Cardiovascular Metabolomics McGarrah, Robert W; Crown, Scott B; Zhang, Guo-Fang ...
Circulation research,
2018-April-27, Letnik:
122, Številka:
9
Journal Article
Recenzirano
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Disturbances in cardiac metabolism underlie most cardiovascular diseases. Metabolomics, one of the newer omics technologies, has emerged as a powerful tool for defining changes in both global and ...cardiac-specific metabolism that occur across a spectrum of cardiovascular disease states. Findings from metabolomics studies have contributed to better understanding of the metabolic changes that occur in heart failure and ischemic heart disease and have identified new cardiovascular disease biomarkers. As technologies advance, the metabolomics field continues to evolve rapidly. In this review, we will discuss the current state of metabolomics technologies, including consideration of various metabolomics platforms and elements of study design; the emerging utility of stable isotopes for metabolic flux studies; and the use of metabolomics to better understand specific cardiovascular diseases, with an emphasis on recent advances in the field.
Skeletal stem cells (SSCs) are postulated to provide a continuous supply of osteoblasts throughout life. However, under certain conditions, the SSC population can become incorrectly specified or is ...not maintained, resulting in reduced osteoblast formation, decreased bone mass, and in severe cases, osteoporosis. Glutamine metabolism has emerged as a critical regulator of many cellular processes in diverse pathologies. The enzyme glutaminase (GLS) deaminates glutamine to form glutamate—the rate-limiting first step in glutamine metabolism. Using genetic and metabolic approaches, we demonstrate GLS and glutamine metabolism are required in SSCs to regulate osteoblast and adipocyte specification and bone formation. Mechanistically, transaminase-dependent α-ketoglutarate production is critical for the proliferation, specification, and differentiation of SSCs. Collectively, these data suggest stimulating GLS activity may provide a therapeutic approach to expand SSCs in aged individuals and enhance osteoblast differentiation and activity to increase bone mass.
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•Skeletal stem cells increase glutamine metabolism during osteoblast differentiation•Glutamine metabolism regulates osteoblast and adipocyte specification•Mice unable to metabolize glutamine have less bone and increased marrow fat•Amino acid transaminase-derived α-ketoglutarate is critical for SSC proliferation
Skeletal stem cells (SSCs) provide a reservoir of bone-forming osteoblasts throughout life. Yu et al. investigate glutamine metabolism in SSCs. Glutamine-derived α-ketoglutarate supports amino acid biosynthesis and proliferation in SSCs. Inhibiting glutamine metabolism in SSCs results in low bone mass and increased marrow adiposity in mice.
High electrocatalytic activity with tunable luminescence is crucial for the development of electrochemiluminescence (ECL) luminophores. In this study, a porphyrin‐based heterobimetallic 2D metal ...organic framework (MOF), (ZnTCPP)Co2(MeIm) (1), is successfully self‐assembled from the zinc(II) tetrakis(4‐carboxyphenyl)porphine (ZnTCPP) linker and cobalt(II) ions in the presence of 2‐methylimidazole (MeIm) by a facile one‐pot reaction in methanol at room temperature. On the basis of the experimental results and the theoretical calculations, the MOF 1 contains paddle–wheel Co2(‐CO2)4 secondary building units (SBUs) axially coordinated by a MeIm ligand, which is very beneficial to the electron transfer between the Co(II) ions and oxygen. Combining the photosensitizers ZnTCPP and the electroactive Co2(‐CO2)4 SBUs, the 2D MOF 1 possesses an excellent ECL performance, and can be used as a novel ECL probe for rapid nonamplified detection of the RdRp gene of SARS‐CoV‐2 with an extremely low limit of detection (≈30 aM).
A novel porphyrin‐based heterobimetallic 2D MOF, (ZnTCPP)Co2(MeIm) (1) is constructed to act as an excellent electrochemiluminescence probe for rapid nonamplified detection of SARS‐CoV‐2.
A simple and rapid photoelectrochemical (PEC) sensor was developed for the label-free detection of a phosphoprotein (α-casein) based on a zirconium based porphyrinic metal–organic framework (MOF), ...PCN-222, which exhibited an enhanced photocurrent response toward dopamine under the O2-saturated aqueous media. In this work, in terms of PEC measurements and cyclic voltammetry, the PEC behaviors of PCN-222 in aqueous media were thoroughly investigated for the first time. Additionally, in the virtue of the steric hindrance effect from the coordination of the phosphate groups and inorganic Zr–O clusters as binding sites in PCN-222, this biosensor showed high sensitivity for detecting α-casein and the limit of detection (LOD) was estimated to be 0.13 μg mL–1. Moreover, the proposed method provides a promising platform for clinic diagnostic and therapeutics.
Cancer metastasis accounts for the majority of cancer-related deaths and remains a clinical challenge. Metastatic cancer cells generally resemble cells of the primary cancer, but they may be ...influenced by the milieu of the organs they colonize. Here, we show that colorectal cancer cells undergo metabolic reprogramming after they metastasize and colonize the liver, a key metabolic organ. In particular, via GATA6, metastatic cells in the liver upregulate the enzyme aldolase B (ALDOB), which enhances fructose metabolism and provides fuel for major pathways of central carbon metabolism during tumor cell proliferation. Targeting ALDOB or reducing dietary fructose significantly reduces liver metastatic growth but has little effect on the primary tumor. Our findings suggest that metastatic cells can take advantage of reprogrammed metabolism in their new microenvironment, especially in a metabolically active organ such as the liver. Manipulation of involved pathways may affect the course of metastatic growth.
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•Colon cancer liver metastasis upregulates ALDOB, an enzyme for fructose metabolism•Metabolized fructose provides fuel for the central carbon metabolism•Targeting ALDOB or its upstream regulator GATA6 reduces liver metastasis growth•Reducing dietary fructose diminishes liver metastatic growth
Bu et al. show that, during colonization of the liver, the liver environment can cause colon cancer cells (CRC) to undergo metabolic reprogramming by upregulating aldolase B, which enhances fructose metabolism and promotes growth of CRC liver metastases. Targeting aldolase B or reducing dietary fructose reduces liver metastasis growth.
Aims and objectives
To investigate burnout among nurses from Australia and China and explore the effects of resilience and turnover intention on nurse burnout between the two countries.
Background
...Nursing shortages and burnout have become serious problems worldwide in recent years. In both developed and developing countries, such as Australia and China, nurse burnout levels are high and therefore attract concern from nurse managers, hospital administrators, nurse educators and researchers. However, few studies have been conducted exploring the differences in burnout and its predictors between Australian and Chinese nurses, particularly investigating the differences in the effect sizes of the predictors.
Design
A comparative cross‐sectional design was employed.
Methods
A total of 100 Australian nurses and 197 Chinese nurses participated in the study. Australian participants completed an online questionnaire, while Chinese participants completed a hardcopy questionnaire. Burnout, resilience and turnover intention were measured.
Results
Burnout was worse for Australian participants than Chinese participants. Only having turnover intention significantly predicted burnout in Australian participants, while low resilience, having turnover intention and low level of regular exercise strongly predicted burnout in Chinese participants. The effect size of turnover intention on burnout in the Australian group was almost twice that of the Chinese group.
Conclusion
The findings of this study show that there are differences in burnout between Australian and Chinese nurses. The effects of resilience and turnover intention on burnout between the two groups are also identified.
Relevance to clinical practice
The differences in nurse burnout and the effects of resilience and turnover intention on burnout should be better understood by nurse managers from Australia and China. Moreover, developing effective strategies relevant to their own country to reduce nurse burnout is recommended.
Osteoblast differentiation is sequentially characterized by high rates of proliferation followed by increased protein and matrix synthesis, processes that require substantial amino acid acquisition ...and production. How osteoblasts obtain or maintain intracellular amino acid production is poorly understood. Here, we identify SLC1A5 as a critical amino acid transporter during bone development. Using a genetic and metabolomic approach, we show SLC1A5 acts cell autonomously to regulate protein synthesis and osteoblast differentiation. SLC1A5 provides both glutamine and asparagine which are essential for osteoblast differentiation. Mechanistically, glutamine and to a lesser extent asparagine support amino acid biosynthesis. Thus, osteoblasts depend on
to provide glutamine and asparagine, which are subsequently used to produce non-essential amino acids and support osteoblast differentiation and bone development.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to ...our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.
A better understanding of the mechanisms underlying PD‐L1 aberrant expression in head and neck squamous cell carcinoma (HNSCC) will help reveal predictive biomarkers and overcome resistance to ...treatment. In this study, the prognostic significance of PD‐L1 in forty‐five HNSCC archival samples was determined by qRT‐PCR. The biological function associated with malignant behaviour was assessed by PD‐L1 depletion, miR‐382‐3p re‐expression and regulation of circ_0000052. The interactions of PD‐L1‐miRNA and miRNA‐circRNA were determined by qRT‐PCR, Western blot analysis, dual‐luciferase reporter assays and RNA immunoprecipitation assays. PD‐L1 was highly expressed in patient samples and cancer cell lines. Higher levels of PD‐L1 were associated with patient recurrences and play a pivotal role in regulating cell proliferation, migration, invasion, clonogenicity and apoptosis. In addition to demonstrating that the IFN‐γ/JAK2/STAT1 signalling pathway can induce PD‐L1 overexpression in HNSCC, a novel mechanism by which upregulated circ_0000052 mediates PD‐L1 overexpression was also demonstrated. To do this, circ_0000052 competitively binds to miR‐382‐3p and alleviates its repression of PD‐L1. This leads to overexpression of PD‐L1, causing the aggressiveness of the cells. Our data demonstrate that circ_0000052 is oncogenic, and the circ_0000052/miR‐382‐3p/PD‐L1 axis is critical in HNSCC progression. The manipulation of circRNAs/miRNAs in combination with anti‐PD‐L1 therapy may improve personalized disease management.
Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases. Here we demonstrate that the major metabolic fate of uniformly-
C-labeled ...α-ketoisovalerate (U-
CKIV) in the heart is reamination to valine. Activation of cardiac branched-chain α-ketoacid dehydrogenase (BCKDH) by treatment with the BCKDH kinase inhibitor, BT2, does not impede the strong flux of U-
CKIV to valine. Sequestration of BCAA and BCKA away from mitochondrial oxidation is likely due to low levels of expression of the mitochondrial BCAA transporter SLC25A44 in the heart, as its overexpression significantly lowers accumulation of
C-labeled valine from U-
CKIV. Finally, exposure of perfused hearts to levels of BCKA found in obese rats increases phosphorylation of the translational repressor 4E-BP1 as well as multiple proteins in the MEK-ERK pathway, leading to a doubling of total protein synthesis. These data suggest that elevated BCKA levels found in obesity may contribute to pathologic cardiac hypertrophy via chronic activation of protein synthesis.
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