The characteristic patterns of individual brain susceptibility networks underlie Alzheimer's disease and white matter hyperintensity-related cognitive impairment.

Excessive iron accumulation in the brain cortex increases the risk of cognitive deterioration. However, interregional relationships (defined as susceptibility connectivity) of local brain iron have not been explored, which could provide new insights into the underlying mechanisms of cognitive decline. Seventy-six healthy controls (HC), 58 participants with mild cognitive impairment due to probable Alzheimer's disease (MCI-AD) and 66 participants with white matter hyperintensity (WMH) were included. We proposed a novel approach to construct a brain susceptibility network by using Kullback‒Leibler divergence similarity estimation from quantitative susceptibility mapping and further evaluated its topological organization. Moreover, sparse logistic regression (SLR) was applied to classify MCI-AD from HC and WMH with normal cognition (WMH-NC) from WMH with MCI (WMH-MCI).The altered susceptibility connectivity in the MCI-AD patients indicated that relatively more connectivity was involved in the default mode network (DMN)-related and visual network (VN)-related connectivity, while more altered DMN-related and subcortical network (SN)-related connectivity was found in the WMH-MCI patients. For the HC vs. MCI-AD classification, the features selected by the SLR were primarily distributed throughout the DMN-related and VN-related connectivity (accuracy = 76.12%). For the WMH-NC vs. WMH-MCI classification, the features with high appearance frequency were involved in SN-related and DMN-related connectivity (accuracy = 84.85%). The shared and specific patterns of the susceptibility network identified in both MCI-AD and WMH-MCI may provide a potential diagnostic biomarker for cognitive impairment, which could enhance the understanding of the relationships between brain iron burden and cognitive decline from a network perspective.

Characteristic patterns of functional connectivity-mediated cerebral small vessel disease-related cognitive impairment and depression.

Cerebral small vessel disease is common in most individuals aged 60 years or older, and it is associated with cognitive dysfunction, depression, anxiety disorder, and mobility problems. Currently, many cerebral small vessel disease patients have both cognitive impairment and depressive symptoms, but the relationship between the 2 is unclear. The present research combined static and dynamic functional network connectivity methods to explore the patterns of functional networks in cerebral small vessel disease individuals with cognitive impairment and depression (cerebral small vessel disease-mild cognitive impairment with depression) and their relationship. We found specific functional network patterns in the cerebral small vessel disease-mild cognitive impairment with depression individuals (P < 0.05). The cerebral small vessel disease individuals with depression exhibited unstable dynamic functional network connectivity states (transitions likelihood: P = 0.040). In addition, we found that the connections within the lateral visual network between the sensorimotor network and ventral attention network could mediate white matter hyperintensity-related cognitive impairment (indirect effect: 0.064; 95% CI: 0.003, 0.170) and depression (indirect effect: -0.415; 95% CI: -1.080, -0.011). Cognitive function can negatively regulate white matter hyperintensity-related depression. These findings elucidate the association between cognitive impairment and depression and provide new insights into the underlying mechanism of cerebral small vessel disease-related cognitive dysfunction and depression.

Identification of a potential prognostic model combining pyroptosis-related gene with immune microenvironment for pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a fatal tumor with grave prognosis. Pyroptosis, a programmed cell death, is involved in tumorigenesis. However, a few studies have elucidated the functions of pyroptosis in PDAC. METHODS: The mRNA expression profiles were downloaded from the TCGA and GEO databases. Univariate and LASSO Cox regression analyses were used to screen out differentially expressed genes (DEGs) and construct the pyroptosis-related genes (PRGs) risk model. The efficiency of model was examined by Kaplan-Meier curve, ROC curve, and nomogram. Univariate and multivariate Cox regression analyses were utilized to assess whether the risk model could be used as an independent prognostic factor. The biological function was analyzed by GO, KEGG, and GSEA enrichment analysis. qRT-PCR and immunohistochemical staining detected gene expression. RESULTS: Totally 9 PRGs with differential expression were identified between normal and PDAC tissues. Then, according to PRGs, we filtered out three key DEGs and constructed the prognostic risk model. Kaplan-Meier curve, ROC curve, and nomogram indicated that the prognostic risk model had high survival prediction efficiency. Meanwhile, the risk model had also shown to be an independent prognostic factor. Further functional enrichment analysis showed that cell adhesion, PI3K-AKT signaling pathway, and dysregulated immune status may be associated with PDAC development. External validation of the model was carried out in the GEO cohort, and the results were similar to that in the TCGA cohort. Finally, the expression of three genes was verified by qRT-PCR and immunohistochemical staining. CONCLUSION: The prognostic risk model established in this study can give a good prediction of the prognosis of PDAC patients, which might provide insights into clinical treatments and prognostic prediction of PDAC.

Altered morphological connectivity mediated white matter hyperintensity-related cognitive impairment.

White matter hyperintensities (WMH) are widely observed in older adults and are closely associated with cognitive impairment. However, the underlying neuroimaging mechanisms of WMH-related cognitive dysfunction remain unknown. This study recruited 61 WMH individuals with mild cognitive impairment (WMH-MCI, n = 61), 48 WMH individuals with normal cognition (WMH-NC, n = 48) and 57 healthy control (HC, n = 57) in the final analyses. We constructed morphological networks by applying the Kullback-Leibler divergence to estimate interregional similarity in the distributions of regional gray matter volume. Based on morphological networks, graph theory was applied to explore topological properties, and their relationship to WMH-related cognitive impairment was assessed. There were no differences in small-worldness, global efficiency and local efficiency. The nodal local efficiency, degree centrality and betweenness centrality were altered mainly in the limbic network (LN) and default mode network (DMN). The rich-club analysis revealed that WMH-MCI subjects showed lower average strength of the feeder and local connections than HC (feeder connections: P = 0.034; local connections: P = 0.042). Altered morphological connectivity mediated the relationship between WMH and cognition, including language (total indirect effect: -0.010; 95 % CI: -0.024, -0.002) and executive (total indirect effect: -0.010; 95 % CI: -0.028, -0.002) function. The altered topological organization of morphological networks was mainly located in the DMN and LN and was associated with WMH-related cognitive impairment. The rich-club connection was relatively preserved, while the feeder and local connections declined. The results suggest that single-subject morphological networks may capture neurological dysfunction due to WMH and could be applied to the early imaging diagnostic protocol for WMH-related cognitive impairment.

Altered static and dynamic functional network connectivity related to cognitive decline in individuals with white matter hyperintensities.

White matter hyperintensities (WMH) of assumed vascular origin are common in elderly individuals and are closely associated with cognitive decline. However, the underlying neural mechanisms of WMH-related cognitive impairment remain unclear. After strict screening, 59 healthy controls (HC, n = 59), 51 patients with WMH and normal cognition (WMH-NC, n = 51) and 68 patients with WMH and mild cognitive impairment (WMH-MCI, n = 68) were included in the final analyses. All individuals underwent multimodal magnetic resonance imaging (MRI) and cognitive evaluations. We investigated the neural mechanism underlying WMH-related cognitive impairment based on static and dynamic functional network connectivity (sFNC and dFNC) approaches. Finally, the support vector machine (SVM) method was performed to identify WMH-MCI individuals. The sFNC analysis indicated that functional connectivity within the visual network (VN) could mediate the impairment of information processing speed related to WMH (indirect effect: 0.24; 95% CI: 0.03, 0.88 and indirect effect: 0.05; 95% CI: 0.001, 0.14). WMH may regulate the dFNC between the higher-order cognitive network and other networks and enhance the dynamic variability between the left frontoparietal network (lFPN) and the VN to compensate for the decline in high-level cognitive functions. The SVM model achieved good prediction ability for WMH-MCI patients based on the above characteristic connectivity patterns. Our findings shed light on the dynamic regulation of brain network resources to maintain cognitive processing in individuals with WMH. Crucially, dynamic reorganization of brain networks could be regarded as a potential neuroimaging biomarker for identifying WMH-related cognitive impairment.

Self-construal priming modulates sonic seasoning.

Introduction: "Sonic seasoning" is when music influences the real taste experiences of consumers. "Self-construal" is how individuals perceive, understand, and interpret themselves. Numerous studies have shown that independent and interdependent self-construal priming can affect a person's cognition and behavior; however, their moderating effect on the sonic seasoning effect remains unclear. Methods: This experiment was a 2 (self-construal priming: independent self-construal or interdependent self-construal) × 2 (chocolate: milk chocolate or dark chocolate) × 2 (emotional music: positive emotional music or negative emotional music) mixed design, and explored the moderating role of self-construal priming and the effect of emotional music on taste by comparing participants' evaluations of chocolates while listening to positive or negative music after different levels of self-construal priming. Results: After initiating independent self-construal, participants increased their ratings of milk chocolate sweetness when listening to music that elicited positive emotions, t(32) = 3.11, p = 0.004, Cohen's d = 0.54, 95% CI = [0.33, 1.61]. In contrast, interdependent self-construal priming led participants to perceive dark chocolate as sweeter when they heard positive music, t(29) = 3.63, p = 0.001, Cohen's d = 0.66, 95%CI = [0.44, 1.56]. Discussion: This study provides evidence for improving people's individual eating experience and enjoyment of food.

Potential role of TREM2 in high cholesterol­induced cell injury and metabolic dysfunction in SH­SY5Y cells.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an important member of the immunoglobulin family of inflammatory stimulating receptors and is involved in a number of pathophysiological processes. The present study aimed to investigate the role of TREM2 in neurotoxicity induced by high cholesterol levels in SH-SY5Y cells and explore the potential mechanism. SH-SY5Y cells were routinely cultured and stimulated with a range of cholesterol concentrations. Cell viability was assessed using an MTT assay, morphological changes were observed, and the cell cycle distribution was measured using flow cytometry. Lipid deposition was measured by Oil red O staining, and the mRNA and protein expression levels of SRBEP-1 and SRBEP-2 were detected by quantitative PCR and western blotting, respectively. Moreover, the protein expression levels of BDNF, Copine-6, TREM1, TREM2, and key molecules of the Wnt signaling pathways were detected by western blotting. Finally, TREM2 was overexpressed to investigate its potential role in high cholesterol-induced neurotoxicity. The results showed that cell viability was significantly decreased in SH-SY5Y cells stimulated with cholesterol (0.1~100 µM) in a dose- and time-dependent manner. Stimulation with 100 µM cholesterol for 24 h resulted in morphological injuries, increased the proportion of SH-SY5Y cells at G0/G1, the degree of lipid accumulation, and the protein expression levels of sterol regulatory element binding protein (SREBP)1 and SREBP2, markedly decreased the protein expression levels of BDNF, Copine-6, and TREM2, and the p-ß-catenin/ß-catenin ratio, and increased the expression levels of nesfatin-1, TREM1 and the p-GSK3ß/GSK3ß ratio. Furthermore, the imbalanced expression of BDNF, Copine-6, nesfatin-1, and p-GSK3ß induced by high cholesterol levels was reversed after overexpression of TREM2. These results suggest that a high concentration of cholesterol could induce cell injury and lipid deposition in SH-SY5Y cells and that the underlying mechanism may be associated with imbalanced TREM2 expression.

Real-Time Monitoring and Early Warning of a Cytokine Storm In Vivo Using a Wearable Noninvasive Skin Microneedle Patch.

A cytokine storm may be the last attack of various diseases, such as sepsis, cancer, and coronavirus disease 2019, that can be life threatening. Real-time monitoring of cytokines in vivo is helpful for assessing the immune status of patients and providing an early warning of a cytokine storm. In this study, a functional carbon nanotube biointerface-based wearable microneedle patches for real-time monitoring of a cytokine storm in vivo via electrochemical analysis are reported. This wearable system has sensitivity with a detection limit of 0.54 pg mL-1 , high specificity, and 5 days of stability with a coefficient of variation of 4.0%. The system also has a quick response of several hours (1-4 h) to increasing cytokines. This wearable microneedle patch may offer a promising route for real-time biomolecule wearables construction. The patch is also the first reported integrated capture and monitoring system that is capable of real-time measurement of protein markers in interstitial fluid.

[Simiaotongzhuo Decoction for the treatment of type III prostatitis: A clinical observation].

OBJECTIVE: To observe the clinical effect of Simiaotongzhuo Decoction (SMTZD) on the symptoms of type III prostatitis with damp-heat stagnation syndrome. METHODS: Using the randomized control method, we divided 140 cases of type III prostatitis with damp-heat stagnation syndrome into two groups and treated them orally with SMTZD at 200 ml per time bid (n = 65) and Tamsulosin Hydrochloride Sustained Release Capsules (THSRC) at 0.2 mg per time qd (n = 75), both for 6 weeks. Before and after medication, we recorded the counts of white blood cells (WBC) and lecithin bodies in the prostatic fluid, NIH-CPSI scores and traditional Chinese medicine syndrome (TCMS) scores, and compared them between the two groups of patients. RESULTS: Compared with the baseline, the WBC count and NIH-CPSI scores were decreased and the number of lecithin bodies increased in both the SMTZD (NIH-CPSI score: ï¼»18±6.47ï¼½ vs ï¼»9±5.02ï¼½) and THSRC groups after medication, with statistically significant difference only in the former group (P<0.05), the TCMS scores were significantly reduced in both the SMTZD (ï¼»21.97±5.12ï¼½ vs ï¼»6.4±4.88ï¼½, P<0.05) and the THSRC group (ï¼»20.73±4.97ï¼½ vs ï¼»11.33±5.93ï¼½, P<0.05), even more significantly in the former. No statistically significant difference was observed in the incidence of adverse reactions between the SMTZD and THSRC groups (9.2% vs 9.3%, P>0.05), and all the adverse reactions were mild. CONCLUSION: Simiaotongzhuo Decoction is safe and effective for the treatment of type III prostatitis with damp-heat stagnation syndrome, which can reduce the WBC count in the prostatic fluid, increase the number of lecithin bodies and improve the NIH-CPSI and TCMS scores of the patient.

Intestinal Stem Cells Damaged by Deoxycholic Acid via AHR Pathway Contributes to Mucosal Barrier Dysfunction in High-Fat Feeding Mice.

High-fat exposure leads to impaired intestinal barrier function by disrupting the function of intestinal stem cells (ISCs); however, the exact mechanism of this phenomenon is still not known. We hypothesize that high concentrations of deoxycholic acid (DCA) in response to a high-fat diet (HFD) affect aryl hydrocarbon receptor (AHR) signalling in ISCs and the intestinal barrier. For this purpose, C57BL/6J mice feeding on a low-fat diet (LFD), an HFD, an HFD with the bile acid binder cholestyramine, and a LFD with the DCA were studied. We found that high-fat feeding induced an increase in faecal DCA concentrations. An HFD or DCA diet disrupted the differentiation function of ISCs by downregulating AHR signalling, which resulted in decreased goblet cells (GCs) and MUC2, and these changes were reversed by cholestyramine. In vitro experiments showed that DCA downregulated the differentiation function of ISCs, which was reversed by the AHR agonist 6-formylindolo [3,2-b]carbazole (FICZ). Mechanistically, DCA caused a reduction in indoleamine 2,3-dioxygenase 1 (IDO1) in Paneth cells, resulting in paracrine deficiency of the AHR ligand kynurenine in crypts. We demonstrated for the first time that DCA disrupts intestinal mucosal barrier function by interfering with AHR signalling in ISCs. Supplementation with AHR ligands may be a new therapeutic target for HFD-related impaired intestinal barrier function.

Identification and Validation of Prognostic Model for Pancreatic Ductal Adenocarcinoma Based on Necroptosis-Related Genes.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a poor prognosis. Recently, necroptosis has been reported to participate in the progression of multiple tumors. However, few studies have revealed the relationship between necroptosis and PDAC, and the role of necroptosis in PDAC has not yet been clarified. Methods: The mRNA expression data and corresponding clinical information of PDAC patients were downloaded from the TCGA and GEO databases. The necroptosis-related genes (NRGs) were obtained from the CUSABIO website. Consensus clustering was performed to divide PDAC patients into two clusters. Univariate and LASSO Cox regression analyses were applied to screen the NRGs related to prognosis to construct the prognostic model. The predictive value of the prognostic model was evaluated by Kaplan-Meier survival analysis and ROC curve. Univariate and multivariate Cox regression analyses were used to evaluate whether the risk score could be used as an independent predictor of PDAC prognosis. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and single-sample gene set enrichment analysis (ssGSEA) were used for functional enrichment analysis. Finally, using qRT-PCR examined NRGs mRNA expression in vitro. Results: Based on the TCGA database, a total of 22 differential expressed NRGs were identified, among which eight NRGs (CAPN2, CHMP4C, PLA2G4F, PYGB, BCL2, JAK3, PLA2G4C and STAT4) that may be related to prognosis were screened by univariate Cox regression analysis. And CAPN2, CHMP4C, PLA2G4C and STAT4 were further selected to construct the prognostic model. Kaplan-Meier survival analysis and ROC curve showed that there was a significant correlation between the risk model and prognosis. Univariate and multivariate Cox regression analyses showed that the risk score of the prognostic model could be used as an independent predictor. The model efficacy was further demonstrated in the GEO cohort. Functional analysis revealed that there were significant differences in immune status between high and low-risk groups. Finally, the qRT-PCR results revealed a similar dysregulation of NRGs in PDAC cell lines. Conclusion: This study successfully constructed and verified a prognostic model based on NRGs, which has a good predictive value for the prognosis of PDAC patients.

Improving the applicability of the thermo-physiological human simulator by correcting its local set point skin temperatures.

The thermo-physiological human simulator has been used in many regions for estimating thermal behavior of the locals. The applicability of the human simulator to populations from different regions is, however, questioned due to its lack of consideration for the ethnic diversities in thermoregulation. This study checked the potential of improving the applicability of the Newton human simulator, one of the most popular simulators, by correcting its local set point skin temperatures according to the target population (Chinese as an example). First, new set point skin temperatures were obtained by conducting tests with 101 Chinese under a thermal neutral condition. Then, simulator tests using the original and new set point skin temperatures were conducted separately for evaluating thermal responses of the Chinese under non-neutral conditions. The evaluated skin and core temperatures by the simulators were compared with those measured from the real human tests. It demonstrated that the evaluated skin temperatures are positively related with the set point skin temperatures of the simulator. Adjusting set point skin temperatures according to the Chinese improved the prediction performance of the local skin temperatures, with the root-mean-square-deviation being reduced for over 50% of the body segments. The proposed idea of correcting local set point skin temperatures would contribute to evaluating the thermal interaction between human body and its surroundings with a higher accuracy.

Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like mice by improving BDNF-related neuropathology.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive decline in cognitive ability. Exosomes derived from bone-marrow mesenchymal stem cells (BMSC-exos) are extracellular vesicles that can execute the function of bone-marrow mesenchymal stem cells (BMSCs). Given the versatile therapeutic potential of BMSC and BMSC-exos, especially their neuroprotective effect, the aim of this study was to investigate the potential effect of BMSC-exos on AD-like behavioral dysfunction in mice and explore the possible molecular mechanism. METHODS: BMSC-exos were extracted from the supernatant of cultured mouse BMSCs, which were isolated from the femur and tibia of adult C57BL/6 mice, purified and sorted via flow cytometry, and cultured in vitro. BMSC-exos were identified via transmission electron microscopy, and typical marker proteins of exosomes were also detected via Western blot. A sporadic AD mouse model was established by intracerebroventricular injection of streptozotocin (STZ). Six weeks later, BMSC-exos were administered via lateral ventricle injection or caudal vein injection lasting five consecutive days, and the control mice were intracerebroventricularly administered an equal volume of solvent. Behavioral performance was observed via the open field test (OFT), elevated plus maze test (EPM), novel object recognition test (NOR), Y maze test (Y-maze), and tail suspension test (TST). The mRNA and protein expression levels of IL-1ß, IL-6, and TNF-α in the hippocampus were measured via quantitative polymerase chain reaction (qPCR) and Western blot, respectively. Moreover, the protein expression of Aß1-42, BACE, IL-1ß, IL-6, TNF-α, GFAP, p-Tau (Ser396), Tau5, synaptotagmin-1 (Syt-1), synapsin-1, and brain-derived neurotrophic factor (BDNF) in the hippocampus was detected using Western blot, and the expression of GFAP, IBA1, Aß1-42 and DCX in the hippocampus was measured via immunofluorescence staining. RESULTS: Lateral ventricle administration, but not caudal vein injection of BMSC-exos improved AD-like behaviors in the STZ-injected mouse model, as indicated by the increased number of rearing, increased frequency to the central area, and increased duration and distance traveled in the central area in the OFT, and improved preference index of the novel object in the NOR. Moreover, the hyperactivation of microglia and astrocytes in the hippocampus of the model mice was inhibited after treatment with BMSC-exos via lateral ventricle administration, accompanied by the reduced expression of IL-1ß, IL-6, TNF-α, Aß1-42, and p-Tau and upregulated protein expression of synapse-related proteins and BDNF. Furthermore, the results of the Pearson test showed that the preference index of the novel object in the NOR was positively correlated with the hippocampal expression of BDNF, but negatively correlated with the expression of GFAP, IBA1, and IL-1ß. Apart from a positive correlation between the hippocampal expression of BDNF and Syt-1, BDNF abundance was found to be negatively correlated with markers of glial activation and the expression of the inflammatory cytokines, Aß1-42, and p-Tau, which are characteristic neuropathological features of AD. CONCLUSIONS: Lateral ventricle administration, but not caudal vein injection of BMSC-exos, can improve AD-like behavioral performance in STZ-injected mice, the mechanism of which might be involved in the regulation of glial activation and its associated neuroinflammation and BDNF-related neuropathological changes in the hippocampus.

Diagnosis and segmentation effect of the ME-NBI-based deep learning model on gastric neoplasms in patients with suspected superficial lesions - a multicenter study.

Background: Endoscopically visible gastric neoplastic lesions (GNLs), including early gastric cancer and intraepithelial neoplasia, should be accurately diagnosed and promptly treated. However, a high rate of missed diagnosis of GNLs contributes to the potential risk of the progression of gastric cancer. The aim of this study was to develop a deep learning-based computer-aided diagnosis (CAD) system for the diagnosis and segmentation of GNLs under magnifying endoscopy with narrow-band imaging (ME-NBI) in patients with suspected superficial lesions. Methods: ME-NBI images of patients with GNLs in two centers were retrospectively analysed. Two convolutional neural network (CNN) modules were developed and trained on these images. CNN1 was trained to diagnose GNLs, and CNN2 was trained for segmentation. An additional internal test set and an external test set from another center were used to evaluate the diagnosis and segmentation performance. Results: CNN1 showed a diagnostic performance with an accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 90.8%, 92.5%, 89.0%, 89.4% and 92.2%, respectively, and an area under the curve (AUC) of 0.928 in the internal test set. With CNN1 assistance, all endoscopists had a higher accuracy than for an independent diagnosis. The average intersection over union (IOU) between CNN2 and the ground truth was 0.5837, with a precision, recall and the Dice coefficient of 0.776, 0.983 and 0.867, respectively. Conclusions: This CAD system can be used as an auxiliary tool to diagnose and segment GNLs, assisting endoscopists in more accurately diagnosing GNLs and delineating their extent to improve the positive rate of lesion biopsy and ensure the integrity of endoscopic resection.

Protective effect of quercetin against the metabolic dysfunction of glucose and lipids and its associated learning and memory impairments in NAFLD rats.

BACKGROUND: Quercetin (QUE) is a flavonol reported with anti-inflammatory and antioxidant activities, and previous results from the group of this study have demonstrated its neuroprotective effect against lipopolysaccharide-induced neuropsychiatric injuries. However, little is known about its potential effect on neuropsychiatric injuries induced or accompanied by metabolic dysfunction of glucose and lipids. METHODS: A nonalcoholic fatty liver disease (NAFLD) rat model was induced via a high-fat diet (HFD), and glucolipid parameters and liver function were measured. Behavioral performance was observed via the open field test (OFT) and the Morris water maze (MWM). The plasma levels of triggering receptor expressed on myeloid cells-1 (TREM1) and TREM2 were measured via enzyme-linked immunosorbent assay (ELISA). The protein expression levels of Synapsin-1 (Syn-1), Synaptatogmin-1 (Syt-1), TREM1 and TREM2 in the hippocampus were detected using western blotting. Morphological changes in the liver and hippocampus were detected by HE and Oil red or silver staining. RESULTS: Compared with the control rats, HFD-induced NAFLD model rats presented significant metabolic dysfunction, hepatocyte steatosis, and impaired learning and memory ability, as indicated by the increased plasma concentrations of total cholesterol (TC) and triglyceride (TG), the impaired glucose tolerance, the accumulated fat droplets and balloon-like changes in the liver, and the increased escaping latency but decreased duration in the target quadrant in the Morris water maze. All these changes were reversed in QUE-treated rats. Moreover, apart from improving the morphological injuries in the hippocampus, treatment with QUE could increase the decreased plasma concentration and hippocampal protein expression of TREM1 in NAFLD rats and increase the decreased expression of Syn-1 and Syt-1 in the hippocampus. CONCLUSIONS: These results suggested the therapeutic potential of QUE against NAFLD-associated impairment of learning and memory, and the mechanism might involve regulating the metabolic dysfunction of glucose and lipids and balancing the protein expression of synaptic plasticity markers and TREM1/2 in the hippocampus.

An elevated deoxycholic acid level induced by high-fat feeding damages intestinal stem cells by reducing the ileal IL-22.

Long-term high-fat diet (HFD) destroys the intestinal mucosal barrier by damaging intestinal stem cells (ISCs). A HFD can increase the concentration of intestinal deoxycholic acid (DCA) and decrease the secretion of interleukin-22 (IL-22), which plays an important role in the proliferation, repair and regeneration of ISCs. We hypothesized that increased level of intestinal DCA induced by a HFD leads to ISC dysfunction by reducing the IL-22 levels in intestinal tissues. In this study, 2 weeks of a DCA diet or a HFD damaged ileal ISC and its proliferation and differentiation, resulting in a decrease in Paneth cells and goblet cells. Importantly, 2 weeks of a DCA diet or a HFD also reduced ileal IL-22 concentration, accompanied by a decreased number of group 3 innate lymphoid cells in ileal mucosa, which produce IL-22 after intestinal injury. Concurrent feeding with bile acid binder cholestyramine prevented all these changes induced by a HFD. In addition, in vitro study further confirmed that exogenous IL-22 reversed the decline in the proliferation and differentiation of ileal ISCs induced by DCA stimulation. Collectively, these results revealed that the decrease in intestinal IL-22 induced by DCA may be a novel mechanism by which HFD damages ISCs. The administration of IL-22 or a bile acid binder may provide novel therapeutic targets for the metabolic syndrome caused by a HFD.

Sodium butyrate alleviates cholesterol gallstones by regulating bile acid metabolism.

Cholesterol overloading and bile acid metabolic disorders play an important role in the onset of cholesterol gallstone (CGS). Short-chain fatty acids (SCFAs) can regulate bile acid metabolism by modulating the gut microbiota. However, the role and mechanism by which sodium butyrate (NaB) targets bile acids to attenuate CGS are still unknown. In this study, continuous administration of 12 mg/day for 8 weeks was decreased the incidence of gallstones induced by lithogenic diet (LD) from 100% to 25%. NaB modulated SCFAs and improved the gut microbiota. The remodeling of the gut microbiota changed the bile acid compositions and decreased cecal tauro-α-muricholic acid (T-α-MCA) and tauro-ß-muricholic acid (T-ß-MCA) which are effective farnesoid X receptor (FXR) antagonists. The quantitative real-time PCR examination showed that NaB significantly increased levels of ileal Fxr, fibroblast growth factor-15 (Fgf-15) and small heterodimer partner (Shp) mRNA and subsequently inhibited bile acid synthesis. In addition, NaB enhanced bile acid excretion by increasing the levels of hepatic multidrug resistance protein 2 (Mdr2) and bile salt export pump (Bsep) mRNA, and it enhanced bile acid reabsorption in the intestine by increasing the levels of ileal bile acid transporter (Ibat) mRNA. In addition, NaB reduced the absorption of cholesterol in the intestine and inhibited the excretion of cholesterol in the liver, which reduced the cholesterol concentration in serum and bile. Furthermore, the protective effects of NaB administration were abolished by FXR antagonists. Taken together, our results suggest that NaB mitigates CGS by modulating the gut microbiota to regulate the FXR-FGF-15/SHP signaling pathway.

Resveratrol Protects SH-SY5Y Cells Against Oleic Acid-Induced Glucolipid Metabolic Dysfunction and Cell Injuries Via the Wnt/ß-Catenin Signalling Pathway.

Resveratrol (RES) is a polyphenol with diverse beneficial biological and pharmacological activities, and our previous results have demonstrated its neuroprotective effects in several metabolic diseases, including non-alcoholic fatty liver disease. The aim of the present study is to investigate the potential effect of RES against oleic acid (OA)-induced cell injuries in SH-SY5Y cells and explore the possible mechanism. Based on the dose- and time-dependent effects of OA on cell proliferation and LDH release, SH-SY5Y cells were challenged with OA and incubated with or without RES (10-5-10-9 mM) or sitagliptin (STG, 10-7 mM). Lipid accumulation, SREBP1 and PPARα protein expression, glucose consumption and IRS1, AKT, ERK phosphorylation under insulin stimulation, and ROS production were detected. The protein expression of brain-derived neurotrophic factor (BDNF), Copine 6, and key molecules in the Wnt/ß-catenin signalling pathway were measured via western blot. The expression of Wnt 1 was also measured via immunofluorescence staining. The results showed that RES treatment could alleviate the neurotoxicity induced by OA, as indicated by the increased cell proliferation and the decreased concentration of LDH in the supernatant. The increased lipid deposition and protein expression of SREBP1 and PPARα induced by OA was also reversed by treatment with RES. Moreover, RES could upregulate glucose consumption and the protein expression of phosphorylated IRS1, AKT, ERK and reduced ROS production in OA-induced SH-SY5Y cells. Furthermore, RES treatment reversed the imbalanced protein expression of BDNF, Copine 6, p-ß-catenin, and Wnt 1 in SH-SY5Y cells induced by OA and decreased the hyperexpression of p-GSK3ß. However, these effects were suppressed by DKK1, which is a specific antagonist of the Wnt signalling pathway. These results suggested that RES has a neuroprotective effect against OA-induced cell injury and dysfunctional glucolipid metabolism, and the mechanism might involve its ability to regulate oxidative stress and insulin resistance via the Wnt/ß-catenin signalling pathway.

Impaired Learning and Memory Ability Induced by a Bilaterally Hippocampal Injection of Streptozotocin in Mice: Involved With the Adaptive Changes of Synaptic Plasticity.

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, psychiatric symptoms and behavioral disorders, resulting in disability, and loss of self-sufficiency. Objective: To establish an AD-like mice model, investigate the behavioral performance, and explore the potential mechanism. Methods: Streptozotocin (STZ, 3 mg/kg) was microinjected bilaterally into the dorsal hippocampus of C57BL/6 mice, and the behavioral performance was observed. The serum concentrations of insulin and nesfatin-1 were measured by ELISA, and the activation of hippocampal microglia and astrocytes was assessed by immunohistochemistry. The protein expression of several molecular associated with the regulation of synaptic plasticity in the hippocampus and the pre-frontal cortex (PFC) was detected via western blotting. Results: The STZ-microinjected model mice showed a slower bodyweight gain and higher serum concentration of insulin and nesfatin-1. Although there was no significant difference between groups with regard to the ability of balance and motor coordination, the model mice presented a decline of spontaneous movement and exploratory behavior, together with an impairment of learning and memory ability. Increased activated microglia was aggregated in the hippocampal dentate gyrus of model mice, together with an increase abundance of Aß1-42 and Tau in the hippocampus and PFC. Moreover, the protein expression of NMDAR2A, NMDAR2B, SynGAP, PSD95, BDNF, and p-ß-catenin/ß-catenin were remarkably decreased in the hippocampus and the PFC of model mice, and the expression of p-GSK-3ß (ser9)/GSK-3ß were reduced in the hippocampus. Conclusion: A bilateral hippocampal microinjection of STZ could induce not only AD-like behavioral performance in mice, but also adaptive changes of synaptic plasticity against neuroinflammatory and endocrinal injuries. The underlying mechanisms might be associated with the imbalanced expression of the key proteins of Wnt signaling pathway in the hippocampus and the PFC.

Deoxycholic acid-stimulated macrophage-derived exosomes promote intestinal metaplasia and suppress proliferation in human gastric epithelial cells.

The crosstalk between macrophages and gastric epithelial cells has emerged as a player in chronic inflammation during intestinal metaplasia. However, the role of bile acid on this modulation remains to be studied. We hypothesized that deoxycholic acid-induced macrophages secreted exosomes to mediate intercellular communication and promoted intestinal metaplasia in human gastric epithelial cells (GES-1 cells). Macrophage-derived exosomes (M-Exos) and deoxycholic acid-induced macrophage-derived exosomes (D-Exos) were isolated by ultracentrifugation. EdU staining and CCK-8 assay were utilized to evaluate the effects of exosomes on the proliferation of GES-1 cells. Intestinal metaplasia was assessed by the expression of caudal-related homeobox transcription factor 2 (CDX2) at both mRNA and protein level. MicroRNA sequencing revealed the microRNA (miRNA) expression profiles of M-Exos and D-Exos. The role of a specific miRNA and mRNA was analyzed by using miRNA mimics, miRNA inhibitors and siRNAs. D-Exos promoted the expression of CDX2 and suppressed the proliferation of GES-1 cells, compared to M-Exos. The miRNA profiles and quantitative real-time PCR examination showed D-Exos enriched a higher level of hsa-miR-30a-5p than M-Exos. Overexpressed has-miR-30a-5p increased CDX2 expression and inhibited the proliferation in GES-1 cells via targeted Forkhead Box D1 (FOXD1), a potential regulatory factor in the process of intestinal metaplasia. D-Exos may promote intestinal metaplasia and suppress proliferation of GES-1 cells via hsa-miR-30a-5p targeting FOXD1, which may be involved in the action mechanism of bile acid on gastric mucosa.