Autophagy is an important homeostatic cellular recycling mechanism responsible for degrading injured or dysfunctional cellular organelles and proteins in all living cells. Aging is a universal phenomenon characterized by progressive deterioration of cells and organs due to accumulation of macromolecular and organelle damage. Growing evidences indicate that the rate of autophagosome formation and maturation and the efficiency of autophagosome/lysosome fusion decline with age. Dysfunctional autophagy has also been observed in age-related diseases. Autophagy disruption resulted accumulation of mutated or misfolded proteins is the essential feature of neurodegenerative disorders. However, in cancers, fibroproliferative diseases or cardiovascular diseases, autophagy can play either a protective or destructive role in different types of disease, and even in different stages of the same disease. The review will discuss the cellular and molecular mechanisms of autophagy and its important role in the pathogenesis of aging and age-related diseases, and the ongoing drug discovery strategies for therapeutic intervention.
Aging ; Autophagy ; Drug Discovery ; Humans ; Lysosomes ; metabolism ; Neurodegenerative Diseases ; Phagosomes ; metabolism ; Protein Folding

The nuclear transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) plays a crucial role in maintaining cellular redox homeostasis. The aberrant NRF2 signaling confers enhanced antioxidant capacity, which is linked to tumor progression and therapeutic resistance. The current study investigates the biological effects and molecular mechanism of tribbles homolog 3 (TRIB3), a stress-induced protein, in regulating cell survival and apoptosis in lung cancer. This study first performed the RNA sequencing data analysis with 576 lung adenocarcinoma patients from the cancer genome atlas (TCGA) database. The NRF2- antioxidant response element (ARE) signature was enriched in patients with high TRIB3 expression. Dual-luciferase reporter assay and real-time quantitative polymerase chain reaction (PCR) were used to confirm the effect of TRIB3 on the kelch-like ECH-associated protein-1 (KEAP1)-NRF2 pathway. Abrogation of TRIB3 impaired NRF2 transcriptional activity and reduced the expression of its target genes. Moreover, TRIB3 enhanced NRF2 stability via blocking KEAP1-NRF2 interaction. TRIB3-depletion promoted reactive oxygen species (ROS) production, restrained cell proliferation, and enhanced carboplatin-induced apoptosis. In addition, NRF2 overexpression recovered the tumor inhibition effect of TRIB3-depletion. Consistently, TRIB3 failed to modulate apoptosis in NRF2 depletion cells. In summary, this study shows that TRIB3 inhibits the KEAP1-NRF2 interaction and upregulates the transcriptional activity of NRF2, thereby promoting lung cancer cell proliferation and reducing the sensitivity to chemotherapy. Targeting the TRIB3-NRF2 signal axis may become a new strategy for ROS homeostasis and lung cancer treatment.

Objective To evaluate the diagnostic value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and conventional-transbronchial needle aspiration (C-TBNA) in mediastinal and lung hilar lesions. Method 301 cases of lung hilar and mediastinal lesions were selected from 2010 to 2016. Among them, 183 cases underwent TBNA, and the other 118 cases received EBUS-TBNA technology. During the research, the associations of diagnostic positive rate and complications were analyzed in order to explore the advantage and the value of EBUS-TBNA. Results The positive rates of EBUS-TBNA in central groups (2R, 4L, 4R, 7) were higher than in the peripheral groups (10R, 10L, 11R, 11L) (P < 0.05). When studying the lymph node group 2R, 4R and 7R, the positive rate of EBUS-TBNA is much more significant than conventional TBNA (P < 0.05); When biopsying at the lymph node group R4 and group 7, one needle positive rate of EBUS-TBNA were much more superior than TBNA (P < 0.05), the three needles cumulative positive rate of EBUS-TBNA almost reach the total positive rate(P > 0.05), an approving effect of puncture can be acquired; The accuracy and sensitivity of EBUS-TBNA in the diagnosis of lung hilar and mediastinal lesions were much better than conventional TBNA (P < 0.05), especially the diagnostic positive rate of EBUS-TBNA in benign diseases was higher (P < 0.05); The complications rates in both two technologies were not significantly different (P > 0.05), there were no severe complications during the operations in all cases. Conclusion EBUS-TBNA is useful in diagnosis of mediastinal and hilar lesions of unknown reason, and significant in diagnosis of bronchial and extrabronchial diseases. It is an efficiency and safe operation while further application studies are needed.

Objective The cytotoxic microbial strains isolated from the deep ocean water and sediments were screened,and the secondary metabolites of bioactive fungus c2b were investi- gated.Methods Active bioactive microbial strains were screened using brine shrimp and chro- nic medulla leucocythemia leukocythemia(K562)cell line.The cytotoxic components of fun- gus c2b were isolated by bioassay-guided fractionation and solvent extraction,silica gel col- umn chromatography and preparative HPLC.Their structures were established by pbysico- chemical properties and spectral analyses.The cytotoxicities of compounds were evaluated by SRB method.Results and Conclusion Twenty-nine strains of fungi were isolated.Among them,seven strains showed cytotoxic activities.Six compounds(1～6)were isolated and i- dentified as N-acetyl histamine(1),chrysogine(2),ergosterol peroxide(3),5,8-epidioxy- 24-methylcholesta-6,22-dien-3?-ol(4)cerevisterol(5)and(4E,8E)-N-[(2'R,3'E)-2'-hy- droxy-3'-hexadecenoyl]-1-O-?-D-glycopyranosyl-9-methyl-4,8-sphingadiene(6),respective- ly.Compound 3 and 4 showed median cytotoxicity.

Aim To investigate the in vitro vasorelax-ant effect of DL0805-0, a Rho kinase inhibitor, on iso-lated rat thoracic aorta and explore its underlying mechanism. Methods Tension was measured to eval-uate the vasorelaxant effect of DL0805-0 on rat endo-thelium-intact and endothelium-denuded thoracic aorta rings. Rho kinase inhibitor fasudil, nitric oxide syn-thase inhibitor Nω-nitro-L-arginine methyl ester ( L-NAME), guanylate cyclase inhibitor methylene blue, cyclooxygenase inhibitor indomethacin, calcium-activa-ted potassium channel blocker tetraethyl ammonium ( TEA ) , ATP-sensitive potassium channel blocker glibenclamide and voltage-dependent potassium chan-nel blocker 4-aminopyridine ( 4-AP ) were used to il-lustrate the mechanisms of vasorelaxant effect of DL0805-0 . Results DL0805-0 exerted vasorelaxation in a dose-dependent manner in KCl (60 mmol·L-1 ) or NE ( 0. 1 μmol · L-1 ) -induced contraction. DL0805-0-induced vasorelaxation was significantly re-duced by L-NAME. However, methylene blue and in-domethacin did not significantly affect vasorelaxation of DL0805-0. In endothelium-denuded rings, TEA re-markably attenuated the vasorelaxant effect of DL0805-0 , while glibenclamide and 4-AP did not affect vasore laxation of DL0805-0 significantly. DL0805-0 also re-duced NE-induced transient contraction and inhibited contraction induced by increasing extracellular calci-um. Conclusion These results suggest that DL0805-0 induces vasorelaxation through an endothelium-depend-ent pathway. The opening of calcium-activated K+channels and blocking of Ca2+ channels in vascular smooth muscle cells may be one of the mechanisms of DL0805-0-induced vasorelaxation.

Objective: To explore the feature and influencing factors of anhedonia in schizophrenia. Methods: A total of 71 schizophrenia patients and 50 healthy controls were recruited during December 2018 and December 2019. Positive and Negative Syndrome Scale (PANSS) was used for assessing psychotic symptoms. Temporal Experience of Pleasure Scale (TEPS) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were applied to the evaluation of anhedonia and cognitive function respectively for each subject. Results: The evaluation result of TEPS showed both anticipatory and consummatory pleasure scores were lowered in patients with schizophrenia than those in healthy people (P=0.000). Stepwise linear regression analysis showed that negative subscale score of PANSS (B=-0.895, P=0.002) and delayed memory score of RBANS (B=0.265, P=0.001) were associated with anhedonia in schizophrenia. Conclusion: Patients with schizophrenia exhibit anticipatory and consummatory anhedonia, both of which are influenced by negative symptoms and delayed memory in schizophrenia.

Depression is a common mental disorder and causes great disease burden. To date people's understanding of genetic mechanisms of depression is lagging far behind that of other psychiatric disorders such as schizophrenia and bipolar disorder. Recently, with the accumulation of clinical samples and the advances of methodology and technology, certain progress in genetics of depression has been made. This review summarizes the genetic research progress in candidate genes, common variants, rare variants and chromosome structure variations of depression.

Objective: To investigate the association between early growth response gene 1 (EGR1) and Alzheimer's disease (AD) in Han Chinese people. Methods: A total of 715 AD patients and 760 health controls were recruited in two independent samples from Eastern China (382 AD patients and 426 normal individuals) and Southwest China (333 AD patients and 334 normal individuals). SNaPshot technique was utilized to analyse the single nucleotide polymorphism (SNP) of rs11743810. A public database was used to explore whether EGR1 gene was differentially expressed in the brain of AD patients and health controls. Then the protein-protein interaction (PPI) assessment was conducted using the STRING database, and the brain eQTL (expression quantitative trait loci) analysis was used to explore the difference in rs11743810 expression between different genotypes in different brain regions. Results: Cross-platform normalized data showed that there was significant difference of EGR1 expression in temporal cortex between AD patients and control subjects (|log2FC|=0.780, P=0.000 before FDR corrected; P=0.001 after FDR corrected). PPI analysis revealed that EGR1 was physically connected with amyloid precursor protein (APP) and clusterin (CLU) protein in the network. However, different genotypes of rs11743810 showed no significant difference in expression in 10 brain regions, and no significant difference in the genotype and allele frequency of rs11743810 between AD patients and controls were found in our two independent samples. Conclusion: The rs11743810 in EGR1 may not be major susceptibility gene site for AD in Han Chinese people.

Objective Helicobacter pylori（ ）， To investigate the infection status of HP and analyze the correlation between HP Methods infection and serum bilirubin in railway drivers. A total of 2 731 railway drivers in Zhengzhou locomotive depot were - selected as study subjects using judgment sampling method. Carbon 13 urea breath test was used to evaluate the HP infection ， status. The metabolic indexes of HP positive group and HP negative group were compared and the relationship between HP Results （ ） ， infection and serum bilirubin was analyzed. The HP infection rate was 42.3% 1 156/2 731 . The older the age the ， （ ）， （ P ） longer the work years and the higher the body mass index BMI the higher the HP infection rate all <0.01 . The infection （P ） rate of HP in married people was higher than that in unmarried people <0.01 . The HP infection rate of smokers was higher - （P ） - ， than that of non smokers <0.01 . Compared with the HP negative group fasting blood glucose and serum levels of total ， （ - ）， （ ） - cholesterol low density lipoprotein cholesterol LDL C triglyceride and homocysteine Hcy were increased in the HP （ P ） （ - ）， ， positive group all <0.05 . The serum levels of high density lipoprotein cholesterol HDL C total bilirubin direct bilirubin （ ） - （ P ） DBIL and indirect bilirubin were lower than those in HP negative group all <0.05 . Logistic regression analysis showed that （ P ） HP infection was associated with low serum total bilirubin and low DBIL all <0.01 after adjusting for the confounding effects ， ， ， ， ， ， ， - ， - ， of age work years marital status smoking history fasting blood glucose total cholesterol triacylglycerol LDL C HDL C Conclusion ， ， ， and Hcy. The age work length BMI smoking and marital status are the influencing factors of HP infection in railway drivers. HP infection is associated with low levels of total bilirubin and DBIL.

Objective To investigate the status of taste changes and self care in cancer patients during chemotherapy in order to provide evidence for nurses to help patients taking self care effectively.Methods A questionnaire regarding self-care strategies to cope with taste changes was given to a total of 118 inpatients after two cycle of chemotherapy for collecting information.Results One hundred and twenty questionnaires were released and 118 were retrieved with a effective response rate of 98％.Among 118 patients,the incidence of taste changes was 79.7％,but 54.2％ of them had not taken any methods to cope with it.Conclusions Taste changes were commonly symptoms and had obvious negative effects to patients in chemotherapy,while the patients are lack of self-management of taste changes.Nurses may take interventions to minimize the negative effects and promote patients to perform self-care actions to improve their quality of life.