Anti-influenza drug screening and inhibition of apigetrin on influenza A virus replication via TLR4 and autophagy pathways.

Activation of Toll-like receptor (TLR) 4 plays important roles in the influenzaA virus (IAV) infection. To explore TLR4 inhibitors, 161 traditional Chinese medicines (TCMs) were screened. Further, we screened out Ixeris sonchifolia Hance, and its active compound, Apigetrin (apigenin-7-O-glucoside). Antiviral activity of Apigetrin was determined by plaque assay. We also further investigated the influence of Apigetrin on immune signaling pathways including TLRs, MAPK, NF-κB and autophagy pathways. The in-vitro results showed that the extract and its several ingredients could significantly inhibit IAV replication. Apigetrin significantly improved IAV-induced oxidative stress, inhibited the IAV-induced cytokine storm by suppressing the excessive activation of TLR3/4/7, JNK/p38 MAPK and NF-κB. Apigetrin decreased autophagosome accumulation and promoted degradation of IAV protein. Interestingly, Apigetrin antiviral activity was reversed by using H2O2 and the agonists of TLR4, JNK/p38, NF-κB and autophagy. Most important, the in-vitro effective concentration is higher than the reported plasma concentration. The in-vivo test showed that Apigetrin significantly increased the average survival time, reduced the lung edema and IAV replication. In conclusion, we have found that Ixeris sonchifolia Hance and its several ingredients can inhibit IAV infection, and the mechanisms of action of Apigetrin against IAV is by regulating TLR4 and autophagy signaling pathways.

Three-vessel coronary infusion of cardiosphere-derived cells for the treatment of heart failure with preserved ejection fraction in a pre-clinical pig model.

Heart failure with preserved ejection fraction (HFpEF) is a major public health concern. Its outcome is poor and, as of today, barely any treatments have been able to decrease its morbidity or mortality. Cardiosphere-derived cells (CDCs) are heart cell products with anti-fibrotic, anti-inflammatory and angiogenic properties. Here, we tested the efficacy of CDCs in improving left ventricular (LV) structure and function in pigs with HFpEF. Fourteen chronically instrumented pigs received continuous angiotensin II infusion for 5 weeks. LV function was investigated through hemodynamic measurements and echocardiography at baseline, after 3 weeks of angiotensin II infusion before three-vessel intra-coronary CDC (n = 6) or placebo (n = 8) administration and 2 weeks after treatment (i.e., at completion of the protocol). As expected, arterial pressure was significantly and similarly increased in both groups. This was accompanied by LV hypertrophy that was not affected by CDCs. LV systolic function remained similarly preserved during the whole protocol in both groups. In contrast, LV diastolic function was impaired (increases in Tau, LV end-diastolic pressure as well as E/A, E/E'septal and E/E'lateral ratios) but CDC treatment significantly improved all of these parameters. The beneficial effect of CDCs on LV diastolic function was not explained by reduced LV hypertrophy or increased arteriolar density; however, interstitial fibrosis was markedly reduced. Three-vessel intra-coronary administration of CDCs improves LV diastolic function and reduces LV fibrosis in this hypertensive model of HFpEF.

Assessment of coronary microcirculation alterations in a porcine model of no-reflow using ultrasound localization microscopy: a proof of concept study.

BACKGROUND: Coronary microvascular obstruction also known as no-reflow phenomenon is a major issue during myocardial infarction that bears important prognostic implications. Alterations of the microvascular network remains however challenging to assess as there is no imaging modality in the clinics that can image directly the coronary microvascular vessels. Ultrasound Localization Microscopy (ULM) imaging was recently introduced to map microvascular flows at high spatial resolution (∼10 µm). In this study, we developed an approach to image alterations of the microvascular coronary flow in ex vivo perfused swine hearts. METHODS: A porcine model of myocardial ischemia-reperfusion was used to obtain microvascular coronary alterations and no-reflow. Four female hearts with myocardial infarction in addition to 6 controls were explanted and placed immediately in a dedicated preservation and perfusion box manufactured for ultrasound imaging. Microbubbles (MB) were injected into the vasculature to perform Ultrasound Localization Microscopy (ULM) imaging and a linear ultrasound probe mounted on a motorized device was used to scan the heart on multiple slices. The coronary microvascular anatomy and flow velocity was reconstructed using dedicated ULM algorithms and analyzed quantitatively. FINDINGS: We were able to image the coronary microcirculation of ex vivo swine hearts at a resolution of tens of microns and measure flow velocities ranging from 10 mm/s in arterioles up to more than 200 mm/s in epicardial arteries. Under different aortic perfusion pressures, we measured in large arteries of a subset of control hearts an increase of flow velocity from 31 ± 11 mm/s at 87 mmHg to 47 ± 17 mm/s at 132 mmHg (N = 3 hearts, P < 0.05). This increase was compared with a control measurement with a flowmeter in the aorta. We also compared 6 control hearts to 4 hearts in which no-reflow was induced by the occlusion and reperfusion of a coronary artery. Using average MB velocity and average density of MB per unit of surface as two ULM quantitative markers of perfusion, we were able to detect areas of coronary no-reflow in good agreement with a control anatomical pathology analysis of the cardiac tissue. In the no-reflow zone, we measured an average perfusion of 204 ± 305 MB/mm2 compared to 3182 ± 1302 MB/mm2 in the surrounding re-perfused area. INTERPRETATION: We demonstrated this approach can directly image and quantify coronary microvascular obstruction and no-reflow on large mammal perfused hearts. This is a first step for noninvasive, quantitative and affordable assessment of the coronary microcirculation function and particularly coronary microvascular anatomy in the infarcted heart. This approach has the potential to be extended to other clinical situations characterized by microvascular dysfunction. FUNDING: This study was supported by the French National Research Agency (ANR) under ANR-21-CE19-0002 grant agreement.

Thermomechanical responses of the drift tube to beam loss at the China spallation neutron source.

The China Spallation Neutron Source drift tube linac (DTL) is a high current intensity linear accelerator operated in pulsed mode. Beam loss is the most important cause of DTL performance degradation. Therefore, control of beam loss is very crucial to the linac's commission and routine operation. The beam loss in beam pulse width (∼several hundreds of microseconds) can be regarded as an instantaneous process, which may cause the local temperature of the drift tubes (DTs) to exceed the melting point or the thermal stress to exceed the material yield strength, resulting in permanent damage to the DTs. RF heating and beam loss are two major heat sources of the DTs during operation. First, temperature rise due to RF power dissipation is evaluated in this paper. Then, the thermomechanical response due to beam loss at different energies is investigated. It is found that the 3-MeV beam loss has the greatest stopping power and causes the largest temperature rise to the DTs. The maximum beam current loss for different working conditions is analyzed by both analytical method and ANSYS simulations, and the details will also be discussed in this paper.

Effects of dazomet combined with Rhodopsesudomonas palustris PSB-06 on root-knot nematode, Meloidogyne incognita infecting ginger and soil microorganisms diversity.

Root-knot nematode, Meloidogyne incognita is one of the most important nematodes affecting ginger crop. Rhodopseudomonas palustris PSB-06, as effective microbial fertilizer in increasing plant growth and suppressing soil-borne disease of many crops has been reported. The combination of R. palustris PSB-06 and dazomet treatments had been proved to inhibit root-knot nematode on ginger and increase ginger yield in our preliminary study. The field experiments were conducted to elucidate the reasons behind this finding, and followed by next-generation sequencing to determine the microbial population structures in ginger root rhizosphere. The results showed that combination of R. palustris PSB-06 and dazomet treatment had a synergetic effect by achieving of 80.00% reduction in root-knot nematode numbers less than soil without treatment, and also could increase 37.37% of ginger yield through increasing the contents of chlorophyll and total protein in ginger leaves. Microbiota composition and alpha diversity varied with treatments and growth stages, soil bacterial diversity rapidly increased after planting ginger. In addition, the combined treatment could increase diversity and community composition of probiotic bacteria, and decrease those of soil-borne pathogenic fungi comparing to the soil treated with dazomet alone. Meanwhile, it could also effectively increase soil organic matter, available phosphorus and available potassium. Analysis of correlation between soil microorganisms and physicochemical properties indicated that the soil pH value and available phosphorus content were important factors that could affect soil microorganisms structure at the harvest stage. The bacterial family was more closely correlated with the soil physicochemical properties than the fungal family. Therefore, the combination of R. palustris PSB-06 and dazomet was considered as an effective method to control root-knot nematode disease and improve ginger soil conditions.

Metagenomic analysis of the dynamical conversion of photosynthetic bacterial communities in different crop fields over different growth periods.

Photosynthetic bacteria are beneficial to plants, but knowledge of photosynthetic bacterial community dynamics in field crops during different growth stages is scarce. The factors controlling the changes in the photosynthetic bacterial community during plant growth require further investigation. In this study, 35 microbial community samples were collected from the seedling, flowering, and mature stages of tomato, cucumber, and soybean plants. 35 microbial community samples were assessed using Illumina sequencing of the photosynthetic reaction center subunit M (pufM) gene. The results revealed significant alpha diversity and community structure differences among the three crops at the different growth stages. Proteobacteria was the dominant bacterial phylum, and Methylobacterium, Roseateles, and Thiorhodococcus were the dominant genera at all growth stages. PCoA revealed clear differences in the structure of the microbial populations isolated from leaf samples collected from different crops at different growth stages. In addition, a dissimilarity test revealed significant differences in the photosynthetic bacterial community among crops and growth stages (P<0.05). The photosynthetic bacterial communities changed during crop growth. OTUs assigned to Methylobacterium were present in varying abundances among different sample types, which we speculated was related to the function of different Methylobacterium species in promoting plant growth development and enhancing plant photosynthetic efficiency. In conclusion, the dynamics observed in this study provide new research ideas for the detailed assessments of the relationship between photosynthetic bacteria and different growth stages of plants.

Anti-influenza A Virus Effects and Mechanisms of Emodin and Its Analogs via Regulating PPARα/γ-AMPK-SIRT1 Pathway and Fatty Acid Metabolism.

The peroxisome proliferator-activated receptor (PPAR) α/γ-adenosine 5'-monophosphate- (AMP-) activated protein kinase- (AMPK-) sirtuin-1 (SIRT1) pathway and fatty acid metabolism are reported to be involved in influenza A virus (IAV) replication and IAV-pneumonia. Through a cell-based peroxisome proliferator responsive element- (PPRE-) driven luciferase bioassay, we have investigated 145 examples of traditional Chinese medicines (TCMs). Several TCMs, such as Polygonum cuspidatum, Rheum officinale Baillon, and Aloe vera var. Chinensis (Haw.) Berg., were found to possess high activity. We have further detected the anti-IAV activities of emodin (EMO) and its analogs, a group of common important compounds of these TCMs. The results showed that emodin and its several analogs possess excellent anti-IAV activities. The pharmacological tests showed that emodin significantly activated PPARα/γ and AMPK, decreased fatty acid biosynthesis, and increased intracellular ATP levels. Pharmaceutical inhibitors, siRNAs for PPARα/γ and AMPKα1, and exogenous palmitate impaired the inhibition of emodin. The in vivo test also showed that emodin significantly protected mice from IAV infection and pneumonia. Pharmacological inhibitors for PPARα/γ and AMPK signal and exogenous palmitate could partially counteract the effects of emodin in vivo. In conclusion, emodin and its analogs are a group of promising anti-IAV drug precursors, and the pharmacological mechanism of emodin is linked to its ability to regulate the PPARα/γ-AMPK pathway and fatty acid metabolism.

Spatial learning and memory impaired after infection of non-neurotropic influenza virus in BALB/c male mice.

During the influenza pandemic or seasonal influenza outbreak, influenza infection can cause acute influenza-associated encephalopathy/encephalitis (IAE), even death. Patients with severe IAE will also have severe neurological sequelae. Neurologic disorders have been demonstrated in the mice treated with peripheral influenza viruses infection, whether neurotropic or non-neurotropic viruses. However, previous studies focused on the acute phase of infection, and rarely paid attention to a longer range of observations. Therefore, the long-term effect of non-neurotropic virus infection on the host is not very clear. In this study, adult mice were infected with influenza virus H1N1/PR8. Then, spontaneous behavior, body weight, expression of cytokines in brain, spatial learning ability and spatial memory ability were observed, until the complete recovery period. The results showed that cytokines in the brain were highly expressed in the convalescent phase (14 day post inoculation, dpi), especially BDNF, IBA1, CX3CL1 and CD200 were still highly expressed in the recovery phase (28 dpi). Otherwise the emotional and spatial memory ability of mice were impacted in the convalescent phase (14 dpi) and the recovery phase (28 dpi). In brief, BALB/c mice infected with non-neurotropic influenza virus H1N1, the weight and motor ability decreased in acute stage. During the recovery period, the body weight and activity ability were completely restored, whereas the emotion disordered, and the ability of spatial learning and memory were impacted in the infected mice. This long-term behavior impact may be the lag injury caused by non-neurotropic influenza infection.

Development and external validation of a novel multihematoma fuzzy sign on computed tomography for predicting traumatic intraparenchymal hematoma expansion.

Acute traumatic intraparenchymal hematoma (tICH) expansion is a devastating neurological complication that is associated with poor outcome after cerebral contusion. This study aimed to develop and validate a novel noncontrast computed tomography (CT) (NCCT) multihematoma fuzzy sign to predict acute tICH expansion. In this multicenter, prospective cohort study, multihematoma fuzzy signs on baseline CT were found in 212 (43.89%) of total 482 patients. Patients with the multihematoma fuzzy sign had a higher frequency of tICH expansion than those without (90.79% (138) vs. 46.71% (71)). The presence of multihematoma fuzzy sign was associated with increased risk for acute tICH expansion in entire cohort (odds ratio [OR]: 16.15; 95% confidence interval (CI) 8.85-29.47; P < 0.001) and in the cohort after propensity-score matching (OR: 9.37; 95% CI 4.52-19.43; P < 0.001). Receiver operating characteristic analysis indicated a better discriminative ability of the presence of multihematoma fuzzy sign for acute tICH expansion (AUC = 0.79; 95% CI 0.76-0.83), as was also observed in an external validation cohort (AUC = 0.76; 95% CI 0.67-0.84). The novel NCCT marker of multihematoma fuzzy sign could be easily identified on baseline CT and is an easy-to-use predictive tool for tICH expansion in the early stage of cerebral contusion.

Scale-Dependent Effects of Growth Stage and Elevational Gradient on Rice Phyllosphere Bacterial and Fungal Microbial Patterns in the Terrace Field.

The variation of phyllosphere bacterial and fungal communities along elevation gradients may provide a potential link with temperature, which corresponds to an elevation over short geographic distances. At the same time, the plant growth stage is also an important factor affecting phyllosphere microorganisms. Understanding microbiological diversity over changes in elevation and among plant growth stages is important for developing crop growth ecological theories. Thus, we investigated variations in the composition of the rice phyllosphere bacterial and fungal communities at five sites along an elevation gradient from 580 to 980 m above sea level (asl) in the Ziquejie Mountain at the seedling, heading, and mature stages, using high-throughput Illumina sequencing methods. The results revealed that the dominant bacterial phyla were Proteobacteria, Actinobacteria, and Bacteroidetes, and the dominant fungal phyla were Ascomycota and Basidiomycota, which varied significantly at different elevation sites and growth stages. Elevation had a greater effect on the α diversity of phyllosphere bacteria than on that phyllosphere fungi. Meanwhile, the growth stage had a great effect on the α diversity of both phyllosphere bacteria and fungi. Our results also showed that the composition of bacterial and fungal communities varied significantly along elevation within the different growth stages, in terms of both changes in the relative abundance of species, and that the variations in bacterial and fungal composition were well correlated with variations in the average elevation. A total of 18 bacterial and 24 fungal genera were significantly correlated with elevational gradient, displaying large differences at the various growth stages. Soluble protein (SP) shared a strong positive correlation with bacterial and fungal communities (p < 0.05) and had a strong significant negative correlation with Serratia, Passalora, unclassified_Trichosphaeriales, and antioxidant enzymes (R > 0.5, p < 0.05), and significant positive correlation with the fungal genera Xylaria, Gibberella, and Penicillium (R > 0.5, p < 0.05). Therefore, it suggests that elevation and growth stage might alter both the diversity and abundance of phyllosphere bacterial and fungal populations.

Dynamic Changes in the Microbiome and Mucosal Immune Microenvironment of the Lower Respiratory Tract by Influenza Virus Infection.

Influenza is a major public health concern, and the high mortality rate is largely attributed to secondary bacterial infections. There are several mechanisms through which the virus increases host susceptibility to bacterial colonization, but the micro-environment in lower respiratory tract (LRT) of host, infected with influenza virus, is unclear. To this end, we analyzed the LRT microbiome, transcriptome of lung and metabolome of bronchoalveolar lavage fluid (BALF) in mice inoculated intra-nasally with H1N1 to simulate human influenza, and we observed significant changes in the composition of microbial community and species diversity in the acute (7 days post inoculation or dpi), convalescent (14 dpi) and the recovery (28 dpi) periods. The dominant bacterial class shifted from Alphaproteobacteria to Gammaproteobacteria and Actinobacteria in the infected mice, with a significant increase in the relative abundance of anaerobes and facultative anaerobes like Streptococcus and Staphylococcus. The dysbiosis in the LRT of infected mice was not normalized even in the recovery phase of the infection. In addition, the infected lung transcriptome showed significant differences in the expression levels of genes associated with bacterial infection and immune responses. Finally, the influenza virus infection also resulted in significant changes in the metabolome of the BALF. These alterations in the microbiome, transcriptome, and metabolome of infected lungs were not only appeared at the acute period, but also observed at the recovery period. Furthermore, the infection of influenza virus induced a long-term effect in LRT micro-environmental homeostasis, which may give a chance for the invasion of potential pathogens.

Physical Predictors of Cognitive Function in Individuals With Hypertension: Evidence from the CHARLS Basline Survey.

The purpose of the study was to examine the independent associations of each individual physical performance measure (i.e., grip strength, walking speed, repeated chair stands, and balance test) with subdomains of cognitive function and to determine predictors for each subdomain of cognitive function. A secondary data analysis was performed using a nationally representative middle-aged and older sample of hypertensive population. The findings showed that after adding all four physical performance measures, stronger grip strength was significantly associated with better visuospatial abilities, episodic memory, orientation/attention, and overall cognitive function. In addition, faster walking speed and faster repeated chair stands were strongly associated with better episodic memory and overall cognitive function, respectively. Because grip strength was significantly associated with several subdomains of cognitive functioning, it seems conceivable that increasing physical activity would improve both grip strength and cognitive function in patients with hypertension.

Clinical observation of the reduced glutathione in the treatment of diabetic chronic kidney disease.

BACKGROUND: Diabetic chronic kidney disease (CKD) has become the main cause of death in diabetic patients, but its pathogenesis has not yet been clear. OBJECTIVE: To investigate the effects of reduced glutathione (GSH) on oxidative stress (OS), angiogenesis factors and lymphocyte subsets in diabetic CKD patients. METHODS: A total of 130 subjects were retrospectively studied. The subjects were divided into the control group (45 cases), treatment group (45 cases, treated with reduced GSH), and a healthy control group (40 cases). The levels of superoxide dismutase (SOD), advanced oxidation protein products (AOPP), malondialdehyde (MDA), endostatin (ES), and vascular endothelial growth factor (VEGF), and the percentages of lymphocyte subsets were detected. RESULTS: After treatment, the indexes of OS and angiogenesis and the percentage of CD3- CD19+ B cells were obviously decreased, and the percentages of T cell subsets and natural killer (NK) cell subsets were markedly increased in the treatment group compared with the control group. AOPP was positively correlated with angiogenesis indexes, MDA and CD3- CD19+ B cells, and negatively correlated with SOD and other lymphocyte subsets. SOD was inversely associated with angiogenesis indexes and MDA, and positively associated with lymphocyte subsets. Moreover, MDA had a positive correlation with angiogenesis indexes, B and T cell subsets, and a negative correlation with NK cell subsets. AOPP, MDA, SOD, VEGF, CD3+ T cells, CD3+ CD8+ T cells, CD3- CDl6+ CD56+ NK cells, and CD3- CDl6+ CD56+ NK T cells were the risk factors of diabetic CKD. CONCLUSION: GSH could inhibit OS and abnormal angiogenesis, and improve cellular immune response in CKD patients.

Usefulness of conventional magnetic resonance imaging, diffusion tensor imaging and neurite orientation dispersion and density imaging in evaluating postoperative function in patients with cervical spondylotic myelopathy.

OBJECTIVE: The objective of this study was to evaluate the usefulness of T2 high signal intensity (T2-HSI) and decreased anteroposterior diameter (APD), diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) in evaluating postoperative cervical cord function. METHODS: The study included 57 postoperative cervical spondylotic myelopathy patients. Clinical evaluation and functional recovery assessments were performed using the modified Japanese Orthopaedic Association (mJOA) score and recovery rate. The presence of T2-HSI and decreased APD was recorded for exploring the relevance. Spearman correlation was applied to investigate the relationships between DTI and NODDI metrics and mJOA score. Multiple comparisons of T2 signal intensity, APD and diffusion metrics were evaluated by using multiple linear regression. RESULTS: Only the recovery rate was significantly different between T2-HSI and non-T2-HSI (nT2-HSI) patients (χ2 = 4.466, p = 0.045). Significant differences were not observed between cervical cords with and without decreased APD. Diffusion metrics, including fractional anisotropy (p = 0.0005), mean diffusivity (p = 0.0008), radial diffusivity (p = 0.0003) and intracellular volume fraction (p = 0.001), were significantly correlated with mJOA score. The ability of T2 signal intensity (p = 0.421) and APD (p = 0.420) to evaluate the postoperative function was inferior to that of fractional anisotropy (p = 0.002), mean diffusivity (p = 0.001), radial diffusivity (p = 0.001) and intracellular volume fraction (p = 0.004). CONCLUSION: Conventional magnetic resonance imaging signs could be considered as a reference to make an approximate assessment, whereas DTI and NODDI could be better quantitative tools for evaluating the postoperative function and may help in interpreting residual symptoms. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: DTI and NODDI could provide reliable postoperative evaluation and analysis for cervical spondylotic myelopathy patients.

Radiomics analysis allows for precise prediction of epilepsy in patients with low-grade gliomas.

Purpose: To investigate the association between imaging features and low-grade gliomas (LGG) related epilepsy, and to propose a radiomics-based model for the prediction of LGG-associated epilepsy. Methods: This retrospective study consecutively enrolled 286 patients with LGGs (194 in the primary cohort and 92 in the validation cohort). T2-weighted MR images (T2WI) were used to characterize risk factors for LGG-related epilepsy: Tumor location features and 3-D imaging features were determined, following which the interactions between these two kinds of features were analyzed. Elastic net was applied to generate a radiomics signature combining key imaging features associated with the LGG-related epilepsy with the primary cohort, and then a nomogram incorporating radiomics signature and clinical characteristics was developed. The radiomics signature and nomogram were validated in the validation cohort. Results: A total of 475 features associated with LGG-related epilepsy were obtained for each patient. A radiomics signature with eleven selected features allowed for discriminating patients with epilepsy or not was detected, which performed better than location and 3-D imaging features. The nomogram incorporating radiomics signature and clinical characteristics achieved a high degree of discrimination with area under receiver operating characteristic (ROC) curve (AUC) at 0.8769 in the primary cohort and 0.8152 in the validation cohort. The nomogram also allowed for good calibration in the primary cohort. Conclusion: We developed and validated an effective prediction model for LGG-related epilepsy. Our results suggested that radiomics analysis may enable more precise and individualized prediction of LGG-related epilepsy.

Differential responses of stressful elements to predatory exposure in behavior-lateralized mice.

BACKGROUND: Predatory stress as a psychological stressor can elicit the activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is involved in the dialogue of the neuroimmunoendocrine network. The brain has been proven to regulate the activity of the HPA axis by way of lateralization. In the present study, we probed the pivotal elements of the HPA circuitry including CRH, GR and a multifunctional cytokine in behavior-lateralized mice to determine their changes when the animals were subjected to predator exposure. METHODS: Behavior-lateralized mice were classified into left-pawed and right-pawed mice through a paw-preference test. Thereafter, mice in the acute stress group received a single 60-min cat exposure, and mice in the chronic group received daily 60-min cat exposure for 14 consecutive days. The plasma CS and TNF-α were determined by ELISA, the hypothalamic CRH mRNA and hippocampal GR mRNA were detected by real-time PCR, and the hippocampal GR protein was detected by western blot analysis. RESULTS: The results revealed that the levels of plasma CS were significantly elevated after chronic predatory exposure in both right-pawed and left-pawed mice; the right-pawed mice exhibited a higher plasma CS level than the left-pawed mice. Similarly, the acute or chronic cat exposure could induce the release of plasma TNF-α, and the left-pawed mice tended to show a higher level after the acute stress. Chronic stress significantly upregulated the expression of hypothalamic CRH mRNA in both left-pawed and right-pawed mice. Normally, the left-pawed mice exhibited a higher GR expression in the hippocampus than the right-pawed mice. After the cat exposure, the expression of GR in both left-pawed and right-pawed mice was revealed to be greatly downregulated. CONCLUSION: Our findings indicate that predatory stress can invoke a differential response of stressful elements in behavior-lateralized mice. Some of these responses shaped by behavioral lateralization might be helpful for facilitating adaption to various stimuli.

Relationship between fatigue symptoms and subjective and objective indicators in hemodialysis patients.

PURPOSE: The purpose of the study was to investigate the major factors affecting fatigue symptoms and to examine the relationships between fatigue symptoms and subjective and objective indicators in patients on hemodialysis (HD). METHODS: Patients on HD who met the inclusion criteria were chosen from two grade A tertiary general hospitals by convenience sampling and cross-sectional survey methods. RESULTS: A total of 511 patients were included in the study. The morbidity rate of fatigue in patients on HD was 61.6%, and the median fatigue level was 3.91. Fatigue and subjective indicators showed a mild-moderate relationship (0.3 < all |r| < 0.6, all P < 0.001), whereas a weak correlation was found between fatigue and objective indicators (all |r| < 0.2, all P < 0.05). Multivariate analysis showed that subjective indicators, including employment, exercise time, appetite, the vitality of 36-item Short Form Health Survey, perceived social support, intrafamilial support, cramping, headache, chest tightness, and whole-body pain, as well objective indicator, such as serum intact parathyroid hormone levels, were the influence factors of fatigue in patients on HD. CONCLUSION: The prevalence of fatigue symptoms was high and the level of fatigue was moderate in patients on HD. Subjective and objective indicators can both affect fatigue symptoms in patients on HD.

Oxymatrine Inhibits Influenza A Virus Replication and Inflammation via TLR4, p38 MAPK and NF-κB Pathways.

Oxymatrine (OMT) is a strong immunosuppressive agent that has been used in the clinic for many years. In the present study, by using plaque inhibition, luciferase reporter plasmids, qRT-PCR, western blotting, and ELISA assays, we have investigated the effect and mechanism of OMT on influenza A virus (IAV) replication and IAV-induced inflammation in vitro and in vivo. The results showed that OMT had excellent anti-IAV activity on eight IAV strains in vitro. OMT could significantly decrease the promoter activity of TLR3, TLR4, TLR7, MyD88, and TRAF6 genes, inhibit IAV-induced activations of Akt, ERK1/2, p38 MAPK, and NF-κB pathways, and suppress the expressions of inflammatory cytokines and MMP-2/-9. Activators of TLR4, p38 MAPK and NF-κB pathways could significantly antagonize the anti-IAV activity of OMT in vitro, including IAV replication and IAV-induced cytopathogenic effect (CPE). Furthermore, OMT could reduce the loss of body weight, significantly increase the survival rate of IAV-infected mice, decrease the lung index, pulmonary inflammation and lung viral titter, and improve pulmonary histopathological changes. In conclusion, OMT possesses anti-IAV and anti-inflammatory activities, the mechanism of action may be linked to its ability to inhibit IAV-induced activations of TLR4, p38 MAPK, and NF-κB pathways.

Anti-influenza A virus activity of rhein through regulating oxidative stress, TLR4, Akt, MAPK, and NF-κB signal pathways.

Rhein, an anthraquinone compound existing in many traditional herbal medicines, has anti-inflammatory, antioxidant, antitumor, antiviral, hepatoprotective, and nephroprotective activities, but its anti-influenza A virus (IAV) activity is ambiguous. In the present study, through plaque inhibition assay, time-of-addition assay, antioxidant assay, qRT-PCR, ELISA, and western blotting assays, we investigated the anti-IAV effect and mechanism of action of rhein in vitro and in vivo. The results showed that rhein could significantly inhibit IAV adsorption and replication, decrease IAV-induced oxidative stress, activations of TLR4, Akt, p38, JNK MAPK, and NF-κB pathways, and production of inflammatory cytokines and matrix metalloproteinases in vitro. Oxidant H2O2 and agonists of TLR4, Akt, p38/JNK and IKK/NF-κB could significantly antagonize the inhibitory effects of rhein on IAV-induced cytopathic effect (CPE) and IAV replication. Through an in vivo test in mice, we also found that rhein could significantly improve the survival rate, lung index, pulmonary cytokines, and pulmonary histopathological changes. Rhein also significantly decreased pulmonary viral load at a high dose. In conclusion, rhein can inhibit IAV adsorption and replication, and the mechanism of action to inhibit IAV replication may be due to its ability to suppress IAV-induced oxidative stress and activations of TLR4, Akt, p38, JNK MAPK, and NF-κB signal pathways.

Catheter Injected Bone Marrow Mesenchymal Stem Cells Induce Efficacious Occlusion of Arteriovenous Nidus in a Swine Model.

OBJECTIVES: Arteriovenous malformations (AVMs) are complex vascular lesions. Surgical excision is the treatment of choice, but is often not achievable. Embolo-sclerotherapy alone is associated with high recurrence rates. This study tested the hypothesis that seeding hydrogel conditioned bone marrow derived mesenchymatous stem cells (BM-MSCs) in an AVM nidus model induces solid microvascular occlusion through endoluminal tissue growth. METHODS: AVMs were modelled as arteriovenous microvascular nidus, using swine rete mirabile, a plexiform intracranial structure composed of arterial microvessels that extensively anastomose. A right carotid-jugular fistula was created to generate high flow in the rete, and bone marrow was aspirated. At day 14, cultured BM-MSCs marked with a red fluorochrome were incorporated into a hyaluronic acid hydrogel, and injected through a catheter into the rete mirabile, using femoral access. In specific groups microsphere embolisation immediately preceded gel injection. At day 28, the swine were euthanased and the rete mirabile harvested for qualitative and quantitative analysis of microvessel lumen occlusion. RESULTS: Actual transfer of PKH26 labelled cells in rete was confirmed. In a first phase of the study, five swine died as a result of neurological events, prompting reductions of the injected volumes. Twenty-three animals survived until day 28. Injection of BM-MSC loaded hydrogel (n=6) significantly increased the occlusion rate compared with injection of acellular hydrogel (n=7) (10% [range, 10-12%] vs. 26% [range, 20-41%], p=.016). Injection of BM-MSC loaded hydrogel immediately after microspheres (n=6) enhanced the occlusion rate compared with embolic microspheres alone (n=6) (50% [range 46-56%] vs. 22% [range, 15-27%] p=.045). Microsphere injection resulted in vascular luminal thrombus formation. Injection of BM-MSCs induced endoluminal growth of vascular smooth muscle cells with cell proliferation and a dense collagen rich extracellular matrix. CONCLUSION: The luminal occlusion pattern of a microvascular AVM like structure can be changed from thrombus to solid cellular accumulation. The possibility of injecting living cells in a microvascular network, in a chronic survival model, provides new tools for research and treatment of AVMs and other microvascular diseases.