Helicobacter pylori induces epithelial-mesenchymal transition in gastric carcinogenesis via the AKT/GSK3β signaling pathway

Helicobacter pylori (H. pylori) is a main risk factor for gastric cancer (GC). Epithelial-mesenchymal transition (EMT) is involved in the development and progression of H. pylori-associated GC. However, the exact molecular mechanism of this process remains unclear. The AKT/GSK3β signaling pathway has been demonstrated to promote EMT in several types of cancer. The present study investigated whether H. pylori infection induced EMT, and promoted the development and metastasis of cancer in the normal gastric mucosa, and whether this process was dependent on AKT activation. The expression levels of the EMT-associated proteins, including E-cadherin and N-cadherin, were determined in 165 gastric mucosal samples of different disease stages by immunohistochemical analysis. The expression levels of E-cadherin, N-cadherin, AKT, phosphorylated (p-)AKT (Ser473), GSK3β and p-GSK3β (Ser9) were further determined in H. pylori-infected Mongolian gerbil gastric tissues and cells co-cultured with H. pylori by immunohistochemical analysis and western blotting. The results indicated that the expression levels of the epithelial marker E-cadherin were decreased, whereas the expression levels of the mesenchymal marker N-cadherin were increased during gastric carcinogenesis. Their expression levels were associated with H. pylori infection. Furthermore, H. pylori infection resulted in downregulation of E-cadherin expression and upregulation of N-cadherin expression in Mongolian gerbils and GES-1 cells. In addition, an investigation of the associated mechanism of action revealed that p-AKT (Ser473) and p-GSK3β (Ser9) were activated in GES-1 cells following co-culture with H. pylori. Furthermore, following pretreatment of the cells with the AKT inhibitor VIII, the expression levels of E-cadherin, N-cadherin, p-AKT and p-GSK3β did not show significant differences between GES-1 cells that were co-cultured with or without H. pylori. The levels of p-AKT and p-GSK3β were increased in H. pylori-infected Mongolian gerbils. In conclusion, the present study demonstrated that H. pylori infection activated AKT and resulted in the phosphorylation and inactivation of GSK3β, which in turn promoted early stage EMT. These effects were AKT-dependent. This mechanism may serve as a prerequisite for GC development.     

Necroptotic TNFα-Syndecan 4-TNFα Vicious Cycle as a Therapeutic Target for Preventing Temporomandibular Joint Osteoarthritis

Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative disease for which the underlying mechanism still remains unclear. Compared with apoptosis and autophagy, necroptosis causes greater harm to tissue homeostasis by releasing damage-associated molecular patterns (DAMPs). However, the role of necroptosis and downstream key DAMPs in TMJOA is unknown. Here, rodent models of TMJOA were established by the unilateral anterior crossbite (UAC). Transmission electron microscopy (TEM) and immunohistochemistry of receptor interacting protein kinase 3 (RIPK3)/phosphorylation of mixed lineage kinase domain-like protein (pMLKL) were conducted to evaluate the occurrence of necroptosis in vivo. The therapeutic effects of blocking necroptosis were achieved by intra-articularly injecting RIPK3 or MLKL inhibitors and using RIPK3 or MLKL knockout mice. In vitro necroptosis of condylar chondrocyte was induced by combination of tumor necrosis factor alpha (TNFα), second mitochondria-derived activator of caspases (SMAC) mimetics and carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]- fluoromethylketone (z-VAD-fmk). The possible DAMPs released by necroptotic chondrocytes were screened by quantitative proteomics and blocked by specific antibody. Translucent cytosol, swollen organelles, and ruptured cell membranes, features of necroptosis, were frequently manifested in chondrocytes at the early stage of condylar cartilage degeneration in TMJOA, which was accompanied by upregulation of RIPK3/pMLKL. Inhibiting or knocking out RIPK3/MLKL significantly prevented cartilage degeneration. DAMPs released by necroptotic condylar chondrocytes, such as syndecan 4 (SDC4) and heat shock protein 90 (HSP90), were verified. Furthermore, blocking the function of SDC4 significantly attenuated the expression of TNFα in cartilage and synovium, and accordingly increased cartilage thickness and reduced synovial inflammation. Thus, the necroptotic vicious cycle of TNFα-SDC4-TNFα contributes to cartilage degeneration and synovitis, and can serve as a potential therapeutic target for treating TMJOA. © 2022 American Society for Bone and Mineral Research (ASBMR).     

No Influence of the Fat Mass and Obesity-Associated Gene rs9939609 Single Nucleotide Polymorphism on Blood Lipids in Young Males

The fat mass and obesity-associated gene (FTO) rs9939609 A-allele is linked to obesity and dyslipidemia, yet the independent influence of this polymorphism on blood lipids remains equivocal. We examined the influence of the FTO rs9939609 polymorphism on fasting and postprandial blood lipids in individuals homozygous for the risk A-allele or T-allele with similar anthropometric and demographic characteristics. 12 AA and 12 TT males consumed a standardized meal after fasting overnight. Blood samples were collected at baseline (−1.5 h), before the meal (0 h), and for five hours postprandially to measure lipid, glucose, and insulin concentrations. Time-averaged total area under the curve (TAUC) values (0–5 h) were calculated and compared between genotypes. Fasting triacylglycerol (TG), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, non-esterified fatty acid (NEFA), glucose, and insulin concentrations were similar between groups (p ≥ 0.293). TAUC for TG was similar in AAs and TTs (95% confidence interval (CI) −0.52 to 0.31 mmol/L/h; p = 0.606). Likewise, TAUC values were similar for NEFA (95% CI −0.04 to 0.03 mmol/L/h; p = 0.734), glucose (95% CI −0.41 to 0.44 mmol/L/h; p = 0.951), and insulin (95% CI −6.87 to 2.83 pmol/L/h; p = 0.395). Blood lipids are not influenced by the FTO rs9939609 polymorphism, suggesting the FTO-dyslipidemia link is mediated by adiposity and weight management is important in preventing FTO-related lipid variations.     

肌少症对老年肝癌术后恢复及预后的影响

目的:肌少症对老年肝癌术后恢复及预后的影响。方法:选取2015年1月至2017年12月收治的114例老年肝癌，根据有无合并肌少症，分为肌少症组（n=35）和非肌少症组（n=79）。比较两组患者的术后恢复及生存情况。结果:肌少症组总并发症发生率、住院时间和30 d再入院率均高于对照组，差异均有统计学意义（P＜0.05）。肌少症组中位生存时间为25.9个月，1年、2年、3年累积总生存率为74.3%、51.1%、24.5%，而非肌少症组中位生存时间为35.7个月，1年、2年、3年累积总生存率为87.3%、75.6%、49.4%，差异有统计学意义（P=0.004）。单因素分析结果显示，老年肝癌术后预后与Charlson合并症指数（CCI）、肌少症、巴塞罗那分期（BCLC）、甲胎蛋白、肿瘤大小、肿瘤个数、肿瘤分化程度、微血管侵犯（MVI）相关（P＜0.05）。Cox多因素分析结果显示，CCI、肌少症、BCLC分期、肿瘤个数、MVI是老年肝癌术后预后的独立危险因素（P＜0.05）。结论:肌少症会增加老年肝癌患者术后并发症发生率，延长住院时间，影响术后恢复，同时也会降低总生存率。     

Effect of group reminiscence therapy on depression and perceived meaning of life of veterans diagnosed with dementia at veteran homes

ABSTRACT

Most senior veterans who live in veteran homes in Taiwan have few interpersonal relationships. Aging is often accompanied by solitude and illness, which causes senior veterans to doubt the meaning of life and to lose confidence in the value of life. This study tested the effectiveness of a group reminiscence therapy protocol on the depression and meaning of life among elderly institutionalized veterans. A quasi-experimental design was applied. A convenience sample of older adults was drawn from two veteran homes in southern Taiwan. Participants were assigned to intervention or control groups based on the veterans' homes they attended. The participants in the intervention group carried out group reminiscence therapy for 8 weeks in addition to their daily activities. The participants in the comparison group maintained their daily activities. Both groups were evaluated using the GDS-SF and MLS scale including two aspects of depression mood and meaning of life in weeks 1 and 8. The overall life satisfaction increased significantly over time for the intervention group compared to the comparison group from week 1 to week 8. The group reminiscence therapy programs showed promising effects in improving the depression and meaning of life of older veterans living in veteran homes.