Mesenchymal stem cell attenuates spinal cord injury by inhibiting mitochondrial quality control-associated neuronal ferroptosis.

Ferroptosis is a newly discovered form of iron-dependent oxidative cell death and drives the loss of neurons in spinal cord injury (SCI). Mitochondrial damage is a critical contributor to neuronal death, while mitochondrial quality control (MQC) is an essential process for maintaining mitochondrial homeostasis to promote neuronal survival. However, the role of MQC in neuronal ferroptosis has not been clearly elucidated. Here, we further demonstrate that neurons primarily suffer from ferroptosis in SCI at the single-cell RNA sequencing level. Mechanistically, disordered MQC aggravates ferroptosis through excessive mitochondrial fission and mitophagy. Furthermore, mesenchymal stem cells (MSCs)-mediated mitochondrial transfer restores neuronal mitochondria pool and inhibits ferroptosis through mitochondrial fusion by intercellular tunneling nanotubes. Collectively, these results not only suggest that neuronal ferroptosis is regulated in an MQC-dependent manner, but also fulfill the molecular mechanism by which MSCs attenuate neuronal ferroptosis at the subcellular organelle level. More importantly, it provides a promising clinical translation strategy based on stem cell-mediated mitochondrial therapy for mitochondria-related central nervous system disorders.

Mechanism of miR-424-5p promoter methylation in promoting epithelial-mesenchymal transition of hepatocellular carcinoma cells.

The current study set out to clarify the role of miR-424-5p promoter methylation in epithelial mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells. The findings of quantitative real-time-polymerase chain reaction and methylation-sensitive high-resolution melting assays elicited that miR-424-5p was poorly expressed in HCC tissues and cells while highly methylated. Meanwhile, upon demethylation, miR-424-5p expression levels were partly recovered in HCC cells. In addition, miR-424-5p upregulation reduced cell viability and elevated apoptosis of HCC cells, in parallel with increased N-cadherin and decreased E-cadherin levels. Dual-luciferase reporter assay further validated that miR-424-5p bound to the kinesin family member 2A (KIF2A), and miR-424-5p overexpression downregulated KIF2A. In addition, KIF2A overexpression reversed the miR-424-5p-driven changes in terms of cell viability, apoptosis and EMT-related protein levels. Furthermore, xenograft tumors were established via injection of Huh7 cells, followed by miR-424-5p overexpression in vivo, which inhabited KIF2A downregulation and attenuated tumor growth along with decreased Ki67 positive expression, diminished N-cadherin and elevated E-cadherin levels. Overall, our findings supported the conclusion that miR-424-5p promoter methylation reduced miR-424-5p expression and upregulated KIF2A, thereby promoting HCC EMT.

Analysis of the relationship between MIR155HG variants and gastric Cancer susceptibility.

BACKGROUND: Gastric cancer is one of the most common cancers in the world and a major cause of cancer-related death. This study aims to determine whether genetic variations in MIR155HG could be associated with gastric cancer risk. MATERIALS & METHODS: A total of 506 gastric cancer patients and 500 healthy controls were enrolled in this study. Genotypes were examined with the MassARRAY platform and data management and analysis were conducted with the Typer Software. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated with logistic regression adjusting for age and gender to evaluate the associations between SNPs with gastric cancer in genetic model analysis. RESULTS: The "CC" genotype of rs4143370 decreased the risk of gastric cancer in genotype model (p = 0.020) and recessive model (p = 0.018). Inversely, the "CC" genotype of rs1893650 increased the risk of gastric cancer in genotype model (p = 0.023) and recessive model (p = 0.014). Stratified analysis showed that rs11911469 was associated with an increased risk of gastric cancer only among the male group in the dominant model (p = 0.039) and additive model (p = 0.030). The haplotype analysis showed a strong linkage disequilibrium among these six SNPs (rs4143370, rs77699734, rs11911469, rs1893650, rs34904192 and rs928883). CONCLUSION: This study confirmed the relationship between SNPs of MIR155HG and the gastric cancer risk among the Chinese Han population. Our data may provide a new perspective to understand the aetiology of gastric cancer.

TNF-α-elicited miR-29b potentiates resistance to apoptosis in peripheral blood monocytes from patients with rheumatoid arthritis.

CD14-positive monocytes from patients with rheumatoid arthritis (RA) are more resistant to apoptosis, which promotes their persistence at the inflammatory site and thereby contributes crucially to immunopathology. We sought to elucidate one mechanism underlying this unique pathogenesis: resistance to apoptosis and the potential involvement of miR-29b in this process. CD14-positive peripheral blood monocytes (PBMs) from RA patients were observed to be resistant to spontaneous apoptosis compared to PBMs from healthy volunteers. Intriguingly, expression of miR-29b was significantly upregulated in PBMs from RA patients than those from healthy volunteers, and this upregulation was correlated with RA disease activity. Functionally, forced expression of the exogenous miR-29b in CD14-positive Ctrl PBMs conferred resistance to spontaneous apoptosis and Fas-induced death, thereafter enhancing the production of major proinflammatory cytokines in there cells. Following identification of the potential miR-29b target transcripts using bioinformatic algorithms, we showed that miR-29b could directly bind to the 3'-UTR of the high-mobility group box-containing protein 1 (HBP1) and inhibited its transcription in PBMs. Importantly, stable expression of the exogenous HBP1 in differentiated THP-1 monocytes effectively abolished miR-29b-elicited resistance to Fas-induced apoptosis. Finally, among patients with RA and good clinical responses to immunotherapy, expression levels of miR-29b were significantly compromised in those treated with infliximab (a TNF-α inhibitor) but not in those treated with tocilizumab (a humanized mAb against the IL-6 receptor), pointing to a potential association between miR-29b activation and TNF-α induction. The available data collectively suggest that TNF-α-elicited miR-29b potentiates resistance to apoptosis in PBMs from RA patients via inhibition of HBP1 signaling, and testing patients for miR-29b/HBP1 expression ratios may provide more accurate prognostic information and could influence the recommended course of immunotherapy.

Cellulosic Biomass-Reinforced Polyvinylidene Fluoride Separators with Enhanced Dielectric Properties and Thermal Tolerance.

Safety issues are critical barriers to large-scale energy storage applications of lithium-ion batteries (LIBs). Using an ameliorated, thermally stable, shutdown separator is an effective method to overcome the safety issues. Herein, we demonstrate a novel, cellulosic biomass-material-blended polyvinylidene fluoride separator that was prepared using a simple nonsolvent-induced phase separation technique. This process formed a microporous composite separator with reduced crystallinity, uniform pore size distribution, superior thermal tolerance, and enhanced electrolyte wettability and dielectric and mechanical properties. In addition, the separator has a superior capacity retention and a better rate capability compared to the commercialized microporous polypropylene membrane. This fascinating membrane was fabricated via a relatively eco-friendly and cost-effective method and is an alternative, promising separator for high-power LIBs.

N-cadherin promotes thyroid tumorigenesis through modulating major signaling pathways.

Epithelial-mesenchymal transition (EMT), a crucial step in disease progression, plays a key role in tumor metastasis. N-cadherin, a well-known EMT marker, acts as a major oncogene in diverse cancers, whereas its functions in thyroid cancer remains largely unclear. This study was designed to explore the biological roles and related molecular mechanism of N-cadherin in thyroid tumorigenesis. Quantitative RT-PCR (qRT-PCR) and immunohistochemistry assays were used to evaluate N-cadherin expression. A series of in vitro studies such as cell proliferation, colony formation, cell cycle, apoptosis, migration and invasion assays were performed to determine the effect of N-cadherin on malignant behavior of thyroid cancer cells. Our results showed that N-cadherin was significantly upregulated in papillary thyroid cancers (PTCs) as compared with non-cancerous thyroid tissues. N-cadherin knockdown markedly inhibited cell proliferation, colony formation, cell migration and invasion, and induced cell cycle arrest and apoptosis. On the other hand, ectopic expression of N-cadherin promoted thyroid cancer cell growth and invasiveness. Mechanically, our data demonstrated that tumor-promoting role of N-cadherin in thyroid cancer was closely related to the activities of the MAPK/Erk, the phosphatidylinositol-3-kinase (PI3K)/Akt and p16/Rb signaling pathways in addition to affecting the EMT process. Altogether, our findings suggest that N-cadherin promotes thyroid tumorigenesis by modulating the activities of major signaling pathways and EMT process, and may represent a potential therapeutic target for this cancer.

Long telomere length predicts poor clinical outcome in esophageal cancer patients.

BACKGROUND: Abnormal telomere length is widely reported in various human cancers, and it is considered to be an important hallmark of cancer. However, there is remarkably little consensus on the value of telomere length in the prognostic evaluation of esophageal cancers. Here, we attempted to determine the association of variable telomere length with clinical outcome of esophageal cancer patients. MATERIALS AND METHODS: Using real-time quantitative PCR, we examined relative telomere lengths (RTL) in a cohort of esophageal cancer and normal esophageal tissues, and statistically investigated the association between RTL and clinical outcomes of esophageal cancer patients. RESULTS: The majority of esophageal cancers in this study had longer RTLs as compared to adjacent non-tumor tissues. Enhanced tumor RTL was associated with smoking habit, poor differentiation, advanced tumor stage, lymph node metastasis and cancer related death. In particular, a close relationship between longer RTL and poor survival was fully demonstrated by using cox regression and Kaplan-Maier survival curves. CONCLUSIONS: We found frequent telomere elongation in esophageal cancer tissues, and demonstrated longer RTL may be an independent poor prognostic factor for esophageal cancer patients.

Increased expression of EHF contributes to thyroid tumorigenesis through transcriptionally regulating HER2 and HER3.

E26 transformation-specific (ETS) transcription factor EHF plays a tumor suppressor role in prostate cancer and esophageal squamous cell carcinoma (ESCC), whereas it is overexpressed and may act as an oncogene in ovarian and mammary cancers. However, its biological role in thyroid cancer remains totally unknown. The aim of this study was to explore the biological functions of EHF and its potential as a therapeutic target in thyroid cancer. Using quantitative RT-PCR (qRT-PCR) assay, we evaluated mRNA expression of EHF in a cohort of primary papillary thyroid cancers (PTCs) and matched non-cancerous thyroid tissues. The functions of knockdown and ectopic expression of EHF in thyroid cancer cells were determine by a series of in vitro and in vivo experiments. Moreover, dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays were performed to identify its downstream targets. Our data showed that EHF expression was significantly increased in PTCs compared with matched non-cancerous thyroid tissues. EHF knockdown significantly inhibited thyroid cancer cell proliferation, colony formation, migration, invasion and tumorigenic potential in nude mice and induced cell cycle arrested and apoptosis by modulating the PI3K/Akt and MAPK/Erk signaling pathways. On the other hand, ectopic expression of EHF in thyroid cancer cells notably promoted cell growth and invasiveness. Importantly, EHF was identified as a new transcription factor for HER2 and HER3, contributing to thyroid tumorigenesis. Altogether, our findings suggest that EHF is a novel functional oncogene in thyroid cancer by transcriptionally regulating HER2 and HER3, and may represent a potential therapeutic target for this cancer.

Analysis of Quasispecies of Avain Leukosis Virus Subgroup J Using Sanger and High-throughput Sequencing.

BACKGROUND: Avian leukosis viruses subgroup J (ALV-J) exists as a complex mixture of different, but closely related genomes named quasispecies subjected to continuous change according to the Principles of Darwinian evolution. METHOD: The present study seeks to compare conventional Sanger sequencing with deep sequencing using MiSeq platform to study quasispecies dynamics of ALV-J. RESULTS: The accuracy and reproducibility of MiSeq sequencing was determined better than Sanger sequencing by running each experiment in duplicate. According to the mutational rate of single position and the ability to distinguish dominant quasispecies with two sequencing methods, conventional Sanger sequencing technique displayed high randomness due to few sequencing samples, while deep sequencing could reflect the composition of the quasispecies more accurately. In the mean time, the research of quasispecies via Sanger sequencing was simulated and analyzed with the aid of re-sampling strategy with replacement for 1000 times repeat from high-throughput sequencing data, which indicated that the higher antibody titer, the higher sequence entropy, the harder analyzing with the conventional Sanger sequencing, resulted in lower ratios of dominant variants. CONCLUSIONS: In sum, deep sequencing is better suited for detecting rare variants comprehensively. The simulation of Sanger sequencing that we propose here will also help to standardize quasispecies researching under different selection pressure based on next-generation sequencing data.

A new kaempferol trioside from Silphium perfoliatum.

A new apiose-containing kaempferol trioside, kaempferol-3-O-α-L-rhamnosyl-(1‴ → 6″)-O-ß-D-galactopyranosyl-7-O-ß-D-apiofuranoside, along with 16 known compounds, were isolated from 50% acetone extract of Silphium perfoliatum L. Their structures were elucidated by acid hydrolysis and spectroscopic techniques including UV, IR, MS, ¹H, ¹³C, and 2D-NMR. In addition, the pharmacological activity of compound 1 was tested with HepG2 and Balb/c mice (splenic lymphocytes and thymic lymphocytes) in vitro, and it exhibited inhibitory effect on the proliferation of HepG2 cells and showed the immunosuppressive activity.

Three new ursane-type triterpenes from the leaves of Rehmannia glutinosa.

Three new ursane-type triterpenes, glutinosalactone A-C (1-3), were isolated from the 50% aqueous acetone extract of the leaves of Rehmannia glutinosa. Their structures were elucidated on the basis of spectral analysis (IR, NMR and MS spectroscopy). The cytotoxic effects of compounds 1-3 against three human cancer cell lines (MCF-7, MG63 and HepG2) were also evaluated. Compound 3 showed cytotoxic activities with IC50 values of 8.35-39.25 µM.