Inhibition of TRF2 Leads to Ferroptosis, Autophagic Death, and Apoptosis by Causing Telomere Dysfunction.

Background: Gastric cancer (GC) is an aggressive malignancy with a high mortality rate and poor prognosis. Telomeric repeat-binding factor 2 (TRF2) is a critical telomere protection protein. Emerging evidence indicates that TRF2 may be an essential treatment option for GC; however, the exact mechanism remains largely unknown. Objective: We aimed to explore the role of TRF2 in GC cells. The function and molecular mechanisms of TRF2 in the pathogenesis of GC were mainly discussed in this study. Methods: Relevant data from GEPIA and TCGA databases regarding TRF2 gene expression and its prognostic significance in GC samples were analyzed. Analysis of 53BP1 foci at telomeres by immunofluorescence, metaphase spreads, and telomere-specific FISH analysis was carried out to explore telomere damage and dysfunction after TRF2 depletion. CCK8 cell proliferation, trypan blue staining, and colony formation assay were performed to evaluate cell survival. Apoptosis and cell migration were determined with flow cytometry and scratch-wound healing assay, respectively. qRT-PCR and Western blotting were carried out to analyze the mRNA and protein expression levels after TRF2 depletion on apoptosis, autophagic death, and ferroptosis. Results: By searching with GEPIA and TCGA databases, the results showed that the expression levels of TRF2 were obviously elevated in the samples of GC patients, which was associated with adverse prognosis. Knockdown of TRF2 suppressed the cell growth, proliferation, and migration in GC cells, causing significant telomere dysfunction. Apoptosis, autophagic death, and ferroptosis were also triggered in this process. The pretreatment of chloroquine (autophagy inhibitor) and ferrostatin-1 (ferroptosis inhibitor) improved the survival phenotypes of GC cells. Conclusion: Our data suggest that TRF2 depletion can inhibit cell growth, proliferation, and migration through the combined action of ferroptosis, autophagic death, and apoptosis in GC cells. The results indicate that TRF2 might be used as a potential target to develop therapeutic strategies for treating GC.

The Regulation of ROS- and BECN1-Mediated Autophagy by Human Telomerase Reverse Transcriptase in Glioblastoma.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor with high morbidity and mortality. Human telomerase reverse transcriptase (hTERT), the catalytic subunit of human telomerase, is overexpressed in most cancers including GBM. It is well known that hTERT can compensate telomere shortening to immortalize cells. However, in addition to the canonical function, hTERT has the roles beyond canonical telomere maintenance. To further understand the effects of hTERT on glioblastoma progression, we investigated the role of hTERT in regulating autophagy-a conserved pathway, by which cells deliver cellular organic material and impaired organelles to the lysosomes for degradation and recycle these cargos to produce energy under a stressful condition. Our results showed that downregulation of hTERT impaired autophagy levels by suppressing BECN1/beclin-1 and induced an increase of reactive oxygen species (ROS), which resulted in cell death ultimately. On the contrary, overexpression of BECN1 or treating cells with the antioxidant N-acetylcysteine (NAC) could restore the survival of hTERT knockdown cells. Our study will provide an additional basis of telomerase-targeting therapy for future clinical anticancer treatment.

Exploring Shared Pathogenesis of Alzheimer's Disease and Type 2 Diabetes Mellitus via Co-expression Networks Analysis.

BACKGROUND: Alzheimer's Disease (AD) and Type 2 Diabetes Mellitus (T2DM) have an increased incidence in modern society. Although increasing evidence has supported the close linkage between these two disorders, the inter-relational mechanisms remain to be fully elucidated. OBJECTIVE: The primary purpose of this study is to explore the shared pathophysiological mechanisms of AD and T2DM. METHODS: We downloaded the microarray data of AD and T2DM from the Gene Expression Omnibus (GEO) database and constructed co-expression networks by Weighted Gene Co-Expression Network Analysis (WGCNA) to identify gene network modules related to AD and T2DM. Then, Gene Ontology (GO) and pathway enrichment analysis were performed on the common genes existing in the AD and T2DM related modules by clusterProfiler and DOSE package. Finally, we utilized the STRING database to construct the protein-protein interaction network and found out the hub genes in the network. RESULTS: Our findings indicated that seven and four modules were the most significant with AD and T2DM, respectively. Functional enrichment analysis showed that AD and T2DM common genes were mainly enriched in signaling pathways such as circadian entrainment, phagosome, glutathione metabolism and synaptic vesicle cycle. Protein-protein interaction network construction identified 10 hub genes (CALM1, LRRK2, RBX1, SLC6A1, TXN, SNRPF, GJA1, VWF, LPL, AGT) in AD and T2DM shared genes. CONCLUSION: Our work identified common pathogenesis of AD and T2DM. These shared pathways might provide a novel idea for further mechanistic studies and hub genes that may serve as novel therapeutic targets for diagnosis and treatment of AD and T2DM.

Thick Sintered Electrode Lithium-Ion Battery Discharge Simulations: Incorporating Lithiation-Dependent Electronic Conductivity and Lithiation Gradient Due to Charge Cycle.

In efforts to increase the energy density of lithium-ion batteries, researchers have attempted to both increase the thickness of battery electrodes and increase the relative fractions of active material. One system that has both of these attributes are sintered thick electrodes comprised of only active material. Such electrodes have high areal capacities, however, detailed understanding is needed of their transport properties, both electronic and ionic, to better quantify their limitations to cycling at higher current densities. In this report, efforts to improve models of the electrochemical cycling of sintered electrodes are described, in particular incorporation of matrix electronic conductivity which is dependent on the extent of lithiation of the active material and accounting for initial gradients in lithiation of active material in the electrode that develop as a consequence of transport limitations during charging cycles. Adding in these additional considerations to a model of sintered electrode discharge resulted in improved matching of experimental cell measurements.

Probing transport limitations in thick sintered battery electrodes with neutron imaging.

Lithium-ion batteries have received significant research interest due to their advantages in energy and power density, which are important to enabling many devices. One route to further increase energy density is to fabricate thicker electrodes in the battery cell; however, careful consideration must be taken when designing electrodes as to how increasing the thickness impacts the multiscale and multiphase molecular transport processes, which can limit the overall battery operating power. Design of these electrodes necessitates probing the molecular processes when the battery cell undergoes electrochemical charge/discharge. One tool for in situ insights into the cell is neutron imaging, because neutron imaging can provide information of where electrochemical processes occur within the electrodes. In this manuscript, neutron imaging is applied to track the lithiation/delithiation processes within electrodes at different current densities for a full cell with a thick sintered Li4Ti5O12 anode and LiCoO2 cathode. The neutron imaging reveals that the molecular distribution of Li+ during discharge within the electrode is sensitive to the current density, or equivalently discharge rate. An electrochemical model provides additional insights into the limiting processes occurring within the electrodes. In particular, the impact of tortuosity and molecular transport in the liquid phase within the interstitial regions in the electrodes are considered, and the influence of tortuosity was shown to be highly sensitive to the current density. Qualitatively, the experimental results suggest that the electrodes behave consistent with the packed hard sphere approximation of Bruggeman tortuosity scaling, which indicates that the electrodes are largely mechanically intact but also that a design that incorporates tunable tortuosity could improve the performance of these types of electrodes.