scholarly journals CNTF enhances aerobic glycolysis and anabolic activities in degenerating retinas

2021 ◽  
Author(s):  
Kun Do Rhee ◽  
Yanjie Wang ◽  
Johanna ten Hoeve ◽  
Linsey Stiles ◽  
Thao T.T. Nguyen ◽  
...  
Keyword(s):  
Aerobic Glycolysis ◽  
Redox Homeostasis ◽  
Chain Complex ◽  
Tca Cycle ◽  
Neuroprotective Activity ◽  
Mitochondrial Morphology ◽  
Cellular Mechanisms ◽  
Expression Of Genes ◽  
The Impact ◽  
Complex Activities

Ciliary neurotrophic factor (CNTF) has potent neuroprotective activity in retinal degeneration animal models, yet the cellular mechanisms underlying its broad neuronal survival effects remain unclear. Here, we investigated the impact of CNTF on retinal metabolism in a mouse model of human retinitis pigmentosa. CNTF treatment resulted in improved mitochondrial morphology in mutant rod photoreceptors, but also led to reduced oxygen consumption and suppression of respiratory chain complex activities. Metabolomics analyses detected significantly higher levels of ATP and the energy currency phospho-creatine post CNTF exposure. In addition, CNTF-treated retinas contained elevated glycolytic metabolites and showed increased expression of genes and active enzymes of the glycolytic pathway. Metabolomics analyses also revealed increased TCA cycle products, lipid biosynthetic pathway intermediates, nucleotides, and amino acids, indicating an overall CNTF-dependent augmentation of anabolic activities. Moreover, CNTF treatment restored the key antioxidant glutathione to the wild type level in the degenerating retina. Taken together, these results demonstrate that CNTF profoundly impacts the metabolic status of degenerating retinas by promoting aerobics glycolysis and anabolism, enhancing energy supply, and restoring redox homeostasis. Our study thus reveals important cellular mechanisms underlying CNTF-mediated neuroprotection and provides novel insight for the on-going CNTF clinical trials treating blinding diseases.

scholarly journals Dihydromyricetin Attenuates Dexamethasone-Induced Muscle Atrophy by Improving Mitochondrial Function via the PGC-1α Pathway

2018 ◽  
Vol 49 (2) ◽  
pp. 758-779 ◽  
Author(s):  
Yujie Huang ◽  
Ka Chen ◽  
Qingbo Ren ◽  
Long Yi ◽  
Jundong Zhu ◽  
...  
Keyword(s):  
Muscle Atrophy ◽  
Mitochondrial Function ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Morphology ◽  
Cross Sectional ◽  
Mitochondrial Respiratory Chain Complex ◽  
Underlying Mechanisms ◽  
Complex Activities

Background/Aims: Skeletal muscle atrophy is an important health issue and can impose tremendous economic burdens on healthcare systems. Glucocorticoids (GCs) are well-known factors that result in muscle atrophy observed in numerous pathological conditions. Therefore, the development of effective and safe therapeutic strategies for GC-induced muscle atrophy has significant clinical implications. Some natural compounds have been shown to effectively prevent muscle atrophy under several wasting conditions. Dihydromyricetin (DM), the most abundant flavonoid in Ampelopsis grossedentata, has a broad range of health benefits, but its effects on muscle atrophy are unclear. The purpose of this study was to evaluate the effects and underlying mechanisms of DM on muscle atrophy induced by the synthetic GC dexamethasone (Dex). Methods: The effects of DM on Dex-induced muscle atrophy were assessed in Sprague-Dawley rats and L6 myotubes. Muscle mass and myofiber cross-sectional areas were analyzed in gastrocnemius muscles. Muscle function was evaluated by a grip strength test. Myosin heavy chain (MHC) content and myotube diameter were measured in myotubes. Mitochondrial morphology was observed by transmission electron microscopy and confocal laser scanning microscopy. Mitochondrial DNA (mtDNA) was quantified by real-time PCR. Mitochondrial respiratory chain complex activities were examined using the MitoProfile Rapid Microplate Assay Kit, and mitochondrial membrane potential was assessed by JC-1 staining. Protein levels of mitochondrial biogenesis and dynamics markers were detected by western blotting. Myotubes were transfected with siRNAs targeting peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), mitochondrial transcription factor A (TFAM) and mitofusin-2 (mfn2) to determine the underlying mechanisms. Results: In vivo, DM preserved muscles from weight and average fiber cross-sectional area losses and improved grip strength. In vitro, DM prevented the decrease in MHC content and myotube diameter. Moreover, DM stimulated mitochondrial biogenesis and promoted mitochondrial fusion, rescued the reduced mtDNA content, improved mitochondrial morphology, prevented the collapse in mitochondrial membrane potential and enhanced mitochondrial respiratory chain complex activities; these changes restored mitochondrial function and improved protein metabolism, contributing to the prevention of Dex-induced muscle atrophy. Furthermore, the protective effects of DM on mitochondrial function and muscle atrophy were alleviated by PGC-1α siRNA, TFAM siRNA and mfn2 siRNA transfection in vitro. Conclusion: DM attenuated Dex-induced muscle atrophy by reversing mitochondrial dysfunction, which was partially mediated by the PGC-1α/TFAM and PGC-1α/mfn2 signaling pathways. Our findings may open new avenues for identifying natural compounds that improve mitochondrial function as promising candidates for the management of muscle atrophy.

scholarly journals Microarray and metabolome analysis of hepatic response to fasting and subsequent refeeding in zebrafish (Danio rerio)

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Jirong Jia ◽  
Jingkai Qin ◽  
Xi Yuan ◽  
Zongzhen Liao ◽  
Jinfeng Huang ◽  
...  
Keyword(s):  
Compensatory Growth ◽  
Tricarboxylic Acid Cycle ◽  
Tca Cycle ◽  
Metabolome Analysis ◽  
Cellular Mechanisms ◽  
Metabolic Adaptations ◽  
Dna Replication And Repair ◽  
The Impact ◽  
Metabolome Data ◽  
Zebrafish Liver

Abstract Background Compensatory growth refers to the phenomenon in which organisms grow faster after the improvement of an adverse environment and is thought to be an adaptive evolution to cope with the alleviation of the hostile environment. Many fish have the capacity for compensatory growth, but the underlying cellular mechanisms remain unclear. In the present study, microarray and nontargeted metabolomics were performed to characterize the transcriptome and metabolome of zebrafish liver during compensatory growth. Results Zebrafish could regain the weight they lost during 3 weeks of fasting and reach a final weight similar to that of fish fed ad libitum when refed for 15 days. When refeeding for 3 days, the liver displayed hyperplasia accompanied with decreased triglyceride contents and increased glycogen contents. The microarray results showed that when food was resupplied for 3 days, the liver TCA cycle (Tricarboxylic acid cycle) and oxidative phosphorylation processes were upregulated, while DNA replication and repair, as well as proteasome assembly were also activated. Integration of transcriptome and metabolome data highlighted transcriptionally driven alterations in metabolism during compensatory growth, such as altered glycolysis and lipid metabolism activities. The metabolome data also implied the participation of amino acid metabolism during compensatory growth in zebrafish liver. Conclusion Our study provides a global resource for metabolic adaptations and their transcriptional regulation during refeeding in zebrafish liver. This study represents a first step towards understanding of the impact of metabolism on compensatory growth and will potentially aid in understanding the molecular mechanism associated with compensatory growth.

scholarly journals Genetic Nrf2 Overactivation Inhibits the Deleterious Effects Induced by Hepatocyte-Specific c-met Deletion during the Progression of NASH

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Pierluigi Ramadori ◽  
Hannah Drescher ◽  
Stephanie Erschfeld ◽  
Athanassios Fragoulis ◽  
Thomas W. Kensler ◽  
...  
Keyword(s):  
Nonalcoholic Steatohepatitis ◽  
Redox Homeostasis ◽  
Murine Models ◽  
Cellular Mechanisms ◽  
Double Knockout ◽  
Cellular Redox ◽  
Triglyceride Accumulation ◽  
Expression Of Genes ◽  
Infiltrating Cells ◽  
Deficient Mice

We have recently shown that hepatocyte-specific c-met deficiency accelerates the progression of nonalcoholic steatohepatitis in experimental murine models resulting in augmented production of reactive oxygen species and accelerated development of fibrosis. The aim of this study focuses on the elucidation of the underlying cellular mechanisms driven by Nrf2 overactivation in hepatocytes lacking c-met receptor characterized by a severe unbalance between pro-oxidant and antioxidant functions. Control mice (c-metfx/fx), single c-met knockouts (c-metΔhepa), and double c-met/Keap1 knockouts (met/Keap1Δhepa) were then fed a chow or a methionine-choline-deficient (MCD) diet, respectively, for 4 weeks to reproduce the features of nonalcoholic steatohepatitis. Upon MCD feeding, met/Keap1Δhepa mice displayed increased liver mass albeit decreased triglyceride accumulation. The marked increase of oxidative stress observed in c-metΔhepa was restored in the double mutants as assessed by 4-HNE immunostaining and by the expression of genes responsible for the generation of free radicals. Moreover, double knockout mice presented a reduced amount of liver-infiltrating cells and the exacerbation of fibrosis progression observed in c-metΔhepa livers was significantly inhibited in met/Keap1Δhepa. Therefore, genetic activation of the antioxidant transcription factor Nrf2 improves liver damage and repair in hepatocyte-specific c-met-deficient mice mainly through restoring a balance in the cellular redox homeostasis.

scholarly journals Phytochemicals as Regulators of Genes Involved in Synucleinopathies

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 624
Author(s):  
Andrei Surguchov ◽  
Libby Bernal ◽  
Alexei A. Surguchev
Keyword(s):  
Regulation Of Gene Expression ◽  
Lewy Bodies ◽  
Nerve Fibers ◽  
Neuroprotective Activity ◽  
Beneficial Effects ◽  
Expression Of Genes ◽  
Genetic And Environmental Factors ◽  
Disease Modifying Treatment ◽  
The Impact

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein aggregates in neurons, nerve fibers or glial cells. Three main types of diseases belong to the synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. All of them develop as a result of an interplay of genetic and environmental factors. Emerging evidence suggests that epigenetic mechanisms play an essential role in the development of synucleinopathies. Since there is no disease-modifying treatment for these disorders at this time, interest is growing in plant-derived chemicals as a potential treatment option. Phytochemicals are substances of plant origin that possess biological activity, which might have effects on human health. Phytochemicals with neuroprotective activity target different elements in pathogenic pathways due to their antioxidants, anti-inflammatory, and antiapoptotic properties, and ability to reduce cellular stress. Multiple recent studies demonstrate that the beneficial effects of phytochemicals may be explained by their ability to modulate the expression of genes implicated in synucleinopathies and other diseases. These substances may regulate transcription directly via transcription factors (TFs) or play the role of epigenetic regulators through their effect on histone modification, DNA methylation, and RNA-based mechanisms. Here, we summarize new data about the impact of phytochemicals on the pathogenesis of synucleinopathies through regulation of gene expression.

scholarly journals Oxidative Stress in the Tumor Microenvironment and Its Relevance to Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 986
Author(s):  
Nada S. Aboelella ◽  
Caitlin Brandle ◽  
Timothy Kim ◽  
Zhi-Chun Ding ◽  
Gang Zhou
Keyword(s):  
Oxidative Stress ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Redox Homeostasis ◽  
Tumor Rejection ◽  
Oxygen Species ◽  
Antitumor Effects ◽  
Key Drivers ◽  
Cancer Immunotherapies ◽  
The Impact

It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. Cancer cells can adapt to maintain redox homeostasis through a variety of mechanisms. The prevalent perception about ROS is that they are one of the key drivers promoting tumor initiation, progression, metastasis, and drug resistance. Based on this notion, numerous antioxidants that aim to mitigate tumor oxidative stress have been tested for cancer prevention or treatment, although the effectiveness of this strategy has yet to be established. In recent years, it has been increasingly appreciated that ROS have a complex, multifaceted role in the tumor microenvironment (TME), and that tumor redox can be targeted to amplify oxidative stress inside the tumor to cause tumor destruction. Accumulating evidence indicates that cancer immunotherapies can alter tumor redox to intensify tumor oxidative stress, resulting in ROS-dependent tumor rejection. Herein we review the recent progresses regarding the impact of ROS on cancer cells and various immune cells in the TME, and discuss the emerging ROS-modulating strategies that can be used in combination with cancer immunotherapies to achieve enhanced antitumor effects.

scholarly journals Impact of Environmental Stressors on Gene Expression in the Embryo of the Italian Wall Lizard

2021 ◽  
Vol 11 (11) ◽  
pp. 4723
Author(s):  
Rosaria Scudiero ◽  
Chiara Maria Motta ◽  
Palma Simoniello
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Membrane Trafficking ◽  
Translational Regulation ◽  
Cellular Protection ◽  
Terrestrial Vertebrate ◽  
Expression Of Genes ◽  
Stress Changes ◽  
Probable Consequence ◽  
The Impact

The cleidoic eggs of oviparous reptiles are protected from the external environment by membranes and a parchment shell permeable to water and dissolved molecules. As a consequence, not only physical but also chemical insults can reach the developing embryos, interfering with gene expression. This review provides information on the impact of the exposure to cadmium contamination or thermal stress on gene expression during the development of Italian wall lizards of the genus Podarcis. The results obtained by transcriptomic analysis, although not exhaustive, allowed to identify some stress-reactive genes and, consequently, the molecular pathways in which these genes are involved. Cadmium-responsive genes encode proteins involved in cellular protection, metabolism and proliferation, membrane trafficking, protein interactions, neuronal transmission and plasticity, immune response, and transcription regulatory factors. Cold stress changes the expression of genes involved in transcriptional/translational regulation and chromatin remodeling and inhibits the transcription of a histone methyltransferase with the probable consequence of modifying the epigenetic control of DNA. These findings provide transcriptome-level evidence of how terrestrial vertebrate embryos cope with stress, giving a key to use in population survival and environmental change studies. A better understanding of the genes contributing to stress tolerance in vertebrates would facilitate methodologies and applications aimed at improving resistance to unfavourable environments.

Importance of Glutamine Metabolism in Leukemia Cells by Energy Production Through TCA Cycle and by Redox Homeostasis

2014 ◽  
Vol 32 (6) ◽  
pp. 241-247 ◽  
Author(s):  
Mineaki Goto ◽  
Hiroshi Miwa ◽  
Masato Shikami ◽  
Norikazu Tsunekawa-Imai ◽  
Kazuto Suganuma ◽  
...  
Keyword(s):  
Energy Production ◽  
Redox Homeostasis ◽  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Leukemia Cells

scholarly journals Metabolic features of mouse and human retinas: rods vs. cones, macula vs. periphery, retina vs. RPE

2020 ◽  
Author(s):  
Bo Li ◽  
Ting Zhang ◽  
Wei Liu ◽  
Yekai Wang ◽  
Rong Xu ◽  
...  
Keyword(s):  
Aerobic Glycolysis ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Lipid Synthesis ◽  
Metabolic Stress ◽  
Tca Cycle ◽  
High Energy ◽  
Metabolic Dysfunction ◽  
Metabolic Demand ◽  
Energy Demands

AbstractPhotoreceptors, especially cones, which are enriched in the human macula, have high energy demands, making them vulnerable to metabolic stress. Metabolic dysfunction of photoreceptors and their supporting retinal pigment epithelium (RPE) is an important underlying cause of degenerative retinal diseases. However, how cones and the macula support their exorbitant metabolic demand and communicate with RPE is unclear. By profiling metabolite uptake and release and analyzing metabolic genes, we have found cone-rich retinas and human macula share specific metabolic features with upregulated pathways in pyruvate metabolism, mitochondrial TCA cycle and lipid synthesis. Human neural retina and RPE have distinct but complementary metabolic features. Retinal metabolism centers on NADH production and neurotransmitter biosynthesis. The retina needs aspartate to sustain its aerobic glycolysis and mitochondrial metabolism. RPE metabolism is directed toward NADPH production and biosynthesis of acetyl-rich metabolites, serine and others. RPE consumes multiple nutrients, including proline, to produce metabolites for the retina.

scholarly journals Mitochondrial genome and its regulator TFAM modulates head and neck tumourigenesis through intracellular metabolic reprogramming and activation of oncogenic effectors

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Yi-Ta Hsieh ◽  
Hsi-Feng Tu ◽  
Muh-Hwa Yang ◽  
Yi-Fen Chen ◽  
Xiang-Yun Lan ◽  
...  
Keyword(s):  
Head And Neck ◽  
Tongue Cancer ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
Cellular Level ◽  
Metabolic Reprogramming ◽  
Transport Chain ◽  
Genetically Manipulated ◽  
The Impact

AbstractMitochondrial transcriptional factor A (TFAM) acts as a key regulatory to control mitochondrial DNA (mtDNA); the impact of TFAM and mtDNA in modulating carcinogenesis is controversial. Current study aims to define TFAM mediated regulations in head and neck cancer (HNC). Multifaceted analyses in HNC cells genetically manipulated for TFAM were performed. Clinical associations of TFAM and mtDNA encoded Electron Transport Chain (ETC) genes in regulating HNC tumourigenesis were also examined in HNC specimens. At cellular level, TFAM silencing led to an enhanced cell growth, motility and chemoresistance whereas enforced TFAM expression significantly reversed these phenotypic changes. These TFAM mediated cellular changes resulted from (1) metabolic reprogramming by directing metabolism towards aerobic glycolysis, based on the detection of less respiratory capacity in accompany with greater lactate production; and/or (2) enhanced ERK1/2-Akt-mTORC-S6 signalling activity in response to TFAM induced mtDNA perturbance. Clinical impacts of TFAM and mtDNA were further defined in carcinogen-induced mouse tongue cancer and clinical human HNC tissues; as the results showed that TFAM and mtDNA expression were significantly dropped in tumour compared with their normal counterparts and negatively correlated with disease progression. Collectively, our data uncovered a tumour-suppressing role of TFAM and mtDNA in determining HNC oncogenicity and potentially paved the way for development of TFAM/mtDNA based scheme for HNC diagnosis.

scholarly journals Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Liou Y Sun ◽  
Adam Spong ◽  
William R Swindell ◽  
Yimin Fang ◽  
Cristal Hill ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Caloric Restriction ◽  
Stress Resistance ◽  
Growth Hormone Releasing Hormone ◽  
Somatotropic Axis ◽  
Releasing Hormone ◽  
Xenobiotic Detoxification ◽  
Expression Of Genes ◽  
Extended Longevity ◽  
The Impact

We examine the impact of targeted disruption of growth hormone-releasing hormone (GHRH) in mice on longevity and the putative mechanisms of delayed aging. GHRH knockout mice are remarkably long-lived, exhibiting major shifts in the expression of genes related to xenobiotic detoxification, stress resistance, and insulin signaling. These mutant mice also have increased adiponectin levels and alterations in glucose homeostasis consistent with the removal of the counter-insulin effects of growth hormone. While these effects overlap with those of caloric restriction, we show that the effects of caloric restriction (CR) and the GHRH mutation are additive, with lifespan of GHRH-KO mutants further increased by CR. We conclude that GHRH-KO mice feature perturbations in a network of signaling pathways related to stress resistance, metabolic control and inflammation, and therefore provide a new model that can be used to explore links between GHRH repression, downregulation of the somatotropic axis, and extended longevity.

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