Constant Light Exposure Alters Gut Microbiota and Promotes the Progression of Steatohepatitis in High Fat Diet Rats

Background: Non-alcoholic fatty liver disease (NAFLD) poses a significant health concern worldwide. With the progression of urbanization, light pollution may be a previously unrecognized risk factor for NAFLD/NASH development. However, the role of light pollution on NAFLD is insufficiently understood, and the underlying mechanism remains unclear. Interestingly, recent studies indicate the gut microbiota affects NAFLD/NASH development. Therefore, the present study explored effects of constant light exposure on NAFLD and its related microbiotic mechanisms. Material and method: Twenty-eight SD male rats were divided into four groups (n=7 each): rats fed a normal chow diet, and exposed to standard light-dark cycle (ND-LD); rats fed a normal chow diet, and exposed to constant light (ND-LL); rats fed a high fat diet, and exposed to standard light-dark cycle (HFD-LD); and rats on a high fat diet, and exposed to constant light (HFD-LL). Body weight, hepatic pathophysiology, gut microbiota, and short/medium chain fatty acids in colon contents, serum lipopolysaccharide (LPS) and liver LPS-binding protein (LBP) mRNA expression were documented post intervention and compared among groups. Result: In normal chow fed groups, rats exposed to constant light displayed glucose abnormalities and dyslipidemia. In HFD-fed rats, constant light exposure exacerbated glucose abnormalities, insulin resistance, inflammation and liver steatohepatitis. Constant light exposure altered composition of gut microbiota in both normal chow and HFD fed rats. Compared with HFD-LD group, HFD-LL rats displayed less Butyricicoccus, Clostridium and Turicibacter, butyrate levels in colon contents, decreased colon expression of occludin-1 and zonula occluden‐1 (ZO-1) , and increased serum LPS and liver LBP mRNA expression. Conclusion: Constant light exposure impacts gut microbiota and its metabolic products, impairs gut barrier function and gut-liver axis, promotes NAFLD/NASH progression in HFD rats

Assessment of Burden Among Family Caregivers of Schizophrenia: Psychometric Testing for Short-Form Zarit Burden Interviews

Objective: Although various short forms of Zarit Burden Interview (ZBI) have been developed, there is a lack of standard psychometric testing and comparison among them. The study aims to examine the psychometric properties of ten short versions of the most frequently used ZBI among a sample of schizophrenia caregivers and to find the one with the best performance.Methods: Cross-sectional door-to-door survey of ZBI-22 and a series of validated instrument data from 327 family caregivers of schizophrenia patients in a Chinese rural community were conducted from October 2015 to January 2016. Reliability was assessed using McDonald's omega coefficient (ω). Validity including concurrent validity, known group's validity, and criterion validity were assessed by Spearman correlations and Mann-Whitney U tests. Overall discrimination ability was evaluated using the area under the receiver operating characteristic curve (AUC).Results: Reliability was generally good for all short forms (ω = 0.69–0.84), except for the Gort ZBI-4 (ω = 0.58), which is acceptable considering its small item numbers. Concurrent validity was good across all various ZBI forms with significant negative correlations with patient's function (r = −0.34 to −0.48, p < 0.01), as well as significant positive correlations with caregiver's depression (r = 0.49–0.65, p < 0.01), and anxiety symptoms (r = 0.45–0.58, p < 0.01). Known groups' validity (carers with disease vs. without disease; carers being parents vs. spouse vs. others) showed inconsistent results among various short forms. Criterion validity was generally good for all short forms with significant positive correlations with Family Burden Interview Schedule (r = 0.67–0.75, p < 0.01), except for the Higginson ZBI-1(r = 0.57, p < 0.01). Discriminative ability was also good for all short forms (AUC range: 0.85–0.99), with various cutpoints proposed. Among all ten short forms, the Ballesteros ZBI-12 and the Gort ZBI-7 outperformed others with almost equally good performance in comprehensive psychometric testing.Conclusions: This study provides support for the reliability, validity, and discriminative ability of the ten various short forms of ZBI for use among schizophrenia family caregivers, with the Ballesteros ZBI-12 and the Gort ZBI-7 endorsed as the best ones

Trace the Accretion Geometry of H 1743--322 with Type C Quasi-periodic Oscillations in Multiple Outbursts

We present a systematic analysis of type C quasi-periodic oscillation (QPO) observations of H 1743--322 throughout the Rossi X-ray Timing Explorer (RXTE) era. We find that, while different outbursts have significant flux differences, they show consistent positive correlations between the QPO fractional root-mean-square (rms) amplitude and non-thermal fraction of the emission, which indicate an independence of the intrinsic QPO rms on individual outburst brightness in H 1743--322. However, the dependence of the QPO rms on frequency is different between the outburst rise and decay phases, where QPO fractional rms of the decay phase is significantly lower than that of the rise phase at low frequencies. The spectral analysis also reveals different ranges of coronal temperature between the two outburst stages. A semi-quantitative analysis shows that the Lense-Thirring precession model could be responsible for the QPO rms differences, requiring a variable coronal geometric shape. However, the variable-Comptonization model could also account for the findings. The fact that the rms differences and the hysteresis traces in the hardness-intensity diagram (HID) accompany each other indicates a connection between the two phenomena. By correlating the findings with QPO phase lags and the quasi-simultaneous radio flux previously published, we propose there could be corona-jet transitions in H 1743--322 similar to those that have been recently reported in GRS 1915+105.Comment: 21 pages, 12 figure

A role of periaqueductal grey NR2B-containing NMDA receptor in mediating persistent inflammatory pain

The midbrain periaqueductal grey (PAG) is a structure known for its roles in pain transmission and modulation. Noxious stimuli potentiate the glutamate synaptic transmission and enhance glutamate NMDA receptor expression in the PAG. However, little is known about roles of NMDA receptor subunits in the PAG in processing the persistent inflammatory pain. The present study was undertaken to investigate NR2A- and NR2B-containing NMDA receptors in the PAG and their modulation to the peripheral painful inflammation. Noxious stimuli induced by hind-paw injection of complete Freund's adjuvant (CFA) caused up-regulation of NR2B-containing NMDA receptors in the PAG, while NR2A-containing NMDA receptors were not altered. Whole-cell patch-clamp recordings revealed that NMDA receptor mediated mEPSCs were increased significantly in the PAG synapse during the chronic phases of inflammatory pain in mice. PAG local infusion of Ro 25-6981, an NR2B antagonist, notably prolonged the paw withdrawal latency to thermal radian heat stimuli bilaterally in rats. Hyperoside (Hyp), one of the flavonoids compound isolated from Rhododendron ponticum L., significantly reversed up-regulation of NR2B-containing NMDA receptors in the PAG and exhibited analgesic activities against persistent inflammatory stimuli in mice. Our findings provide strong evidence that up-regulation of NR2B-containing NMDA receptors in the PAG involves in the modulation to the peripheral persistent inflammatory pain

An novel role of sphingosine kinase-1 (SPHK1) in the invasion and metastasis of esophageal carcinoma

<p>Abstract</p> <p>Background</p> <p>Treatment failure for esophageal carcinoma is frequently due to lymph node metastasis and invasion to neighboring organs. The aim of the present study was to investigate invasion- and metastasis-related genes in esophageal carcinoma cells <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>A metastasis model using a Matrigel invasion clonal selection approach was employed to establish a highly invasive subline EC9706-P4 from the esophageal carcinoma cell (ESCC) line EC9706. The differentially expressed genes of the subline and the parental cells determined by gene microarrays were further analyzed by RT-PCR and Western blotting.</p> <p>Results</p> <p>We identified <it>sphingosine kinase 1 (SPHK1) </it>as an invasion and metastasis-related gene of esophageal cancer. <it>SPHK1 </it>was overexpressed in the EC9706-P4 subline with high invasive capacity. Among six ESCC lines tested, KYSE2 and KYSE30 cells showed the highest <it>SPHK1 </it>mRNA and protein expressions as well as the most invasive phenotype. By Western blotting, in 7/12 cases (58%), SPHK1 expression was higher in esophageal carcinomas than in the companion normal tissue. In 23/30 cases (76%), SPHK1 protein expression was upregulated in the tumors compared to matched normal tissue by immunohistochemistry (IHC). Esophageal carcinoma tissue microarray analysis indicated that SPHK1 expression correlated with the depth of tumor invasion (<it>P </it>< 0.0001) and lymph node metastasis (<it>P </it>= 0.016). By Kaplan-Meier analysis, strong SPHK1 expression was significantly associated with clinical failure (<it>P </it>< 0.01), suggesting the involvement of SPHK1 in aggressiveness of human esophageal carcinoma. <it>SPHK1 </it>overexpression significantly increased the invasiveness of EC9706 cells <it>in vitro </it>and also increased EC9706 cell growth and spontaneous metastasis <it>in vivo</it>, promoting significant increases in tumor growth, tumor burden and spontaneous lung metastasis in nude mice. <it>SPHK1 </it>expression significantly correlated with the expression of many EGFR pathway genes associated with invasion of cancer cells. SPHK1 protein expression also significantly correlated with the phosphorylation of EGFR.</p> <p>Conclusion</p> <p>In summary, our data implicate <it>SPHK1 </it>in the metastasis of esophageal cancer. Our study also identified downstream mediators of SPHK1 in esophageal cancer cells that may mediate enhanced malignant behavior, and several of these mediators may be useful as therapeutic targets.</p

Salmonella Outer Protein B Suppresses Colitis Development via Protecting Cell From Necroptosis

Salmonella effectors translocated into epithelial cells contribute to the pathogenesis of infection. They mediate epithelial cell invasion and subsequent intracellular replication. However, their functions in vivo have not been well-identified. In this study, we uncovered a role for Salmonella outer protein B (SopB) in modulating necroptosis to facilitate bacteria escape epithelial cell and spread to systemic sites through a Salmonella-induced colitis model. Mice infected with SopB deleted strain ΔsopB displayed increased severity to colitis, reduced mucin expression and increased bacterial translocation. In vitro study, we found there was an increased goblet cell necroptosis following ΔsopB infection. Consistently, mice infected with ΔsopB had a strong upregulation of mixed lineage kinase domain-like (MLKL) phosphorylation. Deletion of MLKL rescued severity of tissue inflammatory, improved mucin2 expression and abolished the increased bacterial translocation in mice infected with ΔsopB. Intriguingly, the expression of sopB in LS174T cells was downregulated. The temporally regulated SopB expression potentially switched the role from epithelial cell invasion to bacterial transmission. Collectively, these results indicated a role for SopB in modulating the onset of necroptosis to increased bacteria pathogenesis and translocated to systemic sites

Association Between Acute Kidney Injury and Long-Term Mortality in Patients With Aneurysmal Subarachnoid Hemorrhage: A Retrospective Study

Background: Though acute kidney injury (AKI) in the context of aneurysmal subarachnoid hemorrhage (aSAH) worsens short-term outcomes, its impact on long-term survival is unknown. Aim: We aimed to evaluate the association between long-term mortality and AKI during hospitalization for aSAH. Methods: This was a retrospective study of patients who survived \u3e12 months after aSAH. All patients were evaluated at West China Hospital, Sichuan University, between December 2013 and June 2019. The minimum follow-up time was over 1 year. the maximum follow-up time was about 7.3 years. AKI was defined by the KDIGO (The Kidney Disease Improving Global Outcomes) guidelines, which stratifies patients into three stages of severity. The primary outcome was long-term mortality, which was analyzed with Kaplan-Meier curves and Cox proportional hazards models. Results: During this study period, 238 (9.2%) patients had AKI among 2,592 patients with aSAH. We confirmed that AKI during care for aSAH significantly increased long-term mortality (median 4.3 years of follow-up) and that risk increased with the severity of the kidney failure, with an adjusted hazard ratio (HR) of 2.08 (95% CI 1.49-2.89) for stage 1 AKI, 2.15 (95% CI 1.05-4.43) for stage 2 AKI, and 2.66 (95% CI 1.08-6.53) for stage 3 AKI compared with patients without AKI. Among patients with an AKI episode, those with renal recovery still had increased long-term mortality (HR 1.96; 95% CI 1.40-2.74) compared with patients without AKI but had better long-term outcomes than those without renal recovery (HR 0.51, 95% CI 0.27-0.97). Conclusions: Among 12-month survivors of aSAH, AKI during their initial hospitalization for aSAH was associated with increased long-term mortality, even for patients who had normal renal function at the time of hospital discharge. Longer, multidisciplinary post-discharge follow-up may be warranted for these patients

DNA Sensor IFI204 Contributes to Host Defense Against Staphylococcus aureus Infection in Mice

Interferon-inducible protein (IFI204) (p204, the murine homolog of human IFI16) is known as a cytosolic DNA sensor to recognize DNA viruses and intracellular bacteria. However, little is known about its role during extracellular bacterial infection. Here we show that IFI204 is required for host defense against the infection of Staphylococcus aureus, an extracellular bacterial pathogen. IFI204 deficiency results in decreased survival, increased bacterial loads, severe organs damage, and decreased recruitment of neutrophils and macrophages. Production of several inflammatory cytokines/chemokines including IFN-β and KC is markedly decreased, as well as the related STING-IRF3 and NF-κB pathways are impaired. However, exogenous administration of recombinant KC or IFN-β is unable to rescue the susceptibility of IFI204-deficient mice, suggesting that other mechanisms rather than KC and IFN-β account for IFI204-mediated host defense. IFI204 deficiency leads to a defect in extracellular bacterial killing in macrophages and neutrophils, although bacterial engulf, and intracellular killing activity are normal. Moreover, the defect of bactericidal activity is mediated by decreased extracellular trap formation in the absence of IFI204. Adoptively transferred WT bone marrow cells significantly protect WT and IFI204-deficient recipients against Staphylococcus infection compared with transferred IFI204-deficient bone marrow cells. Hence, this study suggests that IFI204 is essential for the host defense against Staphylococcus infection

ATP synthase ecto-α-subunit: a novel therapeutic target for breast cancer

<p>Abstract</p> <p>Background</p> <p>Treatment failure for breast cancer is frequently due to lymph node metastasis and invasion to neighboring organs. The aim of the present study was to investigate invasion- and metastasis-related genes in breast cancer cells <it>in vitro </it>and <it>in vivo</it>. Identification of new targets will facilitate the developmental pace of new techniques in screening and early diagnosis. Improved abilities to predict progression and metastasis, therapeutic response and toxicity will help to increase survival of breast cancer patients.</p> <p>Methods</p> <p>Differential protein expression in two breast cancer cell lines, one with high and the other with low metastatic potential, was analyzed using two-dimensional liquid phase chromatographic fractionation (Proteome Lab PF 2D system) followed by matrix-assisted laser desorption/time-of-flight mass spectrometry (MALDI-TOF/MS).</p> <p>Results</p> <p>Up regulation of α-subunit of ATP synthase was identified in high metastatic cells compared with low metastatic cells. Immunohistochemical analysis of 168 human breast cancer specimens on tissue microarrays revealed a high frequency of ATP synthase α-subunit expression in breast cancer (94.6%) compared to normal (21.2%) and atypical hyperplasia (23%) breast tissues. Levels of ATP synthase expression levels strongly correlated with large tumor size, poor tumor differentiation and advanced tumor stages (<it>P </it>< 0.05). ATP synthase α-subunit over-expression was detected on the surface of a highly invasive breast cancer cell line. An antibody against the ATP synthase α-subunit inhibited proliferation, migration and invasion in these breast cancer cells but not that of a non-tumor derived breast cell line.</p> <p>Conclusions</p> <p>Over-expression of ATP synthase α-subunit may be involved in the progression and metastasis of breast cancer, perhaps representing a potential biomarker for diagnosis, prognosis and a therapeutic target for breast cancer. This finding of this study will help us to better understand the molecular mechanism of tumor metastasis and to improve the screening, diagnosis, as well as prognosis and/or prediction of responses to therapy for breast cancer.</p