Xinyang tablet alleviated cardiac dysfunction in a cardiac pressure overload model by regulating the receptor-interacting serum/three-protein kinase 3/FUN14 domain containing 1-mediated mitochondrial unfolded protein response and mitophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Xinyang tablet (XYT) has been used for heart failure (HF) for over twenty years in clinical practice, but the underlying molecular mechanism remains poorly understood. AIMS OF THE STUDY: In the present study, we aimed to explore the protective effects of XYT in HF in vivo and in vitro. MATERIALS AND METHODS: Transverse aortic constriction was performed in vivo to establish a mouse model of cardiac pressure overload. Echocardiography, tissue staining, and real-time quantitative PCR (qPCR) were examined to evaluate the protective effects of XYT on cardiac function and structure. Adenosine 5'-triphosphate production, reactive oxygen species staining, and measurement of malondialdehyde and superoxide dismutase was used to detect mitochondrial damage. Mitochondrial ultrastructure was observed by transmission electron microscope. Immunofluorescence staining, qPCR, and Western blotting were performed to evaluate the effect of XYT on the mitochondrial unfolded protein response and mitophagy, and to identify its potential pharmacological mechanism. In vitro, HL-1 cells and neonatal mouse cardiomyocytes were stimulated with Angiotensin II to establish the cell model. Western blotting, qPCR, immunofluorescence staining, and flow cytometry were utilized to determine the effects of XYT on cardiomyocytes. HL-1 cells overexpressing receptor-interacting serum/three-protein kinase 3 (RIPK3) were generated by transfection of RIPK3-overexpressing lentiviral vectors. Cells were then co-treated with XYT to determine the molecular mechanisms. RESULTS: In the present study, XYT was found to exerta protective effect on cardiac function and structure in the pressure overload mice. And it was also found XYT reduced mitochondrial damage by enhancing mitochondrial unfolded protein response and restoring mitophagy. Further studies showed that XYT achieved its cardioprotective role through regulating the RIPK3/FUN14 domain containing 1 (FUNDC1) signaling. Moreover, the overexpression of RIPK3 successfully reversed the XYT-induced protective effects and significantly attenuated the positive effects on the mitochondrial unfolded protein response and mitophagy. CONCLUSIONS: Our findings indicated that XYT prevented pressure overload-induced HF through regulating the RIPK3/FUNDC1-mediated mitochondrial unfolded protein response and mitophagy. The information gained from this study provides a potential strategy for attenuating mitochondrial damage in the context of pressure overload-induced heart failure using XYT.

REC8 regulates neuroblastoma cell proliferation, migration, invasion, and angiogenesis via STAT3/VEGF signaling.

BACKGROUND: Neuroblastoma, one of the most prevalent childhood cancers, is often treated with surgery, radiation, and chemotherapy. However, prognosis and survival are still dismal for children with neuroblastoma at high risk. Consequently, it is vital to identify new and effective treatment targets. As a component of the meiotic cohesion complex, REC8 is involved in a wide range of malignancies. The current work assessed the impact of REC8 knockdown on SH-SY5Y and SK-N-AS neuroblastoma cells and delved into the molecular mechanism behind this effect. METHODS: Knockdown of REC8 using the small interfering (si) RNA technology, and the results were verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot. The Cell Counting Kit-8 (CCK-8) was used to examine cell proliferation, while flow cytometry was used to examine cell cycle progression and apoptosis. Analyses of angiogenesis included tube formation experiments. Transwell tests were used to examine cell migration and invasion. RESULTS: The data showed that downregulation of the REC8 led to a substantial decrease in cell proliferation by stopping the cell cycle in the G1 phase. REC8 knockdown significantly reduced neuroblastoma cell proliferation, migration, invasion, angiogenesis, induced cell cycle arrest, and enhanced apoptosis. We also discovered that repressing REC8 expression in neuroblastoma cell lines SH-SY5Y and SK-N-AS reduced their ability to activate the STAT3/VEGF signaling pathway. CONCLUSIONS: Neuroblastoma therapy may benefit from targeting REC8 and its downstream targets.

YY1 transcription factor induces proliferation and aerobic glycolysis of neuroblastoma cells via LDHA regulation.

The present study investigated the effect of transcription factor yin yang 1 (YY1) on aerobic glycolysis and cell proliferation in neuroblastoma and its mechanism. Neuroblastoma cell lines were used to investigate the association between YY1 and lactate dehydrogenase A (LDHA) expression. Cell Counting Kit (CCK)-8 and clone formation experiments were used to detect the cell viability. The interaction of YY1 and LDHA was detected using chromatin immunoprecipitation assay. Glucose uptake, intra/extracellular lactate and pyruvate and LDHA expression were evaluated using standard methods. Reverse transcription quantitative PCR, western blotting and gene overexpression or silencing were undertaken to explore the biological effects and underlying mechanisms of transcriptional regulators in NB cells. The results demonstrated that YY1 was significantly upregulated in neuroblastoma cell lines. The results of aerobic glycolysis and CCK-8 indicated that YY1 significantly promoted the proliferation and aerobic glycolysis of neuroblastoma cells. In addition, chromatin immunoprecipitation-PCR results demonstrated that YY1 was directly bound to the promoter LDHA. Overexpression of LDHA could reverse the inhibitory effect of sh-YY1 on aerobic glycolysis and proliferation of neuroblastoma cells. In conclusion, YY1 could induce aerobic glycolysis and proliferation of neuroblastoma cell lines, and may directly mediate the regulation of LDHA. These findings may provide novel insight for the treatment of neuroblastoma.

KDM5B promotes cell migration by regulating the noncanonical Wnt/PCP pathway in Hirschsprung's disease.

PURPOSE: We measured the expression of the histone demethylase lysine-specific demethylase 5B (KDM5B) in the bowels of patients with Hirschsprung's disease (HSCR) and investigated the molecular mechanism by which KDM5B promotes the migration of neuronal PC12 cells. METHODS: KDM5B expression was detected in the ganglionic and aganglionic colon of patients with HSCR (n = 10) and controls (n = 10). The expression and localization of KDM5B were assessed using immunohistochemical and immunofluorescence staining. Real-time PCR and Western blotting were performed to quantify KDM5B expression. The migration was determined using Transwell and wound-healing assays. G-LISA, GTPase pulldown and luciferase-based reporter gene assays were performed to evaluate the key components of Wnt/planar cell polarity (PCP) signaling in vitro. RESULTS: Our current study showed that KDM5B colocalized with neurons. KDM5B expression was reduced in HSCR specimens, while the aganglionic segments showed the greatest reduction. KDM5B knockdown inhibited the migration of PC12 cells. Moreover, inhibition of KDM5B decreased the expression of key genes in the Wnt/PCP pathway, and its inhibitory effect on PC12 cell migration was reversed by Wnt5a treatment. CONCLUSIONS: KDM5B promotes neuronal migration via the Wnt/PCP pathway. A potential role for KDM5B in altered enteric nervous system development in HSCR warrants further investigation.

The effect of pro/synbiotics on postoperative infections in colorectal cancer patients: A systematic review and meta-analysis.

In 1954, the term "probiotics" was coined by Ferdinand Vergin in his article. Although there are many clinical reports on the use of pro/synbiotics and other microbial preparations to prevent postoperative infections and related complications in patients with Colorectal cancer (CRC), their effectiveness remains divided. Therefore, we collected relevant high-quality randomized controlled trial (RCT) studies and conducted systematic review and meta-analysis. We electronically searched online databases (the PubMed, EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Allied and Alternative Medieine (AMED), China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu) for literature published until December 2020. These reports were rigorously screened, and the data extracted, assessed for risk of bias (ROB), and subjected to meta-analysis and subgroup analysis. Postoperative infections were the main criteria for outcomes. Nineteen high-quality articles were included, involving 1975 patients. Compared with the control group, the pro/synbiotics group had reduced total postoperative infections ((odds ratio)OR = 0.28, 95% (confidence interval)CI: 0.20; 0.39, p < 0.0001), which included surgical site infections (SSI) (OR = 0.43, 95% CI: 0.31; 0.58, p < 0.0001) and non-surgical site infections (non-SSI) (OR = 0.28 95% CI: 0.20; 0.39, p < 0.0001).What is more, in aspects of inflammatory factors, intestinal dysbiosis, non-infectious complications, and systemic symptoms, the treatment group was better than the control group. However, there were no differences in perineal infections (OR = 0.45, 95% CI: 0.13; 1.50, p = 0.1933), celiac infections (OR = 0.54, 95% CI: 0.11; 2.66, p = 0.4471), or systemic inflammatory response syndrome (SIRS) incidence (OR = 0.63, 95% CI: 0.31; 1.30, p = 0.2139), etc. There were no differences in intervention (probiotics or synbiotics), strain type (multistrain or non-multistrain probiotics), and intervention time (administration preoperatively or pre-and-postoperatively). Pro/synbiotics can effectively prevent postoperative infections and related complications in patients with CRC. The strain type and intervention time did not affect the treatment effects.

[Rules of acupoint selection and drug use in clinical treatment of hypertension with acupoint application therapy].

OBJECTIVE: To explore the rules of acupoint selection and drug use in treatment of hypertension with acupoint application therapy. METHODS: The articles of the clinical research of hypertension treated with acupoint application therapy were retrieved from Chinese journal full-text database (CNKI), VIP database (VIP) and Wanfang databases from the time of establishment to January 20, 2019. The database was set up with Microsoft Excel 2010. Using the cloud platform of the ancient and modern medicine record, the frequency statistical and clustering analyses were conducted. RESULTS: A total of 117 articles were collected, including 191 prescriptions, 60 aucpoints and 236 kinds of herbal drugs. It was found in the frequency statistical analysis that the top 6 acupoints in use frequency were Yongquan (KI 1), Quchi (LI 11), Taichong (LR 3), Shenque (CV 8), Sanyinjiao (SP 6) and Neiguan (PC 6). According to the correlation analysis, corresponding to these top 6 acupoints, the pairs of acupoints were Sanyinjiao (SP 6) and Yongquan (KI 1), Shenque (CV 8) and Yongquan (KI 1), Neiguan (PC 6) and Yongquan (KI 1), Zusanli (ST 36) and Sanyinjiao (SP 6), Sanyinjiao (SP 6) and Neiguan (PC 6) with Yongquan (KI 1), as well as Yongquan (KI 1) and Neiguan (PC 6) with Sanyinjiao (SP 6). The dominant meridians were the kidney meridian, the conception vessel and the bladder meridian. The special acupoints referred to yuan-source point, luo-connecting point, back-shu point and front-mu point. The top 3 herbal drugs in use frequency included fructus evodiae, semen sinapis and rhizoma chuanxiong. The herbs used were mainly warm and slight cold in nature and neutral in property. The frequencies of the drug use were similar in the application for cold and heat purposes. The common flavors of the herbal medicines were pungent, sweat and bitter and the liver, kidney and spleen meridians were generally involved in meridian tropism. CONCLUSION: In treatment of hypertension with acupoint application therapy, the commonly used single acupoint is Yongquan (KI 1), which is generally combined with Sanyinjiao (SP 6), Shenque (CV 8), Neiguan (PC 6) and Zusanli (ST 36). The correlation is emphasized on the application of special acupoints, meridian points and zangfu organs. The vesicatory herbal drugs are predominant in the drug use. In generally, this therapy embodies the treatment principles as tonifying for the deficiency and reducing for the excess, as well as balancing of cold and heat.

The Effect of Acupuncture and Moxibustion on Heart Function in Heart Failure Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Acupuncture and moxibustion (A&M) has been used for treating heart failure in China since the Han Dynasty. This ancient therapy can be applied to many diseases according to the WHO recommendations. Although there are many clinical reports on the treatment of heart failure by A&M, its effectiveness is still not fully demonstrated. We aimed to systematically review the related randomized controlled trial (RCT) studies and conduct a meta-analysis. METHODS: The PubMed, MEDLINE, EMBASE, AMED, CENTRAL, CNKI, Wanfang, and Weipu databases were searched electronically until December 2018. The data were extracted, and the risk of bias was evaluated. Meta-analysis, subgroup analysis, and metaregression were performed. Heart function was the main outcome assessed. The details of the intervention were also investigated. RESULTS: Thirty-two RCTs involving 2499 patients were included. Most studies had an unclear risk regarding blinding and allocation concealment. Compared with the traditional treatment group, the experimental group had a higher efficacy rate (odds ratio (OR) = 2.61, 95% confidence interval (95%CI): = [1.84; 3.72], I 2 = 0%, p < 0.0001) and a significantly improved left ventricular ejection fraction (LVEF) (mean difference (MD) = 6.34, 95%CI = [4.11, 8.57], I 2 = 93%, p < 0.0001), cardiac output (CO) (MD = 1.02, 95%CI = [0.65, 1.39], I 2 = 94%, p < 0.0001), 6-minute walk test (6MWT) (MD = 43.6, 95%CI = [37.43, 49.77], I 2 = 0%, p < 0.0001), and reduced brain-type natriuretic peptide (BNP) (MD = -227.99, 95%CI = [-337.30, -118.68], I2 = 96%, p < 0.0001). Adverse events were inadequately reported in most studies. CONCLUSIONS: A&M may be a promising intervention as an adjunctive therapy to medication for treating heart failure. However, the evidence was inconclusive. Further large and rigorously designed RCTs are needed for verification.

CT-guided minimally-invasive penile fracture repair

ABSTRACT We present the case of a 28 year old patient with an incomplete tear of the tunica albuginea occurred after having sexual intercourse in the female superior position. The diagnostic assessment was performed first clinically, then with CT, owing to its high resolution, allowed to exactly detect the tear location leading to precise preoperative planning. After adequate diagnosis through imaging and proper planning, the patient was performed a selective minimally invasive surgical approach to repair the lesion. The patient had good erection with no angular deformity or plaque formation after a 3-month follow-up.

CT-guided minimally-invasive penile fracture repair.

We present the case of a 28 year old patient with an incomplete tear of the tunica albuginea occurred after having sexual intercourse in the female superior position. The diagnostic assessment was performed first clinically, then with CT, owing to its high resolution, allowed to exactly detect the tear location leading to precise preoperative planning. After adequate diagnosis through imaging and proper planning, the patient was performed a selective minimally invasive surgical approach to repair the lesion. The patient had good erection with no angular deformity or plaque formation after a 3-month follow-up.

TAZ promotes epithelial to mesenchymal transition via the upregulation of connective tissue growth factor expression in neuroblastoma cells.

Neuroblastoma (NB) is a neuroendocrine cancer that occurs most commonly in infants and young children. The Hippo signaling pathway regulates cell proliferation and apoptosis, and its primary downstream effectors are TAZ and yes­associated protein 1 (YAP). The effect of TAZ on the metastatic progression of neuroblastoma and the underlying mechanisms involved remain elusive. In the current study, it was determined by western blot analysis that the migratory and invasive properties of SK­N­BE(2) human neuroblastoma cells are associated with high expression levels of TAZ. Repressed expression of TAZ in SK­N­BE(2) cells was shown to result in a reduction in aggressiveness of the cell line, by Transwell migration and invasion assay. In contrast, overexpression of TAZ in SK­N­SH human neuroblastoma cells was shown by Transwell migration and invasion assays, and western blot analysis, to result in epithelial­mesenchymal transition (EMT) and increased invasiveness. Mechanistically, the overexpression of TAZ was demonstrated to upregulate the expression levels of connective tissue growth factor (CTGF), by western blot analysis and chromatin immunoprecipitation assay, while the knockdown of TAZ downregulated it. Furthermore, TAZ was shown by luciferase assay to induce CTGF expression by modulating the activation of the TGF­ß/Smad3 signaling pathway. In conclusion, the present study is, to the best of our knowledge, the first to demonstrate that the overexpression of TAZ induces EMT, increasing the invasive abilities of neuroblastoma cells. This suggests that TAZ may serve as a potential target in the development of novel therapies for the treatment of neuroblastoma.