retrospectively recruited and analyzed. The serum homocysteine levels ranged from 4.45 to 67.71 (median 12.05) µmol/L. HT was observed in 28 (11.9%) patients, including 7 (3.0%) sICH patients within 24 h of IV rt-PA. Multiple parameters were compared between HT and non-HT patients as well as sICH and non-sICH patients. The serum homocysteine levels were higher in patients with HT than in those without HT (13.00 vs. 11.70 µmol/L, P = 0.025) and an independent association between serum homocysteine level and HT within 24 h of IV rt-PA was identified via multivariable logistic regression analysis (odds ratio [OR] = 1.103, 95% confidence interval [CI] = 1.021-1.191, P = 0.013). Moreover, serum homocysteine levels were also significantly higher in patients with sICH than in those without sICH (15.19 vs. 11.73 µmol/L, P = 0.005).Our study suggests that serum homocysteine level is an independent predictor for HT within 24 h of IV rt-PA in AIS patients.

Multiple administrations of human marrow stromal cells through cerebrospinal fluid prolong survival in a transgenic mouse model of amyotrophic lateral sclerosis.

BACKGROUND AIMS: The blood-brain barrier (BBB) is the main obstacle to cell therapy for neurologic disorders such as amyotrophic lateral sclerosis (ALS). Intrathecal injection is a potential method for cell transplantation because it would bypass the BBB. We investigated the effects of human marrow stromal cells (hMSC) delivered through cerebrospinal fluid (CSF) in a transgenic mouse model of ALS. METHODS: 5 x 10(5) hMSC were delivered into the CSF of SOD1 transgenic mice at the age of 8 weeks (single transplantation group) or 8, 10 and 12 weeks (multiple transplantation group). Clinical observation, weight, hanging wire test and motor neuron count were used to assess the disease progression in the SOD1 mice. Immunohistochemistry was performed with human-specific antibody against HuNu to examine the distribution of hMSC in the lumbar spinal cord parenchyma of SOD1 mice at the age of 15 weeks. RESULTS: Single transplantation of hMSC did not have a beneficial effect in SOD1 mice. Multiple transplantations of hMSC attenuated weight loss, enhanced motor performance, decreased motor neuron loss and, importantly, increased survival in SOD1 transgenic mice. However, only a few hMSC delivered through the CSF migrated into the lumbar spinal cord parenchyma of SOD1 mice. CONCLUSIONS: Multiple administrations of hMSC through CSF may have a therapeutic effect in SOD1 mice, although limited numbers of cells migrate into the lumbar spinal cord parenchyma. It is likely that the hMSC remaining in CSF are responsible for the effect in SOD1 mice.

Ginsenoside Rg1 Exerts Anti-inflammatory Effects via G Protein-Coupled Estrogen Receptor in Lipopolysaccharide-Induced Microglia Activation.

Neuroinflammation plays a pivotal role in the pathogenesis of Parkinson's disease. Ginsenoside Rg1, the most active ingredient of ginseng, has been reported to exert neuroprotective effects via estrogen and glucocorticoid receptors. The present study evaluated the involvement of the G protein-coupled estrogen receptor (GPER) in the anti-inflammatory effects of ginsenoside Rg1 against lipopolysaccharide (LPS)-induced microglia activation in the BV2 microglial cell line and ventral mesencephalic primary microglial culture. The pharmacological blockade and lentivirus-mediated small interfering RNA (siRNA) knockdown of GPER were used to study the underlying mechanism. Rg1 attenuated LPS-induced upregulation of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA and protein levels. The GPER antagonist G15 blocked the inhibitory effects of Rg1 and the GPER-specific agonist G1 on LPS-induced microglia activation. Rg1 mimicked the effects of G1 by inhibiting the LPS-induced activation of nuclear transcription factor-kappa B (NF-κB) and mitogen activated protein kinase signaling pathways, which was also blocked by G15. Moreover, lentivirus-mediated siRNA knockdown of GPER inhibited the anti-inflammatory effects of Rg1. Taken together, our results indicate that GPER is involved in the anti-inflammatory effects of Rg1 against LPS-induced microglia activation. These findings provide a new biological target of Rg1 for the treatment of neuroinflammatory disorders.

MTHFR C677T and A1298C polymorphisms may contribute to the risk of Parkinson's disease: A meta-analysis of 19 studies.

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been reported to be a candidate gene for susceptibility to Parkinson's disease (PD), but results of different studies are conflicting. Here, we conducted a meta-analysis of published case-control studies to evaluate the association between MTHFR C677T and A1298C gene polymorphisms with the risk of PD. Electronic search through PubMed, EmBase, ScienceDirect and Cochrane Library was conducted to identify all relevant studies. A total of 19 studies with 2746 cases and 8967 controls were included. No significant association between MTHFR C677T polymorphism and PD risk was found in the overall population in all five genetic models. In the subgroup analysis stratified by ethnicity, a significant association between MTHFR C677T and PD risk was observed in the dominant model in Caucasians (OR=1.175, 95%CI: 1.008-1.369, P=0.040), but not in Asians. Significant association was found between MTHFR A1298C polymorphism and PD risk in the overall population in the dominant (OR=1.168, 95%CI: 1.008-1.353, P=0.039) and heterozygous model (OR=1.172, 95%CI: 1.004-1.367, P=0.044). But in the subgroup analysis, no association was found between MTHFR A1298C and PD neither in Caucasians nor in Asians. Our meta-analysis suggests that MTHFR C677T polymorphism may be associated with increased PD risk in Caucasians and MTHFR A1298C polymorphism may also increase susceptibility to PD.

Neuroprotective properties of icariin in MPTP-induced mouse model of Parkinson's disease: Involvement of PI3K/Akt and MEK/ERK signaling pathways.

BACKGROUND: Epimedium sagittatum is a traditional Chinese herb normally which is used to treat the osteoporosis, cardiovascular dysfunction, and to improve neurological and sexual function in China, Korea and Japan. Icariin is the major active ingredient in Epimedium sagittatum. In the present research, we examined the neuroprotective effects of icariin on dopaminergic neurons and the possible mechanisms in a mouse model of Parkinson's disease (PD). METHODS: Ovariectomized PD mice were treated with vehicle or icariin (3 days before MPTP injections) with or without the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or mitogen-activated protein kinase kinase (MEK) inhibitor PD98059. The dopamine (DA) content in the striatum was studied by HPLC. Western blot was used to determine the protein expressions of Bcl-2, Bax and Caspase 3 in the striatum. The numbers of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantial nigra pars compacta (SNpc) were assessed by immunohistochemistry. The activation of Akt and ERK by icariin were detected in doparminergic MES23.5 cells. RESULTS: Icariin pretreatment could ameliorate the decreased striatum DA content and the loss of TH-IR neurons in the SNpc induced by MPTP. The MPTP-induced changes of Bcl-2, Bax and caspase 3 protein expressions in the striatum could be reversed by icariin pretreatment. Blockade of PI3K/Akt or MEK/ERK signaling pathway by LY294002 or PD98059 could attenuate the increase of DA content in the striatum and TH-IR in the SNpc induced by icariin in PD mice model. Additionally, icariin treatment alone significantly induced the phosphorylation of Akt and ERK in a time dependent pattern in dopaminergic MES 23.5 cells. These effects were abolished by co-treatment with LY294002 or PD98059. CONCLUSION: These data demonstrated that icariin has neuroprotective effect on dopaminergic neurons in PD mice model and the potential mechanisms might be related to PI3K/Akt and MEK/ERK pathways.

Association of AKT1 gene polymorphisms with sporadic Parkinson's disease in Chinese Han population.

Genetic variants of AKT1 have been shown to influence brain function of Parkinson's disease (PD) patients, and in this paper our aim is to investigate the association between the three single-nucleotide polymorphisms (rs2498799; rs2494732; rs1130214) and PD in Han Chinese. 413 Han Chinese PD patients and 450 healthy age and gender-matched controls were genotyped using the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Both the patient and control groups show similar genotype frequencies at the three loci: rs2498799, rs2494732 and rs1130214. We are able to identify a significant difference in the frequencies of genotype (p=0.019) and G allele (OR=0.764, 95% CI=0.587-0.995, p=0.045) both at rs2498799 between the patient and control groups. Furthermore, the association of subjects with GG genotypes versus those with GA+AA genotype remain significant after adjusting for age in the Han Chinese female cohort (OR=0.538, 95%CI=0.345-0.841, p=0.006), which is especially evident in the late-onset cohort (OR=0.521, 95%CI=0.309-0.877, p=0.012). In contrast, allele frequencies at rs2494732 and rs1130214 were similar between patients and controls in all subgroup analyses. These results suggest that polymorphism of AKT1 locus is associated with risk of PD and that the G allele at rs2498799 may decrease the risk of PD in the North-eastern part of Han Chinese female population.

Association of RAGE gene polymorphisms with sporadic Parkinson's disease in Chinese Han population.

Previous studies have corroborated receptor for advanced glycation end-products (RAGE) ablation had a protective effect on nigral dopaminergic neurons in the MPTP model of Parkinson's disease (PD). Genetic variation of RAGE gene may be associated with the development of onset of sporadic PD. The present study aimed to explore the possible association of RAGE gene polymorphisms namely -374T/A,-429T/C, and G82S with PD. A total of 285 PD patients and 285 healthy-matched individuals in Chinese Han population were enrolled. Genotype analyses were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Only the -429T/C polymorphism denoted a significant difference between PD patients and controls (P=0.015) of the three examined single nucleotide polymorphisms (SNPs). Our data also revealed that -429C allele carriers seem to have a decreased risk of PD (OR=0.617, P=0.007). Moreover, there were significant differences in genotype distribution in female PD group and its healthy-matched control subgroup (P=0.014), as well as between late-onset PD (LOPD) and the controls subgroup (P=0.016). However, for -374T/A and 82GS polymorphisms, there was no significant difference in the genotype and allele frequencies between PD patients and the controls, as well as gender- and age-related differences. Our present findings indicate that the RAGE -429T/C polymorphism may be associated with the susceptibility of PD and the CC genotype of -429T/C may be a protective factor for PD in Chinese Han population.

20(S)-protopanaxadiol, an active ginseng metabolite, exhibits strong antidepressant-like effects in animal tests.

Ginseng has been used for mood adjustment in traditional Chinese medicine for thousands of years. Our previous study has shown that, total ginsenosides, the major pharmacologically functional ingredients of ginseng, possess antidepressant activity. In the present study, we hypothesized that an intestinal metabolite of ginseng, 20(S)-protopanaxadiol (code name S111), as a post metabolism compound (PMC) of ingested ginsenosides, may be responsible for the antidepressant activity of ginseng. To test this hypothesis, antidepressant-like activity of orally given S111 was measured in animal tests including tail suspension test, forced swimming test and rat olfactory bulbectomy depression model. In all those tests, S111 demonstrated antidepressant-like activity as potent as fluoxetine. S111 treated bulbectomy animals had higher levels of monoamine neurotransmitters in the brain and in vitro reuptake assay showed that S111 had a mild inhibitory effect. Furthermore, S111 but not fluoxetine significantly reduced brain oxidative stress and down-regulated serum corticosterone concentration in bulbectomy animals. No disturbance to central nervous system (CNS) normal functions were found in S111 treated animals. These results suggest that the ginseng active metabolite S111 is a potential antidepressant. Since the monoamine reuptake activity of this compound is rather weak, it remains to be investigated whether its antidepressant-like effect is by mechanisms that are different from current antidepressants. Furthermore, this study has demonstrated that post metabolism compounds (PMCs) of herb medicines such as S111 may be a novel source for drug discovery from medicinal herbs.

Effects of human marrow stromal cells on activation of microglial cells and production of inflammatory factors induced by lipopolysaccharide.

There has been an increasing appreciation of the role that microglial cells play in neural damage. Marrow stromal cells (MSCs) can dramatically lessen neural damage in animal models, but the mechanisms involved have not been defined. This study aimed to investigate the effects of human MSCs (hMSCs) on the activation of primary microglia and the attendant production of pro-inflammatory factors stimulated by bacterial endotoxin lipopolysaccharide (LPS). Our study showed that hMSCs in co-cultures and in transwell cultures inhibited the activation of microglial cells, reduced the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), downregulated the expression of inducible nitric oxide synthase (iNOS) and phosphorylated p38 mitogen-activated protein kinase (p38 MAPK), whereas hMSCs conditioned medium did not have any effect on microglial inflammation. To further investigate the mechanisms by which hMSCs exert anti-inflammatory effects, we examined the production of neurotrophic factors by hMSCs with enzyme linked immunosorbent assay (ELISA). Our results showed that the production of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and hepatocyte growth factor (HGF) was significantly increased by hMSCs when cultured in the conditioned medium from activated microglia. We conclude that hMSCs can inhibit microglial activation and the production of attendant inflammatory factors. In addition, hMSCs can interact with microglial cells through diffusible soluble factors, whereas cell contact is not a prerequisite for anti-inflammatory effects. Finally, hMSCs within inflammatory environment can significantly increase the production of neurotrophic factors, which may involve with the anti-inflammatory mechanisms.