Potentiating glymphatic drainage minimizes post-traumatic cerebral oedema.

Cerebral oedema is associated with morbidity and mortality after traumatic brain injury (TBI)1. Noradrenaline levels are increased after TBI2-4, and the amplitude of the increase in noradrenaline predicts both the extent of injury5 and the likelihood of mortality6. Glymphatic impairment is both a feature of and a contributor to brain injury7,8, but its relationship with the injury-associated surge in noradrenaline is unclear. Here we report that acute post-traumatic oedema results from a suppression of glymphatic and lymphatic fluid flow that occurs in response to excessive systemic release of noradrenaline. This post-TBI adrenergic storm was associated with reduced contractility of cervical lymphatic vessels, consistent with diminished return of glymphatic and lymphatic fluid to the systemic circulation. Accordingly, pan-adrenergic receptor inhibition normalized central venous pressure and partly restored glymphatic and cervical lymphatic flow in a mouse model of TBI, and these actions led to substantially reduced brain oedema and improved functional outcomes. Furthermore, post-traumatic inhibition of adrenergic signalling boosted lymphatic export of cellular debris from the traumatic lesion, substantially reducing secondary inflammation and accumulation of phosphorylated tau. These observations suggest that targeting the noradrenergic control of central glymphatic flow may offer a therapeutic approach for treating acute TBI.

Dysregulation of extracellular potassium distinguishes healthy ageing from neurodegeneration.

Progressive neuronal loss is a hallmark feature distinguishing neurodegenerative diseases from normal ageing. However, the underlying mechanisms remain unknown. Extracellular K+ homeostasis is a potential mediator of neuronal injury as K+ elevations increase excitatory activity. The dysregulation of extracellular K+ and potassium channel expressions during neurodegeneration could contribute to this distinction. Here we measured the cortical extracellular K+ concentration ([K+]e) in awake wild-type mice as well as murine models of neurodegeneration using K+-sensitive microelectrodes. Unexpectedly, aged wild-type mice exhibited significantly lower cortical [K+]e than young mice. In contrast, cortical [K+]e was consistently elevated in Alzheimer's disease (APP/PS1), amyotrophic lateral sclerosis (ALS) (SOD1G93A) and Huntington's disease (R6/2) models. Cortical resting [K+]e correlated inversely with neuronal density and the [K+]e buffering rate but correlated positively with the predicted neuronal firing rate. Screening of astrocyte-selective genomic datasets revealed a number of potassium channel genes that were downregulated in these disease models but not in normal ageing. In particular, the inwardly rectifying potassium channel Kcnj10 was downregulated in ALS and Huntington's disease models but not in normal ageing, while Fxyd1 and Slc1a3, each of which acts as a negative regulator of potassium uptake, were each upregulated by astrocytes in both Alzheimer's disease and ALS models. Chronic elevation of [K+]e in response to changes in gene expression and the attendant neuronal hyperexcitability may drive the neuronal loss characteristic of these neurodegenerative diseases. These observations suggest that the dysregulation of extracellular K+ homeostasis in a number of neurodegenerative diseases could be due to aberrant astrocytic K+ buffering and as such, highlight a fundamental role for glial dysfunction in neurodegeneration.

The short- and long-term effects of congenital occlusion loss of the unilateral first permanent molar on the temporomandibular joint morphology and position: A retrospective study based on cone-beam computed tomography.

OBJECTIVE: To investigate the effects of congenital unilateral first permanent molar occlusal loss (CUMOL) on the morphology and position of temporomandibular joint (TMJ). MATERIALS AND METHODS: Cone-beam computed tomography (CBCT) images of 37 patients with CUMOL (18 males and 19 females, mean age: 13.60 ± 4.38 years) were divided into two subgroups according to the status of second molar (G1: the second molar not erupted, n = 18, G2: second molar erupted, n = 19). The control group consisted of 33 normal occlusion patients (9 males and 24 females, mean age: 16.15 ± 5.44 years) and was divided into 2 subgroups accordingly (G3: the second molar had not erupted, n = 18, G4: the second molar had erupted and made contact with the opposing tooth, n = 15). Linear and angular measurements were used to determine the characteristics of TMJ. RESULTS: In G1, the condyle on the side of the CUMOL shifts posteriorly, with significant side differences observed in Anterior space (AS, P < .05) and Posterior space (PS, P < .05). However, with the eruption of the second permanent molars, in G2, the condyle on the CUMOL side moves posteriorly and inferiorly. This results in significant lateral differences in the AS (P < .05), PS (P < .05), and Superior space (SS, P < .05). Additionally, there is an increase in the thickness of the roof of the glenoid fossa (TRF) on the CUMOL side (P < .05), and a decrease in the inclination of the bilateral articular eminences (P < .05). CONCLUSIONS: CUMOL can affect the position and the morphology of the condyle and was associated with the eruption of the second permanent molars. Before the eruption of the second permanent molars, CUMOL primarily affects the position of the condyle. After the emergence of the second permanent molars, CUMOL leads to changes in both the condyle's position and the morphology of the glenoid fossa.

Alleviation of temporomandibular joint osteoarthritis by targeting RIPK1-mediated inflammatory signalling.

Temporomandibular joint osteoarthritis (TMJOA), prevalent in adolescents and the elderly, has serious physical and psychological consequences. TMJOA is a degenerative disease of the cartilage and bone, mostly driven by inflammation, and synoviocytes are the first and most important inflammatory factor releasers. Receptor-interacting serine/threonine-protein kinase (RIPK1) promotes inflammatory response and cell death during an array of illnesses. This research aimed to explore the impacts of RIPK1 inhibitor therapy in TMJOA and the mechanism of RIPK1 in inducing inflammation during TMJOA. Herein, inhibition of RIPK1 suppressed the elevated levels of inflammatory factors, nuclear factor kappa B (NF-κB), along with markers of apoptosis and necroptosis after tumour necrosis factor (TNF)-α/cycloheximide (CHX) treatment in synoviocytes. Moreover, inflammation models were constructed in vivo through complete Freund's adjuvant (CFA) induction and disc perforation, and the findings supported that RIPK1 inhibition protected TMJ articular cartilage against progressive degradation. RIPK1 regulates NF-κB activation via cellular inhibitor of apoptosis proteins (cIAP), apoptosis via caspase-8, and necroptosis via RIPK3/mixed lineage kinase domain-like (MLKL) in synoviocytes, which in turn facilitates TMJOA inflammation progression.

M2 Macrophages-Derived Exosomal miRNA-23a-3p Promotes the Progression of Oral Squamous Cell Carcinoma by Targeting PTEN.

Exosomes from tumor cells and immune cells regulate the tumor microenvironment through the biomolecules or microRNAs (miRNAs) they carry. This research aims to investigate the role of miRNA in exosomes derived from tumor-associated macrophages (TAMs) in the progression of oral squamous cell carcinoma (OSCC). RT-qPCR and Western blotting assays were used to determine the expression of genes and proteins in OSCC cells. CCK-8, Scratch assay and invasion-related proteins were utilized to detect the malignant progression of tumor cells. High-throughput sequencing predicted differentially expressed miRNAs in exosomes secreted by M0 and M2 macrophages. Compared with exosomes from M0 macrophages, exosomes from M2 macrophages led to enhanced proliferation and invasion of OSCC cells and inhibited their apoptosis. High-throughput sequencing results show that miR-23a-3p is differentially expressed in exosomes from M0 and M2 macrophages. MiRNA target gene database predicts that phosphatase and tensin homolog (PTEN) are target genes of miR-23a-3p. Further studies revealed that transfection of miR-23a-3p mimics inhibited PTEN expression in vivo and in vitro and promoted the malignant progression of OSCC cells, which was reversed by miR-23a-3p inhibitors. MiR-23a-3p in exosomes derived from M2 macrophages promotes malignant progression of OSCC. PTEN is a potential intracellular target of miR-23a-3p. MiR-23a-3p, an M2 macrophage-associated exosome, is a promising target for the future treatment of OSCC.

[18F]FDG PET/MRI combined with chest HRCT in early cancer detection: a retrospective study of 3020 asymptomatic subjects.

PURPOSE: PET/MRI has become an important medical imaging approach in clinical practice. In this study, we retrospectively investigated the detectability of fluorine-18 (18F)-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging ([18F]FDG PET/MRI) combined with chest computerized tomography (CT) for early cancer in a large cohort of asymptomatic subjects. METHODS: This study included a total of 3020 asymptomatic subjects who underwent whole-body [18F]FDG PET/MRI and chest HRCT examinations. All subjects received a 2-4-year follow-up for cancer development. Cancer detection rate, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the [18F]FDG PET/MRI with or without chest HRCT were calculated and analyzed. RESULTS: Sixty-one subjects were pathologically diagnosed with cancers, among which 59 were correctly detected by [18F]FDG PET/MRI combined with chest HRCT. Of the 59 patients (32 with lung cancer, 9 with breast cancer, 6 with thyroid cancer, 5 with colon cancer, 3 with renal cancer, 1 with prostate cancer, 1 with gastric cancer, 1 with endometrial cancer, and 1 with lymphoma), 54 (91.5%) were at stage 0 or stage I (according to the 8th edition of the tumor-node-metastasis [TNM] staging system), 33 (55.9%) were detected by PET/MRI alone (27 with non-lung cancers and 6 with lung cancer). Cancer detection rate, sensitivity, specificity, PPV, and NPV for PET/MRI combined with chest CT were 2.0%, 96.7%, 99.6%, 83.1%, and 99.9%, respectively. For PET/MRI alone, the metrics were 1.1%, 54.1%, 99.6%, 73.3%, and 99.1%, respectively, and for PET/MRI in non-lung cancers, the metrics were 0.9%, 93.1%, 99.6%, 69.2%, and 99.9%, respectively. CONCLUSIONS: [18F]FDG PET/MRI holds great promise for the early detection of non-lung cancers, while it seems insufficient for detecting early-stage lung cancers. Chest HRCT can be complementary to whole-body PET/MRI for early cancer detection. TRIAL REGISTRATION: ChiCTR2200060041. Registered 16 May 2022. Public site: https://www.chictr.org.cn/index.html.

Mechanical loading and autophagy: A study on the BoNT-A injection-induced condylar cartilage degeneration.

Botulinum toxin A (BoNT-A) has emerged as a treatment option for temporomandibular disorder (TMD). By injecting BoNT-A into the masseter muscle, it is possible to reduce mechanical loading on the temporomandibular joint (TMJ). However, numerous prior studies have indicated excessive reduction in mechanical loading can have detrimental effects on TMJ cartilage. This study proposes that autophagy, a process influenced by mechanical loading, could play a role in BoNT-A-induced mandibular condyle cartilage degeneration. To explore this hypothesis, we employed both BoNT-A injection and an excessive biting model to induce variations in mechanical loading on the condyle cartilage of C57BL/6 mice, thereby simulating an increase and decrease in mechanical loading, respectively. Results showed a significant reduction in cartilage thickness and downregulation of Runt-related transcription factor 2 (Runx2) expression in chondrocytes following BoNT-A injection. In vitro experiments demonstrated that the reduction of Runx2 expression in chondrocytes is associated with autophagy, possibly dependent on decreased YAP expression induced by low mechanical loading. This study reveals the potential involvement of the YAP/LC3/Runx2 signaling pathway in BoNT-A mediated mandibular condylar cartilage degeneration.

Organoids as a new model system to study neural tube defects.

The neural tube is the first critically important structure that develops in the embryo. It serves as the primordium of the central nervous system; therefore, the proper formation of the neural tube is essential to the developing organism. Neural tube defects (NTDs) are severe congenital defects caused by failed neural tube closure during early embryogenesis. The pathogenesis of NTDs is complicated and still not fully understood even after decades of research. While it is an ethically impossible proposition to investigate the in vivo formation process of the neural tube in human embryos, a newly developed technology involving the creation of neural tube organoids serves as an excellent model system with which to study human neural tube formation and the occurrence of NTDs. Herein we reviewed the recent literature on the process of neural tube formation, the progress of NTDs investigations, and particularly the exciting potential to use neural tube organoids to model the cellular and molecular mechanisms underlying the etiology of NTDs.

IL-37 inhibits M1-like macrophage activation to ameliorate temporomandibular joint inflammation through the NLRP3 pathway.

OBJECTIVES: IL-37 has been identified as an important anti-inflammatory and immunosuppressive factor. This study was undertaken to explore how IL-37 affects M1/M2-like macrophage polarization and thus contributes to anti-inflammatory processes in the temporomandibular joint. METHODS: Western blotting, quantitative real-time PCR (qRT-PCR) and immunofluorescence were used to verify the IL-37-induced polarization shift from the M1 phenotype to the M2 phenotype, and the related key pathways were analysed by western blotting. Human chondrocytes were stimulated with M1-conditioned medium (CM) or IL-37-pretreated M1-CM, and inflammatory cytokines were detected. siRNA-IL-1R8 and MCC-950 were used to investigate the mechanism underlying the anti-inflammatory effects of IL-37. Complete Freund's adjuvant-induced and disc perforation-induced inflammation models were used for in vivo studies. Haematoxylin and eosin, immunohistochemical and safranin-O staining protocols were used to analyse histological changes in the synovium and condyle. RESULTS: Western blotting, qRT-PCR and immunofluorescence showed that IL-37 inhibited M1 marker expression and upregulated M2 marker expression. Western blotting and qRT-PCR showed that pretreatment with IL-37 suppressed inflammatory cytokine expression in chondrocytes. IL-37 inhibited the expression of NLRP3 and upregulated the expression of IL-1R8. Si-IL-1R8 and MCC-950 further confirmed that the anti-inflammatory properties of IL-37 were dependent on the presence of IL-1R8 and NLRP3. In vivo, IL-37 reduced synovial M1 marker expression and cartilage degeneration and increased M2 marker expression. CONCLUSION: IL-37 shifting of the polarization of macrophages from the pro-inflammatory M1 phenotype to the beneficial anti-inflammatory M2 phenotype seems to be a promising therapeutic strategy for treating temporomandibular joint inflammation.

A case of delayed allergic reaction caused by local injection of triamcinolone acetonide. / å±€éƒ¨æ³¨å°„é†‹é ¸æ›²å®‰å¥ˆå¾·è‡´è¿Ÿå‘è¿‡æ•ååº”1例.

Glucocorticoid is a commonly used anti-inflammatory and anti-allergic drug in clinic. Allergic reactions caused by glucocorticoids are rare in clinic. Glucocorticoid allergy is a type of allergic reaction caused by glucocorticoid as an allergen, and its clinical manifestations of hypersensitivity are not specific. Here we reported a case of an allergic reaction in patients with oral lichen planus who received submucosal injection of triamcinolone acetonide in the tongue. The patient showed local erosion, bleeding, and pain in the mucous membrane of the tongue in the Xiangya Stomatological Hospital, Central South University. The allergic symptoms were relieved after the patient was given diclofenac sodium sustained-release tablets, sodium bicarbonate injection for gargle, and Kangfuxin liquid.It is the clinical need to further deepen the understanding of glucocorticoid allergy. The allergens should be cut off as soon as possible, and the corresponding treatment is performed according to the type of hypersensitivity reaction, thereby improving the therapeutic effect.

SOX9 Is an Astrocyte-Specific Nuclear Marker in the Adult Brain Outside the Neurogenic Regions.

Astrocytes have in recent years become the focus of intense experimental interest, yet markers for their definitive identification remain both scarce and imperfect. Astrocytes may be recognized as such by their expression of glial fibrillary acidic protein, glutamine synthetase, glutamate transporter 1 (GLT1), aquaporin-4, aldehyde dehydrogenase 1 family member L1, and other proteins. However, these proteins may all be regulated both developmentally and functionally, restricting their utility. To identify a nuclear marker pathognomonic of astrocytic phenotype, we assessed differential RNA expression by FACS-purified adult astrocytes and, on that basis, evaluated the expression of the transcription factor SOX9 in both mouse and human brain. We found that SOX9 is almost exclusively expressed by astrocytes in the adult brain except for ependymal cells and in the neurogenic regions, where SOX9 is also expressed by neural progenitor cells. Transcriptome comparisons of SOX9+ cells with GLT1+ cells showed that the two populations of cells exhibit largely overlapping gene expression. Expression of SOX9 did not decrease during aging and was instead upregulated by reactive astrocytes in a number of settings, including a murine model of amyotrophic lateral sclerosis (SOD1G93A), middle cerebral artery occlusion, and multiple mini-strokes. We quantified the relative number of astrocytes using the isotropic fractionator technique in combination with SOX9 immunolabeling. The analysis showed that SOX9+ astrocytes constitute ∼10-20% of the total cell number in most CNS regions, a smaller fraction of total cell number than previously estimated in the normal adult brain.SIGNIFICANCE STATEMENT Astrocytes are traditionally identified immunohistochemically by antibodies that target cell-specific antigens in the cytosol or plasma membrane. We show here that SOX9 is an astrocyte-specific nuclear marker in all major areas of the CNS outside of the neurogenic regions. Based on SOX9 immunolabeling, we document that astrocytes constitute a smaller fraction of total cell number than previously estimated in the normal adult mouse brain.

Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease.

Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear whether glymphatic transport affects the distribution of soluble Aß in Alzheimer's disease (AD). In wild type mice, we show that Aß40 (fluorescently labeled Aß40 or unlabeled Aß40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Aß42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to Aß40. Interestingly, pretreatment with Aß40 in the CSF, but not Aß42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-ß deposits, glymphatic transport was reduced, due to the accumulation of toxic Aß species, such as soluble oligomers. CSF-derived Aß40 co-localizes with existing endogenous vascular and parenchymal amyloid-ß plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal Aß accumulation. Importantly, glymphatic failure preceded significant amyloid-ß deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD.

Serum proteomic biomarker investigation of vascular depression using data-independent acquisition: a pilot study.

Background: Vascular depression (VaD) is a depressive disorder closely associated with cerebrovascular disease and vascular risk factors. It remains underestimated owing to challenging diagnostics and limited information regarding the pathophysiological mechanisms of VaD. The purpose of this study was to analyze the proteomic signatures and identify the potential biomarkers with diagnostic significance in VaD. Methods: Deep profiling of the serum proteome of 35 patients with VaD and 36 controls was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Functional enrichment analysis of the quantified proteins was based on Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and Reactome databases. Machine learning algorithms were used to screen candidate proteins and develop a protein-based model to effectively distinguish patients with VaD. Results: There were 29 up-regulated and 31 down-regulated proteins in the VaD group compared to the controls (|log2FC| ≥ 0.26, p ≤ 0.05). Enrichment pathways analyses showed that neurobiological processes related to synaptic vesicle cycle and axon guidance may be dysregulated in VaD. Extrinsic component of synaptic vesicle membrane was the most enriched term in the cellular components (CC) terms. 19 candidate proteins were filtered for further modeling. A nomogram was developed with the combination of HECT domain E3 ubiquitin protein ligase 3 (HECTD3), Nidogen-2 (NID2), FTO alpha-ketoglutarate-dependent dioxygenase (FTO), Golgi membrane protein 1 (GOLM1), and N-acetylneuraminate lyase (NPL), which could be used to predict VaD risk with favorable efficacy. Conclusion: This study offers a comprehensive and integrated view of serum proteomics and contributes to a valuable proteomics-based diagnostic model for VaD.

Risk factors for the development of biliary tract infection after choledochal-malformation surgery.

OBJECTIVE: To explore the risk factors of biliary tract infection after bile duct dilatation surgery. METHODS: The study included 135 patients with choledochal malformation after bile duct dilatation surgery at our hospital from January 2019 to June 2021. We analyzed general data of infected and uninfected groups after bile duct dilatation surgery. Single/multiple factor logistic regression was used to analyse the factors influencing postoperative biliary tract infection in bile duct dilatation. RESULTS: There were statistically significant differences in preoperative history of biliary tract infection, partial hepatectomy, hilar anastomosis, and Todani staging between the two groups. Single factor Logistic regression analysis showed that preoperative history of biliary tract infection, partial hepatectomy, hepatic portal anastomosis and Todani staging IV and V were positively correlated with postoperative biliary tract infection following biliary duct dilatation (P＜0.05). In addition, logistic regression analysis of these general data with differential indicators as independent variables and postoperative biliary tract infection in biliary duct dilatation as a dependent variable showed that history of preoperative biliary tract infection and hepatic portal anastomosis were risk factors of postoperative biliary tract infection following biliary duct dilatation. CONCLUSION: Risk factors of biliary tract infection after bile duct dilatation include a history of preoperative biliary tract infection and hepatoportal anastomosis, which should be noted during clinical procedures to prevent or reduce the development of biliary tract infection after bile duct dilatation.

IL-37 counteracts inflammatory injury in the temporomandibular joint via the intracellular pathway.

Background: The temporomandibular joint is often afflicted by osteoarthritis (TMJOA), causing pain and dysfunction, which is particularly prevalent in the elderly population. IL-37 is effective in avoiding excessive inflammatory damage to the organism. This article investigates the role and mechanism of intracellular IL-37 in TMJOA. Methods: Enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, Western blotting, Senescence-associated ß-galactosidase staining, immunofluorescence, and lentivirus were performed to elucidate the underlying mechanism. Results: The results confirmed that IL-37 in synovial cells decreased with aging. Inflammatory stimulus elevated intracellular IL-37 in synoviocytes, while lentiviral knockdown of IL-37 resulted in more inflammatory factor production. Dynamic changes of IL-37 were observed in the nucleus and supernatant. In addition, Caspease-1 inhibitor hindered intracellular IL-37 maturation, and Smad3 inhibitor caused the loss of nuclear translocation of mature IL-37. Transfection of synovial cells with IL-37-expressing lentivirus resulted in relief not only of synovitis but also of the cartilage damage and inflammation caused by synovitis. Conclusion: This study provides new insights into the intracellular anti-inflammatory mechanism of IL-37. It also confirms that IL-37 decreases with cellular senescence and that increasing intracellular IL-37 can effectively treat synovitis and synovitis-induced inflammatory damage to cartilage.

Enriched environment attenuates hippocampal theta and gamma rhythms dysfunction in chronic cerebral hypoperfusion via improving imbalanced neural afferent levels.

Chronic cerebral hypoperfusion (CCH) is increasingly recognized as a common cognitive impairment-causing mechanism. However, no clinically effective drugs to treat cognitive impairment due to CCH have been identified. An abnormal distribution of neural oscillations was found in the hippocampus of CCH rats. By releasing various neurotransmitters, distinct afferent fibers in the hippocampus influence neuronal oscillations in the hippocampus. Enriched environments (EE) are known to improve cognitive levels by modulating neurotransmitter homeostasis. Using EE as an intervention, we examined the levels of three classical neurotransmitters and the dynamics of neural oscillations in the hippocampus of the CCH rat model. The results showed that EE significantly improved the balance of three classical neurotransmitters (acetylcholine, glutamate, and GABA) in the hippocampus, enhanced the strength of theta and slow-gamma (SG) rhythms, and dramatically improved neural coupling across frequency bands in CCH rats. Furthermore, the expression of the three neurotransmitter vesicular transporters-vesicular acetylcholine transporters (VAChT) and vesicular GABA transporters (VGAT)-was significantly reduced in CCH rats, whereas the expression of vesicular glutamate transporter 1 (VGLUT1) was abnormally elevated. EE partially restored the expression of the three protein levels to maintain the balance of hippocampal afferent neurotransmitters. More importantly, causal mediation analysis showed EE increased the power of theta rhythm by increasing the level of VAChT and VGAT, which then enhanced the phase amplitude coupling of theta-SG and finally led to an improvement in the cognitive level of CCH. These findings shed light on the role of CCH in the disruption of hippocampal afferent neurotransmitter balance and neural oscillations. This study has implications for our knowledge of disease pathways.

Reduced biophotonic activities and spectral blueshift in Alzheimer's disease and vascular dementia models with cognitive impairment.

Background: Although clinically, Alzheimer's disease (AD) and vascular dementia (VaD) are the two major types of dementia, it is unclear whether the biophotonic activities associated with cognitive impairments in these diseases share common pathological features. Methods: We used the ultraweak biophoton imaging system (UBIS) and synaptosomes prepared by modified percoll method to directly evaluate the functional changes in synapses and neural circuits in AD and VaD model animals. Results: We found that biophotonic activities induced by glutamate were significantly reduced and spectral blueshifted in synaptosomes and brain slices. These changes could be partially reversed by pre-perfusion of the ifenprodil, a specific antagonist of the GluN2B subunit of N-methyl-D-aspartate receptors (NMDARs). Conclusion: Our findings suggest that AD and VaD pathology present similar but complex changes in biophotonic activities and transmission at synapses and neural circuits, implying that communications and information processing of biophotonic signals in the brain are crucial for advanced cognitive functions.

High glucose causes developmental abnormalities in neuroepithelial cysts with actin and HK1 distribution changes.

It has been reported that the offspring of diabetic pregnant women have an increased risk for neural tube defects. Previous studies in animal models suggested that high glucose induces cell apoptosis and epigenetic changes in the developing neural tube. However, effects on other cellular aspects such as the cell shape changes were not fully investigated. Actin dynamics plays essential roles in cell shape change. Disruption on actin dynamics is known to cause neural tube defects. In the present study, we used a 3D neuroepithelial cyst model and a rosette model, both cultured from human embryonic stem cells, to study the cellular effects caused by high glucose. By using these models, we observed couple of new changes besides increased apoptosis. First, we observed that high glucose disturbed the distribution of pH3 positive cells in the neuroepithelial cysts. Secondly, we found that high glucose exposure caused a relatively smaller actin inner boundary enclosed area, which was unlikely due to osmolarity changes. We further investigated key glucose metabolic enzymes in our models and the results showed that the distribution of hexokinase1 (HK1) was affected by high glucose. We observed that hexokinase1 has an apical-basal polarized distribution and is highest next to actin at the boundaries. hexokinase1 was more diffused and distributed less polarized under high glucose condition. Together, our observations broadened the cellular effects that may be caused by high glucose in the developing neural tube, especially in the secondary neurulation process.

Maresin 1 improves cognitive decline and ameliorates inflammation and blood-brain barrier damage in rats with chronic cerebral hypoperfusion.

BACKGROUND: Chronic inflammation and blood-brain barrier destruction are interrelated pathological changes in chronic cerebral hypoperfusion (CCH) that promote vascular cognitive impairment (VCI). Therefore, we discussed the impact of the macrophage mediator in resolving inflammation 1 (Maresin 1) on the CCH-induced cognitive impairment and its underlying mechanisms. METHODS: 66 rats were randomly divided into three groups: Sham (n = 22), 2VO (n = 22), and 2VO + MaR1 (n = 22). Rats in three groups received 2-Vessel Occlusion (2VO) or sham operation and received intrathecal delivery of PBS or MaR1. Hippocampal blood flow and Modified neurological severity scores (mNSS) were used to confirm models' effect. Blood-brain barrier (BBB) damage was assessed by Evans blue (EB) leakage experiments and spectrophotometry, the BBB ultrastructure was observed with a transmission electron microscope (TEM), and the expression of zonula occluden-1 (ZO-1), claudin-5, and matrix metalloproteinases-9 (MMP-9) were detected with Enzyme-Linked Immunosorbent Assay (ELISA). Morris water maze (MWM) was used to assess cognitive function. Tumor necrosis factor (TNF-α), interleukin-1ß (IL-1ß), and nuclear factor-κB (NF-κB) expression were examined by Western blotting (WB) and ELISA. Immunofluorescence was used to detect microglia, astrocytes and oligodendrocytes. RESULTS: Rats developed obvious cognitive impairment by CCH. BBB showed EB leakage, ultrastructural destruction, degradation of ZO-1, Claudin-5, and up-regulation of MMP-9. Inactivation of oligodendrocytes, activation of microglia and astrocyte and increased expression of NF-κB, TNF-α, and IL-1ß has been detected. MaR1 administration significantly reverted these changes. CONCLUSION: MaR1 can improve the CCH-induced cognitive impairment. Inflammatory resolution and BBB protection may be the mechanism of MaR1 to prevent CCH-induced cognitive impairment.