The selectins play important roles in the inflammatory process of coronary artery disease (CAD) and myocardial infarction (MI). Previous studies have shown ambiguous findings regarding a possible association between the selectin genes and CAD. The E-selectin Ser128Arg polymorphism and the P-selectin Thr715Pro polymorphism have been investigated widely but with inconsistent results. We performed a comprehensive meta-analysis to shed light on this issue.
Data were extracted by searches of MEDLINE, Embase, CNKI, Wanfang, Google Scholar, PORTA, GeNii, CiNii, J-STAGE, Nurimedia and Koreanstudies Information Service System [Kiss] up to October 2013, in which 10 studies on the Ser128Arg polymorphism with 3369 cases and 2577 controls and 10 studies on the Thr715Pro polymorphism with 5886 cases and 18345 controls. A random-effects model was used to calculate the combined odds ratios. The between-study heterogeneity and publication bias were addressed.
The 128Arg carriers had a significant increased risk of CAD (allele comparison: P = 0.02, OR = 1.33, 95%CI 1.04–1.69, Pheterogeneity = 0.01); The 715Pro conferred a non-significant risk reduction relative to the 715Thr (allele comparison: P = 0.40, OR = 0.94, 95%CI 0.82–1.08, Pheterogeneity = 0.03).Subgroup analyses demonstrated that the 128Arg carriers had a significant increased risk of CAD among Asians (allele comparison: P = 0.001, OR = 2.07, 95%CI 1.33–3.24, Pheterogeneity = 0.77) but not among Caucasians (allele comparison: P = 0.33, OR = 1.13, 95%CI 0.88–1.45, Pheterogeneity = 0.08). Carrier status for the 715Pro was significantly associated with reduced risk of MI (allele comparison: P = 0.04, OR = 0.81, 95%CI 0.67–0.99, Pheterogeneity = 0.14). The asymmetric funnel plot and the Egger's test (P = 0.041) suggested the presence of publication bias for the Ser128Arg polymorphism.
Our results suggested there is an increase in the risk of CAD conferred by the Ser128Arg polymorphism and the thr715Pro polymorphism may be a protective factor of MI.
Yunnan has been severely affected by HIV/AIDS in China. Recently, the reported prevalence of HIV-1 among men who have sex with men (MSM) in Yunnan was high in China. To monitor dynamic HIV-1 epidemic among Yunnan MSM, HIV-1 genetic characteristics and transmitted drug resistance (TDR) were investigated.
Blood samples from 131 newly HIV-1 diagnosed MSM were continuously collected at fixed sites from January 2010 to December 2012 in Kunming City, Yunnan Province. Partial gag, pol and env genes were sequenced. Phylogenetic, evolutionary and genotypic drug resistance analyses were performed.
Multiple genotypes were identified among MSM in Kunming, including CRF01_AE (64.9%), CRF07_BC (25.2%), unique recombinant forms (URFs, 5.3%), subtype B (3.1%) and CRF08_BC (1.5%). CRF01_AE and CRF07_BC were the predominant strains. The mean of genetic distance within CRF01_AE were larger than that within CRF07_BC. The estimated introducing time of CRF01_AE in Yunnan MSM (1996.9) is earlier than that of CRF07_BC (2002.8). In this study, subtype B was first identified in Yunnan MSM. CRF08_BC seems to be the distinctive strain in Yunnan MSM, which was seldom found among MSM outside Yunnan. The proportion of URFs increased, which further contributed to genetic diversity among MSM. Strikingly, genetic relatedness was found among these strains with MSM isolates from multiple provinces, which suggested that a nationwide transmission network may exist. TDR-associated mutations were identified in 4.6% individuals. The multivariate analysis revealed that non-native MSM and divorced/widowed MSM were independently associated with a higher TDR rate.
This work revealed diverse HIV-1 genetics, national transmission networks and a baseline level of TDR in MSM. These findings enhance our understanding of the distribution and evolution of HIV-1 in MSM, and are valuable for developing HIV prevention strategies for MSM.
Whether diabetes increases the risk of Parkinson's disease (PD) is still inconclusive. The objective of this updated meta-analysis is to synthesize evidence from case-control studies that evaluated the association between diabetes and the risk of PD.
Seven databases were searched to identify case-control studies that evaluated the association between diabetes and PD. The methodological quality of included studies was assessed using Newcastle-Ottawa scale. All data were analyzed using Review Manager 5.1 software. Subgroup analyses were also adopted, according to stratification on gender, geographic location, source of the control group, smoking, anti-diabetes drug prescription and duration of DM.
Fourteen studies fulfilled inclusion criteria for meta-analysis, yielding a total of 21395 PD patients and 84579 control subjects. Individuals with diabetes were found to have a negative association with future PD (OR 0.75; 95% CI 0.58–0.98) in spite of significant heterogeneity. In subgroup analyses, the negative correlation was still found in studies from North America, non-PD control groups from general population, never smoking individuals, and DM ascertainment based on questionnaire or self-report. Stratification of gender and DM duration showed no significant association. No association was also found in European and Asian individuals, hospital-based controls, ever smoking subjects, DM assessment by medical record or physician diagnosis, and insulin prescription for DM.
Evidence from case-control studies suggested that diabetic individuals may have a decreased incidence of PD despite significant heterogeneity. More researches are warranted to clarify an understanding of the association between diabetes and risk of PD.
Aims: Some of the well-known functional alcohol dehydrogenase (ADH) gene variants (e.g. ADH1B*2, ADH1B*3 and ADH1C*2) that significantly affect the risk of alcohol dependence are rare variants in most populations. In the present study, we comprehensively examined the associations between rare ADH variants [minor allele frequency (MAF) <0.05] and alcohol dependence, with several other neuropsychiatric and neurological disorders as reference. Methods: A total of 49,358 subjects in 22 independent cohorts with 11 different neuropsychiatric and neurological disorders were analyzed, including 3 cohorts with alcohol dependence. The entire ADH gene cluster (ADH7–ADH1C–ADH1B–ADH1A–ADH6–ADH4–ADH5 at Chr4) was imputed in all samples using the same reference panels that included whole-genome sequencing data. We stringently cleaned the phenotype and genotype data to obtain a total of 870 single nucleotide polymorphisms with 0< MAF <0.05 for association analysis. Results: We found that a rare variant constellation across the entire ADH gene cluster was significantly associated with alcohol dependence in European-Americans (Fp1: simulated global P = 0.045), European-Australians (Fp5: global P = 0.027; collapsing: P = 0.038) and African-Americans (Fp5: global P = 0.050; collapsing: P = 0.038), but not with any other neuropsychiatric disease. Association signals in this region came principally from ADH6, ADH7, ADH1B and ADH1C. In particular, a rare ADH6 variant constellation showed a replicable association with alcohol dependence across these three independent cohorts. No individual rare variants were statistically significantly associated with any disease examined after group- and region-wide correction for multiple comparisons. Conclusion: We conclude that rare ADH variants are specific for alcohol dependence. The ADH gene cluster may harbor a causal variant(s) for alcohol dependence.
HER2 is an oncogenic tumor-associated antigen overexpressed in 20-25% of breast cancers, which is associated with increased invasion, metastasis of the disease and resistance to therapy. Recent studies have further shown that HER2 can increase the population of breast cancer stem cells (BCSCs). However, there is currently no in vivo model for the study of HER2+ BCSCs. In this study, we characterized a mouse breast cancer model for HER2+ BCSCs. This was accomplished by inoculating mouse mammary tumor EO771 cells engineered with human wild-type HER2 (EO771E2) into C57BL/6 HER2 transgenic mice to test and confirm the stable human HER2 expression in the model. More importantly, we detected a subpopulation of EO771E2 cells with a high activity of aldehyde dehydrogenases (ALDHhigh). We demonstrated that the isolated ALDHhigh EO771E2 cells possessed key properties of BCSCs including enhanced tumorigenicity, generation of heterogeneous tumors and the capacity to self-renewal in vitro. In conclusion, the tumors formed in C57BL/6 HER2 transgenic mice with EO771E2 cell injection revealed stable and functional human HER2 expression. These tumors contain a subset of ALDHhigh cells which are small in number, but are enriched in cancer stem cells. This model is deemed to be useful for experiments aimed to develop novel treatments to target HER2+ BCSCs.
HER2; breast cancer; cancer stem cells; mouse model; antitumor immunity.
During meiotic prophase in males, the sex chromosomes partially synapse to form the XY body. This is a unique structure that recruits proteins involved in the DNA damage response, which is believed to be important for silencing of the sex chromosomes. It remains elusive how the DNA damage response in the XY body is regulated. H2AX-MDC1-RNF8 signaling, which is well characterized in somatic cells, is dispensable for the recruitment of proteins to the unsynapsed axes in the XY body. However, the DNA damage response that spreads over the sex chromosomes is largely similar to that in somatic cells. Here we show that accumulation of some components of the DNA damage response pathway on the XY body occurs upstream of H2AX-MDC1-RNF8 signalling, and downstream from this cascade of events for others. This analysis shows that there are important differences between the regulation of the DNA damage response at the XY body and at DNA damage sites in somatic cells.
This study aimed to identify major proteins in the pathogenesis of coronary artery in-stent restenosis (ISR) in diabetic minipigs with sirolimus-eluting stenting, and to investigate the roles of key candidate molecules, particularly ADAM10, in human arterial smooth muscle cells (HASMCs).
Methods and Results
The stents were implanted in the coronary arteries of 15 diabetic and 26 non-diabetic minipigs, and angiography was repeated at six months. The intima of one vascular segment with significant ISR and one with non-ISR in diabetic minipigs were isolated and cultured in conditioned medium (CM). The CM was analyzed by LC-MS/MS to uncover proteins whose levels were significantly increased (≥1.5-fold) in ISR than in non-ISR tissues. After literature searching, we focused on the identified proteins, whose biological functions were most potentially related to ISR pathophysiology. Among them, ADAM10 was significantly increased in diabetic and non-diabetic ISR tissues as compared with non-ISR controls. In cell experiments, retrovirus-mediated overexpression of ADAM10 promoted growth and migration of HASMCs. The effects of ADAM10 were more remarkable in high-glucose culture than in low-glucose culture. Using shRNA and an inhibitor of γ-secretase (GSI), we found that the influences of ADAM10 were in part mediated by Notch1 and notch 3 pathway, which up-regulated Notch downstream genes and enhanced nuclear translocation of the small intracellular component of Notch1 and Notch3.
This study has identified significantly increased expression of ADAM10 in the ISR versus non-ISR segment in diabetic minipigs and implicates ADAM10 in the enhanced neointimal formation observed in diabetes after vascular injury.
In the present study, we investigated the effects of chronic exposure (14 and 28 days) to a 0.5 mT 50 Hz extremely low-frequency magnetic field (ELM) on the dendritic spine density and shape in the superficial layers of the medial entorhinal cortex (MEC). We performed Golgi staining to reveal the dendritic spines of the principal neurons in rats. The results showed that ELM exposure induced a decrease in the spine density in the dendrites of stellate neurons and the basal dendrites of pyramidal neurons at both 14 days and 28 days, which was largely due to the loss of the thin and branched spines. The alteration in the density of mushroom and stubby spines post ELM exposure was cell-type specific. For the stellate neurons, ELM exposure slightly increased the density of stubby spines at 28 days, while it did not affect the density of mushroom spines at the same time. In the basal dendrites of pyramidal neurons, we observed a significant decrease in the mushroom spine density only at the later time point post ELM exposure, while the stubby spine density was reduced at 14 days and partially restored at 28 days post ELM exposure. ELM exposure-induced reduction in the spine density in the apical dendrites of pyramidal neurons was only observed at 28 days, reflecting the distinct vulnerability of spines in the apical and basal dendrites. Considering the changes in spine number and shape are involved in synaptic plasticity and the MEC is a part of neural network that is closely related to learning and memory, these findings may be helpful for explaining the ELM exposure-induced impairment in cognitive functions.
It has been suggested that drugs combining activities of selective serotonin reuptake inhibitor and 5-HT1A receptor agonist may form a novel strategy for higher therapeutic efficacy of antidepressant. The present study aimed to examine the pharmacology of YL-0919, a novel synthetic compound with combined high affinity and selectivity for serotonin transporter and 5-HT1A receptors. We performed in vitro binding and function assays and in vivo behavioral tests to assess the pharmacological properties and antidepressant-like efficacy of YL-0919. YL-0919 displayed high affinity in vitro to both 5-HT1A receptor and 5-HT transporter prepared from rat cortical tissue. It exerted an inhibitory effect on forskolin-stimulated cAMP formation and potently inhibited 5-HT uptake in both rat cortical synaptosomes and recombinant cells. After acute p.o. administration, very low doses of YL-0919 reduced the immobility time in tail suspension test and forced swimming test in mice and rats, with no significant effect on locomotor activity in open field test. Furthermore, WAY-100635 (a selective 5-HT1A receptor antagonist, 0.3 mg/kg) significantly blocked the effect of YL-0919 in tail suspension test and forced swimming test. In addition, chronic YL-0919 treatment significantly reversed the depressive-like behaviors in chronically stressed rats. These findings suggest that YL-0919, a novel structure compound, exerts dual effect on the serotonergic system, as both 5-HT1A receptor agonist and 5-HT uptake blocker, showing remarkable antidepressant effects in animal models. Therefore, YL-0919 may be used as a new option for the treatment of major depressive disorder.
Nicotine improves performance on several cognitive and sensorimotor tasks. The neuronal mechanisms associated with these changes in performance are, however, largely unknown. Functional magnetic resonance imaging (fMRI) was used to examine the effect of nicotine on neuronal response in nineteen healthy subjects while they performed an auditory-paced finger tapping task. Subjects performed the task, after receiving either a nicotine patch or placebo treatment, in a single blind, crossover design. Compared to placebo, nicotine treatment increased response in the cerebellar vermis. Increased vermal activity, in the absence of changes in other task-related regions suggests specificity in nicotine’s effects.
Mapping and decoding brain activity patterns underlying learning and memory represents both great interest and immense challenge. At present, very little is known regarding many of the very basic questions regarding the neural codes of memory: are fear memories retrieved during the freezing state or non-freezing state of the animals? How do individual memory traces give arise to a holistic, real-time associative memory engram? How are memory codes regulated by synaptic plasticity? Here, by applying high-density electrode arrays and dimensionality-reduction decoding algorithms, we investigate hippocampal CA1 activity patterns of trace fear conditioning memory code in inducible NMDA receptor knockout mice and their control littermates. Our analyses showed that the conditioned tone (CS) and unconditioned foot-shock (US) can evoke hippocampal ensemble responses in control and mutant mice. Yet, temporal formats and contents of CA1 fear memory engrams differ significantly between the genotypes. The mutant mice with disabled NMDA receptor plasticity failed to generate CS-to-US or US-to-CS associative memory traces. Moreover, the mutant CA1 region lacked memory traces for “what at when” information that predicts the timing relationship between the conditioned tone and the foot shock. The degraded associative fear memory engram is further manifested in its lack of intertwined and alternating temporal association between CS and US memory traces that are characteristic to the holistic memory recall in the wild-type animals. Therefore, our study has decoded real-time memory contents, timing relationship between CS and US, and temporal organizing patterns of fear memory engrams and demonstrated how hippocampal memory codes are regulated by NMDA receptor synaptic plasticity.
Deep brain stimulation (DBS) of the nucleus accumbens (NAc) is a potential remedial therapy for drug craving and relapse, but the mechanism is poorly understood. We investigated changes in neurotransmitter levels during high frequency stimulation (HFS) of the unilateral NAc on morphine-induced rats. Sixty adult Wistar rats were randomized into five groups: the control group (administration of saline), the morphine-only group (systematic administration of morphine without electrode implantation), the morphine-sham-stimulation group (systematic administration of morphine with electrode implantation but not given stimulation), the morphine-stimulation group (systematic administration of morphine with electrode implantation and stimulation) and the saline-stimulation group (administration of saline with electrode implantation and stimulation). The stimulation electrode was stereotaxically implanted into the core of unilateral NAc and microdialysis probes were unilaterally lowered into the ipsilateral ventral tegmental area (VTA), NAc, and ventral pallidum (VP). Samples from microdialysis probes in the ipsilateral VTA, NAc, and VP were analyzed for glutamate (Glu) and γ-aminobutyric acid (GABA) by high-performance liquid chromatography (HPLC). The levels of Glu were increased in the ipsilateral NAc and VP of morphine-only group versus control group, whereas Glu levels were not significantly changed in the ipsilateral VTA. Furthermore, the levels of GABA decreased significantly in the ipsilateral NAc, VP, and VTA of morphine-only group when compared with control group. The profiles of increased Glu and reduced GABA in morphine-induced rats suggest that the presence of increased excitatory neurotransmission in these brain regions. The concentrations of the Glu significantly decreased while the levels of GABA increased in ipsilateral VTA, NAc, and VP in the morphine-stimulation group compared with the morphine-only group. No significant changes were seen in the morphine-sham stimulation group compared with the morphine-only group. These findings indicated that unilateral NAc stimulation inhibits the morphine-induced rats associated hyperactivation of excitatory neurotransmission in the mesocorticolimbic reward circuit.
Depression is one of the most common and debilitating psychiatric illnesses around the world, but the current antidepressants used to treat depression have many limitations. Progressively more studies have shown that neuropeptide systems are potential novel therapeutic targets for depression. However, whether the neuropeptide trefoil factor 3 (TFF3) participates in the development of depression has not been examined. In the current experiments, we assessed the antidepressant effects of TFF3 using the forced swim test (FST), tail suspension test (TST), and chronic mild stress (CMS) paradigm. Furthermore, we determined the mechanism that underlies the antidepressant-like effects of TFF3 in the rat FST. TFF3 dose-dependently reduced immobility time in both FST and TST. CMS elevated plasma TFF3 and decreased basolateral amygdala (BLA) TFF3 levels in rats, and acute TFF3 (0.1 mg/kg, i.p.) treatment reversed the depressive-like behaviors induced by CMS. Furthermore, TFF3 (0.1 mg/kg, i.p.) significantly increased Fos expression in the BLA, medial prefrontal cortex, and hypothalamus in rats subjected to the FST. Intra-BLA infusions of TFF3 (1 ng/side) exerted rapid antidepressant-like effects in the rat FST. Additionally, acute systemic TFF3 administration increased the level of phosphorylated-Akt (p-Akt) in the BLA. Finally, intra-BLA infusions of LY294002 (5 mM/side), a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, significantly blocked the antidepressant-like effect of TFF3. Our results demonstrated that TFF3 exerts antidepressant-like effects that might be mediated by the PI3K/Akt signaling pathway in the BLA. These findings suggest a novel neuropeptide system target in the development of new antidepressants.
depression; neuropeptide; trefoil factor 3; basolateral amygdala; phosphatidylinositol 3-kinase; chronic mild stress; animal models; behavioral science; biological psychiatry; chronic stress; depression; unipolar/bipolar; neuropeptide
Diabetic peripheral neuropathy (DPN) is very common in people with diabetes. Chinese herbal medicine (CHM) therapy has been developed for DPN empirically over the years. The aim of this systematic review and meta-analysis was to assess the efficacy and safety of CHMs for patients suffering from DPN.
We performed a meta-analysis of randomized-controlled clinical trials (RCTs) evaluating the efficacy and safety of CHM on DPN. Six databases were searched up to November 2012. The primary outcome measures were the absolute values or changing of motor or sensory nerve conduction velocity (NCV), and the secondary outcome measurements were clinical symptoms improvements and adverse events. The methodological quality was assessed by Jadad scale and the twelve criteria recommended by the Cochrane Back Review Group.
One hundred and sixty-three studies claimed RCTs. Ten studies with 653 individuals were further identified based on the Jadad score ≥3. These 10 studies were all of high methodological quality with a low risk of bias. Meta-analysis showed the effects of NCV favoring CHMs when compared with western conventional medicines (WCM) (P<0.05 or P<0.01). There is a significant difference in the total efficacy rate between the two groups (P<0.001). Adverse effects were reported in all of the ten included studies, and well tolerated in all patients with DPN.
Despite of the apparently positive findings and low risk of bias, it is premature to conclude the efficacy of CHMs for the treatment of DPN because of the high clinical heterogeneity and small sample sizes of the included studies. However, CHM therapy was safe for DPN. Further standardized preparation, large sample-size and rigorously designed RCTs are required.
The degree of intellectual impairment in schizophrenia patients and their relatives has been suggested to be associated with the degree of familial loading for schizophrenia. Since other psychiatric disorders are also more present in relatives of schizophrenia patients, the definition of family history should be broadened. The association between family history for psychiatric disorder and intelligence scores was investigated in patients with non-affective psychosis, their unaffected siblings and controls.
A sample of 712 schizophrenia proband families (696 patients and 766 siblings) and 427 healthy control families (517 subjects) participated in this study. Family history of psychiatric disorder was determined while excluding the data of the participating schizophrenia patient. A dichotomous division was made between families with no first- or second degree relative with psychiatric disorder and families with one or more affected relatives. Total intelligence scores were estimated by admission of the short form of the Wechsler Adult Intelligence Scale III.
A significant interaction was found between family history of psychiatric disorder and clinical status (F(2,1086.87)= 4.17; p=.016). Patients with a positive family history of psychiatric disorder obtained higher intelligence scores compared to patients with no family history (mean IQ scores are 95.52 and 92.72) with an opposite effect in controls (mean IQ scores are 108.71 and 111.19). No significant difference was found between siblings of schizophrenia patients with or without a positive family history (mean IQ scores are 102.98 and 103.24).
In patients with schizophrenia, a negative family history of psychiatric disorder was associated with relatively low IQ suggesting that the etiology in these patients may involve environmental or genetic factors which are unique to the patient and are not observed in other relatives. Possible factors include severe environmental stressors containing premature birth or brain injury and genetic factors (e.g de novo Copy Number Variants).
It is becoming increasingly evident that genetic variants contribute to the development of opioid addiction. An elucidation of these genetic factors is crucial for a better understanding of this chronic disease and may help to develop novel therapeutic strategies. In recent years, several candidate genes were implicated in opioid dependence. However, most study findings have not been replicated and additional studies are required before reported associations can be considered robust. Thus, the major objective of this study was to replicate earlier findings and to identify new genetic polymorphisms contributing to the individual susceptibility to opioid addiction, respectively. Therefore, a candidate gene association study was conducted including 142 well-phenotyped long-term opioid addicts undergoing opioid maintenance therapy and 142 well-matched healthy controls. In both study groups, 24 single nucleotide polymorphisms predominantly located in pharmacogenetic candidate genes have been genotyped using an accurate mass spectrometry based method. The most significant associations with opioid addiction (remaining significant after adjustment for multiple testing) were observed for the rs948854 SNP in the galanin gene (GAL, p = 0.001) and the rs2236861 SNP in the delta opioid receptor gene (OPRD1, p = 0.001). Moreover, an association of the ATP binding cassette transporter 1 (ABCB1) variant rs1045642 and the Mu Opioid receptor (OPRM1) variant rs9479757 with opioid addiction was observed. The present study provides further support for a contribution of GAL and OPRD1 variants to the development of opioid addiction. Furthermore, our results indicate a potential contribution of OPRM1 and ABCB1 SNPs to the development of this chronic relapsing disease. Therefore it seems important that these genes are addressed in further addiction related studies.
Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase which metabolizes angiotensin II (Ang II) to generate Ang-(1–7), has been shown to prevent cardiac hypertrophy and injury but the mechanism remains elusive. Irbesartan has the dual actions of angiotensin receptor blockade and peroxisome proliferator-activated receptor-γ (PPARγ) activation. We hypothesized that irbesartan would exert its protective effects on ACE2 deficiency-mediated myocardial fibrosis and cardiac injury via the PPARγ signaling.
10-week-old ACE2 knockout (ACE2KO; Ace2-/y) mice received daily with irbesartan (50 mg/kg) or saline for 2 weeks. The wild-type mice (Ace2+/y) were used to the normal controls. We examined changes in myocardial ultrastructure, fibrosis-related genes and pathological signaling by real-time PCR gene array, Western blotting, Masson trichrome staining and transmission electron microscope analyses, respectively.
Compared with the Ace2+/y mice, cardiac expression of PPARα and PPARγ were reduced in Ace2-/y mice and the myocardial collagen volume fraction (CVF) and expression of fibrosis-related genes were increased, including transforming growth factor-β1 (TGFβ1), connective tissue growth factor (CTGF), collagen I and collagen III. Moreover, ACE2 deficiency triggered cardiac hypertrophy, increased myocardial fibrosis and adverse ultrastructure injury in ACE2KO hearts with higher levels of atrial natriuretic factor (ANF) and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), without affecting cardiac systolic function. Intriguingly, treatment with irbesartan significantly reversed ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in Ace2-/y mice linked with enhancement of plasma Ang-(1–7) level and downregulation of AT1 receptor in heart. Consistent with attenuation of myocardial fibrosis and ultrastructure injury, the myocardial CVF and levels of ANF, TGFβ1, CTGF, collagen I, collagen III and phosphorylated ERK1/2 were lower, and expression of PPARγ was higher in ACE2KO mice in response to irbesartan treatment, without affecting cardiac expression of PPARα, PPARδ, β-myosin heavy chain, TGFβ2 and fibronectin.
We conclude that irbesartan prevents ACE2 deficiency-mediated pathological hypertrophy and myocardial fibrosis in ACE2 mutant mice via activation of the PPARγ signaling and suppression of the TGFβ−CTGF−ERK signaling, resulting in attenuation of myocardial injury. Drugs targeting ACE2 and PPARγ represent potential candidates to prevent and treat myocardial injury and related cardiac disorders.
Angiotensin-converting enzyme 2; Irbesartan; Peroxisome proliferator-activated receptor-γ; Connective tissue growth factor; Myocardial injury
Empathy is an important psychological capacity that involves the ability to recognize and share emotions with others. In humans, empathy for others is facilitated by having had a similar prior experience. It increases with the intensity of distress that observers believe is occurring to others, and is associated with acute emotional responses to witnessing others’ distress. We sought to develop a relatively simple and fast mouse model of human empathy that resembled these characteristics. We modeled empathy by measuring the freezing of observer mice to observing the footshock of a subject mouse. Observer mice froze to subject footshocks only when they had a similar shock experience 24 hours earlier. Moreover, this freezing increased with the number of footshocks given to the subject and it was accentuated within seconds after footshock delivery. Freezing was not seen in naïve observers or in experienced observers that observed a subject who was spared footshock. Observers did not freeze to a subject’s footshock when they had experienced a swim stress 24 hours prior, demonstrating a specific effect for shared experience, as opposed to a generalized stressor in eliciting observer mouse freezing. We propose that this two-day experimental protocol resembles many aspects of human empathy in a mouse model that is amenable to transgenic analysis of neural substrates for empathy and its impairment in certain clinical disorders.
Observational and experimental studies have thus far been unable to resolve whether the CYBA C242T polymorphism is associated with coronary artery disease (CAD). Therefore, we undertook a comprehensive meta-analysis to more precisely evaluate the influence of this polymorphism on CAD and potential biases.
We screened MEDLINE, Embase, CNKI, Wanfang and CBM up to January 2013 and extracted data from 22 studies with 9,279 CAD patients and 9,349 controls. A random-effects model was exploited to synthesize the inconsistent outcomes of the individual studies, while addressing between-study heterogeneity and publication bias.
The CYBA C242T polymorphism conformed to Hard-Weinberg Equilibrium for all studies (P>0.05). Overall comparison of the T allele with the C allele produced a non-significant risk estimate for CAD but with striking heterogeneity (T versus C: P = 0.87, OR = 0.99, 95%CI 0.89–1.11, Pheterogeneity<0.0001, I2 = 67.8%). However, subgroup analysis by ethnicity documented that the T allele carriers had a marginal risk increase (21%) of CAD among Caucasians (recessive genetic model: P = 0.05, 95%CI 1.00–1.46, Pheterogeneity = 0.15, I2 = 29.1%). Then data were divided into study design, the significance of CAD risk increase was substantially strengthened in matched case-control studies (allele comparison: P = 0.02, OR = 1.13, 95%CI 1.02–1.26, Pheterogeneity = 0.24, I2 = 21.6%).Further meta-regression analysis identified that a large proportion of heterogeneity was explained by body mass index (BMI) (P = 0.03, OR = 1.07, 95%CI 1.01–1.15) and study design (P = 0.03, OR = 1.30, 95%CI 1.02–1.64).There was no obvious publication bias as verified by funnel plot and Egger's linear regression test (t = −0.25, P = 0.81 for allele comparison).
Taken together, our results suggested the CYBA C242T polymorphism might be a risk-conferring factor on developing CAD and BMI and study design were probable sources of between-study heterogeneity.
Glutamate N-methyl-d-aspartate (NMDA) receptor antagonists exert fast-acting antidepressant effects, providing a promising way to develop a new classification of antidepressant that targets the glutamatergic system. In the present study, we examined the potential antidepressant action of 7-chlorokynurenic acid (7-CTKA), a glycine recognition site NMDA receptor antagonist, in a series of behavioural models of depression and determined the molecular mechanisms that underlie the behavioural actions of 7-CTKA.
We administered the forced swim test, novelty-suppressed feeding test, learned helplessness paradigm and chronic mild stress (CMS) paradigm in male rats to evaluate the possible rapid antidepressant-like actions of 7-CTKA. In addition, we assessed phospho-glycogen synthase kinase-3β (p-GSK3β) level, mammalian target of rapamycin (mTOR) function, and postsynaptic protein expression in the medial prefrontal cortex (mPFC) and hippocampus.
Acute 7-CTKA administration produced rapid antidepressant-like actions in several behavioural tests. It increased p-GSK3β, enhanced mTOR function and increased postsynaptic protein levels in the mPFC. Activation of GSK3β by LY294002 completely blocked the antidepressant-like effects of 7-CTKA. Moreover, 7-CTKA did not produce rewarding properties or abuse potential.
It is possible that 7-CTKA modulates glutamatergic transmission, thereby causing enduring alterations of GSK3β and mTOR signalling, although we did not provide direct evidence to support this possibility. Thus, the therapeutic involvement of synaptic adaptions engaged by 7-CTKA requires further study.
Our findings demonstrate that acute 7-CTKA administration produced rapid antidepressant-like effects, indicating that the behavioural response to 7-CTKA is mediated by GSK3β and mTOR signalling function in the mPFC.
The classical serotonergic psychedelics LSD, psilocybin, mescaline are not known to cause brain damage and are regarded as non-addictive. Clinical studies do not suggest that psychedelics cause long-term mental health problems. Psychedelics have been used in the Americas for thousands of years. Over 30 million people currently living in the US have used LSD, psilocybin, or mescaline.
To evaluate the association between the lifetime use of psychedelics and current mental health in the adult population.
Data drawn from years 2001 to 2004 of the National Survey on Drug Use and Health consisted of 130,152 respondents, randomly selected to be representative of the adult population in the United States. Standardized screening measures for past year mental health included serious psychological distress (K6 scale), mental health treatment (inpatient, outpatient, medication, needed but did not receive), symptoms of eight psychiatric disorders (panic disorder, major depressive episode, mania, social phobia, general anxiety disorder, agoraphobia, posttraumatic stress disorder, and non-affective psychosis), and seven specific symptoms of non-affective psychosis. We calculated weighted odds ratios by multivariate logistic regression controlling for a range of sociodemographic variables, use of illicit drugs, risk taking behavior, and exposure to traumatic events.
21,967 respondents (13.4% weighted) reported lifetime psychedelic use. There were no significant associations between lifetime use of any psychedelics, lifetime use of specific psychedelics (LSD, psilocybin, mescaline, peyote), or past year use of LSD and increased rate of any of the mental health outcomes. Rather, in several cases psychedelic use was associated with lower rate of mental health problems.
We did not find use of psychedelics to be an independent risk factor for mental health problems.
Tardive dyskinesia (TD) is a human hyperkinetic movement disorder as a result of potentially irreversible long-term chronic first-generation antipsychotic medications. Unfortunately, mechanisms involved in the development of TD have been poorly understood. Previous studies have indicated that some genetic polymorphisms of immune system and dopamine beta-hydroxylase (DBH) genes may be involved in the pathogenesis of TD. Rs1800872 and rs72393728 are located on the promoter of interleukin-10 (IL10) and DBH gene, respectively. The genetic association between the rs1800872 and TD is unclear. Previous studies have indicated that genetic variations of IL 10 and DBH are implicated in the positive and negative symptoms in schizophrenia. However, the interaction of two variations with severity of TD and symptoms of schizophrenic patients with TD has not been reported. The present study investigated whether these variations and their interaction were associated with clinical phenotypes of TD with schizophrenia in a genetically homogeneous northern Chinese Han population.
Rs1800872 and rs72393728 were genotyped in schizophrenic patients with TD (n = 372) and without TD (NTD; n = 412). The Abnormal Involuntary Movement Scale (AIMS) and Positive and Negative Syndrome Scale (PANSS) were applied to assess the severity of TD and psychopathology of schizophrenia, respectively.
The allele and genotype frequencies of rs1800872 and rs72393728 did not significantly differ between TD and NTD patients (p>0.05). No significant difference was found in the AIMS total score among the genotypes of two loci (p>0.05). Interestingly, the interaction of rs1800872 and rs72393728 showed a significant association with the PANSS general score (p = 0.011), and a trend toward to the PANSS total score (p = 0.055).
These findings suggest that the interaction of rs1800872 and rs72393728 variants may play a role in psychopathology of the general symptoms on PANSS in schizophrenic patients with TD in a northern Chinese Han population.