Regulatory principles in metabolism–then and now

2016 ◽  
Vol 473 (13) ◽  
pp. 1845-1857 ◽  
Author(s):  
Rui Curi ◽  
Philip Newsholme ◽  
Gabriel Nasri Marzuca-Nassr ◽  
Hilton Kenji Takahashi ◽  
Sandro Massao Hirabara ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Metabolic Regulation ◽  
Whole Body ◽  
Thermodynamic Structure ◽  
Oxford University ◽  
Cell Tissue ◽  
A Cell ◽  
Multiple Species ◽  
Metabolic Biochemistry ◽  
Metabolic Disruption

The importance of metabolic pathways for life and the nature of participating reactions have challenged physiologists and biochemists for over a hundred years. Eric Arthur Newsholme contributed many original hypotheses and concepts to the field of metabolic regulation, demonstrating that metabolic pathways have a fundamental thermodynamic structure and that near identical regulatory mechanisms exist in multiple species across the animal kingdom. His work at Oxford University from the 1970s to 1990s was groundbreaking and led to better understanding of development and demise across the lifespan as well as the basis of metabolic disruption responsible for the development of obesity, diabetes and many other conditions. In the present review we describe some of the original work of Eric Newsholme, its relevance to metabolic homoeostasis and disease and application to present state-of-the-art studies, which generate substantial amounts of data that are extremely difficult to interpret without a fundamental understanding of regulatory principles. Eric's work is a classical example of how one can unravel very complex problems by considering regulation from a cell, tissue and whole body perspective, thus bringing together metabolic biochemistry, physiology and pathophysiology, opening new avenues that now drive discovery decades thereafter.

Proteomics: Opportunities and Challenges

2011 ◽  
Vol 3 (4) ◽  
pp. 1165-1172 ◽  
Author(s):  
Parag A Pathade ◽  
Vinod A Bairagi ◽  
Yogesh S. Ahire ◽  
Neela M Bhatia
Keyword(s):  
Biomedical Research ◽  
Therapy Monitoring ◽  
Dynamic State ◽  
Data Sets ◽  
Protein Markers ◽  
Drug Target Discovery ◽  
Proteomic Data ◽  
Cell Tissue ◽  
A Cell ◽  
Analytical Tools

‘‘Proteomics’’, is the emerging technology leading to high-throughput identification and understanding of proteins. Proteomics is the protein equivalent of genomics and has captured the imagination of biomolecular scientists, worldwide. Because proteome reveals more accurately the dynamic state of a cell, tissue, or organism, much is expected from proteomics to indicate better disease markers for diagnosis and therapy monitoring. Proteomics is expected to play a major role in biomedical research, and it will have a significant impact on the development of diagnostics and therapeutics for cancer, heart ailments and infectious diseases, in future. Proteomics research leads to the identification of new protein markers for diagnostic purposes and novel molecular targets for drug discovery.  Though the potential is great, many challenges and issues remain to be solved, such as gene expression, peptides, generation of low abundant proteins, analytical tools, drug target discovery and cost. A systematic and efficient analysis of vast genomic and proteomic data sets is a major challenge for researchers, today. Nevertheless, proteomics is the groundwork for constructing and extracting useful comprehension to biomedical research. This review article covers some opportunities and challenges offered by proteomics.   

scholarly journals Syntaxin 1A Gene Is Negatively Regulated in a Cell/Tissue Specific Manner by YY1 Transcription Factor, Which Binds to the −183 to −137 Promoter Region Together with Gene Silencing Factors Including Histone Deacetylase

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 146
Author(s):  
Takahiro Nakayama ◽  
Toshiyuki Fukutomi ◽  
Yasuo Terao ◽  
Kimio Akagawa
Keyword(s):  
Transcription Factor ◽  
Gene Silencing ◽  
Protein Complex ◽  
Promoter Region ◽  
Neuronal Cell ◽  
Syntaxin 1A ◽  
Tissue Specific ◽  
Cell Tissue ◽  
Specific Manner ◽  
A Cell

The HPC-1/syntaxin 1A (Stx1a) gene, which is involved in synaptic transmission and neurodevelopmental disorders, is a TATA-less gene with several transcription start sites. It is activated by the binding of Sp1 and acetylated histone H3 to the −204 to +2 core promoter region (CPR) in neuronal cell/tissue. Furthermore, it is depressed by the association of class 1 histone deacetylases (HDACs) to Stx1a–CPR in non-neuronal cell/tissue. To further clarify the factors characterizing Stx1a gene silencing in non-neuronal cell/tissue not expressing Stx1a, we attempted to identify the promoter region forming DNA–protein complex only in non-neuronal cells. Electrophoresis mobility shift assays (EMSA) demonstrated that the −183 to −137 OL2 promoter region forms DNA–protein complex only in non-neuronal fetal rat skin keratinocyte (FRSK) cells which do not express Stx1a. Furthermore, the Yin-Yang 1 (YY1) transcription factor binds to the −183 to −137 promoter region of Stx1a in FRSK cells, as shown by competitive EMSA and supershift assay. Chromatin immunoprecipitation assay revealed that YY1 in vivo associates to Stx1a–CPR in cell/tissue not expressing Stx1a and that trichostatin A treatment in FRSK cells decreases the high-level association of YY1 to Stx1a-CPR in default. Reporter assay indicated that YY1 negatively regulates Stx1a transcription. Finally, mass spectrometry analysis showed that gene silencing factors, including HDAC1, associate onto the −183 to −137 promoter region together with YY1. The current study is the first to report that Stx1a transcription is negatively regulated in a cell/tissue-specific manner by YY1 transcription factor, which binds to the −183 to −137 promoter region together with gene silencing factors, including HDAC.

The life and work of Dermot Hedley (‘Derek’) Williamson (1929–1998)

2001 ◽  
Vol 29 (2) ◽  
pp. 237-240
Author(s):  
R. D. Evans ◽  
M. Stubbs ◽  
G. F. Gibbons ◽  
E. A. Newsholme
Keyword(s):  
Metabolic Pathways ◽  
Metabolic Regulation ◽  
Ketone Body ◽  
Scientific Discovery ◽  
Lipid Synthesis ◽  
Acid Oxidation ◽  
Citation Classic ◽  
Integrated Regulation ◽  
Ketone Body Metabolism

Derek Williamson's scientific career spanned the ‘Golden Age’ of research into metabolic regulation, to which he made an important and sustained contribution. Derek joined Hans Krebs' laboratory at Sheffield University in 1946 and moved to Krebs' MRC Unit in Oxford in 1960. He elaborated an enzymic method for the determination of acetoacetate and 3-hydroxybutyrate [Williamson, Mellanby and Krebs, Biochem. J. (1962) 82, 90–96], which opened up the field of ketone body metabolism and its regulation and became a Citation Classic. Another Citation Classic followed [Williamson, Lund and Krebs, Biochem. J. (1967) 103, 514–527]. He moved with Krebs to the Metabolic Research Laboratory at the Radcliffe Infirmary in 1967, where he blossomed, formulating his ideas about the integrated regulation of metabolic pathways, particularly with regard to fatty acid oxidation, lipid synthesis and ketone body metabolism. His success was illustrated by more than 200 publications. Derek implanted and nurtured a sense of the excitement of scientific discovery in his colleagues and students, and he worked hard to provide a friendly, supportive and encouraging environment. Many lives have been enriched by the privilege of working with him.

scholarly journals Epigenetic mechanisms mediating cell state transitions in chondrocytes

2020 ◽  
Author(s):  
Manuela Wuelling ◽  
Christoph Neu ◽  
Andrea M. Thiesen ◽  
Simo Kitanovski ◽  
Yingying Cao ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Cell Lineage ◽  
Cell Types ◽  
State Transitions ◽  
Epigenetic Mechanisms ◽  
Cell Type ◽  
Transition Analysis ◽  
Lineage Differentiation ◽  
A Cell ◽  
Cell Type Specific

AbstractEpigenetic modifications play critical roles in regulating cell lineage differentiation, but the epigenetic mechanisms guiding specific differentiation steps within a cell lineage have rarely been investigated. To decipher such mechanisms, we used the defined transition from proliferating (PC) into hypertrophic chondrocytes (HC) during endochondral ossification as a model. We established a map of activating and repressive histone modifications for each cell type. ChromHMM state transition analysis and Pareto-based integration of differential levels of mRNA and epigenetic marks revealed that differentiation associated gene repression is initiated by the addition of H3K27me3 to promoters still carrying substantial levels of activating marks. Moreover, the integrative analysis identified genes specifically expressed in cells undergoing the transition into hypertrophy.Investigation of enhancer profiles detected surprising differences in enhancer number, location, and transcription factor binding sites between the two closely related cell types. Furthermore, cell type-specific upregulation of gene expression was associated with a shift from low to high H3K27ac decoration. Pathway analysis identified PC-specific enhancers associated with chondrogenic genes, while HC-specific enhancers mainly control metabolic pathways linking epigenetic signature to biological functions.

scholarly journals MMP-14-targeted Nanoprobe for in vivo Fluorescence Imaging of Rupture-prone Carotid Plaques

2021 ◽  
Author(s):  
Mengtao Han ◽  
Kaining Liu ◽  
Hongqiu Xiao ◽  
Tao Sun ◽  
Fei Wang ◽  
...  
Keyword(s):  
Fluorescence Imaging ◽  
Fluorescence Signal ◽  
Plaque Progression ◽  
Carotid Plaques ◽  
In Vivo Fluorescence ◽  
Cell Tissue ◽  
A Cell ◽  
In Vivo Fluorescence Imaging ◽  
Membrane Anchoring

Abstract Background: The identification of rupture-prone carotid plaques for preventing stroke remains a clinical challenge. Macrophage matrix metalloproteinase (MMP)-14, which contributes to plaque progression and destabilisation, could be a promising biomarker for plaque imaging. This study aimed to design and synthesise an MMP-14-targeted nanoprobe to noninvasively visualise the behaviour of M1 macrophages in atherosclerotic plaques.Methods: A fluorescence molecular imaging probe ([email protected]) was constructed by covalently attaching the fluorescent dye cyanine (Cy) 5.5, an MMP-14 substrate, and polyethylene glycol (PEG) 5000-wrapped gold nanoparticles (AuNPs), and then administered via tail vein injection to carotid atherosclerosis models for in vivo fluorescence imaging. Additionally, carotid tissues and cultured macrophages were analysed for nanoprobe binding, and MMP-14 and inflammation-related marker expression was evaluated by polymerase chain reaction, western blotting, and immunohistochemistry.Results: MMP-14 expression significantly increased with plaque progression, along with the upregulation of MMP-2 and inflammatory M1 markers, CD68 and F4/80, and significant downregulation of the M2 marker CD206. All of cell, tissue and in vivo fluorescence imaging exhibited a favourable targeting efficacy of [email protected] for MMP-14.Conclusions: MMP-14, a cell membrane-anchoring enzyme, can serve as a biomarker of vulnerable plaques, and MMP-14 substrate-based [email protected], with an intense fluorescence signal after activation and good biocompatibility, can be applied to screen for and monitor plaque progression in vivo.

scholarly journals Subcellular Localization of Disease-Associated Proteins in Psoriasis

2020 ◽  
Vol 2 (1) ◽  
pp. 8
Keyword(s):  
Subcellular Localization ◽  
Metabolic Pathways ◽  
Inflammatory Disorder ◽  
Protein Protein Interaction ◽  
Extracellular Region ◽  
Associated Proteins ◽  
A Cell ◽  
Pathway Analyses ◽  
Cellular Compartments ◽  
Molecular Pathophysiology

Psoriasis is an autoimmune, persisting, inflammatory disorder that extremely affects the skin and joints of the system. In spite of the field under investigation across the globe roots toward the origin and the molecular pathophysiology of the disease, yet, the mechanism is vaguely presumed. The pathology has its basis in the underlying genes, the protein interactomes, and the metabolic pathways. Subcellular localization of the proteins (Sl) imparts geometrical details of proteins in a cell. In Sl, Proteins conjoin with suitable proteins to assemble into active complexes in signaling routes and metabolic pathways. Variations in the disease set of genes modify the production of gene outcomes as well alters the choosing steps of appropriate Sl, which interrupts the vital roles of the proteins. Proteins related to the disease are predominantly accumulated in typical Sl, which is why apt recognition of protein Sl guides to track down disease bound proteins and the interdependence between them. To do so, in the current investigation, the GOnet tool has been utilized to identify Sl of the proteins by the input of genes and by modeling and visualizing collaborative graphs in conjunction with GO terms and genes. The results obtained displays that the Psoriasis proteins have been localized in respective cellular compartments such as Golgi apparatus, cytoplasm, nucleolus, mitochondria, peroxisomes cytoskeleton, cytoplasm, endosomes, endoplasmic reticulum, extracellular region, nucleoplasm, cilium, vacuole, protein-containing complex, and nuclear chromosome. Further exploration of subcellular localization followed by protein-protein interaction and molecular pathway analyses may be the bedrock to a deeper insight towards disease development and molecular centered relations alongside multimorbidity interactions in Psoriasis.

scholarly journals Adipose tissue in control of metabolism

2016 ◽  
Vol 231 (3) ◽  
pp. R77-R99 ◽  
Author(s):  
Liping Luo ◽  
Meilian Liu
Keyword(s):  
Adipose Tissue ◽  
Metabolic Pathways ◽  
The Body ◽  
The Other ◽  
Whole Body ◽  
Endocrine Organ ◽  
Lipid Mobilization ◽  
Adipose Tissue Dysfunction ◽  
Body Energy ◽  
Beige Adipose Tissue

Adipose tissue plays a central role in regulating whole-body energy and glucose homeostasis through its subtle functions at both organ and systemic levels. On one hand, adipose tissue stores energy in the form of lipid and controls the lipid mobilization and distribution in the body. On the other hand, adipose tissue acts as an endocrine organ and produces numerous bioactive factors such as adipokines that communicate with other organs and modulate a range of metabolic pathways. Moreover, brown and beige adipose tissue burn lipid by dissipating energy in the form of heat to maintain euthermia, and have been considered as a new way to counteract obesity. Therefore, adipose tissue dysfunction plays a prominent role in the development of obesity and its related disorders such as insulin resistance, cardiovascular disease, diabetes, depression and cancer. In this review, we will summarize the recent findings of adipose tissue in the control of metabolism, focusing on its endocrine and thermogenic function.

scholarly journals Noninvasive Whole-Body Imaging of Phosphatidylethanolamine as a Cell Death Marker Using99mTc-Duramycin During TNF-Induced SIRS

2018 ◽  
Vol 59 (7) ◽  
pp. 1140-1145 ◽  
Author(s):  
Tinneke Delvaeye ◽  
Leonie wyffels ◽  
Steven Deleye ◽  
Kelly Lemeire ◽  
Amanda Gonçalves ◽  
...  
Keyword(s):  
Cell Death ◽  
Whole Body ◽  
Whole Body Imaging ◽  
Body Imaging ◽  
A Cell

scholarly journals Gene Therapy: The Molecular Bandage for Treating Genetic Disorders

1970 ◽  
Vol 3 (1) ◽  
pp. 24-27
Author(s):  
Md Manjurul Karim
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Genetic Disorders ◽  
Clinical Status ◽  
Genetic Material ◽  
Review Article ◽  
Cell Tissue ◽  
Efficient Gene ◽  
Effective Delivery ◽  
A Cell

The concept of gene therapy involves the transfer of genetic material into a cell, tissue, or whole organ, with a view to curing a disease or at least improving the clinical status of a patient. Much of its success relies heavily on the development of an effective delivery system that is capable of efficient gene transfer in a variety of tissues, without causing any associated pathogenic effects. Viral vectors currently offer the best choice for efficient gene delivery, what has been discussed in this review article. Their performance and pathogenecity has been evaluated in animal models, and encouraging results form the basis for clinical trials to treat genetic disorders and acquired diseases. Despite some initial success in these trials, vector development remains a seminal concern for improved gene therapy technologies. DOI: http://dx.doi.org/10.3329/akmmcj.v3i1.10110 AKMMCJ 2012; 3(1): 24-27

scholarly journals Alterations in glutamine metabolism and its conversion to citrulline in sepsis

2013 ◽  
Vol 304 (12) ◽  
pp. E1359-E1364 ◽  
Author(s):  
Christina Kao ◽  
Jean Hsu ◽  
Venkata Bandi ◽  
Farook Jahoor
Keyword(s):  
Severe Sepsis ◽  
Plasma Concentration ◽  
Metabolic Pathways ◽  
Plasma Concentrations ◽  
Glutamine Metabolism ◽  
Whole Body ◽  
Healthy Controls ◽  
Metabolic Fate ◽  
Sequential Administration ◽  
Gut Function

In enterocytes, glutamine serves as the major source of energy; another metabolic fate of glutamine is conversion to citrulline. Because sepsis can affect gut function and integrity, alterations in glutamine metabolism may exist and lead to decreased citrulline production. This study aimed to investigate how sepsis affects glutamine metabolism, including its conversion to citrulline, by measuring glutamine and citrulline flux, fractional splanchnic extraction of glutamine and leucine, and the contribution of glutamine nitrogen to citrulline in septic patients and healthy controls. Eight patients with severe sepsis and 10 healthy controls were given primed, constant intravenous infusion of [2H2]citrulline and sequential administration of intravenous and enteral [α-15N]glutamine and [13C]leucine in the postabsorptive state. The results showed that, compared with healthy controls, septic patients had a significantly lower whole body citrulline flux and plasma concentration, higher endogenous leucine flux, and higher glutamine clearance. Fractional splanchnic extraction of leucine was higher in septic patients than in controls, but fractional extraction of glutamine was not different. The majority of the 15N label transferred from glutamine to citrulline was found at the α-position. These results demonstrate that lower glutamine plasma concentrations in sepsis were a result of increased glutamine clearance. Despite adequate splanchnic uptake of glutamine, there is decreased production of citrulline, suggesting a defect in the metabolic conversion of glutamine to citrulline, decreased uptake of glutamine by the enterocyte but increased uptake by the liver, and/or shunting of glutamine to other metabolic pathways.

Sign in / Sign up

Export Citation Format

Share Document