scholarly journals Lactate favours the dissociation of skeletal muscle 6-phosphofructo-1-kinase tetramers down-regulating the enzyme and muscle glycolysis

2007 ◽  
Vol 408 (1) ◽  
pp. 123-130 ◽  
Author(s):  
Tiago Costa Leite ◽  
Daniel Da Silva ◽  
Raquel Guimarães Coelho ◽  
Patricia Zancan ◽  
Mauro Sola-Penna
Keyword(s):  
Tissue Repair ◽  
Quaternary Structure ◽  
Glucose Consumption ◽  
Glycolytic Enzyme ◽  
Glycolytic Flux ◽  
Physiological Processes ◽  
Dead End ◽  
Signalling Molecule ◽  
Inhibitory Site

For a long period lactate was considered as a dead-end product of glycolysis in many cells and its accumulation correlated with acidosis and cellular and tissue damage. At present, the role of lactate in several physiological processes has been investigated based on its properties as an energy source, a signalling molecule and as essential for tissue repair. It is noteworthy that lactate accumulation alters glycolytic flux independently from medium acidification, thereby this compound can regulate glucose metabolism within cells. PFK (6-phosphofructo-1-kinase) is the key regulatory glycolytic enzyme which is regulated by diverse molecules and signals. PFK activity is directly correlated with cellular glucose consumption. The present study shows the property of lactate to down-regulate PFK activity in a specific manner which is not dependent on acidification of the medium. Lactate reduces the affinity of the enzyme for its substrates, ATP and fructose 6-phosphate, as well as reducing the affinity for ATP at its allosteric inhibitory site at the enzyme. Moreover, we demonstrated that lactate inhibits PFK favouring the dissociation of enzyme active tetramers into less active dimers. This effect can be prevented by tetramer-stabilizing conditions such as the presence of fructose 2,6-bisphosphate, the binding of PFK to f-actin and phosphorylation of the enzyme by protein kinase A. In conclusion, our results support evidence that lactate regulates the glycolytic flux through modulating PFK due to its effects on the enzyme quaternary structure.

scholarly journals Gcn5p and Ubp8p Affect Protein Ubiquitylation and Cell Proliferation by Altering the Fermentative/Respiratory Flux Balance in Saccharomyces cerevisiae

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Antonella De Palma ◽  
Giulia Fanelli ◽  
Elisabetta Cretella ◽  
Veronica De Luca ◽  
Raffaele Antonio Palladino ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Glucose Consumption ◽  
Redox Balance ◽  
Glycolytic Enzymes ◽  
Glycolytic Flux ◽  
Direct Role ◽  
Content Type ◽  
Proteomic Approach ◽  
Altered Glucose

ABSTRACT Protein ubiquitylation regulates not only endocellular trafficking and proteasomal degradation but also the catalytic activity of enzymes. In Saccharomyces cerevisiae, we analyzed the composition of the ubiquitylated proteomes in strains lacking acetyltransferase Gcn5p, Ub-protease Ubp8p, or both to understand their involvement in the regulation of protein ubiquitylation. We analyzed His6Ub proteins with a proteomic approach coupling micro-liquid chromatography and tandem mass spectrometry (μLC-MS/MS) in gcn5Δ, ubp8Δ and ubp8Δ gcn5Δ strains. The Ub-proteome altered in the absence of Gcn5p, Ubp8p, or both was characterized, showing that 43% of the proteins was shared in all strains, suggesting their functional relationship. Remarkably, all major glycolytic enzymes showed increased ubiquitylation. Phosphofructokinase 1, the key enzyme of glycolytic flux, showed a higher and altered pattern of ubiquitylation in gcn5Δ and ubp8Δ strains. Severe defects of growth in poor sugar and altered glucose consumption confirmed a direct role of Gcn5p and Ubp8p in affecting the REDOX balance of the cell. IMPORTANCE We propose a study showing a novel role of Gcn5p and Ubp8p in the process of ubiquitylation of the yeast proteome which includes main glycolytic enzymes. Interestingly, in the absence of Gcn5p and Ubp8p glucose consumption and redox balance were altered in yeast. We believe that these results and the role of Gcn5p and Ubp8p in sugar metabolism might open new perspectives of research leading to novel protocols for counteracting the enhanced glycolysis in tumors.

scholarly journals The role of hydrogen peroxide in regulation of plant metabolism and cellular signalling in response to environmental stresses.

2007 ◽  
Vol 54 (1) ◽  
pp. 39-50 ◽  
Author(s):  
Ireneusz Slesak ◽  
Marta Libik ◽  
Barbara Karpinska ◽  
Stanislaw Karpinski ◽  
Zbigniew Miszalski
Keyword(s):  
Hydrogen Peroxide ◽  
Redox Homeostasis ◽  
Carbon Assimilation ◽  
Environmental Stresses ◽  
Oxygenic Photosynthesis ◽  
C3 Plants ◽  
Physiological Processes ◽  
Signalling Molecule ◽  
Defence Responses

Hydrogen peroxide (H2O2) is produced predominantly in plant cells during photosynthesis and photorespiration, and to a lesser extent, in respiration processes. It is the most stable of the so-called reactive oxygen species (ROS), and therefore plays a crucial role as a signalling molecule in various physiological processes. Intra- and intercellular levels of H2O2 increase during environmental stresses. Hydrogen peroxide interacts with thiol-containing proteins and activates different signalling pathways as well as transcription factors, which in turn regulate gene expression and cell-cycle processes. Genetic systems controlling cellular redox homeostasis and H2O2 signalling are discussed. In addition to photosynthetic and respiratory metabolism, the extracellular matrix (ECM) plays an important role in the generation of H2O2, which regulates plant growth, development, acclimatory and defence responses. During various environmental stresses the highest levels of H2O2 are observed in the leaf veins. Most of our knowledge about H2O2 in plants has been obtained from obligate C3 plants. The potential role of H2O2 in the photosynthetic mode of carbon assimilation, such as C4 metabolism and CAM (Crassulacean acid metabolism) is discussed. We speculate that early in the evolution of oxygenic photosynthesis on Earth, H2O2 could have been involved in the evolution of modern photosystem II.

scholarly journals PFKFB3 Promotes Liver Fibrosis by Regulating Aerobic Glycolysis of Hepatic Stellate Cells

2021 ◽  
Vol 21 (5) ◽  
Author(s):  
Ming-yu Zhou ◽  
Xue-ke Zhao ◽  
Tao Huang ◽  
Gao-liang Zou ◽  
Rui-Han Hu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Liver Tissue ◽  
Aerobic Glycolysis ◽  
Glucose Consumption ◽  
Stellate Cells ◽  
Glycolytic Flux ◽  
Type I ◽  
Fibrotic Liver

Background: Hepatic stellate cells (HSCs) are the key effector cells in the occurrence and development of liver fibrosis, while aerobic glycolysis is one of the important metabolic characteristics of HSC activation. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a homodimeric bifunctional enzyme, which is a rate-limiting enzyme in glycolysis. This metabolite is important for the dynamic regulation of glycolytic flux. However, little is known about the role of PFKFB3 in liver fibrosis. Objectives: In this study, we aimed to explore the effects of PFKFB3 on aerobic glycolysis in the process of HSC trans-differentiation and liver fibrosis. Methods: Immunohistochemical (IHC) staining and immunofluorescence assays were used to examine PFKFB3 expression in mice fibrotic liver tissue. The determination of extracellular acidification rate was used to examine changes in aerobic glycolytic flux, lactate production levels, and glucose consumption levels in HSCs upon TGF-β1 stimulation. Western blot analysis of the expression of PFKFB3, α-SMA protein, and type I collagen was done. Liver histopathology was also examined. Besides, glycolytic inhibition by pharmacologic approaches was used to demonstrate the critical role of glycolysis in liver fibrosis. Results: The PFKFB3 protein expression was increased in mouse fibrotic liver tissue. In addition, immunofluorescence revealed the colocalization of PFKFB3 and alpha-smooth muscle actin (α-SMA) protein. In vitro experiments showed that PFKFB3 could promote glycolysis flux, lactic acid production, and glucose consumption of hepatic stellate cells. The PFKFB3 inhibitor was used in a mouse model of liver fibrosis, and the inhibition of PFKFB3 reduced the degree of liver inflammation and liver fibrosis. Conclusions: PFKFB3 can promote HSC aerobic glycolysis, which, in turn, promotes HSC activation and liver fibrosis.

Hyperferritinaemia: An Iron Sword of Autoimmunity

2019 ◽  
Vol 25 (27) ◽  
pp. 2909-2918 ◽  
Author(s):  
Joanna Giemza-Stokłosa ◽  
Md. Asiful Islam ◽  
Przemysław J. Kotyla
Keyword(s):  
Immune Response ◽  
Macrophage Activation ◽  
Inflammatory Diseases ◽  
Acute Phase Reactant ◽  
Catastrophic Antiphospholipid Syndrome ◽  
Inflammatory Conditions ◽  
Phase Reactant ◽  
Signalling Molecule ◽  
Cytokine Synthesis

Background:: Ferritin is a molecule that plays many roles being the storage for iron, signalling molecule, and modulator of the immune response. Methods:: Different electronic databases were searched in a non-systematic way to find out the literature of interest. Results:: The level of ferritin rises in many inflammatory conditions including autoimmune disorders. However, in four inflammatory diseases (i.e., adult-onset Still’s diseases, macrophage activation syndrome, catastrophic antiphospholipid syndrome, and sepsis), high levels of ferritin are observed suggesting it as a remarkable biomarker and pathological involvement in these diseases. Acting as an acute phase reactant, ferritin is also involved in the cytokine-associated modulator of the immune response as well as a regulator of cytokine synthesis and release which are responsible for the inflammatory storm. Conclusion:: This review article presents updated information on the role of ferritin in inflammatory and autoimmune diseases with an emphasis on hyperferritinaemic syndrome.

scholarly journals Overview on the Different Patterns of Tumor Vascularization

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 639
Author(s):  
Domenico Ribatti ◽  
Francesco Pezzella
Keyword(s):  
Vasculogenic Mimicry ◽  
Endothelial Cell Proliferation ◽  
Published Data ◽  
Alternative Mechanism ◽  
Tumor Vascularization ◽  
Angiogenic Therapy ◽  
Physiological Processes ◽  
Inhibition Of Angiogenesis ◽  
Therapeutic Development

Angiogenesis is a crucial event in the physiological processes of embryogenesis and wound healing. During malignant transformation, dysregulation of angiogenesis leads to the formation of a vascular network of tumor-associated capillaries promoting survival and proliferation of the tumor cells. Starting with the hypothesis formulated by Judah Folkman that tumor growth is angiogenesis-dependent, this area of research has a solid scientific foundation and inhibition of angiogenesis is a major area of therapeutic development for the treatment of cancer. Over this period numerous authors published data of vascularization of tumors, which attributed the cause of neo-vascularization to various factors including inflammation, release of angiogenic cytokines, vasodilatation, and increased tumor metabolism. More recently, it has been demonstrated that tumor vasculature is not necessarily derived by endothelial cell proliferation and sprouting of new capillaries, but alternative vascularization mechanisms have been described, namely vascular co-option and vasculogenic mimicry. In this article, we have analyzed the mechanisms involved in tumor vascularization in association with classical angiogenesis, including post-natal vasculogenesis, intussusceptive microvascular growth, vascular co-option, and vasculogenic mimicry. We have also discussed the role of these alternative mechanism in resistance to anti-angiogenic therapy and potential therapeutic approaches to overcome resistance.

scholarly journals Pannexins and Connexins: Their Relevance for Oocyte Developmental Competence

2021 ◽  
Vol 22 (11) ◽  
pp. 5918
Author(s):  
Paweł Kordowitzki ◽  
Gabriela Sokołowska ◽  
Marta Wasielak-Politowska ◽  
Agnieszka Skowronska ◽  
Mariusz T. Skowronski
Keyword(s):  
Assisted Reproductive Technologies ◽  
Mammalian Species ◽  
Atp Release ◽  
Reproductive Technologies ◽  
High Energy ◽  
Developmental Competence ◽  
Physiological Processes ◽  
Protein Group ◽  
Multicellular Organisms

The oocyte is the major determinant of embryo developmental competence in all mammalian species. Although fundamental advances have been generated in the field of reproductive medicine and assisted reproductive technologies in the past three decades, researchers and clinicians are still trying to elucidate molecular factors and pathways, which could be pivotal for the oocyte’s developmental competence. The cell-to-cell and cell-to-matrix communications are crucial not only for oocytes but also for multicellular organisms in general. This latter mentioned communication is among others possibly due to the Connexin and Pannexin families of large-pore forming channels. Pannexins belong to a protein group of ATP-release channels, therefore of high importance for the oocyte due to its requirements of high energy supply. An increasing body of studies on Pannexins provided evidence that these channels not only play a role during physiological processes of an oocyte but also during pathological circumstances which could lead to the development of diseases or infertility. Connexins are proteins that form membrane channels and gap-junctions, and more precisely, these proteins enable the exchange of some ions and molecules, and therefore they do play a fundamental role in the communication between the oocyte and accompanying cells. Herein, the role of Pannexins and Connexins for the processes of oogenesis, folliculogenesis, oocyte maturation and fertilization will be discussed and, at the end of this review, Pannexin and Connexin related pathologies and their impact on the developmental competence of oocytes will be provided.

scholarly journals Syndecans and Pancreatic Ductal Adenocarcinoma

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 349
Author(s):  
Nausika Betriu ◽  
Juan Bertran-Mas ◽  
Anna Andreeva ◽  
Carlos E. Semino
Keyword(s):  
Extracellular Matrix ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Types ◽  
Ductal Adenocarcinoma ◽  
Physiological Processes ◽  
Extracellular Matrix Components ◽  
Detection And Diagnosis ◽  
And Migration ◽  
Early Detection And Diagnosis

Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease.

scholarly journals Role of Insulin in Health and Disease: An Update

2021 ◽  
Vol 22 (12) ◽  
pp. 6403
Author(s):  
Md Saidur Rahman ◽  
Khandkar Shaharina Hossain ◽  
Sharnali Das ◽  
Sushmita Kundu ◽  
Elikanah Olusayo Adegoke ◽  
...  
Keyword(s):  
Insulin Signaling ◽  
Basic Research ◽  
Future Research ◽  
Protective Effects ◽  
Glucose Levels ◽  
Physiological Processes ◽  
Blood Glucose Levels ◽  
Wide Range ◽  
Health And Disease

Insulin is a polypeptide hormone mainly secreted by β cells in the islets of Langerhans of the pancreas. The hormone potentially coordinates with glucagon to modulate blood glucose levels; insulin acts via an anabolic pathway, while glucagon performs catabolic functions. Insulin regulates glucose levels in the bloodstream and induces glucose storage in the liver, muscles, and adipose tissue, resulting in overall weight gain. The modulation of a wide range of physiological processes by insulin makes its synthesis and levels critical in the onset and progression of several chronic diseases. Although clinical and basic research has made significant progress in understanding the role of insulin in several pathophysiological processes, many aspects of these functions have yet to be elucidated. This review provides an update on insulin secretion and regulation, and its physiological roles and functions in different organs and cells, and implications to overall health. We cast light on recent advances in insulin-signaling targeted therapies, the protective effects of insulin signaling activators against disease, and recommendations and directions for future research.

scholarly journals Alteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuya Yoshida ◽  
Naoya Matsunaga ◽  
Takaharu Nakao ◽  
Kengo Hamamura ◽  
Hideaki Kondo ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Clock Genes ◽  
Serum Levels ◽  
Serum Retinol ◽  
Cardiac Inflammation ◽  
Physiological Processes ◽  
G Protein Coupled ◽  
Clock Protein

AbstractDysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. The CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induces the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.

Sign in / Sign up

Export Citation Format

Share Document