Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability.

AIMS: Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored. METHODS AND RESULTS: FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study. CONCLUSION: FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.

Anion-driven supramolecular modulation of spin-crossover properties in mononuclear iron(III) Schiff-base complexes.

A series of Fe(III) complexes [Fe(5-F-sal-N-1,4,7,10)]Y (Y = PF6- for 1, Y = ClO4- for 2, Y = I- for 3 and Y = NO3- for 4) have been prepared. Single-crystal X-ray crystallographic studies show that complex 1 crystallizes in the orthorhombic Pna21 space group and complexes 2-4 have an isomorphous structure and crystallize in the same monoclinic space group, P21/n. Complexes 2-4 have two independent molecules (Fe1 and Fe2) in the unit cell. Magnetic susceptibility measurements demonstrated that complexes 1 and 3 showed a gradual one-step SCO behavior (T1/2 for 1 = 177 K and for 3 = 227 K) without thermal hysteresis. The magnetic behavior of 2 shows an incomplete two-step SCO process at T1/2 = 114 K and 170 K, respectively, while 4 is in a high-spin state at all measured temperatures. A careful evaluation of the supramolecular structures of these complexes revealed correlation between the supramolecular packing forces and their SCO behavior. The crystal structure of 1 consists of a three-dimensional (3D) extended network constructed from N-H⋯F and C-H⋯F hydrogen bonds, and C-H⋯π and C⋯C short contacts. In compounds 2-4, the crystal packing is governed by C⋯C, C-H⋯π and p-π interactions for the Fe1 centers and by C-H⋯π/O interactions for the Fe2 centers, which form 1D chains. Additional interactions (C-H⋯F and N-H⋯O/I) connect the neighboring chains and planes to form a complex supramolecular network. The anion⋯π interactions in 4 provide a means for preventing SCO occurring at low temperatures. This suggests that the supramolecular connectivity of the anions influences the magnetic properties.

Senkyunolide I protect against lung injury via inhibiting formation of neutrophil extracellular trap in a murine model of cecal ligation and puncture.

BACKGROUND: Senkyunolide I (SEI), a component of a Chinese herb named Ligusticum Chuanxiong hort, which is included in the formulation of Xuebijing Injection, a medication used to treat sepsis in China. Our previous study showed that SEI was protective against sepsis-associated encephalopathy and the present study was performed to investigate the role of SEI in sepsis-induced lung injury in a murine model of cecal ligation and puncture (CLP). METHODS: SEI (36 mg/kg in 200 µl) or vehicle was administered immediately after CLP surgery. The lung injury was assessed 24 h later by histopathological tests, protein concentration in the bronchoalveolar lavage fluid (BALF), neutrophil recruitment in the lung tissue (myeloperoxidase fluorescence, MPO), pro-inflammatory cytokines and oxidative responses. Platelet activation was detected by CD42d/GP5 immunofluorescence and neutrophil extracellular trap (NET) were determined by immunofluorescence assays and enzyme linked immunosorbent assay (ELISA) of MPO-DNA. In vitro experiments were performed to detect the level of MPO-DNA complex released by SEI-treated neutrophils stimulated with phorbol 12-myristate 13-acetate (PMA) or co-cultured with platelets from CLP mice. RESULTS: SEI administration relieved the injury degree in CLP mice according to the histopathological tests (P < 0.05 compared with DMSO + CLP group). Protein level in the BALF and neutrophil infiltration were remarkably reduced by SEI after CLP surgery (P < 0.05 compared with DMSO + CLP group). TNF-α, IL-1ß and IL-6 were decreased in the plasma and lung tissues from CLP mice treated with SEI (P < 0.05 compared with DMSO + CLP group). The phosphorylation of JNK, ERK, p38 and p65 were all inhibited by SEI (P < 0.05 compared with DMSO + CLP group). Immunofluorescence of MPO showed that neutrophil number was significantly lower in SEI treated CLP mice than in vehicle treated CLP mice (P < 0.05). The CD42d/GP5 staining suggested that platelet activation was significantly reduced and the NET level in the lung tissue and plasma was greatly attenuated by SEI treatment (P < 0.05 compared with DMSO + CLP group). In vitro experiments showed that the MPO-DNA level stimulated by PMA was significantly reduced by SEI treatment (P < 0.05 compared with DMSO treatment). Co-culture neutrophils with platelets from CLP mice resulted in higher level of MPO-DNA complex, while SEI partly reversed such effects of platelet on NET formation. CONCLUSIONS: SEI was protective against lung injury induced by CLP in mice. The NET formation was significantly reduced by SEI treatment, which might be involved in the mechanism of the protective effect.

Melatonin safeguards against fatty liver by antagonizing TRAFs-mediated ASK1 deubiquitination and stabilization in a ß-arrestin-1 dependent manner.

Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal-regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high-fat diet (HFD)-induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho-ASK1, phospho-MKK3/6, phospho-p38, phospho-MKK4/7, and phospho-JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor-associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein ß-arrestin-1 and enabled it to bind to ASK1, which antagonized the TRAFs-mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of ß-arrestin-1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs-mediated ASK1 deubiquitination and stabilization in a ß-arrestin-1 dependent manner.

Bradyrhizobium nanningense sp. nov., Bradyrhizobium guangzhouense sp. nov. and Bradyrhizobium zhanjiangense sp. nov., isolated from effective nodules of peanut in Southeast China.

Nine slow-growing rhizobia isolated from effective nodules on peanut (Arachis hypogaea) were characterized to clarify the taxonomic status using a polyphasic approach. They were assigned to the genus Bradyrhizobium on the basis of 16S rRNA sequences. MLSA of concatenated glnII-recA-dnaK genes classified them into three species represented by CCBAU 53390T, CCBAU 51670T and CCBAU 51778T, which presented the closest similarity to B. guangxiense CCBAU 53363T, B. guangdongense CCBAU 51649T and B. manausense BR 3351T, B. vignae 7-2T and B. forestalis INPA 54BT, respectively. The dDDH (digital DNA-DNA hybridization) and ANI (Average Nucleotide Identity) between the genomes of the three representative strains and type strains for the closest Bradyrhizobium species were less than 42.1% and 91.98%, respectively, below the threshold of species circumscription. Effective nodules could be induced on peanut and Lablab purpureus by all representative strains, while Vigna radiata formed effective nodules only with CCBAU 53390T and CCBAU 51778T. Phenotypic characteristics including sole carbon sources and growth features supported the phylogenetic results. Based on the genotypic and phenotypic features, strains CCBAU 53390T, CCBAU 51670T and CCBAU 51778T are designated the type strains of three novel species, for which the names Bradyrhizobium nanningense sp. nov., Bradyrhizobium guangzhouense sp. nov. and Bradyrhizobium zhanjiangense sp. nov. are proposed, respectively.

Isolation of two bis(silyl)nickel complexes with Si-Si bond formation in a single-crystal-to-single-crystal fashion.

A unique penta-coordinate nickel complex [{1,2-C6H4(SiMe2)(SiH)}2Ni(PEt3)(depe)] (6) that generates two new Si-Si single bonds has been prepared exclusively by the reaction of a chelating silyl hydride 1-(dimethylsilyl)-2-silylbenzene (4) and Ni(depe)(PEt3)2 (depe = Et2PCH2CH2PEt2) in a 2 : 1 ratio. Complex 6 is the first example of mononuclear silyl nickel complexes containing a Si-Si single bond formed in situ. Interestingly, framework 6 exhibits reversible single-crystal-to-single-crystal transformations upon the removal and rebinding of the coordinating PEt3 molecule, which give rise to a PEt3-free complex [{1,2-C6H4(SiMe2)(SiH)}2Ni(depe)] (6'), concomitant with the alteration of the coordination geometry of central metal atoms.

Intrabullous Adhesion Pexia (IBAP) by Percutaneous Pulmonary Bulla Centesis: An Alternative for the Surgical Treatment of Giant Pulmonary Bulla (GPB).

Background and Objective: Most patients with giant pulmonary bulla (GPB) are treated by surgery; however, there is a subset for whom surgery is not a viable option, such as those with contraindications, or those unwilling to undergo operation. Therefore, an alternative minimally invasive method is desired for this subpopulation. The aim of this study was to explore an alternative procedure for treating GPB. Methods: This was a prospective, nonrandomized, single-arm, unblinded study evaluating the efficacy and safety of intrabulla adhesion pexia (IBAP) procedure in GPB patients. The study was conducted between December 2004 and April 2017. Results: There were 38 cases in 36 patients (33 males and 3 females) with the target GPB cavities varying in size (range, 10 cm × 7 cm × 5 cm to 15 cm × 8 cm × 30 cm (anteroposterior diameter × medial-lateral diameter × superoinferior diameter)). After IBAP treatment, the closure ratio of GPB in one month was 86.84% (33/38), while the dyspnea index significantly decreased from 4.11 ± 1.11 to 2.24 ± 1.15 (P < 0.01). In addition, the mean FEV1 (L) increased from 1.06 ± 0.73 to 1.57 ± 1.13 (P < 0.01), while RV (L) decreased from 2.77 ± 0.54 to 2.36 ± 0.38 (P < 0.01) and TLC (L) decreased from 6.46 ± 1.21 to 5.86 ± 1.08 (P < 0.01). Moreover, PaO2 (mmHg) increased from 52.18 ± 8.31 to 68.29 ± 12.34, while the 6 MWD increased by 129.36% from 131.58 ± 105.24 to 301.79 ± 197.90 (P < 0.01). Collectively, these data indicated significant improvement in pulmonary function and exercise tolerance after IBAP treatment. Furthermore, no deaths occurred during IBAP treatment, and no cases of aggravated GPB relapse were reported during the 12-month follow-up period. Conclusions: IBAP is a promising strategy for the treatment of GPB. Our findings demonstrated that IBAP had a noteworthy therapeutic effect, desirable safety, and ideal long-term efficacy for GPB.

MiR-135a Protects Vascular Endothelial Cells Against Ventilator-Induced Lung Injury by Inhibiting PHLPP2 to Activate PI3K/Akt Pathway.

BACKGROUND/AIMS: Loss of endothelial barrier function plays an important role in the development of ventilator-induced lung injury (VILI). This study aimed to investigate the effects of miR135a on VILI in a model of mechanical stretch (MS)-induced human umbilical vein endothelial cell (HUVEC) injury. METHODS: HUVECs were randomly assigned to 7 groups: blank, negative control (NC), NC+MS, miR135a over-expression (mi-miR135a), mi-miR135a + MS, miR135a silencing (si-miR135a) and si-miR135a + MS groups. MS was induced by subjecting cells to cyclic stretch at 20% stretch for 4 h. After 24 h, levels of reactive oxygen species (ROS) were measured by DCFH-DA fluorescence intensity. Apoptosis was measured using annexin V-FITC/propidium iodide assay with flow cytometry. Inflammatory cytokine levels were determined by ELISA. Barrier integrity was determined using FITC-conjugated dextran assay. Expression levels of PI3K, p-PI3K, Akt, p-Akt, Bcl-2 and Bax were examined using western blotting. The interaction between miR135a and PHLPP2 was evaluated by dual-luciferase reporter assay. RESULTS: Our results showed that MS reduced cell numbers, increased the number of apoptotic cells, increased ROS, barrier dysfunction and inflammatory cytokines in HUVECs, and reduced p-PI3K and p-Akt expression; silencing of miR135a worsened MS-induced HUVEC injury. However, miR135a over-expression protected HUVECs against MS-induced increases in apoptotic cells, ROS, barrier dysfunction and inflammatory cytokines, which were accompanied by activation of the PI3K/Akt signaling pathway. Simultaneous silencing of miR135a and PHLPP2 partially salvaged the effects of miR135a silencing, and miR135a was found to interact with PHLPP2. CONCLUSION: miR135a may protect HUVECs from MS-induced injury by inhibiting PHLPP2 to activate PI3k/Akt signaling pathway.

Cholinergic anti-inflammatory pathway inhibits neointimal hyperplasia by suppressing inflammation and oxidative stress.

Neointimal hyperplasia as a consequence of vascular injury is aggravated by inflammatory reaction and oxidative stress. The α7 nicotinic acetylcholine receptor (α7nAChR) is a orchestrator of cholinergic anti-inflammatory pathway (CAP), which refers to a physiological neuro-immune mechanism that restricts inflammation. Here, we investigated the potential role of CAP in neointimal hyperplasia using α7nAChR knockout (KO) mice. Male α7nAChR-KO mice and their wild-type control mice (WT) were subjected to wire injury in left common carotid artery. At 4 weeks post injury, the injured aortae were isolated for examination. The neointimal hyperplasia after wire injury was significantly aggravated in α7nAChR-KO mice compared with WT mice. The α7nAChR-KO mice had increased collagen contents and vascular smooth muscle cells (VSMCs) amount. Moreover, the inflammation was significantly enhanced in the neointima of α7nAChR-KO mice relative to WT mice, evidenced by the increased expression of tumor necrosis factor-α/interleukin-1ß, and macrophage infiltration. Meanwhile, the chemokines chemokine (C-C motif) ligand 2 and chemokine (CXC motif) ligand 2 expression was also augmented in the neointima of α7nAChR-KO mice compared with WT mice. Additionally, the depletion of superoxide dismutase (SOD) and reduced glutathione (GSH), and the upregulation of 3-nitrotyrosine, malondialdehyde and myeloperoxidase were more pronounced in neointima of α7nAChR-KO mice compared with WT mice. Accordingly, the protein expression of NADPH oxidase 1 (Nox1), Nox2 and Nox4, was also higher in neointima of α7nAChR-KO mice compared with WT mice. Finally, pharmacologically activation of CAP with a selective α7nAChR agonist PNU-282987, significantly reduced neointima formation, arterial inflammation and oxidative stress after vascular injury in C57BL/6 mice. In conclusion, our results demonstrate that α7nAChR-mediated CAP is a neuro-physiological mechanism that inhibits neointima formation after vascular injury via suppressing arterial inflammation and oxidative stress. Further, these results imply that targeting α7nAChR may be a promising interventional strategy for in-stent stenosis.

Gene losses and partial deletion of small single-copy regions of the chloroplast genomes of two hemiparasitic Taxillus species.

Numerous variations are known to occur in the chloroplast genomes of parasitic plants. We determined the complete chloroplast genome sequences of two hemiparasitic species, Taxillus chinensis and T. sutchuenensis, using Illumina and PacBio sequencing technologies. These species are the first members of the family Loranthaceae to be sequenced. The complete chloroplast genomes of T. chinensis and T. sutchuenensis comprise circular 121,363 and 122,562 bp-long molecules with quadripartite structures, respectively. Compared with the chloroplast genomes of Nicotiana tabacum and Osyris alba, all ndh genes as well as three ribosomal protein genes, seven tRNA genes, four ycf genes, and the infA gene of these two species have been lost. The results of the maximum likelihood and neighbor-joining phylogenetic trees strongly support the theory that Loranthaceae and Viscaceae are monophyletic clades. This research reveals the effect of a parasitic lifestyle on the chloroplast structure and genome content of T. chinensis and T. sutchuenensis, and enhances our understanding of the discrepancies in terms of assembly results between Illumina and PacBio.

The novel exercise-induced hormone irisin protects against neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotection of physical exercise in cerebral ischemia.

BACKGROUND: Irisin is a novel exercise-induced myokine involved in the regulation of adipose browning and thermogenesis. In this study, we investigated the potential role of irisin in cerebral ischemia and determined whether irisin is involved in the neuroprotective effect of physical exercise in mice. MATERIALS AND METHODS: The middle cerebral artery occlusion (MCAO) model was used to produce cerebral ischemia in mice. First, the plasma irisin levels and changes in expression of the irisin precursor protein FNDC5 in skeletal muscle were determined post ischemic stroke. Second, the association between plasma irisin levels and the neurological deficit score, brain infarct volume, or plasma concentrations of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1ß in mice with MCAO were evaluated. Third, the therapeutic effect of irisin on ischemic brain injury was evaluated in vivo and in vitro. Recombinant irisin was injected directly into the tail vein 30min after the MCAO operation, and then the effects of irisin treatment on brain infarct volume, neurological deficit, neuroinflammation, microglia activation, monocyte infiltration, oxidative stress and intracellular signaling pathway activation (Akt and ERK1/2) were measured. Irisin was also administered in cultured PC12 neuronal cells with oxygen and glucose deprivation (OGD). Finally, to assess the potential involvement of irisin in the neuroprotection of physical exercise, mice were exercised for 2weeks and an irisin neutralizing antibody was injected into these mice to block irisin 1h before the MCAO operation. RESULTS: The plasma irisin concentration and intramuscular FNDC5 protein expression decreased after ischemic stroke. Plasma irisin levels were negatively associated with brain infarct volume, the neurological deficit score, plasma TNF-α and plasma IL-6 concentrations. In OGD neuronal cells, irisin protected against cell injury. In mice with MCAO, irisin treatment reduced the brain infarct volume, neurological deficits, brain edema and the decline in body weight. Irisin treatment inhibited activation of Iba-1+ microglia, infiltration of MPO-1+ monocytes and expression of both TNF-α and IL-6 mRNA. Irisin significantly suppressed the levels of nitrotyrosine, superoxide anion and 4-hydroxynonenal (4-HNE) in peri-infarct brain tissues. Irisin treatment increased Akt and ERK1/2 phosphorylation, while blockade of Akt and ERK1/2 by specific inhibitors reduced the neuroprotective effects of irisin. Finally, the exercised mice injected with irisin neutralizing antibody displayed more severe neuronal injury than the exercised mice injected with control IgG. CONCLUSION: Irisin reduces ischemia-induced neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotective effect of physical exercise against cerebral ischemia, suggesting that irisin may be a factor linking metabolism and cardio-cerebrovascular diseases.

Dynamic Network Connectivity Analysis to Identify Epileptogenic Zones Based on Stereo-Electroencephalography.

Objectives: Accurate localization of epileptogenic zones (EZs) is essential for successful surgical treatment of refractory focal epilepsy. The aim of the present study is to investigate whether a dynamic network connectivity analysis based on stereo-electroencephalography (SEEG) signals is effective in localizing EZs. Methods: SEEG data were recorded from seven patients who underwent presurgical evaluation for the treatment of refractory focal epilepsy and for whom the subsequent resective surgery gave a good outcome. A time-variant multivariate autoregressive model was constructed using a Kalman filter, and the time-variant partial directed coherence was computed. This was then used to construct a dynamic directed network model of the epileptic brain. Three graph measures (in-degree, out-degree, and betweenness centrality) were used to analyze the characteristics of the dynamic network and to find the important nodes in it. Results: In all seven patients, the indicative EZs localized by the in-degree and the betweenness centrality were highly consistent with the clinically diagnosed EZs. However, the out-degree did not indicate any significant differences between nodes in the network. Conclusions: In this work, a method based on ictal SEEG signals and effective connectivity analysis localized EZs accurately. The results suggest that the in-degree and betweenness centrality may be better network characteristics to localize EZs than the out-degree.

TNF-α enhances vascular cell adhesion molecule-1 expression in human bone marrow mesenchymal stem cells via the NF-κB, ERK and JNK signaling pathways.

The migration of circulating mesenchymal stem cells (MSCs) to injured tissue is an important step in tissue regeneration and requires adhesion to the microvascular endothelium. The current study investigated the underlying mechanism of MSC adhesion to endothelial cells during inflammation. In in vitro MSC culture, tumor necrosis factor­α (TNF­α) increased the level of vascular cell adhesion molecule­1 (VCAM­1) expression in a dose­dependent manner. The nuclear factor-κB (NF-κB), extracellular signal­regulated kinase (ERK) and c­Jun N­terminal kinase (JNK) signaling pathway inhibitors, pyrrolidine dithiocarbamate (PDTC), U0126 and SP600125, respectively, suppressed VCAM­1 expression induced by TNF­α at the mRNA and protein levels (P<0.05). TNF­α augmented the activation of NF­κB, ERK and JNK, and promoted MSC adhesion to human umbilical vein endothelial cells; however, the inhibitors of NF­κB, ERK and JNK did not affect this process in these cells. The results of the current study indicate that adhesion of circulating MSCs to the endothelium is regulated by TNF-α-induced VCAM-1 expression, which is potentially mediated by the NF­κB, ERK and JNK signaling pathways.

Neuron-derived FGF10 ameliorates cerebral ischemia injury via inhibiting NF-κB-dependent neuroinflammation and activating PI3K/Akt survival signaling pathway in mice.

FGF10 is a member of fibroblast growth factors (FGFs). We previously showed that FGF10 protects neuron against oxygen-glucose deprivation injury in vitro; however, the effect of FGF10 in ischemic stroke in vivo is unknown. In the present study, we showed that FGF10 was mainly expressed in neurons but not astrocytes, and detected FGF10 in mouse cerebrospinal fluid. The FGF10 levels in neurons culture medium and cell lysate were much higher than those in astrocytes. FGF10 expression in brain tissue and FGF10 level in CSF were increased in mouse middle cerebral artery occlusion (MCAO) model. Administration of FGF10 into lateral cerebroventricle not only decreased MCAO-induced brain infarct volume and neurological deficit, but also reduced the number of TUNEL-positive cells and activities of Caspases. Moreover, FGF10 treatment depressed the triggered inflammatory factors (TNF-α and IL-6) and NF-κB signaling pathway, and increased phosphorylation of PI3K/Akt signaling pathway. Blockade of PI3K/Akt signaling pathway by wortmannin and Akt1/2-kinase inhibitor, partly compromised the neuroprotection of FGF10. However, blockade of PI3K/Akt signaling pathway did not impair the anti-inflammation action of FGF10. Collectively, our results demonstrate that neuron-derived FGF10 ameliorates cerebral ischemia injury via inhibiting NF-κB-dependent neuroinflammation and activating PI3K/Akt survival signaling pathway in mice.

[Relation of MBL ExonI 54 and NFκB1-94ins/del ATTG Polymorphism with Fever during Neutropenia in Patients with Acute Leukaemia after Chemotherapy].

OBJECTIVE: To explore the correlation between MBL ExonI 54 and NFκB1-94ins/del ATTG polymorphism and fever during neutropenia in patients with acute leukaemia (AL) (except M3) after first chemotherapy in Chinese Han population. METHODS: Blood samples obtained from 76 fever patients with AL during neutropenia episodes were detected to analyse single nucleotide polymorphism (SNP) in the MBL ExonI 54 and NFκB1-94ins/del ATTG gene, and analyse the correlation between above-mentioned 2 polymorphisms and fever during neutropenia of AL patients after chemotherapy. RESULTS: In 76 patients, no correlation were found between MBL ExonI 54 and NFκB1-94ins/del ATTG polymorphism and fever during neutropenia in patients with acute leukaemia after chemotherapy (P > 0.05). No significant relation were found in sex, age, underlying disease, disease status or degrees of neutropenia in febrile neutropenia between MBL ExonI 54 and NFκB1-94ins/del ATTG polymorphism (P > 0.05). However, patients with MBL ExonI 54 mutation presented longer febrile duration with a median of 5 days compared to 3 days of patients with wildtype MBL ExonI 54 genotype (P < 0.05). CONCLUSIONS: There is no clear correlation between MBL ExonI 54 and NFκB1-94ins/del ATTG polymorphism and fever during neutropenia in patients with acute leukaemia after chemotherapy. However, the patients with MBL ExonI 54 mutation have been observed to present a longer febrile duration.

Fibroblast growth factor 10 protects neuron against oxygen-glucose deprivation injury through inducing heme oxygenase-1.

Fibroblast growth factors (FGFs) are a family of structurally related heparin-binding proteins with diverse biological functions. FGFs participate in mitogenesis, angiogenesis, cell proliferation, development, differentiation and cell migration. Here, we investigated the potential effect of FGF10, a member of FGFs, on neuron survival in oxygen-glucose deprivation (OGD) model. In primary cultured mouse cortical neurons upon OGD, FGF10 treatment (100 and 1000 ng/ml) attenuated the decrease of cell viability and rescued the LDH release. Tuj-1 immunocytochemistry assay showed that FGF10 promoted neuronal survival. Apoptosis assay with Annexin V+PI by flow cytometry demonstrated that FGF10 treatment reduced apoptotic cell proportion. Moreover, immunoblotting showed that FGF10 alleviated the cleaved caspase-3 upregulation caused by OGD. FGF10 treatment also depressed the OGD-induced increase of caspase-3, -8 and -9 activities. At last, we found FGF10 triggered heme oxygenase-1 (HO-1) protein expression rather than hypoxia-inducible factor-1 (HIF-1), AMP-activated protein kinase (AMPK) signaling and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling. Knockdown of HO-1 by siRNA partly abolished the neuroprotection of FGF10 in OGD model. In summary, our observations provide the first evidence for the neuroprotective function of FGF10 against ischemic neuronal injury and suggest that FGF10 may be a promising agent for treatment of ischemic stroke.

Knockdown of TNFAIP1 inhibits growth and induces apoptosis in osteosarcoma cells through inhibition of the nuclear factor-κB pathway.

Tumor necrosis factor-α-inducible protein-1 (TNFAIP1) plays a role in DNA synthesis, DNA repair, cell apoptosis and human diseases including cancer, and may be involved in tumor progression and metastases. However, little is known concerning the function of TNFAIP1 in human osteosarcoma (OS). The aim of the present study was to investigate the function and underlying mechanisms of TNFAIP1 in human OS. The expression of TNFAIP1 was examined by immunohistochemical assay using a tissue microarray procedure. A loss-of-function experiment was performed to explore the effects of lentiviral-mediated TNFAIP1 siRNA (siTNFAIP1) on cell proliferation, invasive potential and apoptosis by MTT and Transwell assays and flow cytometric analysis in OS (MG-63 and U-2 OS) cells. The results showed that the expression of TNFAIP1 protein was significantly increased in OS tissues compared with that in adjacent non-cancerous tissues (ANCTs) (73.3 vs. 48.9%, P=0.018), and was correlated with the distant metastasis of the patients with OS (P=0.029). Knockdown of TNFAIP1 suppressed cell proliferation and invasion, and induced cell apoptosis in the OS cells together with the downregulation of p65 nuclear factor-κB (NF-κB), proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-2 (MMP-2) and upregulation of caspase-3. Collectively, our findings indicate that high expression of TNFAIP1 is associated with distant metastasis of OS, and knockdown of TNFAIP1 inhibits the growth and invasion, and induces apoptosis in OS cells through inhibition of the NF-κB pathway, suggesting that TNFAIP1 may act as a potential therapeutic target for the treatment of cancer.