Autophagy Balances Neuroinflammation in Alzheimer's Disease.

Autophagy is a highly evolutionary conserved process that degrades cytosolic macromolecules or damaged organelles (e.g., mitochondria), as well as intracellular pathogens for energy and survival. Dysfunction of autophagy has been associated with the pathologies of Alzheimer's disease (AD), including Aß plaques and neurofibrillary tangles. Recently, the presence of sustained immune response in the brain has been considered a new core pathology in AD. Accumulating evidence suggests that autophagy activation may suppress inflammation response through degrading inflammasomes or pro-inflammatory cytokines and improving immune system function in both clinical trials and preclinical studies. This review provides an overview of updated information on autophagy and inflammation and their potential mediators in AD. In summary, we believe that understanding the relationship between autophagy and inflammation will provide insightful knowledge for future therapeutic implications in AD.

Early age at menarche is associated with an increased risk of preeclampsia and adverse neonatal outcomes: a 6­year retrospective study.

PURPOSE: Preeclampsia affects between 2 to 8% of pregnancies worldwide and is associated with significant adverse outcomes for both mothers and their offspring. The present study aims to investigate whether there is a correlation between early age at menarche and an increased risk of developing preeclampsia and experiencing adverse neonatal outcomes. METHODS: The study involved a review of medical records of 4227 pregnant women who gave birth at The First Affiliated Hospital of Chengdu Medical College between January 2017 and December 2022. The collected data included demographic characteristics, clinical manifestations of preeclampsia, laboratory indicators, gestational complications, and neonatal outcomes. Pregnant women were categorized into four groups based on their age at menarche (≤ 12, 13, 14, and ≥ 15 years). Logistic regression analysis was conducted to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between different menarche age groups and the risk of preeclampsia and adverse neonatal outcomes. RESULTS: Pregnant women who had an age at menarche of ≤ 12 years had a higher risk of preeclampsia than women who had their menarche at 13, 14, and ≥ 15 years of age, with adjusted ORs (95% CIs) for preeclampsia of 1.00 (reference), 0.78 (0.45-0.91), 0.76 (0.59-0.88), and 0.73 (0.56-0.94), respectively. The predictive efficacy of age at menarche for preeclampsia was assessed with a sensitivity and specificity of 85.2% and 76.4%, respectively, and an AUC of 0.82. Moreover, infants born to women with an age at menarche of ≤ 12 years had a higher risk of adverse neonatal outcomes, including small for gestational age, preterm birth, low birth weight, neonatal respiratory distress syndrome, and neonatal intensive care unit admission. CONCLUSION: Our findings suggest that an early age at menarche is associated with an increased risk of preeclampsia and adverse neonatal outcomes. This information could be useful for obstetricians to identify women at risk for preeclampsia early on and implement timely interventions to reduce the incidence of preeclampsia and associated adverse neonatal outcomes.

Maternal serum Numb in the first trimester of pregnancy as a biomarker for early prediction of pre-eclampsia: A prospective cohort study.

OBJECTIVE: Early identification of women at risk of developing pre-eclampsia is beneficial as it allows for timely intervention strategies. This study aimed to evaluate the potential of serum Numb in the first trimester as a biomarker for early prediction of pre-eclampsia. METHODS: This prospective observational cohort study was carried out at a tertiary teaching hospital between January 2021 and December 2022. A total of 1024 women were recruited during their 8-13 weeks of pregnancy and were followed up until delivery. Serum Numb levels were measured during 8-13 weeks of gestation for all participants. At the same time, the participants' anthropometric, clinical, and laboratory data were collected. A logistic regression model was used to investigate the potential association between serum Numb levels and the risk of pre-eclampsia. Receiver operating characteristic curves (ROCs) and area under the curves (AUCs) were utilized to evaluate the predictive efficacy of serum Numb levels for pre-eclampsia in the first trimester. RESULTS: Serum Numb levels were found to be significantly higher in pregnant women who developed pre-eclampsia compared to those who did not develop pre-eclampsia. Increased serum Numb levels were identified as an independent risk factor for pre-eclampsia, with an odds ratio (OR) of 3.27 (95% CI: 2.05-4.53) for the risk of pre-eclampsia. Numb levels showed a significant positive correlation with the risk of pre-eclampsia. Furthermore, Numb levels demonstrated a strong predictive efficacy for pre-eclampsia in the first trimester of pregnancy, with an AUC value of 0.86, a cutoff value of 48.73 ng/mL, a sensitivity of 79.24%, and a specificity of 75.73%. CONCLUSION: Serum Numb in the first trimester of pregnancy can serve as a biomarker for the early prediction of pre-eclampsia. This provides a valuable approach in clinical practice to identify pregnant women in the first trimester of pregnancy, who are at a higher risk of developing pre-eclampsia.

Bufalin inhibits the proliferation of lung cancer cells by suppressing Hippo-YAP pathway.

Lung cancer has high morbidity and mortality. This study demonstrated that Bufalin inhibits the proliferation of lung cancer cells in vivo / in vitro by suppressing Hippo-YAP pathway. Here, we found that Bufalin promoted the binding of LATS and YAP to elevate the level of YAP phosphorylation. Phosphorylated YAP could not successfully enter the nucleus to activate the expression of downstream proliferation-related target genes Cyr61 and CTGF, whereas the YAP retained in the cytoplasm further bound to ß-TrCP and underwent ubiquitination and degradation. This study verified the key role of YAP in stimulating the proliferation of lung cancer and revealed the anticancer target of Bufalin. Therefore, this study provides a theoretical basis for the anticancer effect of Bufalin, and suggests that Bufalin can be a potential anticancer drug.

A novel enterocyte-related 4-gene signature for predicting prognosis in colon adenocarcinoma.

Background: Colon adenocarcinoma (COAD) is a fatal disease, and its cases are constantly increasing worldwide. Further, the therapeutic and management strategies for patients with COAD are still unsatisfactory due to the lack of accurate patient classification and prognostic models. Therefore, our study aims to identify prognostic markers in patients with COAD and construct a cell subtype-specific prognostic model with high accuracy and robustness. Methods: Single-cell transcriptomic data of six samples were retrieved from the Gene expression omnibus (GEO) database. The cluster annotation and cell-cell communication analysis identified enterocytes as a key player mediating signal communication networks. A four-gene signature prognostic model was constructed based on the enterocyte-related differentially expressed genes (ERDEGs) in patients with COAD of the Cancer Genome Atlas cohort. The prognostic model was validated on three external validation cohorts from the GEO database. The correlation between immune cell infiltration, immunotherapy response, drug sensitivity, and the four-gene signature prognostic model was investigated. Finally, immunohistochemistry (IHC) was performed to determine the expression of the four genes. Results: We found that the proportion of epithelial cells was obviously large in COAD samples. Further analysis of epithelial cells showed that the activity of the enterocytes was highest in the cell-cell communication network. Based on enterocyte data, 30 ERDEGs were identified and a 4-gene prognostic model including CPM, CLCA4, ELOVL6, and ATP2A3 was developed and validated. The risk score derived from this model was considered as an independent variable factor to predict overall survival. The patients were divided into high- and low-risk groups based on the median riskscore value. The correlation between immune cell infiltration, immunotherapy response, immune status, clinical characteristics, drug sensitivity, and risk score was analyzed. IHC confirmed the expression of signature genes in tissues from normal individuals, patients with polyps, and COAD. Conclusion: In this study, we constructed and validated a novel four-gene signature prognostic model, which could effectively predict the response to immunotherapy and overall survival in patients with COAD. More importantly, this model provides useful insight into the management of colon cancer patients and aids in designing personalized therapy.

[Analysis of gene expression profiles in gastric cancer cell cycle].

OBJECTIVE: To detect the gene expression profile in gastric cancer cell cycle and explain the mechanism of gastric cancer cell proliferation by a genomic study. METHODS: Gastric cancer cells MKN45 were synchronized at G2/M and G1/S point by nocodazole-thymidine and double thymidine methods. The synchronizing degree of cells was monitored by flow cytometry. The gene expression profiles at G2/M point, M/G1 transition, G1 early phase, G1 late phase, G1/S point, S early phase, S late phase, G2 early phase and G2 late phase in MKN45 cell cycling were examined using cDNA microarray chips. Hierarchy analysis was conducted with a professional software package and the up-regulated genes at G1 late and G2 phase were analyzed according to gene database. Furthermore, the mRNA level of cyclin E, cyclin B, plk1 and STK15 in above mentioned nine points were measured by quatitative PCR. RESULTS: 2001 genes were detected to be available at all 9 points via software processing, out of which 959 appeared up-regulated or down-regulated. 379 genes showed to be up-regulated at late G1 (147) or G2 phases (232), 40 at S and M phases (also up-regulated at G1 late and G2 phases). The 147 up-regulated genes at G1 late phase are involved in DNA metabolism, transcription and translation, protein transportation, ubiquitination and signal transduction, etc. The 232 up-regulated genes in G2 phase are involved in RNA synthesis and processing, intracellular protein transportation, cytoskeleton synthesis, signal transduction, apoptosis and anti-apoptosis, transcription regulation, ubiquitination, mitosis regulation and oncogene expression, etc. The mRNA level of 4 genes detected by quantitative PCR during cell cycle was in agreement with that detected by microarray. CONCLUSION: During MKN45 cell cycling, the preparation for DNA synthesis and chromosome separation are conducted in G1 and G2, which are implicated in multiple genes, may be the main impetus of driving MKN45 cell cycle. Some of these genes may be related to tumor over-proliferation. The cDNA microarray technique has characteristic features such as reliability and can provide a great deal for future research on cell cycle related genes in gastric cancer.

[Study of growth inhibition of gastric cancer cells by sRNA targeting polo like kinase 1 in vitro and vivo].

OBJECTIVE: To observe the effect of polo like kinase 1 (plk1) gene depletion on the growth of gastric cancer cell line-MKN45 cells in vitro and vivo and discuss the feasibility and effectiveness of arranging plk1 as gene therapeutic target for gastric cancer. METHODS: The plk1 expression of MKN45 cells was inhibited by RNA interference (RNAi). The plk1 mRNA and protein level were measured by real-time quantitative PCR and western blotting, and the change of cell cycle distribution and apoptosis rate were detected by flow-cytometry, and the MKN45 cells proliferation was measured by MTT method. MKN45 cells treated with plk1 siRNA were transplanted subcutaneously in nude mice and their tumorgenesis ability were observed, the plk1 protein levels of the samples from nude mice in different groups were compared. RESULTS: After treatment with plk1 siRNA, plk1 mRNA and protein level decreased obviously in certain time, more MKN45 cells accumulated at G(2)/M (P < 0.05). Apoptosis rate of MKN45 cells treated with plk1 siRNA was higher than that of control cells at 48 h and 72 h (P < 0.05), and MKN45 cells proliferated slowly than control groups (P < 0.05), while the tumorgenesis ability obviously decreased, but the plk1 protein levels of the samples from nude mice in different groups were not different. CONCLUSIONS: siRNA targeting plk1 can inhibit the proliferation of MKN45 cells in vitro and vivo. Plk1 may be a novel therapeutic target for gastric cancer.

[Inhibition of polo like kinase gene expression induces apoptosis in gastric cancer cells].

OBJECTIVE: To observe the effect of inhibition of polo like kinase1 (plk1) gene expression on apoptosis induction in gastric cancer cell line-MKN45 and discuss the vital role of plk1 proliferation and viability of gastric cancer cells. METHODS: The plk1 expression was inhibited by chemically synthesized siRNA. The plk1 mRNA and protein level were respectively measured by real-time quantitative PCR and Western blotting. The spindle morphological change was observed by immunofluorescence staining and confocal microscopy. The change of cell cycle distribution and apoptosis rate was detected by flow-cytometry. Pro caspase3 level was also detected by western blotting. RESULTS: After treatment by siRNA targeting plk1, plk1 mRNA and protein level decreased obviously, the cell mitotic spindle became obscure and lost cohesiveness, more MKN45 cells accumulated at G(2)/M phase (P< 0.05), apoptosis rate of plk1 siRNA treated MKN45 cells was higher than that of control cells at 48 h and 72 h (P< 0.05) with pro-caspase3 level decreasing at 72 h. CONCLUSIONS: Inhibition of plk1 gene expression induces apoptosis in MKN45 cells through the pathway of caspase3. Plk1 gene play a key role in viability of MKN45 cells.