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Aims: Metabolic disorders may play key roles in oxidative stress and neuronal apoptosis in response to early brain injury (EBI) after subarachnoid hemorrhage (SAH). Pyruvate dehydrogenase (PDH) is ...

The purpose of this study was to investigate the correlation between the expression of cystathionine β-synthase (CBS) in lung squamous cell carcinoma (LUSC) and the microvascular density (MVD) and clinicopathological features. Firstly, the expression status of CBS in diffuse carcinoma and LUSC was searched through the public bioinformatics database. Subsequently, immunohistochemical staining and scoring were performed on tumor tissues and matched normal tissues from 108 LUSC patients to assess CBS expression; the MVD of tumor tissues was also detected. The results showed that CBS was overexpressed in some tumor tissues, including LUSC. Immunohistochemical results showed that the positive expression rate of CBS in tumor tissues (63.0%) was higher than that in normal tissues (17.6%). The expression of CBS was correlated with T (p=0.01), N (p=0.004), TNM (p=0.011) stages, and tumor differentiation degrees (p0.001), with the increase of T, N, and TNM stages or the decrease of differentiation, the expression level of CBS also increased. In addition, the expression level of CBS was positively correlated with MVD (r=0.6997, p0.0001). Survival analysis showed that the survival rate of the CBS negative expression group was better than that of the positive expression group (p=0.004). Cox multivariate analysis showed that CBS expression status (p0.001), T stages (p=0.020), and TNM stages (p=0.021) were independent factors affecting the prognosis of LUSC. In conclusion, the high expression of CBS affects tumor development and is associated with the poor prognosis of LUCS, which may be used as a biomarker to evaluate prognosis and find a new direction for the treatment of LUSC.

Oxidative stress is a key component of the pathological cascade in subarachnoid hemorrhage (SAH). Fucoxanthin (Fx) possesses a strong antioxidant property and has shown neuroprotective effects in acute brain injuries such as ischemic stroke and traumatic brain injury. Here, we investigated the beneficial effects of Fx against SAH-induced oxidative insults and the possible molecular mechanisms. Our data showed that Fx could significantly inhibit SAH-induced reactive oxygen species production and lipid peroxidation, and restore the impairment of endogenous antioxidant enzymes activities. In addition, Fx supplementation improved mitochondrial morphology, ameliorated neural apoptosis, and reduced brain edema after SAH. Moreover, Fx administration exerted an improvement in short-term and long-term neurobehavior functions after SAH. Mechanistically, Fx inhibited oxidative damage and brain injury after SAH by deacetylation of forkhead transcription factors of the O class and p53 via sirtuin 1 (Sirt1) activation. EX527, a selective Sirt1 inhibitor, significantly abated Fx-induced Sirt1 activation and abrogated the antioxidant and neuroprotective effects of Fx after SAH. In primary neurons, Fx similarly suppressed oxidative insults and improved cell viability. These effects were associated with Sirt1 activation and were reversed by EX527 treatment. Taken together, our study explored that Fx provided protection against SAH-induced oxidative insults by inducing Sirt1 signaling, indicating that Fx might serve as a potential therapeutic drug for SAH.

Objective Increasing evidence has revealed that mechanical stress and elevated mechanical signals promote malignant tumor transformation and metastasis. This study aimed to explore the function of the mechanically activated ion-channel Piezo1 in the colon cancer metastasis and its potential regulatory mechanism. Methods First, we examined the expression levels of Piezo1 and mitochondrial calcium uniporter (MCU) both in colon cancer tissues and assessed the prognostic value of Piezo1 and MCU in a colon cancer cohort (n = 110). Second, functional assays were performed to investigate the effects of Piezo1 and MCU on colon cancer cell migration, invasion, and mitochondrial membrane potential. Third, we analyzed the expression of Piezo1, MCU, and HIF-1α by overexpressing/silencing each other’s expression. Results We found that Piezo1 was up-regulated and MCU was down-regulated in colon cancer tissues. Piezo1 and MCU were both correlated with poor prognosis of patients with colon cancer. Overexpressing Piezo1 and silencing MCU could promote colon cancer cell migration and metastasis, reduce mitochondrial membrane potential, and promote each other’s expression. We also found that HIF-1α was up-regulated in colon cancer tissues. Additionally, silencing Piezo1 inhibited the expression of HIF-1α and VEGF, which was contrary to MCU silencing. Intriguingly, Piezo1-overexpressing cells did not regain their migration behaviors when HIF-1α expression was inhibited, which was accompanied with the re-expression of MCU and VEGF. Conclusion In our study, Piezo1 is involved in colon cancer cell metastasis. Furthermore, our findings indicated a possible Piezo1-MCU-HIF-1α-VEGF axis, which still need further exploration.

Long noncoding RNAs (lncRNAs) are emerging as key players in the development and progression of cancer. Several malignancies involve dysregulated long noncoding ribonucleic acids (lncRNAs) in non-small cell lung cancer cell growth and their aggressive phenotypes. LncRNA B4GALT1-AS1 is important in the advancement of various malignancies, although its contribution to non-small cell lung cancer (NSCLC) remains unexplored.LncRNA B4GALT1-AS1 in NSCLC tissues was detected and further validated in a cohort of non-small cell lung cancer tissues. The effects of lncRNA B4GALT1-AS1 on proliferation were determined byWe showed significant upregulation of B4GALT1-AS1 in cell lines and tissues of NSCLC. B4GALT1-AS1 knockdown impeded theIn summary, the progression of NSCLC was facilitated by lncRNA B4GALT1-AS1 via interaction with miR-144-3p and positive regulation of ZEB1 expression.

Neuronal apoptosis has an important role in early brain injury (EBI) following subarachnoid hemorrhage (SAH). TRAF3 was reported as a promising therapeutic target for stroke management, which covered several neuronal apoptosis signaling cascades. Hence, the present study is aimed to determine whether downregulation of TRAF3 could be neuroprotective in SAH-induced EBI. An in vivo SAH model in mice was established by endovascular perforation. Meanwhile, primary cultured cortical neurons of mice treated with oxygen hemoglobin were applied to mimic SAH in vitro. Our results demonstrated that TRAF3 protein expression increased and expressed in neurons both in vivo and in vitro SAH models. TRAF3 siRNA reversed neuronal loss and improved neurological deficits in SAH mice, and reduced cell death in SAH primary neurons. Mechanistically, we found that TRAF3 directly binds to TAK1 and potentiates phosphorylation and activation of TAK1, which further enhances the activation of NF-κB and MAPKs pathways to induce neuronal apoptosis. Importantly, TRAF3 expression was elevated following SAH in human brain tissue and was mainly expressed in neurons. Taken together, our study demonstrates that TRAF3 is an upstream regulator of MAPKs and NF-κB pathways in SAH-induced EBI via its interaction with and activation of TAK1. Furthermore, the TRAF3 may serve as a novel therapeutic target in SAH-induced EBI.

The persistent emergence of new network applications, along with encrypted network communication, has make traffic analysis become a challenging issue in network management and cyberspace security. Currently, virtual private network (VPNs) has become one of the most popular encrypted communication services for bypassing censorship and guarantee remote access to geographically locked services. In this paper, a novel identification scheme of VoIP traffic tunneled through VPN is proposed. We employed a set of Flow Spatio-Temporal Features (FSTF) to six well-known classifiers, including decision trees, K-Nearest Neighbor (KNN), Bagging and Boosting via C4.5, and Multi-Layer perceptron (MLP). The overall accuracy, precision, sensitivity, and F-measure verify that the proposed scheme can effectively distinguish between the VoIP flows and Non-VoIP ones in VPN traffic.

BackgroundInhibin subunit beta A (INHBA) is a member of the TGF-beta (transforming growth factor-beta) superfamily proteins, which plays a fundamental role in various cancers. However, there is little systematical analysis on the exact role of INHBA in patients with gastric cancer (GC). Herein, we explored the exact role and the underlying mechanisms of INHBA regarding GC using multiple bioinformatic approaches. MethodsThe expression levels of INHBA in GC were analyzed in TIMER, GEPIA2, GEO, Oncomine and UALCAN databases. Protein and PCR test were performed to verify the expression states of INHBA in GC tissues. The correlation of INHBA and prognosis of GC was analyzed based on Kaplan Meier plotter database. Besides, the relationship between INHBA expression and immune infiltration levels and the type markers of immune cells in GC was explored in the TIMER database. What’s more, we studied INHBA mutations, promoter methylation, functional enrichment analysis in GC patients based on cBioportal, MEXPRESS, Metascape and LinkedOmics databases. Besides, we performed immunohistochemistry (IHC) and polymerase chain reaction (qRT-PCR ) verification in tissues from patients with gastric cancerResultsINHBA was elevated in GC and high expression level of INHBA in GC was significantly related to the unfavorable prognosis. Protein and PCR test verified the highly expression states of INHBA in GC tissues. Further analysis showed that INHBA was negatively correlated with B cell while positively correlated with the marker type of CD8+ T cells, macrophage, neutrophil and dendritic cell infiltration. High INHBA expression level had a poor prognosis in different enriched immune cells subgroups in GC. And there is week significant methylation level change between tumor and normal tissues. Moreover, INHBA mainly enriched cancer-related signaling pathways, including TGF-beta signaling pathway, ECM-receptor signaling pathway, PID ALK1/2 pathway, and AGE-RAGE signaling pathway. ConclusionsThe present study implies that INHBA may serve as a potential biomarkers for predicting prognosis in GC patients. High INHBA expression in GC may affect prognosis through immune infiltration.

Background Early brain injury (EBI) has been thought to be a key factor affecting the prognosis of subarachnoid hemorrhage (SAH). Many pathologies are involved in EBI, with inflammation and neuronal death being crucial to this process. Resolvin D1 (RvD1) has shown superior anti-inflammatory properties by interacting with lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) in various diseases. However, it remains not well described about its role in the central nervous system (CNS). Thus, the goal of the present study was to elucidate the potential functions of the RvD1-ALX/FPR2 interaction in the brain after SAH. Methods We used an in vivo model of endovascular perforation and an in vitro model of hemoglobin (Hb) exposure as SAH models in the current study. RvD1 was used at a concentration of 25 nM in our experiments. Western blotting, quantitative polymerase chain reaction (qPCR), immunofluorescence, and other chemical-based assays were performed to assess the cellular localizations and time course fluctuations in ALX/FPR2 expression, evaluate the effects of RvD1 on Hb-induced primary microglial activation and neuronal damage, and confirm the role of ALX/FPR2 in the function of RvD1. Results ALX/FPR2 was expressed on both microglia and neurons, but not astrocytes. RvD1 exerted a good inhibitory effect in the microglial pro-inflammatory response induced by Hb, possibly by regulating the IRAK1/TRAF6/NF-κB or MAPK signaling pathways. RvD1 could also potentially attenuate Hb-induced neuronal oxidative damage and apoptosis. Finally, the mRNA expression of IRAK1/TRAF6 in microglia and GPx1/bcl-xL in neurons was reversed by the ALX/FPR2-specific antagonist Trp-Arg-Trp-Trp-Trp-Trp-NH2 (WRW4), indicating that ALX/FPR2 could mediate the neuroprotective effects of RvD1. Conclusions The results of the present study indicated that the RvD1-ALX/FPR2 interaction could potentially play dual roles in the CNS, as inhibiting Hb promoted microglial pro-inflammatory polarization and ameliorating Hb induced neuronal oxidant damage and death. These results shed light on a good therapeutic target (ALX/FPR2) and a potential effective drug (RvD1) for the treatment of SAH and other inflammation-associated brain diseases.

Background Aucubin (Au), an iridoid glycoside from natural plants, has antioxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored the potential role of Au in an H2O2-induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model. Methods In vitro experiments, the various concentrations of Au (50 μg/ml, 100 μg/ml, or 200 μg/ml) were added in culture medium at 0 h and 6 h after neurons stimulated by H2O2 (100 μM). After exposed for 12 h, neurons were collected for western blot (WB), immunofluorescence, and M29,79-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. In vivo experiments, Au (20 mg/kg or 40 mg/kg) was administrated intraperitoneally at 30 min, 12 h, 24 h, and 48 h after modeling. Brain water content, neurological deficits, and cognitive functions were measured at specific time, respectively. Cortical tissue around focal trauma was collected for WB, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry, and enzyme linked immunosorbent assay (ELISA) at 72 h after TBI. RNA interference experiments were performed to determine the effects of nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with Au (40 mg/kg) treatment. Mice were intracerebroventricularly administrated with lentivirus at 72 h before TBI establishment. The cortex was obtained at 72 h after TBI and used for WB and q-PCR. Results Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS), and reduced cell apoptosis both in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages, and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1 (HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au. Conclusions Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system.

Massive neuron loss is the key reason for poor prognoses in patients with traumatic brain injury (TBI), and astrocytes function as nutrition-providing neurons. Therefore, researchers must determine the potential role of astrocytes in neural regeneration after TBI. Our previous studies established that upregulating CD24 in the hippocampus might improve cognitive functions after TBI. However, whether CD24 in hippocampal astrocytes is involved in neural regeneration after TBI remains unknown. Therefore, we detected the CD24 expression in the ipsilateral hippocampus via western blot and quantitative real-time PCR. We further investigated the CD24 expression patterns in hippocampal astrocytes via immunofluorescence staining. We then injected adeno-associated virus-Gfa2-siRNA-CD24 (AAV-CD24) into the astrocytes to downregulate CD24 and analyzed the related cellular signals. Golgi-Cox staining and the growth associated protein-43 (GAP43) level were used to observe neuronal morphology and neural regeneration around the astrocytes in the ipsilateral hippocampus, and the Morris water maze test was used to assess neural functional recovery. The CD24 protein and mRNA levels in the cornu ammonis and dentate gyrus regions of the ipsilateral hippocampus were elevated after TBI, and high CD24 expression was widespread in the hippocampal astrocytes after TBI. Specific inhibition of CD24 in the hippocampal astrocytes interfered with the activation of Src homology region 2 containing protein tyrosine phosphatase 2 (SHP2) and extracellular signal regulated kinase (ERK), shortened the neuronal dendritic spines, decreased the GAP43 level and impaired the cognitive functions of the TBI-model mice. These results revealed that elevated hippocampal CD24 in astrocytes participated in neural regeneration in mice after TBI, possibly by activating the SHP2/ERK pathway.

Excessive inflammation is a major cause contributing to early brain injury (EBI) and is associated with negative or catastrophic outcomes of subarachnoid hemorrhage (SAH). Resolvin D1 (RvD1) exerts strong anti-inflammatory and pro-resolving effects on either acute or chronic inflammation of various origin. Henceforth, we hypothesized that RvD1 potentially attenuates excessive inflammation in EBI following SAH. Therefore, we generated a filament perforation SAH model and administered 3 different doses (0.3, 0.6, and 1.2 nmol) of RvD1 after experimental SAH. Neurological scores, brain edema, and blood-brain barrier integrity were evaluated; besides, neutrophil infiltration, neuronal deaths, and microglial pro-inflammatory polarization were observed using histopathology or immunofluorescence staining, western blots, and qPCR. After confirming the effectiveness of RvD1 in SAH, we administered the FPR2-specific antagonist Trp-Arg-Trp-Trp-Trp-Trp-NH2 (WRW4) 30 min before SAH establishment to observe whether this compound could abolish the anti-inflammatory effect of RvD1. Altogether, our results showed that RvD1 exerted a strong anti-inflammatory effect and markedly reduced neutrophil infiltration and microglial pro-inflammatory activation, leading to remarkable improvements in neurological function and brain tissue restoration. After addition of WRW4, the anti-inflammatory effects of RvD1 were abolished. These results indicated that RvD1 could exert a good anti-inflammatory effect and alleviate EBI, which suggested that RvD1 might be a novel therapeutic alternative for SAH-induced injury.

Background Increasing evidence suggests microglial polarization plays an important role in the pathological processes of neuro-inflammation following subarachnoid hemorrhage (SAH). Previous studies indicated that milk fat globule-EGF factor-8 (MFG-E8) has the potential in anti-apoptosis and anti-inflammation in cerebral ischemia. However, the effects of MFG-E8 on microglial polarization have not been evaluated after SAH. Therefore, the aim of this study was to explore the role of MFG-E8 on anti-inflammation, and its potential mechanism on microglial polarization following SAH. Methods We established the SAH model via prechiasmatic cistern Blood injection in mice. Double-immunofluorescence staining, Western blotting and quantitative real-time polymerase chain reaction (q-PCR) were performed to investigate the expression and cellular distribution of MFG-E8. Two different dosages (1 μg and 5 μg) of recombinant human MFG-E8 (rhMFG-E8) were injected intracerebroventricular (i.c.v.) at 1 h after SAH. Brain water content, neurological scores, beam-walking score, Fluoro-Jade C (FJC) and terminal deoxynucleotidyl transferase dUTP nick endlabeling staining (TUNEL) were measured at 24 h. Intervention of MFG-E8, integrin β3 and phosphorylation of STAT3 were achieved by specific siRNAs (500 pmol/5 µl) and STAT3 inhibitor Stattic (5 µM). The potential signal pathway and microglial polarization were measured by immunofluorescence labeling and Western blotting. Results SAH induction increased the levels of inflammation mediators, the proportion of M1 and caused neuronal apoptosis in mice at 24 h. Treatment with rhMFG-E8 (5 µg) remarkably decreased brain edema, improved neurological functions, reduced the levels of pro-inflammation factors, and promoted microglia shifted to M2 phenotype. However, knockdown MFG-E8 and integrin β3 via siRNA abolished the effects of MFG-E8 on anti-inflammation and M2 phenotype polarization. STAT3 inhibitor Stattic further clarified the role of rhMFG-E8 on microglial polarization through regulating the protein levels of integrin β3/SOCS3/STAT3 pathway. Conclusions rhMFG-E8 inhibits neuron-inflammation through transformation microglial phenotype towards M2 after SAH, which may be mediated by modulation of the integrin β3/SOCS3/STAT3 signaling pathway, and highlighting rhMFG-E8 as a potentially therapeutic target for the treatment of SAH patients.

Microglial activation and sustained inflammation in the brain can lead to neuronal damage. Hence, limiting microglial activation and brain inflammation is a good therapeutic strategy for inflammatory-associated central nervous disease. MiR-146a is a promising therapeutic microRNA, since it can negatively regulate the inflammatory response. We thus investigated the expression changes of miR-146a after experimental induction of a subarachnoid hemorrhage (SAH) in vivo and in vitro, and we assessed the anti-inflammatory effects of miR-146a in microglial cells in vitro. Primary microglial cells were preincubated with miR-146a before hemoglobin (Hb) treatment. The results indicated that miR-146a decreased gene expression of Hb-induced pro-inflammatory cytokines (TNF-α and IL-1β) and phenotype-related genes (iNOS and CD86) through IRAK1/TRAF6/NF-κB or MAPK signaling pathways, suggesting its pro-resolution activity in microglia. However, contrary to the LPS-induced microglia or macrophage activation model, we did not observe an elevation in miR-146a after activation. Overall, our findings demonstrated that miR-146a was involved in the regulation of brain inflammation and could be considered a novel therapeutic agent for treating brain inflammation.

Transcobalamin (TCN1) is a vitamin B12 (cobalamin)-binding protein that regulates cobalamin homeostasis. Recent studies and bioinformatic analyses have found that TCN1 is highly expressed in cancer tissues and is associated with tumour aggressiveness and poor prognosis. The present study aimed to detect TCN1 as a novel biomarker for prognosis and chemosensitivity of colon cancer. Next-generation sequencing showed that TCN1 was one of several upregulated mRNAs in colon cancer, which was verified by further bioinformatics analyses. Western blotting (n = 9) and quantitative real time polymerase chain reaction (qRT-PCR, n = 30) revealed that TCN1 was highly expressed in colon cancer tissues at both the protein and mRNA level. A total of 194 cases of colon cancer were examined by immunohistochemistry and revealed that TCN1 expression level was related to advanced stages (P P = 0.008). In addition, TCN1 was highly expressed in pulmonary metastatic tumour tissues (n = 37, P = 0.025) and exhibited higher levels in right-sided colon cancer than in left-sided colon cancer (P = 0.029). TCN1 expression in specimens that had received neoadjuvant chemotherapy decreased compared with that in colonoscopy biopsy tissues (n = 42, P = 0.009). Further bioinformatics analyses verified that apoptosis pathways might have a role in high TCN1 expression. All the studies revealed that TCN1 expression in colon cancer was significantly associated with malignant biological behaviour. Therefore, TCN1 could be used as a novel biomarker for colon cancer aggressiveness and prognosis and might also be a potential biomarker for predicting neoadjuvant chemosensitivity.

Subarachnoid hemorrhage (SAH) elicits destruction of neuronal cells and neurological function, which is exacerbated by neuro-inflammation in EBI, and toll-like receptor 4 (TLR4) plays an important role in inflammatory cascade via modulation microglia polarization. Curcumin (Cur), as a natural phytochemical compound, has the potential characteristics on anti-inflammatory and microglia phenotype transformation. In this study, we verified the hypothesis curcumin promotes M2 polarization to inhibiting neuro-inflammation, which through suppressing TLR4 signaling pathway after SAH. In tlr4–/– mice and wild type (WT) subjected to prechiasmatic cistern blood injection, Western blotting, brain water content, neurological score, enzyme-linked immunosorbent assay (ELISA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were performed to investigate the role of TLR4 on neuro-inflammation response and microglia polarization. Curcumin with three different concentrations (50 mg/kg, 100 mg/kg and 200 mg/kg) were injected intraperitoneally (i.p.) at 15 min after SAH. The levels of TLR4, myeloid differentiation factor 88 (MyD88), nuclear factor- κB (NF-κB), Iba-1, CD86, CD206 and pro/anti-inflammation cytokines were measured by Western blotting and immunofluorescence staining at 24 h after SAH. SAH induction increased the protein levels of TLR4, pro-inflammation cytokines and proportion of M1 phenotype. Curcumin with 100 mg/kg treatment dramatically inhibited the release of pro-inflammatory mediators, and elevated the protein levels of anti-inflammatory cytokines and promoted microglia switch to M2. Meanwhile, curcumin treatment also decreased the expressions of TLR4, Myd88 and NF-κB at 24 h post SAH. TLR4 deficiency ameliorated brain water content, neurological deficit and reduced pro-inflammation cytokines after SAH. Moreover, curcumin treatment in tlr4–/– mice further induced M2 polarization, while had no statistic difference on brain water content and neurological score at 24 h post SAH. Our results indicated that curcumin treatment alleviated neuro-inflammation response through promoting microglia phenotype shift toward M2, and which might inhibiting TLR4/MyD88/NF-κB signaling pathway after SAH.

Background Microglia are resident immune cells in the central nervous system and central to the innate immune system. Excessive activation of microglia after subarachnoid haemorrhage (SAH) contributes greatly to early brain injury, which is responsible for poor outcomes. Dehydroepiandrosterone (DHEA), a steroid hormone enriched in the brain, has recently been found to regulate microglial activation. The purpose of this study was to address the role of DHEA in SAH. Methods We used in vivo models of endovascular perforation and in vitro models of haemoglobin exposure to illustrate the effects of DHEA on microglia in SAH. Results In experimental SAH mice, exogenous DHEA administration increased DHEA levels in the brain and modulated microglial activation. Ameliorated neuronal damage and improved neurological outcomes were also observed in the SAH mice pretreated with DHEA, suggesting neuronal protective effects of DHEA. In cultured microglia, DHEA elevated the mRNA and protein levels of Jumonji d3 (JMJD3, histone 3 demethylase) after haemoglobin exposure, downregulated the H3K27me3 level, and inhibited the transcription of proinflammatory genes. The devastating proinflammatory microglia-mediated effects on primary neurons were also attenuated by DHEA; however, specific inhibition of JMJD3 abolished the protective effects of DHEA. We next verified that DHEA-induced JMJD3 expression, at least in part, through the tropomyosin-related kinase A (TrkA)/Akt signalling pathway. Conclusions DHEA has a neuroprotective effect after SAH. Moreover, DHEA increases microglial JMJD3 expression to regulate proinflammatory/anti-inflammatory microglial activation after haemoglobin exposure, thereby suppressing inflammation.

With the rapid development of mobile internet and cloud computing, numerous digital me-dia files in mobile social networking and media sharing software have become the important carriers of steganography. However, these digital media files may be resampled by the media server when being pushed to the intelligent mobile terminals. The resampling of digital media files is a transfor-mation which enlarges or shrinks objects by a scale factor that is the same in all dimensions. In order to reduce embedding distortion while ensuring the correct extraction of secret messages under resam-pling mechanism, a steganographic coding scheme based on dither convolutional trellis is proposed in this paper. The resampling mapping is estimated with finite sample pairs. The resampling stego media files with secret messages embedded are generated from the estimated resampling cover media files by syndrome-trellis codes (STCs). According to the estimated resampling mapping, the dither convolutional trellis for one dimensional resampling is constructed to generate the source stego me-dia files from source cover media files and resampling stego media files. The steganographic coding scheme is also extended to the circumstance of two dimensional resampling such as image scaling. The experimental results show that the proposed steganographic scheme can achieve less embedding dis-tortion while ensuring the accuracy of secret messages extraction under multi-dimensional resampling mechanism.

Increasing evidence suggests that microglial polarization plays an important role in the pathological processes of neuroinflammation following subarachnoid hemorrhage (SAH). Previous studies indicated that milk fat globule-epidermal growth factor-8 (MFG-E8) has potential anti-apoptotic and anti-inflammatory effects in cerebral ischemia. However, the effects of MFG-E8 on microglial polarization have not been evaluated after SAH. Therefore, the aim of this study was to explore the role of MFG-E8 in anti-inflammation, and its effects on microglial polarization following SAH. We established the SAH model via prechiasmatic cistern blood injection in mice. Double-immunofluorescence staining, western blotting and quantitative real-time polymerase chain reaction (q-PCR) were performed to investigate the expression and cellular distribution of MFG-E8. Two different dosages (1 and 5 μg) of recombinant human MFG-E8 (rhMFG-E8) were injected intracerebroventricularly (i.c.v.) at 1 h after SAH. Brain water content, neurological scores, beam-walking score, Fluoro-Jade C (FJC), and terminal deoxynucleotidyl transferase dUTP nick endlabeling staining (TUNEL) were measured at 24 h. Suppression of MFG-E8, integrin β3 and phosphorylation of STAT3 were achieved by specific siRNAs (500 pmol/5 μl) and the STAT3 inhibitor Stattic (5 μM). The potential signaling pathways and microglial polarization were measured by immunofluorescence labeling and western blotting. SAH induction increased the levels of inflammatory mediators and the proportion of M1 cells, and caused neuronal apoptosis in mice at 24 h. Treatment with rhMFG-E8 (5 μg) remarkably decreased brain edema, improved neurological functions, reduced the levels of proinflammatory factors, and promoted the microglial to shift to M2 phenotype. However, knockdown of MFG-E8 and integrin β3 via siRNA abolished the effects of MFG-E8 on anti-inflammation and M2 phenotype polarization. The STAT3 inhibitor Stattic further clarified the role of rhMFG-E8 in microglial polarization by regulating the protein levels of the integrin β3/SOCS3/STAT3 pathway. rhMFG-E8 inhibits neuronal inflammation by transformation the microglial phenotype toward M2 and its direct protective effect on neurons after SAH, which may be mediated by modulation of the integrin β3/SOCS3/STAT3 signaling pathway, highlighting rhMFG-E8 as a potential therapeutic target for the treatment of SAH patients.

Background Peroxiredoxin (Prx) protein family have been reported as important damage-associated molecular patterns (DAMPs) in ischemic stroke. Since peroxiredoxin 2 (Prx2) is the third most abundant protein in erythrocytes and the second most protein in the cerebrospinal fluid in traumatic brain injury and subarachnoid hemorrhage (SAH) patients, we assessed the role of extracellular Prx2 in the context of SAH. Methods We introduced a co-culture system of primary neurons and microglia. Prx2 was added to culture medium with oxyhemoglobin (OxyHb) to mimic SAH in vitro. Neuronal cell viability was assessed by lactate dehydrogenase (LDH) assay, and neuronal apoptosis was determined by TUNEL staining. Inflammatory factors in culture medium were measured by ELISA, and their mRNA levels in microglia were determined by qPCR. Toll-like receptor 4 knockout (TLR4-KO) mice were used to provide TLR4-KO microglia; ST-2825 was used to inhibit MyD88, and pyrrolidine dithiocarbamate (PDTC) was used to inhibit NF-κB. Related cellular signals were analyzed by Western blot. Furthermore, we detected the level of Prx2 in aneurysmal SAH patients’ cerebrospinal fluids (CSF) and compared its relationship with Hunt-Hess grades. Results Prx2 interacted with TLR4 on microglia after SAH and then activated microglia through TLR4/MyD88/NF-κB signaling pathway. Pro-inflammatory factors were expressed and released, eventually caused neuronal apoptosis. The levels of Prx2 in SAH patients positively correlated with Hunt-Hess grades. Conclusions Extracellular Prx2 in CSF after SAH is a DAMP which resulted in microglial activation via TLR4/MyD88/NF-κB pathway and then neuronal apoptosis. Prx2 in patients’ CSF may be a potential indicator of brain injury and prognosis. Electronic supplementary material The online version of this article (10.1186/s12974-018-1118-4) contains supplementary material, which is available to authorized users.

Hydrogen sulfide (H2S) is believed to be involved in numerous physiological and pathophysiological processes, and now it is recognized as the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide; however, the effects of H2S on inflammatory factors in acute myocardial ischemia injury in rats have not been clarified. In the present study, sodium hydrosulfide (NaHS) was used as the H2S donor. Thirty-six male Sprague Dawley rats were randomly divided into five groups: Sham, ischemia, ischemia + low-dose (0.78 mg/kg) NaHS, ischemia + medium-dose (1.56 mg/kg) NaHS, ischemia + high-dose (3.12 mg/kg) NaHS and ischemia + propargylglycine (PPG) (30 mg/kg). The rats in each group were sacrificed 6 h after the surgery for sample collection. Compared with the ischemia group, the cardiac damage in the rats in the ischemia + NaHS groups was significantly reduced, particularly in the high-dose group; in the ischemia + PPG group, the myocardial injury was aggravated compared with that in the ischemia group. Compared with the ischemia group, the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in the serum of rats in the ischemia + medium- and high-dose NaHS groups were significantly reduced, and the expression of intercellular adhesion molecule-1 (ICAM-1) mRNA and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) protein in the myocardial tissues of rats was significantly reduced. In the ischemia + PPG group, the TNF-α, IL-1β and IL-6 levels in the serum were significantly increased, the expression of ICAM-1 mRNA was increased, although without a significant difference, and the expression of NF-κB was increased. The findings of the present study provide novel evidence for the dual effects of H2S on acute myocardial ischemia injury via the modulation of inflammatory factors.

As a continuous effort to develop a realistic mist impingement cooling scheme, this paper focuses on simulating mist impingement cooling under typical gas turbine operating conditions of high temperature and pressure in a simplified model of transform piece (double chamber model). Based on the heat-mass transfer analogy, the results of mist cases compare with the none droplet case could be enhanced 320% (the maximum enhancement of adiabatic cooling effectiveness) cooling effectiveness and reduce 108 K of wall temperature.

In this paper, oscillatory properties of solutions for neutral type nonlinear impulsive hyperbolic partial differential equations with several delays are investigated and a series of sufficient conditions for oscillation of the equations are established.

The wild species in genus Oryza are important resources of genes resistant to brown planthopper (Nilaparvata lugens, BPH). The objective of this study was to identify quantitative trait loci (QTLs) in Dongxiang wild rice (O. rufipogon Griff.). A BC1F5 population and a BC3F3 population were developed for QTL mapping from the cross between Dongxiang wild rice and an indica rice cultivar, Xieqingzao B (O. sativa L. subsp. indica) as the recurrent parent. The BC1F5 population was infested with BPH collected from paddy fields. Two QTLs were identified, of which qBph2 was located in the interval of RM29-RG157 on chromosome 2 and qBph7 in the interval of RM11-RM234 on chromosome 7. The alleles from Dongxiang wild rice on qBph2 and qBph7, which explained 21.8% and 67.1% of the phenotypic variations, respectively, and reduced seedling mortality by 22.2% and 43.7%. These QTLs were validated using the BC3F3 population infested by BPH biotypes I, II, and III. This result shows that qBph2 confers resistance to biotypes I and II, and qBph7 confers resistance to biotypes I and III. Both QTLs show a great potential for improving BPH resistance in rice cultivars.

Objective: Peripheral nerve injury elicits an aversive state of spontaneous neuropathic pain, and up to now, the modulation of this concomitant aversive state remains a major therapeutic challenge. NMDA receptor subunits NR2B in the rACC are critically involved in the processing of this aversive state and then a strategy targeted at the NR2B subunit might be promising for modulation of the aversive state. Thus, in the present study, using negative reinforcement animal model to reveal spontaneous pain, we investigated the effect of oral immunization with recombinant adenovirus serotype 5-mediated NR2B gene transfer (rAd5/NR2B) on the modulation of the tonic pain. Material and methods: Following oral administration of the rAd5/NR2B vaccine, NR2B-specific antibodies were induced in serum. And the humoral response was involved in the decreased expression of NR2B protein in the rACC. Results: The present study demonstrated that CPP achieved by spinal administration of clonidine in spinal nerve ligation (SNL) rats revealed the presence of aversive state of spontaneous neuropathic pain. Notably, the humoral autoimmune response blocked the CPP by spinal clonidine, suggesting the relief of the concomitant aversive of spontaneous neuropathic pain in the SNL rats. Conclusion: These data proved the feasibility of oral immunization with rAd5/NR2B for modulation of concomitant aversive of spontaneous neuropathic pain due to peripheral nerve injury.

The effective durations of pesticide-induced susceptibility of rice to brown planthopper (BPH), Nilaparvata lugens (Stal) (Homoptera: Delphacidae), and physiological and biochemical changes in rice plants following pesticide applications, were studied. The effective duration of the herbicide butachlor on the susceptibility of rice variety Zhengdao 2 to BPH exceeded 16 days. The difference in damage rating between rice plants with pesticide treatments and control plants gradually decreased with days after treatment (DAT). There was a significant correlation between damage rating and DAT. The number of rice tillers at 3 – 10 DAT and plant heights at 7 – 10 DAT declined on Zhengdao 2 with the butachlor treatment. On the other hand, there were no effects of butachlor on damage rating, number of rice tillers and plant height for Xiushui 63. This might be related to tolerance of Xiushui 63 to butachlor. For Zhengdao 2, the fungicide jingganmycin and the insecticide bisultap had a significant influence on BPH da...

To describe the clinical features of IgG4-related lung disease.The clinical symptoms, laboratory tests, radiographic patterns, histopathological features and therapeutic management of a patient with IgG4-related lung disease were described and the literatures were reviewed.A 41-year-old male without significant symptoms was admitted to our department because of diffuse opacities on regular X-ray examination. Chest HRCT revealed diffuse ground-glass opacities (GGOs) and reticular opacities in both lungs, predominantly in the middle fields. Thoracoscopic lung biopsy was performed, and pathological examination of the lung tissues found massive lympho-plasma cell infiltration and collagen deposition along the alveolar septa and bronchovascular bundles on HE staining. Obliterative phlebitis and thickening of alveolar septa were observed. IgG4 immunostaining revealed predominant IgG4(+) plasma cells. IgG4-related lung disease was diagnosed combined with elevation of serum IgG4 concentration (3.07 g/L). The patient received oral prednisone at the dose of 30 mg per day for one month and then the dose was tapered. Four months later a CT scan revealed that the GGOs disappeared and only some reticular opacities and honeycombing changes remained. The serum IgG4 concentration decreased to 1.99 g/L. Twenty-one articles with 65 cases of IgG4-related lung disease were collected through PubMed search engine. Extrapulmonary organs were involved in 38 cases, especially the pancreas. Serum IgG4 concentrations were assessed in 36 cases and elevated in 34. Four radiographic patterns were identified: solid nodule type (55.4%), alveolar interstitial type (26.2%), bronchovascular type (13.8%) and round-shaped GGO type (4.6%). Glucocorticoids were prescribed to 23 patients with a favorable response except one treatment failure.IgG4-related lung disease is a rare disorder and easily overlooked in clinical practice. The lung maybe the only target organ, but extrapulmonary organ involvement is the most common discoveries. The diagnosis of IgG4-related lung disease depends on the elevation of serum IgG4 and characteristic histopathological features. Glucocorticoid therapy is very effective and most patients have a good prognosis.

We must pay attention and find defects, defects through the prediction to quantify the quality management and quality in order to achieve this goal, requires an estimate of the various defect detection process. Software defects are the departure of software are products' anticipative function. This paper collecting the data of the software defects, then, using the SVM model the predictive values are gained analyzing the predictive results, software are organizations can improve software control measure software process and allocate testing resources effectively.

HIV-1 p24 detection provides a means to aid the early diagnosis of HIV-1 infection, track the progression of disease and assess the efficacy of antiretroviral therapy. In the present study, three monoclonal antibodies (mAbs) p3JB9, p5F1 and p6F4 against HIV-1 p24 were generated. All mAbs could detect p24 of HIV-1IIIB, HIV-1Ada-M, HIV-174V mAbs p5F1 and p6F4 could detect HIV-1KM018, while p3JB9 could not. Three mAbs did not react with HIV-2ROD, HIV-2CBL-20 and SIVagmTYO-1. The recognized epitope of p5F1 was located on the Gag amino acid region DCKTILKALGPAATLEEMMTAC. The p5F1 was used to establish a modified sandwich ELISA with rabbit anti-p24 serum and showed good specificity and high sensitivity, which has been used to measure HIV-1 p24 antigen levels in research.

p53 is an important tumor suppressor and stress response mediator. Proper control of p53 level and activity is tightly associated with its function. Posttranslational modifications and the interactions with Mdm2 and Mdm4 are major mechanisms controlling p53 activity and stability. As p53 protein is short-lived and hardly detectable in unstressed situations, less is known on its basal level expression and the corresponding controlling mechanisms in vivo. In addition, it also remains obscure how p53 expression might contribute to its functional regulation. In this study, we established bacterial artificial chromosome transgenic E.coli β-galactosidase Z gene reporter mice to monitor p53 expression in mouse tissues and identify important regulatory elements critical for the expression in vivo. We revealed preferentially high level of p53 reporter expressions in the proliferating, but not the differentiated compartments of the majority of tissues during development and tissue homeostasis. In addition, tumors as well as regenerating tissues in the p53 reporter mice also expressed high level of β-gal. Furthermore, both the enhancer box sequence (CANNTG) in the p53 promoter and the 3′ terminal untranslated region element were critical in mediating the high-level expression of the reporter. We also provided evidence that cellular myelocytomatosis oncogene was a critical player regulating p53 mRNA expression in proliferating cells and tissues. Finally, we found robust p53 activation preferentially in the proliferating compartment of mouse tissues upon DNA damage and the proliferating cells exhibited an enhanced p53 response as compared with cells in a quiescent state. Together, these results suggested a highly regulated expression pattern of p53 in the proliferating compartment controlled by both transcriptional and posttranscriptional mechanisms, and such regulated p53 expression may impose functional significance upon stress by setting up a precautionary mode in defense of cellular transformation and tumorigenesis.