Estrogen deficiency is associated with increased incidence of cardiovascular diseases. But merely estrogen supplementary treatment can induce many severe complications such as breast cancer. The present study was designed to elucidate molecular mechanisms underlying increased susceptibility of arrhythmogenesis during myocardial infarction with estrogen deprivation, which provides us a new target to cure cardiac disease accompanied with estrogen deprivation. We successfully established a rat model of myocardial ischemia (MI) accompanied with estrogen deprivation by coronary artery ligation and ovariectomy (OVX). Vulnerability and mortality of ventricular arrhythmias increased in estrogen deficiency rats compared to non estrogen deficiency rats when suffered MI, which was associated with down-regulation of microRNA-151-5p (miR-151-5p). Luciferase Reporter Assay demonstrated that miR-151-5p can bind to the 3′-UTR of FXYD1 (coding gene of phospholemman, PLM) and inhibit its expression. We found that the expression of PLM was increased in (OVX+MI) group compared with MI group. More changes such as down-regulation of Kir2.1/IK1, calcium overload had emerged in (OVX+MI) group compared to MI group merely. Transfection of miR-151-5p into primary cultured myocytes decreased PLM levels and [Ca2+]i, however, increased Kir2.1 levels. These effects were abolished by the antisense oligonucleotides against miR-151-5p. Co-immunoprecipitation and immunofluorescent experiments confirmed the co-localization between Kir2.1 and PLM in rat ventricular tissue. We conclude that the increased ventricular arrhythmias vulnerability in response to acute myocardial ischemia in rat is critically dependent upon down-regulation of miR-151-5p. These findings support the proposal that miR-151-5p could be a potential therapeutic target for the prevention of ischemic arrhythmias in the subjects with estrogen deficiency.
The increasing prevalence of metabolic syndrome (MS) poses a serious public health problem worldwide. Effective prevention and intervention require improved understanding of the factors that contribute to MS. We analyzed data on a large twin cohort to estimate genetic and environmental contributions to MS and to major MS components and their inter-correlations: waist circumference, systolic and diastolic blood pressure, fasting plasma glucose, triglycerides, and high density lipoprotein cholesterol. We applied structural equation modeling to determine genetic and environmental structure of MS and its major components, using 1,617 adult female twin pairs recruited from rural China. The heritability estimate for MS was 0.42 (95% CI: 0.00–0.83) in this sample with low MS prevalence (4.4%). For MS components, heritability estimates were statistically significant and ranged from 0.13 to 0.64 highest for WC, followed by TG, SBP, DBP, HDL-C, and FPG. HDL-C was mainly influenced by common environmental factors (0.62, 95%CI: 0.58–0.62), while the other five MS components were largely influenced by unique environmental factors (0.32–0.44). Bivariate Cholesky decomposition analysis indicated that the clinical clustering of MS components may be explained by shared genetic and/or environmental factors. Our study underscores the importance of examining MS components as inter-correlated traits, and to carefully consider environmental and genetic factors in studying MS etiology.
metabolic syndrome; twin study; heritability; Chinese
Vitamin nutritional status may influence some xenobiotic metabolism or vice versa.
This analysis examines the relationship between B-vitamin concentrations and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDT) isomers and metabolites in healthy women. Serum pp′DDT, pp′DDE, pp′DDD, op′DDT, op′DDE, and serum folate, cysteine, and vitamins B6 and B12 were measured in 296 nonsmoking female textile workers (21–34 yr) in Anhui, China. Mean (SD) age and body mass index of this cohort were 24.9 (1.5) y and 19.7 (2.0) kg/m2, respectively.
Median pp′DDT, pp′DDE, pp′DDD, op′DDT, and op′DDE were 1.5, 29.2, 0.22, 0.17, and 0.09 ng/g, respectively. Median folate and cysteine were 9.2 and 200.0 nmol/L, respectively. Folate was significantly inversely associated with pp′DDT and pp′DDE: β (95% confidence interval [CI]) = −0.23 (−0.39, −0.07) and −0.20 (−0.36, −0.05), respectively, and it was marginally associated with pp′DDD. Cysteine was significantly inversely associated with pp′DDT, β (95% CI) = −0.69 (−1.00, −0.37); pp′DDE, β (95% CI) = −0.32 (−0.62, −0.02); pp′DDD, β (95% CI) = −0.31 (−0.59, −0.03); and op′DDT, β (95% CI) = −0.35 (−0.68, −0.02).
Folate and cysteine are independently inversely associated with DDT isomers, adjusting for vitamins B6 and B12, age, and body mass index. These nutrients may play a role in DDT metabolism; however, it is also possible that DDT may exert a negative impact on folate and cysteine levels. Longitudinal studies are needed to ascertain the direction of this association.
DDT isomers/metabolites; folate; cysteine; vitamin B6; vitamin B12
Deafness is a heterogeneous trait with many known genetic and environmental causes. Hereditary hearing loss is an extremely common disorder in the general population. Mutations in mitochondrial DNA (mtDNA) are known to be associated with nonsyndromic deafness (NSD) and syndromic deafness. The objective of this article is to investigate the frequency of common mitochondrial mutations (A1555G, G7444A, and A3243G) in an ethnically diverse cohort of probands with NSD from South Florida. These patients were ascertained at the University of Miami. Polymerase chain reaction–restriction fragment length polymorphism analysis and direct sequencing methods were used for mutation screening in a cohort of 217 patients with NSD. The frequency of common mitochondrial mutations is 1.84% (4/217) in this cohort. A1555G and G7444A accounted for four patients with NSD. Our mutation frequencies are comparable with those previously reported in other populations, indicating that mutations in mtDNA are an important cause of NSD in our patient cohort.
There are limited data about the role of gender on the relationship between sleep duration and blood pressure (BP) from rural populations.
We conducted a cross-sectional rural population-based study. This report includes 1,033 men and 783 women aged 18–65 years from a cohort of twins enrolled in Anhui, China, between 2005 and 2008. Sleep duration was derived from typical bedtime, wake-up time, and sleep latency as reported on a standard sleep questionnaire. Primary outcomes included measured systolic blood pressure (SBP) and diastolic blood pressure (DBP). High blood pressure (HBP) was defined as SBP≥130 mmHg, DBP ≥85 mmHg, or physician diagnosed hypertension. Linear and logistic regression models were used to assess gender-specific associations between sleep duration and BP or HBP, respectively, with adjustment for known risk factors including adiposity and sleep-related disorder risk from the questionnaires. Generalized estimating equations were used to account for intra-twin pair correlations.
Compared with those sleeping 7 to less than 9 hours, women sleeping <7 hours had a higher risk of HBP (odds ratios [ORs] 3.0, 95% confidence interval [CI], 1.4–6.6); men sleeping ≥9 hours had a higher risk of HBP (ORs=1.5, 95%CI: 1.1–2.2).
Among rural Chinese adults, a gender-specific association of sleep duration with BP exists such that HBP is associated with short sleep duration in women and long sleep duration in men. Longitudinal studies are needed to further examine the temporal relationship and biological mechanisms underlying sleep duration and BP in this population. Our findings underscore the potential importance of appropriate sleep duration for optimal blood pressure.
sleep duration; high blood pressure; gender difference; rural Chinese
To explore the effects and potential mechanisms of curcumin on retinal Müller cell in early diabetic rats.
Diabetic rats were induced by a single intraperitoneal injection of streptozotocin (STZ). Male Sprague-Dawley (SD) rats were randomly assigned into 4 groups: control group (naïve SD rats administered with a single intraperitoneal injection of citric buffer), diabetic group (STZ-diabetic rats), dimethyl sulfoxide (DMSO) group (diabetic rats intraperitoneally administered with mixture of DMSO and normal saline, once a day) and curcumin group (diabetic rats intraperitoneally administered with curcumin, 80mg/kg, once a day). Three months after diabetes onset, malondialdehyde (MDA, indication of oxidative stress level) and reduced glutathione (GSH) in retina were detected with kits, glial fibrillary acidic protein (GFAP) in retina was revealed by immunohistochemistry and Western blot, and retinal glutamine synthetase (GS) were observed by Western blot.
Compared with control group, retinal MDA was increased, and GSH was decreased in diabetic and DMSO groups (P<0.05, respectively). While, retinal MDA and GSH in curcumin group showed no difference compared with control group (P>0.05). Furthermore, up-regulation of retinal GFAP and down-regulation of retinal GS were detected in diabetic and DMSO groups, and no alteration could be observed in curcumin group revealed with Western blot. Compared with control group, retinal Müller cells showed significant increase in GFAP immunochemistry staining in diabetic and DMSO groups. Moreover, GFAP-positive staining was decreased in curcumin group compared with diabetic group.
Curcumin inhibits diabetic retinal oxidative stress, protects Müller cell, and prevents the down-regulation of GS in diabetic retina. Therefore, curcumin has a therapeutic potential in the treatment of diabetic retinopathy (DR).
diabetic retinopathy; curcumin; oxidative stress; Müller cell
A glycosylated polypeptide, β-defensin 126 (DEFB126), derived from the epididymis and adsorbed onto the sperm surface, has been implicated in immunoprotection and efficient movement of sperm in mucosal fluids of the female reproductive tract. Here, we report a sequence variant in DEFB126 that has a 2-nucleotide deletion in the open reading frame, which generates a non-stop mRNA. The allele frequency of this variant sequence is high in both a European (0.47) and a Chinese (0.45) population cohort. Binding of the Agaricus bisporus lectin to the sperm surface glycocalyx was significantly lower in men with the homozygous variant (del/del) genotype than in those with either a del/wt or wt/wt genotype, suggesting an altered sperm glycocalyx with fewer O-linked oligosaccharides in del/del men. Moreover, sperm from the del/del donors exhibited an 84% reduction in the rate of penetration of a hyaluronic acid (HA) gel, a surrogate for cervical mucus, compared to the other genotypes. This reduction in sperm performance in HA gels was not a result of decreased progressive motility (average curvilinear velocity) or morphological deficits. However, DEFB126 genotype and lectin binding were highly correlated with performance in the penetration assays. In a prospective cohort study of newly married couples who were trying to conceive by natural means, couples were less likely to become pregnant and took longer to achieve a live birth if the male partner was homozygous for the variant sequence. This common sequence variation in DEFB126, and its apparent cause of impaired reproductive function, provides an opportunity to better understand, clinically evaluate, and possibly treat human infertility.
Abscisic acid (ABA) is the most important hormone for plants to resist drought and other abiotic stresses. ABA binds directly to the PYR/PYL family of ABA receptors, resulting in inhibition of type 2C phosphatases (PP2C) and activation of downstream ABA signaling. It is envisioned that intervention of ABA signaling by small molecules could help plants to overcome abiotic stresses such as drought, cold and soil salinity. However, chemical instability and rapid catabolism by plant enzymes limit the practical application of ABA itself. Here we report the identification of a small molecule ABA mimic (AM1) that acts as a potent activator of multiple members of the family of ABA receptors. In Arabidopsis, AM1 activates a gene network that is highly similar to that induced by ABA. Treatments with AM1 inhibit seed germination, prevent leaf water loss, and promote drought resistance. We solved the crystal structure of AM1 in complex with the PYL2 ABA receptor and the HAB1 PP2C, which revealed that AM1 mediates a gate-latch-lock interacting network, a structural feature that is conserved in the ABA-bound receptor/PP2C complex. Together, these results demonstrate that a single small molecule ABA mimic can activate multiple ABA receptors and protect plants from water loss and drought stress. Moreover, the AM1 complex crystal structure provides a structural basis for designing the next generation of ABA-mimicking small molecules.
abscisic acid; plant hormone; drought resistance; crystal structure; ABA-mimicking ligand
To investigate the effect of obstructive sleep apnea and continuous positive airway pressure treatment on serum butyrylcholinesterase activity and ischemia-modified albumin levels.
Thirty-two patients with obstructive sleep apnea and 30 age- and sex-matched controls were enrolled and underwent a diagnostic polysomnogram. The serum butyrylcholinesterase activity, ischemia-modified albumin levels, metabolic parameters, and polysomnography scores were detected and evaluated. Nine patients were studied before and after treatment with continuous positive airway pressure.
The serum ischemia-modified albumin levels were significantly higher and the butyrylcholinesterase activity was significantly lower in patients with obstructive sleep apnea than in the controls (p<0.001). The continuous positive airway pressure treatment decreased the modified albumin levels and elevated the buthrylcholinesterase activity (p = 0.019 and p = 0.023, respectively). The modified albumin levels were positively correlated with the apnea-hypopnea index (r = 0.462, p = 0.008) at baseline. Elevated ischemia-modified albumin levels can be more accurate than butyrylcholinesterase activity at reflecting the presence of obstructive sleep apnea. Receiver operating characteristic curves revealed a significant difference between the areas under the curve 0.916 for ischemia-modified albumin and 0.777 for butyrylcholinesterase (z = 2.154, p = 0.031).
The elevated ischemia-modified albumin level was significantly associated with obstructive sleep apnea and was more sensitive than butyrylcholinesterase activity in reflecting obstructive sleep apnea. The continuous positive airway pressure treatment helped to ameliorate the imbalance.
Ischemia-Modified Albumin; Butyrylcholinesterase; Obstructive Sleep Apnea; Biomarker
MicroRNAs are a class of non-coding RNAs that function as key regulators of gene expression at the post-transcriptional level. In our previous research, we found that miR-23a was significantly up-regulated in human gastric adenocarcinoma cells. In the current study, we demonstrate that miR-23a suppresses paclitaxel-induced apoptosis and promotes the cell proliferation and colony formation ability of gastric adenocarcinoma cells. We have identified tumor suppressor interferon regulator factor 1 (IRF1) as a direct target gene of miR-23a. We performed a fluorescent reporter assay to confirm that miR-23a bound to the IRF1 mRNA 3′UTR directly and specifically. The ectopic expression of IRF1 markedly promoted paclitaxel-induced apoptosis and inhibited cell viability and colony formation ability, whereas the knockdown of IRF1 had the opposite effects. The restoration of IRF1 expression counteracted the effects of miR-23a on the paclitaxel-induced apoptosis and cell proliferation of gastric adenocarcinoma cells. Quantitative real-time PCR showed that miR-23a is frequently up-regulated in gastric adenocarcinoma tissues, whereas IRF1 is down-regulated in cancer tissues. Altogether, these results indicate that miR-23a suppresses paclitaxel-induced apoptosis and promotes cell viability and the colony formation ability of gastric adenocarcinoma cells by targeting IRF1 at the post-transcriptional level.
Cadmium (Cd) is an extremely toxic metal, capable of severely damaging several organs, including the brain. Studies have shown that Cd disrupts intracellular free calcium ([Ca2+]i) homeostasis, leading to apoptosis in a variety of cells including primary murine neurons. Calcium is a ubiquitous intracellular ion which acts as a signaling mediator in numerous cellular processes including cell proliferation, differentiation, and survival/death. However, little is known about the role of calcium signaling in Cd-induced apoptosis in neuronal cells. Thus we investigated the role of calcium signaling in Cd-induced apoptosis in primary rat cerebral cortical neurons. Consistent with known toxic properties of Cd, exposure of cerebral cortical neurons to Cd caused morphological changes indicative of apoptosis and cell death. It also induced elevation of [Ca2+]i and inhibition of Na+/K+-ATPase and Ca2+/Mg2+-ATPase activities. This Cd-induced elevation of [Ca2+]i was suppressed by an IP3R inhibitor, 2-APB, suggesting that ER-regulated Ca2+ is involved. In addition, we observed elevation of reactive oxygen species (ROS) levels, dysfunction of cytochrome oxidase subunits (COX-I/II/III), depletion of mitochondrial membrane potential (ΔΨm), and cleavage of caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP) during Cd exposure. Z-VAD-fmk, a pan caspase inhibitor, partially prevented Cd-induced apoptosis and cell death. Interestingly, apoptosis, cell death and these cellular events induced by Cd were blocked by BAPTA-AM, a specific intracellular Ca2+ chelator. Furthermore, western blot analysis revealed an up-regulated expression of Bcl-2 and down-regulated expression of Bax. However, these were not blocked by BAPTA-AM. Thus Cd toxicity is in part due to its disruption of intracellular Ca2+ homeostasis, by compromising ATPases activities and ER-regulated Ca2+, and this elevation in Ca2+ triggers the activation of the Ca2+-mitochondria apoptotic signaling pathway. This study clarifies the signaling events underlying Cd neurotoxicity, and suggests that regulation of Cd-disrupted [Ca2+]i homeostasis may be a new strategy for prevention of Cd-induced neurodegenerative diseases.
Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1−/− B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and -deficient mice. The TRPV1+ neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1-dependent neuropeptides such as substance P. In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy.
Cytomegalovirus (CMV) gene expression is repressed in latency due to heterochromatinization of viral genomes. In murine CMV (MCMV) latently infected mice, viral genomes are bound to histones with heterochromatic modifications, to enzymes that mediate these modifications, and to adaptor proteins that may recruit co-repressor complexes. Kinetic analyses of repressor binding show that these repressors are recruited at the earliest time of infection, suggesting that latency may be the default state. Kidney transplantation leads to epigenetic reprogramming of latent viral chromatin and reactivation of immediate early gene expression. Inflammatory signaling pathways, which activate transcription factors that regulate the major immediate early promoter (MIEP), likely mediate the switch in viral chromatin.
cytomegalovirus; latency; reactivation; epigenetics; chromatin; intrinsic immunity; transplantation
In the title compound, C13H13NO3, the isoxazole ring is approximately coplanar with the phenyl ring, the dihedral angle between their planes being 7.37 (19)°. In the crystal, centrosymmetrically related molecules are linked into dimers by pairs of C—H⋯O hydrogen bonds, generating a ring of graph-set motif R
Calcium-sensing receptor (CaSR) belongs to the family C of G-protein coupled receptors. We have previously demonstrated that CaSR could induce apoptosis of cultured neonatal rat ventricular cardiomyocytes in simulated ischemia/reperfusion. It remains unknown whether the CaSR has function in lipopolysaccharide (LPS)-induced myocardial injure. The aim of this study was to investigate whether the CaSR plays a role in LPS-induced myocardial injury. Cultured neonatal rat cardiomyocytes were treated with LPS, with or without pretreatment with the CaSR-specific agonist gadolinium chloride (GdCl3) or the CaSR-specific antagonist NPS2390. Release of TNF-α and IL-6 from cardiomyocytes was observed. Levels of malonaldehyde (MDA), lactate dehydrogenase (LDH), and activity of superoxide dismutase (SOD) were measured. In addition, apoptosis of the cardiomyocytes, [Ca2+]i and level of CaSR expression were determined. The results showed that LPS increased cardiomyocytes apoptosis, [Ca2+]i, MDA, LDH, TNF-α, IL-6 release, and CaSR protein expression. Compared with LPS treatment alone, pretreatment with GdCl3 further increased apoptosis of cardiomyocytes, MDA, LDH, TNF-α, IL-6 release, [Ca2+]i, and the expression of the CaSR protein. Conversely, pretreatment with NPS2390 decreased apoptosis of cardiomyocytes, MDA, LDH, TNF-α, IL-6 release, [Ca2+]i and the expression of the CaSR protein. These results demonstrate that LPS could induce cardiomyocyte injury. Moreover, LPS-induced cardiomyocyte injury was related to CaSR-mediated cardiomyocytes apoptosis, TNF-α, IL-6 release, and increase of intracellular calcium.
Calcium-sensing receptor; Cardiomyocyte; Lipopolysaccharide; TNF-α; IL-6; Apoptosis
Chronic pain hypersensitivity depends upon N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects from suppressing physiological functions of these receptors. Here we report a means to suppress pain hypersensitivity without blocking NMDARs but rather by inhibiting the binding of a key enhancer of NMDAR function, the protein tyrosine kinase Src. We show that a peptide consisting of amino acids 40-49 of Src fused to the protein transduction domain of the HIV Tat protein (Src40-49Tat) prevented pain behaviors induced by intraplantar formalin and reversed pain hypersensitivity produced by intraplantar injection of complete Freund’s adjuvant or by peripheral nerve injury. Src40-49Tat had no effect on basal sensory thresholds, acute nociceptive responses, or cardiovascular, respiratory, locomotor or cognitive functions. Thus, by targeting Src-mediated enhancement of NMDARs, inflammatory and neuropathic pain are suppressed without deleterious consequences of directly blocking NMDARs, an approach that may be of broad relevance to managing chronic pain.
PMID: 19011637 CAMSID: cams2737
Insulin resistance (IR) links Alzheimer’s disease (AD) with oxidative damage, cholinergic deficit, and cognitive impairment. Peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone previously used to treat type 2 diabetes mellitus (T2DM) has also been demonstrated to be effective in anti-inflammatory reaction and anti-oxidative stress in the animal models of AD and other neuroinflammatory diseases. Here, we investigated the effect of pioglitazone on learning and memory impairment and the molecular events that may cause it in fructose-drinking insulin resistance rats. We found that long-term fructose-drinking causes insulin resistance, oxidative stress, down-regulated activity of cholinergic system, and cognitive deficit, which could be ameliorated by pioglitazone administration. The results from the present study provide experimental evidence for using pioglitazone in the treatment of brain damage caused by insulin resistance.
Protein tyrosine kinase 6 (PTK6), also known as breast tumor kinase (Brk), was a nonreceptor tyrosine kinase containing SH3, SH2, and tyrosine kinase catalytic domains. The deregulated expression of PTK6 was observed in various human cancers. However, little was known about PTK6 expression and its clinicopathological significance in human laryngeal squamous cell carcinoma (LSCC).
PTK6 expression was evaluated in 7 pairs of surgically resectable laryngeal tissues by Western blotting and in 13 pairs of surgically resectable laryngeal tissues by reverse transcription-PCR (RT-PCR). Using immunohistochemistry, we performed a retrospective study of the PTK6 expression levels on 134 archival LSCC paraffin-embedded samples. Prognostic outcomes correlated with PTK6 were examined using Kaplan–Meier analysis and Cox proportional hazards model.
The PTK6 expression level was lower in LSCC tissues than in the adjacent noncancerous epithelial laryngeal tissues by Western blots and RT-PCR. By immunohistochemical analysis, we observed high expression of PTK6 in 25 of 76 (32.9%) adjacent noncancerous epithelial laryngeal tissues and in 39 of 134 (29.1%) of LSCC, respectively. Multivariate analysis demonstrated that pN status and the expression level of PTK6 (P < 0.05) were independent and significant prognostic factors. In the primary LSCC category, median DFS (disease free survival) of high, medium and low PTK6 expression patients were 88.5 months ,74.5 months and 49.0 months (log-rank test, P = 0.002); median OS (overall survival) of high, medium and low PTK6 expression patients were 88.5 months ,76.3 months and 65.7 months (log-rank test, P = 0.002). Reduced cytoplasmic PTK6 expression in LSCC was significantly associated with late pN status (P =0.005, r = 0.27), advanced pTNM stages (III and IV) (P =0.027, r = 0.147), and poor differentiated LSCC (P <0.0001, r = 0.486). In adjacent paracancerous laryngeal epithelial samples, median DFS of high, medium and low PTK6 expression patients were 92.6 months ,75.6 months and 48.5 months (log-rank test, P = 0.020); median OS of high, medium and low PTK6 expression patients were 92.9 months ,78.9 months and 74.6 months (log-rank test, P = 0.042).
The present findings indicated that cytoplasmic PTK6 expression is a potential prognostic factor for survival in LSCC patients. High expression of PTK6 was associated with favorable OS and DFS in LSCC patients.
PTK6/Brk; Laryngeal squamous cell carcinoma; Prognosis
Glutamate is the major excitatory neurotransmitter in the central nervous system. Considerable evidence suggests that both ionotropic and metabotropic glutamate receptors are involved in pain hypersensitivity. However, glutamate receptor-based therapies are limited by side effects because the activities of glutamate receptors are essential for many important physiological functions. Here, we highlight recent key findings in molecular and cellular mechanisms of glutamate receptor regulation and their roles in triggering and sustaining pain hypersensitivity. Targeting these molecular mechanisms could form the basis for new therapeutic strategies for the treatment of chronic pain.
PMID: 20629726 CAMSID: cams2732
Silent brain infarctions are the silent cerebrovascular events that are distinguished from symptomatic lacunar infarctions by their ‘silence'; the origin of these infarctions is still unclear. This study analyzed the characteristics of silent and symptomatic lacunar infarctions and sought to explore the mechanism of this ‘silence'.
In total, 156 patients with only silent brain infarctions, 90 with only symptomatic lacunar infarctions, 160 with both silent and symptomatic lacunar infarctions, and 115 without any infarctions were recruited. Vascular risk factors, leukoaraiosis, and vascular assessment results were compared. The National Institutes of Health Stroke Scale scores were compared between patients with only symptomatic lacunar infarctions and patients with two types of infarctions. The locations of all of the infarctions were evaluated. The evolution of the two types of infarctions was retrospectively studied by comparing the infarcts on the magnetic resonance images of 63 patients obtained at different times.
The main risk factors for silent brain infarctions were hypertension, age, and advanced leukoaraiosis; the main factors for symptomatic lacunar infarctions were hypertension, atrial fibrillation, and atherosclerosis of relevant arteries. The neurological deficits of patients with only symptomatic lacunar infarctions were more severe than those of patients with both types of infarctions. More silent brain infarctions were located in the corona radiata and basal ganglia; these locations were different from those of the symptomatic lacunar infarctions. The initial sizes of the symptomatic lacunar infarctions were larger than the silent brain infarctions, whereas the final sizes were almost equal between the two groups.
Chronic ischemic preconditioning and nonstrategic locations may be the main reasons for the ‘silence' of silent brain infarctions.
Silent Brain Infarctions; Symptomatic Lacunar Infarctions; Small Vessel Disease; Leukoaraiosis
Endothelial dysfunction and oxLDL are believed to be early and critical events in atherogenesis. 6-Shogaol is the major bioactive compound present in Zingiber officinale and possesses the anti-atherosclerotic effect. However, the mechanisms remain poorly understood. The goal of this study was to investigate the effects of 6-shogaol on oxLDL-induced Human umbilical vein endothelial cells (HUVECs) injuries and its possible molecular mechanisms. Hence, we studied the effects of 6-shogaol on cell apoptosis, cellular reactive oxygen species (ROS), NF-κB activation, Bcl-2 expression, and caspase -3, -8, -9 activities. In addition, E-selectin, MCP-1, and ICAM-1 were determined by ELISA. Our study show that oxLDL increased LOX-1 expression, ROS levels, NF-κB, caspases-9 and -3 activation and decreased Bcl-2 expression in HUVECs. These alterations were attenuated by 6-shogaol. Cotreatment with 6-shogaol and siRNA of LOX-1 synergistically reduced oxLDL-induced caspases -9, -3 activities and cell apoptosis. Overexpression of LOX-1 attenuated the protection by 6-shogaol and suppressed the effects of 6-shogaol on oxLDL-induced oxidative stress. In addition, oxLDL enhanced the activation of NF-κB and expression of adhesion molecules. Pretreatment with 6-shogaol, however, exerted significant cytoprotective effects in all events. Our data indicate that 6-shogaol might be a potential natural antiapoptotic agent for the treatment of atherosclerosis.
Immunohistochemical studies have revealed that cystatin C (CysC) co-localizes with amyloid-β (Αβ) in amyloid-laden vascular walls and in the senile plaque cores of amyloid. In vitro and in vivo animal studies suggest that CysC protects against neurodegeneration by inhibition of cysteine proteases, inhibition of Αβ aggregation, induction of autophagy and induction of cell division. CysC levels may be altered and may have a potential link with cerebrospinal fluid (CSF) Aβ levels in various types of dementia with characteristic amyloid deposits, such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and the atrophic form of general paresis (AF-GP). We assessed the serum and CSF levels of CysC and the CSF levels of Aβ40 and Aβ42 in patients with AD (n = 51), DLB (n = 26) and AF-GP (n = 43) and normal controls (n = 30). Using these samples, we explored the correlation between CSF CysC and CSF Aβ levels. We found that in comparison to the normal control group, both CSF CysC and CSF Aβ42 levels were significantly lower in all three dementia groups (all p<0.001); serum CysC levels were the same in the AD and DLB groups, and were lower in the AF-GP group (p = 0.008). The CSF CysC levels were positively correlated with both the CSF Aβ40 and Aβ42 levels in the AD, AF-GP and normal control groups (r = 0.306∼0.657, all p<0.05). Lower CSF CysC levels might be a common feature in dementia with characteristic amyloid deposits. Our results provide evidence for the potential role of CysC involvement in Aβ metabolism and suggest that modulation of the CysC level in the brain might produce a disease-modifying effect in dementia with characteristic amyloid deposits.
Background: Hyperhomocysteinemia was believed to be an independent risk factor for stroke and associate with small vessel disease (SVD) related stroke and large vessel disease (LVD) related stroke differently. However it's still unclear which type of stroke associated with homocysteine (HCY) more strongly because the conclusions of previous studies were contradictory. In this study we focused on the subclinical angiopathies of stroke, i.e., SVD and LVD instead of stroke subtypes and sought to compare the associations between HCY level and different angiopathies. Methods: 324 non-stroke patients were enrolled. Sex, age, HCY level and other vascular risk factors were collected. MRI and angiographies were used to determine the type of angiopathies and their severity, i.e., the scores of leukoaraiosis (LA), plaques and numbers of silent brain infarctions (SBI). LVD was defined as the presence of atherosclerotic plaques of cerebral arteries. SVD was defined as the presence of either LA or SBI. 230 patients were deemed to have LVD; 180 patients were deemed to have SVD. Spearman's correlation test and logistic regression were used to analyze the association between HCY level and different angiopathies. Results: The correlation between HCY level and scores of plaques was weaker than that of the scores of LA and numbers of SBI. Hyperhomocysteinemia was an independent risk factor for SVD (OR = 1.315, P <0.001), whereas the association between HCY level and LVD was not that significant (OR = 1.058, P = 0.075). Conclusion: HCY level associated with SVD more strongly than LVD.
Hyperhomocysteinemia; small vessel disease; large vessel disease; homocysteine.
Aconitine is a well-known arrhythmogenic toxin and induces triggered activities through cardiac voltage-gated Na+ channels. However, the effects of aconitine on intracellular Ca2+ signals were previously unknown. We investigated the effects of aconitine on intracellular Ca2+ signals in rat ventricular myocytes and explored the possible mechanism of arrhythmogenic toxicity induced by aconitine. Ca2+ signals were evaluated by measuring L-type Ca2+ currents, caffeine-induced Ca2+ release and the expression of NCX and SERCA2a. Action potential and triggered activities were recorded by whole-cell patch-clamp techniques. In rat ventricular myocytes, the action potential duration was significantly prolonged by 1 µM aconitine. At higher concentrations (5 µM and 10 µM), aconitine induced triggered activities and delayed after-depolarizations (6 of 8 cases), which were inhibited by verapamil. Aconitine (1 µM) significantly increased the ICa-L density from 12.77 ± 3.12 pA/pF to 18.98 ± 3.89 pA/pF (n=10, p<0.01). The activation curve was shifted towards more negative potential, while the inactivation curve was shifted towards more positive potential by 1 μM aconitine. The level of Ca2+ release induced by 10 mM caffeine was markedly increased. Aconitine (1 µM) increased the expression of NCX, while SERCA2a expression was reduced. In conclusion, aconitine increased the cytosolic [Ca2+]i by accelerating ICa-L and changing the expression of NCX and SERCA2a. Then, the elevation of cytosolic [Ca2+]i induced triggered activities and delayed after-depolarizations. Arrhythmogenesis toxicity of aconitine is related to intracellular Ca2+ signals.
Aconitine; arrhythmias; L-type Ca2+ current; caffeine-induced Ca2+ release; NCX; SERCA2a
Background: Leukoaraiosis, microbleeds, and silent brain infarctions are phenotypes of small vessel disease. Leukoaraiosis is the most prevalent, and advanced periventricular leukoaraiosis is regarded as a strong predictor of cognitive dysfunction. Microbleeds and silent brain infarctions sometimes coexist with leukoaraiosis. This study aims to analyze the effects of microbleeds and silent brain infarctions on cognitive function of patients with advanced periventricular leukoaraiosis.
Methods: 227 patients with advanced periventricular leukoaraiosis were divided into control, MB, SBI, and MB&SBI groups. The presence and locations of microbleeds and silent brain infarctions were evaluated. Mini-Mental State Examination, Montreal Cognitive Assessment, Clock Drawing Test and Verbal Fluency Test were performed. Chi-square test and ANOVA to compare the characteristics of four groups, multiple linear regressions to identify the risk factors for cognitive dysfunction.
Results: The scores in all four tests were lower in the MB and MB&SBI groups while only the scores in Clock Drawing Test and Verbal Fluency Test were lower in the SBI group than in the control group. Age and the presence of microbleeds were independent risk factors for the lower scores in all four tests, whereas the presence of silent brain infarctions was the only independent risk factor for the lower scores in Clock Drawing Test and Verbal Fluency Test. Lobar microbleeds had the most significant effect on cognitive function.
Conclusion: Microbleeds and silent brain infarctions were associated differently with cognitive impairment of patients with advanced periventricular leukoaraiosis. The effect of lobar microbleeds was the most significant.
small vessel disease; leukoaraiosis; silent brain infarctions; microbleeds; cognitive dysfunction.