Carbon-dots-referenced metal-organic frameworks for chemical sensing of tumor/mood biomarker 5-hydroxyindoleacetic acid in human urine: Covalent grafting blue-emitting carbon dots onto red-emitting MOF.

5-HIAA (5-hydroxyindoleacetic acid) is a metabolite for 5-hydroxytryptamine which is excreted in urine and reflects human homeostatic sate. Thus, its monitoring is of great important for clinical diagnosis. In this work, blue-emitting carbon dots (BCD) were firstly synthesize and then covalently grafted onto red-emitting MOF (EuBTC), resulting in a composite sensing platform (BCD@EuBTC) with two emission bands (blue emission peaking at 441 nm and red emission peaking at 616 nm). This composite structure was characterized by means of XRD, IR, TGA, N2 adsorption/desorption, and SEM/TEM. It was found that BCD was grafted on EuBTC surface, not loaded in its micropores, with doping level of 5.02 wt%. 5-HIAA replaced and released the BCD in BCD@EuBTC. The released BCD showed strong blue emission. In the meanwhile, EuBTC red emission was quenched by 5-HIAA thermal relaxation. As a consequence, a ratiometric sensing signal was observed for 5-HIAA. A linear working calibration curve was fitted as F/F0 = 0.588 + 1.598*[5-HIAA], R2 = 0.999, with detection of limit (LOD) determined as 0.3 µM, working region of 0.3-70 µM, and good selectivity. The practical sensing performance of BCD@EuBTC for 5-HIAA in human urine was confirmed, with recovery of 103%.

Associations among Body Mass Index, Waist-to-Hip Ratio, and Cognitive Impairment Tend to Follow an Opposite Trend and Are Sex Specific: A Population-Based Cross-Sectional Study in a Rural Area of Xi'an, China.

INTRODUCTION: The relationship between obesity and cognitive impairment (CI) is highly heterogeneous in previous studies, which may be due to insufficient consideration of anthropometric indicators and sex. This study compared the cross-sectional relationships among body mass index (BMI), waist-to-hip ratio (WHR), and CI among people aged ≥40 years, and sex-specific relationships were also considered. METHODS: This was a population-based cross-sectional study with a cluster sampling design. CI was defined as a Mini-Mental State Examination score lower than the cutoff value. Multivariate logistic regression was used. BMI and WHR were fitted as both restricted cubic splines and categorical data. Stratified analysis and interaction analysis were performed to explore the sex-specific relationship. RESULTS: A total of 1,792 subjects (40.5% male) were analyzed, and 230 were confirmed to have CI. The relationships among BMI, WHR, and CI were significant (poverall = 0.023, pnonlinear = 0.097; poverall = 0.017, pnonlinear = 0.078, respectively) but exhibited an opposite trend in the total population in the analyses with BMI and WHR as restricted cubic splines. Further categorical analyses showed that subjects with a BMI <23 kg/m2 tended to have a higher risk of CI than those with BMI ≥23 kg/m2 (16.2% vs. 11.8%, p = 0.017; OR = 1.366 [0.969-1.926], p = 0.075), and subjects with a WHR >0.92 had a significantly higher risk of CI than those with a WHR ≤0.92 (11.7% vs. 16.2%, p = 0.011; OR = 1.619 [1.161-2.258], p = 0.005). In addition, the relationship between a low BMI and CI was more significant in males (p = 0.034), while the relationship between a high WHR and CI was more significant in females (p = 0.002). Further studies are needed to confirm the sex differences because of the marginal significance result in the interaction analysis (p = 0.051 for interaction term BMI × sex; p = 0.056 for interaction term WHR × sex). CONCLUSION: The relationships among BMI, WHR, and CI exhibit an opposite trend. A low BMI or high WHR was positively associated with CI, which was more prominent in males for a low BMI and females for a high WHR.

The Relationship Between Pre-existing Coronary Heart Disease and Cognitive Impairment Is Partly Explained by Reduced Left Ventricular Ejection Fraction in the Subjects Without Clinical Heart Failure: A Cross-Sectional Study.

Background: Coronary heart disease (CHD) is closely associated with cognitive impairment, especially in severe cases of heart failure. However, it is unclear whether cardiac systolic function plays a role in the relationship between pre-existing CHD and cognitive impairment in subjects without clinical heart failure. Methods: In total, 208 subjects from the First Affiliated Hospital of Xi'an Jiaotong University were recruited from June 2014 to January 2015, and were divided into CHD (n = 118) and non-CHD (n = 90) groups according to the inclusion and exclusion criteria. The global cognitive function of all subjects was assessed by the Mini-Mental State Examination (MMSE) and cognitive impairment was defined as the score lower than the cutoff value. Left ventricular ejection fraction (LVEF) was measured using transthoracic echocardiograms. The relationship among pre-existing CHD, LVEF, and cognitive impairment was analyzed by multivariate logistic regression. Results: In total, 34 subjects met the criteria of cognitive impairment. Univariate analysis showed that the cognitive impairment prevalence in the CHD group was significantly higher than that in the non-CHD group (22.0 vs. 8.9%, p = 0.011). Multivariate logistic analysis revealed that CHD was significantly associated with a higher risk of cognitive impairment (odds ratio [OR] = 3.284 [95% CI, 1.032-10.450], p = 0.044) after adjusting for confounds except for LVEF. However, the OR of CHD decreased (OR = 2.127 [95% CI, 0.624-7.254], p = 0.228) when LVEF was further corrected as a continuous variable, and LVEF was negatively associated with the risk of cognitive impairment (OR = 0.928 [95% CI, 0.882-0.976], p = 0.004). Conclusion: Pre-existing CHD is associated with a higher risk of cognitive impairment, and such an association can be considerably explained by reduced LVEF. An impaired cardiac systolic function may play a key role in the relationship between CHD and cognitive impairment among patients with pre-heart failure conditions.

Up-Converting Nanocrystals Modified With Fluorescent Markers for the Detection of Amino Acids: Preparation, Characterization, and Sensing Performance.

The present work was devoted to developing rhodamine-like chemosensing systems for cysteine (Cys) optical recognition. Aiming at low background light and minimal photobleaching effect, up-converting nanocrystals were firstly synthesized and latterly coated by α-cyclodextrin, and finally used as an exciting host. An energy transfer procedure from these nanocrystals and rhodamine sensors was established via their spectroscopic analysis and emissive decay dynamics comparison. The binding dynamics of our chemosensors for Cys were revealed to have uncomplicated recognition with a stoichiometric ratio of 1 vs. 1. The addition of cysteine increased the emission intensity of the chemosensors. As a consequence, the luminescence off-on effect with sensing selectivity and linear sensing behavior for Cys was demonstrated. Sulfur modification on our chemosensors was shown to be effective in improving their selectivity and photostability.

Glypican 4 Regulates Aß Internalization in Neural Stem Cells Partly via Low-Density Lipoprotein Receptor-Related Protein 1.

Neural stem cell (NSC) damage has been reported in patients with Alzheimer's disease. Intracellular Aß plays a vital role in NSC damage. Heparan sulfate proteoglycans are potent mediators of Aß enrichment in the brain. We hypothesized the heparan sulfate proteoglycan glypican 4 (Gpc4) regulates Aß internalization by NSCs. We evaluated Gpc4 expression in NSCs from P0-P2 generations using immunofluorescence. Adenovirus and lentivirus were used to regulate Gpc4 expression in NSCs and APP/PS1 mice, respectively. Co-immunoprecipitation was used to determine the relationship between Gpc4, Aß, and low-density lipoprotein receptor-related protein 1 (LRP1). Intracellular Aß concentrations were detected using enzyme-linked immunosorbent assay and immunofluorescence. The role of Gpc4/LRP1 on toxic/physical Aß-induced effects was evaluated using the JC-1 kit, terminal deoxynucleotidyl transferase dUPT nick end labeling, and western blotting. Gpc4 was stably expressed in NSCs, neurons, and astrocytes. Gpc4 was upregulated by Aß in NSCs and regulated Aß internalization. Gpc4 attenuation reduced Aß uptake; Gpc4 overexpression increased Aß uptake. Gpc4 regulated Aß internalization through LRP1 and contributed to Aß internalization and toxic/physical concentrations of Aß-induced mitochondrial membrane potential and cell apoptosis, partly via LRP1. Therefore, Gpc4 is a key regulator of Aß enrichment in NSCs. Inhibiting Gpc4 rescued the Aß-induced toxic effect and attenuated the nontoxic Aß enrichment into intracellular toxic concentrations. Gpc4 contributed to Aß internalization and toxic/physical concentrations of Aß-induced mitochondrial membrane potential damage and cell apoptosis, partly via LRP1. These findings suggest a potential role of Gpc4 in treating Alzheimer's disease at an early stage, by targeting NSCs.

Comorbid SUNCT Syndrome and Opalski Syndrome Caused by Dorsolateral Medullary Infarction.

Opalski syndrome is a rare variation of lateral medullary syndrome (LMS) accompanied by ipsilateral hemiparesis. Short-lasting unilateral neuralgiform headaches with conjunctival injection and tearing (SUNCT) is a rare headache syndrome which belongs to the trigeminal autonomic cephalalgias. SUNCT syndrome has been previously described in association with LMS. We here describe a case of SUNCT syndrome with Opalski syndrome caused by dorsolateral medullary infarction.

Interactive relations of type 2 diabetes and abdominal obesity to cognitive impairment: A cross-sectional study in rural area of Xi'an in China.

AIMS: Type 2 diabetes and obesity, which are frequently comorbid, have been associated with cognitive impairment. We aim to examine the potential modulating effect between obesity and diabetes on cognitive impairment. METHODS: We recruited 865 adults (aged ≥55years) lived in a village of Xi'an in China from October 2014 to March 2015. All participants underwent biomedical and neuropsychological assessment. Relations of diabetes and abdominal obesity to cognitive impairment were examined in multiple regression models. RESULTS: A total of 155 participants (17.9%) presented with the diagnosis of cognitive impairment. Diabetes or obesity alone wasn't significantly associated with cognitive impairment. Interaction analysis showed a significant interaction between abdominal obesity and diabetes on cognitive impairment. Stratified multivariate analysis revealed that the association between diabetes and cognitive impairment was positive in participants with abdominal obesity (OR 2.436, 95% CI 1.345-4.411, p=0.003, in diabetics with high WC, and OR 2.348, 95% CI 1.373-4.014, p=0.002, in diabetics with high WHR), but negative in those without abdominal obesity. CONCLUSIONS: Type 2 diabetes interacts with abdominal obesity to be associated with an increased risk of cognitive impairment by more than two times.

The Research on the Relationship of RAGE, LRP-1, and Aß Accumulation in the Hippocampus, Prefrontal Lobe, and Amygdala of STZ-Induced Diabetic Rats.

Diabetes mellitus (DM) has been regarded as an important risk factor for Alzheimer's disease (AD), and diabetic patients and animals have shown cognitive dysfunction. More research has shown that the amyloid-ß (Aß), which is a hallmark of AD, was found deposited in the hippocampus of diabetic rats. This Aß accumulation is regulated by the receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein (LRP-1). However, the expression of RAGE and LRP-1 in diabetic rats is not very clear. In the present study, we used streptozotocin (STZ)-induced diabetic rats to investigate whether the expression of RAGE and LRP-1 is related to Aß1-42 deposition at the hippocampus, prefrontal lobe, and amygdala in DM. We found that diabetic rats had longer escape latency and less frequency of entrance into the target zone than that of the control group (P < 0.05) in the Morris water maze (MWM) test. The Aß1-42 expression in the hippocampus and prefrontal lobe significantly increased in the DM group compared to the control group (P < 0.05). RAGE increased (P < 0.05), while LRP-1 decreased (P < 0.05) in the hippocampus tissue and prefrontal lobe tissue of DM rats. The Aß1-42 deposition was correlated with RAGE positively (P < 0.05), but with LRP-1 negatively (P < 0.05). Further, the expression levels of Aß1-42, RAGE, and LRP-1 were not changed in the amygdala between the diabetic rats and the control group. These findings indicated that upregulating RAGE and/or downregulating LRP-1 at the hippocampus and the prefrontal lobe contributed to the Aß1-42 accumulation and then further promoted the cognitive impairment of diabetic rats.

Tongxinluo improves cognition by decreasing ß-amyloid in spontaneous hypertensive rats.

ß-Amyloid (Aß) accumulation in the brain is the major pathophysiology of Alzheimer disease (AD). Hypertension is a risk factor for AD by promoting Aß deposition. Traditional Chinese medicinal compound tongxinluo (TXL) can improve blood circulation and endothelium-dependent vasodilation. This study investigates the effects of TXL on cognition and Aß using spontaneously hypertensive rats (SHRs). TXL was intragastrically administered to SHRs at low-dose, mid-dose and high-dose for 15, 30 or 60days. Cognition was evaluated with a Morris Water Maze (MWM). Aß in the brain was detected by western blot, ELISA and Thioflavin-S staining. Western blot and RT-PCR were employed to exam the expression of receptor for advanced glycation end products (RAGE), low-density lipoprotein receptor-related protein-1 (LRP-1) and amyloid precursor protein (APP). After TXL treatment for 60days, compared with the vehicle, the number of crossed platform and the time spent in the target quadrant increased in parallel with the increasing length of treatment in MWM. Moreover, the Aß in the hippocampus significantly decreased compared to the vehicle group, both in western blot and ELISA. Additionally, TXL reduced RAGE expression in a dose- and time-depended manner, but LRP-1 expression had no difference between TXL groups and vehicle groups. Furthermore, the ß-secretase expression was significantly decreased compared to the vehicle group, but APP expression had no difference. In conclusion, TXL improved cognition and decreased Aß in SHRs in a dose- and time-dependent manner, the underlying mechanism may involved in inhibiting RAGE and ß-secretase expression.

Autophagy-lysosome dysfunction is involved in Aß deposition in STZ-induced diabetic rats.

ß-Amyloid (Aß) deposition has a central role in the pathogenesis of Alzheimer disease (AD). Previous studies have indicated that as a risk factor for AD, diabetes mellitus (DM) could induce Aß deposition in the brain, but the mechanism is not fully elucidated. Autophagy-lysosome is a cellular pathway involved in protein and organelle degradation. In the present study, we used streptozotocin (STZ)-induced diabetic rats to investigate whether autophagy-lysosome is related to Aß1-42 clearance in DM. We found that DM rats had a longer escape latency and less frequent entry into the target zone than that of the control group (p<0.05) in the Morris water maze test. Meanwhile, hippocampal neuron damage and apoptosis (p<0.05) were found in the DM rats. The Aß1-42 expression in the hippocampus significantly increased in the DM group compared with the control group (p<0.05). The markers of autophagy, beclin-1 and LC3 II, were increased (p<0.05), whereas LC3 I was decreased (p<0.05), and the ratio of LC3 II / I was increased as the time advanced (p<0.01). LAMP1 and LAMP2, which are the markers of lysosome function, were decreased in the hippocampus of DM rats (p<0.05). The Aß1-42 deposition was correlated with beclin-1, LC3 II, and LC3 I positively (p<0.05), but with LAMP1 and LAMP2 negatively (p<0.05). These findings indicate that DM activated autophagy, but lysosome function was impaired. Autophagy-lysosome dysfunction may be involved in the Aß deposition in diabetic cognitive impairment.

Treatment effects of tanshinone IIA against intracerebroventricular streptozotocin induced memory deficits in mice.

Our previous studies demonstrated that tanshinone IIA (tan IIA) has significant protective effects against the neurotoxicity induced by ß-amyloid protein (Aß) in cultured cortical neurons and PC12 cells. This study was designed to investigate the protective effects of tan IIA against memory deficits induced by streptozotocin (STZ) in a model of sporadic Alzheimer's disease (AD). STZ was injected twice intracerebroventrically (3mg/kg ICV) on alternate days (day 1 and day 3) in mice. Daily treatment with tan IIA (20, 40, and 80mg/kg, i.g.) starting from the first dose of STZ for 28 days showed a dose dependent improvement in STZ induced memory deficits as assessed by Morris water maze (MWM) test. Nissl staining results confirmed the protective effects of tan IIA on cerebral cortical and hippocampal neurons damage induced by STZ. In addition, tan IIA markedly reduced STZ induced elevation in acetylcholinesterase (AChE) activity and malondialdehyde (MDA) level, and significantly inhibited STZ induced reduction in superoxide dismutases (SOD) and glutathione peroxidase (GSH-Px) activities in the parietal cortex and hippocampus. Moreover, tan IIA attenuated p38 mitogen activated protein kinase (MAPK) phosphorylation in the parietal cortex and hippocampus. These findings demonstrate that tan IIA prevents STZ induced memory deficits may be attributed to ameliorating neuronal damage, restoring cholinergic function, attenuating oxidative stress and blocking p38 MAPK signal pathway activation. Based on our previous studies, the present study provides further support for the potential use of tan IIA in the treatment of AD.

Association of Vitamin D Receptor Cdx-2 Polymorphism With Cancer Risk: A Meta-Analysis.

Vitamin D receptor (VDR) Cdx-2 polymorphism (rs11568820) has been indicated to be associated to cancer susceptibility. However, published studies reported mixed results. This meta-analysis was conducted to get a more accurate estimation of the association between Cdx-2 polymorphism and cancer risk.We identified 25 independent studies with a total of 34,018 subjects published prior to March 2015. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the susceptibility to cancer. Separate analyses were conducted on features of the population such as ethnicity, source of controls, and cancer types.Meta-analysis results showed that Cdx-2 polymorphism significantly increased cancer risk in the homozygous model in overall analysis. According to the further stratified analysis, significant association was found between Cdx-2 variant and cancer risk in American-Africans in the homozygous, recessive, and dominant comparison models. However, no significant associations were found in Caucasians and Asians. When stratified by different cancer types, significant association was observed between Cdx-2 variant and an increased risk of colorectal cancer in the homozygous, recessive, and dominant models. In addition, ovarian cancer susceptibility increased based on the homozygous and dominant comparison models.Our study indicated that VDR Cdx-2 polymorphism was associated with an increased cancer risk, particularly in American-Africans, colorectal, and ovarian cancers. However, other factors may impact on the association. Further multicenter studies are needed to confirm the effects of Cdx-2 polymorphism on cancer susceptibility.