Tauopathies, including Alzheimer's disease (AD), are a series of neurodegenerative diseases characterized by pathological accumulation of the microtubule-associated protein tau. Since the abnormal modification and deposition of tau in nerve cells are crucial for tauopathy etiology, methods for reducing tau levels, such as promoting tau degradation, may become effective strategies for disease treatment. Herein, we identified that sorafenib significantly reduced total tau and phosphorylated tau levels through screening FDA-approved drugs. We showed that sorafenib treatment attenuated cognitive deficits and tau pathologies in PS19 tauopathy model mice. Mechanistically, we found that sorafenib inhibited multiple kinases involved in tau phosphorylation and promoted autophagy. Importantly, we further demonstrated that sorafenib also promoted the expression of the E3 ubiquitin ligase FBXW7, which could bind tau and mediate tau degradation through the ubiquitin-proteasome pathway. Finally, we showed that FBXW7 expression decreased in the brains of AD patients and tauopathy model mice, and that overexpression of FBXW7 in the hippocampus attenuated cognitive deficits and tau pathologies in PS19 mice. These results suggest that sorafenib may be a promising treatment option for tauopathies by promoting tau degradation and reducing tau phosphorylation, and that targeting FBXW7 could also serve as an alternative therapeutic strategy for tauopathies.

Objective To investigate the relationship between serum levels of hepatocyte growth factor(HGF)and lipoxygenase-4(LXA4)in patients with acute exacerbation of bronchiectasis and the severity of the disease,and their evaluation value for the prognosis.Methods A total of 138 patients diagnosed with and treated for acute exacerbation of bronchiectasis between January 2019 and January 2021 in the hospital were selected as acute exacerbation group.Based on the bronchiectasis severity index(BSI score),patients were di-vided into mild group(40 cases),moderate group(46 cases),and severe group(52 cases).Additionally,pa-tients were categorized into a good prognosis group(85 cases)and a poor prognosis group(53 cases)based on their clinical outcomes.70 stable bronchiectasis patients treated concurrently were selected as the stable stage group.Furthermore,70 healthy individuals who underwent physical examinations during the same period was included as the control group.Serum HGF and LXA4 levels were measured by enzyme-linked immunosorbent assay.Logistic regression model was used to explore the factors affecting the prognosis of patients with acute exacerbation of bronchiectasis.The predictive effect of serum HGF and LXA4 levels on the prognosis of pa-tients with acute exacerbation of bronchiectasis was analyzed by receiver operating characteristic(ROC)curve.Results Compared with the stable stage group and the control group,the acute exacerbation group had higher serum HGF levels and lower LXA4 levels(all P＜0.05).The more severe the condition was in the a-cute exacerbation group,the higher the serum HGF level and the lower the LXA4 level.Compared with the good prognosis group,the poor prognosis group had lower levels of hemoglobin,albumin,and serum LXA4,while the number of acute exacerbations,proportion of severe BSI scores,and serum HGF levels were higher(all P＜0.05).In the acute exacerbation group,the more severe the disease,the higher the serum HGF level and the lower the LxA4 level.The number of acute exacerbations(OR=1.185,P＜0.001),BSI score(OR=1.280,P＜0.001),and serum HGF(OR=1.189,P＜0.001)were risk factors for poor prognosis in patients,while serum LXA4(OR=0.827,P＜0.001)was a protective factor.The area under the curve of the combined detection of serum HGF and LXA4 for evaluating poor prognosis in patients was 0.912(95％CI:0.862-0.955),which was larger than that of the single detection(Z=4.254,3.819,all P＜0.001).Conclusion The serum HGF level increases and LXA4 level decreases in patients with acute exacerbation of bronchiectasis,which are related to the severity of the disease.Combined detection has high predictive value for poor progno-sis in patients.

The teaching of geriatrics requires the combination of basic medicine,clinical medicine,nursing,rehabilitation medicine and pharmacy,and the intersection of medical science and humanities.In order to meet the problems of coping with much disease coexistance in geriatrics,poor efficacy,long course of disease,slow recovery and adverse drug reactions,the article puts forward the combination of blackboard and multimedia,the combination of teacher teaching and student lectures,the combination of PBL and CBL,and the combination of theoretical knowledge and clinical practice.It also puts forward carrying out reforms from such measures as the classroom teaching,teaching rounds,case discussion,literature reading,academic research,humanistic influence,going to community pension center for social practice and so on,to improve the quality of gerontology teaching.

To observe the effects of Shoushen Granule, a compound traditional Chinese herbal medicine, on telomere length and telomerase activity in peripheral leukocytes and vascular cells, artery wall lesions and blood lipid in a Sprague-Dawley (SD) rat model of atherosclerosis.