Hepatitis C: From inflammatory pathogenesis to anti-inflammatory/hepatoprotective therapy

Hepatitis C virus (HCV) infection commonly causes progressive liver diseases that deteriorate from chronic inflammation to fibrosis, cirrhosis and even to hepatocellular carcinoma. A long-term, persistent and uncontrolled inflammatory response is a hallmark of these diseases and further leads to hepatic injury and more severe disease progression. The levels of inflammatory cytokines and chemokines change with the states of infection and treatment, and therefore, they may serve as candidate biomarkers for disease progression and therapeutic effects. The mechanisms of HCV-induced inflammation involve classic pathogen pattern recognition, inflammasome activation, intrahepatic inflammatory cascade response, and oxidative and endoplasmic reticulum stress. Direct-acting antivirals (DAAs) are the first-choice therapy for effectively eliminating HCV, but DAAs alone are not sufficient to block the uncontrolled inflammation and severe liver injury in HCV-infected individuals. Some patients who achieve a sustained virologic response after DAA therapy are still at a long-term risk for progression to liver cirrhosis and hepatocellular carcinoma. Therefore, coupling with anti-inflammatory/hepatoprotective agents with anti-HCV effects is a promising therapeutic regimen for these patients during or after treatment with DAAs. In this review, we discuss the relationship between inflammatory mediators and HCV infection, summarize the mechanisms of HCV-induced inflammation, and describe the potential roles of anti-inflammatory/hepatoprotective drugs with anti-HCV activity in the treatment of advanced HCV infection

Low CO_2 levels of the entire Pleistocene epoch

Quantifying ancient atmospheric pCO_2 provides valuable insights into the interplay between greenhouse gases and global climate. Beyond the 800-ky history uncovered by ice cores, discrepancies in both the trend and magnitude of pCO_2 changes remain among different proxy-derived results. The traditional paleosol pCO_2 paleobarometer suffers from largely unconstrained soil-respired CO_2 concentration (S(z)). Using finely disseminated carbonates precipitated in paleosols from the Chinese Loess Plateau, here we identified that their S(z) can be quantitatively constrained by soil magnetic susceptibility. Based on this approach, we reconstructed pCO_2 during 2.6–0.9 Ma, which documents overall low pCO_2 levels (<300 ppm) comparable with ice core records, indicating that the Earth system has operated under late Pleistocene pCO_2 levels for an extended period. The pCO_2 levels do not show statistically significant differences across the mid-Pleistocene Transition (ca. 1.2–0.8 Ma), suggesting that CO_2 is probably not the driver of this important climate change event

Functional deficiency of MHC class i enhances LTP and abolishes LTD in the nucleus accumbens of mice

Major histocompatibility complex class I (MHCI) molecules were recently identified as novel regulators of synaptic plasticity. These molecules are expressed in various brain areas, especially in regions undergoing activity-dependent synaptic plasticity, but their role in the nucleus accumbens (NAc) is unknown. In this study, we investigated the effects of genetic disruption of MHCI function, through deletion of β2-microblobulin, which causes lack of cell surface expression of MHCI. First, we confirmed that MHCI molecules are expressed in the NAc core in wild-type mice. Second, we performed electrophysiological recordings with NAc core slices from wild-type and β2-microglobulin knock-out mice lacking cell surface expression of MHCI. We found that low frequency stimulation induced long-term depression in wild-type but not knock-out mice, whereas high frequency stimulation induced long-term potentiation in both genotypes, with a larger magnitude in knock-out mice. Furthermore, we demonstrated that knock-out mice showed more persistent behavioral sensitization to cocaine, which is a NAc-related behavior. Using this model, we analyzed the density of total AMPA receptors and their subunits GluR1 and GluR2 in the NAc core, by SDS-digested freeze-fracture replica labeling. After repeated cocaine exposure, the density of GluR1 was increased, but there was no change in total AMPA receptors and GluR2 levels in wildtype mice. In contrast, following repeated cocaine exposure, increased densities of total AMPA receptors, GluR1 and GluR2 were observed in knock-out mice. These results indicate that functional deficiency of MHCI enhances synaptic potentiation, induced by electrical and pharmacological stimulation

Exogenous Application of Jasmonic Acid Induces Volatile Emissions in Rice and Enhances Parasitism of Nilaparvata lugens Eggs by theParasitoid Anagrus nilaparvatae

Jasmonate signaling pathway plays an important role in induced plant defense against herbivores and pathogens, including the emission of volatiles that serve as attractants for natural enemies of herbivores. We studied the volatiles emitted from rice plants that were wounded and treated with jasmonic acid (JA) and their effects on the host-searching behavior of the rice brown planthopper, Nilaparvata lugens (Stål), and its mymarid egg parasitoid Anagrus nilaparvatae Pang et Wang. Female adults of N. lugens significantly preferred to settle on JA-treated rice plants immediately after release. The parasitoid A. nilaparvatae showed a similar preference and was more attracted to the volatiles emitted from JA-treated rice plants than to volatiles from control plants. This was also evident from greenhouse and field experiments in which parasitism of N. lugens eggs by A. nilaparvatae on plants that were surrounded by JA-treated plants was more than twofold higher than on control plants. Analyses of volatiles collected from rice plants showed that JA treatment dramatically increased the release of volatiles, which included aliphatic aldehydes and alcohols, monoterpenes, sesquiterpenes, methyl salicylate, n-heptadecane, and several as yet unidentified compounds. These results confirm an involvement of the JA pathway in induced defense in rice plants and demonstrate that the egg parasitoid A. nilaparvatae exploits plant-provided cues to locate hosts. We explain the use of induced plant volatiles by the egg parasitoid by a reliable association between planthopper feeding damage and egg presenc

贴片式动态心电记录仪在临床教学中可行性研究

Objective: To explore effectiveness of clinical application of the patch type dynamic ecg recorder by comparing with conventional dynamic ecg recorder Holter. And the clinical ecg teaching models is discussed in this paper. Methods: Using parallel controlled trial method, 60 patients in two hospitals received Holter examination, and patch heart testing at the same time. A comparative analysis of two kinds of inspection methods on testing the average heart rate, supraventricular premature beats and ventricular premature beat was made. Results: The average heart rate of patch type ECG and Holter were 71.87±9.28 and 72.55±9.06 (P = 0.0879). Two kinds of detection methods, chamber on the coincidence rate of premature beat (PPS) was 98.33%, 95% CI (91.06, 99.96), Kappa = 0.9462, 95% CI (0.84, 1.00), good consistency. The accuracy of ventricular premature beat (PPS) was 98.33%, 95% CI (91.06, 99.63), Kappa = 0.9850, 95% CI (0.90, 1.00), good consistency. Patch type heart all platform is suitable for self-study and clinical care study, and professional skill assessment,etc.Conclusion: The effectiveness of patch type heart all on testing the average heart rate, supraventricular premature beat is the same as Holter. it is also suitable for to carry out clinical ECG teaching at the same time.目的 通过和常规动态心电记录仪 Holter比较，研究贴片式的动态心电记录仪临床应用的有效性。并探讨其在临床心电教学中的模式。方法 采用自身平行对照试验方法，在两医院60例患者用Holter检查时，同时用贴片心电仪检测，比较分析两种检查方法在检测平均心率、室上性早搏和室性早搏方面的情况。结果 贴片式心电仪和Holter的平均心率分别为71.87±9.28和72.55±9.06（P＝0.0879）。两种检测方法，室上性早搏的符合率（PPS）为 98.33%，95%CI为（91.06,99.96），Kappa=0.9462, 95%CI为（0.84,1.00）,一致性良好。室性早搏的符合率（PPS）为 98.33%，95%CI为（91.06,99.63），Kappa=0.9850, 95%CI为（0.90, 1.00）。贴片式心电仪平台适合自学、临床监护学习、大课和专业技能考核等临床心电教学。结论 贴片式心电仪在检测平均心率、室上性早搏和室性早搏方面的有效性和Holter相同。同时也适合以此平台开展临床心电教学

Apoptosis Induction by MEK Inhibition in Human Lung Cancer Cells Is Mediated by Bim

AZD6244 (ARRY-142886) is an inhibitor of MEK1/2 and can inhibit cell proliferation or induce apoptosis in a cell-type dependent manner. The precise molecular mechanism of AZD6244-induced apoptosis is not clear. To investigate mechanisms of AZD6244 induced apoptosis in human lung cancer, we determined the molecular changes of two subgroups of human lung cancer cell lines that are either sensitive or resistant to AZD6244 treatment. We found that AZD6244 elicited a large increase of Bim proteins and a smaller increase of PUMA and NOXA proteins, and induced cell death in sensitive lung cancer cell lines, but had no effect on other Bcl-2 related proteins in those cell lines. Knockdown of Bim by siRNA greatly increased the IC50 and reduced apoptosis for AZD6244 treated cells. We also found that levels of endogenous p-Thr32-FOXO3a and p-Ser253-FOXO3a were lower in AZD6244-sensitive cells than in AZD6244-resistant cells. In the sensitive cells, AZD6244 induced FOXO3a nuclear translocation required for Bim activation. Moreover, the silencing of FOXO3a by siRNA abrogated AZD6244-induced cell apoptosis. In addition, we found that transfection of constitutively active AKT up-regulated p-Thr32-FOXO3a and p-Ser253-FOXO3a expression and inhibited AZD6244-induced Bim expression in sensitive cells. These results show that Bim plays an important role in AZD6244-induced apoptosis in lung cancer cells and that the PI3K/AKT/FOXO3a pathway is involved in Bim regulation and susceptibility of lung cancer cells to AZD6244. These results have implications in the development of strategies to overcome resistance to MEK inhibitors