Muscle-targeted nanoparticles strengthen the effects of small-molecule inhibitors in ameliorating sarcopenia.

Background: Sarcopenia is an aging-related degeneration of muscle mass and strength. Small-molecule inhibitor SW033291 has been shown to attenuate muscle atrophy. Targeted nanodrug-delivery systems can improve the efficacy of small-molecule inhibitors. Methods: The skeletal muscle cell-targeted nanoparticle was called AP@SW033291, which consisted of SW033291, modular peptide ASSLNIAGGRRRRRG and PEG-DSPE. Nanoparticles were featured with particle size, fluorescence emission spectra and targeting ability. We also investigated their effects on muscle mass and function. Results: The size of AP@SW033291 was 125.7 nm and it demonstrated targeting effects on skeletal muscle; thus, it could improve muscle mass and muscle function. Conclusion: Nanoparticle AP@SW033291 could become a potential strategy to strengthen the treatment effects of small-molecule inhibitors in sarcopenia.

Cross Domain Correlation Maximization for Enhancing the Target Recognition of SSVEP-Based Brain-Computer Interfaces.

The target recognition performance of steady-state visual evoked potential (SSVEP)-based brain-computer interfaces can be significantly improved with a training-based approach. However, the training procedure is time consuming and often causes fatigue. Consequently, the number of training data should be limited, which may reduce the classification performance. Thus, how to improve classification accuracy without increasing the training time is crucial to SSVEP-based BCI system. This study proposes a transfer-related component analysis (TransRCA) method for addressing the above issue. In this method, the SSVEP-related components are extracted from a small number of training data of the current individual and combined with those extracted from a large number of existing training data of other individuals. The TransRCA method maximizes not only the inter-trial covariances between the source and target subjects, but also the correlation between the reference signals and SSVEP signals from the source and target subjects. The proposed method was validated on the SSVEP public Benchmark and BETA datasets, and the classification accuracy and information transmission rate of the ensemble version of the proposed TransRCA method were compared with those of the state-of-the-art eCCA, eTRCA, ttCCA, LSTeTRCA, and eIISMC methods on both datasets. The comparison results indicate that the proposed method provides a superior performance compared with these state-of-the-art methods, and thus has high potential for the development of a SSVEP-based brain-computer interface system with high classification performance that only uses a small number of training data.

Involvement of adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 in diallyl trisulfide-induced cytotoxicity in hepatocellular carcinoma cells.

It has been demonstrated that APPL1 (adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1) is involved in the regulation of several growth-related signaling pathways and thus closely associated with the development and progression of some cancers. Diallyl trisulfide (DAT), a garlic-derived bioactive compound, exerts selective cytotoxicity to various human cancer cells through interfering with pro-survival signaling pathways. However, whether and how DAT affects survival of human hepatocellular carcinoma (HCC) cells remain unclear. Herein, we tested the hypothesis of the involvement of APPL1 in DAT-induced cytotoxicity in HCC HepG2 cells. We found that Lys 63 (K63)-linked polyubiquitination of APPL1 was significantly decreased whereas phosphorylation of APPL1 at serine residues remained unchanged in DAT-treated HepG2 cells. Compared with wild-type APPL1, overexpression of APPL1 K63R mutant dramatically increased cell apoptosis and mitigated cell survival, along with a reduction of phosphorylation of STAT3, Akt, and Erk1/2. In addition, DAT administration markedly reduced protein levels of intracellular TNF receptor-associated factor 6 (TRAF6). Genetic inhibition of TRAF6 decreased K63-linked polyubiquitination of APPL1. Moreover, the cytotoxicity impacts of DAT on HepG2 cells were greatly attenuated by overexpression of wild-type APPL1. Taken together, these results suggest that APPL1 polyubiquitination probably mediates the inhibitory effects of DAT on survival of HepG2 cells by modulating STAT3, Akt, and Erk1/2 pathways.

Heat Shock Protein 70 Mediates the Protective Effect of Naringenin on High-Glucose-Induced Alterations of Endothelial Function.

Endothelial dysfunction plays a pivotal role in the development and progression of diabetic vascular complications. Naringenin (Nar) is a flavanone bioactive isolated from citrus fruits known to have in vitro and in vivo antidiabetic properties. However, whether Nar affects endothelial function remains unclear in diabetes or under high-glucose (HG) condition. Using an in vitro model of hyperglycemia in human umbilical vein endothelial cells (HUVECs), we found that Nar administration markedly attenuated HG-induced alterations of endothelial function, evidenced by the mitigation of oxidative stress and inflammation, the reduction of cell adhesion molecular expressions, and the improvement of insulin resistance. We also found that HG exposure significantly reduced the levels of intracellular heat shock protein 70 (iHSP70 or iHSPA1A) and the release of HSP70 from HUVECs. HSP70 depletion mimicked and clearly diminished the protective effects of Nar on HG-induced alterations of endothelial function. In addition, Nar treatment significantly enhanced iHSP70 protein levels through a transcription-dependent manner. These results demonstrated that Nar could protect HUVECs against HG-induced alterations of endothelial function through upregulating iHSP70 protein levels. These findings are also helpful in providing new therapeutic strategies that are promising in the clinical use of Nar for the treatment of diabetes and diabetic complications.

A Novel lncRNA Panel Related to Ferroptosis, Tumor Progression, and Microenvironment is a Robust Prognostic Indicator for Glioma Patients.

Objective: To establish a lncRNA panel related to ferroptosis, tumor progression, and microenvironment for prognostic estimation in patients with glioma. Methods: LncRNAs associated with tumor progression and microenvironment were screened via the weighted gene co-expression network analysis (WGCNA). Overlapped lncRNAs highlighted in WGCNA, related to ferroptosis, and incorporated in Chinese Glioma Genome Atlas (CGGA) were identified as hub lncRNAs. With expression profiles of the hub lncRNA, we conducted the least absolute shrinkage and selection operator (LASSO) regression and built a ferroptosis-related lncRNA signature to separate glioma patients with distinct survival outcomes. The lncRNA signature was validated in TCGA, the CGGA_693, and CGGA_325 cohorts using Kaplan-Meier survival analysis and ROC curves. The ferroptosis-related lncRNA panel was validated with 15 glioma samples using quantitative real-time PCR (qRT-PCR). Multivariate Cox regression was performed, and a nomogram was mapped and validated. Immune infiltration correlated to the signature was explored using TIMER and CIBERSORT algorithms. Results: The present study identified 30 hub lncRNAs related to ferroptosis, tumor progression, and microenvironment. With the 30 hub lncRNAs, we developed a lncRNA signature with distinct stratification of survival chance in patients with glioma in two independent cohorts (HRs>1, p < 0.05). The lncRNA signature revealed a panel of 14 lncRNAs, i.e., APCDD1L-AS1, H19, LINC00205, LINC00346, LINC00475, LINC00484, LINC00601, LINC00664, LINC00886, LUCAT1, MIR155HG, NEAT1, PVT1, and SNHG18. These lncRNA expressions were validated in clinical specimens using qRT-PCR. Robust predictive accuracies of the signature were present across different datasets at multiple timepoints. With univariate and multivariate regressions, we demonstrated that the risk score based on the lncRNA signature is an independent prognostic indicator after clinical factors were adjusted. A nomogram was constructed with these prognostic factors, and it has demonstrated decent classification and accuracy. Additionally, the signature-based classification was observed to be correlated with multiple clinical characteristics and molecular subtypes. Further, extensive immune cells were upregulated in the high-risk group, such as CD8+ T cell, neutrophil, macrophage, and myeloid dendritic cell, indicating increased immune infiltrations. Conclusion: We established a novel ferroptosis-related lncRNA signature that could effectively stratify the prognosis of glioma patients with adequate predictive performance.

Integrated Analysis Reveals Prognostic Value and Immune Correlates of CD86 Expression in Lower Grade Glioma.

BACKGROUND: CD86 has great potential to be a new target of immunotherapy by regulating cancer immune response. However, it remains unclear whether CD86 is a friend or foe in lower-grade glioma (LGG). METHODS: The prognostic value of CD86 expression in pan-cancer was analyzed using Cox regression and Kaplan-Meier analysis with data from the cancer genome atlas (TCGA). Cancer types where CD86 showed prognostic value in overall survival and disease-specific survival were identified for further analyses. The Chinese Glioma Genome Atlas (CGGA) dataset were utilized for external validation. Quantitative real-time PCR (qRT-PCR), Western blot (WB), and Immunohistochemistry (IHC) were conducted for further validation using surgical samples from Jiangsu Province hospital. The correlations between CD86 expression and tumor immunity were analyzed using the Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm, Tumor IMmune Estimation Resource (TIMER) database, and expressions of immune checkpoint molecules. Gene Set Enrichment Analysis (GSEA) was performed using clusterprofiler r package to reveal potential pathways. RESULTS: Pan-cancer survival analysis established CD86 expression as an unfavorable prognostic factor in tumor progression and survival for LGG. CD86 expression between Grade-II and Grade-III LGG was validated using qRT-PCR and WB. Additionally, CD86 expression in LGG with unmethylated O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter was significantly higher than those with methylated MGMT (P<0.05), while in LGG with codeletion of 1p/19q it was significantly downregulated as opposed to those with non-codeletion (P<2.2*10-16). IHC staining validated that CD86 expression was correlated with MGMT status and X1p/19q subtypes, which was independent of tumor grade. Multivariate regression validated that CD86 expression acts as an unfavorable prognostic factor independent of clinicopathological factors in overall survival of LGG patients. Analysis of tumor immunity and GSEA revealed pivotal role of CD86 in immune response for LGG. CONCLUSIONS: Integrated analysis shows that CD86 is an unfavorable prognostic biomarker in LGG patients. Targeting CD86 may become a novel approach for immunotherapy of LGG.

Effects of core stability exercise for patients with neck pain: A protocol for systematic review and meta-analysis.

BACKGROUND: Neck pain is an important cause of disability. In spite of its high prevalence rate, treatment of the disorder is a challenging topic. Exercise therapy appears to be effective at decreasing pain and improving function for patients with NP in practice guidelines. Core stability exercise is becoming increasingly popular for NP. However, it is currently unknown whether core stability exercise produces more beneficial effects than general exercise in patients with NP. The aim of this study is to explore the therapeutic effect of core stability exercise for neck pain. METHODS: This review will only include randomized controlled trials (RCTs). Published articles from July 2009 to July 2019 will be identified using electronic searches. Search strategy will be performed in 3 English databases, 1 Chinese database, and the WHO International Clinical Trials Registry Platform. Two reviewers will screen, select studies, extract data, and assess quality independently. The methodological quality including the risk of bias of the included studies will be evaluated using a modified assessment form, which is based on Cochrane assessment tool and Physiotherapy Evidence Database scale. Review Manager Software (Revman5.3) will be used for heterogeneity assessment, generating funnel-plots, data synthesis, subgroup analysis, and sensitivity analysis. We will use GRADE system to evaluate the quality of our evidence. RESULTS: We will provide some more practical and targeted results investigating the effect of Core Stability Exercise (CSE) for Neck Pain (NP) in the current meta-analysis. Meanwhile, we will ascertain study progress of Core Stability Exercise for Neck Pain and find out defects or inadequacies of previous studies, so that future researchers could get beneficial guidance for more rigorous study. CONCLUSION: The stronger evidence about Neck Pain's rehabilitative effect and safety will be provided for clinicians and policymakers. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017055711. ETHICS AND DISSEMINATION: We do not apply for formal ethical approval from ethics committee because all of the study data in our review will be obtained in an anonymous way. Findings of this study are projected to be disseminated through peer-review publications.

[Clinical efficacy of electroacupuncture combined with motor imagery therapy on hemiplegic cerebral infarction].

OBJECTIVE: To explore the effects of electroacupuncture (EA) combined with motor imagery therapy on motor function and activity of daily living in patients with hemiplegic cerebral infarction. METHODS: Ninety patients with hemiplegic cerebral infarction were randomly divided into a rehabilitation group, an EA group and a comprehensive group, 30 patients in each one. The patients in the rehabilitation group were treated with regular care, medication and rehabilitation training; based on the rehabilitation group, the patients in the EA group were treated mainly with electroacupuncture at Baihui (GV 20), Dingnieqianxiexian (MS 6), Dingniehouxiexian (MS 7), Jianyu (LI 15), Waiguan (TE 5), Fengshi (GB 31) and Sanyinjiao (SP 6); with the arrival of qi. EA device was connected for 30 min. The patients in the comprehensive group were treated with EA as the EA group and motor imagery therapy, 20 min per treatment. The treatment was given once a day, five treatments per week, and totally 4-week treatment was performed. The Barthel index and Brunnstrom score before and after treatment were observed in the three groups. RESULTS: Three cases did not finish the trial and finally 87 cases were included into analysis, including 30 cases in the rehabilitation group, 29 cases in the EA group and 28 cases in the comprehensive group. Compared before treatment, the Barthel index and Brunnstrom score were significantly improved after treatment in the three groups (all P<0.01); after treatment, the Barthel index in the EA group and comprehensive group was significantly higher than that in the rehabilitation group (both P<0.01); the lower extremity score of Brunnstrom score in the comprehensive group was better than those in the EA group and rehabilitation group (both P<0.05). CONCLUSION: EA combined with motor imagery therapy and rehabilitation can significantly improve the motor function and activity of daily living in patients with hemiplegic cerebral infarction, which is superior to rehabilitation alone or EA alone.