Early loss of grafted islets is the main obstacle to achieve favorable outcomes of islet transplantation. Mesenchymal stem cells are known to have a protective effect; however, its mechanism remains ...unclear. We hypothesized that bone marrow‐derived mesenchymal stem cells (BMSCs) can protect grafted islets against endoplasmic reticulum stress (ERS)‐induced apoptosis. In syngeneic streptozocin‐induced diabetic BALB/c mice, islet grafts decreased blood glucose levels; however, the effect was not fully functional from the immediate post‐transplant phase. β‐Cell apoptosis was proven on days 1 and 3 after transplantation. Ultra‐structural evidence of ERS was observed along with increased expressions of marker protein BIP and apoptosis‐related protein CHOP. In contrast, BMSC co‐transplantation maintained glucose hemostasis, inhibited apoptosis and alleviated ERS. In ex vivo culture, BMSCs improved viability of islets and decreased apoptosis. Increased ERS were observed in cultured islets exposed to hypoxia, but not in the islets cocultured with BMSCs. Furthermore, cocultured BMSCs protected islets against ERS‐induced apoptosis as well as improved their insulin secretion, and BMSCs alleviated ERS by improving Myc expression through both stromal cell‐derived factor 1 signal and contact effect. In conclusion, BMSCs protected the grafted islets against ERS‐induced apoptosis during the early stage after transplantation. This study opens a new arena for ERS‐targeted therapy to improve outcomes of islet transplantation. Stem Cells 2018;36:1045–1061
Mechanisms of bone marrow‐derived mesenchymal stem cells (BMSCs) protecting grafted islets against endoplasmic reticulum stress (ERS)‐induced apoptosis. β‐Cells in the islet grafts develop ERS and ERS‐induced apoptosis at the very beginning post‐transplant due to transplant‐related trauma and hypoxia, which results in graft loss and poor outcome. BMSCs can both secrete soluble stromal cell‐derived factor‐1 that binds to its receptor chemokine(C‐X‐C motif) receptor on β‐cell membrane and directly contact with islets, which improves Myc expression to alleviate ERS, resulting in a decrease in ERS‐induced β‐cell apoptosis and improvement of islet function. Abbreviations: BMSCs, bone marrow‐derived mesenchymal stem cells; CXCR4, chemokine(C‐X‐C motif) receptor 4; ERS, endoplasmic reticulum stress; SDF1, stromal cell‐derived factor 1.
Anticancer therapies are often compromised by nonspecific effects and challenged by tumour environments' inherent physicochemical and biological characteristics. Often, therapeutic effect can be ...increased by addressing multiple parameters simultaneously. Here we report on exploiting extravasation due to inherent vascular leakiness for the delivery of a pH-sensitive polymer carrier. Tumours' acidic microenvironment instigates a charge reversal that promotes cellular internalization where endosomes destabilize and gene delivery is achieved. We assess our carrier with an aggressive non-small cell lung carcinoma (NSCLC) in vivo model and achieve >30% transfection efficiency via systemic delivery. Rejuvenation of the p53 apoptotic pathway as well as expression of KillerRed protein for sensitization in photodynamic therapy (PDT) is accomplished. A single administration greatly suppresses tumour growth and extends median animal survival from 28 days in control subjects to 68 days. The carrier has capacity for multiple payloads for greater therapeutic response where inter-individual variability can compromise efficacy.
This study proposes an innovative fall detection system that leverages the capabilities of depth sensors and a Convolutional Neural Network (CNN) model. The objective is to enhance fall detection ...accuracy by using raw data from depth images for ground reference establishment and to distinguish foreground elements by using a background subtraction algorithm for comprehensive analysis. The performance of the proposed CNN-based system was compared with that of systems based on three learning methods: support vector machine, multilayer perceptron, and radial basis function neural network models. Experimental results indicated that the proposed system achieved an accuracy rate of approximately 95% and a Kappa coefficient of 0.96 in fall detection, thereby outperforming the other systems. These findings indicate that the proposed system has high efficacy and reliability; thus, it has potential applications in real-world scenarios requiring accurate fall detection.
Topotecan produces DNA damage that induces autophagy in cancer cells. In this study, sensitising topotecan to colon cancer cells with different P53 status via modulation of autophagy was examined.
...The DNA damage induced by topotecan treatment resulted in cytoprotective autophagy in colon cancer cells with wild-type p53. However, in cells with mutant p53 or p53 knockout, treatment with topotecan induced autophagy-associated cell death. In wild-type p53 colon cancer cells, topotecan treatment activated p53, upregulated the expression of sestrin 2, induced the phosphorylation of the AMPKα subunit at Thr172, and inhibited the mTORC1 pathway. Furthermore, the inhibition of autophagy enhanced the anti-tumour effect of topotecan treatment in wild-type p53 colon cancer cells but alleviated the anti-tumour effect of topotecan treatment in p53 knockout cells in vivo.
These results imply that the wild-type p53-dependent induction of cytoprotective autophagy is one of the cellular responses that determines the cellular sensitivity to the DNA-damaging drug topotecan. Therefore, our study provides a potential therapeutic strategy that utilises a combination of DNA-damaging agents and autophagy inhibitors for the treatment of colon cancer with wild-type p53.
OBJECTIVES
Currently, most treatment guidelines suggest lowering hypertriglyceridemia of any severity, even in elderly individuals. However associations of serum triglycerides (TGs) with adverse ...health and mortality risk decrease with age, it remains unclear among the oldest old (aged 80 years and older). The study was to investigate the relationship of serum TG concentrations with cognitive function, activities of daily living (ADLs), frailty, and mortality among the oldest old in a prospective cohort study.
DESIGN
Longitudinal prospective cohort study.
SETTING
Community‐based setting in longevity areas in China.
PARTICIPANTS
A total of 930 (mean age = 94.0 years) Chinese oldest old.
MEASUREMENTS
The TG concentrations were measured at baseline survey in 2009. Cognitive function, ADLs, frailty, and mortality were determined over 5 years of follow‐up. Cox proportional hazards models and competing risk models were performed to explore the association, adjusting for potential confounders.
RESULTS
Each 1‐mmol/L increase in TGs was associated with a nearly 20% lower risk of cognitive decline, ADL decline, and frailty aggravation during the 5 years of follow‐up. Consistently, higher TGs (each 1 mmol/L) was associated with lower 5‐year all‐cause mortality after fully adjustment (hazard ratio HR = 0.79; 95% confidence interval CI = 0.69‐0.89). Nonelevated TG concentrations (less than 2.26 mmol/L) were associated with higher mortality risk (HR = 1.72; 95% CI = 1.22‐2.44), relative to TGs of 2.26 mmol/L or more. We observed similar results regarding TG concentrations and mortality in 1‐year lag analysis and when excluding participants with identified chronic disease.
CONCLUSION
In the oldest old, a higher concentration of TGs was associated with a lower risk of cognitive decline, ADL decline, frailty aggravation, and mortality. This paradox suggests the clinical importance of revisiting the concept of “the lower the better” for the oldest old. J Am Geriatr Soc 67:741–748, 2019.
Cohort evidence linking long-term survival with exposure to multiple air pollutants (e.g., fine particulate matter PM2.5 and ozone) was extensively sparse in low- and middle-income countries, ...especially among older adults. This study aimed to investigate potential associations of long-term exposures to PM2.5 and ozone with all-cause mortality in Chinese older adults.
A dynamic nationwide prospective cohort comprising 20,352 adults aged ≥65 years were enrolled from the Chinese Longitudinal Healthy Longevity Study and followed up through 2005–2018. Participants’ annual exposures to warm-season ozone and year-round PM2.5 were assigned using satellite-derived spatiotemporal estimates. A directed acyclic graph (DAG) was developed to identify confounding variables. Associations of annual mean exposures to PM2.5 and ozone with mortality were evaluated using single- and two-pollutant Cox proportional hazards models, adjusting for time-dependent individual risk factors and ambient temperature.
During 100 thousand person-years of follow-up (median: 3.6 years), a total of 14,313 death events occurred. The participants were averagely aged 87.1 years at baseline and exposed to a wide range of annual average concentrations of warm-season maximum 8-hour ozone (mean, 54.4 ppb; range, 23.3–81.6 ppb) and year-round PM2.5 (mean, 65.5 μg/m3; range, 10.1–162.9 μg/m3). Approximately linear concentration-response relationship was identified for ozone, whereas significant increases in PM2.5-associated mortality risks were observed only when concentrations were above 60 μg/m3. Rises of 10 ppb in ozone and 10 µg/m3 in PM2.5 above 60 µg/m3 were associated with increases in all-cause mortality of 13.2% (95% confidence interval CI: 10.2–16.2%) and 6.2% (95% CI: 4.6–7.7%) in DAG-based single-pollutant model, and of 9.7% (95% CI: 6.6–13.0%) and 5.3% (95% CI: 3.7–6.9%) in DAG-based two-pollutant model, respectively. We detected significant effect modification by temperature in associations of mortality with ozone (P <0.001 for interaction), suggesting greater ozone-related risks among participants in warmer locations.
This study provided longitudinal evidence that long-term exposure to ambient PM2.5 and ozone significantly and independently contributed to elevated risks of all-cause mortality among older adults in China.
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•Later-life exposure to ozone and PM2.5 hinders long-term survival of Chinese older adults.•An approximately linear concentration-response relationship was identified for ozone.•Significant increases in PM2.5-associated mortality risks were observed only above 60 μg/m3.•Ozone-mortality associations were more prominent in older adults living in warmer locations.
The histone methyl transferase enhancer of zeste homolog 2 (EZH2) is a master transcriptional regulator involved in histone H3 lysine 27 trimethylation. We aimed to elucidate the precise ...post-translational regulations of EZH2 and their role in cancer pathogenesis. Here, we show that SET and MYND domain containing 2 (SMYD2) directly methylates EZH2 at lysine 307 (K307) and enhances its stability, which can be relieved by the histone H3K4 demethylase lysine-specific demethylase 1 (LSD1). SMYD2 is critical for EZH2 function in repressing a cohort of genes governing several cancer-associated pathways. In addition, SMYD2 promotes breast cancer cell proliferation, epithelial-mesenchymal transition, and invasion through EZH2 K307 methylation, and it is markedly upregulated in various human cancers. Our data suggest that dynamic crosstalk between SMYD2-mediated EZH2 methylation plays an important role in fine-tuning EZH2 functions in chromatin recruitment and transcriptional repression.
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•EZH2 is methylated by SMYD2 and is demethylated by LSD1 on lysine (K) 307•EZH2 K307 methylation enhances the protein stability of EZH2•SMYD2 and EZH2 collaboratively participate in transcriptional repression•SMYD2 coordinates EZH2 to promote breast cancer tumorigenesis and metastasis
Post-translational modification of proteins is involved in protein stability regulation. Zeng et al. demonstrate that EZH2 K307 is methylated by SMYD2 and demethylated by LSD1. This modification protects EZH2 from degradation. The dynamic crosstalk between SMYD2-mediated EZH2 methylation plays an important role in the transcriptional repression of EZH2.
In contrast to traditional short-lived fluorescent probes, long-lived phosphorescent probes based on transition-metal complexes can effectively eliminate unwanted background interference by using ...time-resolved luminescence imaging techniques, such as photoluminescence lifetime imaging microscopy. Hence, phosphorescent probes have become one of the most attractive candidates for investigating biological events in living systems. However, most of them are based on single emission intensity changes, which might be affected by a variety of intracellular environmental factors. Ratiometric measurement allows simultaneous recording of two separated wavelengths instead of measuring mere intensity changes and thus offers built-in correction for environmental effects. Herein, for the first time, a soft salt based phosphorescent probe has been developed for ratiometric and lifetime imaging of intracellular pH variations in real time. Specifically, a pH sensitive cationic complex (
C1
) and a pH insensitive anionic complex (
A1
) are directly connected through electrostatic interaction to form a soft salt based probe (
S1
), which exhibits a ratiometric phosphorescent response to pH with two well-resolved emission peaks separated by about 150 nm (from 475 to 625 nm). This novel probe was then successfully applied for ratiometric and lifetime imaging of intracellular pH variations. Moreover, quantitative measurements of intracellular pH fluctuations caused by oxidative stress have been performed for
S1
based on the pH-dependent calibration curve.
A novel soft salt based phosphorescent probe has been successfully developed for ratiometric and lifetime imaging of intracellular pH variations in real time.
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