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Thoracic aortic aneurysm (TAA) is a localized or diffuse dilatation of the thoracic aortas, and causes many sudden deaths each year worldwide. However, there is no effective pharmacologic therapy. Here, we show that AGGF1 effectively blocks TAA-associated arterial inflammation and remodeling in three different mouse models (mice with transverse aortic constriction, Fbn1 C1041G/+ mice, and β-aminopropionitrile-treated mice). AGGF1 expression is reduced in the ascending aortas from the three models and human TAA patients. Aggf1 +/- mice and vascular smooth muscle cell (VSMC)-specific Aggf1 smcKO knockout mice show aggravated TAA phenotypes. Mechanistically, AGGF1 enhances the interaction between its receptor integrin α7 and latency-associated peptide (LAP)-TGF-β1, blocks the cleavage of LAP-TGF-β1 to form mature TGF-β1, and inhibits Smad2/3 and ERK1/2 phosphorylation in VSMCs. Pirfenidone, a treatment agent for idiopathic pulmonary fibrosis, inhibits TAA-associated vascular inflammation and remodeling in wild type mice, but not in Aggf1 +/- mice. In conclusion, we identify an innovative AGGF1 protein therapeutic strategy to block TAA-associated vascular inflammation and remodeling, and show that efficacy of TGF-β inhibition therapies require AGGF1. Thoracic aortic aneurysm (TAA) causes many sudden deaths each year, however, no effective drug treatment is available. Here, the authors show that AGGF1 protein therapy attenuates TAA in three different mouse models through integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signalling.

Background Skeletal muscle atrophy is a common condition without a pharmacologic therapy. AGGF1 encodes an angiogenic factor that regulates cell differentiation, proliferation, migration, apoptosis, autophagy and endoplasmic reticulum stress, promotes vasculogenesis and angiogenesis and successfully treats cardiovascular diseases. Here, we report the important role of AGGF1 in the pathogenesis of skeletal muscle atrophy and attenuation of muscle atrophy by AGGF1. Methods In vivo studies were carried out in impaired leg muscles from patients with lumbar disc herniation, two mouse models for skeletal muscle atrophy (denervation and cancer cachexia) and heterozygous Aggf1+/− mice. Mouse muscle atrophy phenotypes were characterized by body weight and myotube cross‐sectional areas (CSA) using H&E staining and immunostaining for dystrophin. Molecular mechanistic studies include co‐immunoprecipitation (Co‐IP), western blotting, quantitative real‐time PCR analysis and immunostaining analysis. Results Heterozygous Aggf1+/− mice showed exacerbated phenotypes of reduced muscle mass, myotube CSA, MyHC (myosin heavy chain) and α‐actin, increased inflammation (macrophage infiltration), apoptosis and fibrosis after denervation and cachexia. Intramuscular and intraperitoneal injection of recombinant AGGF1 protein attenuates atrophy phenotypes in mice with denervation (gastrocnemius weight 81.3 ± 5.7 mg vs. 67.3 ± 5.1 mg for AGGF1 vs. buffer; P < 0.05) and cachexia (133.7 ± 4.7 vs. 124.3 ± 3.2; P < 0.05). AGGF1 expression undergoes remodelling and is up‐regulated in gastrocnemius and soleus muscles from atrophy mice and impaired leg muscles from patients with lumbar disc herniation by 50–60% (P < 0.01). Mechanistically, AGGF1 interacts with TWEAK (tumour necrosis factor‐like weak inducer of apoptosis), which reduces interaction between TWEAK and its receptor Fn14 (fibroblast growth factor‐inducing protein 14). This leads to inhibition of Fn14‐induced NF‐kappa B (NF‐κB) p65 phosphorylation, which reduces expression of muscle‐specific E3 ubiquitin ligase MuRF1 (muscle RING finger 1), resulting in increased MyHC and α‐actin and partial reversal of atrophy phenotypes. Autophagy is reduced in Aggf1+/− mice due to inhibition of JNK (c‐Jun N‐terminal kinase) activation in denervated and cachectic muscles, and AGGF1 treatment enhances autophagy in two atrophy models by activating JNK. In impaired leg muscles of patients with lumbar disc herniation, MuRF1 is up‐regulated and MyHC and α‐actin are down‐regulated; these effects are reversed by AGGF1 by 50% (P < 0.01). Conclusions These results indicate that AGGF1 is a novel regulator for the pathogenesis of skeletal muscle atrophy and attenuates skeletal muscle atrophy by promoting autophagy and inhibiting MuRF1 expression through a molecular signalling pathway of AGGF1‐TWEAK/Fn14‐NF‐κB. More importantly, the results indicate that AGGF1 protein therapy may be a novel approach to treat patients with skeletal muscle atrophy.

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers. To elucidate new regulatory mechanisms for heptocarcinogenesis, we investigated the regulation of p21, a cyclin-dependent kinase (CDK) inhibitor encoded by CDKN1A , in HCC. The expression level of p21 is decreased with the progression of HCC. Luciferase assays with a luciferase-p21-3′ UTR reporter and its serial deletions identified a 15-bp repressor element at the 3′-UTR of CDKN1A , which contains a binding site for miR-95-3p . Mutation of the binding site eliminated the regulatory effect of miR-95-3p on p21 expression. Posttranscriptional regulation of p21 expression by miR-95-3p is mainly on the protein level (suppression of translation). Overexpression of miR-95-3p in two different HCC cell lines, HepG2 and SMMC7721, significantly promoted cell proliferation, cell cycle progression and cell migration, whereas a miR-95-3p specific inhibitor decreased cell proliferation, cell cycle progression and cell migration. The effects of miR-95-3p on cellular functions were rescued by overexpression of p21. Overexpression of miR-95-3p promoted cell proliferation and tumor growth in HCC xenograft mouse models. Expression of miR-95-3p was significantly higher in HCC samples than in adjacent non-cancerous samples. These results demonstrate that miR-95-3p is a potential new marker for HCC and regulates hepatocarcinogenesis by directly targeting CDKN1A /p21 expression.

Glutamine (Gln), known as the most abundant free amino acid, is widely spread in human body. In this study, we demonstrated the protective effects of glutamine against mouse abdominal aortic aneurysm (AAA) induced by both angiotensin II (AngII) and calcium phosphate (Ca (PO ) ) , which was characterized with lower incidence of mouse AAA. Moreover, histomorphological staining visually presented more intact elastic fiber and less collagen deposition in abdominal aortas of mice treated by glutamine. Further, we found glutamine inhibited the excessive production of reactive oxide species (ROS), activity of matrix metalloproteinase (MMP), M1 macrophage activation, and apoptosis of vascular smooth muscle cells (VSMCs) in suprarenal abdominal aortas of mice, what's more, the high expressions of MMP-2 protein, MMP-9 protein, pro-apoptotic proteins, and IL-6 as well as TNF-α in protein and mRNA levels in cells treated by AngII were down-regulated by glutamine. Collectively, these results revealed that glutamine protected against mouse AAA through inhibiting apoptosis of VSMCs, M1 macrophage activation, oxidative stress, and extracellular matrix degradation.

This paper addresses the issue of exponential stability for discrete-time switched neural networks (DSNNs) with time-varying delays. The considered system switches from one mode to another according to the mode-dependent average dwell-time (MDADT), which is more practical than classical average dwell-time (ADT) switching. Moreover, the specific goal is to use some improved zero equations with unrestricted weight matrices, which are provided to obtain more free variables. In addition, the augmented Lyapunov-Krasovskii functionals (LKFs) containing some new state-related vectors are proposed under MDADT switching signal, which effectively obviate the appearance for high-order polynomials. Furthermore, an augmented delay-product-type LKF is also established for enhancing the stability conditions of DSNNs. Then, based on the above methods and some classic inequalities, less conservative stability conditions are provided for DSNNs with time-varying delays. Finally, two numerical examples are offered to show the validity of obtained results.

The TiCxN1−x(001)/TiC(001) interface was studied by the first-principles method to provide the theoretical basis for developing TiCxN1−x/TiC coatings. The partial density of state (PDOS), charge density, charge density difference, and Mulliken population analysis were utilized to investigate the bonding nature and the electronic characteristic of the TiC0.25N0.75/TiC interface. The corresponding results indicate that the bonding nature at the interface is ionic and covalent characteristics, which also exist in bulk materials. The extreme similarity of PDOS among interfacial C, N, and Ti atoms and their bulk counterparts reveals that the electronic structure transition at the interface is smooth. The results of Mulliken population analysis and plots of charge density and charge density difference demonstrate that the charge increased for C in the TiC side is less than that for N in the TiC0.25N0.75 side, which reveals that the ionic bond in TiC0.25N0.75 is stronger than that in TiC. Therefore, TiC0.25N0.75 coating can be an alternative choice to combine with TiC coating in the actual production process of multilayer coatings.

The TiC x N 1− x (001)/TiC(001) interface was studied by the first-principles method to provide the theoretical basis for developing TiC x N 1− x /TiC coatings. The partial density of state (PDOS), charge density, charge density difference, and Mulliken population analysis were utilized to investigate the bonding nature and the electronic characteristic of the TiC 0.25 N 0.75 /TiC interface. The corresponding results indicate that the bonding nature at the interface is ionic and covalent characteristics, which also exist in bulk materials. The extreme similarity of PDOS among interfacial C, N, and Ti atoms and their bulk counterparts reveals that the electronic structure transition at the interface is smooth. The results of Mulliken population analysis and plots of charge density and charge density difference demonstrate that the charge increased for C in the TiC side is less than that for N in the TiC 0.25 N 0.75 side, which reveals that the ionic bond in TiC 0.25 N 0.75 is stronger than that in TiC. Therefore, TiC 0.25 N 0.75 coating can be an alternative choice to combine with TiC coating in the actual production process of multilayer coatings.

Background Spontaneous spheroid culture is a novel three-dimensional (3D) culture strategy for the rapid and efficient selection of progenitor cells. The objectives of this study are to investigate the pluripotency and differentiation capability of spontaneous spheroids from alveolar bone-derived mesenchymal stromal cells (AB-MSCs); compare the advantages of spontaneous spheroids to those of mechanical spheroids; and explore the mechanisms of stemness enhancement during spheroid formation from two-dimensional (2D) cultured cells. Methods AB-MSCs were isolated from the alveolar bones of C57BL/6 J mice. Spontaneous spheroids formed in low-adherence specific culture plates. The stemness, proliferation, and multi-differentiation capacities of spheroids and monolayer cultures were investigated by reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, alkaline phosphatase (ALP) activity, and oil-red O staining. The pluripotency difference between the spontaneous and mechanical spheroids was analyzed using RT-qPCR. Hypoxia-inducible factor (HIFs) inhibition experiments were performed to explore the mechanisms of stemness maintenance in AB-MSC spheroids. Results AB-MSCs successfully formed spontaneous spheroids after 24 h. AB-MSC spheroids were positive for MSC markers and pluripotency markers (Oct4, KLF4, Sox2, and cMyc). Spheroids showed higher Ki67 expression and lower Caspase3 expression at 24 h. Under the corresponding conditions, the spheroids were successfully differentiated into osteogenic and adipogenic lineages. AB-MSC spheroids can induce neural-like cells after neurogenic differentiation. Higher expression of osteogenic markers, adipogenic markers, and neurogenic markers (NF-M, NeuN, and GFAP) was found in spheroids than in the monolayer. Spontaneous spheroids exhibited higher stemness than mechanical spheroids did. HIF-1α and HIF-2α were remarkably upregulated in spheroids. After HIF-1/2α-specific inhibition, spheroid formation was significantly reduced. Moreover, the expression of the pluripotency genes was suppressed. Conclusions Spontaneous spheroids from AB-MSCs enhance stemness and pluripotency. HIF-1/2α plays an important role in the stemness regulation of spheroids. AB-MSC spheroids exhibit excellent multi-differentiation capability, which may be a potent therapy for craniomaxillofacial tissue regeneration.