Positron Emission Tomography with [18F]ROStrace Reveals Progressive Elevations in Oxidative Stress in a Mouse Model of Alpha-Synucleinopathy.

The synucleinopathies are a diverse group of neurodegenerative disorders characterized by the accumulation of aggregated alpha-synuclein (aSyn) in vulnerable populations of brain cells. Oxidative stress is both a cause and a consequence of aSyn aggregation in the synucleinopathies; however, noninvasive methods for detecting oxidative stress in living animals have proven elusive. In this study, we used the reactive oxygen species (ROS)-sensitive positron emission tomography (PET) radiotracer [18F]ROStrace to detect increases in oxidative stress in the widely-used A53T mouse model of synucleinopathy. A53T-specific elevations in [18F]ROStrace signal emerged at a relatively early age (6-8 months) and became more widespread within the brain over time, a pattern which paralleled the progressive development of aSyn pathology and oxidative damage in A53T brain tissue. Systemic administration of lipopolysaccharide (LPS) also caused rapid and long-lasting elevations in [18F]ROStrace signal in A53T mice, suggesting that chronic, aSyn-associated oxidative stress may render these animals more vulnerable to further inflammatory insult. Collectively, these results provide novel evidence that oxidative stress is an early and chronic process during the development of synucleinopathy and suggest that PET imaging with [18F]ROStrace holds promise as a means of detecting aSyn-associated oxidative stress noninvasively.

Identification of osteoporosis ferroptosis-related markers and potential therapeutic compounds based on bioinformatics methods and molecular docking technology.

RESEARCH BACKGROUND AND PURPOSE: Osteoporosis (OP) is one of the most common bone diseases worldwide, characterized by low bone mineral density and susceptibility to pathological fractures, especially in postmenopausal women and elderly men. Ferroptosis is one of the newly discovered forms of cell death regulated by genes in recent years. Many studies have shown that ferroptosis is closely related to many diseases. However, there are few studies on ferroptosis in osteoporosis, and the mechanism of ferroptosis in osteoporosis is still unclear. This study aims to identify biomarkers related to osteoporosis ferroptosis from the GEO (Gene Expression Omnibus) database through bioinformatics technology, and to mine potential therapeutic small molecule compounds through molecular docking technology, trying to provide a basis for the diagnosis and treatment of osteoporosis in the future. MATERIALS AND METHODS: We downloaded the ferroptosis-related gene set from the FerrDb database ( http://www.zhounan.org/ferrdb/index.html ), downloaded the data sets GSE56815 and GSE7429 from the GEO database, and used the R software "limma" package to screen differentially expressed genes (DEGs) from GSE56815, and intersected with the ferroptosis gene set to obtain ferroptosis-related DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by the R software "clusterProfiler" package. The random forest model was further screened to obtain essential ferroptosis genes. R software "corrplot" package was used for correlation analysis of essential ferroptosis genes, and the Wilcox test was used for significance analysis. The lncRNA-miRNA-mRNA-TF regulatory network was constructed using Cytoscape software. The least absolute shrinkage and selection operator (LASSO) was used to construct a disease diagnosis model, and a Receiver operating characteristic (ROC) curve was drawn to evaluate the diagnostic performance, and then GSE7429 was used to verify the reliability of the diagnosis model. Molecular docking technology was used to screen potential small molecule compounds from the Drugbank database. Finally, a rat osteoporosis model was constructed, and peripheral blood mononuclear cells were extracted for qRT-PCR detection to verify the mRNA expression levels of crucial ferroptosis genes. RESULT: Six DEGs related to ferroptosis were initially screened out. GO function and KEGG pathway enrichment analysis showed that ferroptosis-related DEGs were mainly enriched in signaling pathways such as maintenance of iron ion homeostasis, copper ion binding function, and ferroptosis. The random forest model identified five key ferroptosis genes, including CP, FLT3, HAMP, HMOX1, and SLC2A3. Gene correlation analysis found a relatively low correlation between these five key ferroptosis genes. The lncRNA-miRNA-mRNA-TF regulatory network shows that BAZ1B and STAT3 may also be potential molecules. The ROC curve of the disease diagnosis model shows that the model has a good diagnostic performance. Molecular docking technology screened out three small molecule compounds, including NADH, Midostaurin, and Nintedanib small molecule compounds. qRT-PCR detection confirmed the differential expression of CP, FLT3, HAMP, HMOX1 and SLC2A3 between OP and normal control group. CONCLUSION: This study identified five key ferroptosis genes (CP, FLT3, HAMP, HMOX1, and SLC2A3), they were most likely related to OP ferroptosis. In addition, we found that the small molecule compounds of NADH, Midostaurin, and Nintedanib had good docking scores with these five key ferroptosis genes. These findings may provide new clues for the early diagnosis and treatment of osteoporosis in the future.

The Effects of Perineural Dexamethasone on Rebound Pain After Nerve Block in Patients with Unicompartmental Knee Arthroplasty A Randomized Controlled Trial.

OBJECTIVES: A single nerve block provides excellent analgesia in a short time, but rebound pain after the nerve block disappears has attracted researchers' attention. The aim of this study is to evaluate the effect of perineural dexamethasone on rebound pain after sciatic nerve block and femoral nerve block in patients undergoing unicompartmental knee arthroplasty (UKA). METHODS: In a double-blinded fashion, We recruited 72 patients undergoing UKA, each of whom received sciatic and femoral nerve block. Patients were randomly assigned to two groups (n=36): X (ropivacaine only) and D (ropivacaine combined with dexamethasone). The primary outcome was the incidence of rebound pain. The secondary outcomes were rebound pain score, the duration of rebound pain, the duration of nerve block, pain score, sufentanil consumption and rescue analgesic, patient-controlled intravenous analgesia, distance walked, sleep quality score, C-reactive protein levels, and adverse effects. RESULTS: Compared with group X, the incidence of rebound pain in group D was higher, the rebound pain score was higher and the duration of nerve block was prolonged (P<0.05). At 12, 16, and 20 hours postoperatively, the pain scores at rest in group D was lower. At 32 and 36 hours postoperatively, the pain scores at rest in group D was higher (P<0.05). Moreover, patients in group D had lower levels of C-reactive protein after surgery (P<0.05). DISCUSSION: Addition of dexmedetomidine to ropivacaine for UKA effectively prolonged the duration of nerve block and decreased c-reactive protein levels, but increased the incidence of rebound pain and rebound pain score, and had no beneficial effects on the postoperative analgesia.

Improve the diagnosis of idiopathic normal pressure hydrocephalus by combining abnormal cortical thickness and ventricular morphometry.

Background: The primary imaging markers for idiopathic Normal Pressure Hydrocephalus (iNPH) emphasize morphological measurements within the ventricular system, with no attention given to alterations in brain parenchyma. This study aimed to investigate the potential effectiveness of combining ventricular morphometry and cortical structural measurements as diagnostic biomarkers for iNPH. Methods: A total of 57 iNPH patients and 55 age-matched healthy controls (HC) were recruited in this study. Firstly, manual measurements of ventricular morphology, including Evans Index (EI), z-Evans Index (z-EI), Cella Media Width (CMW), Callosal Angle (CA), and Callosal Height (CH), were conducted based on MRI scans. Cortical thickness measurements were obtained, and statistical analyses were performed using surface-based morphometric analysis. Secondly, three distinct models were developed using machine learning algorithms, each based on a different input feature: a ventricular morphology model (LVM), a cortical thickness model (CT), and a fusion model (All) incorporating both features. Model performances were assessed using 10-fold cross validation and tested on an independent dataset. Model interpretation utilized Shapley Additive Interpretation (SHAP), providing a visualization of the contribution of each variable in the predictive model. Finally, Spearman correlation coefficients were calculated to evaluate the relationship between imaging biomarkers and clinical symptoms. Results: iNPH patients exhibited notable differences in cortical thickness compared to HC. This included reduced thickness in the frontal, temporal, and cingulate cortices, along with increased thickness in the supracentral gyrus. The diagnostic performance of the fusion model (All) for iNPH surpassed that of the single-feature models, achieving an average accuracy of 90.43%, sensitivity of 90.00%, specificity of 90.91%, and Matthews correlation coefficient (MCC) of 81.03%. This improvement in accuracy (6.09%), sensitivity (11.67%), and MCC (11.25%) compared to the LVM strategy was significant. Shap analysis revealed the crucial role of cortical thickness in the right isthmus cingulate cortex, emerging as the most influential factor in distinguishing iNPH from HC. Additionally, significant correlations were observed between the typical triad symptoms of iNPH patients and cortical structural alterations. Conclusion: This study emphasizes the significant role of cortical structure changes in the diagnosis of iNPH, providing a novel insights for assisting clinicians in improving the identification and detection of iNPH.

A combined transcriptomics and proteomics approach to reveal the mechanism of AEE relieving hyperlipidemia in ApoE-/- mice.

Hyperlipidemia caused by abnormal lipid metabolism has reached epidemic proportions. This phenomenon is also common in companion animals. Previous studies showed that AEE significantly improves abnormal blood lipids in hyperlipidemia rats and mice, but its mechanism is still not clear enough. In this study, the mechanism and potential key pathways of AEE on improving hyperlipidemia in mice were investigated through the transcriptome and proteome study of ApoE-/- mice liver and the verification study on high-fat HepG2 cells. The results showed that AEE significantly decreased the serum TC and LDL-C levels of hyperlipidemia ApoE-/- mice, and significantly increased the enzyme activity of CYP7A1. After AEE intervention, the results of mice liver transcriptome and proteome showed that differential genes and proteins were enriched in lipid metabolism-related pathways. The results of RT-qPCR showed that AEE significantly regulated the expression of genes related to lipid metabolism in mice liver tissue. AEE significantly upregulated the protein expression of CYP7A1 in hyperlipidemia ApoE-/- mice liver tissue. The results in vitro showed that AEE significantly decreased the levels of TC and TG, and improved lipid deposition in high-fat HepG2 cells. AEE significantly increased the expression of CYP7A1 protein in high-fat HepG2 cells. AEE regulates the expression of genes related to lipid metabolism in high-fat HepG2 cells, mainly by FXR-SHP-CYP7A1 and FGF19-TFEB-CYP7A1 pathways. To sum up, AEE can significantly improve the hyperlipidemia status of ApoE-/- mice and the lipid deposition of high-fat HepG2 cells, and its main pathway is probably the bile acid metabolism-related pathway centered on CYP7A1.

Targeting vulnerable microcircuits in the ventral hippocampus of male transgenic mice to rescue Alzheimer-like social memory loss.

BACKGROUND: Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease (AD), which is closely related to tau pathology and hippocampal impairment. Due to the heterogeneity of brain neurons, the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear. Therefore, further investigation is necessary. METHODS: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis, social behavioural tests, hippocampal electrophysiology, immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine the effects of these agents on social memory in mice. RESULTS: The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, vCA1, especially its excitatory and parvalbumin (PV) neurons, were fully filled with mislocated and phosphorylated tau (p-Tau). This finding was not observed for dorsal hippocampal CA1 (dCA1). The overexpression of human tau (hTau) in excitatory and PV neurons mimicked AD-like tau accumulation, significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory. Notably, 1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB (TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory. CONCLUSION: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future.

MicroRNA in the Exosomes Mediated by Resveratrol to Activate Neuronal Cells.

Resveratrol (RSV), a polyphenol, is known to have a wide range of pharmacological properties in vitro. RSV may have therapeutic value for various neurodegenerative diseases via neuroprotective effects. However, it is not yet clear whether RSV can induce intestinal-brain interactions. It is assumed that the intestinal cells may secrete some factors after being stimulated by other substances. These secreted factors may activate nerve cells through gut-brain interaction, such as exosomes. In this study, it was discovered that Caco-2 cells treated with RSV secrete exosomes to activate SH-SY5Y neuronal cells. The results showed that secreted factors from RSV-treated Caco-2 cells activated SH-SY5Y. The exosomes of RSV-treated Caco-2 cells activated SH-SY5Y cells, which was manifested in the lengthening of the nerve filaments of SH-SY5Y cells. The exosomes were characterized using transmission electron microscopy and sequenced using the Illumina NovaSeq 6000 sequencer. The results showed that the miRNA expression profile of exosomes after RSV treatment changed, and twenty-six kinds of miRNAs were identified which expressed differentially between the control group and the RSV-treated group. Among them, three miRNAs were selected as candidate genes for inducing SH-SY5Y neural cell activation. Three miRNA mimics could activate SH-SY5Y neurons. These results suggested that the miRNA in intestinal exocrine cells treated with RSV may play an important role in the activation of SH-SY5Y neurons.

Generation of tau dephosphorylation-targeting chimeras for the treatment of Alzheimer's disease and related tauopathies.

Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer's disease (AD) and many other tauopathies. Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases. We have conceptualized a strategy, named dephosphorylation-targeting chimeras (DEPTACs), for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation. Here, we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau. Specifically, for one of the selected chimeras, D16, we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro. Moreover, intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice. These results suggested DEPTACs as targeted modulators of tau phosphorylation, which hold therapeutic potential for AD and other tauopathies.

Abnormal characteristic static and dynamic functional network connectivity in idiopathic normal pressure hydrocephalus.

AIMS: Idiopathic Normal pressure hydrocephalus (iNPH) is a neurodegenerative disease characterized by gait disturbance, dementia, and urinary dysfunction. The neural network mechanisms underlying this phenomenon is currently unknown. METHODS: To investigate the resting-state functional connectivity (rs-FC) abnormalities of iNPH-related brain connectivity from static and dynamic perspectives and the correlation of these abnormalities with clinical symptoms before and 3-month after shunt. We investigated both static and dynamic functional network connectivity (sFNC and dFNC, respectively) in 33 iNPH patients and 23 healthy controls (HCs). RESULTS: The sFNC and dFNC of networks were generally decreased in iNPH patients. The reduction in sFNC within the default mode network (DMN) and between the somatomotor network (SMN) and visual network (VN) were related to symptoms. The temporal properties of dFNC and its temporal variability in state-4 were sensitive to the identification of iNPH and were correlated with symptoms. The temporal variability in the dorsal attention network (DAN) increased, and the average instantaneous FC was altered among networks in iNPH. These features were partially associated with clinical symptoms. CONCLUSION: The dFNC may be a more sensitive biomarker for altered network function in iNPH, providing us with extra information on the mechanisms of iNPH.

Synthesis and antibacterial activity of FST and its effects on inflammatory response and intestinal barrier function in mice infected with Escherichia coli O78.

Pathogenic Escherichia coli (E. coli) can cause intestinal diseases in humans and livestock, damage the intestinal barrier, increase systemic inflammation, and seriously threaten human health and the development of animal husbandry. In this study, we designed and synthesized a novel conjugate florfenicol sulfathiazole (FST) based on drug combination principles, and investigated its antibacterial activity in vitro and its protective effect on inflammatory response and intestinal barrier function in E. coli O78-infected mice in vivo. The results showed that FST had superior antibacterial properties and minimal cytotoxicity compared with its prodrugs as florfenicol and sulfathiazole. FST protected mice from lethal E. coli infection, reduced clinical signs of inflammation, reduced weight loss, alleviated intestinal structural damage. FST decreased the expression of inflammatory cytokines IL-1ß, IL-6, TNF-α, and increased the expression of claudin-1, Occludin, and ZO-1 in the jejunum, improved the intestinal barrier function, and promoted the absorption of nutrients. FST also inhibited the expression of TLR4, MyD88, p-p65, and p-p38 in the jejunum. The study may lay the foundation for the development of FST as new drugs for intestinal inflammation and injury in enteric pathogen infection.

A novel transgenic mouse line with hippocampus-dominant and inducible expression of truncated human tau.

BACKGROUND: Intraneuronal accumulation of hyperphosphorylated tau is a defining hallmark of Alzheimer's disease (AD). However, mouse models imitating AD-exclusive neuronal tau pathologies are lacking. METHODS: We generated a new tet-on transgenic mouse model expressing truncated human tau N1-368 (termed hTau368), a tau fragment increased in the brains of AD patients and aged mouse brains. Doxycycline (dox) was administered in drinking water to induce hTau368 expression. Immunostaining and Western blotting were performed to measure the tau level. RNA sequencing was performed to evaluate gene expression, and several behavioral tests were conducted to evaluate mouse cognitive functions, emotion and locomotion. RESULTS: Dox treatment for 1-2 months at a young age induced overt and reversible human tau accumulation in the brains of hTau368 transgenic mice, predominantly in the hippocampus. Meanwhile, the transgenic mice exhibited AD-like high level of tau phosphorylation, glial activation, loss of mature neurons, impaired hippocampal neurogenesis, synaptic degeneration and cognitive deficits. CONCLUSIONS: This study developed a well-characterized and easy-to-use tool for the investigations and drug development for AD and other tauopathies.

AEE alleviates ox-LDL-induced lipid accumulation and inflammation in macrophages.

Atherosclerosis is a chronic immune inflammatory disease. Aspirin eugenol ester (AEE) is a novel safe and non-toxic compound with many pharmacological effects such as anti-inflammatory, anti-hyperlipidemic and anti-thrombotic action. In order to investigate the effect of AEE on the inhibition of aortic lipid plaque formation and macrophage-derived foam cell formation induced by oxidized low density lipoprotein (ox-LDL), in vivo atherosclerosis model by feeding ApoE-/- mice with a high-fat diet and foam cells formation in vitro model by ox-LDL-induced RAW264.7 macrophages were established. It was found that AEE decreased the levels of TC and LDL-C in serum, and the plaque formation area and lipid accumulation in the aortic intima of ApoE-/- mice. In vitro studies showed that AEE could prevent the uptake of ox-LDL and reduce the contents of TC and FC in cells. AEE enhanced the cholesterol efflux by increasing the expression of ABCA1, ABCG1 and PPARγ, which effectively alleviated excess cholesterol accumulated in the cells. Meanwhile, AEE also reduced the secretion and expression of inflammatory factors in the cells. In addition, AEE could reverse the action of PPARγ inhibitor T0070907 and/or ox-LDL. Therefore, AEE may become an effective candidate drug for the prevention of atherosclerosis.

Short-term joint effects of ambient PM2.5 and O3 on mortality in Beijing, China.

Introduction: In recent years, air pollution caused by co-occurring PM2.5 and O3, named combined air pollution (CAP), has been observed in Beijing, China, although the health effects of CAP on population mortality are unclear. Methods: We employed Poisson generalized additive models (GAMs) to evaluate the individual and joint effects of PM2.5 and O3 on mortality (nonaccidental, respiratory, and cardiovascular mortality) in Beijing, China, during the whole period (2014-2016) and the CAP period. Adverse health effects were assessed for percentage increases (%) in the three mortality categories with each 10-µg/m3 increase in PM2.5 and O3. The cumulative risk index (CRI) was adopted as a novel approach to quantify the joint effects. Results: The results suggested that both PM2.5 and O3 exhibited the greatest individual effects on the three mortality categories with cumulative lag day 01. Increases in the nonaccidental, cardiovascular, and respiratory mortality categories were 0.32%, 0.36%, and 0.43% for PM2.5 (lag day 01) and 0.22%, 0.37%, and 0.25% for O3 (lag day 01), respectively. There were remarkably synergistic interactions between PM2.5 and O3 on the three mortality categories. The study showed that the combined effects of PM2.5 and O3 on nonaccidental, cardiovascular, and respiratory mortality were 0.34%, 0.43%, and 0.46%, respectively, during the whole period and 0.58%, 0.79%, and 0.75%, respectively, during the CAP period. Our findings suggest that combined exposure to PM2.5 and O3, particularly during CAP periods, could further exacerbate their single-pollutant health risks. Conclusion: These findings provide essential scientific evidence for the possible creation and implementation of environmental protection strategies by policymakers.

Multi-omics reveals aspirin eugenol ester alleviates neurological disease.

BACKGROUND: Exosomes play an essential role in maintaining normal brain function due to their ability to cross the blood-brain barrier. Aspirin eugenol ester (AEE) is a new medicinal compound synthesized by the esterification of aspirin with eugenol using the prodrug principle. Aspirin has been reported to have neuroprotective effects and may be effective against neurodegenerative diseases. PURPOSE: This study wanted to investigate how AEE affected neurological diseases in vivo and in vitro. EXPERIMENTAL APPROACH: A multi-omics approach was used to explore the effects of AEE on the nervous system. Gene and protein expression changes of BDNF and NEFM in SY5Y cells after AEE treatment were detected using RT-qPCR and Western Blot. KEY RESULTS: The multi-omics results showed that AEE could regulate neuronal synapses, neuronal axons, neuronal migration, and neuropeptide signaling by affecting transport, inflammatory response, and regulating apoptosis. Exosomes secreted by AEE-treated Caco-2 cells could promote the growth of neurofilaments in SY5Y cells and increased the expression of BDNF and NEFM proteins in SY5Y cells. miRNAs in the exosomes of AEE-treated Caco-2 cells may play an important role in the activation of SY5Y neuronal cells. CONCLUSIONS: In conclusion, AEE could play positive effects on neurological-related diseases.

Pathogen-Targeting Bimetallic Nanozymes as Ultrasonic-Augmented ROS Generator against Multidrug Resistant Bacterial Infection.

Clinical treatment of multidrug resistant (MDR) pathogens-induced infection is emerging as a growing challenge in global public health due to the limited selection of clinically available antibiotics. Nanozymes as artificial enzymes that mimicked natural enzyme-like activities, are received great attention for combating MDR pathogens. However, the relatively deficient catalytic activity in the infectious microenvironment and inability to precisely targeting pathogen restrains their clinical anti-MDR applications. Here, pathogen-targeting bimetallic BiPt nanozymes for nanocatalytic therapy against MDR pathogen are reported. Benefiting from electronic coordination effect, BiPt nanozymes exhibit dual-enzymatic activities, including peroxidase-mimic and oxidase-mimic activities. Moreover, the catalytic efficiency can be efficiently increased 300-fold by ultrasound under inflammatory microenvironment. Notably, BiPt nanozyme is further cloaked with a platelet-bacteria hybrid membrane (BiPt@HMVs), thus presenting excellent homing effect to infectious sites and precise homologous targeting to pathogen. By integrating accurate targeting with highly efficient catalytic, BiPt@HMVs can eliminate carbapenem-resistant Enterobacterales and methicillin-resistant Staphylococcus aureus in osteomyelitis rats model, muscle-infected mice model, and pneumonia mice model. The work provides an alternative strategy based on nanozymes for clinically addressing MDR bacteria-induced infections.

The Transport and Uptake of Resveratrol Mediated via Glucose Transporter 1 and Its Antioxidant Effect in Caco-2 Cells.

Resveratrol has anti-inflammatory, anti-cancer, and anti-aging pharmacological activities. There is currently a gap in academic research regarding the uptake, transport, and reduction of H2O2-induced oxidative damage of resveratrol in the Caco-2 cell model. This study investigated the role of resveratrol in the uptake, transport, and alleviation of H2O2-induced oxidative damage in Caco-2 cells. In the Caco-2 cell transport model, it was observed that the uptake and transport of resveratrol (10, 20, 40, and 80 µM) were time dependent and concentration dependent. Different temperatures (37 °C vs. 4 °C) could significantly affect the uptake and transportation of resveratrol. The apical to basolateral transport of resveratrol was markedly reduced by STF-31, a GLUT1 inhibitor, and siRNA intervention. Furthermore, resveratrol pretreatment (80 µM) improves the viability of Caco-2 cells induced by H2O2. In a cellular metabolite analysis combined with ultra-high performance liquid chromatography-tandem mass spectrometry, 21 metabolites were identified as differentials. These differential metabolites belong to the urea cycle, arginine and proline metabolism, glycine and serine metabolism, ammonia recycling, aspartate metabolism, glutathione metabolism, and other metabolic pathways. The transport, uptake, and metabolism of resveratrol suggest that oral resveratrol could prevent intestinal diseases caused by oxidative stress.

Research Advances in the Treatment of Bone Marrow Edema Syndrome.

Bone marrow edema syndrome (BMES) is a relatively uncommon clinical condition. It has been poorly reported in the literature. Hence, doctors are not sufficiently aware of the disease and are prone to misdiagnosis and mistreatment, which can undoubtedly prolong the course of the disease, reduce the quality of life of patients and even affect their function. This paper reviews the literature and summarizes the treatment options for bone marrow edema syndrome, such as symptomatic treatment, extracorporeal shock waves therapy (ESWT), pulsed electromagnetic fields (PEFs), hyperbaric oxygen (HBO), vitamin D, iloprost, bisphosphonates, denosumab, and surgery, etc. This informs clinicians in treating bone marrow edema syndrome, hopefully improving patients' quality of life and shortening the duration of their disease.

Targeting a vulnerable septum-hippocampus cholinergic circuit in a critical time window ameliorates tau-impaired memory consolidation.

BACKGROUND: Abnormal tau accumulation and cholinergic degeneration are hallmark pathologies in the brains of patients with Alzheimer's disease (AD). However, the sensitivity of cholinergic neurons to AD-like tau accumulation and strategies to ameliorate tau-disrupted spatial memory in terms of neural circuits still remain elusive. METHODS: To investigate the effect and mechanism of the cholinergic circuit in Alzheimer's disease-related hippocampal memory, overexpression of human wild-type Tau (hTau) in medial septum (MS)-hippocampus (HP) cholinergic was achieved by specifically injecting pAAV-EF1α-DIO-hTau-eGFP virus into the MS of ChAT-Cre mice. Immunostaining, behavioral analysis and optogenetic activation experiments were used to detect the effect of hTau accumulation on cholinergic neurons and the MS-CA1 cholinergic circuit. Patch-clamp recordings and in vivo local field potential recordings were used to analyze the influence of hTau on the electrical signals of cholinergic neurons and the activity of cholinergic neural circuit networks. Optogenetic activation combined with cholinergic receptor blocker was used to detect the role of cholinergic receptors in spatial memory. RESULTS: In the present study, we found that cholinergic neurons with an asymmetric discharge characteristic in the MS-hippocampal CA1 pathway are vulnerable to tau accumulation. In addition to an inhibitory effect on neuronal excitability, theta synchronization between the MS and CA1 subsets was significantly disrupted during memory consolidation after overexpressing hTau in the MS. Photoactivating MS-CA1 cholinergic inputs within a critical 3 h time window during memory consolidation efficiently improved tau-induced spatial memory deficits in a theta rhythm-dependent manner. CONCLUSIONS: Our study not only reveals the vulnerability of a novel MS-CA1 cholinergic circuit to AD-like tau accumulation but also provides a rhythm- and time window-dependent strategy to target the MS-CA1 cholinergic circuit, thereby rescuing tau-induced spatial cognitive functions.

An initial study on the predictive value using multiple MRI characteristics for Ki-67 labeling index in glioma.

BACKGROUND AND PURPOSE: Ki-67 labeling index (LI) is an important indicator of tumor cell proliferation in glioma, which can only be obtained by postoperative biopsy at present. This study aimed to explore the correlation between Ki-67 LI and apparent diffusion coefficient (ADC) parameters and to predict the level of Ki-67 LI noninvasively before surgery by multiple MRI characteristics. METHODS: Preoperative MRI data of 166 patients with pathologically confirmed glioma in our hospital from 2016 to 2020 were retrospectively analyzed. The cut-off point of Ki-67 LI for glioma grading was defined. The differences in MRI characteristics were compared between the low and high Ki-67 LI groups. The receiver operating characteristic (ROC) curve was used to estimate the accuracy of each ADC parameter in predicting the Ki-67 level, and finally a multivariate logistic regression model was constructed based on the results of ROC analysis. RESULTS: ADCmin, ADCmean, rADCmin, rADCmean and Ki-67 LI showed a negative correlation (r = - 0.478, r = - 0.369, r = - 0.488, r = - 0.388, all P < 0.001). The Ki-67 LI of low-grade gliomas (LGGs) was different from that of high-grade gliomas (HGGs), and the cut-off point of Ki-67 LI for distinguishing LGGs from HGGs was 9.5%, with an area under the ROC curve (AUROC) of 0.962 (95%CI 0.933-0.990). The ADC parameters in the high Ki-67 group were significantly lower than those in the low Ki-67 group (all P < 0.05). The peritumoral edema (PTE) of gliomas in the high Ki-67 LI group was higher than that in the low Ki-67 LI group (P < 0.05). The AUROC of Ki-67 LI level assessed by the multivariate logistic regression model was 0.800 (95%CI 0.721-0.879). CONCLUSIONS: There was a negative correlation between ADC parameters and Ki-67 LI, and the multivariate logistic regression model combined with peritumoral edema and ADC parameters could improve the prediction ability of Ki-67 LI.