Chronic intermittent hypoxia induces oxidative stress and inflammation via Angiotensin II Receptor 1 in rat liver

Poster Presentation: no. P17Chronic intermittent hypoxia (IH) associated with obstructive sleep apnea (OSA) is characterized by repetitive cycles of hypoxia and reoxygenation, leading to excessive production of reactive oxygen species and oxidative stress in tissues and organs. However the mechanistic effects of chronic IH on the liver are not clear at present. We hypothesized that renin-angiotensin system (RAS) plays a role in the IH-induced oxidative stress and tissue inflammation in the rat liver. Adult Sprague-Dawley rats were exposed to air (normoxic (Nx) control) or IH treatment (with inspired oxygen fraction in the normobaric chamber cyclic between 5-21% ± 0.5% per min, 8 hours per day) for 14 days. Rats were fed with an angiotensin II type 1 (AT1) receptors blocker telmisartan (10mg/kg body weight), or vehicle daily before the IH treatment. Hepatic expression levels of pro-inflammatory …postprin

The potential yield of Tai Chi in cancer survivorship

The purpose of the current paper is to encourage research into all areas of Tai Chi and cancer survivorship. Tai Chi is defined here as a combination of Chinese philosophy, martial and healing arts. Tai Chi is a form of physical activity that is carried out at either a light or moderate intensity. The practice of Tai Chi integrates mental concentration and breathing control [1,2]. We first discuss the role of light physical activity in cancer survivorship and then narrow our focus to Tai Chi per se

Involvement of autophagy in the effect of exercise on left ventricular hypertrophy induced by high fat diet in rats

Chaired Posters PresentationObjectives: Left ventricular hypertrophy (LVH) associated with obesity increases the morbidity and mortality of cardiovascular disease, which could be attenuated by exercise in overweight and hypertensive patients. The lysosomal degradation pathway − autophagy is reportedly mediated the beneficial effect of exercise on glucose and lipid homeostasis. The present study aimed to investigate the involvement of autophagy in the effect of exercise on LVH induced by high fat diet in rats. Methods: Female adult SD rats were divided into 4 groups namely: (i) high fat diet (HFD), (ii) HFD+exercise, (iii) exercise, (iv) control. Rats in the HFD groups were orally fed with high-fat chow (30% fat) daily for 12 weeks, and rats in the exercise groups had exercise with a motorized wheel in the last 4 weeks. Noninvasive measures of systolic pressure and fat composition were assessed, respectively by tail cuff and MRI. The expression of markers for cardiac hypertrophy and the protein expression in autophagic pathway were determined by quantitative real time-PCR and western blot, respectively. Statistical significance was at p<0.05 with ANOVA analysis followed by post-hoc tests. Results: Rats fed with HFD had LVH (increased heart weight and LV/ RV+septum ratio) with higher levels of body weight, arterial pressures and fat composition than that of the control rat. In addition, the QTc interval and the diameter and disarray of ventricular myocytes were significantly increased in the HFD group, supported by elevated levels of the expression of hypertrophic markers (ANP, BNP, β-MHC). These parameters were attenuated by exercise in the HFD-fed rats. Moreover, we found elevated levels of LC3II in the HFD heart, which were also attenuated by exercise, suggesting an involvement of autophagy in the beneficial effect of exercise. Furthermore, the expression level of AMPKα was also increased in the exercise groups. Conclusion: We demonstrated that exercise lowers the body weight and attenuates the HFD-induced LVH in rats, which probably involves autophagy. Future studies will focus on the role of autophagy in the pathogenesis.published_or_final_versio

Oxidative stress induced by intermittent hypoxia exacerbates lipid accumulation and inflammation in a cell model of non-alcoholic steatohepatitis

Oral PresentationBackground/Aims: The prevalence of obstructive sleep apnea (OSA) is high in patients with non-alcoholic fatty liver disease (NAFLD) and NASH is a progressive hallmark of the pathogenesis of NAFLD. Chronic intermittent hypoxia is associated with recurrent episodes of oxygen desaturation and reoxygenation in OSA patients, leading to excessive production of reactive oxygen species (ROS). The causal link between OSA and NAFLD is not known and the mechanistic effect of intermittent hypoxia (IH) on the pathogenesis of NAFLD remains elusive. Here we tested the hypothesis that IH-induced oxidative stress aggravates lipid accumulation and inflammation induced by sodium palmitate in HepG2 cells. Materials and Methods: HepG2 cells were treated with sodium palmitate or vehicle under normoxia (Nx) or IH condition for 72 hours in the present or absence of a ROS scavenger MnTBAP. Cell viability was detected by MTT assay and intracellular lipid deposit was examined by oil red staining. Lipid peroxidation was measured by malondialdehyde (MDA) assay and levels of reactive oxygen species (ROS) were detected by CM-H2DCFDA staining. The expressions of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6), fatty acid uptake-associated genes (caveolin-1 and FATP5), fatty acid synthesis genes (SREBP1 and ACC1) and fatty acid β-oxidation gene ACOX were determined by real-time PCR. Results: Results showed that sodium palmitate increased lipid deposit in the cells and it also decreased cell viability. The effect of sodium palmitate was more prominent in the group co-treated with hypoxia. Levels of MDA and ROS and the expressions of IL-1β, TNF-α, IL-6 and caveolin-1, but not FATP5, were significantly increased in the palmitate- or hypoxia-treated group and were remarkably elevated in the co-treated group. These effects were abolished by MnTBAP treatment. In addition, levels of the expression of ACOX, SREBP1 and ACC1 were significantly lowered in the cells treated with palmitate or hypoxia and the expressions were much less in the cotreated group. Treatment of MnTBAP prevented the decreased expression of ACOX but had no effect on the SREBP1 and ACC1 expression. Conclusion: IH-induced oxidative stress exacerbates lipid accumulation and inflammation induced by sodium palmitate in HepG2 cells, probably mediated by an increase in lipid uptake and a decrease in the fatty acid β-oxidation.published_or_final_versio

Integrity of H1 helix in prion protein revealed by molecular dynamic simulations to be especially vulnerable to changes in the relative orientation of H1 and its S1 flank

In the template-assistance model, normal prion protein (PrPC), the pathogenic cause of prion diseases such as Creutzfeldt-Jakob (CJD) in human, Bovine Spongiform Encephalopathy (BSE) in cow, and scrapie in sheep, converts to infectious prion (PrPSc) through an autocatalytic process triggered by a transient interaction between PrPC and PrPSc. Conventional studies suggest the S1-H1-S2 region in PrPC to be the template of S1-S2 $\beta$-sheet in PrPSc, and the conformational conversion of PrPC into PrPSc may involve an unfolding of H1 in PrPC and its refolding into the $\beta$-sheet in PrPSc. Here we conduct a series of simulation experiments to test the idea of transient interaction of the template-assistance model. We find that the integrity of H1 in PrPC is vulnerable to a transient interaction that alters the native dihedral angles at residue Asn$^{143}$, which connects the S1 flank to H1, but not to interactions that alter the internal structure of the S1 flank, nor to those that alter the relative orientation between H1 and the S2 flank.Comment: A major revision on statistical analysis method has been made. The paper now has 23 pages, 11 figures. This work was presented at 2006 APS March meeting session K29.0004 at Baltimore, MD, USA 3/13-17, 2006. This paper has been accepted for pubcliation in European Biophysical Journal on Feb 2, 200

Elevated CO₂ does not increase eucalypt forest productivity on a low-phosphorus soil

Rising atmospheric CO2 stimulates photosynthesis and productivity of forests, offsetting CO2 emissions. Elevated CO2 experiments in temperate planted forests yielded ~23% increases in productivity over the initial years. Whether similar CO2 stimulation occurs in mature evergreen broadleaved forests on low-phosphorus (P) soils is unknown, largely due to lack of experimental evidence. This knowledge gap creates major uncertainties in future climate projections as a large part of the tropics is P-limited. Here,we increased atmospheric CO2 concentration in a mature broadleaved evergreen eucalypt forest for three years, in the first large-scale experiment on a P-limited site. We show that tree growth and other aboveground productivity components did not significantly increase in response to elevated CO2 in three years, despite a sustained 19% increase in leaf photosynthesis. Moreover, tree growth in ambient CO2 was strongly P-limited and increased by ~35% with added phosphorus. The findings suggest that P availability may potentially constrain CO2-enhanced productivity in P-limited forests; hence, future atmospheric CO2 trajectories may be higher than predicted by some models. As a result, coupled climate-carbon models should incorporate both nitrogen and phosphorus limitations to vegetation productivity in estimating future carbon sinks

The iron-chelating drug M30 down-regulates carbon tetrachloride (CCI4)-induced hepatic oxidative stress, inflammation and apoptosis in vitro

Topic: 2 Acute Liver FailureThis journal suppl. entitled: APASL Liver Week 2013BACKGROUND/AIMS: The novel multifunctional brain permeable ironchelator M30 possesses neuroprotective activities against several insults applicable to various neurodegenerative diseases. However, the effect of M30 on CCl4 induced acute liver damage is still unknown. The aim of this study is to investigate whether the multifunctional drug M30 could ameliorate CCl4 induced hepatic injury in human HepG2 cell line. METHODS: HepG2 cells were grown in DMEM supplemented with ...postprin

Intercomparison of the northern hemisphere winter mid-latitude atmospheric variability of the IPCC models

We compare, for the overlapping time frame 1962-2000, the estimate of the northern hemisphere (NH) mid-latitude winter atmospheric variability within the XX century simulations of 17 global climate models (GCMs) included in the IPCC-4AR with the NCEP and ECMWF reanalyses. We compute the Hayashi spectra of the 500hPa geopotential height fields and introduce an integral measure of the variability observed in the NH on different spectral sub-domains. Only two high-resolution GCMs have a good agreement with reanalyses. Large biases, in most cases larger than 20%, are found between the wave climatologies of most GCMs and the reanalyses, with a relative span of around 50%. The travelling baroclinic waves are usually overestimated, while the planetary waves are usually underestimated, in agreement with previous studies performed on global weather forecasting models. When comparing the results of various versions of similar GCMs, it is clear that in some cases the vertical resolution of the atmosphere and, somewhat unexpectedly, of the adopted ocean model seem to be critical in determining the agreement with the reanalyses. The GCMs ensemble is biased with respect to the reanalyses but is comparable to the best 5 GCMs. This study suggests serious caveats with respect to the ability of most of the presently available GCMs in representing the statistics of the global scale atmospheric dynamics of the present climate and, a fortiori, in the perspective of modelling climate change.Comment: 39 pages, 8 figures, 2 table

Pathways to new drug discovery in neuropsychiatry

There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. In this commentary, the sources of this dilemma and potential avenues to redress the issue are explored. These include a critical review of diagnostic issues and of selection of participants for clinical trials, and the mechanisms for identifying new drugs and new drug targets. Historically, the vast majority of agents have been discovered serendipitously or have been modifications of existing agents. Serendipitous discoveries, based on astute clinical observation or data mining, remain a valid option, as is illustrated by the suggestion in the paper by Wahlqvist and colleagues that treatment with sulfonylurea and metformin reduces the risk of affective disorder. However, the identification of agents targeting disorder-related biomarkers is currently proving particularly fruitful. There is considerable hope for genetics as a purist, pathophysiologically valid pathway to drug discovery; however, it is unclear whether the science is ready to meet this promise. Fruitful paradigms will require a break from the orthodoxy, and creativity and risk may well be the fingerprints of success