Metabolism has been reported to associate with the progression of vascular diseases. However, how vascular calcification in chronic kidney disease (CKD) is regulated by metabolic status remains ...poorly understood. Using a model of 5/6 nephrectomy, we demonstrated that the aortic tissues of CKD mice had a preference for using oxidative phosphorylation (OXPHOS). Both high phosphate and human uremic serum-stimulated vascular smooth muscle cells (VSMCs) had enhanced mitochondrial respiration capacity, while the glycolysis level was not significantly different. Besides, 2-deoxy-d-glucose (2-DG) exacerbated vascular calcification by upregulating OXPHOS. The activity of cytochrome c oxidase (COX) was higher in the aortic tissue of CKD mice than those of sham-operated mice. Moreover, the expression levels of COX15 were higher in CKD patients with aortic arch calcification (AAC) than those without AAC, and the AAC scores were correlated with the expression level of COX15. Suppressing COX sufficiently attenuated vascular calcification. Our findings verify the relationship between OXPHOS and calcification, and may provide potential therapeutic approaches for vascular calcification in CKD.
Hypoxia, a fundamental characteristic of glioma, is considered to promote tumor malignancy by inducing process of epithelial mesenchymal transition (EMT). Ferritin Light Chain (FTL) is one of the ...iron metabolism regulators and is overexpressed in glioma. However, relationship between hypoxia and FTL expression and its role in regulating EMT remains unclear.
Immunohistochemistry (IHC), western blot and public datasets were used to evaluate FTL level in glioma. Wound healing, transwell assays, CCK8, annexin V staining assay were used to measure migration, invasion, proliferation and apoptosis of glioma cells in vitro. Interaction between HIF1A and FTL was assessed by luciferase reporter and Chromatin immunoprecipitation (ChIP) assays. Subcutaneous xenograft model was established to investigate in vivo growth.
FTL expression was enriched in high grade glioma (HGG) and its expression significantly associated with IDH1/2 wildtype and unfavorable prognosis of glioma patients. FTL expression positively correlated with HIF1A in glioma tissues and obviously increased in U87 and U251 cells under hypoxia in a time-dependent manner. Mechanistically, HIF-1α regulates FTL expression by directly binding to HRE-3 in FTL promoter region. Furthermore, we found that knockdown FTL dramatically repressed EMT and reduced migration and invasion of glioma by regulating AKT/GSK3β/ β-catenin signaling both in vitro and in vivo. Moreover, our study found downregulation FTL decreased the survival rate and increased the apoptosis of glioma cells treated with temozolomide (TMZ). FTL expression segregated glioma patients who were treated with TMZ or with high MGMT promoter methylation into survival groups in TCGA dataset. Patients with methylated MGMT who had high FTL expression presented similar prognosis with patients with unmethylated MGMT.
Our study strongly suggested that hypoxia-inducible FTL was a regulator of EMT and acted not only as a prognostic marker but also a novel biomarker of response to TMZ in glioma.
Abstract
Background
Subjective memory impairment (SMI) is common in older people. The aim of this study was to investigate the factors influencing SMI among older people in China, with specific focus ...on the interaction effect of midday napping duration and depressive symptoms on the risk of SMI.
Methods
Using a dataset representative of the Chinese population from a longitudinal study of health and retirement in China, subjects with SMI were screened using the question “how do you feel about your memory now?” and the Mini-Mental State Examination. A logistic regression model was applied to explore the factors affecting SMI. Additive and multiplicative models were used to analyze the interaction effect of midday napping duration and depressive symptoms on the risk of SMI.
Results
We enrolled 8,254 subjects included and the incidence of SMI was 63.9%. Depressive symptoms, nap time, and physical activity were influencing factors of SMI. Midday napping duration and depressive symptoms had positive additive interaction effects on the risk of SMI. When extended-length naps and depressive symptoms coexisted, the risk of SMI was 1.06 times greater than that for either alone (RERI, relative excess risk due to interaction = 0.27, 95% CI = 0.07–0.43; AP, attributable proportion = 0.14, 95% CI = 0.01–0.23; S, synergy index = 1.06, 95% CI = 0.57–1.62). When short naps and depressive symptoms coexisted, the risk of SMI was 1.2 times higher than that for either alone (RERI = 0.12, 95% CI=-0.14–0.39; AP = 0.13, 95% CI=-0.07–0.22; S = 1.20, 95% CI = 0.79–1.82).
Limitations
Since this was a cross-sectional study, the cause-and-effect relationships between the associated variables cannot be inferred.
Conclusions
The interaction effect that exists between nap time and depressive symptoms in older people is important for the identification and early intervention of people at risk for SMI.
Epidemiological and clinical features of patients with corona virus disease 2019 (COVID-19) were well delineated. However, no researches described the patients complicated with pleural effusion (PE). ...In the present study, we aimed to clinically characterize the COVID-19 patients complicated with PE and to create a predictive model on the basis of PE and other clinical features to identify COVID-19 patients who may progress to critical condition.
This retrospective study examined 476 COVID-19 inpatients, involving 153 patients with PE and 323 without PE. The data on patients' past history, clinical features, physical checkup findings, laboratory results and chest computed tomography (CT) findings were collected and analyzed. LASSO regression analysis was employed to identify risk factors associated with the severity of COVID-19.
Laboratory findings showed that patients with PE had higher levels of white blood cells, neutrophils, lactic dehydrogenase, C-reactive protein and D-dimer, and lower levels of lymphocytes, platelets, hemoglobin, partial pressure of oxygen and oxygen saturation. Meanwhile, patients with PE had higher incidence of severe or critical illness and mortality rate, and longer hospital stay time compared to their counterparts without pleural effusion. Moreover, LASSO regression analysis exhibited that pleural effusion, lactic dehydrogenase (LDH), D-dimer and total bilirubin (TBIL) might be risk factors for critical COVID-19.
Pleural effusion could serve as an indicator for severe inflammation and poor clinical outcomes, and might be a complementary risk factor for critical type of COVID-19.
Nitrogen (N) is one of the most important mineral elements for plant growth and development and a key factor for improving crop yield. Rapeseed,
, is the largest oil crop in China, producing more ...than 50% of the domestic vegetable oil. However, high N fertilizer input with low utilization efficiency not only increases the production cost but also causes serious environmental pollution. Therefore, the breeding of rapeseed with high N efficiency is of great strategic significance to ensure the security of grain and oil and the sustainable development of the rapeseed industry. In order to provide reference for genetic improvement of rapeseed N-efficient utilization, in this article, we mainly reviewed the recent research progress of rapeseed N efficiency, including rapeseed N efficiency evaluation, N-efficient germplasm screening, and N-efficient physiological and molecular genetic mechanisms.
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and therapeutic agents for this malignancy are lacking. MicroRNAs play critical roles in carcinogenesis and present ...tremendous therapeutic potential. Here, we report that microRNA‐206 is a robust tumor suppressor that plays important roles in the development of HCC by regulating cell‐cycle progression and the cMet signaling pathway. MicroRNA‐206 was underexpressed in livers of two HCC mouse models, human individuals bearing HCC, and human HCC cell lines. Combining bioinformatic prediction and molecular and cellular approaches, we identified cMET (Met proto‐oncogene), cyclin D1 (CCND1), and cyclin‐dependent kinase 6 (CDK6) as functional targets of microRNA‐206. By inhibiting expression of cMET, CCND1, and CDK6, microRNA‐206 delayed cell‐cycle progression, induced apoptosis, and impaired proliferation of three distinct human HCC cell lines. Systemic administration of microRNA‐206 completely prevented HCC development in both cMyc and V‐Akt murine thymoma viral oncogene homolog 1/neuroblastoma RAS viral oncogene homolog (AKT/Ras) HCC mice, whereas 100% of control mice died from lethal tumor burdens. Conversely, reintroduction of cMet or Cdk6 into livers of cMyc and AKT/Ras HCC mice recovered growth of HCC inhibited by microRNA‐206. These results strongly suggested that cMet and Cdk6 were two functional targets that mediated the inhibitory effect of microRNA‐206 on the development of HCC. MicroRNA‐206 overexpression demonstrated a profound therapeutic effect on HCC in xenograft and cMyc HCC mice. Conclusion: In summary, this study defines a potentially critical role of microRNA‐206 in preventing the growth of HCC and suggests its use as a potential therapeutic strategy for this malignancy. (Hepatology 2017;66:1952–1967)
The miR-133b, a commonly recognized muscle-specific miRNA, was reported to be deregulated in many kinds of cancers. However, its potential roles in tumorigenesis remain greatly elusive. Herein, we ...demonstrate that miR-133b is significantly suppressed in human breast cancer specimens, which is reversely correlated to histological grade of the cancer. Ectopic expression of miR-133b suppresses clonogenic ability and metastasis-relevant traits in vitro, as well as carcinogenesis and pulmonary metastasis in vivo. Further studies have identified Sox9, c-MET, and WAVE2 as direct targets of miR-133b, in which Sox9 contributes to all miR-133b-endowed effects including cell proliferation, colony formation, as well as cell migration and invasion in vitro. Moreover, re-expression of Sox9 reverses miR-133b-mediated metastasis suppression in vivo. Taken together, these findings highlight an important role for miR-133b in the regulation of tumorigenesis and metastatic potential of breast cancer and suggest a potential application of miR-133b in cancer treatment.
Emerging evidence has suggested that exposure to PM2.5 is a significant contributing factor to the development of chronic obstructive pulmonary disease (COPD). However, the underlying biological ...effects and mechanisms of PM2.5 in COPD pathology remain elusive. In this study, we aimed to investigate the implication and regulatory effect of biomass fuels related-PM2.5 (BRPM2.5) concerning the pathological process of fibroblast-to-myofibroblast transition (FMT) in the context of COPD. In vivo experimentation revealed that exposure to biofuel smoke was associated with airway inflammation in rats. After 4 weeks of exposure, there was inflammation in the small airways, but no significant structural changes in the airway walls. However, after 24 weeks, airway remodeling occurred due to increased collagen deposition, myofibroblast proliferation, and tracheal wall thickness. In vitro, cellular immunofluorescence results showed that with stimulation of BRPM2.5 for 72 h, the cell morphology of fibroblasts changed significantly, most of the cells changed from spindle-shaped to star-shaped irregular, α-SMA stress fibers appeared in the cytoplasm and the synthesis of type I collagen increased. The collagen gel contraction experiment showed that the contractility of fibroblasts was enhanced. The expression level of TRPC1 in fibroblasts was increased. Specific siRNA-TRPC1 blocked BRPM2.5-induced FMT and reduced cell contractility. Additionally, specific siRNA-TRPC1 resulted in a decrease in the augment of intracellular Ca2+ concentration (Ca2+i) induced by BRPM2.5. Notably, it was found that the PI3K inhibitor, LY294002, inhibited enhancement of AKT phosphorylation level, FMT occurrence, and elevation of TRPC1 protein expression induced by BRPM2.5. The findings indicated that BRPM2.5 is capable of inducing the FMT, with the possibility of mediation by PI3K/AKT/TRPC1. These results hold potential implications for the understanding of the molecular mechanisms involved in BRPM2.5-induced COPD and may aid in the development of novel therapeutic strategies for pathological conditions characterized by fibrosis.
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•BRPM2.5 promoted fibroblast-to-myofibroblast transition (FMT).•TRPC1 was involved in the transition of fibroblasts into myofibroblasts.•PI3K/AKT was required for the increased expression of TRPC1 induced by BRPM2.5
Frailty is the third most common complication of diabetes after macrovascular and microvascular complications. The aim of this study was to develop a validated risk prediction model for frailty in ...patients with diabetes.
The research used data from the China Health and Retirement Longitudinal Study (CHARLS), a dataset representative of the Chinese population. Twenty-five indicators, including socio-demographic variables, behavioral factors, health status, and mental health parameters, were analyzed in this study. The study cohort was randomly divided into a training set and a validation set at a ratio of 70 to 30%. LASSO regression analysis was used to screen the variables for the best predictors of the model based on a 10-fold cross-validation. The logistic regression model was applied to explore the associated factors of frailty in patients with diabetes. A nomogram was constructed to develop the prediction model. Calibration curves were applied to evaluate the accuracy of the nomogram model. The area under the receiver operating characteristic curve and decision curve analysis were conducted to assess predictive performance.
One thousand four hundred thirty-six patients with diabetes from the CHARLS database collected in 2013 (n = 793) and 2015 (n = 643) were included in the final analysis. A total of 145 (10.9%) had frailty symptoms. Multivariate logistic regression analysis showed that marital status, activities of daily living, waist circumference, cognitive function, grip strength, social activity, and depression as predictors of frailty in people with diabetes. These factors were used to construct the nomogram model, which showed good concordance and accuracy. The AUC values of the predictive model and the internal validation set were 0.912 (95%CI 0.887-0.937) and 0.881 (95% CI 0.829-0.934). Hosmer-Lemeshow test values were P = 0.824 and P = 0.608 (both > 0.05). Calibration curves showed significant agreement between the nomogram model and actual observations. ROC and DCA indicated that the nomogram had a good predictive performance.
Comprehensive nomogram constructed in this study was a promising and convenient tool to evaluate the risk of frailty in patients with diabetes, and contributed clinicians to screening the high-risk population.
MicroRNA (miRNA) is involved in the progression and metastasis of diverse human cancers, including breast cancer, as strong evidence has been found that miRNAs can act as oncogenes or tumor ...suppressor genes. Here, we show that miR-494 is decreased in human breast cancer specimens and breast cancer cell lines. Ectopic expression of miR-494 in basal-like breast cancer cell lines MDA-MB-231-LUC-D2H3LN and BT-549 inhibits clonogenic ability and metastasis-relevant traits in vitro. Moreover, ectopic expression of miR-494 suppresses neoplasm initiation as well as pulmonary metastasis in vivo. Further studies have identified PAK1, as a direct target gene of miR-494, contributes to the functions of miR-494. Remarkably, the expression of PAK1 is inversely correlated with the level of miR-494 in human breast cancer samples. Furthermore, re-expression of PAK1 partially reverses miR-494-mediated proliferative and clonogenic inhibition as well as migration and invasion suppression in breast cancer cells. Taken together, these findings highlight an important role for miR-494 in the regulation of progression and metastatic potential of breast cancer and suggest a potential application of miR-494 in breast cancer treatment.
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