Two-dimensional MoSi2As4-based field-effect transistors integrating switching and gas-sensing functions.

Multifunctional nanoscale devices integrating multiple functions are of great importance for meeting the requirements of next-generation electronics. Herein, using first-principles calculations, we propose multifunctional devices based on the two-dimensional monolayer MoSi2As4, where a single-gate field-effect transistor (FET) and FET-type gas sensor are integrated. After introducing the optimizing strategies, such as underlap structures and dielectrics with a high dielectric constant (κ), we designed a 5 nm gate-length MoSi2As4 FET, whose performance fulfilled the key criteria of the International Technology Roadmap for Semiconductors (ITRS) for high-performance semiconductors. Under the joint adjustment of the underlap structure and high-κ dielectric material, the on/off ratio of the 5 nm gate-length FET reached up to 1.38 × 104. In addition, driven by the high-performance FET, the MoSi2As4-based FET-type gas sensor showed a sensitivity of 38% for NH3 and 46% for NO2. Moreover, the weak interaction between NH3 (NO2) and MoSi2As4 favored the recycling of the sensor. Furthermore, the sensitivity of the sensor could be effectively improved by the gate voltage, and was increased up to 67% (74%) for NH3 (NO2). Our work provides theoretical guidance for the fabrication of multifunctional devices combining a high-performance FET and sensitive gas sensor.

Self-Priming DNA Polymerization-Propelled Stochastic Walkers on Magnetic Microbeads for Amplified Detection of miRNA.

Sensitive detection of miRNA targets in complex biological samples possesses great value in biopsy analysis and disease diagnosis but is still challenging because of low abundance and nonspecific interferences. In this work, self-primer DNA polymerization-propelled stochastic walkers (SWs) were proposed to detect miRNA-24 by combining magnetic microbeads (MMBs) and flow cytometry. The MMBs not only provide a three-dimensional interface for DNA walkers but also facilitate the enrichment and isolation of RNA targets from complex biological samples such as serum. The SWs can be initiated to walk through the entire surface of MMBs and transduce RNA walking into amplified fluorescence signals, with the detection limit of miRNA-24 at 0.95 pM. Moreover, this strategy integrating with flow cytometry was demonstrated to have good specificity with other homologous miRNAs. This platform offers promising applications in RNA biosensing and biomedical diagnostics.

Effect of home-based cardiac rehabilitation for patients with heart failure: a systematic review and meta-analysis / Rehabilitación para pacientes con insuficiencia cardíaca: una revisión sistemática y metanálisis

SUMMARY: This study is to investigate the effect of home-based cardiac rehabilitation (HBCR) on quality of life, functional capacity, and readmission rates in patients with heart failure. Randomized controlled trials (RCTs) were screened from Cochrane Library, CINAHL, EMBASE, and MEDLINE. The intervention group received a standardized HBCR or a comprehensive rehabilitation strategy that included HBCR. The participants in the control group received CR at a medical center or usual care without CR intervention. The main outcome measurements included quality of life, exercise capacity, mortality and re-hospitalization. This meta-analysis included 20 RCTs, in which 16 studies compared HBCR with usual care, and 4 studies compared HBCR with center-based CR. In comparison with the usual care, HBCR improved the total quality of life score [MD=-5.85, 95 % CI (-9.76, - 1.94), P=0.003, I2=75 %]. Patients with HBCR and usual care were significantly different in VO2max [MD=1.05 mL/kg/min, 95 % CI (0.35, 1.75), P=0.003, I2=46 %]. However, VO2max of patients with HBCR was not significantly different from those with center-based CR [MD=0.08 mL/kg/min, 95 % CI (-1.29, 1.44), P=0.91, I2=0 %]. There was statistically significant difference in the 6-min Walk Distance between usual care and HBCR (for distance [MD=11.84, 95 % CI (7.41, 16.28), P<0.00001, I2=0 %]; and for feet [MD=98.93, 95 % CI (26.79, 171.08), P=0.007, I2=56 %]). However, there was no significant difference in 6-min Walk Distance between patients with HBCR and center-based CR [MD=12.45, 95 % CI (-9.81, 34.72), P=0.27, I2=0 %] , or in anxiety and depression between patients with usual care and HBCR (for anxiety, [MD=-0.25, 95 % CI (-0.56, 0.05), P=0.11, I2=0 %]; for depression, [MD=-0.18, 95 % CI (-0.51, 0.16), P=0.30, I2=0 %] . No significant difference was found in death number [RR=1.04, 95 % CI (0.55, 1.98), P=0.90, I2=0 %] or in the number of re-hospitalization [RR=0.88, 95 % CI (0.66, 1.18), P=0.40, I2=0 %] between usual care and HBCR. For patients with heart failure, compare with usual care and center-based CR, HBCR can improve the total quality of life. Compare with usual care, HBCR can improve VO2max and 6-min Walk Distance, but compare with center- based CR, there are no differences in mortality, re-hospitalization rate or incidence of anxiety and depression. Additionally, center- based CR and HBCR showed similar outcomes and medical costs.

El objetivo de este estudio fue investigar el efecto de la rehabilitación cardíaca domiciliaria (HBCR) sobre la calidad de vida, la capacidad funcional y las tasas de reingreso en pacientes con insuficiencia cardíaca. Se seleccionaron ensayos controlados aleatorios (ECA) de la Biblioteca Cochrane, CINAHL, EMBASE y MEDLINE. El grupo de intervención recibió un HBCR estandarizado o una estrategia de rehabilitación integral que incluía HBCR. Los participantes del grupo de control recibieron RC en un centro médico o atención habitual sin intervención de RC. Las principales medidas de resultado incluyeron la calidad de vida, la capacidad de ejercicio, la mortalidad y la rehospitalización. Este metanálisis incluyó 20 ECA, en los que 16 estudios compararon HBCR con la atención habitual y 4 estudios compararon que mejoró la puntuación total de calidad de vida [DM=-5,85, IC del 95 % (-9,76, -1,94), P=0,003, I2=75 %]. Los pacientes con HBCR y atención habitual fueron significativamente diferentes en el VO2máx [DM = 1,05 ml/kg/ min, IC del 95 % (0,35, 1,75), P = 0,003, I2 = 46 %]. Sin embargo, el VO2max de los pacientes con HBCR no fue significativamente diferente de aquellos con CR basada en el centro [DM = 0,08 ml/kg/min, IC del 95 % (-1,29, 1,44), P = 0,91, I2 = 0 %]. Hubo una diferencia estadísticamente significativa en la distancia de caminata de 6 minutos entre la atención habitual y HBCR (para la distancia [DM=11,84, IC del 95 % (7,41, 16,28), P<0,00001, I2=0 %]; y para los pies [DM= 98,93, IC 95 % (26,79, 171,08), P=0,007, I2=56 %]). Sin embargo, no hubo una diferencia significativa en la distancia de caminata de 6 minutos entre los pacientes con HBCR y CR basada en el cen- tro [DM = 12,45, IC del 95 % (-9,81, 34,72), P = 0,27, I2 = 0 %], o en la ansiedad y depresión entre pacientes con atención habitual y HBCR (para ansiedad, [DM=-0,25, IC del 95 % (-0,56, 0,05), P=0,11, I2=0 %]; para depresión, [DM=-0,18, 95 % IC (- 0,51, 0,16), P=0,30, I2=0 %] No se encontraron diferencias significativas en el número de muertes [RR=1,04, IC del 95 % (0,55, 1,98), P=0,90, I2=0 %] o en el número de reingresos [RR=0,88, IC 95 % (0,66, 1,18), P=0,40, I2=0 %] entre atención habitual y HBCR. Para los pacientes con insuficiencia cardíaca, en comparación con la atención habitual y la CR en un centro, la HBCR puede mejorar la calidad de vida total. En comparación con la atención habitual, la HBCR puede mejorar el VO2máx y la distancia recorrida en 6 minutos, pero en comparación con la CR basada en un centro, no hay diferencias en la mortalidad, la tasa de rehospitalización o la incidencia de ansiedad y depresión. Además, CR y HBCR basados en el centro mostraron resultados y costos médicos similares.

Catalyst-Accelerated Circular Cascaded DNA Circuits: Simpler Design, Faster Speed, Higher Gain.

DNA cascaded circuits have great potential in detecting low abundance molecules in complex biological environment due to their powerful signal amplification capability and nonenzymatic feature. However, the problem of the cascaded circuits is that the design is relatively complex and the kinetics is slow. Herein, a new design paradigm called catalyst-accelerated circular cascaded circuits is proposed, where the catalyst inlet is implanted and the reaction speed can be adjusted by the catalyst concentration. This new design is very simple and only requires three hairpin probes. Meanwhile, the results of a series of studies demonstrate that the reaction speed can be accelerated and the sensitivity can be also improved. Moreover, endogenous mRNA can also be used as a catalyst to drive the circuits to amplify the detection of target miRNA in live cells and in mice. These catalyst-accelerated circular cascaded circuits can substantially expand the toolbox for intracellular low abundance molecular detection.

Diminished miR-374c-5p negatively regulates IL (interleukin)-6 in unexplained recurrent spontaneous abortion.

Unexplained recurrent spontaneous abortion (URSA) is commonly observed, and seriously affects women's reproductive health. Excessive interleukin-6 (IL-6) production has been shown to frequently occur and relate to URSA pathogenesis. In this study, the miRNA expression profile in peripheral blood mononuclear cells (PBMCs) from URSA patients and normal pregnant (NP) women was assessed by miRNA microarray and real-time quantitative reverse-transcription polymerase chain reaction (qPCR). MiRNA target prediction tools and luciferase reporter assay were used to detect direct binding between miRNAs and IL6. Functional study of administering anti-IL-6 neutralizing antibody and miR-374c-5p mimics to an URSA animal model was performed to evaluate embryo resorption rates. In the results, compared with NP women, the expression of IL-6 increased markedly in PBMCs and decidual tissues at both mRNA and protein levels, while miR-374c-5p expression decreased significantly. Prediction software and luciferase reporter assay showed that miR-374c-5p binds with IL6 3'UTR via the complementary bases. Transfection of miR-374c-5p mimics into an in vitro HeLa cell line significantly downregulated the expression of IL-6, while transfection of the miR-374c-5p inhibitor induced an opposite result. In the URSA mouse model, miR-374c-5p overexpression reduced the embryo resorption rate significantly, accompanied with decreased expression of IL-6 in the decidua. To sum up, downregulated miR-374c-5p was involved in the pathogenesis of URSA by enhancing IL-6 expression. Modulation of miR-374c-5p expression may be used to regulate IL-6 production for the treatment of URSA.

C16 Peptide and Ang-1 Improve Functional Disability and Pathological Changes in an Alzheimer's Disease Model Associated with Vascular Dysfunction.

Alzheimer's disease (AD) is a neurological disorder characterized by neuronal cell death, tau pathology, and excessive inflammatory responses. Several vascular risk factors contribute to damage of the blood-brain barrier (BBB), secondary leak-out of blood vessels, and infiltration of inflammatory cells, which aggravate the functional disability and pathological changes in AD. Growth factor angiopoietin-1 (Ang-1) can stabilize the endothelium and reduce endothelial permeability by binding to receptor tyrosine kinase 2 (Tie2). C16 peptide (KAFDITYVRLKF) selectively binds to integrin ανß3 and competitively inhibits leukocyte transmigration into the central nervous system by interfering with leukocyte ligands. In the present study, 45 male Sprague-Dawley (SD) rats were randomly divided into three groups: vehicle group, C16 peptide + Ang1 (C + A) group, and sham control group. The vehicle and C + A groups were subjected to two-vessel occlusion (2-VO) with artery ligation followed by Aß1-42 injection into the hippocampus. The sham control group underwent sham surgery and injection with an equal amount of phosphate-buffered saline (PBS) instead of Aß1-42. The C + A group was administered 1 mL of drug containing 2 mg of C16 and 400 µg of Ang-1 daily for 2 weeks. The sham control and vehicle groups were administered 1 mL of PBS for 2 weeks. Our results showed that treatment with Ang-1 plus C16 improved functional disability and reduced neuronal death by inhibiting inflammatory cell infiltration, protecting vascular endothelial cells, and maintaining BBB permeability. The results suggest that these compounds may be potential therapeutic agents for AD and warrant further investigation.

Neuroprotective effect of pseudoginsenoside-F11 on permanent cerebral ischemia in rats by regulating calpain activity and NR2A submit-mediated AKT-CREB signaling pathways.

BACKGROUND: N-methyl-d-aspartate receptors (NMDARs) have been demonstrated to play central roles in stroke pathology and recovery, including dual roles in promoting either neuronal survival or death with their different subtypes and locations. PURPOSE: We have previously demonstrated that pseudoginsenoside-F11 (PF11) can provide long-term neuroprotective effects on transient and permanent ischemic stroke-induced neuronal damage. However, it is still needed to clarify whether NMDAR-2A (NR2A)-mediated pro-survival signaling pathway is involved in the beneficial effect of PF11 on permanent ischemic stroke. MATERIAL AND METHODS: PF11 was administrated in permanent middle cerebral artery occlusion (pMCAO)-operated rats. The effect of PF11 on oxygen-glucose deprivation (OGD)-exposed primary cultured neurons were further evaluated. The regulatory effect of PF11 on NR2A expression and the activation of its downstream AKT-CREB pathway were detected by Western blotting and immunofluorescence in the presence or absence of a specific NR2A antagonist NVP-AAM077 (NVP) both in vivo and in vitro. RESULTS: PF11 dose- and time-dependently decreased calpain1 (CAPN1) activity and its specific breakdown product α-Fodrin expression, while the expression of Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII-α) was significantly upregulated in the cortex and striatum of rats at 24 h after the onset of pMCAO operation. Moreover, PF11 prevented the downregulation of NR2A, p-AKT/AKT, and p-CREB/CREB in both in vivo and in vitro stroke models. Finally, the results indicated treatment with NVP can abolish the effects of PF11 on alleviating the ischemic injury and activating NR2A-mediated AKT-CREB signaling pathway. CONCLUSIONS: Our results demonstrate that PF11 can exert neuroprotective effects on ischemic stroke by inhibiting the activation of CAPN1 and subsequently enhancing the NR2A-medicated activation of AKT-CREB pathway, which provides a mechanistic link between the neuroprotective effect of PF11 against cerebral ischemia and NR2A-associated pro-survival signaling pathway.

The emerging roles of TLR and cGAS signaling in tumorigenesis and progression of ovarian cancer.

Ovarian cancer is fatal to women and has a high mortality rate. Although on-going efforts are never stopped in identifying diagnostic and intervention strategies, the disease is so far unable to be well managed. The most important reason for this is the complexity of pathogenesis for OC, and therefore, uncovering the essential molecular biomarkers accompanied with OC progression takes the privilege for OC remission. Inflammation has been reported to participate in the initiation and progression of OC. Both microenvironmental and tumor cell intrinsic inflammatory signals contribute to the malignancy of OC. Inflammation responses can be triggered by various kinds of stimulus, including endogenous damages and exogenous pathogens, which are initially recognized and orchestrated by a series of innate immune system related receptors, especially Toll like receptors, and cyclic GMP-AMP synthase. In this review, we will discuss the roles of innate immune system related receptors, including TLRs and cGAS, and responses both intrinsic and exogenetic in the development and treatment of OC.

Combined treatment with C16 peptide and angiopoietin-1 confers neuroprotection and reduces inflammation in 3-nitropropionic acid-induced dystonia mice.

Dystonia is a disorder associated with abnormalities in many brain regions including the basal ganglia and cerebellum. The toxin 3-Nitropropionic acid (3-NP) can induce neuropathologies in the mice striatum and nigra substance, including excitotoxicity, neuroinflammation, and extensive neuronal atrophy, characterized by progressive motor dysfunction, dystonia, and memory loss, mimicking those observed in humans. We established a mouse model of dystonia by administering 3-NP. Given the reported neuroprotective effects of the endothelial growth factor angiopoietin-1 (Ang-1) and the anti-inflammatory integrin αvß3 binding peptide C16, we performed this study to evaluate their combined effects on 3-NP striatal toxicity and their therapeutic potential with multiple methods using an in vivo mouse model. Sixty mice were equally and randomly divided into three groups: control, 3-NP treatment, and 3-NP+C16+Ang-1 treatment. Behavioral and electrophysiological tests were conducted and the effect of the combined C16+Ang-1 treatment on neural function recovery was determined. We found that C16+Ang-1 treatment alleviated 3-NP-induced behavioral, biochemical, and cellular alterations in the central nervous system and promoted function recovery by restoring vascular permeability and reducing inflammation in the micro-environment. In conclusion, our results confirmed the neuroprotective effect of combined C16+Ang-1 treatment and suggest their potential as a complementary therapeutic against 3-NP-induced dystonia.

Contribution of Thrombospondin-1 and -2 to Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome.

Thrombospondin (TSP) proteins have been shown to impact T-cell adhesion, migration, differentiation, and apoptosis. Thrombospondin-1 (TSP-1) is specifically upregulated in several inflammatory diseases and can effectively promote lipopolysaccharide- (LPS-) induced inflammation. In contrast, thrombospondin-2 (TSP-2) has been associated with activation of "anti-inflammatory" T-regulatory cells (Tregs). In this study, we investigated the effects of both TSP-1 and TSP-2 overexpression on macrophage polarization and activation in vitro and in vivo. We analyzed the effects of TSP-1 and TSP-2 on inflammation, vascular endothelial permeability, edema, ultrastructural morphology, and apoptosis in lung tissues of an ARDS mouse model and cultured macrophages. Our results demonstrated that TSP-2 overexpression effectively attenuated LPS-induced ARDS in vivo and promoted M2 macrophage phenotype polarization in vitro. Furthermore, TSP-2 played a role in regulating pulmonary vascular barrier leakage by activating the PI3K/Akt pathway. Overall, our findings indicate that TSP-2 can modulate inflammation and could therefore be a potential therapeutic target against LPS-induced ARDS.

An ultra-sensitive gas sensor based on a two-dimensional manganese porphyrin monolayer.

The development of highly sensitive, low-power consuming, stable and recyclable gas sensing devices at room temperature has become an important solution for environmental safety detection. Utilizing a two-dimensional metalloporphyrin monolayer for gas sensing is appealing due to its large specific surface area and high surface activity. A two-dimensional manganese porphyrin monolayer (2DMnPr) is selected from 2D metalloporphyrins with 3d metal centers due to its semi-metallicity to explore its gas sensing properties. Using first-principles calculations, we systematically investigate the electronic structures and adsorption characteristics of gas molecules with toxicity and greenhouse effect on the surface of 2DMnPr, including H2S, CO, CO2, SO2, NO and NO2. The strength of the interaction and charge transfer between the 2DMnPr surface and the adsorbed molecules have a direct effect on the electronic properties and the sensing properties of the adsorbent surface. The sensing performance of the 2DMnPr adsorbent is evaluated via two observable parameters: work function and electrical conductivity. The work functions of 2DMnPr after the adsorption of CO, SO2, NO and NO2 gas molecules increase by different degrees depending on the charge transfer, and those of the H2S and CO2 cases decrease. In our simulation, adsorption of CO, SO2, NO and NO2 gas molecules affects the electronic properties of 2DMnPr markedly, and current-voltage characteristics within a low bias range uncover the superior sensitivity of the conductivity of the 2DMnPr monolayer to these molecules. Besides, the sensing performance is demonstrated to be stable under strain and at room temperature. The desorption time of a gas is positively related to its adsorption energy. The recovery time of CO is predicted to be short enough to realize sustainable detection at room temperature, and the SO2, NO and NO2 gases can also be desorbed at higher temperatures. These results demonstrate that 2DMnPr enables the sensitive detection of these gases and predict the potential application of 2DMnPr as an ultra-sensitive, low-power, stable and recyclable gas sensor at room temperature.

CAPN1 (Calpain1)-Mediated Impairment of Autophagic Flux Contributes to Cerebral Ischemia-Induced Neuronal Damage.

Background and Purpose: CAPN1 (calpain1)­an intracellular Ca2+-regulated cysteine protease­can be activated under cerebral ischemia. However, the mechanisms by which CAPN1 activation promotes cerebral ischemic injury are not defined. Methods: In the present study, we used adeno-associated virus-mediated genetic knockdown and pharmacological blockade (MDL-28170) of CAPN1 to investigate the role of CAPN1 in the regulation of the autophagy-lysosomal pathway and neuronal damage in 2 models, rat permanent middle cerebral occlusion in vivo model and oxygen-glucose­deprived primary neuron in vitro model. Results: CAPN1 was activated in the cortex of permanent middle cerebral occlusion­operated rats and oxygen-glucose deprivation­exposed neurons. Genetic and pharmacological inhibition of CAPN1 significantly attenuated ischemia-induced lysosomal membrane permeabilization and subsequent accumulation of autophagic substrates in vivo and in vitro. Moreover, inhibition of CAPN1 increased autophagosome formation by decreasing the cleavage of the autophagy regulators BECN1 (Beclin1) and ATG (autophagy-related gene) 5. Importantly, the neuron-protective effect of MDL-28170 on ischemic insult was reversed by cotreatment with either class III-PI3K (phosphatidylinositol 3-kinase) inhibitor 3-methyladenine or lysosomal inhibitor chloroquine (chloroquine), suggesting that CAPN1 activation-mediated impairment of autophagic flux is crucial for cerebral ischemia-induced neuronal damage. Conclusions: The present study demonstrates for the first time that ischemia-induced CAPN1 activation impairs lysosomal function and suppresses autophagosome formation, which contribute to the accumulation of substrates and aggravate the ischemia-induced neuronal cell damage. Our work highlights the vital role of CAPN1 in the regulation of cerebral ischemia­mediated autophagy-lysosomal pathway defects and neuronal damage.

Meta-analysis based gene expression profiling reveals functional genes in ovarian cancer.

BACKGROUND: Ovarian cancer causes high mortality rate worldwide, and despite numerous attempts, the outcome for patients with ovarian cancer are still not well improved. Microarray-based gene expressional analysis provides with valuable information for discriminating functional genes in ovarian cancer development and progression. However, due to the differences in experimental design, the results varied significantly across individual datasets. METHODS: In the present study, the data of gene expression in ovarian cancer were downloaded from Gene Expression Omnibus (GEO) and 16 studies were included. A meta-analysis based gene expression analysis was performed to identify differentially expressed genes (DEGs). The most differentially expressed genes in our meta-analysis were selected for gene expression and gene function validation. RESULTS: A total of 972 DEGs with P-value < 0.001 were identified in ovarian cancer, including 541 up-regulated genes and 431 down-regulated genes, among which 92 additional DEGs were found as gained DEGs. Top five up- and down-regulated genes were selected for the validation of gene expression profiling. Among these genes, up-regulated CD24 molecule (CD24), SRY (sex determining region Y)-box transcription factor 17 (SOX17), WFDC2, epithelial cell adhesion molecule (EPCAM), innate immunity activator (INAVA), and down-regulated aldehyde oxidase 1 (AOX1) were revealed to be with consistent expressional patterns in clinical patient samples of ovarian cancer. Gene functional analysis demonstrated that up-regulated WFDC2 and INAVA promoted ovarian cancer cell migration, WFDC2 enhanced cell proliferation, while down-regulated AOX1 was functional in inducing cell apoptosis of ovarian cancer. CONCLUSION: Our study shed light on the molecular mechanisms underlying the development of ovarian cancer, and facilitated the understanding of novel diagnostic and therapeutic targets in ovarian cancer.

The protective effects of C16 peptide and angiopoietin-1 compound in lipopolysaccharide-induced acute respiratory distress syndrome.

C16 peptide and angiopoietin-1 (Ang-1) have been found to have anti-inflammatory activity in various inflammation-related diseases. However, their combined role in acute respiratory distress syndrome (ARDS) has not been investigated yet. The objective of this study was to investigate the effects of C16 peptide and Ang-1 in combination with lipopolysaccharide (LPS)-induced inflammatory insult in vitro and in vivo. Human pulmonary microvascular endothelial cells and human pulmonary alveolar epithelial cells were used as cell culture systems, and an ARDS rodent model was used for in vivo studies. Our results demonstrated that C16 and Ang-1 in combination significantly suppressed inflammatory cell transmigration by 33% in comparison with the vehicle alone, and decreased the lung tissue wet-to-dry lung weight ratio to a maximum of 1.53, compared to 3.55 in the vehicle group in ARDS rats. Moreover, C + A treatment reduced the histology injury score to 60% of the vehicle control, enhanced arterial oxygen saturation (SO2), decreased arterial carbon dioxide partial pressure (PCO2), and increased oxygen partial pressure (PO2) in ARDS rats, while also improving the survival rate from 47% (7/15) to 80% (12/15) and diminishing fibrosis, necrosis, and apoptosis in lung tissue. Furthermore, when C + A therapy was administered 4 h following LPS injection, the treatment showed significant alleviating effects on pulmonary inflammatory cell infiltration 24 h postinsult. In conclusion, our in vitro and in vivo studies show that C16 and Ang-1 exert protective effects against LPS-induced inflammatory insult. C16 and Ang-1 hold promise as a novel agent against LPS-induced ARDS. Further studies are needed to determine the potential for C16 and Ang-1 in combination in treating inflammatory lung diseases.

C16 peptide and angiopoietin-1 protect against LPS-induced BV-2 microglial cell inflammation.

AIMS: Pathological alterations in the brain can cause microglial activation (MA). Thus, inhibiting MA could provide a new approach for treating neurodegenerative disorders. MAIN METHODS: To investigate the effect of C16 peptide and angiopoietin-1 (Ang1) on inflammation following MA, we stimulated microglial BV-2 cells with lipopolysaccharide (LPS) and used dexmedetomidine (DEX) as a positive control. Specific inhibitors of Tie2, αvß3 and α5ß1 integrins, and PI3K/Akt were applied to investigate the neuron-protective and anti-inflammatory effects and signaling pathway of C16 + Ang1 treatment in the LPS-induced BV-2 cells. KEY FINDINGS: Our results showed that C16 + Ang1 treatment reduced the microglia M1 phenotype but promoted the microglia M2 phenotype. In addition, C16 + Ang1 treatment suppressed leukocyte migration across human pulmonary microvascular endothelial cells, reduced the levels of pro-inflammatory factors [inducible nitric oxide synthase (iNOS), interleukin (IL)-1ß, tumor necrosis factor (TNF-α)], and cellular apoptosis factors (caspase-3 and p53), and decreased lactate dehydrogenase (LDH) release, but promoted anti-inflammatory cytokine (IL-10) expression and cell proliferation in the LPS-activated BV-2 cells. The signaling pathways underlying the neuron-protective and anti-inflammatory effects of C16 + Ang1 may be mediated by Tie2-PI3K/Akt, Tie2-integrin and integrin-PI3K/Akt. SIGNIFICANCE: The neuron-protective and anti-inflammatory effects of C16 + Ang1 treatment included M1 to M2 microglia phenotype switching, blocking leukocyte transmigration, decreasing apoptotic and inflammatory factors, and promoting cellular viability.

Neuronal-targeted TFEB rescues dysfunction of the autophagy-lysosomal pathway and alleviates ischemic injury in permanent cerebral ischemia.

Mounting attention has been focused on defects in macroautophagy/autophagy and the autophagy-lysosomal pathway (ALP) in cerebral ischemia. TFEB (transcription factor EB)-mediated induction of ALP has been recently considered as the common mechanism in ameliorating the pathological lesion of myocardial ischemia and neurodegenerative diseases. Here we explored the vital role of TFEB in permanent middle cerebral artery occlusion (pMCAO)-mediated dysfunction of ALP and ischemic insult in rats. The results showed that ALP function was first enhanced in the early stage of the ischemic process, especially in neurons of the cortex, and this was accompanied by increased TFEB expression and translocation to the nucleus, which was mediated at least in part through activation by PPP3/calcineurin. At the later stages of ischemia, a gradual decrease in the level of nuclear TFEB was coupled with a progressive decline in lysosomal activity, accumulation of autophagosomes and autophagy substrates, and exacerbation of the ischemic injury. Notably, neuron-specific overexpression of TFEB significantly enhanced ALP function and rescued the ischemic damage, starting as early as 6 h and even lasting to 48 h after ischemia. Furthermore, neuron-specific knockdown of TFEB markedly reversed the activation of ALP and further aggravated the neurological deficits and ischemic outcome at the early stage of pMCAO. These results highlight neuronal-targeted TFEB as one of the key players in the pMCAO-mediated dysfunction of ALP and ischemic injury, and identify TFEB as a promising target for therapies aimed at neuroprotection in cerebral ischemia. Abbreviations: AAV, adeno-associated virus; AIF1/IBA1, allograft inflammatory factor 1; ALP, autophagy-lysosomal pathway; CQ, chloroquine; CTSB, cathepsin B; CTSD, cathepsin D; CsA, cyclosporin A; GFAP, glial fibrillary acidic protein; LAMP, lysosomal-associated membrane protein; LC3, microtubule-associated protein 1 light chain 3; MAP2, microtubule-associated protein 2; mNSS, modified Neurological Severity Score; MTOR, mechanistic target of rapamycin kinase; OGD, oxygen and glucose deprivation; pMCAO, permanent middle cerebral artery occlusion; RBFOX3/NeuN, RNA binding fox-1 homolog 3; SQSTM1, sequestosome1; TFEB, transcription factor EB; TTC, 2,3,5-triphenyltetrazolium chloride.

[DNA methylation of HDAC4 gene affects the trans-differentiation process of hMSCs into sweat gland like cells].

OBJECTIVE: To investigate the changesof DNA methylation in histone deacetylases 4 gene (HDAC4) and its effectduring the trans-differentiation process of human mesenchymal stem cells (hMSCs) into sweat gland like cells (SGLCs). METHODS: Selected cell lines of human mesenchymal stem cells (hMSCs) were cultured and expended in vitro, the third generation ofhMSCs and heat-shocked sweat gland cells were picked up, and were co-culturedwith adding inducible factor in the transwell chamber. The sweat gland like cells (SGLCs)in experiment group and the hMSCs in control group were collected, the changes of DNA methylation degree of CpG dinucleotide sitesin histone deacetylases 4 gene (HDAC4) promotor were detected by methylation specific PCR (MSP)andMaldi-TOF Mass Array. And then, the hMSCs in experiment group were treated with 5-aza-CdR (5-aza-2-deoxycytidine, 10 µmol/L), while the hMSCsin control group were culturedwith PBS at the same time. ThemRNA expressions of HDAC4 gene and carcino-embryonic antigen (CEA)gene in the two groups were measured by RT-PCR. RESULTS: The methylation of HDAC4gene in hMSCs was in high level before induction, the methylation degreeof CpG dinucleotide sites located in cg2463009 was 0.901, and the methylation degree of HDAC4gene in SGLCs was markedly decreased by 37% after induction, which was 0.531. The methylationlevel of CpG dinucleotide sites located in cg14823429was changed from 0.687to 0.386 after induction. The mRNA expression of HDAC4 gene was upregulated in test group after treated with 5-aza-CdR for 48 hours, the mRNA expression of CEA gene related with transdifferentiation was enhanced too at the same term, there was significantly statistic difference compared with control group (P<0.05). CONCLUSIONS: Methylation of HDAC4 gene participates in the regulation of the trans-differentiation of hMSCs into sweet gland like cells.

Tripartite Motif 8 (TRIM8) Positively Regulates Pro-inflammatory Responses in Pseudomonas aeruginosa-Induced Keratitis Through Promoting K63-Linked Polyubiquitination of TAK1 Protein.

Pseudomonas aeruginosa (PA)-induced keratitis is a rapidly progressive ocular infectious disease that often leads to inflammatory epithelial edema, stromal infiltration, tissue destruction, corneal ulceration, and vision loss. In this study, we investigate the role of tripartite motif 8 (TRIM8) in regulating the inflammatory process of PA-induced keratitis. The expression of TRIM8 was increased in mouse corneas and in vitro-cultured macrophages after PA infection. Knockdown of the expression of TRIM8 significantly inhibited the activation of NF-κB signaling and decreased the production of pro-inflammatory cytokines both in vivo and in vitro after infected with PA. Furthermore, we investigated the potential mechanism and we found after PA infection that TRIM8 could promote K63-linked polyubiquitination of transforming growth factor ß-activated kinase 1 (TAK1), leading to the activation of TAK1 and enhanced inflammatory responses. Taken together, we demonstrated that TRIM8 has pro-inflammatory effect on PA-induced keratitis and suggest TRIM8 as a potential therapeutic target for keratitis.