Activity of the vascular large conductance Ca(2+)-activated K(+) (BK) channel is tightly regulated by its accessory β(1) subunit (BK-β(1)). Downregulation of BK-β(1) expression in diabetic vessels is associated with upregulation of the forkhead box O subfamily transcription factor-3a (FOXO-3a)-dependent F-box-only protein (FBXO) expression. However, the upstream signaling regulating this process is unclear. Overproduction of reactive oxygen species (ROS) is a common finding in diabetic vasculopathy. We hypothesized that ROS signaling cascade facilitates the FOXO-3a/FBXO-mediated BK-β(1) degradation and leads to diabetic BK channel dysfunction. Using cellular biology, patch clamp, and videomicroscopy techniques, we found that reduced BK-β(1) expression in streptozotocin (STZ)-induced diabetic mouse arteries and in human coronary smooth muscle cells (SMCs) cultured with high glucose was attributable to an increase in protein kinase C (PKC)-β and NADPH oxidase expressions and accompanied by attenuation of Akt phosphorylation and augmentation of atrogin-1 expression. Treatment with ruboxistaurin (a PKCβ inhibitor) or with GW501516 (a peroxisome proliferator-activated receptor δ activator) reduced atrogin-1 expression and restored BK channel-mediated coronary vasodilation in diabetic mice. Our results suggested that oxidative stress inhibited Akt signaling and facilitated the FOXO-3a/FBXO-dependent BK-β(1) degradation in diabetic vessels. Suppression of the FOXO-3a/FBXO pathway prevented vascular BK-β(1) degradation and protected coronary function in diabetes.

We have reported that epoxyeicosatrienoic acids (EETs), the cytochrome P450 (CYP) epoxygenase metabolites of arachidonic acid (AA), are potent sarcolemmal ATP-sensitive K+ (KATP) channel activators. However, activation of cardiac and vascular KATP channels by endogenously produced EETs under physiological intracellular conditions has not been demonstrated and direct comparison of the mechanisms whereby EETs activate the KATP channels in cardiac myocytes versus vascular smooth muscle cells has not been made. In this study, we examined the effects of AA on KATP channels in freshly isolated cardiac myocytes from rats, wild-type (WT) and transgenic mice overexpressing CYP2J2 cDNA, and mesenteric arterial smooth muscle cells from rats. We also compared the activation of cardiac and vascular KATP channels by extracellularly and intracellularly applied 11,12-EET. We found that 1 microm AA enhanced KATP channel activities in both cardiac and vascular smooth muscle cells, and the AA effects were inhibited by preincubation with CYP epoxygenase inhibitors. Baseline cardiac KATP current densities in CYP2J2 transgenic mice were 190% higher than those of WT mice, and both were reduced to similar levels by CYP epoxygenase inhibition. Western blot analysis showed that expression of Kir6.2 and SUR2A was similar between WT and CYP2J2 transgenic hearts. 11,12-EET (5 microm) applied intracellularly enhanced the KATP currents by 850% in cardiac myocytes, but had no effect in vascular smooth muscle cells. In contrast, 11,12-EET (5 microm) applied extracellularly increased KATP currents by 520% in mesenteric arterial smooth muscle cells, but by only 209% in cardiac myocytes. Preincubation with 100 microm m-iodobenzylguanidine or 5 microm myristoylated PKI amide did not alter the activation of cardiac KATP channels by 5 microm 11,12-EET, but significantly inhibited activation of vascular KATP channels. Moreover, EET only enhanced the inward component of cardiac KATP currents, but activated both the inward and outward components of vascular KATP currents. Our results indicate that endogenously derived CYP metabolites of AA potently activate cardiac and vascular KATP channels. EETs regulate cardiac electrophysiology and vascular tone by KATP channel activation, albeit through different mechanisms: the cardiac KATP channels are directly activated by EETs, whereas activation of the vascular KATP channels by EETs is protein kinase A dependent.

Increasing evidence has demonstrated that circular RNAs (circRNAs) may play an important role in oncogenesis and tumor development; however, their role in lung adenocarcinoma (LUAD) remains unclear. We identified the differentially expressed circRNAs in LUAD and investigated the potential mechanisms for cancer progression.

Visceral pleural invasion (VPI) has been identified as an adverse prognostic factor for non-small cell lung cancer (NSCLC). Accurate nodal staging for NSCLC correlates with improved survival, but it is unclear whether tumors with VPI require a more extensive lymph nodes (LNs) dissection to optimize survival. We aimed to evaluate the impact of VPI status on the optimal extent of LNs dissection in stage I NSCLC, using the Surveillance, Epidemiology, and End Results (SEER) database. We identified 9297 surgically treated T1-2aN0M0 NSCLC patients with at least one examined LNs. Propensity score matching was conducted to balance the baseline clinicopathologic characteristics between the VPI group and non-VPI group. Log-rank tests along with Cox proportional hazards regression methods were performed to evaluate the impact of extent of LNs dissection on survival. VPI was correlated with a significant worse survival, but there was no significant difference in survival rate between PL1 and PL2. Patients who underwent sublobectomy had slightly decreased survival than those who underwent lobectomy. Pathologic LNs examination was significantly correlated with survival. Examination of 7-8 LNs and 14-16 LNs conferred the lowest hazard ratio for T1-sized/non-VPI tumors (stage IA) and T1-sized/VPI tumors (stage IB), respectively. The optimal extent of LNs dissection varied by VPI status, with T1-sized/VPI tumors (stage IB) requiring a more extensive LNs dissection than T1-sized/non-VPI tumors (stage IA). These results might provide guidelines for surgical procedure in early stage NSCLC.

Rituximab is standard care in a number of lymphoma subtypes, including follicular lymphoma (FL), although many patients are resistant to rituximab, or develop resistance with repeated treatment, and a high proportion relapse. Obinutuzumab is a novel anti-CD20 monoclonal antibody with improved efficacy over rituximab. It is approved for previously untreated chronic lymphocytic leukaemia (CLL), and for use with bendamustine in patients with rituximab-relapsed/refractory FL.

Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (CmeanIND ) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial.

Purpose: The rapidly rising incidence of esophageal adenocarcinoma (EAC), which is usually diagnosed late with a poor prognosis, has become a growing problem. This study investigated the potential transcription factor (TF)-related molecular mechanisms of EAC by using bioinformatics analysis and qRT-PCR validation. Methods: Expression profile datasets for mRNAs (GSE92396, GSE13898, GSE26886 and GSE1420) and miRNAs (GSE16456) were downloaded from the GEO database. Overlapping differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were identified through integrative analysis. Then, a TF-miRNA-mRNA network was constructed based on bioinformatics data from the TRRUST, TRED and miRTarBase database. Furthermore, overall survival analysis for the mRNAs and miRNAs in the TF-miRNA-mRNA network was performed with data from TCGA, and qRT-PCR was used to validate the results. Results: A total of 294 overlapping DEGs were identified in EAC tissues compared to normal tissues, including 181 downregulated and 113 upregulated genes. Then, 16 TFs that could target the DEGs and were related to cancer were predicted based on public databases, and 41 DEGs that could be targeted were identified as key genes. Additionally, 12 DEMs were predicted through miRTarBase to be associated with the key genes, and TP53-(miR-125b)-ID2 and JUN-(miR-30a)-IL1A from the TF-miRNA-mRNA network were identified to potentially play significant roles in EAC. Furthermore, CCL20, IL1A, ABCC3, hsa-miR-23b, and hsa-miR-191, which are involved in the TF-miRNA-mRNA network, were found to be significantly associated with patient survival in EAC. Finally, the expression of a miRNA-mRNA pair (hsa-miR-30a-5p and IL1A) was revealed to be correlated with prognosis. Conclusion: In this study, a TF-miRNA-mRNA network was constructed to analyze the potential molecular mechanisms of EAC. Key genes and miRNAs associated with patient survival were identified, which may reveal promising approaches for EAC diagnosis and therapy.

The gastric cancer is the second most malignant tumor in the world. HER-2 is one of the key targets for the gastric cancer therapy. Anti-HER-2 antibodies like trastuzumab, exhibits the satisfactory therapeutic effect in clinical. However, the drug resistance problem limits its application.

Membranes allowing the sustained release of drugs that can achieve cell adhesion are very promising for guided bone regeneration. Previous studies have suggested that aspirin has the potential to promote bone regeneration. The purpose of this study was to prepare a local drug delivery system with aspirin-loaded chitosan nanoparticles (ACS) contained in an asymmetric collagen-chitosan membrane (CCM).

Colon cancer is one of the most commonly diagnosed cancers worldwide. Both environmental and molecular characters can influence its development. DNA methylation has been heralded as a promising marker for use in cancer prevention, diagnosis, and treatment. It has been shown to facilitate cancer progression through multiple mechanisms. Changes in DNA methylation can inhibit or promote the binding of transcription factors (TFs) and further disturb gene regulation. Detection of DNA methylation-mediated regulatory events in colon cancer are critical for mining novel biomarkers. Here, we explore the influence of CpG sites located at promoter regions of differentially expressed genes and identify methylation-gene relationships using expression-methylation quantitative trait loci. We find that promoter methylation sites mainly negatively regulate the corresponding genes. We also identify candidate TFs that can bind to these sites in a sequence-dependent manner. By integrating transcriptome and methylome profiles, we construct a TF-CpG-gene regulatory network for colon cancer, which is used to determine the roles of TFs and methylation in the transcription process. Finally, based on TF-CpG-gene relationships, we design a framework to evaluate patient prognosis, which shows that one TF-CpG-gene triplet is significantly associated with patient survival rate and represents a potential novel biomarker for use in colon cancer prognosis and treatment.

Cisplatin is a first-line drug for the treatment of human non-small cell lung cancer (NSCLC); however, the majority of patients will develop drug resistance after treatment. In order to overcome cisplatin resistance, it is important to understand the mechanisms underlying the resistance.

Human facial morphology varies considerably among individuals and can be influenced by gene polymorphisms. We explored the effects of single nucleotide polymorphisms (SNPs) on facial features in the Uygur youth population of the Kashi area in Xinjiang, China. Saliva samples were collected from 578 volunteers, and 10 SNPs previously associated with variations in facial physiognomy were genotyped. In parallel, 3D images of the subjects' faces were obtained using grating facial scanning technology. After delimitation of 15 salient landmarks, the correlation between SNPs and the distances between facial landmark pairs was assessed. Analysis of variance revealed that ENPP1 rs7754561 polymorphism was significantly associated with RAla-RLipCn and RLipCn-Sbn linear distances (p = 0.044 and p = 0.012, respectively) as well as RLipCn-Stm curve distance (p = 0.042). The GHR rs6180 polymorphism correlated with RLipCn-Stm linear distance (p = 0.04), while the GHR rs6184 polymorphism correlated with RLipCn-ULipP curve distance (p = 0.047). The FGFR1 rs4647905 polymorphism was associated with LLipCn-Nsn linear distance (p = 0.042). These results reveal that ENPP1 and FGFR1 influence lower anterior face height, the distance from the upper lip to the nasal floor, and lip shape. FGFR1 also influences the lower anterior face height, while GHR is associated with the length and width of the lip.

The large conductance Ca2+-activated K+ (BK) channel β1-subunit (BK-β1) is a key modulator of BK channel electrophysiology and the downregulation of BK-β1 protein expression in vascular smooth muscle cells (SMCs) underlies diabetic vascular dysfunction. In this study, we hypothesized that the nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway plays a significant role in the regulation of coronary BK channel function and vasodilation in high-fat diet (HFD)-induced obese/diabetic mice. We found that the protein expressions of BK-β1 and Nrf2 were markedly downregulated, whereas those of the nuclear factor-κB (NF-κB) and the muscle ring finger protein 1 (MuRF1 [a ubiquitin E3 ligase for BK-β1]) were significantly upregulated in HFD mouse arteries. Adenoviral expression of Nrf2 suppressed the protein expressions of NF-κB and MuRF1 but enhanced BK-β1 mRNA and protein expressions in cultured coronary SMCs. Knockdown of Nrf2 resulted in reciprocal changes of these proteins. Patch-clamp studies showed that coronary BK-β1-mediated channel activation was diminished in HFD mice. Importantly, the activation of Nrf2 by dimethyl fumarate significantly reduced the body weight and blood glucose levels of HFD mice, enhanced BK-β1 transcription, and attenuated MuRF1-dependent BK-β1 protein degradation, which in turn restored coronary BK channel function and BK channel-mediated coronary vasodilation in HFD mice. Hence, Nrf2 is a novel regulator of BK channel function with therapeutic implications in diabetic vasculopathy.

As a novel reactive oxygen species (ROS) scavenger, deuterohemin His peptide‑6 (DhHP‑6) has been demonstrated to prolong the lifespan of Caenorhabditis elegans and has also exhibited protective effects in myocardial ischemia‑reperfusion injury. Whether similar effects occur during cerebral ischemia‑reperfusion (CIR) injury remains to be elucidated. The present study evaluated the function of DhHP‑6 and its underlying mechanisms in a middle cerebral artery occlusion (MCAO) model in rats. The focal transient MCAO model was implemented using the Longa method of ischemia for 2 h followed by reperfusion for 22 h in male Wistar rats. DhHP‑6 was administered at the onset of reperfusion via intraperitoneal injection. The infarct volume, brain edema, brain apoptosis and neurological function were evaluated 24 h following stroke. To further determine the role of DhHP‑6 in CIR injury, the levels of ROS and malondialdehyde (MDA), the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH‑Px), and the protein expression levels of B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax), cleaved caspase‑3, cytochrome c, Bcl‑2 and phosphorylated‑Akt/Akt were measured in ischemic cortex tissues. The results demonstrated that DhHP‑6 significantly improved infarct volume, brain edema and neurological deficits, and reduced the percentage of TUNEL‑positive cells. The levels of ROS and MDA were decreased, whereas no significant changes in the activities of SOD, CAT and GSH‑Px were observed. The levels of Bax, cleaved caspase‑3, and cytochrome c were downregulated, whereas the levels of Bcl‑2 and p‑Akt/Akt were upregulated. The results of the present study indicated that DhHP‑6 may offer therapeutic potential for cerebral ischemia. The neuroprotective effects of DhHP‑6 maybe mediated by its anti‑oxidative properties, anti‑apoptotic activities, or activation of the phosphoinositide 3‑kinase/Akt survival pathway.

The L-type calcium channel (LTCC) is one of the major ion channels that are known to be associated with the electrical remodeling of atrial fibrillation (AF). In AF, there is significant downregulation of the LTCC, but the underlying mechanism for such downregulation is not clear. We have previously reported that microRNA-499 (miR-499) is significantly upregulated in patients with permanent AF and that KCNN3, the gene that encodes the small-conductance calcium-activated potassium channel 3 (SK3), is a target of miR-499. We found that CACNB2, an important subunit of the LTCC, is also a target of miR-499. We hypothesize that miR-499 plays an important role in AF electrical remodeling by regulating the expression of CACNB2 and the LTCC. In atrial tissue from patients with permanent AF, CACNB2 was significantly downregulated by 67% (n = 4, p < 0.05) compared to those from patients with no history of AF. Transfection of miR-499 mimic into HL-1 cells, a mouse hyperplastic atrial cardiac myocyte cell-line, resulted in the downregulation of CACNB2 protein expression, while that of miR-499 inhibitor upregulated CACNB2 protein expression. Binding of miR-499 to the 3' untranslated region of CACNB2 was confirmed by luciferase reporter assay and by the increased presence of CACNB2 mRNA in Argonaute pulled-down microRNA-induced silencing complexes after transfection with the miR-499 mimic. In addition, downregulation of CACNB2 resulted in the downregulation of protein levels of the pore-forming α-subunit (CACNA1C). In conclusion, upregulation of atrial miR-499 induces the downregulation of CACNB2 expression and may contribute to the electrical remodeling in AF.

In order to explore a new strategy to characterize the texture of raw meat, based on the ultrasonic tenderized wooden breast (WB), this study proposed stress relaxation and creep to determine the rheological properties. Results showed that hardness was significantly decreased from 3625.61 g to 2643.64 g, and elasticity increased, after 600 W ultrasound treatment at 20 kHz for 20 min (on-time 2 s and off-time 3 s) at 4 °C. In addition, based on the transformation of creep data, a new indicator, slope ε'(t), was innovatively used to simulate a sensory feedback of hardness from the touch sensation, proving WB became tender at 600 W treatment due to the feedback speed to external force. These above results were confirmed by the reduced shear force, increased myofibril fragmentation index (MFI), decreased particle size, and increased myofibrillar protein degradation. Histology analysis and collagen suggested the tenderizing results was caused by muscle fiber rather than connective tissue. Overall, stress relaxation and creep had a potential to predict meat texture characteristics and 600 W ultrasound treatment was an effective strategy to reduce economic losses of WB.

Colorectal cancer (CRC) is a multifactorial tumor and a leading cause of cancer-specific deaths worldwide. Recent research has shown that the alteration of intestinal flora contributes to the development of CRC. However, the molecular mechanism by which intestinal flora influences the pathogenesis of CRC remains unclear. This study aims to explore the key genes underlying the effect of intestinal flora on CRC and therapeutic drugs for CRC.

Probiotic supplementation has been shown to be beneficial and is now widely promoted as an auxiliary medicine for maternal health, but the underlying mechanism is still unclear. Thus, this study aimed to explore the effects of probiotic supplementation on the placental autophagy-related proteins LC3 and Beclin1.

Acute myocardial infarction (AMI) is considered one of the most prominent causes of death from cardiovascular disease worldwide. Knowledge of the molecular mechanisms underlying AMI remains limited. Accurate biomarkers are needed to predict the risk of AMI and would be beneficial for managing the incidence rate. The gold standard for the diagnosis of AMI, the cardiac troponin T (cTnT) assay, requires serial testing, and the timing of measurement with respect to symptoms affects the results. As attractive candidate diagnostic biomarkers in AMI, circulating microRNAs (miRNAs) are easily detectable, generally stable and tissue specific.

The large conductance Ca2+-activated K+ (BK) channels, composed of the pore-forming α subunits (BK-α, encoded by KCNMA1 gene) and the regulatory β1 subunits (BK-β1, encoded by KCNMB1 gene), play a unique role in the regulation of coronary vascular tone and myocardial perfusion by linking intracellular Ca2+ homeostasis with excitation-contraction coupling in coronary arterial smooth muscle cells (SMCs). The nuclear factor erythroid 2-related factor 2 (Nrf2) belongs to a member of basic leucine zipper transcription factor family that regulates the expression of antioxidant and detoxification enzymes by binding to the antioxidant response elements (AREs) of these target genes. We have previously reported that vascular BK-β1 protein expression was tightly regulated by Nrf2. However, the molecular mechanism underlying the regulation of BK channel expression by Nrf2, particularly at transcription level, is unknown. In this study, we hypothesized that KCNMA1 and KCNMB1 are the target genes of Nrf2 transcriptional regulation. We found that BK channel protein expression and current density were diminished in freshly isolated coronary arterial SMCs of Nrf2 knockout (KO) mice. However, BK-α mRNA expression was reduced, but not that of BK-β1 mRNA expression, in the arteries of Nrf2 KO mice. Promoter-Nrf2 luciferase reporter assay confirmed that Nrf2 binds to the ARE of KCNMA1 promoter, but not that of KCNMB1. Adenoviral expression and pharmacological activation of Nrf2 increased BK-α and BK-β1 protein levels and enhanced BK channel activity in coronary arterial SMCs. Hence, our results indicate that Nrf2 is a key determinant of BK channel expression and function in vascular SMCs. Nrf2 facilitates BK-α expression through a direct increase in gene transcription, whereas that on BK-β1 is through a different mechanism.