MicroRNA-137 and microRNA-195* inhibit vasculogenesis in brain arteriovenous malformations.

OBJECTIVE: Brain arteriovenous malformations (AVMs) are the most common cause of nontraumatic intracerebral hemorrhage in young adults. The genesis of brain AVM remains enigmatic. We investigated microRNA (miRNA) expression and its contribution to the pathogenesis of brain AVMs. METHODS: We used a large-scale miRNA analysis of 16 samples including AVMs, hemangioblastoma, and controls to identify a distinct AVM miRNA signature. AVM smooth muscle cells (AVMSMCs) were isolated and identified by flow cytometry and immunohistochemistry, and candidate miRNAs were then tested in these cells. Migration, tube formation, and CCK-8-induced proliferation assays were used to test the effect of the miRNAs on phenotypic properties of AVMSMCs. A quantitative proteomics approach was used to identify protein expression changes in AVMSMCs treated with miRNA mimics. RESULTS: A distinct AVM miRNA signature comprising a large portion of lowly expressed miRNAs was identified. Among these miRNAs, miR-137 and miR-195* levels were significantly decreased in AVMs and constituent AVMSMCs. Experimentally elevating the level of these microRNAs inhibited AVMSMC migration, tube formation, and survival in vitro and the formation of vascular rings in vivo. Proteomics showed the protein expression signature of AVMSMCs and identified downstream proteins regulated by miR-137 and miR-195* that were key signaling proteins involved in vessel development. INTERPRETATION: Our results indicate that miR-137 and miR-195* act as vasculogenic suppressors in AVMs by altering phenotypic properties of AVMSMCs, and that the absence of miR-137 and miR-195* expression leads to abnormal vasculogenesis. Ann Neurol 2017;82:371-384.

Screening and Function Analysis of MicroRNAs Involved in Exercise Preconditioning-Attenuating Pathological Cardiac Hypertrophy.

Exercise preconditioning (EP) attenuates pathological cardiac hypertrophy by increasing the functional capacity of the cardiovascular system; however, the underlying molecular mechanisms remain unclear. MicroRNAs (miRNAs) play important roles in various physiological and pathological processes by regulating the expression of the targeted gene. In this study, we aimed to screen the miRNAs involved in EP-attenuating pathological cardiac hypertrophy. The histological and echocardiographic parameters assessment showed that pathological cardiac hypertrophy induced by transverse aortic constriction (TAC) was significantly alleviated in EP treated rats. The left ventricular tissues (n = 3) from Sham, TAC and EP + TAC groups were subjected to small RNA deep sequencing. A total of 570 known mature miRNAs and 530 putative novel miRNAs were detected. DEGseq analysis showed that there were 37 and 88 differentially expressed miRNAs in the comparisons of TAC versus Sham and EP + TAC versus TAC, respectively. Among them, EP treatment could relieve the expression changes of 32 miRNAs, which were supposed to be involved in EP-attenuating pathological cardiac hypertrophy. After miRNAs target genes prediction by miRDB algorithm, pathway analysis showed that the most frequently represented pathways were involved in Calcium signaling pathway and MAPK signaling pathway. The results would provide valuable clues to finding therapeutic targets for the treatment of pathological cardiac hypertrophy.

Protective effects of hyperbaric oxygen preconditioning against LPS-induced acute lung injury in rats.

INTRODUCTION: Acute lung injury (ALI) is generally caused by oxidative damages and pulmonary overinflammations. Hyperbaric oxygen preconditioning (HBO2-PC) has been proven protective against oxidative-stress-related injuries. In this study, we investigated the effect of HBO2-PC on lipopolysaccharide (LPS)-induced ALI in rats. METHODS: Thirty-two Sprague-Dawley rats randomly assigned into Sham, HBO2-PC, ALI and HBO2-PC÷ALI groups (eight in each group) were sacrificed at 12 hours after the injection of LPS. The severity of ALI in rats was assessed in terms of histopathological changes in addition to wet/dry weight ratios. The levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1ß in serum and lung homogenates were measured by enzyme-linked immunosorbent and qRT-PCR assays. Activities by hydrogen peroxide (H2O2), malondialdehyde (MDA), myeloperoxidase (MPO) as well as superoxide dismutase (SOD) in rat lungs were tested for neutrophil infiltration. Meanwhile the oxidative stress molecular markers nuclear factor-kappa B(NF-κB) p65 and nuclear factor erythroid 2-related factor 2 (Nrf2), together with its downstream heme-oxygenase 1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) were also quantified. RESULTS: HBO2-PC significantly alleviated LPS-induced ALI, lowered the lung injury scores, reduced lung water content, and reduced H2O2, MDA levels as well as MPO activity, while simultaneously improving the arterial partial oxygen pressure (PaO2) and SOD activity. Furthermore, HBO2-PC inhibited the nuclear translocation of NF-κB p65 while enhancing the nuclear translocation of Nrf2, thus upregulating HO-1 and NQO1. CONCLUSIONS: Our results suggest that HBO2-PC was potentially protective for LPS-induced ALI lungs in rats, with a presumed mechanism that suppressed NF-κB while activating Nrf2. We propose that HBO2-PC should be considered a potential therapeutic strategy against ALI in rats.

HSF1 and NF-κB p65 participate in the process of exercise preconditioning attenuating pressure overload-induced pathological cardiac hypertrophy.

Pathological cardiac hypertrophy, often accompanied by hypertension, aortic stenosis and valvular defects, is typically associated with myocyte remodeling and cardiac dysfunction. Exercise preconditioning (EP) has been proven to enhance the tolerance of the myocardium to cardiac ischemia-reperfusion injury. However, the effects of EP in pathological cardiac hypertrophy are rarely reported. 10-wk-old male Sprague-Dawley rats (n = 80) were randomly divided into four groups: sham, TAC, EP + sham and EP + TAC. Two EP groups were subjected to 4 weeks of treadmill training, and the EP + TAC and TAC groups were followed by TAC operations. The sham and EP + sham groups underwent the same operation without aortic constriction. Eight weeks after the surgery, we evaluated the effects of EP by echocardiography, morphology, and histology and observed the expressions of the associated proteins. Compared with the respective control groups, hypertrophy-related indicators were significantly increased in the TAC and EP + TAC groups (p < 0.05). However, between the TAC and EP + TAC groups, all of these changes were effectively inhibited by EP treatment (p < 0.05). Furthermore, EP treatment upregulated the expression of HSF1 and HSP70, increased the HSF1 levels in the nuclear fraction, inhibited the expression of the NF-κB p65 subunit, decreased the NF-κB p65 subunit levels in the nuclear fraction, and reduced the IL2 levels in the myocardia of rats. EP could effectively reduce the cardiac hypertrophic responses induced by TAC and may play a protective role by upregulating the expressions of HSF1 and HSP70, activating HSF1 and then inhibiting the expression of NF-κB p65 and nuclear translocation.

[Exercise preconditioning attenuates pressure overload-induced pathological cardiac hypertrophy: potential role of HSF1 and NF-κB p65 signaling].

OBJECTIVE: To observe the effect of exercise preconditioning (EP) on pressure overload-induced pathological cardiac hypertrophy and explore related mechanisms. METHODS: Ten-week-old male Sprague-Dawley rats (n = 80) were randomly divided into four groups via random number table method: sham, TAC, EP + sham and EP + TAC. Two EP groups were subjected to 4 weeks of treadmill training, and followed by sham and TAC operations. Eight weeks after the surgery, mean arterial pressure (MAP), cardiac morphology, mRNA expressions of the B-type natriuretic peptide (BNP) and heat shock protein (HSP) 70 and protein expression of the BNP, heat shock transcription factor 1 (HSF1), HSP70, nuclear factor κB (NF-κB) p65, and interleukin-2 (IL-2) were examined. RESULTS: (1) Pathological cardiac hypertrophy index: eight weeks after TAC, MAP, heart size, HW/BW, cross-sectional area of the cardiomyocytes (CSA) and mRNA and protein expressions of BNP in the LV were all significantly higher in the TAC and EP + TAC groups than respective sham groups (all P < 0.05). HW/BW, CSA, and mRNA and protein expressions of BNP in the LV were significantly lower in EP + TAC group than in TAC group (all P < 0.05). (2) mRNA and protein expressions of HSF1 and HSP70 and nuclear HSF1 levels were significantly downregulated post TAC, however, EP treatment significantly increased the expression of HSF1 and nuclear HSF1 levels in TAC rats (all P < 0.05). (3) mRNA and protein expressions of NF-κB p65 and IL-2 were significantly increased in the TAC and EP + TAC groups compared with the respective sham groups (all P < 0.05), which were significantly downregulated in EP + TAC group compared to TAC group (all P < 0.05). CONCLUSIONS: EP could effectively reduce the cardiac hypertrophic responses induced by TAC possibly through upregulating the expressions of HSF1 and HSP70 and inhibiting the expression of NF-κB p65 and its nuclear translocation.

Recent Progress in MXene Hydrogel for Wearable Electronics.

Recently, hydrogels have attracted great attention because of their unique properties, including stretchability, self-adhesion, transparency, and biocompatibility. They can transmit electrical signals for potential applications in flexible electronics, human-machine interfaces, sensors, actuators, et al. MXene, a newly emerged two-dimensional (2D) nanomaterial, is an ideal candidate for wearable sensors, benefitting from its surface's negatively charged hydrophilic nature, biocompatibility, high specific surface area, facile functionalization, and high metallic conductivity. However, stability has been a limiting factor for MXene-based applications, and fabricating MXene into hydrogels has been proven to significantly improve their stability. The unique and complex gel structure and gelation mechanism of MXene hydrogels require intensive research and engineering at nanoscale. Although the application of MXene-based composites in sensors has been widely studied, the preparation methods and applications of MXene-based hydrogels in wearable electronics is relatively rare. Thus, in order to facilitate the effective evolution of MXene hydrogel sensors, the design strategies, preparation methods, and applications of MXene hydrogels for flexible and wearable electronics are comprehensively discussed and summarized in this work.

Expression of OPN3 in lung adenocarcinoma promotes epithelial-mesenchymal transition and tumor metastasis.

BACKGROUND: Lung adenocarcinoma is the most common pathological lung cancer and an important cause of cancer-related death. Metastasis is a major underlying reason for poor prognosis of lung adenocarcinoma. Opsin3 (OPN3), a member of the guanine nucleotide-binding protein-coupled receptor superfamily, has been identified to affect the apoptosis of hepatoma cells by modulating the phosphorylation of Akt and Bcl2/Bax. However, the expression and role of OPN3 in lung adenocarcinoma remains unclear. METHODS: Opsin3 expression in lung adenocarcinoma tissues was detected by western blot, qPCR, and immunohistochemistry. Changes in cell migration and invasion ability resulting from the change of OPN3 expression level were detected by wound healing and transwell migration assays. Changes in the markers of epithelial-mesenchymal transformation were detected by western blot and qPCR. RESULTS: Opsin3 expression in lung adenocarcinoma tissues was higher than that in normal lung tissues. Patients with high expression of OPN3 had lower survival rates. Owing to overexpression of OPN3, the HCC827 cells showed enhanced invasion and migration ability in vitro. Upon decreasing the expression of OPN3, the invasion and migration ability of the A549 cells decreased. CONCLUSION: Our study demonstrated for the first time that OPN3 gene enhanced the metastasis in lung adenocarcinoma, and its overexpression promoted epithelial-mesenchymal transition. KEY POINTS: A significant finding of the study was that OPN3 acted an oncogene in promoting lung adenocarcinoma metastasis. Our study complemented the research on the expression and function of OPN3 in lung adenocarcinoma.

Protective effect of baicalin against severe burn­induced remote acute lung injury in rats.

Baicalin exhibits antibacterial, anti­viral, anti­oxidative, antipyretic, analgesic, anti­inflammatory and anti­tumor properties. The chemical scavenges oxygen free radicals, protects the cardiovascular system and neurons, protects the liver, and has been used for the prevention and treatment of diabetes­associated complications. The present study investigated the effect of baicalin on severe burn­induced remote acute lung injury (ALI). The present study demonstrated that baicalin significantly decreased the lung wet­to­dry weight ratio, improved pulmonary histological alterations and reduced the expression of high mobility group protein B1 in the rat model of ALI. In addition, treatment with baicalin decreased tumor necrosis factor­α, interleukin (IL)­8, IL­1ß and IL­18 concentrations in the serum, reduced myeloperoxidase activity and malondialdehyde content, and increased the level of superoxide dismutase in the serum in treated model rats with ALI. As a result, baicalin significantly suppressed nucleotide­binding oligomerization, NACHT, LRR and PYD domains­containing protein 3 (NLRP3), caspase­1, nuclear factor­κB and matrix metalloproteinase­9 protein expression in the rat model of ALI. The results of the present study suggested that baicalin may serve a protective role against ALI in rats through the NLRP3 signaling pathway.

Exercise preconditioning attenuates pressure overload-induced pathological cardiac hypertrophy.

Pathological cardiac hypertrophy, a common response of the heart to a variety of cardiovascular diseases, is typically associated with myocytes remodeling and fibrotic replacement, cardiac dysfunction. Exercise preconditioning (EP) increases the myocardial mechanical load and enhances tolerance of cardiac ischemia-reperfusion injury (IRI), however, is less reported in pathological cardiac hypertrophy. To determine the effect of EP in pathological cardiac hypertrophy, Male 10-wk-old Sprague-Dawley rats (n=30) were subjected to 4 weeks of EP followed by 4-8 weeks of pressure overload (transverse aortic constriction, TAC) to induce pathological remodeling. TAC in untrained controls (n=30) led to pathological cardiac hypertrophy, depressed systolic function. We observed that left ventricular wall thickness in end diastole, heart size, heart weight-to-body weight ratio, heart weight-to-tibia length ratio, cross-sectional area of cardiomyocytes and the reactivation of fetal genes (atrial natriuretic peptide and brain natriuretic peptide) were markedly increased, meanwhile left ventricular internal dimension at end-diastole, systolic function were significantly decreased by TAC at 4 wks after operation (P < 0.01), all of which were effectively inhibited by EP treatment (P < 0.05), but the differences of these parameters were decreased at 8 wks after operation. Furthermore, EP treatment inhibited degradation of IκBα, and decreased NF-κB p65 subunit levels in the nuclear fraction, and then reduced IL2 levels in the myocardium of rats subject to TAC. EP can effectively attenuate pathological cardiac hypertrophic responses induced by TAC possibly through inhibition of degradation of IκB and blockade of the NF-κB signaling pathway in the early stage of pathological cardiac hypertrophy.

Transcatheter pulmonary valve replacement by hybrid approach using a novel polymeric prosthetic heart valve: proof of concept in sheep.

BACKGROUND: Since 2000, transcatheter pulmonary valve replacement has steadily advanced. However, the available prosthetic valves are restricted to bioprosthesis which have defects like poor durability. Polymeric heart valve is thought as a promising alternative to bioprosthesis. In this study, we introduced a novel polymeric transcatheter pulmonary valve and evaluated its feasibility and safety in sheep by a hybrid approach. METHODS: We designed a novel polymeric trileaflet transcatheter pulmonary valve with a balloon-expandable stent, and the valve leaflets were made of 0.1-mm expanded polytetrafluoroethylene (ePTFE) coated with phosphorylcholine. We chose glutaraldehyde-treated bovine pericardium valves as control. Pulmonary valve stents were implanted in situ by a hybrid transapical approach in 10 healthy sheep (8 for polymeric valve and 2 for bovine pericardium valve), weighing an average of 22.5±2.0 kg. Angiography and cardiac catheter examination were performed after implantation to assess immediate valvular functionality. After 4-week follow-up, angiography, echocardiography, computed tomography, and cardiac catheter examination were used to assess early valvular function. One randomly selected sheep with polymeric valve was euthanized and the explanted valved stent was analyzed macroscopically and microscopically. FINDINGS: Implantation was successful in 9 sheep. Angiography at implantation showed all 9 prosthetic valves demonstrated orthotopic position and normal functionality. All 9 sheep survived at 4-week follow-up. Four-week follow-up revealed no evidence of valve stent dislocation or deformation and normal valvular and cardiac functionality. The cardiac catheter examination showed the peak-peak transvalvular pressure gradient of the polymeric valves was 11.9±5.0 mmHg, while that of two bovine pericardium valves were 11 and 17 mmHg. Gross morphology demonstrated good opening and closure characteristics. No thrombus or calcification was seen macroscopically. CONCLUSIONS: This design of the novel ePTFE transcatheter pulmonary valve is safe and effective to deploy in sheep by hybrid approach, and the early valvular functionality is good.