Sacubitril/valsartan attenuates atrial electrical and structural remodelling in a rabbit model of atrial fibrillation.

Atrial structural and electrical remodelling play important roles in atrial fibrillation (AF). Sacubitril/valsartan attenuates cardiac remodelling in heart failure. However, the effect of sacubitril/valsartan on AF is unclear. The aim of this study was to evaluate the effect of sacubitril/valsartan on atrial electrical and structural remodelling in AF and investigate the underlying mechanism of action. Thirty-three rabbits were randomized into sham, RAP, and sac/val groups. HL-1 cells were subjected to control treatment or rapid pacing with or without LBQ657 and valsartan. Echocardiography, atrial electrophysiology, and histological examination were performed. The concentration of Ca2+ and expression levels of calcineurin, NFAT, p-NFAT, Cav1.2, collagen Ⅰ and Ⅲ, ANP, BNP, CNP, NT-proBNP, and ST2 in HL-1 cells, and IcaL in left atrial cells, were determined. We observed that compared to that in the sham group, the atrium and right ventricle were enlarged, myocardial fibrosis was markedly higher, AF inducibility was significantly elevated, and atrial effective refractory periods were shortened in the RAP group. These effects were significantly reversed by sacubitril/valsartan. Compared to that in the sham group, collagen Ⅰ and Ⅲ, NT-proBNP, ST2, calcineurin, and NFAT were significantly up-regulated, while p-NFAT and Cav1.2 were down-regulated in the RAP group, and sacubitril/valsartan inhibited these changes. Ca2+ concentration increased and ICaL density decreased in in vivo and in vitro AF models, reversed by sacubitril/valsartan. Sacubitril/valsartan attenuates atrial electrical remodelling and ameliorates structure remodelling in AF. This study paves the way for the possibility of clinical use of sacubitril/valsartan in AF patients.

The lncRNA CRNDE promotes colorectal cancer cell proliferation and chemoresistance via miR-181a-5p-mediated regulation of Wnt/ß-catenin signaling.

BACKGROUND: With more than 600,000 mortalities each year, colorectal cancer (CRC) is the third most commonly diagnosed type of cancer worldwide. Recently, mechanisms involving noncoding RNAs have been implicated in the development of CRC. METHODS: We examined expression levels of lncRNA CRNDE and miR-181a-5p in 64 cases of CRC tissues and cell lines by qRT-PCR. Gain-of-function and loss-of-function assays were performed to examine the effect of CRNDE and miR-181a-5p on proliferation and chemoresistance of CRC cells. Using fluorescence reporter and western blot assays, we also explored the possible mechanisms of CRNDE in CRC cells. RESULTS: In this study, we found that the expression levels of the CRNDE were upregulated in CRC clinical tissue samples. We identified microRNA miR-181a-5p as an inhibitory target of CRNDE. Both CRNDE knockdown and miR-181a-5p overexpression in CRC cell lines led to inhibited cell proliferation and reduced chemoresistance. We also determined that ß-catenin and TCF4 were inhibitory targets of miR-181a-5p, and that Wnt/ß-catenin signaling was inhibited by both CRNDE knockdown and miR-181a-5p overexpression. Significantly, we found that the repression of cell proliferation, the reduction of chemoresistance, and the inhibition of Wnt/ß-catenin signaling induced by CRNDE knockdown would require the increased expression of miR-181a-5p. CONCLUSIONS: Our study demonstrated that the lncRNA CRNDE could regulate the progression and chemoresistance of CRC via modulating the expression levels of miR-181a-5p and the activity of Wnt/ß-catenin signaling.

Risk factors of infected pancreatic necrosis secondary to severe acute pancreatitis.

BACKGROUND: Severe acute pancreatitis (SAP) remains a clinical challenge with considerable morbidity and mortality. An early identification of infected pancreatic necrosis (IPN), a life-threatening evolution secondary to SAP, is obliged for a more preferable prognosis. Thus, the present study was conducted to identify the risk factors of IPN secondary to SAP. METHODS: The clinical data of patients with SAP were retrospectively analyzed. Univariate and multivariate logistic regression analyses were sequentially performed to assess the associations between the variables and the development of IPN secondary to SAP. A receiver operating characteristic (ROC) curve was created for each of the qualified independent risk factors. RESULTS: Of the 115 eligible patients, 39 (33.9%) progressed to IPN, and the overall in-hospital mortality was 11.3% (13/115). The early enteral nutrition (EEN) (P=0.0092, OR=0.264), maximum intra-abdominal pressure (IAP) (P=0.0398, OR=1.131) and maximum D-dimer level (P=0.0001, OR=1.006) in the first three consecutive days were independent risk factors associated with IPN secondary to SAP. The area under ROC curve (AUC) was 0.774 for the maximum D-dimer level in the first three consecutive days and the sensitivity was 90% and the specificity was 58% at a cut-off value of 933.5 µg/L; the AUC was 0.831 for the maximum IAP in the first three consecutive days and the sensitivity was 95% and specificity was 58% at a cut-off value of 13.5 mmHg. CONCLUSIONS: The present study suggested that the maximum D-dimer level and/or maximum IAP in the first three consecutive days after admission were risk factors of IPN secondary to SAP; an EEN might be helpful to prevent the progression of IPN secondary to SAP.

External Versus Internal Pancreatic Duct Drainage for the Early Efficacy After Pancreaticoduodenectomy: A Retrospectively Comparative Study.

PURPOSE: To compare the early efficacy of external versus internal pancreatic duct drainage after pancreaticoduodenectomy (PD), providing clinical evidence for selecting the optimal approach to pancreatic duct drainage. MATERIAL AND METHODS: The clinical data of 395 consecutive patients undergoing PD from 2006 to 2013 were analyzed retrospectively. All the patients were divided into external and internal drainage group. Intraoperative blood loss, surgery duration, postoperative hospitalization duration, mortality rate, PF, and other complications were compared between the two groups. The perioperative relative risk factors that might induce PF were analyzed. RESULTS: External drainage significantly reduced the incidences of post-PD PF, delayed gastric emptying, abdominal infection, bowel obstruction, overall complications, and shortened the healing time of PF (p < .05). The univariate analysis showed that the pancreatic duct drainage method, body mass index (BMI), preoperative serum bilirubin level, perioperative blood transfusion, pancreaticojejunostomy approach, pancreatic texture, pancreatic duct diameter, and primary disease differed markedly between the two groups (p < .05). A multivariate analysis revealed that BMI ≥ 25 kg/m(2), internal pancreatic duct drainage, pancreatic duct diameter <3 mm, soft pancreatic texture, and ampullary disease were independent risk factors for PF. CONCLUSIONS: External pancreatic duct drainage can effectively reduce the morbidity of PF and overall complications after PD.

Necroptosis: a potential, promising target and switch in acute pancreatitis.

Pancreatic acinar cell death is the major pathophysiological change in early acute pancreatitis (AP), and the death modalities are important factors determining its progression and prognosis. During AP, acinar cells undergo two major modes of death, including necrosis and apoptosis. Acinar necrosis can lead to intensely local and systemic inflammatory responses, which both induce and aggravate the lesion. Necrosis has long been considered an unregulated, and passive cell death process. Since the effective interventions of necrosis are difficult to perform, its relevant studies have not received adequate attention. Necroptosis is a newly discovered cell death modality characterized by both necrosis and apoptosis, i.e., it is actively regulated by special genes, while has the typical morphological features of necrosis. Currently, necroptosis is gradually becoming an important topic in the fields of inflammatory diseases. The preliminary results from necroptosis in AP have confirmed the existence of acinar cell necroptosis, which may be a potential target for effectively regulating inflammatory injuries and improving its outcomes; however, the functional changes and mechanisms of necroptosis still require further investigation. This article reviewed the progress of necroptosis in AP to provide a reference for deeply understanding the pathogenic mechanisms of AP and identifying new therapeutic targets.