Accumulation of ß-aminoisobutyric acid mediates hyperalgesia in ovariectomized mice through Mas-related G protein-coupled receptor D signaling.

Hyperalgesia is typified by reduced pain thresholds and heightened responses to painful stimuli, with a notable prevalence in menopausal women, but the underlying mechanisms are far from understood. ß-Aminoisobutyric acid (BAIBA), a product of valine and thymine catabolism, has been reported to be a novel ligand of the Mas-related G protein coupled receptor D (MrgprD), which mediates pain and hyperalgesia. Here, we established a hyperalgesia model in 8-week-old female mice through ovariectomy (OVX). A significant increase in BAIBA plasma level was observed and was associated with decline of mechanical withdrawal threshold, thermal and cold withdrawal latency in mice after 6 weeks of OVX surgery. Increased expression of MrgprD in dorsal root ganglion (DRG) was shown in OVX mice compared to Sham mice. Interestingly, chronic loading with BAIBA not only exacerbated hyperalgesia in OVX mice, but also induced hyperalgesia in gonadally intact female mice. BAIBA supplementation also upregulated the MrgprD expression in DRG of both OVX and intact female mice, and enhanced the excitability of DRG neurons in vitro. Knockout of MrgprD markedly suppressed the effects of BAIBA on hyperalgesia and excitability of DRG neurons. Collectively, our data suggest the involvement of BAIBA in the development of hyperalgesia via MrgprD-dependent pathway, and illuminate the mechanisms underlying hyperalgesia in menopausal women.

Revealing the novel autophagy-related genes for ligamentum flavum hypertrophy in patients and mice model.

Background: Fibrosis is a core pathological factor of ligamentum flavum hypertrophy (LFH) resulting in degenerative lumbar spinal stenosis. Autophagy plays a vital role in multi-organ fibrosis. However, autophagy has not been reported to be involved in the pathogenesis of LFH. Methods: The LFH microarray data set GSE113212, derived from Gene Expression Omnibus, was analyzed to obtain differentially expressed genes (DEGs). Potential autophagy-related genes (ARGs) were obtained with the human autophagy regulator database. Functional analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) were conducted to elucidate the underlying biological pathways of autophagy regulating LFH. Protein-protein interaction (PPI) network analyses was used to obtain hub ARGs. Using transmission electron microscopy, quantitative RT-PCR, Western blotting, and immunohistochemistry, we identified six hub ARGs in clinical specimens and bipedal standing (BS) mouse model. Results: A total of 70 potential differentially expressed ARGs were screened, including 50 up-regulated and 20 down-regulated genes. According to GO enrichment and KEGG analyses, differentially expressed ARGs were mainly enriched in autophagy-related enrichment terms and signaling pathways related to autophagy. GSEA and GSVA results revealed the potential mechanisms by demonstrating the signaling pathways and biological processes closely related to LFH. Based on PPI network analysis, 14 hub ARGs were identified. Using transmission electron microscopy, we observed the autophagy process in LF tissues for the first time. Quantitative RT-PCR, Western blotting, and immunohistochemistry results indicated that the mRNA and protein expression levels of FN1, TGFß1, NGF, and HMOX1 significantly higher both in human and mouse with LFH, while the mRNA and protein expression levels of CAT and SIRT1 were significantly decreased. Conclusion: Based on bioinformatics analysis and further experimental validation in clinical specimens and the BS mouse model, six potential ARGs including FN1, TGFß1, NGF, HMOX1, CAT, and SIRT1 were found to participate in the fibrosis process of LFH through autophagy and play an essential role in its molecular mechanism. These potential genes may serve as specific therapeutic molecular targets in the treatment of LFH.

BPV associated with imaging features of SSI on MRI.

OBJECTIVES: A retrospective study was performed to investigate the relationship between blood pressure variability (BPV) and imaging features of single small infarction (SSI) on magnetic resonance imaging (MRI). MATERIALS AND METHODS: Two hundreds and five patients with SSI and 120 healthy subjects matched with age and sex as the control group were enrolled into this study. All subjects came from the Affiliated Hospital to Qingdao University and Qingdao Municipal Hospital from October 2011 to June 2016. Research subjects were classified into different groups. Blood pressure was measured once a day and recorded during the hospitalization period (7-10 days). The followed up data of patients after discharging from hospital was collected from the follow-up records. RESULTS: Twenty-four hours BPV (SBPMean , DSBPMax , DSBPSD , NDBPMax , NDBPSD, and DDBPCV ), day-to-day, and visit-to-visit BPV (SBPMax , SBPSD , DBPMax, and DBPSD ) in the SSI group were significantly higher than that in control group. Compared with the giant lacunar group, day-to-day BPV (SBPMean , SBPMax , SBPSD , SBPCV , DBPMean , DBPMax , DBPSD ), and visit-to-visit BPV (SBPMean , SBPMax , SBPSD , DBPMean , DBPMax , DBPSD ) were significantly higher in the small lacunar infarct group (p < .05). The 24 hr BPV (SBPMean , DDBPMax , DDBPMean ), day-to-day BPV (SBPMax , SBPSD , SBPCV ), and visit-to-visit SBPMax in nonround lesion group were significantly higher than that in round group (p < .05). Compared with nondeep lesion group, some parameters in day-to-day BPV and visit-to-visit BPV were significantly higher in the deep small lesion group (p < .05). CONCLUSION: Increased BPV parameters such as day-to-day and visit-to-visit (SBPMax , SBPSD , DBPMax ) were related to the SSI characterized by small lesion in deep brain region.

Urinary kynurenine as a biomarker for Parkinson's disease.

OBJECTIVE: To examine whether urine kynurenine (KYN) levels were associated with early-stage Parkinson's disease (PD), as well as the value of urine KYN as a potential biomarker in early-stage PD. METHOD: Eighty-two participants including 41 PD patients and 41 healthy controls were enrolled into this study. Urine KYN levels were measured with a KYN enzyme-linked immunoassay kit. In order to explore the correlation between some clinical parameters and urine KYN, the clinical parameters for these participants were recorded. Diagnostic value and clinical relevance of urine KYN were assessed by using receiver operator characteristic (ROC) curve and correlation analysis. RESULTS: Urine KYN levels were significantly higher in the PD group than in the healthy group (891.95 ± 276.65 pg/ml vs. 640.11 ± 122.37 pg/ml, p = 0.000). The correlations between urine KYN levels and clinical parameters are as follows: Hoehn-Yahr stage (r = 0.676, p = 0.000), disease duration (r = 0.772, p = 0.000), Mini-Mental State Examination scores (r = -0.434, p = 0.005). There was no statistically significant correlation between urine KYN with age, low-density cholesterol (LDL), triglycerides (TG), cholesterol (TC), homocysteine (HCY), uric acid (UA), and glomerular filtration rate (GFR). The ROC analysis showed that urine KYN optimal cutoff value of 751.88 pg/ml had a sensitivity of 65.9% and a specificity of 90.2% for distinguishing between PD and controls, with an area under the curve (AUC) of 0.776. CONCLUSION: Urine KYN were significantly associated with PD severity and mild cognitive impairment. Urine KYN may be a new biomarker for early-stage PD.

Corrigendum to "A Hypothesis: Hydrogen Sulfide Might Be Neuroprotective against Subarachnoid Hemorrhage Induced Brain Injury".

[This corrects the article DOI: 10.1155/2014/432318.].

The Vulnerability of Vessels Involved in the Role of Embolism and Hypoperfusion in the Mechanisms of Ischemic Cerebrovascular Diseases.

Accurate definition and better understanding of the mechanisms of stroke are crucial as this will guide the effective care and therapy. In this paper, we review the previous basic and clinical researches on the causes or mechanisms of ischemic cerebrovascular diseases (ICVD) and interpret the correlation between embolism and hypoperfusion based on vascular stenosis and arterial intimal lesions. It was suggested that if there is no embolus (dynamic or in situ emboli), there might be no cerebral infarction. Three kinds of different clinical outcomes of TIA were theoretically interpreted based on its mechanisms. We suppose that there is a correlation between embolism and hypoperfusion, and which mechanisms (hypoperfusion or hypoperfusion induced microemboli) playing the dominant role in each type of ICVD depends on the unique background of arterial intimal lesions (the vulnerability of vessels). That is to say, the vulnerability of vessels is involved in the role of embolism and hypoperfusion in the mechanisms of ischemic cerebrovascular diseases. This inference might enrich and provide better understandings for the underlying etiologies of ischemic cerebrovascular events.

The Infarct Shape Predicts Progressive Motor Deficits in Patients with Acute Lacunae-sized Infarctions in the Perforating Arterial Territory.

OBJECTIVE: This study was performed to analyze the lesion patterns of lacunae-sized infarctions on diffusion-weighted imaging (DWI) findings in the perforating arterial territory, and to determine whether this pattern of satellite lesions affected progressive motor defect (PMD). METHODS: Seventy-five patients with acute lacunae-sized infarctions in the perforating arterial territory (pons or territory of the lenticulostriate arteries), which was confirmed by cranial magnetic resonance image (MRI), were enrolled in this study. These patients were divided into PMD (n=30) and non-progressive motor defect (NPMD) (n=45) groups according to the dynamic scores of the National Institutes of Health Stroke Scale (NIHSS) within 7 days after stroke. The lesion patterns of lacunae-sized infarctions were divided into single oval or satellite lesions signs based on DWI. The risk factors of stroke and the clinical characteristics of all the subjects, including neurological deficits, infarction lesion patterns in image, and the condition of the basilar artery, were comparatively analyzed. RESULTS: The constituent ratio of satellite lesions signs [20/30 (66.7%)] in the PMD group was higher than that [10/45 (22.2%)] of the NPMD group (χ(2)= 6.1, p=0.013). Mean NIHSS scores in the PMD group on admission were higher than that of the NPMD group (4.60±1.40 vs. 3.75±1.2, t=2.81, p=0.003). A logistic regression analysis showed that the pattern of satellite lesions was associated with PMD. 〔odds ratio (OR): 3.0, 95% confidence interval (CI) 1.25-7.17, p=0.014〕. CONCLUSION: Satellite lesions are one of the features of lacunae-sized infarctions patterns, which might be an independent predictor in DWI findings for PMD in patients with lacunae-sized infarctions in the perforating arterial territory.

A hypothesis: hydrogen sulfide might be neuroprotective against subarachnoid hemorrhage induced brain injury.

Gases such as nitric oxide (NO) and carbon monoxide (CO) play important roles both in normal physiology and in disease. Recent studies have shown that hydrogen sulfide (H2S) protects neurons against oxidative stress and ischemia-reperfusion injury and attenuates lipopolysaccharides (LPS) induced neuroinflammation in microglia, exhibiting anti-inflammatory and antiapoptotic activities. The gas H2S is emerging as a novel regulator of important physiologic functions such as arterial diameter, blood flow, and leukocyte adhesion. It has been known that multiple factors, including oxidative stress, free radicals, and neuronal nitric oxide synthesis as well as abnormal inflammatory responses, are involved in the mechanism underlying the brain injury after subarachnoid hemorrhage (SAH). Based on the multiple physiologic functions of H2S, we speculate that it might be a promising, effective, and specific therapy for brain injury after SAH.

Giant aneurysm of the basilar artery in an 86 year old woman.

In this article we present an 80 year old female patient with an unruptured giant aneurysm of the basilar artery presenting with posterior circulation ischemic symptoms. Angiography and CT revealed giant basilar aneurysmal dilatation with severe and wide intracranial arteriosclerosis. We described the uniqueness of this case. Giant basilar aneurysm is associated with various complications particularly brain stem infarction. It is emphasized that arteriosclerosis plays an important role in the formation of giant basilar aneurysms.

Association between Interleukin-1 gene single nucleotide polymorphisms and ischemic stroke classified by TOAST criteria in the Han population of northern China.

Increasing evidence suggests that IL-1 ß (C-511T) and IL-1 α (C-889T) genes polymorphisms are associated with the susceptibility to cardiocerebral vascular disease. In this paper, we investigated the relationships between these polymorphisms and the risk of ischemic stroke (IS) classified by TOAST criteria in the north Chinese Han population. 440 cases of IS and 486 age- and gender-matched controls of Chinese Han population were enrolled. Association study showed that the TT genotype and T allele of IL-1 α -889 C/T were significantly associated with IS of a large artery atherosclerosis (LAA) (TT: OR = 2.01, 95% CI = 1.34-3.0, and P < 0.001; T: OR = 1.44, 95% CI = 1.18-1.78, and P = 0.001). However, there was no significant difference in the distribution of IL-1 α -889 C/T genotypes and allele frequencies between the two subgroups (small-artery occlusion (SVD) and cardioembolism (CE)) of IS and control groups. No significant association was also found between the IL-1 ß -511 TT genotype and T allele (TT: OR = 0.79, 95% CI = 0.56-1.11, and P = 0.175; T: OR = 0.83, 95% CI = 0.68-1.01, and P = 0.066) and IS as well as subgroups of CE and SVD. Our results implicated that IL-1 α -889 C/T gene polymorphism might be associated with the susceptibility to IS, especially to IS with LAA, in a north Chinese Han population.

Hydrogen sulfide as an effective and specific novel therapy for acute carbon monoxide poisoning.

Hydrogen sulfide (H(2)S) has been recognized as a toxic gas and environment pollutant. So, it is seldom regarded as a therapeutic gas. H(2)S has been recognized recently as a novel gaseous messenger and serves as an important neuromodulator in the central nervous system. Many researches have been focused on the protective role of H(2)S in treatment of several diseases. Like nitric oxide (NO) and carbon monoxide (CO), which are considered as two gaseous transmitters, H(2)S has been regarded as the third one. Recent studies provided evidence that H(2)S exerted antioxidant and anti-apoptotic effects, which protected neurons, cardiomyocytes, pancreatic ß-cells and vascular smooth muscle cells against oxidative stress by scavenging reactive oxygen species (ROS) and reactive nitrogen species (RNS). It has been known that multiple factors, including oxidative stress, free radicals and neuronal nitric oxide syntheses as well as abnormal inflammatory responses are involved in the mechanism underlying the brain injury after acute CO poisoning. Studies have shown that free radical scavengers can display neuroprotective properties. Therefore, we hypothesize that H(2)S might be an interesting potential strategy for curing acute CO poisoning.

Lysophosphatidic acid level and the incidence of silent brain infarction in patients with nonvalvular atrial fibrillation.

Lysophosphatidic acid (LPA), which is proposed to play an important role in normal physiological situations such as wound healing, vascular tone, vascular integrity and reproduction, may be involved in the etiology of some diseases such as atherosclerosis, cancer, obesity or myocardial infarction. Abnormal findings, including silent brain infarction (SBI), are frequently observed by magnetic resonance imaging (MRI) in patients with nonvalvular atrial fibrillation (NVAF). However, whether there is a relationship between LPA level and the prevalence of SBI has not been extensively studied. In the present study, the association between them was investigated. 235 patients with NVAF, 116 cases of SBI without NVAF and 120 cases of healthy volunteers (control group), who did not receive any antithrombotic therapy, were enrolled in this study. Plasma LPA levels in the NVAF with SBI group were significantly higher than that in the control group (p < 0.01), NVAF without SBI group (p < 0.01) and SBI without NVAF group (p < 0.01). The LPA levels are lower in the control group than in the NVAF without SBI and SBI without NVAF groups (p < 0.01), however, the latter two groups did not significantly differ from each other for LPA levels (p > 0.05) There were significant differences in the positive rate of platelet activation between each of the groups (p < 0.01). The positive rate of platelet activation was significantly higher in the NVAF with SBI group. We suggest that LPA might be a novel marker for estimation of the status of platelet activation and the risk factor for SBI onset in NVAF patients. We expected that plasma LPA levels could predict the occurrence of SBI in NVAF patients.

Acupuncture inhibits oxidative stress and rotational behavior in 6-hydroxydopamine lesioned rat.

Increasing evidence suggests the beneficial effects of acupuncture on Parkinson's disease (PD). Although clinical evidence for the acupuncture anti-Parkinson's disease effect has been demonstrated, the precise mechanism still remains elusive. It has been suggested a relationship between PD and reactive oxygen species (ROS) can result in neurodegeneration. The aim of this study was to evaluate the status of oxidative stress, as well as the antioxidant enzyme response, and the role of acupuncture stimulation at GB34 (Yanglingquan), LR3 (Taichong), ST36 (Zusanli) and SP10 (Xuehai) acupoints on regulating oxidative stress in the nigrostriatal system in the 6-hydroxydopamine (6-OHDA) lesioned rat. Two weeks after unilateral injection of 6-OHDA into the left medial forebrain bundle (MFB), an apomorphine induced rotational behavior test was performed. The levels of enzymatic, viz., superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and nonenzymatic, viz., reduced glutathione (GSH), and the levels of malondialdehyde (MDA) in the nigrostriatal system were measured to assess the oxidative stress status. Brain MDA levels significantly increased, while GSH levels were decreased in impaired groups with 6-OHDA injection only, accompanied by a marked reduction in the level of SOD and GSH-Px. The levels of oxidative stress related parameters except CAT, as well as the rotational asymmetry, were reversed by acupuncture stimulation. These results showed that acupuncture treatment displayed antioxidative and/or neuroprotective properties in the 6-OHDA lesioned rat and these protective properties might be mediated, at least in part, by involving regulation of the antioxidant defense system.