Amyloid beta (Aβ) precursor protein (APP) is a key protein in the pathogenesis of Alzheimer's disease (AD). Both APP and its paralogue APLP1 (amyloid beta precursor-like protein 1) have multiple functions in cell adhesion and proliferation. Previously it was thought that autophagy is a novel beta-amyloid peptide (Aβ)-generating pathway activated in AD. However, the protein proteolysis of APLP1 is still largely unknown. The present study shows that APLP1 is rapidly degraded in neuronal cells in response to stresses, such as proteasome inhibition. Activation of the endoplasmic reticulum (ER) stress by proteasome inhibitors induces autophagy, causing reduction of mature APLP1/APP. Blocking autophagy or JNK stress kinase rescues the protein expression for both APP and APLP1. Therefore, our results suggest that APP/APLP1 is degraded through autophagy and the APLP1 proteolysis is mainly mediated by autophagy-lysosome pathway.
Amyloid beta-Protein Precursor ; genetics ; metabolism ; Animals ; Autophagy ; Cell Line ; Endoplasmic Reticulum ; metabolism ; JNK Mitogen-Activated Protein Kinases ; antagonists & inhibitors ; metabolism ; Leupeptins ; pharmacology ; Mice ; Neurons ; cytology ; metabolism ; Proteasome Endopeptidase Complex ; metabolism ; Proteasome Inhibitors ; Protein Stability ; Rats

We investigate the role of β-catenin signaling in the response of macrophage to lipopolysaccharide (LPS) using RAW264.7 cells. LPS rapidly stimulated cytosolic β-catenin accumulation. β-catenin-mediated transcription was showed to be required for LPS induced gene expression and cell migration. Mechanically, ERK activation-primed GSK3β inactivation by Akt was demonstrated to mediate the LPS induced β-catenin accumulation. Overall, our findings suggest that suppression of GSK3β by ERK stimulates β-catenin signaling therefore contributes to LPS induced cell migration in macrophage activation.
Animals ; Cell Line ; Cell Movement ; drug effects ; Enzyme Activation ; drug effects ; Extracellular Signal-Regulated MAP Kinases ; metabolism ; Gene Expression Regulation, Enzymologic ; drug effects ; Glycogen Synthase Kinase 3 ; metabolism ; Glycogen Synthase Kinase 3 beta ; Lipopolysaccharides ; pharmacology ; Macrophages ; cytology ; drug effects ; enzymology ; metabolism ; Matrix Metalloproteinase 9 ; genetics ; Mice ; Proto-Oncogene Proteins c-akt ; metabolism ; Signal Transduction ; drug effects ; Transcription, Genetic ; drug effects ; Wnt Proteins ; metabolism ; beta Catenin ; metabolism

The Wnt/β-catenin and bone morphogenetic proteins (BMPs) pathways play important roles in controlling osteogenesis. Using a cell-based kinase inhibitor screening assay, we identified the compound bisindoylmaleimide I (BIM) as a potent agonist of the cytosolic β-catenin accumulation in preosteoblast cells. Through suppressing glycogen synthase kinase 3β enzyme activities, BIM upregulated β-catenin responsive transcription and extended duration of BMP initiated signal. Functional analysis revealed that BIM promoted osteoblast differentiation and bone formation. The treatment of human mesenchymal stem cells with BIM promoted osteoblastogenesis. Our findings provide a new strategy to regulate mesenchymal stem cell differentiation by integration of the cellular signaling pathways.
Animals ; Bone Morphogenetic Proteins ; metabolism ; Cell Differentiation ; drug effects ; Cell Line, Tumor ; Glycogen Synthase Kinase 3 ; metabolism ; Glycogen Synthase Kinase 3 beta ; Indoles ; chemistry ; pharmacology ; Maleimides ; chemistry ; pharmacology ; Mesenchymal Stem Cells ; cytology ; metabolism ; Mice ; Osteoblasts ; cytology ; drug effects ; metabolism ; RNA Interference ; RNA, Small Interfering ; metabolism ; Signal Transduction ; drug effects ; Wnt Proteins ; metabolism ; beta Catenin ; antagonists & inhibitors ; genetics ; metabolism

Objective: Empirical findings confirmed that autistic and schizotypal traits are associated with attentional function as well as include various dimensions. So far, no study has reported which dimension of these traits relates to attentional networks. This study aimed to find out whether there are associations between attentional networks and autistic traits; and between attentional networks and schizotypal traits. Methods: A total of 449 volunteers was included in this study, and autism-spectrum quotient (AQ), schizotypal personality questionnaire (SPQ), and attention network test (ANT) were used to measure autistic traits and schizotypal traits. The three independent attentional networks, including alerting network, orienting network, and executive control network, were also measured. Results: Autistic traits were associated with the orienting network, whereas schizotypal traits were associated with the orienting network and executive control network. Furthermore, attentional networks could be predicted by specific dimensions of autistic and schizotypal traits. AQ-attention switching [0.104 (-1.175– -0.025), p=0.041] and AQ-attention to detail [-0.097 (-0.798– -0.001), p=0.049] were significant predictors of orienting network and gender were significant predictor of executive network (Beta=0.107; 95% CI=-0.476–10.139; p=0.031). Whereas, schizotypal dimension “interpersonal” was a significant predictor of all three attentional networks [Alerting: 0.147 (-0.010–0.861), p=0.045; Orienting: 0.147 (0.018–0.733), p=0.040; Executive: 0.198 (0.215–1.309), p=0.006]. Conclusion This study demonstrated that autistic and schizotypal traits were associated with attentional networks. The specific dimensions of autistic and schizotypal traits could predict attentional networks. Nevertheless, the attentional networks predicted with these two traits were different.

Objective To study the features and neural mechanism of pain empathy in autistic individuals.MethodsTotally 21 subjects with high level autistic traits and 22 subjects with low level autism traits completed the pain empathy task,recording RT and accuracy automatically.The event-related potentials(ERPs) were recorded by Neuroscan system simultaneously.Results(1)From the behavioral results,the IRI scores of the two groups had significant differences in the factors of perspective taking ((23.71±4.16) vs (26.95±3.24)),empathy concerning ((24.10±4.04) vs (26.36±2.82)) and personal distress ((24.19±3.59) vs (19.82±3.96)) (t=-2.86,P<0.01;t=-2.14,P<0.05;t=3.79,P<0.01).The factor of fantasy of the two groups didn't exit significant differences (t=-1.50,P>0.05).(2) According to the behavioral result of pain empathy test,the main effect of task type in reaction time and accuracy of the two groups had significant difference (F(1,41)=24.21,P<0.01;F(1,41)=152.10,P<0.01),but the main effect of emotion type and group didn't reach significant level (F(1,41)=1.11,P>0.05,F(1,41)=0.29,P>0.05;F(1,41)=3.20,P>0.05,F(1,41)=0.14,P>0.05).(3)From the results of ERP,the main effect of emotion type,task type and group didn't reach the significant level in the N2 amplitude of the two groups(F(1,41)=0.04,P>0.05;F(1,41)=0.08,P>0.05;F(1,41)=3.86,P>0.05).The main effect of emotion type had significant difference in the P3 amplitude of the two groups(F(1,41)=8.27,P<0.01),but there was no significant difference in the main effect of task type and group(F(1,41)=2.48,P>0.05,F(1,41)=0.25,P>0.05).It had significant difference in LPP amplitude in the main effect of emotion type,task type and group(F(1,41)=32.07,P<0.01;F(1,41)=8.63,P<0.01;F(1,41)=4.73,P<0.05).ConclusionsThere are differences in the abilities of empathy between the high and low level autistic traits groups,especially in the late processing of pain empathy.

Objective: Empirical findings confirmed that autistic and schizotypal traits are associated with attentional function as well as include various dimensions. So far, no study has reported which dimension of these traits relates to attentional networks. This study aimed to find out whether there are associations between attentional networks and autistic traits; and between attentional networks and schizotypal traits. Methods: A total of 449 volunteers was included in this study, and autism-spectrum quotient (AQ), schizotypal personality questionnaire (SPQ), and attention network test (ANT) were used to measure autistic traits and schizotypal traits. The three independent attentional networks, including alerting network, orienting network, and executive control network, were also measured. Results: Autistic traits were associated with the orienting network, whereas schizotypal traits were associated with the orienting network and executive control network. Furthermore, attentional networks could be predicted by specific dimensions of autistic and schizotypal traits. AQ-attention switching [0.104 (-1.175– -0.025), p=0.041] and AQ-attention to detail [-0.097 (-0.798– -0.001), p=0.049] were significant predictors of orienting network and gender were significant predictor of executive network (Beta=0.107; 95% CI=-0.476–10.139; p=0.031). Whereas, schizotypal dimension “interpersonal” was a significant predictor of all three attentional networks [Alerting: 0.147 (-0.010–0.861), p=0.045; Orienting: 0.147 (0.018–0.733), p=0.040; Executive: 0.198 (0.215–1.309), p=0.006]. Conclusion This study demonstrated that autistic and schizotypal traits were associated with attentional networks. The specific dimensions of autistic and schizotypal traits could predict attentional networks. Nevertheless, the attentional networks predicted with these two traits were different.

Transforming growth factor-β (TGF-β) members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-β type II (TβR II) and type I (TβRI) and serine/threonine kinases receptors. Aberrant activation of TGF-β signaling leads to diseases, including cancer. In advanced cancer, the TGF-β/SMAD pathway can act as an oncogenic factor driving tumor cell invasion and metastasis, and thus is considered to be a therapeutic target. The activity of TGF-β/SMAD pathway is known to be regulated by ubiquitination at multiple levels. As ubiquitination is reversible, emerging studies have uncovered key roles for ubiquitin-removals on TGF-β signaling components by deubiquitinating enzymes (DUBs). In this paper, we summarize the latest findings on the DUBs that control the activity of the TGF-β signaling pathway. The regulatory roles of these DUBs as a driving force for cancer progression as well as their underlying working mechanisms are also discussed.
Animals ; Humans ; Molecular Targeted Therapy ; Receptors, Transforming Growth Factor beta ; metabolism ; Signal Transduction ; Smad Proteins ; physiology ; Transforming Growth Factor beta ; physiology ; Ubiquitin Thiolesterase ; metabolism ; Ubiquitin-Specific Proteases ; Ubiquitination

Objective:To observe the effect of stellate ganglion block(SGB)on serum inflammatory factors and the expression of α7nAChR protein in rats with acute peritonitis,so as to further explore the mechanism of SGB on the inflammatory response of acute peritonitis in rats.Methods:40 SPF grade male rats were randomly divided into 4 groups:blank group(Control),acute peritonitis group(AP),acute peritonitis+stellate ganglion block group(AP+SGB),acute peritonitis+stellate ganglion block+α7nAChR inhibitor methyllycaconitine group(AP+SGB+MLA),with 10 rats in each group.Inject 2％acetic acid at a dose of 1 ml/100 g into the peritoneal cavity of rats to establish an acute peritonitis model in the AP group,AP+SGB group,and AP+SGB+MLA group.Blood samples were collected from the tail vein of the rats,and the concentrations of IL-18 and TNF-α in serum were detected by ELISA.Western Blot method was used to detect the level of α7nAChR protein in the peritoneal tissues,and RT-qPCR method was used to detect the expression of α7nAChR mRNA in the peritoneal tissues.Results:Compared with Control group,the levels of IL-18 and TNF-α were increased in the other three groups(P＜0.05).Compared with AP group,serum levels of IL-18 and TNF-α in AP+SGB group were decreased(P＜0.05).Compared with AP+SGB group,serum levels of IL-18 and TNF-α were increased in AP+SGB+MLA group(P＜0.05).The expression of α7nAChR mRNA protein were higher in the three groups than group Control,(P＜0.05).Compared with AP group,α7nAChR protein and α7nAChR mRNA expression levels were higher in AP+SGB group and AP+SGB+MLA group(P＜0.05).Compared with AP+SGB group,α7nAChR protein and α7nAChR mRNA expression levels in AP+SGB+MLA group were lower(P＜0.05).Conclusion:Stellate ganglion block treatment can reduce the production of inflammatory factors and inhibit the inflammatory response of acute peritonitis in rats,and its anti-inflammatory mechanism may be related to the cholinergic anti-inflammatory pathway(CAP)mediated by α7nAChR.

Objective To investigate the curative effect of lateral position ventilation combined with vibration sputum drainage on the patients with acute respiratory distress syndrome (ARDS). Methods A prospective randomized controlled trial was conducted. The patients with ARDS undergoing mechanical ventilation (MV) admitted to intensive care unit (ICU) of Linyi Central Hospital from January 2013 to June 2017 were enrolled, and they were divided into simple ventilation group and combined treatment group according to random number table. The patients in both groups received etiological treatment, protective ventilation strategy, sensitive antibiotics for anti-infection, and calefacient and humidifying treatment. The patients in the simple ventilation group received bilateral discontinuous alternative lateral position ventilation [pressure controlled ventilation (PCV), tidal volume (VT) ≤ 6 mL/kg, the inhaled oxygen concentration (FiO2) and positive end expiratory pressure (PEEP) was adjusted to maintain the airway plateau pressure (Pplat) ≤ 30 cmH2O (1 cmH2O = 0.098 kPa)], and those in the combined treatment group received lateral position ventilation combined with vibration sputum drainage, twice a day, 15 minutes each time. The parameters of respiratory function and inflammation as well as excretion of sputum before and after treatment were compared between the two groups, and the complication and prognosis were recorded. Results A total of 200 patients with ARDS were included, 4 patients were excluded because of severe pneumothorax, massive hemorrhage of the digestive tract, or elevated intracranial pressure, so 196 patients were finally enrolled in the analysis. There were 98 patients in the simple ventilation group and the combined treatment group, respectively. There were no significant differences in parameters of respiratory function and inflammation as well as excretion of sputum before treatment between the two groups. After treatment, the above parameters in both groups were improved, and the effect of combined treatment was more significant. Compared with the simple ventilation group, white blood cell count (WBC), procalcitonin (PCT), C-reactive protein (CRP) at 24 hours of treatment in the combined treatment group were significantly decreased [WBC (×109/L):9.1±1.6 vs. 11.8±3.6, PCT (μg/L): 14.5±2.4 vs. 22.7±3.2, CRP (mg/L): 32.2±6.3 vs. 67.2±7.2, all P < 0.01], the quantity of sputum excretion was significantly increased (mL: 49.3±12.5 vs. 36.8±11.8, P < 0.01); 72 hours after treatment, the oxygenation index (PaO2/FiO2) in the combined treatment group was significantly increased [mmHg (1 mmHg = 0.133 kPa): 278±28 vs. 238±39, P < 0.01], and PEEP, FiO2, airway resistance (Raw) were significantly lowered [PEEP (cmH2O): 5±2 vs. 7±3, FiO2: 0.40±0.11 vs. 0.49±0.12, Raw (cmH2O): 12.8±0.7 vs. 16.2±0.8, all P < 0.01]. There was no significant difference in static lung compliance (Cst) or Pplat between the two groups. Compared with the simple ventilation group, the duration of MV (days: 5.5±3.0 vs. 8.6±2.1), the length of ICU stay (days: 7.5±5.4 vs. 11.3±4.6) and the extraction time of artificial airway (days: 6.6±2.8 vs. 9.4±3.3) in the combined treatment group were significantly shortened (all P < 0.01). However, there was no significant difference in the 28-day mortality rate [4.1% (4/98) vs. 3.1% (3/98)], the rate of tracheotomy [2.0% (2/98) vs. 3.1% (3/98)] or the incidence ofⅠ-Ⅱ skin pressure sore [1.0% (1/98) vs. 2.0% (2/98)] between simple ventilation group and the combined treatment group (all P > 0.05). No artificial airway disappearance, pneumothorax, grade Ⅲ or Ⅳ pressure sore was found in the two groups. Conclusions Compared with lateral position ventilation alone, the treatment of combined with vibration sputum drainage is more effective for improving the respiratory function of patients with ARDS, reducing infection action, shortening the duration of MV and the length of ICU stay, and improve the recovery, promote the rehabitation of patients.

Objective:To investigate the risk factors of thrombocytopenia in elderly patients with sepsis-associated acute kidney injury(SA-AKI), and to further evaluate whether the degree of thrombocytopenia is related to the increased risk of death on day 28.Methods:Elderly patients with SA-AKI admitted to ICU of our hospital from June 2017 to June 2020 were selected.The patients were divided into normal platelet group(56 cases)and thrombocytopenia group(72 cases)according to the platelet(PLT)count, and according to the degree of thrombocytopenia, they were further divided into three groups: PLT<20×10 9/L(group A, 22 cases), 20×10 9/L≤ PLT<50×10 9/L(group B, 27 cases), 50×10 9/L≤ PLT<100×10 9/L(group C, 23 cases).The general data, clinical baseline indicators and prognostic indicators of each group were compared to evaluate the risk factors of thrombocytopenia.At the same time, the impact of platelet count on the prognosis of elderly patients with SA-AKI was evaluated according to the length of stay in ICU, total length of stay and whether the patient died, and the correlation between the degree of thrombocytopenia and survival was analyzed. Results:A total of 128 elderly patients with SA-AKI were enrolled, including 73 males and 55 females.59.4 % of the patients were hospitalized in the department of internal medicine.The APACHEⅡ score was(15.5 ± 3.3)points, invasive mechanical ventilation accounted for 78.9%, positive inotropic therapy accounted for 12.8%, and 56 patients had normal platelet count.Thrombocytopenia occurred in 72 patients, including 22 patients with PLT<20×10 9/L, 27 patients with platelet count in 20-50×10 9/L, and 23 patients with platelet count in 50-100×10 9/L.There were significant differences in bloodstream infection, Gram-negative bacteria, APACHEⅡ score and procalcitonin(PCT)among the four groups( P<0.05).Further multivariate logistic regression showed that PCT was an independent risk factor for thrombocytopenia in elderly patients with SA-AKI( OR=1.05, 95% CI: 1.00-1.10, P=0.042).Compared with the normal platelet group, the 28-day mortality rate of the thrombocytopenia group was significantly higher than that of the normal platelet group, while the length of stay in ICU and the total length of stay were prolonged( P<0.05).Kaplan-Meier survival curve showed that the 28-day cumulative survival rate of thrombocytopenia group was lower than that of normal platelet group, and the risk of death increased with the degree of thrombocytopenia( χ2=31.479, P<0.001).Univariate Cox regression analysis showed that thrombocytopenia, bloodstream infection, APACHEⅡ score and PCT were risk factors for 28-day death in elderly patients with SA-AKI.Multivariate Cox analysis showed that bloodstream infection and APACHEⅡ score were independent risk factors for 28-day death.After adjusting these confounding factors, thrombocytopenia was an independent risk factor for death, and the degree of thrombocytopenia was related to the increased risk of death. Conclusions:Thrombocytopenia is common in elderly patients with SA-AKI, and elevated PCT levels increase the risk of thrombocytopenia.The degree of thrombocytopenia is an independent risk factor for 28-day mortality in such patients.