The SCN5A gene encodes the alpha subunit of the main cardiac sodium channel Nav1.5. This channel predominates inward sodium current (INa) and plays a critical role in regulation of cardiac electrophysiological function. Since 1995, SCN5A variants have been found to be causatively associated with Brugada syndrome, long QT syndrome, cardiac conduction system dysfunction, dilated cardiomyopathy, etc. Previous genetic, electrophysiological, and molecular studies have identified the arrhythmic and cardiac structural characteristics induced by SCN5A variants. However, due to the variation of disease manifestations and genetic background, impact of environmental factors, as well as the presence of mixed phenotypes, the detailed and individualized physiological mechanisms in various SCN5A-related syndromes are not fully elucidated. This review summarizes the current knowledge of SCN5A genetic variations in different SCN5A-related cardiac disorders and the newly developed therapy strategies potentially useful to prevent and treat these disorders in clinical setting.

Alpha-lipoic acid (α-LA), a well-known antioxidant, was proved to active ALDH2 in nitrate tolerance and diabetic animal model. However, the therapeutic advantage of α-LA for heart failure and related signaling pathway have not been explored. This study was designed to examine the role of α-LA–ALDH2 in heart failure injury and mitochondrial damage. ALDH2 knockout (ALDH2−/−) mice and primary neonatal rat cardiomyocytes (NRCMs) were subjected to assessment of myocardial function and mitochondrial autophagy. Our data demonstrated α-LA significantly reduced the degree of TAC-induced LV hypertrophy and dysfunction in wild-type mice, not in ALDH2−/− mice. In molecular level, α-LA significantly restored ALDH2 activity and expression as well as increased the expression of a novel mitophagy receptor protein FUNDC1 in wild-type TAC mice. Besides, we confirmed that ALDH2 which was activated by α-LA governed the activation of Nrf1–FUNDC1 cascade. Our data suggest that α-LA played a positive role in protecting the heart against adverse effects of chronic pressure overload.

Background Kidney Renal Clear Cell Carcinoma (KIRC) accounts for 75% of all renal cancers. Previous study had conflict evidences regarding NR1B2 role in cancer, and its expression and biological role in KIRC remained unclear. Our aims were to characterize the role of NR1B2 in KIRC. Methods NR1B2 expression in TCGA database were analyzed. Clinical KIRC samples were examined by RT-PCR, western blot and tissue microarray (TMA). The relationship between NR1B2 expression and the clinical characteristics were evaluated. KIRC cell line were stably overexpressed NR1B2 or with an NR1B2 knocked down using lentivirus system. The cells were analyzed by migration and invasion assay, then injected into nude mice to assess tumor growth and metastasis. EMT marker expression and LATS 1/2-YAP pathway demonstration were detected by the TCGA database and western blot. Results The expression of NR1B2 in KIRC was significantly down-regulated in the TCGA database and our clinical samples. Moreover, NR1B2 expression negatively correlated with tumor stage and positively correlated with overall and disease-free survival rate. Univariate and multivariate analyses indicated the expression level of NR1B2 could be used as an independent factor for predicting the prognosis of KIRC. Overexpression NR1B2 significantly inhibited and knockdown NR1B2 markedly promoted KIRC cell invasion and metastasis both in vitro and in vivo. Mechanistic investigations revealed that NR1B2 might be a tumor suppressor to inhibit EMT through the LATS1/2-YAP pathway. Conclusions our results defined NR1B2 as a tumor suppressor in KIRC that restricted EMT by the LATS1/2-YAP pathway. Electronic supplementary material The online version of this article (10.1186/s13046-019-1344-3) contains supplementary material, which is available to authorized users.

Background: Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent malignancies in the world, and tumor metastasis is still the main reason for disease progression. Accumulating evidence shows that SH3BGRL2 may play a key role in tumor progression and metastasis. However, the role of SH3BGRL2 in ccRCC has not been systematically investigated and remains elusive. Methods: The clinical significance of SH3BGRL2 was evaluated by bioinformatic analysis and tissue microarray (TMA) samples. SH3BGRL2 expression was determined by RT-PCR, western blot and immunohistochemistry staining. Tumor suppressive effect of SH3BGRL2 was determined by both in vitro and in vivo studies. Western blot, chromatin immunoprecipitation assay and luciferase report assay were applied for mechanism dissection. Findings: SH3BGRL2 was crucial for epithelial-mesenchymal transition (EMT) progression and metastasis in ccRCC. Clinically, SH3BGRL2 was identified as an independent prognostic factor for ccRCC patients. Gain-and loss-of-function results suggested that SH3BGRL2 played a critical role in cell proliferation, migration and invasion. Mechanistically, we found that SH3BGRL2 acted as a tumor suppressor through Hippo/TEAD1 signaling, then TEAD1 altered Twist1 expression at the transcriptional level via directly binding to its promoter region. Interpretation: Our findings established that SH3BGRL2 performed as a tumor suppressor and modulator via Hippo/TEAD1-Twist1 signaling in ccRCC, and the alteration of SH3BGRL2 could serve as a functional response biomarker of tumor progression and metastasis in ccRCC.

The roles of M2 macrophages on promoting tumor progression and chemotherapy resistance have been well studied in many cancers, such as pancreatic cancer, kidney cancer and so on, but its linkage to HCC cells still remains unclear. Here we found that M2 macrophages could alter miR-149-5p to increase MMP9 expression in HCC cells and mechanism dissection revealed that miR-149-5p might directly target the 3'UTR of MMP9-mRNA to suppress its translation. The in vivo orthotopic xenografts mouse model with oemiR-149-5p also validated in vitro data. Together, these findings suggest that M2 macrophages may through altering the miR-149-5p to promote HCC progression and targeting the M2 macrophages/ miR149-5P/MMP9 signaling may help in the development of the novel therapies to better suppress the HCC progression.

Background There is growing recognition of the association of CP/CPPS accompany with ED. However, the specific mechanism of action remains unclear. The aim of this study was to investigate structural and functional abnormalities of cavernous endothelial cells in EAP rat, which may result in the ED. Methods we use rat prostate protein extract supplemented with immunoadjuvant to induce EAP rat, ICP and MAP were measured and inflammatory factor infiltration, Akt, eNOS, AR, nNOS and iNOS in the corpus cavernosum were tested. Subsequently, the normal rat and EAP rat cavernosum endothelial cells were purified by MACS, and the metabolism, oxidative stress, MMP, Akt, eNOS, AR and iNOS were evaluated. Results The EAP rat model was successfully constructed. The ratio of max ICP/MAP in EAP rat was significantly lower and TNF-α infiltration in corpus cavernosum was significantly higher than normal rats. Besides, Akt, eNOS and AR were decreased, iNOS was significantly increased. The growth and metabolism of endothelial cells in the EAP rats corpus cavernosum decreased and inflammatory factor mRNA was increased and intracellular oxidative stress was also increased significantly. The MMP of EAP rats cavernosum endothelial cells decreased and the expression of Akt, eNOS and AR were also significantly decreased, iNOS was significantly increased. Conclusion The prostate suffer local inflammatory infiltrate and promotes cytokines infiltrated into corpus cavernosum caused the oxidative stress increases and the metabolism or MMP decreases. In addition, AR, Akt and eNOS expression and phosphorylation are also reduced, thereby inhibiting the diastolic function of the corpus cavernosum, resulting in decreased erectile function.

The ER tethers tightly to mitochondria and the mitochondrial protein FUNDC1 recruits Drp1 to ER-mitochondria contact sites, subsequently facilitating mitochondrial fission and preventing mitochondria from undergoing hypoxic stress. However, the mechanisms by which the ER modulates hypoxia-induced mitochondrial fission are poorly understood. Here, we show that USP19, an ER-resident deubiquitinase, accumulates at ER-mitochondria contact sites under hypoxia and promotes hypoxia-induced mitochondrial division. In response to hypoxia, USP19 binds to and deubiquitinates FUNDC1 at ER-mitochondria contact sites, which facilitates Drp1 oligomerization and Drp1 GTP-binding and hydrolysis activities, thereby promoting mitochondrial division. Our findings reveal a unique hypoxia response pathway mediated by an ER protein that regulates mitochondrial dynamics.

Purpose: Increased attention has been focused on the survival of renal cell carcinoma (RCC) patients with bone metastasis. This study proposed to establish and evaluate a nomogram for predicting the overall survival (OS) and cancer-specific survival (CSS) of RCC patients with bone metastasis. Materials and Methods: RCC patients with bone metastasis between 2010 and 2015 were captured from the surveillance, epidemiology and end results (SEER) database. Univariate and multivariate cox regressions were performed to assess the effects of clinical variables on OS and CSS. The nomogram based on the Cox hazards regression model was developed. Concordance index (C-index) and calibration curve were performed to evaluate the accuracy of nomogram models, receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were conducted to assess the predict performance. Results: A total of 2.471 eligible patients were enrolled in this study. The patients were assigned to primary (n=1.672) and validation (n=799) cohorts randomly. The 1-, 2-, and 3-year OS and CSS nomogram models were constructed based on age at diagnosis, sex, marital status, pathological grade, T-stage, N-stage, brain/liver/lung metastasis, surgery, radiotherapy and chemotherapy. The c for OS and CSS prediction was 0.730 (95% confidence interval [CI]: 0.719-0.741) and 0.714 (95%CI:0.702-0.726). The calibration curves showed significant agreement between nomogram models and actual observations. ROC and DCA indicated nomograms had better predict performance. Conclusions: The nomograms for predicting prognosis provided an accurate prediction of OS and CSS in RCC patients with bone metastasis, and contributed clinicians to optimize individualized treatment plans.