Effects of amyloid ß (Aß)42 and Gasdermin D on the progression of Alzheimer's disease in vitro and in vivo through the regulation of astrocyte pyroptosis.

PURPOSE: The study aimed to investigate whether astrocyte pyroptosis, and the subsequent neuroinflammatory response that exerts amyloid ß (Aß) neurotoxic effects, has an effect on endothelial cells, along with the underlying mechanisms. METHODS: In vivo, 5 µL of disease venom was injected into the lateral ventricle of APP/PS1 mice for treatment. Pyroptosis was induced by treating astrocytes with Aß42 in vitro. Small interfering RNA (siRNA) was used to silence caspase-1 and Gasdermin D (GSDMD) mRNA expression. Cell viability was determined using a CCK-8 detection kit. Scanning electron microscopy (SEM), Annexin V/propidium iodide (PI) double staining, RT-qPCR, immunofluorescence, western blotting, and enzyme-linked immunosorbent assay (ELISA) were used to detect cell pyroptosis. The degree of pathological damage to the brain and aortic tissue was assessed by hematoxylin-eosin staining and immunohistochemistry. RESULTS: Aß42 induced astrocyte pyroptosis dependent on the GSDMD/Gasdermin E (GSDME)/Caspase 11/NLRP3 pathway, releasing large amounts of inflammatory factors, such as TNF-α, IL-1α, IL-1ß, and IL-18. Astrocyte pyroptosis caused endothelial cell dysfunction and release of large amounts of vasoconstrictors (ET and vWF). Knockdown of GSDMD reduced astrocyte pyroptosis in the cerebral cortex and hippocampal tissue, decreased the release of inflammatory factors IL-1 ß and IL-18, reduced Aß deposition and tau protein, increased the release of peripheral vasodilator substances (eNOS), and decreased the release of vasoconstrictor substances (ET, vWF), thereby reducing brain tissue damage and vascular injury in APP/PS1 mice. CONCLUSION: Aß42 induced astrocyte pyroptosis, while GSDMD knockout inhibited astrocyte pyroptosis, reduced the release of inflammatory factors, and alleviated brain tissue damage and vascular damage in APP/PS1 mice. Therefore, GSDMD is a novel therapeutic target for Alzheimer's disease. PURPOSE: The study aimed to investigate whether astrocyte pyroptosis, and the subsequent neuroinflammatory response that exerts amyloid ß (Aß) neurotoxic effects, has an effect on endothelial cells, along with the underlying mechanisms. METHODS: In vivo, 5 µL of disease venom was injected into the lateral ventricle of APP/PS1 mice for treatment. Pyroptosis was induced by treating astrocytes with Aß42 in vitro. Small interfering RNA (siRNA) was used to silence caspase-1 and Gasdermin D (GSDMD) mRNA expression. Cell viability was determined using a CCK-8 detection kit. Scanning electron microscopy (SEM), Annexin V/propidium iodide (PI) double staining, RT-qPCR, immunofluorescence, western blotting, and enzyme-linked immunosorbent assay (ELISA) were used to detect cell pyroptosis. The degree of pathological damage to the brain and aortic tissue was assessed by hematoxylin-eosin staining and immunohistochemistry. RESULTS: Aß42 induced astrocyte pyroptosis dependent on the GSDMD/Gasdermin E (GSDME)/Caspase 11/NLRP3 pathway, releasing large amounts of inflammatory factors, such as TNF-α, IL-1α, IL-1ß, and IL-18. Astrocyte pyroptosis caused endothelial cell dysfunction and release of large amounts of vasoconstrictors (ET and vWF). Knockdown of GSDMD reduced astrocyte pyroptosis in the cerebral cortex and hippocampal tissue, decreased the release of inflammatory factors IL-1 ß and IL-18, reduced Aß deposition and tau protein, increased the release of peripheral vasodilator substances (eNOS), and decreased the release of vasoconstrictor substances (ET, vWF), thereby reducing brain tissue damage and vascular injury in APP/PS1 mice. CONCLUSION: Aß42 induced astrocyte pyroptosis, while GSDMD knockout inhibited astrocyte pyroptosis, reduced the release of inflammatory factors, and alleviated brain tissue damage and vascular damage in APP/PS1 mice. Therefore, GSDMD is a novel therapeutic target for Alzheimer's disease.

Risk factors, clinical correlates, and social functions of Chinese schizophrenia patients with drug-induced parkinsonism: A cross-sectional analysis of a multicenter, observational, real-world, prospective cohort study.

Background: Drug-induced parkinsonism (DIP) is the most prevalent neurological side effect of antipsychotics in the Chinese population. Early prevention, recognition, and treatment of DIP are important for the improvement of treatment outcomes and medication adherence of schizophrenia patients. However, the risk factors of DIP and the impact on the clinical syndromes of schizophrenia remain unknown. Aim: The goal of this study was to explore the risk factors, clinical correlates, and social functions of DIP in Chinese schizophrenia patients. Methods: A cross-sectional analysis of a multicenter, observational, real-world, prospective cohort study of the Chinese schizophrenia population with a baseline assessment was conducted from the year 2012 to 2018. Participants were recruited from four mental health centers in Shanghai and totaled 969 subjects. Sociodemographic data, drug treatment, and clinical variables were compared between the DIP group and the non-DIP group. Variables that correlated with the induction of DIP, and with p≤ 0.1, were included in the binary logistic model for analyzing the risk factors of DIP. First generation antipsychotics (FGA)/second generation antipsychotics (SGA) model and high and low/medium D2 receptor antipsychotics were analyzed respectively to control the bias of co-linearity. All risk factors derived from the a forementioned models and clinical variables with p≤ 0.1 were included in the multivariate analysis of clinical correlates and social function of DIP patients. The Positive and Negative Syndrome Scale (PANSS) model and the personal and social performance (PSP) model were analyzed separately to control for co-linearity bias. Results: Age (OR = 1.03, p< 0.001), high D2 receptor antagonist antipsychotic dose (OR = 1.08, p = 0.032), and valproate dose (OR = 1.01, p = 0.001) were the risk factors of DIP. FGA doses were not a significant contributor to the induction of DIP. Psychiatric symptoms, including more severe negative symptoms (OR = 1.09, p< 0.001), lower cognition status (OR = 1.08, p = 0.033), and lower excited symptoms (OR = 0.91, p = 0.002), were significantly correlated with DIP induction. Social dysfunction, including reduction in socially useful activities (OR = 1.27, p = 0.004), lower self-care capabilities (OR = 1.53, p< 0.001), and milder disturbing and aggressive behavior (OR = 0.65, p< 0.001), were significantly correlated with induction of DIP. Valproate dose was significantly correlated with social dysfunction (OR = 1.01, p = 0.001) and psychiatric symptoms (OR = 1.01, p = 0.004) of DIP patients. Age may be a profound factor that affects not only the induction of DIP but also the severity of psychiatric symptoms (OR = 1.02, p< 0.001) and social functions (OR = 1.02, p< 0.001) of schizophrenia patients with DIP. Conclusion: Age, high D2 receptor antagonist antipsychotic dose, and valproate dose are risk factors for DIP, and DIP is significantly correlated with psychiatric symptoms and social performance of Chinese schizophrenia patients. The rational application or discontinuation of valproate is necessary. Old age is related to psychotic symptoms and social adaption in Chinese schizophrenic patients, and early intervention and treatment of DIP can improve the prognosis and social performance of schizophrenia patients. Clinical Trial Registration: Identifier: NCT02640911.

Usefulness of candidate mRNAs and miRNAs as biomarkers for mild cognitive impairment and Alzheimer's disease.

OBJECTIVE: To explore potential molecular mechanisms and novel biomarkers of mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: The mRNA expression datasets GSE63060 and GSE63061 and the miRNA expression dataset GSE120584 were obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) and miRNA (DEmiRs) were identified in the normal, MCI, and AD groups. Mfuzz clustering and weighted correlation network analyses (WGCNA) were conducted, followed by pathway and functional enrichment analyses and miRNA-mRNA network construction. Furthermore, phenotypic correlation analysis and experimental verification were performed on key DEGs and DEmiRs. RESULTS: In total, 3,000 intersected DEGs from GSE63060/GSE63061 and 817 DEmiRs from GSE120584 were obtained. Mfuzz and WGCNA analyses revealed 106 DEGs including ribosomal protein L11 (RPL11) and 28 DEmiRs including miR-6764-5p. These DEGs and DEmiRs were mainly enriched in pathways like Ribosome. Moreover, 5 key DEGs including cytohesin 4 (CYTH4) and 6 crucial DEmiRs including miR-6734-3p were identified by miRNA-mRNA interaction network analysis. Phenotypic correlation analysis showed that CYTH4 and miR-6734-3p were correlated with patients' age. The results of quantitative polymerase chain reaction analysis confirmed that RPL11 expression was significantly downregulated in the MCI and AD groups compared to that in the normal group, while the expression of CYTH4, miR-6764-5p, and miR-6734-3p was remarkably upregulated in the MCI and AD groups. CONCLUSIONS: miR-6764-5p might contribute to MCI and AD by targeting RPL11 in the ribosome pathway. Therefore, miR-6734-3p and its target mRNA CYTH4 might be used as novel biomarkers for MCI and AD.

Premenstrual dysphoric disorder is associated with the longer length from clitoris to urethra.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is a common, recently recognized, psychiatric condition among reproductive women, reflecting abnormal responsivity to ovarian steroids. Moreover, the potential organizational effect of prenatal sex hormones during PMDD has got attentions, but there have been considerably less of researches on this topic. The aim of this research was to investigate the possible role of prenatal androgen in the PMDD. METHODS: Anogenital distance (AGD), the distance between a woman's clitoris and her urethral meatus (CUMD), left and right 2D:4D ratios were measured in 77 subjects (25 patients with PMDD), as these anthropometric indicators are considered to indirectly reflect prenatal androgen exposures in utero. RESULTS: Patients with PMDD had a longer CUMD than controls (25.03 ± 4.73 vs. 22.07 ± 4.30, P = 0.008), while there were no significant difference between PMDD group and control group in the AGD and right and left 2D:4D ratios. CONCLUSION: Atypical high prenatal androgen exposure might predispose individuals to be susceptible to PMDD.

Analysis of Medication Adherence and Its Influencing Factors in Patients with Schizophrenia in the Chinese Institutional Environment.

BACKGROUND: Factors related to medication adherence in patients with schizophrenia have always been key to the treatment and rehabilitation of these patients. However, the treatment modes in different countries are not the same, and there is no research on the factors influencing medication adherence under different mental health service modes. OBJECTIVES: The purpose of this study was to explore medication adherence and its influencing factors in patients with schizophrenia in the Chinese institutional environment. METHODS: We conducted a cross-sectional study of hospitalized persons living with schizophrenia from November 2018 to January 2019. A systematic sampling method was used to select 217 hospitalized persons living with schizophrenia. The Medication Adherence Rating Scale (MARS), Positive and Negative Syndrome Scale (PANSS), General Self-Efficacy Scale (GSES), Schizophrenia Quality of Life Scale (SQLS), and Scale of Social Skills for Psychiatric Inpatients (SSPI) were used to explore medication compliance and its influencing factors in the Chinese institutional environment. RESULTS: The descriptive analysis and ANOVA showed that there were no significant differences in medication adherence when assessed by demographic characteristics such as sex, marital status, and education level (p > 0.05). A correlation analysis showed that there was no significant correlation between medication adherence and mental symptoms (p > 0.05) but that there was a positive correlation with self-efficacy, quality of life, and activities of daily living (p < 0.01). The linear regression analysis showed that self-efficacy, psychosocial factors, symptoms/side effects, and activities of daily living had significant effects on medication adherence (F = 30.210, p < 0.001). CONCLUSIONS: Our findings show that the self-efficacy, quality of life, and social function of patients with schizophrenia are important self-factors influencing medication adherence in the Chinese institutional environment.

Correlation between sleep characteristics and cognitive decline in the elderly people: A cross-sectional study in China.

STUDY OBJECTIVES: In this study, we conducted a cross-sectional analysis of the sleep characteristics in the elderly Chinese people to comprehensively investigate the association between sleep and cognitive function in the elderly people. We aimed to evaluate the most important demographic factors, conventional physiological indices and living habits that may influence sleep. METHODS: We surveyed 2901 elderly people (age ≥60 years old) face-to-face from 1 July to 31 December 2017, who were recruited from 17 communities of the Pudong New Area (Shanghai, China) by probability proportional to size. The Pittsburgh sleep quality index (PSQI) scale was used to describe the sleep features of each participant. Cognitive assessment was performed using the mini-mental state examination (MMSE) scale, Montreal cognitive assessment (MoCA) and the clinical dementia rating (CDR) scale. Those factors which potentially influence sleep and consequentially may impact cognition in the elderly people were evaluated, and the correlations of sleep characteristics and cognitive function were explored by the linear regression analysis. RESULTS: Altogether, there were 1287 (44.4%) people taking part in the investigation. Sleep quality was significantly correlated with MMSE and MoCA total scores. Healthy sleep (especially enough sleep) was correlated with better cognitive functions. Besides recognised relative factors (such as age, sex and living alone), the number of children was found to be a strong risk factor of poor sleep. Anxiety before sleep and light/noise interference significantly damaged sleep while an exercise routine was associated with better sleep. Moderate levels of reading, watching TV and household work were correlated with superior sleep quality. CONCLUSION: In conclusion, sleep characteristics correlate with cognitive decline in the elderly people, and they can be influenced by multiple demographic factors and living habits. To improve sleep quality, it may be important to change sleep environment, to be relax, to increase physical exercise and recreational activities moderately.

The Psychometric Properties of General Adherence Scale in Chinese (GAS-C) in Patients with Type 2 Diabetes Using Insulin.

PURPOSE: Translate General Adherence Scale (GAS) into Chinese and test its psychometric properties in middle-aged and elderly type 2 diabetes (T2D) patients using insulin in the Han people of urban China. SUBJECTS AND METHODS: We translated the GAS into Chinese and established General Adherence Scale in Chinese (GAS-C). 136 T2D subjects were selected for testing GAS-C's reliability and validity, of which 100 study subjects were retested with GAS-C two weeks later. The other 200 T2D subjects were selected for performing Confirmatory Factor Analysis(CFA). The ceiling effect and floor effect of GAS-C data were checked. RESULTS: No data was lost in our research. In exploratory factor analysis(EFA), the Kaiser-Meyer-Olkin measure of sampling adequacy (KMO) =0.899, Bartlett's Test's χ2=611.821 (df=10 p<0.001). The communalities of the items were between 0.740 and 0.862; The values of Measure of Sampling Adequacy (MSA) were between 0.883 and 0.945. All five items entered the factor analysis process. A common factor was extracted, and it could explain 81.403% of the total variance. CFA validated the.one-factor model was good fits with the data of GAS-C (Ratio of Chi-square to Degrees of Freedom (CMIN/DF)=2.032, Goodness of Fit Index (GFI) =0.981, Comparative Fit Index (CFI) =0.996, Tucker-Lewis Index (TLI) =0.992, Root Mean Square Residual (RMR) =0.011, Root Mean Square Error of Approximation (RMSEA) =0.072). Correlation analysis was performed between GAS-C and MMAS-8 to calculate the criterion-related validity (r=0.542 p<0.001). The internal consistency reliability α=0.942, Intraclass Correlation Coefficient (ICC)= 0.941 (95% CI 0.924-0.955). The correlation coefficient r of the test-retest reliability was 0.772 (p<0.001). Spearman-Brown coefficient of split-half was 0.939. There was no floor effect and ceiling effect on the data. CONCLUSION: GAS-C has good reliability and validity. It can be used for general adherence studies of middle-aged and elderly type 2 diabetic patients using insulin in the Han people of Chinese cities.

Investigation of risk factors for the conversion of mild cognitive impairment to dementia.

BACKGROUND: Mild cognitive impairment (MCI) is an intermediate state between normal aging and dementia and is characterized by pathological cognitive decline. The study aimed at revealing the risk of MCI progressing to dementia through a follow-up investigation. METHODS: In 2011, 441 MCI subjects were recruited, and the disease status was tracked by the follow-up survey in 2017. Subjects with MCI stable (MCIs; N = 356) and MCI progressed into dementia (MCIp; N = 77) were analysed in our study. Community-dwelling old people of age ≥ 55 were recruited from 30 streets and 24 committees (or communities) of the Pudong New District (Shanghai, China). Neuropsychological tests of MMSE, MoCA, 17-item HAMD-17, ADL and HIS were performed. Additionally, the correlations of neuropsychological items and MCIp were explored by univariate and multivariate regression analyses. RESULTS: MCIp patients had the lower MMSE and MoCA total scores, whereas the ADL, and HIS total score in MCIp group were higher than in MCIs group. The univariate analysis revealed age, attention (MoCA), visuospatial/executive, number of births, marital status and attention and calculation were significant predictors of MCI progression. In multivariate analysis, age was an independent risk factor of MCI aggravating, while attention (MoCA) was independent protective factor for MCI progression. CONCLUSIONS: Age and worsening attention but not depression in MCI patients were independently associated with the progression of dementia in a 6-year follow-up period.

Later-Onset Hypertension Is Associated With Higher Risk of Dementia in Mild Cognitive Impairment.

To investigate the correlation between hypertension development and the progression of mild cognitive impairment (MCI) to dementia in middle-aged and elderly people. A population-based longitudinal cognition survey of people aged 55+ was conducted. The hypertension onset age was estimated by self-reported information and medical insurance card records. To study the effect of later-onset hypertension on dementia, the incidence of dementia was compared between the two groups. Of 277 hypertensive MCI participants without dementia, 56 (20.22%) progressed to dementia (MCIp) over the 6-year follow-up. The proportion of MCIp participants in the old-age-onset hypertension group (≥65 years) was higher than that in the middle-age-onset hypertension group (27.0 vs. 15.4%, respectively; X 2 = 5.538, P = 0.019). In the old-age-onset hypertension group, the proportion of MCIp without diabetes mellitus was higher than those with diabetes mellitus (24.7 vs. 12.6%, respectively; X 2 = 5.321, P = 0.021) and those with increased pulse pressure was higher than those without increased pulse pressure (33.3 vs. 15.4%, respectively; X 2 = 3.902, P = 0.048). However, the cox proportional hazard showed that older age was the only risk factor for MCIp (HR = 0.618, p = 0.000). These results suggest that individuals with later-onset hypertension may have greater cognition decline, even with blood pressure maintained at 130/80 mmHg with antihypertensive management.

Correlation Analysis of the Quality of Family Functioning and Subjective Quality of Life in Rehabilitation Patients Living with Schizophrenia in the Community.

Background: Recently, the community rehabilitation model for schizophrenia patients has become increasingly popular, and the Shanghai Pudong New Area has developed a relatively complete community rehabilitation model. This study analyzed the correlation between family function and subjective quality of life in the rehabilitation of patients living with schizophrenia in the community. Methods: This study evaluated persons living with schizophrenia using the Family Assessment Device and the Subjective Quality of Life Scale. A convenient sampling method was used to select 281 rehabilitation patients living with schizophrenia in the community and 166 hospitalized persons living with schizophrenia. Results: There was a significant difference in the Family Assessment Device scores between rehabilitation patients living with schizophrenia in the community and hospitalized persons living with schizophrenia (p < 0.0001). The difference in the scores of the subjective quality of life assessment between rehabilitation patients living with schizophrenia in the community and hospitalized persons living with schizophrenia was not statistically significant (p > 0.05). The regression analysis showed that quality of family function had a significant effect on the subjective quality of life in rehabilitation patients living with schizophrenia in the community and hospitalized persons living with schizophrenia. (F = 10.770 p < 0.001), (F = 2.960 p < 0.01). Conclusions: The quality of family function plays an important role in improving the subjective quality of life in rehabilitation patients living with schizophrenia in the community. It may be beneficial to add some methods to improve family function in the current model of rehabilitation in the community.

Demographic Factors and Cognitive Function Assessments Associated with Mild Cognitive Impairment Progression for the Elderly.

OBJECTIVES: In this study, we aimed to conduct a 6-year follow-up and acquire a large sample dataset to analyze the most important demographic factors and cognitive function scale variables associated with mild cognitive impairment (MCI) progression for an elderly cohort (age ≥ 60 years old). Patients and Methods. We analyzed the subjects who had participated in a survey in 2011 and were successfully contacted in the later survey in 2017. For each subject, the basic demographic information was recorded, including sex, age, education level, marital status, working status, income level, and physical mental illness history. Cognitive assessments were performed using the following scales if possible: (1) the mini-mental state examination (MMSE) scale, (2) Montreal cognitive assessment (MoCA), (3) the clinical dementia rating (CDR) scale, and (4) Hamilton Depression Scale (HAMD-17). RESULTS: The progression outcomes were different between sexes, among age brackets, education degrees, occupations types, and income levels; different progression groups had distinct children numbers (p < 0.001), heights (p < 0.001), heights (p < 0.001), heights (p < 0.001), heights (. CONCLUSIONS: In conclusion, the MCI progression outcomes were associated with sex, age, education degrees, occupations types, income level, children number, height, and weight. MoCA and MMSE scales are supporting tools to predict the progression outcomes, especially combined with the demographic data.

Aiweixin, a Traditional Uyghur Medicinal Formula, Extends the Lifespan of Caenorhabditis elegans.

Aiweixin (AWX) is a traditional Uyghur medicine prescription, which has been used to treat senile diseases for a long time. We investigate whether the AWX extends the lifespan of Caenorhabditis elegans. The AWX decoction was the conventional product for clinical use. The wild-type Caenorhabditis elegans (N2) and mutational worms, daf-16(mu86), glp-1(e2141), daf-2(e1370), and eat-2(ad465), were applied for the lifespan analysis. We found that the lifespan of the N2 adults' worm received 0.005 and 0.01 volume of AWX/total volume was extended significantly, compared to the control without treatment of AWX. The AWX at 0.01 volume of AWX/total volume significantly prolonged the life of both mutational worms, daf-16 (mu86) and eat-2(ad465), but did not increase the lifespan of the mutational worms, daf-2(e1370) and glp-1(e2141). These results indicated that the AWX significantly extended the lifespan of wild-type nematodes, and the life extension effect of AWX was related to the germline longevity pathway and IIS signaling pathway but independent of DAF-16/FOXO.

Aiweixin, a traditional Uyghur medicinal formula, protects against chromium toxicity in Caenorhabditis elegans.

BACKGROUND: Aiweixin (AWX) is a traditional Uyghur medicine prescription, and has been mainly used to treat heart and brain diseases for a long time. Previous studies indicated that AWX had therapeutic effects in a rat model of myocardial ischemia reperfusion injury. In this study, we investigate whether AWX has protective effects against chromium toxicity in Caenorhabditis elegans (C. elegans). METHODS: The AWX decoction was the conventional product for clinical use. It was added into M9 buffer in a certain volume for the treatment to the wild-type C. elegans and mutational worms, daf-16, glp-1(notch), daf-2, rsks-1 and eat-2. Assays for hexavalent chromium {Cr(VI)} stress and reactive oxygen species (ROS) production were used. RESULTS: We found that AWX at moderate contents (0.083, 0.1, 0.125 volume of AWX/total volume) increased resistance of C. elegans to Cr(VI) exposure, although higher contents of AWX are toxic for C. elegans. The protective effect of AWX was DAF-16-dependent, but independent on the DAF-2, GLP-1, RSKS-1 and EAT-2. AWX (0.1 volume of AWX/total volume) significantly reduced ROS production of C. elegans induced by Cr(VI) exposure. CONCLUSION: These results indicated the AWX protected against the toxicity of Cr(VI) in C. elegans, and the oxidative stress protective mechanism in worms should be involved.

Optimal dosages of fluoxetine in the treatment of hypoxic brain injury induced by 3-nitropropionic acid: implications for the adjunctive treatment of patients after acute ischemic stroke.

AIM: The serotonin selective reuptake inhibitor fluoxetine (Flx) has tried to treat patients suffered acute ischemic stroke because of its possible neuroprotective actions. However, besides the neuroprotective effect, Flx at high concentration also induces some actions in contradiction to neuroprotection in the brain. The purpose of this study was to investigate whether Flx presents neuroprotective effect against 3-nitropropionic acid (3-NP)-induced hypoxic brain injury, and what is the most suitable dosage of Flx. METHODS: Mouse model was established by subacute systemic administration of 3-NP. Rotarod and pole tests were used to evaluate motor deficit. The oxidative stress and oxidative DNA damage were assessed respectively by measuring malondialdehyde and 8-hydroxydeoxyguanosine content in brain homogenates. RESULTS: According to measurements in the rotarod test, 7 days pretreatment plus 5 days treatment of Flx at low (2.5 mg/kg/day) and, to a lesser degree, medium (5 mg/kg/day) doses exerted a rapid and strong protection against the neurotoxicity induced by 3-NP, whereas Flx at high dose (10mg/kg/day) showed a much late and light effect. Similarly, in the pole test, Flx at 2.5 mg/kg/day had the strongest protective effects. Again, only Flx administration at 2.5 mg/kg/day canceled out the enhancement of malondialdehyde and 8-hydroxydeoxyguanosine in striatum following 3-NP neurotoxication. CONCLUSIONS: Flx attenuated the motor deficits induced by 3-NP in a dose-dependent manner. In contrary to the high dose, Flx at the lower doses had a more remarkable effect against 3-NP insult, similar to acute ischemic stroke.

SUN1 and SUN2 play critical but partially redundant roles in anchoring nuclei in skeletal muscle cells in mice.

How the nuclei in mammalian skeletal muscle fibers properly position themselves relative to the cell body is an interesting and important cell biology question. In the syncytial skeletal muscle cells, more than 100 nuclei are evenly distributed at the periphery of each cell, with 3-8 nuclei anchored beneath the neuromuscular junction (NMJ). Our previous studies revealed that the KASH domain-containing Syne-1/Nesprin-1 protein plays an essential role in anchoring both synaptic and nonsynaptic myonuclei in mice. SUN domain-containing proteins (SUN proteins) have been shown to interact with KASH domain-containing proteins (KASH proteins) at the nuclear envelope (NE), but their roles in nuclear positioning in mice are unknown. Here we show that the synaptic nuclear anchorage is partially perturbed in Sun1, but not in Sun2, knockout mice. Disruption of 3 or all 4 Sun1/2 wild-type alleles revealed a gene dosage effect on synaptic nuclear anchorage. The organization of nonsynaptic nuclei is disrupted in Sun1/2 double-knockout (DKO) mice as well. We further show that the localization of Syne-1 to the NE of muscle cells is disrupted in Sun1/2 DKO mice. These results clearly indicate that SUN1 and SUN2 function critically in skeletal muscle cells for Syne-1 localization at the NE, which is essential for proper myonuclear positioning.

No spatial memory deficit exists in Kunming mice that recently recovered from motor defects following 3-nitropropionic acid intoxication.

OBJECTIVE: Numerous studies have described both motor defects and cognitive impairments in several strains of rodents following 3-nitropropionic acid (3-NP) intoxication. In the present study, we investigated spatial recognition memory in Kunming mice that just recovered from motor defects induced by 3-NP. METHODS: Mouse model was made by systemic subacute 3-NP treatment, and spatial recognition memory was measured through the Y-maze Test, a simple two-trial recognition test. RESULTS: (1) On day 15 following 3-NP treatment, affected Kunming mice did not show motor defects in the Rotarod test and presented normal gait again. (2) In the following Y-maze test after 1h interval, the percentage (90.0%) of mice showing novel arm preference in 3-NP treatment group was significantly higher than the random chance level (50%), although it was only slightly higher than that (83.3%) in control group. On day 45 after 3-NP treatment, mice failed to choose unfamiliar novel arm as first choice, and the same occured in the control group. (3) For both post-intoxicated (on day 15 and day 45 following 3-NP treatment) and control groups, the duration in the novel arm and the frequency of entering it, were longer and higher compared with familiar start and other arms. For these mice that recently recovered from motor defects following 3-NP intoxication, no spatial memory deficits were observed through Y-maze Test. CONCLUSION: Kunming mice used in our assays might possess resistance to cognitive impairment induced by 3-NP, which is consistent with previous findings in Swiss EPM-M1 mice.

Depressive-like behavior in mice recently recovered from motor disorders after 3-nitropropionic acid intoxication.

OBJECTIVE: Striatum may be involved in depressive disorders according to the neuroimaging analysis and clinical data. However, no animal model at present supported the possible role of striatum in the pathogenesis of depression. In the present study, we have investigated the depressive-like behavior in mice recently intoxicated with 3-nitropropionic acid (3-NP), a widely known toxin that selectively damages the striatum in the brain. METHODS: Mouse model was made with subacute systemic 3-NP treatment, and the depressive-like behavior was measured using the duration of immobility during forced swimming test (FST). RESULTS: When the mice at day 15 post-intoxication just totally recovered from motor deficits, the duration of immobility in FST was significantly longer than that in controls. The depressive-like behavior was not due to the fatigue or general sickness following 3-NP intoxication and could be reversed by the antidepressant, desipramine hydrochloride. In two successive FST in 24 h interval, the depressive-like behavior could be observed again in subsequent FST (at day 16 post-intoxication), and the mice presented a normal "learned helplessness". CONCLUSION: A novel depression animal model could be established in mice during the initial period of recovery from 3-NP intoxication. The depression-like behavior might occur independently without involvement of cognitive defects, and the striatal lesions may underlie the depression-like behavior attributable to 3-NP intoxication.

Diazoxide prevents abdominal adiposity and fatty liver in obese OLETF rats at prediabetic stage.

Epidemiological studies in both humans and experimental animals have shown an association between visceral obesity and cardiovascular risk factors such as dyslipidemia, hyperinsulinemia, and type 2 diabetes mellitus. The objective of this study was to evaluate the effects of diazoxide, an inhibitor of glucose-stimulated insulin secretion, on the prevention of fat deposition in the liver and in the abdominal cavity of prediabetic rats. Otsuka Long-Evans Tokushima Fatty (OLETF) rats, which are a well-established animal model of human obesity, were used. Diazoxide (25 mg/kg/day) was administered from 8 to 30 weeks of age. Various fat distribution parameters, including computerized tomography imaging, histopathological examination, lipid metabolism, and insulin resistance, were determined in prediabetic OLETF rats. Occurrences of abdominal adiposity and fatty liver were markedly reduced by diazoxide treatment. Diazoxide significantly lowered hyperinsulinemia, triglycerides, free fatty acid levels, insulin resistance, weight gain, and food intake. In addition, it inhibited the development of diabetes in these animals. Linear regression assay demonstrated a close correlation between decreasing hyperinsulinemia and the protective effects of diazoxide. The present study demonstrates that diazoxide treatment in obese OLETF rats at prediabetic stage prevents abdominal obesity and fat deposition in the liver. These metabolic changes may occur through a direct effect on beta-cells through reduction of their workload and suppression of insulin secretion.

Chemical hypoxia facilitates alternative splicing of EAAT2 in presymptomatic APP23 transgenic mice.

Hypoxia is one of the major common components of vascular risk factors for pathogenesis of Alzheimer's disease. This study investigated the possible relationship between hypoxia and alternative splicing of the excitatory amino acid transporter 2 (EAAT2) in a transgenic model for Alzheimer's disease. We used an APP23 mouse model prior to amyloid deposition and subjected it to chemical hypoxia treatment as induced by 3-nitropropionic acid. One hour after administration of 3-nitropropionic acid changes in the expression of the 5'-splice forms mEAAT2/5UT3, mEAAT2/5UT4, and mEAAT2/5UT5 were found in the frontal cortex, hippocampus and cerebellum of the APP23 model. In untreated APP23 animals the expression of EAAT2 splice variants was unchanged. Our results demonstrate that hypoxia facilitates alternative splicing of EAAT2 in the APP23 model. This may be a molecular mechanism linking vascular factors to early pathophysiology of Alzheimer's disease.

Syne-1 and Syne-2 play crucial roles in myonuclear anchorage and motor neuron innervation.

Proper nuclear positioning is important to cell function in many biological processes during animal development. In certain cells, the KASH-domain-containing proteins have been shown to be associated with the nuclear envelope, and to be involved in both nuclear anchorage and migration. We investigated the mechanism and function of nuclear anchorage in skeletal muscle cells by generating mice with single and double-disruption of the KASH-domain-containing genes Syne1 (also known as Syne-1) and Syne2 (also known as Syne-2). We showed that the deletion of the KASH domain of Syne-1 abolished the formation of clusters of synaptic nuclei and disrupted the organization of non-synaptic nuclei in skeletal muscle. Further analysis indicated that the loss of synaptic nuclei in Syne-1 KASH-knockout mice significantly affected the innervation sites and caused longer motor nerve branches. Although disruption of neither Syne-1 nor Syne-2 affected viability or fertility, Syne-1; Syne-2 double-knockout mice died of respiratory failure within 20 minutes of birth. These results suggest that the KASH-domain-containing proteins Syne-1 and Syne-2 play crucial roles in anchoring both synaptic and non-synaptic myonuclei that are important for proper motor neuron innervation and respiration.