Genome-wide investigation of lncRNAs revealed their tight association with gastric cancer.

BACKGROUND: Gastric cancer (GC) is a significant health issue globally, ranking as the fifth most common cancer with over 10,000 new cases reported annually. Long non-coding RNA (lncRNA) has emerged as a critical player in cellular functions, influencing GC's development, growth, metastasis, and prognosis. However, our understanding of lncRNA's role in the pathogenesis of GC remains limited. Therefore, it is particularly important to explore the relationship between lncRNA and gastric cancer. METHODS: we conducted a comprehensive analysis of RNA sequencing data from the GEO database and stomach adenocarcinoma (STAD) data from the TCGA database to identify lncRNAs that exhibit altered expression levels in GC and the mechanisms underlying lncRNA-mediated transcription and post-transcriptional regulation were explored. RESULTS: This study uncovered 94 lncRNAs with differential expression and, through co-expression analysis, linked these to 1508 differentially expressed genes (DEGs). GO functional enrichment analysis highlighted that these DEGs are involved in critical pathways, such as cell adhesion and the positive regulation of cell migration. By establishing a lncRNA-miRNA-mRNA regulatory network, we found that the ceRNA mechanism, particularly involving RP11-357H14.17 and CTD-2377D24.4, could play a role in GC progression. Experimental validation of selected differentially expressed lncRNAs and mRNAs (including RP11-357H14.17-CLDN1, BBOX1, TRPM2-AS, CLDN1, PLAU, HOXB7) confirmed the RNA-seq results. CONCLUSIONS: Overall, our findings highlight the critical role of the lncRNA-mRNA regulatory network in the development and progression of GC, offering potential biomarkers for diagnosis and targets for innovative treatment strategies.

New Insights into Rate Control: Time in Target Range of Resting Heart Rate and Major Adverse Outcomes in Atrial Fibrillation.

Background: Few studies have examined the relationship between the fluctuation of heart rate control over time and cardiovascular outcomes in patients with atrial fibrillation. Our study sought to evaluate the independent association between time in target range (TIR) of resting heart rate and cardiovascular outcomes in the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) study. Methods: Target range of resting heart was defined as less than 80 beats per minute (bpm) for both rate and rhythm control groups. Time in target range was estimated over the first 8 months of follow-up using Rosendaal interpolation method. The association between TIR of resting heart rate and cardiovascular outcomes was estimated using adjusted Cox proportional hazards regression models. Results: Time in target range of resting heart rate (months 0 through 8) was 71 ± 34% in the rate control group and 83 ± 27% in the rhythm control group. Each 1-SD increase in TIR of resting heart rate was significantly associated with lower risk of major adverse cardiovascular events after full adjustment for demographics, medical history and history of prior heart surgery, as well as all-cause mortality. Conclusions: Time in target range of resting heart rate independently predicts the risk of cardiovascular outcomes in patients with atrial fibrillation. Long-term maintenance of heart rate on target is of great importance for patients with atrial fibrillation.

A novel HDGF-ALCAM axis promotes the metastasis of Ewing sarcoma via regulating the GTPases signaling pathway.

Ewing sarcoma (ES) is a type of highly aggressive pediatric tumor in bones and soft tissues and its metastatic spread remains the most powerful predictor of poor outcome. We previously identified that the transcription factor hepatoma-derived growth factor (HDGF) promotes ES tumorigenesis. However, the mechanisms underlying ES metastasis remain unclear. Here, we show that HDGF drives ES metastasis in vitro and in vivo, and HDGF reduces metastasis-free survival (MFS) in two independent large cohorts of human ES patients. Integrative analyses of HDGF ChIP-seq and gene expression profiling in ES cells reveal that HDGF regulates multiple metastasis-associated genes, among which activated leukocyte cell adhesion molecule (ALCAM) emerges as a major HDGF target and a novel metastasis-suppressor in ES. HDGF down-regulates ALCAM, induces expression and activation of the downstream effectors Rho-GTPase Rac1 and Cdc42, and promotes actin cytoskeleton remodeling and cell-matrix adhesion. In addition, repression of ALCAM and activation of Rac1 and Cdc42 are required for the pro-metastatic functions of HDGF in vitro. Moreover, analyses in murine models with ES tumor orthotopic implantation and experimental metastasis, as well as in human ES samples, demonstrate the associations among HDGF, ALCAM, and GTPases expression levels. Furthermore, high HDGF/low ALCAM expression define a subgroup of patients harboring the worst MFS. These findings suggest that the HDGF/ALCAM/GTPases axis represents a promising therapeutic target for limiting ES metastasis.

Overdrive pacing mapping: An alternative approach used in scar associated localized atrial tachycardia.

BACKGROUND: Mapping and ablation of localized reentry atrial tachycardia (AT) can be challenging, especially in those with varying cycle length (CL). OBJECTIVE: We attempted to use the traditional maneuver of overdrive pacing to facilitate AT mapping. METHODS: Data were collected from 12 patients with localized ATs. All patients had prior cardiac surgery or prior atrial fibrillation ablation. Overdrive pacing mapping (ODPM) was performed to find independent local activity (ILA) and compared with conventional activation mapping (CAM) during ongoing AT to determine its accuracy and efficacy. Patients with macro-reentry AT around the tricuspid or mitral annulus were excluded. RESULTS: Twelve patients with 14 localized ATs were included. All 14 ATs including 4 (29%) with varying CL successfully completed ODPM and had the ILA, although two ATs terminated during ODP and required repeated mapping. Radiofrequency ablation focused on critical sites with ILA was successful in all 12 patients. Using CAM, however, 6 of 14 ATs (43%) mapping attempts were aborted due to AT termination (2 ATs) or varying CL (4 ATs), and only 5 of 8 (63%) located "critical sites" were ultimately confirmed by entrainment and ablation results. After 25 ± 9 months of follow-up, no patient had AT recurrence. CONCLUSION: Our preliminary results demonstrated that ODPM is superior to CAM in ATs that were poorly sustained or with varying CL and is a useful supplement to CAM.

AMPK attenuates ventricular remodeling and dysfunction following aortic banding in mice via the Sirt3/Oxidative stress pathway.

Although recent findings have suggested that AMP-activated protein kinase (AMPK) exerts inhibitory effects on cardiac remodeling secondary to hypertension, the mechanism and optimal duration of treatment remain unknown. Mice with descending aortic banding (AB) or subjected to sham operation received subcutaneous injection of either AICAR (0.5mgg-1day-1) or vehicle over 4 week periods. At the end of 4 week treatment, left ventricular (LV) remodeling and function were evaluated with histological analysis and echocardiography. Collagen deposition within the LV myocardium was detected with Masson's trichrome staining. Collagen I, Collagen III, Smad 2, Smad 3, NOX2, NOX4 and Sirt3 (an important antioxidant factor) within the LV tissue were also evaluated. Compared with the sham group, the vehicle-treated AB group exhibited significant elevations in cardiac remodeling and heart failure, characterized by an increase in LV weight relative to body weight, an increase in the area of collagen deposition, an increase in LV end-diastolic diameter, an increase in mitral E inflow velocity to mitral A inflow velocity and increases in the gene expressions of the fibrosis markers Collagen I, III and Smad 2, 3 mRNA and decreases in EF and fractional shortening. AMPK attenuate the cardiac remodeling parameters and improve cardiac function. Moreover, the expressions of NOX2, NOX4 were significantly elevated in vehicle-treated AB group. AMPK was able to significantly inhibit NOX2, NOX4 expression, while activate Sirt3 expression. AMPK significantly attenuated hypertension-induced Ventricular remodeling and dysfunction, which may be mediated by the Sirt3/Oxidative stress signaling pathway.

Adenosine monophosphate-activated protein kinase attenuates cardiomyocyte hypertrophy through regulation of FOXO3a/MAFbx signaling pathway.

Control of cardiac muscle mass is thought to be determined by a dynamic balance of protein synthesis and degradation. Recent studies have demonstrated that atrophy-related forkhead box O 3a (FOXO3a)/muscle atrophy F-box (MAFbx) signaling pathway plays a central role in the modulation of proteolysis and exert inhibitory effect on cardiomyocyte hypertrophy. In this study, we tested the hypothesis that adenosine monophosphate-activated protein kinase (AMPK) activation attenuates cardiomyocyte hypertrophy by regulating FOXO3a/MAFbx signaling pathway and its downstream protein degradation. The results showed that activation of AMPK with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) attenuated cardiomyocyte hypertrophy induced by angiotensin II (Ang II). The antihypertrophic effects of AICAR were blunted by AMPK inhibitor Compound C. In addition, AMPK dramatically increased the activity of transcription factor FOXO3a, up-regulated the expression of its downstream ubiquitin ligase MAFbx, and enhanced cardiomyocyte proteolysis. Meanwhile, the effects of AMPK on protein degradation and cardiomyocyte hypertrophy were blocked after MAFbx was silenced by transfection of cardiomyocytes with MAFbx-siRNA. These results indicate that AMPK plays an important role in the inhibition of cardiomyocyte hypertrophy by activating protein degradation via FOXO3a/MAFbx signaling pathway.

Catheter Ablation of Right-Sided Accessory Pathways in Adults Using the Three-Dimensional Mapping System: A Randomized Comparison to the Conventional Approach.

Three-dimensional (3D) mapping and navigation systems have been widely used for the ablation of atrial fibrillation and ventricular tachycardia, but the applicability of these systems for the ablation of supraventricular tachycardia (SVT) due to right-sided accessory pathways (RAPs) remains unknown. The goal of this prospective randomized study was to compare the safety, efficiency, and efficacy of nonfluoroscopic and conventional fluoroscopic mapping techniques in guiding catheter ablation of SVT due to RAPs. Of the 393 consecutive patients with SVT who were randomized to receive either conventional fluoroscopic or Ensite NavX mapping-guided ablation, 64 patients with RAPs were included for analysis. Endpoints for ablation were no evidence of RAP conduction and no inducible atrioventricular reentrant tachycardia (AVRT). The 3D group showed fewer ablation pulses and a shorter total ablation time compared to the conventional group, although the acute procedural success did not differ significantly between the two groups. Total procedure time, electrophysiological study time, total fluoroscopy time, and cumulative radiation doses were also significantly reduced in the 3D group. Patients in the conventional group with a right atrium diameter (RAD) ≥ 47 mm required a longer fluoroscopy time. There was no significant difference in the recurrence rates between the two groups over a follow-up period of 3 to 29 months. There were no permanent complications. The 3D mapping system may be a preferred alternative for patients with AVRT due to RAPs, especially for patients with a large RAD (≥ 47 mm).

Proapoptotic PEDF functional peptides inhibit prostate tumor growth--a mechanistic study.

PEDF inhibits tumor growth via anti-angiogenic activity; however, the direct effect of PEDF on prostate carcinoma and its functional epitope as well as the underlying mechanism regulating the pathway from extracellular receptors to nuclear transcription factors has not been fully elucidated. This study investigates the ability and mechanism by which the functional PEDF peptides PEDF34 and PEDF44 suppress tumor growth. The results showed that death receptor pathway was activated by PEDF34 through up-regulation of FasL and activation of caspase-8 in both xenograft tumor tissues and PC-3 cells. FasL knockdown by siRNA or JNK-p inhibition attenuated apoptosis induced by PEDF34. NF-κB and PPARγ are crucial transcription factors for FasL expression. PEDF34 up-regulated PPARγ but did not affect NF-κB. PEDF34-induced up-regulation of FasL was abolished by siRNA-mediated PPARγ knockdown or using PPARγ inhibitor GW9662, whereas inhibition of NF-κB by the inhibitor PDTC or by siRNA had no effect. Furthermore, activation of JNK is necessary for PEDF34-induced up-regulation of FasL. PEDF34 has stronger hydropathicity and more interactions with laminin receptor than PEDF44. Blocking the laminin receptor abolished the up-regulation of FasL and PPARγ by PEDF34. Moreover, PEDF34 uses a similar mechanism to induce apoptosis in both endothelial and cancer cells. This study provides evidence that PEDF34, not PEDF44, serves as the proapoptotic epitope and exerts proapoptotic activity in both cancer and endothelial cells through activation of the extrinsic death receptor pathway. The dual anti-tumor and anti-angiogenic activities of PEDF34 suggest that it may be a promising agent for the treatment of prostate cancer.

Loss of E-cadherin promotes the growth, invasion and drug resistance of colorectal cancer cells and is associated with liver metastasis.

The recent studies indicated that the epithelial cell adhesion molecule E-cadherin is a well-recognized molecule that is important in cell adhesion. To further investigate the molecular basis of this notion, we used small-interfering RNA to inhibit E-cadherin function and found that loss of E-cadherin promoted Colorectal cancer cell growth, invasion and drug resistance through induction of ß-catenin nuclear translocation and epithelial-to-mesenchymal transition. Further analysis of E-cadherin expression with clinicopathologic parameters showed that E-cadherin expression decreased in Colorectal cancer patients who developed liver metastasis (P = 0.043). These findings indicate that E-cadherin loss in tumors contributes to progression and metastatic dissemination. Thus, E-cadherin can act as a central modulator of the cell biological phenotypes and a potential prognostic marker in Colorectal cancer.

Activation of AMPK inhibits cardiomyocyte hypertrophy by modulating of the FOXO1/MuRF1 signaling pathway in vitro.

AIM: To examine the inhibitory effects of adenosine monophosphate-activated protein kinase (AMPK) activation on cardiac hypertrophy in vitro and to investigate the underlying molecular mechanisms. METHODS: Cultured neonatal rat cardiomyocytes were treated with the specific AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and the specific AMPK antagonist Compound C, and then stimulated with phenylephrine (PE). The Muscle RING finger 1 (MuRF1)-small interfering RNA (siRNA) was transfected into cardiomyocytes using Lipofectamine 2000. The surface area of cultured cardiomyocytes was measured using planimetry. The protein degradation was determined using high performance liquid chromatography (HPLC). The expression of beta-myosin heavy chain (beta-MHC) and MuRF1, as well as the phosphorylation levels of AMPK and Forkhead box O 1 (FOXO1), were separately measured using Western blot or real-time polymerase chain reaction. RESULTS: Activation of AMPK by AICAR 0.5 mmol/L inhibited PE-induced increase in cardiomyocyte area and beta-MHC protein expression and PE-induced decrease in protein degradation. Furthermore, AMPK activation increased the activity of transcription factor FOXO1 and up-regulated downstream atrogene MuRF1 mRNA and protein expression. Treatment of hypertrophied cardiomyocytes with Compound C 1 micromol/L blunted the effects of AMPK on cardiomyocyte hypertrophy and changes to the FOXO1/MuRF1 pathway. The effects of AICAR on cardiomyocyte hypertrophy were also blocked after MuRF1 was silenced by transfection of cardiomyocytes with MuRF1-siRNA. CONCLUSION: The present study demonstrates that AMPK activation attenuates cardiomyocyte hypertrophy by modulating the atrophy-related FOXO1/MuRF1 signaling pathway in vitro.

Rosiglitazone-induced myocardial protection against ischaemia-reperfusion injury is mediated via a phosphatidylinositol 3-kinase/Akt-dependent pathway.

1. Rosiglitazone is widely used in the treatment of Type 2 diabetes. However, in recent years it has become evident that the therapeutic effects of peroxisome proliferator-activated receptor gamma ligands reach far beyond their use as insulin sensitizers. Recently, the ability of rosiglitazone pretreatment to induce cardioprotection following ischaemia-reperfusion (I/R) has been well documented; however, the protective mechanisms have not been elucidated. In the present study, examined the role of the phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway in rosiglitazone cardioprotection following I/R injury. 2. Mice were pretreated with 3 mg/kg per day rosiglitazone for 14 days before hearts were subjected to ischaemia (30 min) and reperfusion (2 h). Wortmannin (1.4 mg/kg, i.p.), an inhibitor of PI3-K, was administered 10 min prior to myocardial I/R. Then, activation of the PI3-K/Akt/glycogen synthase kinase (GSK)-3alpha signalling pathway was examined. The effects of PI3-K inhibition on rosiglitazone-induced cardioprotection were also evaluated. 3. Compared with control rats, the ratio of infarct size to ischaemic area (area at risk) and the occurrence of sustained ventricular fibrillation in rosiglitazone-pretreated rats was significantly reduced (P < 0.05). Rosiglitazone pretreatment attenuated cardiac apoptosis, as assessed by ELISA to determine cardiomyocyte DNA fragmentation. Rosiglitazone pretreatment significantly increased levels of phosphorylated (p-) Akt and p-GSK-3alpha in the rat myocardium. Pharmacological inhibition of PI3-K by wortmannin markedly abolished the cardioprotection induced by rosiglitazone. 4. These results indicate that rosiglitazone-induced cardioprotection in I/R injury is mediated via a PI3-K/Akt/GSK-3alpha-dependent pathway. The data also suggest that modulation of PI3-K/Akt/GSK-3alpha-dependent signalling pathways may be a viable strategy to reduce myocardial I/R injury.

MicroRNA-141 regulates Smad interacting protein 1 (SIP1) and inhibits migration and invasion of colorectal cancer cells.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in the world. Despite recent advances in diagnostics and treatment, prognosis for patients with advanced disease is still poor. microRNAs (miRNAs) are a class of endogenous, small noncoding RNA molecules which are crucial regulators of gene expression at the posttranscriptional level. miRNAs participate in many biological events and play an important role in various human diseases, including CRC. AIMS: This study is to identify the role of miR-141 in migration and invasion of CRC cells. METHODS: Expression of miR-141 and Smad interacting protein 1 (SIP1) were detected by real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western blotting. The effect of miR-141 on migration and invasion of CRC cells was investigated using wound healing assay and Matrigel invasion assay in vitro. The regulation effect of miR-141 on SIP1 was evaluated by dual-luciferase reporter assay. RESULTS: We demonstrated that miR-141 levels correlate inversely with SIP1 protein levels as well as cell migration and invasion of CRC cells. SIP1 was identified as a functional target of miR-141. CONCLUSIONS: miR-141 regulates SIP1 to inhibit migration and invasion of CRC cells. miR-141 and SIP1 might be candidate therapeutic targets in CRC.

Identification of the role of Smad interacting protein 1 (SIP1) in glioma.

Glioma is an extremely aggressive and lethal form of brain cancer. Despite recent advances in diagnostics and treatments, prognosis for advanced patients suffering from these diseases remains poor. Therefore, identification of new therapeutic targets for glioma is of significant importance. In this study, we identified the important role of Smad interacting protein 1 (SIP1; also known as ZEB2) in glioma. We firstly found that SIP1 expression was high in four tumorigenic glioma cell lines but low in two nontumorigenic glioma cell lines. By knockdown or overexpression assay, we discovered that knockdown of SIP1 expression statistically significantly inhibited cell migration and invasion of tumorigenic glioma cells, while overexpression of SIP1 promoted cell migration and invasion of nontumorigenic glioma cells. SIP1 knockdown inhibits and overexpression promotes glioma cell clonogenicity in vitro. Further studies identified that SIP1 overexpression inhibits expression of E-cadherin and enhances expression of mesenchymal proteins such as fibronectin and vimentin. This study supports the rationale for developing SIP1 as a potential therapeutic and diagnostic target for gliomas.