Emerging evidence suggests that epithelial‐mesenchymal transitions (EMTs) play important roles in tumor metastasis and recurrence. Understanding molecular mechanisms that regulate the EMT process is ...crucial for improving treatment of hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) play important roles in HCC; however, the mechanisms by which miRNAs target the EMT and their therapeutic potential remains largely unknown. To better explore the roles of miRNAs in the EMT process, we established an EMT model in HCC cells by transforming growth factor beta 1 treatment and found that several tumor‐related miRNAs were significantly decreased. Among these miRNAs, miR‐125b expression was most strongly suppressed. We also found down‐regulation of miR‐125b in most HCC cells and clinical specimens, which correlated with cellular differentiation in HCC patients. We then demonstrated that miR‐125b overexpression attenuated EMT phenotype in HCC cancer cells, whereas knockdown of miR‐125b promoted the EMT phenotype in vitro and in vivo. Moreover, we found that miR‐125b attenuated EMT‐associated traits, including chemoresistance, migration, and stemness in HCC cells, and negatively correlated with EMT and cancer stem cell (CSC) marker expressions in HCC specimens. miR‐125b overexpression could inhibit CSC generation and decrease tumor incidence in the mouse xenograft model. Mechanistically, our data revealed that miR‐125b suppressed EMT and EMT‐associated traits of HCC cells by targeting small mothers against decapentaplegic (SMAD)2 and 4. Most important, the therapeutic delivery of synthetic miR‐125b mimics decreased the target molecule of CSC and inhibited metastasis in the mice model. These findings suggest a potential therapeutic treatment of miR‐125b for liver cancer. Conclusion: miR‐125b exerts inhibitory effects on EMT and EMT‐associated traits in HCC by SMAD2 and 4. Ectopic expression of miR‐125b provides a promising strategy to treat HCC. (Hepatology 2015;62:801–815)
Traditional Chinese medicinal herbs Cortex Moutan and Radix Salviae Milthiorrhizaeare are prescribed together for their putative cardioprotective effects in clinical practice. However, the rationale ...of the combined use remains unclear. The present study was designed to investigate the cardioprotective effects of paeonol and danshensu (representative active ingredient of Cortex Moutan and Radix Salviae Milthiorrhizae, respectively) on isoproterenol-induced myocardial infarction in rats and its underlying mechanisms.
Paeonol (80 mg kg(-1)) and danshensu (160 mg kg(-1)) were administered orally to Sprague Dawley rats in individual or in combination for 21 days. At the end of this period, rats were administered isoproterenol (85 mg kg(-1)) subcutaneously to induce myocardial injury. After induction, rats were anaesthetized with pentobarbital sodium (35 mg kg(-1)) to record electrocardiogram, then sacrificed and biochemical assays of the heart tissues were performed.
Induction of rats with isoproterenol resulted in a marked (P<0.001) elevation in ST-segment, infarct size, level of serum marker enzymes (CK-MB, LDH, AST and ALT), cTnI, TBARS, protein expression of Bax and Caspase-3 and a significant decrease in the activities of endogenous antioxidants (SOD, CAT, GPx, GR, and GST) and protein expression of Bcl-2. Pretreatment with paeonol and danshensu combination showed a significant (P<0.001) decrease in ST-segment elevation, infarct size, cTnI, TBARS, protein expression of Bax and Caspase-3 and a significant increase in the activities of endogenous antioxidants and protein expression of Bcl-2 and Nrf2 when compared with individual treated groups.
This study demonstrates the cardioprotective effect of paeonol and danshensu combination on isoproterenol-induced myocardial infarction in rats. The mechanism might be associated with the enhancement of antioxidant defense system through activating of Nrf2 signaling and anti-apoptosis through regulating Bax, Bcl-2 and Caspase-3. It could provide experimental evidence to support the rationality of combinatorial use of traditional Chinese medicine in clinical practice.
Abstract
This study aims to determine whether miR-1271-5p inhibits cell proliferation and enhances the radiosensitivity by targeting cyclin-dependent kinase 1 (CDK1) in hepatocellular carcinoma ...(HCC). Its expression levels in the HCC cell lines were significantly lower than those in normal human liver cell line. Bioinformatics analysis indicated CDK1 was a potential target of miR-1271-5p. Dual-Luciferase Reporter Assay confirmed that CDK1 is a direct target gene of miR-1271-5p. With overexpression of miR-1271-5p in SMMC-7721 and HuH-7 cells, cell proliferation was decreased, radiosensitivity was enhanced, cell cycle distribution was altered and the growth of transplanted tumours in nude mice was significantly reduced. miR-1271-5p overexpression enhanced radiosensitivity, which could be reduced by CDK1 overexpression. Overall, our findings suggested that miR-1271-5p inhibits cell proliferation and enhances the radiosensitivity of HCC cell lines by targeting CDK1.
Systemic lupus erythematosus (SLE) is an autoimmune disease in which the immune system attacks its own tissues and organs. However, the causes of SLE remain unknown. Dyslipidemia is a common symptom ...observed in SLE patients and animal models and is closely correlated to disease activity. Lipid metabolic reprogramming has been considered as a hallmark of the dysfunction of T cells in patients with SLE, therefore, manipulating lipid metabolism provides a potential therapeutic target for treating SLE. A better understanding of the underlying mechanisms for the metabolic events of immune cells under pathological conditions is crucial for tuning immunometabolism to manage autoimmune diseases such as SLE. In this review, we aim to summarize the cross-link between lipid metabolism and the function of T cells as well as the underlying mechanisms, and provide light on the novel therapeutic strategies of active compounds from herbals for the treatment of SLE by targeting lipid metabolism in immune cells.
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•Dyslipidemia is a common symptom observed in SLE patients, which is also a hallmark of the dysfunction of T cells.•Increased lipid rafts, associated glycosphingolipids, and adipokines affect various T cell functions in SLE patients.•Recovering defective lipid signaling pathways (CTLA4\ BTLA\ACC1) or transcription factors (FLI1\ LXRβ\PPARs) attenuates SLE.•Active compounds from herb medicine have the potential to treat SLE by reprogramming the metabolism of lupus T cells.
Skeletal muscle differentiation is controlled by multiple cell signaling pathways, however, the JNK/MAPK signaling pathway dominating this process has not been fully elucidated. Here, we report that ...the JNK/MAPK pathway was significantly downregulated in the late stages of myogenesis, and in contrast to P38/MAPK pathway, it negatively regulated skeletal muscle differentiation. Based on the PAR-CLIP-seq analysis, we identified six elevated miRNAs (miR-1a-3p, miR-133a-3p, miR-133b-3p, miR-206-3p, miR-128-3p, miR-351-5p), namely myogenesis-associated miRNAs (mamiRs), negatively controlled the JNK/MAPK pathway by repressing multiple factors for the phosphorylation of the JNK/MAPK pathway, including MEKK1, MEKK2, MKK7, and c-Jun but not JNK protein itself, and as a result, expression of transcriptional factor MyoD and mamiRs were further promoted. Our study revealed a novel double-negative feedback regulatory pattern of cell-specific miRNAs by targeting phosphorylation kinase signaling cascade responsible for skeletal muscle development.
Introduction： In the past several decades, declining incidences of nasopharyngeal carcinoma （NPC） have been observed in Chinese populations in Hong Kong, Taiwan, Los Angeles, and Singapore. A ...previous study indicated that the incidence of NPC in Sihui County, South China remained stable until 2002, but whether age, diagnosis period, and birth cohort affect the incidence of NPC remains unknown. Methods： Age-standardized rates （ASRs） of NPC incidence based on the world standard population were examined in both males and females in Sihui County from 1987 to 2011. Joinpoint regression analysis was conducted to quantify the changes in incidence trends. A Poisson regression age-period-cohort model was used to assess the effects of age, diagnosis period, and birth cohort on the risk of NPC. Results： The ASRs of NPC incidence during the study period were 30.29/100,000 for males and 13.09/100,000 for females. The incidence of NPC remained stable at a non-significant average annual percent change of 0.2% for males and -1.6% for females throughout the entire period, A significantly increased estimated annual percent change of 6.8% （95% confidence interval, 0.1%-14.0%） was observed from 2003 to 2009 for males. The relative risk of NPC increased with advancing age up to 50-59 and decreased at ages 〉60 years. The period effect curves on NPC were nearly fiat for males and females. The birth cohort effect curve for males showed an increase from the 1922 cohort to the 1957 cohort and a decrease thereafter. In females, there was an undulating increase in the relative risk from the 1922 cohort to the 1972 cohort. Conclusions： The incidence trends for NPC remained generally stable in Sihui from 1987 to 2011, with an increase from 2003 to 2009. The relative risks of NPC increased in younger females.
Cardiac MRI feature-tracking (FT) with breath-holding (BH) cine balanced steady state free precession (bSSFP) imaging is well established. It is unclear whether FT-strain measurements can be reliably ...derived from free-breathing (FB) compressed sensing (CS) bSSFP imaging.
To compare left ventricular (LV) strain analysis and image quality of an FB CS bSSFP cine sequence with that of a conventional BH bSSFP sequence in children.
Prospective.
40 children able to perform BHs (cohort 1 12.1 ± 2.2 years) and 17 children unable to perform BHs (cohort 2 5.2 ± 1.8 years).
3T, bSSFP sequence with and without CS.
Acquisition times and image quality were assessed. LV myocardial deformation parameters were compared between BH cine and FB CS cine studies in cohort 1. Strain indices and image quality of FB CS cine studies were also assessed in cohort 2. Intraobserver and interobserver variability of strain parameters was determined.
Paired t-test, Wilcoxon signed-rank test, intraclass correlation coefficient (ICC), and Bland-Altman analysis. A P-value <0.05 was considered statistically significant.
In cohort 1, the mean acquisition time of the FB CS cine study was significantly lower than for conventional BH cine study (15.6 s vs. 209.4 s). No significant difference were found in global circumferential strain rate (P = 0.089), global longitudinal strain rate (P = 0.366) and EuroCMR image quality scores (P = 0.128) between BH and FB sequences in cohort 1. The overall image quality score of FB CS cine in cohort 2 was 3.5 ± 0.5 with acquisition time of 14.7 ± 2.1 s. Interobserver and intraobserver variabilities were good to excellent (ICC = 0.810 to 0.943).
FB CS cine imaging may be a promising alternative technique for strain assessment in pediatric patients with poor BH ability.
1 TECHNICAL EFFICACY: Stage 1.
Enantioselective hydroarylation of unactivated terminal akenes constitutes a prominent challenge in organic chemistry. Herein, we reported a Cp*Co(III)-catalyzed asymmetric hydroarylation of ...unactivated aliphatic terminal alkenes assisted by a new type of tailor-made amino acid ligands. Critical to the chiral induction was the engaging of a novel noncovalent interaction (NCI), which has seldomly been disclosed in the C–H activation area, arising from the molecular recognition among the organocobalt(III) intermediate, the coordinated alkene, and the well-designed chiral ligand. A broad range of C2-alkylated indoles were obtained in high yields and excellent enantioselectivities. DFT calculations revealed the reaction mechanism and elucidated the origins of chiral induction in the stereodetermining alkene insertion step.
Early detection of subclinical myocardial dysfunction in patients with diabetes mellitus (DM) is essential for recommending therapeutic interventions that can prevent or reverse heart failure, ...thereby improving the prognosis in such patients. This study aims to quantitatively evaluate left ventricular (LV) myocardial deformation and perfusion using cardiovascular magnetic resonance (CMR) imaging in patients with type 2 diabetes mellitus (T2DM), and to investigate the association between LV subclinical myocardial dysfunction and coronary microvascular perfusion.
We recruited 71 T2DM patients and 30 healthy individuals as controls who underwent CMR examination. The T2DM patients were subdivided into two groups, namely the newly diagnosed DM group (n = 31, patients with diabetes for ≤ 5 years) and longer-term DM group (n = 40, patients with diabetes > 5 years). LV deformation parameters, including global peak strain (PS), peak systolic strain rate, and peak diastolic strain rate (PSDR), and myocardial perfusion parameters such as upslope, time to maximum signal intensity (TTM), and max signal intensity (Max SI, were measured and compared among the three groups. Pearson's correlation was used to evaluate the correlation between LV deformation and perfusion parameters.
Pooled data from T2DM patients showed a decrease in global longitudinal, circumferential, and radial PDSR compared to healthy individuals, apart from lower upslope. In addition, increased TTM and reduced Max SI were found in the longer-term diabetics compared to the normal subjects (p < 0.017 for all). Multivariable linear regression analysis showed that T2DM was independently associated with statistically significant CMR parameters, except for TTM (β = 0.137, p = 0.195). Further, longitudinal PDSR was significantly associated with upslope (r = - 0.346, p = 0.003) and TTM (r = 0.515, p < 0.001).
Our results imply that a contrast-enhanced 3.0T CMR can detect subclinical myocardial dysfunction and impaired myocardial microvascular perfusion in the early stages of T2DM, and that the myocardial dysfunction is associated with impaired coronary microvascular perfusion.
Myocardial fibrosis is being increasingly recognised as a common final pathway of a wide range of diseases. Thus, the development of an accurate and convenient method to evaluate myocardial fibrosis ...is of major importance. Although T1 mapping is a potential alternative for myocardial biopsy, validation studies are limited to small numbers and vary regarding technical facets, and include only a restricted number of disease. A systematic review and meta-analysis was conducted to objectively and comprehensively evaluate the performance of T1 mapping on the quantification of myocardial fibrosis using cardiovascular magnetic resonance (CMR).
PubMed, EMBASE and the Cochrane Library databases were searched for studies applying T1 mapping to measure myocardial fibrosis and that validated the results via histological analysis. A pooled correlation coefficient between the CMR and histology measurements was used to evaluate the performance of the T1 mapping.
A total of 15 studies, including 308 patients who had CMR and myocardial biopsy were included and the pooled correlation coefficient between ECV measured by T1 mapping and biopsy for the selected studies was 0.884 (95% CI: 0.854, 0.914) and was not notably heterogeneous chi-squared = 7.44; P = 0.489 for the Q test and I^2 = 0.00%).
The quantitative measurement of myocardial fibrosis via T1 mapping is associated with a favourable overall correlation with the myocardial biopsy measurements. Further studies are required to determine the calibration of the T1 mapping results for the biopsy findings of different cardiomyopathies.
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