3, 4-dihydroxyl-phenyl lactic acid restores NADH dehydrogenase 1 α subunit 10 to ameliorate cardiac reperfusion injury.

The present study aimed to detect the role of 3, 4-dihydroxyl-phenyl lactic acid (DLA) during ischemia/reperfusion (I/R) induced myocardial injury with emphasis on the underlying mechanism of DLA antioxidant. Male Spragu-Dawley (SD) rats were subjected to left descending artery occlusion followed by reperfusion. Treatment with DLA ameliorated myocardial structure and function disorder, blunted the impairment of Complex I activity and mitochondrial function after I/R. The results of 2-D fluorescence difference gel electrophoresis revealed that DLA prevented the decrease in NDUFA10 expression, one of the subunits of Complex I. To find the target of DLA, the binding affinity of Sirtuin 1 (SIRT1) to DLA and DLA derivatives with replaced two phenolic hydroxyls was detected using surface plasmon resonance and bilayer interferometry. The results showed that DLA could activate SIRT1 after I/R probably by binding to this protein, depending on phenolic hydroxyl. Moreover, the importance of SIRT1 to DLA effectiveness was confirmed through siRNA transfection in vitro. These results demonstrated that DLA was able to prevent I/R induced decrease in NDUFA10 expression, improve Complex I activity and mitochondrial function, eventually attenuate cardiac structure and function injury after I/R, which was possibly related to its ability of binding to and activating SIRT1

Exploring the causal factor effects of hypothyroidism on ischemic stroke: a two-sample Mendelian randomization study

BackgroundObservational studies have suggested a possible association between hypothyroidism and increased risk of ischemic stroke. However, a causal relationship remains unclear.MethodsData on single nucleotide polymorphisms (SNPs) associated with hypothyroidism and ischemic stroke were sourced from the FinnGens database and the UK Biobank of European descent. Both databases underwent separate two-sample Mendelian randomization (MR) analyses. A subsequent meta-analysis of MR results using a random-effects model was conducted to determine the causal relationship between hypothyroidism and ischemic stroke.ResultsAll five analyses indicated a positive causal relationship between hypothyroidism and ischemic stroke. MR analysis of the association between hypothyroidism and ischemic stroke yielded a result of the inverse variance weighted (IVW) method at 4.7411 (1.3598–16.5308), p = 0.0146. The analysis of ischemic stroke (without excluding controls) yielded a result of the IVW method of 4.5713 (1.3570–15.3986), p = 0.0142. MR analysis with cerebral infarction yielded a result of the IVW method at 1.0110 (1.0006–1.0215), p = 0.0373. The MR analysis with cerebrovascular disease sequelae yielded an IVW method result of 2.4556 (1.0291–5.8595), p = 0.0429. Analysis for the sequelae of cerebrovascular disease (without excluding controls) yielded an IVW method result of 2.4217 (1.0217–5.7402), p = 0.0446. No evidence of heterogeneity or horizontal pleiotropy was found. The meta-analysis of the five MR results was 2.24 (1.18–4.26), p = 0.025.ConclusionOur two-sample Mendelian randomization study suggested a causal relationship between hypothyroidism and ischemic stroke, indicating that hypothyroidism could be a risk factor for ischemic stroke. However, further studies are required to elucidate the underlying biological mechanisms

Propofol Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-Alpha Expression and Myocardial Depression through Decreasing the Generation of Superoxide Anion in Cardiomyocytes

TNF-α has been shown to be a major factor responsible for myocardial depression in sepsis. The aim of this study was to investigate the effect of an anesthetic, propofol, on TNF-α expression in cardiomyocytes treated with LPS both in vivo and in vitro. In cultured cardiomyocytes, compared with control group, propofol significantly reduced protein expression of gp91phox and phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) and p38 MAPK, which associates with reduced TNF-α production. In in vivo mice studies, propofol significantly improved myocardial depression and increased survival rate of mice after LPS treatment or during endotoxemia, which associates with reduced myocardial TNF-α production, gp91phox, ERK1/2, and p38 MAPK. It is concluded that propofol abrogates LPS-induced TNF-α production and alleviates cardiac depression through gp91phox/ERK1/2 or p38 MAPK signal pathway. These findings have great clinical importance in the application of propofol for patients enduring sepsis

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

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

Incidence of chemotherapy-induced amenorrhea associated with epirubicin, docetaxel and navelbine in younger breast cancer patients

<p>Abstract</p> <p>Background</p> <p>The rates of chemotherapy-induced amenorrhea (CIA) associated with docetaxel-based regimens reported by previous studies are discordant. For navelbine-based chemotherapies, rates of CIA have seldom been reported.</p> <p>Methods</p> <p>Of 170 premenopausal patients recruited between January 2003 and September 2008, 78 were treated with fluorouracil plus epirubicin and cyclophosphamide (FEC), 66 were treated with docetaxel plus epirubicin (TE), and 26 were treated with navelbine plus epirubicin (NE). Patient follow-up was carried up every 3-4 months during the first year, then every 9-12 months during subsequent years.</p> <p>Results</p> <p>In univariate analysis, the rates of CIA were 44.87% for the FEC regimen, 30.30% for the TE regimen and 23.08% for the NE regimen (<it>P </it>= 0.068). Significant differences in the rates of CIA were not found between the FEC and TE treatment groups (<it>P </it>> 0.05), but were found between the FEC and NE treatment groups (<it>P </it>< 0.05). Furthermore, no significant differences were found between the TE and NE regimens (<it>P </it>> 0.05). Tamoxifen use was a significant predictor for CIA (<it>P </it>= 0.001), and age was also a significant predictor (<it>P </it>< 0.001). In multivariate analysis, age (<it>P </it>< 0.001), the type of chemotherapy regimens (<it>P </it>= 0.009) and tamoxifen use (<it>P </it>= 0.003) were all significant predictors.</p> <p>Conclusions</p> <p>Age and administration of tamoxifen were found to be significant predictive factors of CIA, whereas docetaxel and navelbine based regimens were not associated with higher rates of CIA than epirubicin-based regimen.</p

HBsAg Inhibits the Translocation of JTB into Mitochondria in HepG2 Cells and Potentially Plays a Role in HCC Progression

Background and Aims: The expression of the jumping translocation breakpoint (JTB) gene is upregulated in malignant liver tissues; however, JTB is associated with unbalanced translocations in many other types of cancer that suppress JTB expression. No comprehensive analysis on its function in human hepatocellular carcinoma (HCC) has been performed to date. We aimed to define the biological consequences for interaction between JTB and HBsAg in HCC cell lines. Methods: We employed the stable transfection to establish small HBsAg expressing HepG2 cell line, and stably silenced the JTB expression using short hairpin RNA in HepG2 cell line. The effects of JTB and small HBsAg in vitro were determined by assessing cell apoptosis and motility. Results: Silencing of JTB expression promoted cancer cell motility and reduced cell apoptosis, which was significantly enhanced by HBs expression. Expression of HBsAg inhibited the translocation of JTB to the mitochondria. Furthermore, silencing of the JTB resulted in an increase in the phosphorylation of p65 in HepG2 cells and HepG2-HBs cells, whereas HBsAg expression decreased the phosphorylation of p65. The silencing of JTB in HepG2-HBs cells conferred increased advantages in cell motility and anti-apoptosis. Conclusion: HBsAg inhibited the translocation of JTB to the mitochondria and decreased the phosphorylation of p65 through the interaction with JTB, After JTB knockdown, HBsAg exhibited a stronger potential to promote tumor progression. Our data suggested that JTB act as a tumor suppressor gene in regards to HBV infection and its activation might be applied as a therapeutic strategy for in control of HBV related HCC development.National Natural Science Foundation of China [30971362, 81072013]; Fundamental Research Funds for the Central Universities in China [2010111082]; Key Projects for Technology Plan of Fujian Province in China [2009D020]; Foundation of Health Bureau of Fujian in China [2007CXB8, 3502z20077046]; Foundation of Health Bureau of Xiamen in China [2007CXB8, 3502z20077046