Deficiency of leucine-rich repeat kinase 2 aggravates thioacetamide-induced acute liver failure and hepatic encephalopathy in mice.

BACKGROUND: Hepatic encephalopathy (HE) is closely associated with inflammatory responses. However, as a crucial regulator of the immune and inflammatory responses, the role of leucine-rich repeat kinase 2 (LRRK2) in the pathogenesis of HE remains unraveled. Herein, we investigated this issue in thioacetamide (TAA)-induced HE following acute liver failure (ALF). METHODS: TAA-induced HE mouse models of LRRK2 wild type (WT), LRRK2 G2019S mutation (Lrrk2G2019S) and LRRK2 knockout (Lrrk2-/-) were established. A battery of neurobehavioral experiments was conducted. The biochemical indexes and pro-inflammatory cytokines were detected. The prefrontal cortex (PFC), striatum (STR), hippocampus (HIP), and liver were examined by pathology and electron microscopy. The changes of autophagy-lysosomal pathway and activity of critical Rab GTPases were analyzed. RESULTS: The Lrrk2-/--HE model reported a significantly lower survival rate than the other two models (24% vs. 48%, respectively, p < 0.05), with no difference found between the WT-HE and Lrrk2G2019S-HE groups. Compared with the other groups, after the TAA injection, the Lrrk2-/- group displayed a significant increase in ammonium and pro-inflammatory cytokines, aggravated hepatic inflammation/necrosis, decreased autophagy, and abnormal phosphorylation of lysosomal Rab10. All three models reported microglial activation, neuronal loss, disordered vesicle transmission, and damaged myelin structure. The Lrrk2-/--HE mice presented no severer neuronal injury than the other genotypes. CONCLUSIONS: LRRK2 deficiency may exacerbate TAA-induced ALF and HE in mice, in which inflammatory response is evident in the brain and aggravated in the liver. These novel findings indicate a need of sufficient clinical awareness of the adverse effects of LRRK2 inhibitors on the liver.

Associative role of HLA-DRB1 as a protective factor for susceptibility and progression of Parkinson's disease: a Chinese cross-sectional and longitudinal study.

Background: Previous genome-wide association studies investigating the relationship between the HLA-DRB1 and the risk of Parkinson's disease (PD) have shown limited racial diversity and have not explored clinical heterogeneity extensively. Methods: The study consisted of three parts: a case-control study, a cross-sectional study, and a longitudinal cohort study. The case-control study included 477 PD patients and 477 healthy controls to explore the relationship between rs660895 and PD susceptibility. The cross-sectional study utilized baseline data from 429 PD patients to examine the correlation between rs660895 and PD features. The longitudinal study included 388 PD patients who completed a 3-year follow-up to investigate the effects of rs660895 on PD progression. Results: In the case-control study, HLA-DRB1 rs660895-G allele was associated with a decreased risk of PD in allele model (adjusted OR=0.72, p = 0.003) and dominant model (AG + GG vs. AA: adjusted OR = 0.67, p = 0.003). In the cross-sectional analysis, there was no association between rs660895 and the onset age, motor phenotype, or initial motor symptoms. In the longitudinal analysis, PD patients with the G allele exhibited a slower progression of motor symptoms (MDS-UPDRS-III total score: ß = -5.42, p < 0.001, interaction ptime × genotype < 0.001) and non-motor symptoms (NMSS score: ß = -4.78, p = 0.030, interaction ptime × genotype < 0.001). Conclusion: Our findings support HLA-DRB1 rs660895-G allele is a protective genetic factor for PD risk in Chinese population. Furthermore, we also provide new evidence for the protective effect of rs660895-G allele in PD progression.

AhR agonists screening and identification in indoor dust based on non-target chemical analysis by GC-Q-TOFMS and biological effect evaluation referring to ToxCast/Tox21 database.

Numerous studies reported the concentration of agonists of aryl hydrocarbon receptor (AhR) in indoor dust by target chemical analysis or the biological effects of activating the AhR by indoor extracts, but the major AhR agonists identification in indoor dust were rarely researched. In the present study, the indoor dust samples were collected for 7-ethoxyresorufin O-deethylase (EROD) assay and both non-targeted and targeted chemical analysis for AhR agonists by gas chromatography quadrupole time-of-flight mass spectrometry and gas chromatography-mass spectrometry analysis. Coupled with non-targeted analysis and toxicity Forecaster (ToxCast)/Tox21 database, 104 ToxCast chemicals were screened to be able to induce EROD response. The combination of targeted chemical analyses and biological effects evaluation indicated that PAHs, dibutyl phthalate (DBP) and Cypermethrin might be the important AhR-agonists in different indoor dust and mainly contributed in 1.84%-97.56 % (median: 26.62%) of total observed biological effects through comparing toxic equivalency quotient derived from chemical analysis with biological equivalences derived from bioassay. DBP and cypermethrin seldom reported in the analysis of AhR agonists should raise great concern. In addition, the present results in experiment of synthetic solution of 4 selected AhR-agonists pointed out that some unidentified AhR agonists existed in indoor dust.

Accelerated biological aging as potential mediator mediates the relationship between pro-inflammatory diets and the risk of depression and anxiety: A prospective analysis from the UK biobank.

BACKGROUND: The relationship between inflammatory dietary patterns and the risk of depression/anxiety has not been clearly established due to differences in study populations, geographic regions, sex, and methods of calculating the inflammatory index. METHODS: We drew upon a prospective cohort in the UK Biobank and calculated the energy-adjusted dietary inflammatory index (E-DII). The follow-up time was defined from the date of completing the last dietary survey questionnaire to the date of diagnosis of depression, anxiety, phobic anxiety, other types of anxiety, death, loss to follow-up, or the respective censoring dates for England (September 30, 2021), Scotland (July 31, 2021), and Wales (February 28, 2018). The final follow-up times end on September 30, 2021, July 31, 2021, and February 28, 2018, for England, Scotland, and Wales, respectively. During the follow-up process, if a participant develops the condition, dies, or is lost to follow-up, the follow-up is terminated. We used Cox regression to evaluate the connection between E-DII and depression/anxiety. We employed restricted cubic spline curves for nonlinear relationships. We also conducted mediation analyses to explore whether biological age mediated the relationship between E-DII and depression. Additionally, we investigated whether genetic susceptibility modified the relationship between E-DII and depression through interaction modeling. RESULTS: In the final analysis, we included a total of 151,295, 159,695, 165,649, and 160,097 participants for the analysis of depression, all types of anxiety, specific phobia anxiety, and other types of anxiety, respectively. For every one-unit increase in E-DII, the risk of experiencing depression and anxiety increased by 5 % and 4 %, respectively. We identified a "J"-shaped nonlinear relationship (P for nonlinear = 0.003) for both depression and anxiety. A significant association with an elevated risk of depression was observed when E-DII exceeded 0.440, and an increased risk of anxiety was noted when E-DII was more than -0.196. Mediation analysis demonstrated that PhenoAge age acceleration (AA) (For depression, proportion of mediation = 9.6 %; For anxiety, proportion of mediation = 10.1 %) and Klemera-Doubal method Biological Age (KDM AA) (For depression, proportion of mediation = 2.9 %; For anxiety, proportion of mediation = 5.1 %) acted as mediators between E-DII and the development of depression and anxiety (P < 0.05). CONCLUSIONS: Diets with pro-inflammatory characteristics are associated with a heightened risk of depression and anxiety. Furthermore, the association of pro-inflammatory diets and depression is mediated by biological age.

Cortical thickness and white matter microstructure predict freezing of gait development in Parkinson's disease.

The clinical applications of the association of cortical thickness and white matter fiber with freezing of gait (FoG) are limited in patients with Parkinson's disease (PD). In this retrospective study, using white matter fiber from diffusion-weighted imaging and cortical thickness from structural-weighted imaging of magnetic resonance imaging, we investigated whether a machine learning-based model can help assess the risk of FoG at the individual level in patients with PD. Data from the Parkinson's Disease Progression Marker Initiative database were used as the discovery cohort, whereas those from the Fujian Medical University Union Hospital Parkinson's Disease database were used as the external validation cohort. Clinical variables, white matter fiber, and cortical thickness were selected by random forest regression. The selected features were used to train the support vector machine(SVM) learning models. The median area under the receiver operating characteristic curve (AUC) was calculated. Model performance was validated using the external validation cohort. In the discovery cohort, 25 patients with PD were defined as FoG converters (15 men, mean age 62.1 years), whereas 60 were defined as FoG nonconverters (38 men, mean age 58.5 years). In the external validation cohort, 18 patients with PD were defined as FoG converters (8 men, mean age 66.9 years), whereas 37 were defined as FoG nonconverters (21 men, mean age 65.1 years). In the discovery cohort, the model trained with clinical variables, cortical thickness, and white matter fiber exhibited better performance (AUC, 0.67-0.88). More importantly, SVM-radial kernel models trained using random over-sampling examples, incorporating white matter fiber, cortical thickness, and clinical variables exhibited better performance (AUC, 0.88). This model trained using the above mentioned features was successfully validated in an external validation cohort (AUC, 0.91). Furthermore, the following minimal feature sets that were used: fractional anisotropy value and mean diffusivity value for right thalamic radiation, age at baseline, and cortical thickness for left precentral gyrus and right dorsal posterior cingulate gyrus. Therefore, machine learning-based models using white matter fiber and cortical thickness can help predict the risk of FoG conversion at the individual level in patients with PD, with improved performance when combined with clinical variables.

The cumulative live birth rates of 18 593 women with progestin-primed ovarian stimulation-related protocols and frozen-thawed transfer cycles.

STUDY QUESTION: What are the odds of achieving pregnancy when adopting progestin-primed ovarian stimulation (PPOS)-related protocols combined with repetitive frozen-thawed transfer (FET) cycles in patients with different clinical characteristics? SUMMARY ANSWER: The cumulative live birth rates (CLBRs) of women undergoing different PPOS-related protocols can be significantly and consistently enhanced within six FET cycles when the female age is <40 years (or even <45 years) and when >5 oocytes are retrieved, regardless of antral follicle count (AFC). WHAT IS KNOWN ALREADY: There have been numerous studies on the live birth rate of the first FET cycle in patients with PPOS-related protocols. These studies have focused mainly on comparing pregnancy outcomes with those of other stimulation protocols. However, owing to the unique features of the PPOS-related strategy, such as its flexible timing of oocyte retrieval and repeated transfer of frozen embryos, studies using the CLBR as an overall indicator of success and investigating which types of patients would benefit from this protocol are lacking. STUDY DESIGN SIZE DURATION: This retrospective cohort study included 18 593 women who underwent PPOS-related protocols (dydrogesterone + hMG, medroxyprogesterone acetate + hMG, micronized progesterone + hMG treatment, and luteal-phase ovarian stimulation protocol) from 1 March 2011 to 31 September 2022 in our centre. PARTICIPANTS/MATERIALS SETTING METHODS: The population was categorized by female age, number of oocytes retrieved, and AFC in the analysis of CLBR within six FET cycles. The age groups (Groups 1-5, respectively) were <30, 30-34, 35-39, 40-44, and ≥45 years. The number of oocytes retrieved was grouped as 1-5, 6-10, 11-15, 16-20, and >20. AFC was grouped as <5, 5-10, 11-15, and >15. The Kaplan-Meier analysis (optimistic method), which hypothesized that patients who did not continue treatment had the same chance of achieving a live birth as those who continued, and the competing risk method (conservative method) which hypothesized they had no chance of achieving a live birth, were applied. In further analyses, the Cox model and Fine-Gray model were adopted: the former corresponds to the optimistic scenario, and the latter corresponds to the pessimistic scenario. MAIN RESULTS AND THE ROLE OF CHANCE: CLBR had a declining trend with female age over six FET cycles (Groups 1-5, respectively: optimistic: 96.9%, 96.6%, 91.4%, 67.3%, and 11.7%; conservative: 87.3%, 85.0%, 74.0%, 41.3%, and 7.5%), requiring more FET cycles to achieve a success rate of at least 50% (Groups 1-5, respectively: optimistic: 2, 2, 2, 4, and >6 cycles; conservative: 2, 2, 2, >,6 and >6 cycles). CLBR showed an increasing trend with the number of oocytes retrieved (Groups 1-5, respectively: optimistic: 93.8%, 94.3%, 95.8%, 96.0%, and 95.6%; conservative: 66.2%, 78.3%, 85.6%, 88.9%, and 91.0%). All groups needed the same number of FET cycles to achieve a success rate of at least 50% (Groups 1-5, respectively: optimistic: 2, 2, 2, 2, and 2 cycles; conservative: 2, 2, 2, 2, and 2 cycles). Furthermore, the CLBR within six FET cycles had an increasing trend with AFC number (Groups 1-4, respectively: optimistic: 89.2%, 94.8%, 95.9%, and 96.3%; conservative: 67.4%, 78.2%, 83.9%, and 88.1%), with all four groups achieving a success rate of at least 50% by the second FET cycle. LIMITATIONS REASONS FOR CAUTION: The current research is limited by its retrospective design and single-centre nature, which may restrict the generalizability of our findings. WIDER IMPLICATIONS OF THE FINDINGS: This work describes two models (the Kaplan-Meier analysis and the competing risk method) to evaluate the clinical outcome of patients using PPOS-related protocols, which are especially useful for patients of advanced age or those with diminished ovarian reserve. Our findings encourage patients below 45 years old, especially younger than 40 years, and patients with lower AFCs and fewer retrieved oocytes to try this new protocol. Moreover, this study demonstrates the degree of improvement in the CLBR within six FET cycles for patients with different clinical characteristics, providing a valuable point of reference to determine whether to continue ART after a transfer failure. STUDY FUNDING/COMPETING INTERESTS: The study was supported by grants from the National Natural Science Foundation of China (82071603 to L.W., 82001502 to Y.L.). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Optimizing intra-arterial hypothermia scheme for acute ischemic stroke in an MCAO/R rat model.

Hypothermia is a promising neuroprotective treatment. This study aims to explore and optimize the intervention scheme of intra-arterial hypothermia (IAH) in a middle cerebral artery occlusion and reperfusion (MCAO/R) rat model. The MCAO/R model was established with a thread that could be retracted 2 h after occlusion. Cold normal saline was injected into the internal carotid artery (ICA) through a microcatheter in different infusion conditions. Grouping followed an orthogonal design (L9[34]) based on three critical factors closely associated with IAH: perfusate temperature (4, 10, 15 °C), infusion flow rate (1/3, 1/2, 2/3 blood flow rate of ICA), and duration (10, 20, 30 min), resulting in 9 subgroups (H1, H2 to H9). A myriad of indexes were monitored, such as vital signs, blood parameters, changes in local ischemic brain tissue temperature (Tb), ipsilateral jugular venous bulb temperature (Tjvb), and the core temperature of the anus (Tcore). After 24 h and 72 h of cerebral ischemia, cerebral infarction volume, cerebral water content, and neurological function were assessed to explore the optimal IAH conditions. The results revealed that the three critical factors were independent predictors for cerebral infarction volume, cerebral water content, and neurological function. The optimal perfusion conditions were 4 °C, 2/3 RICA (0.50 ml/min) for 20 min, and there was a significant correlation between Tb and Tjvb (R = 0.994, P < 0.001). The vital signs, blood routine tests and biochemical indexes showed no significant abnormal changes. These findings revealed that IAH was safe and feasible with the optimized scheme in an MCAO/R rat model.

ß Oscillations of Dorsal STN as a Potential Biomarker in Parkinson's Disease Motor Subtypes: An Exploratory Study.

Parkinson's disease (PD) can be divided into postural instability and difficult gait (PIGD) and tremor dominance (TD) subtypes. However, potential neural markers located in the dorsal ventral side of the subthalamic nucleus (STN) for delineating the two subtypes of PIGD and TD have not been demonstrated. Therefore, this study aimed to investigate the spectral characteristics of PD on the dorsal ventral side. The differences in the ß oscillation spectrum of the spike signal on the dorsal and ventral sides of the STN during deep brain stimulation (DBS) were investigated in 23 patients with PD, and coherence analysis was performed for both subtypes. Finally, each feature was associated with the Unified Parkinson's Disease Rating Scale (UPDRS). The ß power spectral density (PSD) in the dorsal STN was found to be the best predictor of the PD subtype, with 82.6% accuracy. The PSD of dorsal STN ß oscillations was greater in the PIGD group than in the TD group (22.17% vs. 18.22%; p < 0.001). Compared with the PIGD group, the TD group showed greater consistency in the ß and γ bands. In conclusion, dorsal STN ß oscillations could be used as a biomarker to classify PIGD and TD subtypes, guide STN-DBS treatment, and relate to some motor symptoms.

Specific Distribution of Digital Gait Biomarkers in Parkinson's Disease Using Body-Worn Sensors and Machine Learning.

Gait impairment leads to reduced social activities and low quality of life in people with Parkinson's disease (PD). PD is associated with unique gait signs and distributions of gait features. The assessment of gait characteristics is crucial in the diagnosis and treatment of PD. At present, the number and distribution of gait features associated with different PD stages are not clear. Here, we used whole-body multinode wearable devices combined with machine learning to build a classification model of early PD (EPD) and mild PD (MPD). Our model exhibited significantly improved accuracy for the EPD and MPD groups compared with the healthy control (HC) group (EPD vs HC accuracy = 0.88, kappa = 0.75, AUC = 0.88; MPD vs HC accuracy = 0.94, kappa = 0.84, AUC = 0.90). Furthermore, the distribution of gait features was distinguishable among the HC, EPD, and MPD groups (EPD based on variability features [40%]; MPD based on amplitude features [30%]). Here, we showed promising gait models for PD classification and provided reliable gait features for distinguishing different PD stages. Further multicenter clinical studies are needed to generalize the findings.

Inhalation bioacessibility and lung cell penetration of indoor PM2.5-bound PAEs and its implication in risk assessment.

Several studies have evaluated the human exposure of phthalate esters (PAEs) in PM2.5 via inhalation route, however, inhalation bioaccessibility and the lung cell penetration of PAEs were barely considered in risk assessment. In the present study, PM2.5 samples collected from indoor environments were investigated for inhalation bioaccessibility of PAEs using two simulated lung fluids (gamble's solution (GMB) and artificial lysosomal fluid (ALF)). The results showed that the inhalation bioaccessibility of PAEs (except for diethyl phthalate) under healthy state (GMB: 8.9%-62.8%) was lower than that under the inflammatory condition (ALF: 14.5%-67.6%). Lung cell permeation and metabolism of three selected PAEs (diethyl phthalate, di(n-butyl)phthalate and di-2-ethylhexyl phthalate) was tested using equivalent lung cell (A549) model. The inhalation bioavailability obtained by combination of the bioaccessibility of PAEs in indoor PM2.5 and permeability data of A549 cell ranged from 11.7% to 51.1% in health condition, and 13.5%-55.0% in inflammatory state. The calibration parameter (Fc) based on the inhalation bioavailability was established in present study and could provide a reference for a more accurate risk assessment of PM2.5-bound PAEs.

Fish oil supplementation, physical activity and risk of incident Parkinson's disease: results of longitudinal analysis from the UK Biobank.

Objective: Evidence on the individual and combined relationship of physical activity (PA) and fish oil supplement use on the incidence of Parkinson's disease (PD) risk remains lacking. Materials and methods: This UK population-based prospective cohort study, involving 385,275 UK Biobank participants, collected PA and fish oil supplement data via touchscreen questionnaires. Using Cox proportional hazards models and restricted cubic splines to examined the associations between use of fish oil supplements, PA and PD risk. Results: During a median 12.52-year follow-up, 2,131 participants incident PD. Analysis showed that fish oil supplement users had a lower PD risk [hazard ratio (HR), 0.89; 95% confidence interval (CI), 0.82-0.98]. The adjusted HRs for the PD incidence were 0.96 (95% CI, 0.95-0.98) for total PA; 0.93 (95% CI, 0.90-0.96) for moderate PA; 0.95 (95% CI, 0.91-0.99) for vigorous PA and 0.93 (95% CI, 0.89-0.98) for walking activity. Significant interactions were found between fish oil supplement use and total PA (P for interaction = 0.011), moderate PA (P for interaction = 0.015), and walking activity (P for interaction = 0.029) in relation to PD incidence. Conclusion: Both fish oil supplement use and PA were associated with a reduced risk of PD, and the effect of PA in reducing the risk of PD was more pronounced when fish oil supplement was used.

Outcomes of stent grafts for treatment of central venous disease in hemodialysis patients.

BACKGROUND: To evaluate the effectiveness of stent graft (SG) for the treatment of central venous disease (CVD) in hemodialysis patients. METHODS: Between January 2014 and April 2022, 122 patients on hemodialysis with symptomatic CVD were treated with percutaneous transluminal angioplasty (PTA) and bare-metal stent (BMS) or SG placement. The mean follow-up was 14.5 months (IQR: 8.0, 24.2). Patency rates of the target sites were calculated using Kaplan-Meier and log-rank studies. Multivariate Cox proportional hazard models were used to evaluate the association between various characteristics and target site primary patency. RESULTS: Technical success rate was 100%. At 3, 6, 12, and 24 months, the target sites primary patency rates were 86.4%, 74.2%, 45.1%, and 30.4% for PTA; 94.7%, 78.6%, 60.8%, and 45.6% for BMS; and 94.0%, 92.0%, 82.4%, and 66.8% for SG, respectively, and the assisted primary patency rates were 86.5%, 80.4%, 63.8%, and 46.0% for PTA; 94.7%, 89.5%, 77.5%, and 71.1% for BMS; 100%, 100%, 97.8%, and 83.4% for SG, respectively. The Kaplan-Meier analysis indicated that SGs achieved better primary and assisted primary patency than PTA or BMS (p<0.05). SG use and concomitant stenosis were the independent predictors of target site primary patency dysfunction in the multivariate analysis. CONCLUSIONS: This study confirmed the better long-term patency of SG in comparison with PTA and BMS for the treatment of CVD in hemodialysis patients.

The treatment efficacy of pharmacotherapies for rapid eye movement sleep behavior disorder with polysomnography evaluation: A systematic review and meta-analysis.

Clonazepam and melatonin are commonly used as first-line medications for the treatment of rapid eye movement (REM) sleep behavior disorder (RBD), with other medications used in the clinic including pramipexole, ramelteon, and rotigotine. We performed a systematic review and meta-analysis of randomized and non-randomized controlled trials to assess the efficacy of these treatment options in RBD patients with polysomnography. We systematically retrieved results of randomized and non-randomized controlled trials using the PubMed, Embase, and Cochrane databases. Of the 454 studies identified, 13 were considered eligible for inclusion in the study. In comparison to baseline, clonazepam was found to significantly decrease the percentage of stage 2 sleep [4.00 (95% CI = 0.90 to 7.10)] in RBD patients. Melatonin was found to significantly improve patients' sleep efficiency [2.51(95% CI = 0.75 to 4.28)], significantly reduce the time spent in bed (TIB) [-11.71(95% CI = -23.05 to -0.37)], phasic activity[-25.79(95% CI = -42.13 to -9.46)] and tonic activity[-10.44(95% CI = -12.24 to -8.64)]. RWA[-5.87 (95% CI = -8.25 to -3.50)] significantly improve with the use of ramelteon. Pramipexole was found to significantly increase the total sleep time (TST) [27.17 (95% CI = 0.06 to 54.29)], and significantly reduce the periodic limb movements of sleep (PLMS) index [-11.42(95% CI = -21.38 to -1.47)]. We also found that pramipexole had different effects on idiopathic RBD (iRBD) and secondary RBD (sRBD). These results will help to guide the clinical use of medication in patients with RBD.

Cyclic Thermal Shock Damage Behavior in CVI SiC/SiC High-Pressure Turbine Twin Guide Vanes.

In this paper, the SiC/SiC high-pressure turbine twin guide vanes were fabricated using the chemical vapor infiltration (CVI) method. Cyclic thermal shock tests at different target temperatures (i.e., 1400, 1450, and 1480 °C) in a gas environment were conducted to investigate the damage mechanisms and failure modes. During the thermal shock test, large spalling areas appeared on the leading edge and back region. After 400 thermal shock cycles, the spalling area of the coating at the basin and back region of the guide vane was more than 30%, and the whole guide vane turned gray, due to the formation of SiO2. When the thermal shock temperature increased from 1400 to 1450 and 1480 °C, the spalling area of the basin and the back region of the guide vane did not increase significantly, but the delamination occurred at the tenon, upper surface of the guide vane near the trailing edge of the guide vane. Through the X-ray Computed Tomography (XCT) analysis for the guide vanes before and after thermal shock, there was no obvious damage inside of guide vanes. The oxidation of SiC coating and the formation of SiO2 protects the internal fibers from oxidation and damage. Further investigation on the effect of thermal shock on the mechanical properties of SiC/SiC composites should be conducted in the future.

Tripchlorolide attenuates ß-amyloid generation by inducing NEP activity in N2a/APP695 cells.

BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is a neurodegeneration disease. The previous work from our research group demonstrated the neuroprotective effects of tripchlorolide (T4) in AD animal models. MATERIALS AND METHODS: Neprilysin (NEP) is known as an important physiological amyloid-ß protein (Aß) peptide-degrading enzyme in the brain due to its apparent rate-limiting function. In this study, we explored the effect of NEP on AD model N2a/APP695 cells. Western blots and enzyme-linked immunosorbent assays were performed to assess the expression of proteins, while quantitative real-time polymerase chain reaction assays were used to evaluate RNA levels. Cell vitality was detected by the MTT assay, and reactive oxygen species (ROS) levels were assessed using a ROS activity assay kit. RESULTS: We discovered that T4 was able to enhance the enzyme activity of NEP. T4 administration decreased the protein levels of the soluble amyloid precursor protein. In further experiments, we found that by using thiorphan the secretion of Aß, oxidative stress, nitrosative stress, and inflammatory factors, which were suppressed by T4, were reversed. Due to its ability to attenuate Aß generation and to protect neurons against the neurotoxicity of Aß, T4 may be a potential therapy in the regulation of Aß-related pathology in AD by affecting NEP activity. CONCLUSION: Tripchlorolide attenuates Aß generation by inducing NEP activity in N2a/APP695 cells.

The comprehensive landscape of miR-34a in cancer research.

MicroRNA-34 (miR-34) plays central roles in human diseases, especially cancers. Inactivation of miR-34 is detected in cancer cell lines and tumor tissues versus normal controls, implying its potential tumor-suppressive effect. Clinically, miR-34 has been identified as promising prognostic indicators for various cancers. In fact, members of the miR-34 family, especially miR-34a, have been convincingly proved to affect almost the whole cancer progression process. Here, a total of 512 (miR-34a, 10/21), 85 (miR-34b, 10/16), and 114 (miR-34c, 10/14) putative targets of miR-34a/b/c are predicted by at least ten miRNA databases, respectively. These targets are further analyzed in gene ontology (GO), KEGG pathway, and the Reactome pathway dataset. The results suggest their involvement in the regulation of signal transduction, macromolecule metabolism, and protein modification. Also, the targets are implicated in critical signaling pathways, such as MAPK, Notch, Wnt, PI3K/AKT, p53, and Ras, as well as apoptosis, cell cycle, and EMT-related pathways. Moreover, the upstream regulators of miR-34a, mainly including transcription factors (TFs), lncRNAs, and DNA methylation, will be summarized. Meanwhile, the potential TF upstream of miR-34a/b/c will be predicted by PROMO, JASPAR, Animal TFDB 3.0, and GeneCard databases. Notably, miR-34a is an attractive target for certain cancers. In fact, miR-34a-based systemic delivery combined with chemotherapy or radiotherapy can more effectively control tumor progression. Collectively, this review will provide a panorama for miR-34a in cancer research.

Inhalation bioacessibility and absorption of polycyclic aromatic hydrocarbons (PAHs) in indoor PM2.5 and its implication in risk assessment.

Inhalation bioaccessibility of polycyclic aromatic hydrocarbons (PAHs) in PM2.5 was assessed in numerous studies, however, the lung cell uptake and penetration of PAHs was seldom taken into account in risk assessment. In the present study, eighteen indoor PM2.5 samples collected from Guangzhou, China were analyzed for the inhalation bioavailability of PAHs combining the inhalation bioaccessibility and cell absorption of PAHs. Two simulated epithelial lung fluid mimicking the healthy condition (as represented by gamble's solution (GMB), pH = 7.4) and the inflammatory condition (as represented by artificial lysosomal fluid (ALF), pH = 4.5) were employed to evaluate the inhalation bioaccessibility. The results indicated that the bioaccessibility of PAHs under the inflammatory condition (1.28%-87.7%) was higher than that under healthy condition (0.88%-87.6%). Naphthalene, phenanthrene, pyrene and benzo[a]pyrene were selected for absorption assay of lung epithelial cells (A549). The absorption rate of PAHs ranged from 64.7 to 90.7% and it was inversely proportional to the number of aromatic rings. Taken together, the inhalation bioavailability based on the bioaccessibility of PAHs and the lung cell absorption ratio ranged from 9.9 to 56.9% under the healthy state, from 12.7 to 65.6% under inflammatory condition. The correction parameter (Fc) was thus established and can be used to improve the risk assessment of human exposure to PAHs via PM2.5 inhalation in future work.

Adipocyte-Derived Leptin Promotes PAI-1 -Mediated Breast Cancer Metastasis in a STAT3/miR-34a Dependent Manner.

The crosstalk between cancer cells and adipocytes is critical for breast cancer progression. However, the molecular mechanisms underlying these interactions have not been fully characterized. In the present study, plasminogen activator inhibitor-1 (PAI-1) was found to be a critical effector of the metastatic behavior of breast cancer cells upon adipocyte coculture. Loss-of-function studies indicated that silencing PAI-1 suppressed cancer cell migration. Furthermore, we found that PAI-1 was closely related to the epithelial-mesenchymal transition (EMT) process in breast cancer patients. A loss-of-function study and a mammary orthotopic implantation metastasis model showed that PAI-1 promoted breast cancer metastasis by affecting the EMT process. In addition, we revealed that leptin/OBR mediated the regulation of PAI-1 through the interactions between adipocytes and breast cancer cells. Mechanistically, we elucidated that leptin/OBR further activated STAT3 to promote PAI-1 expression via miR-34a-dependent and miR-34a-independent mechanisms in breast cancer cells. In conclusion, our study suggests that targeting PAI-1 and interfering with its upstream regulators may benefit breast cancer patients.

Brominated flame retardants in home dust and its contribution to brominated flame retardants bioaccumulation in children hair.

Brominated flame retardants (BFRs) in house dust have raised significant concern around the world. However, few studies have reported the correlation between BFR concentrations in house dust and children's hair samples. In this study, BFR concentrations in house dust and children's hair were measured. Chemical analysis showed that the total concentrations of polybrominated diphenyl ethers (PBDEs) in house dust ranged from 334 to 4444 ng g-1, with a median of 442 ng g-1, and the concentrations in children's hair ranged from 352 to 655 ng g-1, with a median of 530 ng g-1. In addition, two alternative flame retardants, pentabromoethylbenzene (PBEB) and hexabromobenzene, were frequently detected in house dust and human hair. BDE209 was the most abundant PBDE congener detected in both house dust and children's hair. A significant correlation was found between the integrated PCA score of BFR concentrations in house dust and in children's hair (r2 = 0.31, P < 0.05), indicating the great contribution of house dust to the bodily burden of PBDEs in children. Risk assessment indicated that children's exposure to PBDEs via non-dietary intake of house dust should be recognized as an important exposure pathway.

Endoplasmic Reticulum Stress Induces the Early Appearance of Pro-apoptotic and Anti-apoptotic Proteins in Neurons of Five Familial Alzheimer's Disease Mice.

BACKGROUND: Amyloid ß (Aß) deposits and the endoplasmic reticulum stress (ERS) are both well established in the development and progression of Alzheimer's disease (AD). However, the mechanism and role of Aß-induced ERS in AD-associated pathological progression remain to be elucidated. METHODS: The five familial AD (5×FAD) mice and wild-type (WT) mice aged 2, 7, and 12 months were used in the present study. Morris water maze test was used to evaluate their cognitive performance. Immunofluorescence and Western blot analyses were used to examine the dynamic changes of pro-apoptotic (CCAAT/enhancer-binding protein homologous protein [CHOP] and cleaved caspase-12) and anti-apoptotic factors (chaperone glucose-regulated protein [GRP] 78 and endoplasmic reticulum-associated protein degradation-associated ubiquitin ligase synovial apoptosis inhibitor 1 [SYVN1]) in the ERS-associated unfolded protein response (UPR) pathway. RESULTS: Compared with age-matched WT mice, 5×FAD mice showed higher cleaved caspase-3, lower neuron-positive staining at the age of 12 months, but earlier cognitive deficit at the age of 7 months (all P < 0.05). Interestingly, for 2-month-old 5×FAD mice, the related proteins involved in the ERS-associated UPR pathway, including CHOP, cleaved caspase-12, GRP 78, and SYVN1, were significantly increased when compared with those in age-matched WT mice (all P < 0.05). Moreover, ERS occurred mainly in neurons, not in astrocytes. CONCLUSIONS: These findings suggest that compared with those of age-matched WT mice, ERS-associated pro-apoptotic and anti-apoptotic proteins are upregulated in 2-month-old 5×FAD mice, consistent with intracellular Aß aggregation in neurons.