A porcine model of heart failure with preserved ejection fraction:magnetic resonance imaging and metabolic energetics

Aims A significant proportion of heart failure (HF) patients have HF preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF remains a critical unmet need. A key obstacle to therapeutic innovation in HFpEF is the paucity of pre-clinical models. Although several large animal models have been reported, few demonstrate progression to decompensated HF. We have established a model of HFpEF by enhancing a porcine model of progressive left ventricular (LV) pressure overload and characterized HF in this model including advanced cardiometabolic imaging using cardiac magnetic resonance imaging and hyperpolarized carbon-13 magnetic resonance spectroscopy. Methods and results Pigs underwent progressive LV pressure overload by means of an inflatable aortic cuff. Pigs developed LV hypertrophy (50% increase in wall thickness, P <0.001, and two-fold increase in mass compared to sham control, P <0.001) with no evidence of LV dilatation but a significant increase in left atrial volume (P = 0.013). Cardiac magnetic resonance imaging demonstrated T1 modified Look-Locker inversion recovery values increased in 16/17 segments compared to sham pigs (P <0.05-P <0.001) indicating global ventricular fibrosis. Mean LV end-diastolic (P = 0.047) and pulmonary capillary wedge pressures (P = 0.008) were elevated compared with sham control. One-third of the pigs demonstrated clinical signs of frank decompensated HF, and mean plasma BNP concentrations were raised compared with sham control (P = 0.008). Cardiometabolic imaging with hyperpolarized carbon-13 magnetic resonance spectroscopy agreed with known metabolic changes in the failing heart with a switch from fatty acid towards glucose substrate utilization. Conclusions Progressive aortic constriction in growing pigs induces significant LV hypertrophy with cardiac fibrosis associated with left atrial dilation, raised filling pressures, and an ability to transition to overt HF with raised BNP without reduction in LVEF. This model replicates many aspects of clinical HFpEF with a predominant background of hypertension and can be used to advance understanding of underlying pathology and for necessary pre-clinical testing of novel candidate therapies

Catalytic upgrading of bio-oils by esterification

Biomass is the term given to naturally-produced organic matter resulting from photosynthesis, and represents the most abundant organic polymers on Earth. Consequently, there has been great interest in the potential exploitation of lignocellulosic biomass as a renewable feedstock for energy, materials and chemicals production. The energy sector has largely focused on the direct thermochemical processing of lignocellulose via pyrolysis/gasification for heat generation, and the co-production of bio-oils and bio-gas which may be upgraded to produce drop-in transportation fuels. This mini-review describes recent advances in the design and application of solid acid catalysts for the energy efficient upgrading of pyrolysis biofuels

Inhibiting Glycine Decarboxylase Suppresses Pyruvate-to-Lactate Metabolism in Lung Cancer Cells

Glycine decarboxylase (GLDC) gene is frequently upregulated in various types of cancer including lung, prostate and brain. It catabolizes glycine to yield 5,10-methylenetetrahydrofolate, an important substrate in one-carbon metabolism for nucleotide synthesis. In this study, we used exon splicing modulating steric hindrance antisense oligonucleotide (shAON) to suppress GLDC expression and investigated its effect on pyruvate metabolism via hyperpolarized carbon-13 magnetic resonance spectroscopy (MRS). The MRS technique allows us to study in vivo metabolic flux in tumor tissues with/without GLDC-shAON intervention. Here, we show that GLDC-shAON treatment is able to suppress lung cancer cell growth and tumorigenesis, both in vitro and in vivo. The carbon-13 MRS results indicated that the conversion of pyruvate into lactate in GLDC-shAON-treated tumor tissues was significantly reduced, when compared with the control groups. This observation corroborated with the reduced activity of lactate dehydrogenase and pyruvate dehydrogenase in GLDC-shAON-treated lung cancer cells and tumor tissues. Glycolysis stress test showed that extracellular acidification rate was significantly suppressed after GLDC-shAON treatment. Besides lung cancer, the antitumor effect of GLDC-shAON was also observed in brain, liver, cervical, and prostate cancer cell lines. Furthermore, it enhanced the treatment efficacy of cisplatin in lung cancer cells. Taken together, our findings illustrate that pyruvate metabolism decreases upon GLDC inhibition, thereby starving cancer cells from critical metabolic fuels

table_1_Inhibiting Glycine Decarboxylase Suppresses Pyruvate-to-Lactate Metabolism in Lung Cancer Cells.docx

<p>Glycine decarboxylase (GLDC) gene is frequently upregulated in various types of cancer including lung, prostate and brain. It catabolizes glycine to yield 5,10-methylenetetrahydrofolate, an important substrate in one-carbon metabolism for nucleotide synthesis. In this study, we used exon splicing modulating steric hindrance antisense oligonucleotide (shAON) to suppress GLDC expression and investigated its effect on pyruvate metabolism via hyperpolarized carbon-13 magnetic resonance spectroscopy (MRS). The MRS technique allows us to study in vivo metabolic flux in tumor tissues with/without GLDC-shAON intervention. Here, we show that GLDC-shAON treatment is able to suppress lung cancer cell growth and tumorigenesis, both in vitro and in vivo. The carbon-13 MRS results indicated that the conversion of pyruvate into lactate in GLDC-shAON-treated tumor tissues was significantly reduced, when compared with the control groups. This observation corroborated with the reduced activity of lactate dehydrogenase and pyruvate dehydrogenase in GLDC-shAON-treated lung cancer cells and tumor tissues. Glycolysis stress test showed that extracellular acidification rate was significantly suppressed after GLDC-shAON treatment. Besides lung cancer, the antitumor effect of GLDC-shAON was also observed in brain, liver, cervical, and prostate cancer cell lines. Furthermore, it enhanced the treatment efficacy of cisplatin in lung cancer cells. Taken together, our findings illustrate that pyruvate metabolism decreases upon GLDC inhibition, thereby starving cancer cells from critical metabolic fuels.</p

image_1_Inhibiting Glycine Decarboxylase Suppresses Pyruvate-to-Lactate Metabolism in Lung Cancer Cells.tif

<p>Glycine decarboxylase (GLDC) gene is frequently upregulated in various types of cancer including lung, prostate and brain. It catabolizes glycine to yield 5,10-methylenetetrahydrofolate, an important substrate in one-carbon metabolism for nucleotide synthesis. In this study, we used exon splicing modulating steric hindrance antisense oligonucleotide (shAON) to suppress GLDC expression and investigated its effect on pyruvate metabolism via hyperpolarized carbon-13 magnetic resonance spectroscopy (MRS). The MRS technique allows us to study in vivo metabolic flux in tumor tissues with/without GLDC-shAON intervention. Here, we show that GLDC-shAON treatment is able to suppress lung cancer cell growth and tumorigenesis, both in vitro and in vivo. The carbon-13 MRS results indicated that the conversion of pyruvate into lactate in GLDC-shAON-treated tumor tissues was significantly reduced, when compared with the control groups. This observation corroborated with the reduced activity of lactate dehydrogenase and pyruvate dehydrogenase in GLDC-shAON-treated lung cancer cells and tumor tissues. Glycolysis stress test showed that extracellular acidification rate was significantly suppressed after GLDC-shAON treatment. Besides lung cancer, the antitumor effect of GLDC-shAON was also observed in brain, liver, cervical, and prostate cancer cell lines. Furthermore, it enhanced the treatment efficacy of cisplatin in lung cancer cells. Taken together, our findings illustrate that pyruvate metabolism decreases upon GLDC inhibition, thereby starving cancer cells from critical metabolic fuels.</p

Effect of ACS84 on oxidative stress induced by 6-OHDA in SH-SY5Y cells.

<p>(A) Dose dependent effect of ACS84 on ROS generation in the 6-OHDA-treated (50 µM) SH-SY5Y cells. Cells were pretreated with ACS84 at different concentrations for 4 h. DCFDAH₂ (10 µM) was given 30 min before the addition of 6-OHDA (50 µM). The results were obtained after the treatment with 6-OHDA for 1 h. (B–C) Effect of ACS84, L-Dopa and NaHS at 10 µM on ROS generation (B) and SOD (C) in SH-SY5Y cells treated with 6-OHDA. SOD activity was measured 4 h after 6-OHDA treatment. Data are presented as mean ± SEM, n = 4–8, ^###<i>P</i><0.001 versus control; *<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001, versus 6-OHDA-treated cells; ^†††<i>P</i><0.001, versus ACS84-treated cells.</p

Effect of ACS84 on 6-OHDA-induced TH+ neuronal degeneration.

<p>Immunofluorescence staining showed that ACS84 (10 mg kg⁻¹ day⁻¹, i.g) alleviated TH+ neuron loss in SN of 6-OHDA-lesioned PD rats. Photos were taken at x100 magnification, and the white bar indicated 0.1 µm. Samples were collected from two independent experiments.</p

Effect of ACS84 on oxidative stress in the striatum of unilateral 6-OHDA-lesioned PD rat model.

<p>ACS84 treatment (10 mg kg⁻¹ day⁻¹, i.g) alleviated the increased MDA production. Data are presented as mean ± SEM, n = 4–6. *<i>P</i><0.05 versus lesion site of Sham group and ^#<i>P</i><0.05 versus lesion site of Vehicle group.</p