Exploring the association between COVID-19 and male genital cancer risk in European population: evidence from mendelian randomization analysis.

BACKGROUND: Recently accumulated evidence indicates a potential association between COVID-19 and elevated susceptibility to cancer, including male genital cancer. However, the causal nature of this relationship remains unclear. METHODS: In this Mendelian randomization (MR) study, we investigated the potential causal relationship between COVID-19 and male genital cancer using genetic variants as instrumental variables. We utilized summary statistics from two large-scale genome-wide association studies of COVID-19 hospitalized Vs. controls, as well as data from a population-based male genital cancer database based on European ancestry. We applied stringent quality control measures to select instrumental variables, including checking for linkage disequilibrium, removing low-quality variants, and assessing the strength of the instruments using the F-statistic. We conducted the MR  analysis using the inverse-variance weighted method and several sensitivity analyses (including MR Egger and Weighted Median MR analysis) to test the robustness of our results. RESULTS: Our MR analysis revealed no causal associations between COVID-19 hospitalization and the incidence of male genital cancer. In the inverse-variance weighted analysis, no causal associations were observed between patients with COVID-19 hospitalization and the incidence of male genital cancer (odds ratio = 1.000 and 95% confidence interval = 0.998-1.001, p = 0.668). The estimated causal effect was consistent across all sensitivity analyses (including the Weighted Median, the MR Egger analysis, and the MR PROSSO analysis). The leave-one-out analysis showed that there was no any sing Single-nucleotide polymorphism significantly influencing our results. CONCLUSIONS: Our study provides evidence that there is no causal association between COVID-19 hospitalization and male genital cancer.

Analysis of the spatio-temporal evolution of sustainable land use in China under the carbon emission trading scheme: A measurement idea based on the DID model.

Sustainable development is the theme of world economic development in the 21st century. As a key part of sustainable development, sustainable land use (SLU) encompasses economic development and environmentally friendly and social progress. In recent decades, China has formulated many environmental regulatory policies to achieve sustainable development and "carbon peaking and carbon neutrality (double-carbon)" goals, among which the carbon emission trading scheme (CETS) is the most representative and provides valuable research. In this paper, we aimed to reflect the spatio-temporal evolution of SLU in China under the influence of environmental regulatory policies through an indicator measurement strategy based on the DID estimation method. The study conclusions are as follows: (1) The CETS can effectively improve SLU from the perspectives of economic development and environmentally friendly progress, and the impact has primarily been in the pilot areas. And, its effectiveness is closely linked to local locational factors. (2) With respect to the dimension of economic development, the CETS has not changed the provincial distribution patterns of SLU; rather, it continues to remain "high to low, east to west". However, regarding the environmentally friendly progress dimension, the CETS has significantly changed the provincial distribution patterns of SLU, which are characterized by spatial agglomeration with urban agglomerations such as the Pearl River Delta (PRD) and the Yangtze River Delta (YRD) as the core. (3) The screening results of the SLU indicators based on economic development showed that the CETS primarily improved the innovation capacities of pilot regions, and the impacts on economic levels were relatively small. Similarly, the screening results of the SLU indicators based on environmentally friendly progress showed that the CETS had primarily acted on reducing pollution emission intensity and strengthening greening construction, revealing only short-term effects on improving energy use efficiency. Based on the above, this paper explored the meaning and role of the CETS in more detail, with a view to providing insight into the implementation and formulation of environmental regulation policies.

An F-box protein from wheat, TaFBA-2A, negatively regulates JA biosynthesis and confers improved salt tolerance and increased JA responsiveness to transgenic rice plants.

Soil salinity is a serious problem encountered by agriculture worldwide, which will lead to many harmful effects on plant growth, development, and even crop yield. F-box protein is the core subunit of the Skp1-Cullin-F-box (SCF) complex E3 ligase and plays crucial roles in regulating the growth, development, biotic & abiotic stresses, as well as hormone signaling pathway in plants. In this study, an FBA type F-box gene TaFBA-2A was isolated from wheat (Triticum aestivum L.). This study showed that TaFBA-2A could interact with TaSKP1, and TaOPR2, the crucial enzyme involving in jasmonic acid (JA) biosynthesis. TaFBA-2A negatively regulates JA biosynthesis, probably by mediating the degradation of TaOPR2 via the ubiquitin-26S proteasome pathway. Ectopic expression of TaFBA-2A improved the salt tolerance and increased the JA responsiveness of the transgenic rice lines. In addition, some agronomic traits closely related to crop yield were significantly enhanced in the rice lines ectopic expressing TaFBA-2A. The data obtained in this study shed light on the function and mechanisms of TaFBA-2A in JA biosynthesis and the responses to salt stress and JA treatment; this study also suggested that TaFBA-2A has the potential in improving the salt tolerance and crop yield of transgenic rice plants.

Predictive value of machine learning in diagnosing cognitive impairment in patients with Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND: The current process used to diagnose cognitive impairment in patients with Parkinson's disease (PD) is unsatisfactory. More and more researchers had introduced machine learning into this field in recent years. This study explored the application of machine learning and its diagnostic performance in this field. METHODS: Since Parkinson's concurrent cognitive impairment is currently divided into different periods, most studies focus on the prodromal or early stages of Parkinson's cognitive impairment, and a few focuses on the dementia stage of Parkinson's. To ensure comprehensiveness, and model stability, we included patients with Parkinson's concurrent cognitive impairment in different periods who met the nadir criteria. A comprehensive literature search was carried out of the PubMed, Cochrane, Embase, and Web of Science databases. We used Prediction Model Risk of Bias Assessment Tool (PROBAST) to assess the risk of bias for the machine learning models covered by the included original studies. The outcome indicators included the concordance-index (C-index), sensitivity, and specificity. A meta-analysis using the random-effects model was conducted to determine the C-index, and a double variable mixed-effects model was used to determine the sensitivity and specificity. The meta-analysis in this article was completed in STATA. RESULTS: A total of 32 articles, comprising 10,778 patients and 51 prognostic models [summary c-statistic: 0.857, 95% confidence interval (CI) (0.842-0.873)], met the selection criteria and were included in this analysis. The total sensitivity and specificity of all models were 0.77 (95% CI: 0.72-0.81) and 0.83 (95% CI: 0.80-0.85), respectively, and those of the testing test were 0.85 (95% CI: 0.79-0.89), and 0.74 (95% CI: 0.70-0.78), respectively. A large part of the model showed a high risk of bias mainly because the study design was almost retrospective investigation. CONCLUSIONS: This study constitutes a detailed mapping and assessment of the machine learning for prediction in PD patients with cognitive decline, which may provide stronger discriminative performance and can be used as a potential tool for early diagnosis.

Dysfunction in Automatic Processing of Emotional Facial Expressions in Patients with Obstructive Sleep Apnea Syndrome: An Event-Related Potential Study.

AIM: Obstructive sleep apnea syndrome (OSAS) is a prevalent chronic disease characterized by sleep fragmentation and intermittent hypoxemia. Several studies suggested that electrophysiological changes and neurocognitive abnormalities occurred in OSAS patients. In this study, we compared automatic processing of emotional facial expressions schematic in OSAS patients and matched healthy controls via assessing expression-related mismatch negativity (EMMN). METHODS: Twenty-two OSAS patients (mean age 44.59 years) and twenty-one healthy controls (mean age 42.71 years) were enrolled in this study. All participants underwent Montreal Cognitive Assessment (MoCA) scale test and polysomnographic recording. An expression-related oddball paradigm was used to elicit EMMN and the electroencephalogram was recorded and analyzed. Furthermore, Pearson's correlations were calculated to discuss the correlation between neuropsychological test scores, clinical variables and electrophysiological data. RESULTS: Compared with healthy controls, OSAS sufferers demonstrated significantly reduced EMMN mean amplitudes within corresponding time intervals, regardless of happy or sad conditions. Meanwhile, we observed that amplitude of sad EMMN was larger (more negative) than happy EMNN in healthy controls, while not in patients. Moderate correlations were found between MoCA test scores, sleep parameters and EMMN amplitudes. CONCLUSION: Our findings suggested pre-attentive dysfunction of processing emotional facial expressions in patients with OSAS, without the existence of negative bias effect. Moreover, correlation analysis showed that clinical characteristics of OSAS patients could affect EMMN amplitudes. Further studies on the advantages of EMMN as clinical and electrophysiological indicators of OSAS are warranted.

Pre-attentive dysfunction of processing emotional faces in interictal migraine revealed by expression-related visual mismatch negativity.

BACKGROUND: Several investigations have indicated emotional processing impairment in migraineurs, while no report is available considering the automatic processing of emotional information. In this study, we aimed to characterize the pre-attentive processing of facial expressions in migraine sufferers by recording and analyzing expression-related visual mismatch negativity (EMMN). METHODS: Altogether, 30 migraineurs (19 females) during the interictal period and 30 age-matched healthy controls (17 females) were recruited. An expression-related oddball paradigm was used to investigate automatic emotional processing, and a group of schematic emotional faces (neutral, happy, sad) unrelated to the participant's task were employed in the experiment in order to avoid low-level processing. RESULTS: There was no significant difference in behavioral performance (the response accuracy and reaction time) between migraine patients and healthy controls. Nevertheless, the mean EMMN amplitudes within the ranges of 150-250 ms and 250-350 ms were markedly attenuated in patients compared with controls, regardless of happy or sad condition (happy minus neutral or sad minus neutral), and sad EMMN was observed to be larger than happy EMMN only in healthy participants. Moreover, these electrophysiological data directly correlated with frequency and duration of migrainous attacks. CONCLUSIONS: Our findings implied that the pre-attentive dysfunction of processing both happy and sad expressions was demonstrated in interictal migraineurs, without the existence of negative bias (sad superiority) effect. Further studies on the availability of EMMN as an evaluative marker for migraine are warranted.

Performance of facial expression classification tasks in patients with obstructive sleep apnea.

STUDY OBJECTIVES: People show a facial recognition speed advantage, termed positive classification advantage (PCA), when judging whether a facial expression is happy compared to angry or sad. This study investigated emotional face recognition by patients with obstructive sleep apnea (OSA) with impaired neurocognition. METHODS: Thirty-four patients with OSA and 26 healthy control patients who underwent 1 night of polysomnographic evaluation before recruitment were asked to complete an emotion recognition task. Accuracy rates and reaction times were recorded and analyzed using repeated-measures analysis of variance. RESULTS: When participants were asked to classify positive (happy) versus negative (sad) emotional expressions, the phenomenon of PCA disappeared. Importantly, however, compared with the control patients who showed PCA, patients with OSA identified sad faces faster but were similar in processing happy faces. CONCLUSIONS: In accordance with previous studies that showed depressive emotion in patients with OSA, our results indicate that patients with OSA show negative bias in facial expression recognition, which might lead to decline in ability of social communication.

Tidal Effects on the Longitudinal Structures of the Martian Thermosphere and Topside Ionosphere Observed by MAVEN.

Longitudinal structures in the Martian thermosphere and topside ionosphere between 150 and 200 km altitudes are studied using in situ electron and neutral measurements from the NASA Mars Atmosphere and Volatile EvolutioN (MAVEN) mission. Four time intervals are selected for comparison, during which MAVEN sampled similar local time (9.3-10.3 h) and latitude (near 20°S) regions but at different solar longitude positions (two near northern summer solstice, one each at northern vernal and autumnal equinoxes). Persistent and pronounced tidal oscillations characterize the ionosphere and thermosphere, whose longitudinal variations in density are generally in-phase with each other. Our analysis of simultaneous and collocated neutral and electron data provides direct observational evidence for thermosphere-ionosphere coupling through atmospheric tides. We conclude that the ionosphere is subject to modulation by upward-propagating thermal tides, via both tide-induced vertical displacement and photochemical reactions. Atmospheric tides constitute a ubiquitous and significant perturbation source to the ionospheric electron density, up to ~15% near 200 km.

Oral delivery of lycopene-loaded microemulsion for brain-targeting: preparation, characterization, pharmacokinetic evaluation and tissue distribution.

Lycopene is considered as a promising neuroprotector with multiple bioactivities, while its therapeutic use in neurological disorders is restricted due to low solubility, instability and limited bioavailability. Our work aimed to develop lycopene-loaded microemulsion (LME) and investigate its potentials in improving bioavailability and brain-targeting efficiency following oral administration. The blank microemulsion (ME) excipients were selected based on orthogonal design and pseudo-ternary phase diagrams, and LME was prepared using the water titration method and characterized in terms of stability, droplet size distribution, zeta potential, shape and lycopene content. The optimized LME encompassed lycopene, (R)-(+)-limonene, Tween 80, Transcutol HP and water and lycopene content was 463.03 ± 8.96 µg/mL. This novel formulation displayed transparent appearance and satisfactory physical and chemical stabilities. It was spherical and uniform in morphology with an average droplet size of 12.61 ± 0.46 nm and a polydispersity index (PDI) of 0.086 ± 0.028. The pharmacokinetics and tissue distributions of optimized LME were evaluated in rats and mice, respectively. The pharmacokinetic study revealed a dramatic 2.10-fold enhancement of relative bioavailability with LME against the control lycopene dissolved in olive oil (LOO) dosage form in rats. Moreover, LME showed a preferential targeting distribution of lycopene toward brain in mice, with the value of drug targeting index (DTI) up to 3.45. In conclusion, the optimized LME system demonstrated excellent physicochemical properties, enhanced oral bioavailability and superior brain-targeting capability. These findings provide a basis for the applications of ME-based strategy in brain-targeted delivery via oral route, especially for poorly water-soluble drugs.

Contingent negative variation for the periodicity of migraine attacks without aura.

Migraine is a primary neuropsychological disorder, although its etiology and pathogenesis are unknown. It has been reported that using contingent negative variation, the periodicity of migraine attacks is three days in adults. However, there is still a lack of relevant reports about the periodicity of migraine without aura in adults. Therefore, we investigated the changes of contingent negative variation in adults with migraine without aura from three to seven days after migraine attacks in order to provide the basis for exploring the circulation periodicity of migraine without aura. This prospective, observational study involved a group of 34 individuals with migraine without aura, who were screened during the three to seven days after a migraine attack without aura. A healthy group (31 individuals) was used as controls to assess the amplitudes of contingent negative variation and habituation of early contingent negative variation. Indices of the amplitudes included overall contingent negative variation, initial contingent negative variation, terminal contingent negative variation, and postoperative negative contingent variation. Differences between these indicators were analyzed. No significant difference was found between the patient and control groups for either the amplitudes of these measures of contingent negative variation or habituation of the early contingent negative variation for three to seven days after a migraine attack without aura (all P > 0.05). Thus, the study reported here found that the periodicity of migraine attacks without aura in adults is more than three days.

Mars Upper Atmospheric Responses to the 10 September 2017 Solar Flare: A Global, Time-Dependent Simulation.

We report the first global, time-dependent simulation of the Mars upper atmospheric responses to a realistic solar flare event, an X8.2 eruption on 10 September 2017. The Mars Global Ionosphere-Thermosphere Model runs with realistically specified flare irradiance, giving results in reasonably good agreement with the Mars Atmosphere and Volatile EvolutioN spacecraft measurements. It is found that the ionized and neutral regimes of the upper atmosphere are significantly disturbed by the flare but react differently. The ionospheric electron density enhancement is concentrated below ~110-km altitude due to enhanced solar X-rays, closely following the time evolution of the flare. The neutral atmospheric perturbation increases with altitude and is important above ~150-km altitude, in association with atmospheric upwelling driven by solar extreme ultraviolet heating. It takes ~2.5 hr past the flare peak to reach the maximum disturbance and then additional ~10 hr to generally settle down to preflare levels.

Facial expression recognition in patients with type 2 diabetes mellitus.

BACKGROUND: Facial expression recognition is an important social cognitive skill. Type 2 diabetes mellitus (T2DM) affects cognitive function. Whether facial expression recognition deficits and attention bias exist in T2DM is unknown. Facial expression search task is a commonly used paradigm to measure emotional processing. In this study, facial expression recognition features of T2DM patients were studied by facial expression search task. METHODS: Thirty outpatients with T2DM and 30 normal controls matched by sex, age and education etc. were selected. Standardized stick drawings with happy, neutral and sad emotion expressions were selected as stimulus materials, and facial expression search task was used to Search for expression targets in neutral interferers to compare the response time between the two groups. RESULTS: The reaction time of identifying the positive expression (happy) in the diabetic group and the control group was greater than that of the negative expression (sad). The response time of the diabetic group to identify positive expressions and negative expressions was greater than that of the control group. The slope of the search for positive expressions in the diabetic group was 419.14 ms, and the search slope for negative expressions in the diabetic group was 237.97 ms. The slope of the search for positive expressions in the control group was 300.4 ms, and that of the control group for negative expressions was 119.07 ms. CONCLUSIONS: In the diabetic group and the control group, the reaction time of identifying the positive expression was positively delayed compared with the negative expression, which showed a negative attention bias; Patients with type 2 diabetes significantly prolonged the response time of recognizing positive expression and negative expression without obvious clinical cognitive impairment.

Selective attention network impairment during the interictal period of migraine without aura.

Attention deficits have been demonstrated in migraine patients during the interictal period, but these findings are not consistent across all studies. These inconsistencies may arise due to the different aspects of attention measured by various psychometric tests. Current theories divide attention into three separate domains subserved by separate networks: alerting, orienting, and executive control. The attention network test (ANT) was developed to measure all three attention networks and so may reveal more specific attention deficits among migraineurs. The aim of this study was to evaluate the attention function of migraine without aura (MwoA) patients using a series of neuropsychological scales and the ANT, and to assess the relationships between attention function and headache characteristics (e.g., history, frequency, and duration of each attack). Our results showed that MwoA patients exhibited significantly longer response times (RTs) of the executive control network, whereas no significant differences were observed in alerting and orienting network RTs between groups. MwoA patients also exhibited poorer performance than health control (HC) on the Stroop III and Shape Trail test B (STT B) tests. Spearman's analysis revealed positive correlations between executive control network RTs and both frequency and duration of migraine attack. MwoA patients demonstrate impairments of the executive control network, which appear to be exacerbated by more frequent and longer migraine attacks.

Selective Impairment of Attentional Networks of Executive Control in Middle-Aged Subjects with Type 2 Diabetes Mellitus.

BACKGROUND The influence of type 2 diabetes mellitus (T2DM) on attention has been elusive. The Attention Network Test (ANT) was developed to evaluate the functioning of 3 individual attentional networks: orienting, alerting, and executive control. The purpose of this study was to use the ANT to assess attentional function and its sub-components in T2DM patients ages 40-60 years. MATERIAL AND METHODS Thirty T2DM patients and 30 healthy controls ages 40-60 years were recruited in this investigation. The ANT was used to statistically compare the efficiency among 3 sub-components of the attention networks between middle-aged T2DM patients (n=30) and gender-, age-, and education-matched healthy controls (n=30). RESULTS The ANT demonstrated a significant difference in executive control network between the T2DM patients and healthy controls (t=3.242, P=0.002), whereas no significant difference was observed regarding the domains of alerting (t=0.515, P=0.609) and orienting control (t=0.078, P=0.938) between the T2DM patient group and the healthy control group. Moreover, the mean reaction time in the ANT in the T2DM patients was significantly longer compared with that in the healthy controls (t=3.561, P=0.001). CONCLUSIONS The ANT reveals significant impairment in the executive control of middle-aged patients diagnosed with T2DM, whereas no significant impairment was observed in the domains of alerting and orienting.

Flavonoids extracted from leaves of Diospyros kaki regulates RhoA activity to rescue synapse loss and reverse memory impairment in APP/PS1 mice.

Synapse dysfunction is an early hallmark of Alzheimer's disease (AD), and was considered to be closely related to memory loss. The molecular mechanisms that trigger synapse loss and dysfunction remain poorly understood. Increasing evidence shows a link between Rho GTPases and synapse plasticity. Rho GTPases play a role in controlling synapse function by regulating actin cytoskeleton and dendritic spines. Observations have suggested that phytochemicals, such as flavonoids, alleviate cognition impairment in AD. However, to date, the link between the protective effect of flavonoids on AD and the activity of Rho GTPases remains uninvestigated. In this study, APP/PS1 mice were used as an AD model, and we found that synapse loss occurred in AD mice brain. Flavonoids extracted from leaves of Diospyros kaki (FLDK) were used to investigate whether its protective effects on synapse were related to Rho GTPases activity in AD mice. The Rho GTPases Activation Kit showed that Ras homologous member A (RhoA)-GTP was significantly higher and Ras-related C3 botulinum toxin substrate 1 (Rac1)-GTP was significantly lower in APP/PS1 mice than in normal mice, and RhoA-GTP activity was significantly inhibited by FLDK. We also found that FLDK improved learning and memory function, and antagonized the downregulation expressions of synapse-related proteins such as synaptophysin and drebrin. These findings suggest that FLDK is a potential therapeutic agent for AD, and modulation of Rho GTPases activity might contribute toward its protective effect.

Atmospheric escape from the TRAPPIST-1 planets and implications for habitability.

The presence of an atmosphere over sufficiently long timescales is widely perceived as one of the most prominent criteria associated with planetary surface habitability. We address the crucial question of whether the seven Earth-sized planets transiting the recently discovered ultracool dwarf star TRAPPIST-1 are capable of retaining their atmospheres. To this effect, we carry out numerical simulations to characterize the stellar wind of TRAPPIST-1 and the atmospheric ion escape rates for all of the seven planets. We also estimate the escape rates analytically and demonstrate that they are in good agreement with the numerical results. We conclude that the outer planets of the TRAPPIST-1 system are capable of retaining their atmospheres over billion-year timescales. The consequences arising from our results are also explored in the context of abiogenesis, biodiversity, and searches for future exoplanets. In light of the many unknowns and assumptions involved, we recommend that these conclusions must be interpreted with due caution.

Flavonoid-rich ethanol extract from the leaves of Diospyros kaki attenuates cognitive deficits, amyloid-beta production, oxidative stress, and neuroinflammation in APP/PS1 transgenic mice.

Amyloid-ß peptide (Aß) initiates a cascade of pathological events, including activation of microglial cells, oxidative stress, and inflammation, leading to neuronal death and the typical pathological changes in Alzheimer's disease (AD). Flavonoids have been reported to exert neuroprotective activities, not only through their generally accepted antioxidant effects, but also through their ability to protect against neurotoxin-induced injury. Flavonoids reduce Aß production, inhibit neuroinflammation, increase cerebrovascular function, and improve cognitive performance. Here, we analyzed the effects of a flavonoid-rich ethanol extract from the leaves of Diospyros kaki (FLDK) in APP/PS1 transgenic mice. We found that oral treatment with FLDK reversed learning and memory impairment, reduced Aß burden and expression of ß-site amyloid precursor protein cleavage enzyme 1 (BACE1), and decreased microglial activation in senile plaques. FLDK restored antioxidant enzyme activities, as well as reduced the lipid peroxidation product, malondialdehyde, and inflammatory mediators. These results demonstrate that FLDK alleviates cognitive decline and reduces Aß burden, microglial activation, oxidative stress, and inflammation responses. Thus, FLDK treatment may be a potential therapeutic strategy for preventing and treating AD, at least in part via its anti-oxidant and anti-inflammatory biological activities and its effect on the Aß producing enzyme BACE1.

Flavonoid-Rich Ethanol Extract from the Leaves of Diospyros kaki Attenuates D-Galactose-Induced Oxidative Stress and Neuroinflammation-Mediated Brain Aging in Mice.

Aging is a major factor that contributes to neurological impairment and neuropathological changes, such as inflammation, oxidative stress, neuronal apoptosis, and synaptic dysfunction. Flavonoids act as protective antioxidant and anti-inflammatory agents against various age-related neurodegenerative diseases. Here, we investigated the protective effect and mechanisms of the flavonoid-rich ethanol extract from the leaves of Diospyros kaki (FELDK) in the cortex and hippocampus of D-galactose- (gal-) aged mice. Our results showed that FELDK treatment restored memory impairment in mice as determined by the Y-maze and Morris water maze tests. FELDK decreased oxidative stress levels via inhibiting reactive oxygen species (ROS) and malondialdehyde (MDA) production and elevating antioxidative enzymes. FELDK also alleviated D-gal-induced neuroinflammation via suppressing the expression of advanced glycation end products (AGEs) and receptor for AGEs (RAGE) and activating microgliosis and astrocytosis, nuclear factor kappa B (NF-κB) nuclear translocation, and downstream inflammatory mediators. Moreover, FELDK inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt and C-jun N-terminal kinase (JNK) apoptotic signaling pathways and ameliorated the impairment of synapse-related proteins. Hence, these results indicate that FELDK exerts neuroprotective effects on D-gal-induced brain aging. Thus, FELDK may be a potential therapeutic strategy for preventing and treating age-related neurodegenerative diseases such as Alzheimer's disease.

RAGE-Specific Inhibitor FPS-ZM1 Attenuates AGEs-Induced Neuroinflammation and Oxidative Stress in Rat Primary Microglia.

Advanced glycation end products (AGEs) enhance microglial activation and intensify the inflammatory response and oxidative stress in the brain. This process may occur due to direct cytotoxicity or interacting with AGEs receptors (RAGE), which are expressed on the surface of microglia. FPS-ZM1 is a high-affinity but nontoxic RAGE-specific inhibitor that has been recently shown to attenuate the Aß-induced inflammatory response by blocking the ligation of Aß to RAGE. In this study, we further investigated the effect of FPS-ZM1 on the AGEs/RAGE interaction and downstream elevation of neuroinflammation and oxidative stress in primary microglia cells. The results suggested that FPS-ZM1 significantly suppressed AGEs-induced RAGE overexpression, RAGE-dependent microglial activation, nuclear translocation of nuclear factor kappaB p65 (NF-κB p65), and the expression of downstream inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) and inducible nitric oxide synthase (iNOS)/nitric oxide (NO). Furthermore, FPS-ZM1 attenuated AGEs-stimulated NADPH oxidase (NOX) activation and reactive oxygen species (ROS) expression. Finally, FPS-ZM1 elevated the levels of transcription factors nuclear-factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1), as well as decreased antioxidant capacity and increased production of oxidative species. Our results suggest that FPS-ZM1 may be neuroprotective through attenuating microglial activation, oxidative stress and inflammation by blocking RAGE.

Effects of RAGE-Specific Inhibitor FPS-ZM1 on Amyloid-ß Metabolism and AGEs-Induced Inflammation and Oxidative Stress in Rat Hippocampus.

An increased level of advanced glycation end products (AGEs) is observed in brains of patients with Alzheimer's disease (AD). AGEs and receptor for AGEs (RAGE) play important roles in the pathogenesis of AD. FPS-ZM1 is a high-affinity RAGE-specific blocker that inhibits amyloid-ß binding to RAGE, neurological damage and inflammation in the APP(sw/0) transgenic mouse model of AD. FPS-ZM1 is not toxic to mice and can easily cross the blood-brain barrier. In this study, an AGEs-RAGE-activated rat model were established by intrahippocampal injection of AGEs, then these rats were treated with intraperitoneal administration of FPS-ZM1 and the possible neuroprotective effects were investigated. We found that AGEs administration induced an-regulation of Abeta production, inflammation, and oxidative stress, and an increased escape latency of rats in the Morris water maze test, all of these are significantly reduced by FPS-ZM1 treatment. Our results suggest that the AGEs-RAGE pathway is responsible for cognitive deficits, and therefore may be a potential treatment target. FPS-ZM1 might be a novel therapeutic agent to treat AD patients.