Inflammation and polyamine catabolism: the good, the bad and the ugly

2007 ◽  
Vol 35 (2) ◽  
pp. 300-304 ◽  
Author(s):  
N. Babbar ◽  
T. Murray-Stewart ◽  
R.A. Casero
Keyword(s):  
Cell Growth ◽  
Cell Types ◽  
Tumour Cells ◽  
Good Effect ◽  
Relative Role ◽  
Infectious Agents ◽  
Inflammatory Stress ◽  
Polyamine Catabolism ◽  
Polyamine Analogues ◽  
Mediators Of Inflammation

The induction of polyamine catabolism by specific anti-tumour polyamine analogues has increased interest in the roles polyamine catabolism play in cell growth, death and response to various anti-tumour agents. The relatively recent finding of an inducible mammalian spermine oxidase (SMO/PAOh1), in addition to the two-step spermidine/spermine N1-acetyltransferanse (SSAT)/N1-acetylpolyamine oxidase (APAO) catabolic pathway, underscores the complexities of the regulation of polyamine catabolism by various stimuli. Furthermore, recent data indicate that infectious agents and mediators of inflammation can also up-regulate polyamine catabolism. Induction of SSAT by these agents can reduce intracellular polyamine concentrations and cell growth rate, thus providing a beneficial mechanism by which cells may adapt to inflammatory stress. However, increased polyamine catabolism can also result in substantial increases in intracellular reactive oxygen species (ROS) through the production of H2O2 as a by-product of either APAO or SMO/PAOh1 activity. This increased generation of ROS can have different results, depending on the mechanism of induction and cell types involved. Targeted killing of tumour cells by agents that stimulate SSAT/APAO and/or SMO/PAOh1 is obviously a ‘good’ effect. However, induction of SMO/PAOh1 by inflammation or infectious agents has the potential to produce sufficient ROS in normal, non-tumour cells to lead to DNA damage, mutation and, potentially, carcinogenic transformation (‘bad’). The variation in the induction of these polyamine catabolic enzymes, as well as the level and timing of this induction will dictate the cellular outcome in the presence of both desirable and undesirable effects (‘ugly’). Here we discuss the relative role of each of the steps in polyamine catabolism in response to inflammatory stress.

scholarly journals Exploring the Intracrine Functions of VEGF-A

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 128
Author(s):  
Sophie Wiszniak ◽  
Quenten Schwarz
Keyword(s):  
Cell Growth ◽  
Molecular Mechanisms ◽  
Direct Action ◽  
Cancer Therapeutics ◽  
Cell Types ◽  
Vascular Endothelial ◽  
Signalling Molecule ◽  
Endothelial Growth Factor ◽  
Important Signalling Molecule ◽  
Vegf Signalling

Vascular endothelial growth factor A (VEGF-A or VEGF) is a highly conserved secreted signalling protein best known for its roles in vascular development and angiogenesis. Many non-endothelial roles for VEGF are now established, with the discovery that VEGF and its receptors VEGFR1 and VEGFR2 are expressed in many non-vascular cell-types, as well as various cancers. In addition to secreted VEGF binding to its receptors in the extracellular space at the cell membrane (i.e., in a paracrine or autocrine mode), intracellularly localised VEGF is emerging as an important signalling molecule regulating cell growth, survival, and metabolism. This intracellular mode of signalling has been termed “intracrine”, and refers to the direct action of a signalling molecule within the cell without being secreted. In this review, we describe examples of intracrine VEGF signalling in regulating cell growth, differentiation and survival, both in normal cell homeostasis and development, as well as in cancer. We further discuss emerging evidence for the molecular mechanisms underpinning VEGF intracrine function, as well as the implications this intracellular mode of VEGF signalling may have for use and design of anti-VEGF cancer therapeutics.

scholarly journals Investigations of the mechanism by which mammalian cell growth is inhibited by N1N12-bis(ethyl)spermine

1993 ◽  
Vol 291 (1) ◽  
pp. 131-137 ◽  
Author(s):  
L Albanese ◽  
R J Bergeron ◽  
A E Pegg
Keyword(s):  
Mitochondrial Dna ◽  
Cell Growth ◽  
Cell Lines ◽  
Ornithine Decarboxylase ◽  
Polyamine Analogues ◽  
Proliferative Effect ◽  
L1210 Cells ◽  
Inhibition Of Growth ◽  
Variant Cell ◽  
Mammalian Cell Growth

N1N12-Bis(ethyl)spermine (BESM) and related compounds are powerful inhibitors of cell growth that may have potential as anti-neoplastic agents [Bergeron, Neims, McManis, Hawthorne, Vinson, Bortell and Ingeno (1988) J. Med. Chem. 31, 1183-1190]. The mechanism by which these compounds bring about their effects was investigated by using variant cell lines in which processes thought to be altered by these agents are perturbed. Comparisons between the response of these cells and of their parental equivalents to BESM, N1N11-bis(ethyl)norspermine, N1N14-bis(ethyl)homospermine and N1N8-bis(ethyl)spermidine were then made. It was found that D-R cells, an L1210-derived line that over-expresses ornithine decarboxylase, were not resistant to these compounds. This indicates that the decrease in ornithine decarboxylase is not critical for the action of the compounds on cell growth. Furthermore, although polyamine levels were decreased in the D-R cells, the content was not totally depleted, indicating that such depletion is also not essential for the anti-proliferative effect. Two cell lines lacking mitochondrial DNA (human 143B206 cells and chicken DU3 cells) did not differ in sensitivity to BESM from their parental 143BTK- and DU24 cells. Furthermore, the inhibition of respiration in L1210 cells in response to BESM developed more slowly than the inhibition of growth. Thus it appears that the inhibitions of mitochondrial DNA synthesis and of mitochondrial respiration are also not primary factors in the anti-proliferative effects of these polyamine analogues. The inhibition of growth did, however, correlate with the intracellular accumulation of the analogues. It appears that the bis(ethyl)polyamine derivatives act by binding to intracellular target molecules and preventing macromolecular synthesis. The decline in normal polyamines may facilitate such binding, but is not essential for growth arrest.

scholarly journals Cell growth dilutes the cell cycle inhibitor Rb to trigger cell division

2018 ◽  
Author(s):  
Evgeny Zatulovskiy ◽  
Daniel F. Berenson ◽  
Benjamin R. Topacio ◽  
Jan M. Skotheim
Keyword(s):  
Cell Cycle ◽  
Cell Division ◽  
Cell Growth ◽  
Cell Size ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Inverse Correlation ◽  
Cell Types ◽  
Similar Amount ◽  
Cell Cycle Inhibitor

Cell size is fundamental to function in different cell types across the human body because it sets the scale of organelle structures, biosynthesis, and surface transport1,2. Tiny erythrocytes squeeze through capillaries to transport oxygen, while the million-fold larger oocyte divides without growth to form the ~100 cell pre-implantation embryo. Despite the vast size range across cell types, cells of a given type are typically uniform in size likely because cells are able to accurately couple cell growth to division3–6. While some genes whose disruption in mammalian cells affects cell size have been identified, the molecular mechanisms through which cell growth drives cell division have remained elusive7–12. Here, we show that cell growth acts to dilute the cell cycle inhibitor Rb to drive cell cycle progression from G1 to S phase in human cells. In contrast, other G1/S regulators remained at nearly constant concentration. Rb is a stable protein that is synthesized during S and G2 phases in an amount that is independent of cell size. Equal partitioning to daughter cells of chromatin bound Rb then ensures that all cells at birth inherit a similar amount of Rb protein. RB overexpression increased cell size in tissue culture and a mouse cancer model, while RB deletion decreased cell size and removed the inverse correlation between cell size at birth and the duration of G1 phase. Thus, Rb-dilution by cell growth in G1 provides a long-sought cell autonomous molecular mechanism for cell size homeostasis.

scholarly journals Cancer treatment scheduling and dynamic heterogeneity in social dilemmas of tumour acidity and vasculature

2016 ◽  
Author(s):  
Artem Kaznatcheev ◽  
Robert Vander Velde ◽  
Jacob G. Scott ◽  
David Basanta
Keyword(s):  
Growth Factor ◽  
Public Good ◽  
Aerobic Glycolysis ◽  
Evolutionary Game ◽  
Cell Types ◽  
Tumour Cells ◽  
Order Effects ◽  
Dynamic Heterogeneity ◽  
Factor Production ◽  
Growth Factor Production

AbstractBackgroundTumours are diverse ecosystems with persistent heterogeneity in various cancer hallmarks like self-sufficiency of growth factor production for angiogenesis and reprogramming of energy-metabolism for aerobic glycolysis. This heterogeneity has consequences for diagnosis, treatment, and disease progression.MethodsWe introduce the double goods game to study the dynamics of these traits using evolutionary game theory. We model glycolytic acid production as a public good for all tumour cells and oxygen from vascularization via VEGF production as a club good benefiting non-glycolytic tumour cells. This results in three viable phenotypic strategies: glycolytic, angiogenic, and aerobic non-angiogenic.ResultsWe classify the dynamics into three qualitatively distinct regimes: (1) fully glycolytic, (2) fully angiogenic, or (3) polyclonal in all three cell types. The third regime allows for dynamic heterogeneity even with linear goods, something that was not possible in prior public good models that considered glycolysis or growth-factor production in isolation.ConclusionThe cyclic dynamics of the polyclonal regime stress the importance of timing for antiglycolysis treatments like lonidamine. The existence of qualitatively different dynamic regimes highlights the order effects of treatments. In particular, we consider the potential of vascular renormalization as a neoadjuvant therapy before follow up with interventions like buffer therapy.

scholarly journals Characteristic of infectious status in patients with acutely decompencated chronic heart failure and its impact on annual prognosis

Kardiologiia ◽  
2019 ◽  
Vol 59 (8S) ◽  
pp. 56-62
Author(s):  
V. A. Kostenko ◽  
M. Yu. Sitnikova ◽  
E. A. Skorodumova ◽  
E. G. Skorodumova ◽  
A. N. Fedorov ◽  
...  
Keyword(s):  
Heart Failure ◽  
Intestinal Bacteria ◽  
Mycoplasma Hominis ◽  
Chronic Obstructive ◽  
Infectious Agents ◽  
Gram Negative ◽  
Inflammatory Stress ◽  
Barr Virus ◽  
Epstein Barr ◽  
One Year

Aim. The assessment of infectious status in patients with acutely decompensated chronic heart faiure (ADCHF) without evident signs of acute inflammatory stress and its impact on the 1 year prognosis.Material and methods. Totally, 65 patients with ADCHF of ischemic origin investigated, age 67,3±2,3 y.o. All patients were taken markers of phagocytosis and inflammatory stress as well as antibodies to Streptococcus, Cytomegalovirus (CMV), Epstein-Barr virus (VEB), Candida albicans, Toxoplasma gondii, Aspergillus, Mycoplasma hominis and pneumonia and also level of lipopolysaccharids (LPS) of gram-negative bacteriae.Results. More often LPS of gram-negative bacteriae were revealed in patients with ADCHF and further in decreasing order – antibodies to CMV, VEB, Streptococcus, Candida, Aspergillus and LPS. All patients have been infected by at least 2 pathogens, more than 90 % of them had 3 ones or more. Mortality in first 12 months observation correlated with quantity of patient`s pathogenic patterns (r=0,52, p=0,004). Dependency of one-year mortality from degree of viral-bacterial mixt contamination was almost linear. CMV was a monopathogen with strongest correlation with mortality (r=0,39, p=0,001). In patients with more significant infection bigger rate of re-hospitalizations about new ADCHF correlated with number of pathogens was observed (r=0,61, p=0,001).Conclusion. Chronic latent infection with a significant number of pathogens is characteristic of patients with low-ejection ADCHF of ischemic genesis with a significant number of pathogens: more than 90 % of patients had three or more. The most common exogenous pathogens in the study sample of patients with chronic obstructive heart failure were CMV, EBV, and hemolytic streptococcus, of the potentially endogenous ones, gram-negative intestinal bacteria. The number of infectious agents in patients with chronic obstructive heart failure has a direct correlation with deaths and re-admission to hospital with total heart failure within 1 year after discharge from the hospital.

Therapeutic targets in COVID-19 coagulopathy

2021 ◽  
Author(s):  
М.В. Кондашевская
Keyword(s):  
Viral Infections ◽  
Cell Types ◽  
Infectious Agents ◽  
Therapeutic Goals ◽  
Extracellular Traps ◽  
Activated Neutrophils ◽  
Life Threatening ◽  
Tight Connection ◽  
New Type

В обзоре представлены сведения о некоторых биохимических и клеточных механизмах патогенеза потенциально смертельного вирусного заболевания, получившего название COVID-19, провоцируемого вирусами из семейства коронавирусов SARS-CoV-2. Наибольшую опасность для жизни и здоровья пациентов представляет коагулопатия, обусловленная ответной реакцией на инфекцию — чрезмерной генерацией клетками пациента внеклеточных мембранных нановезикул (ВМН), которые могут спровоцировать активизацию гемостаза, приводящую к разрушительной полиорганной недостаточности. Вирусы также способны генерировать внеклеточные везикулы, называемые виросомами. Встраивая вирусные компоненты в свои виросомы, вирусы повышают персистентность за счет маскировки своих геномов, умножая вирусную инфекцию. В статье охарактеризованы свойства нейтрофильных гранулоцитов, активирующихся при инфицировании, и представлены сведения о молекулярных механизмах действия их компонентов при попадании во внеклеточное пространство. ВМН уже имеют практическое применение в качестве вакцинных носителей для иммунизации человека и животных против многих инфекционных заболеваний. В настоящее время актуальнейшей темой, обуславливающей большой практический интерес, стала роль ВМН в индуцировании иммунитета против коронавирусной инфекции. Охарактеризованы другие возможные терапевтические мишени. Virus-induced coagulopathy is a typical example of the tight connection between inflammation and thrombosis. These two reactions are linked by pro-inflammatory agents, generated by activated neutrophils and their neutrophil extracellular traps (NETs). Extracellular membrane nanobubbles (EMNs), formed by a wide variety of cell types, have recently been identified as new entrants that play a key role in coagulopathy. EMNs directly and indirectly activate coagulation systems that lead to the further upregulation of inflammation and life-threatening organ dysfunction and thrombosis. EMNs are known to be responsible for the secretion, exchange, and transmission of important active biomolecules in COVID-19. Indeed, EMNs represent an essential mechanism in intercellular communication, and the roles of EMNs in infection and thrombosis have been increasingly recognized. The extracellular microvesicles of viruses, virosomes, represent a new type of infectious agents, which determines new therapeutic goals in solving the problems of controlling viral infections. Understanding the biological nature of all these microvesicles when studying them in vivo is of paramount importance for the development of diagnostic and therapeutic methods.

scholarly journals Epidermal growth factor inhibits growth of A431 human epidermoid carcinoma in serum-free cell culture.

1982 ◽  
Vol 93 (1) ◽  
pp. 1-4 ◽  
Author(s):  
D W Barnes
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Epidermal Growth Factor ◽  
Culture Medium ◽  
Cell Types ◽  
Inhibitory Effect ◽  
Free Cell ◽  
Bovine Insulin ◽  
A431 Cell ◽  
Epidermal Growth

A medium consisting of a rich basal nutrient mixture supplemented with bovine insulin (10 micrograms/ml), human transferrin (10 micrograms/ml), human cold-insoluble globulin (5 micrograms/ml), and ethanolamine (0.5 mM) supported the growth of the A431 human epidermoid cell line in the absence of serum with a generation time equal to that of cells in serum-containing medium. Addition of epidermal growth factor (EGF) to this culture medium at concentration mitogenic for other cell types resulted in a marked inhibition of A431 cell growth. Inhibitory effects of EGF were observed at 1 ng/ml and near-maximal effects were observed at 10 ng/ml. The inhibitory effect of EGF could be reversed by the omission of EGF in subsequent medium changes and could be prevented by the addition of anti-EGF antibody to the culture medium. Inhibition of A431 cell growth by EGF also could be demonstrated in serum-containing medium.

scholarly journals The Role of Sphingosine-1-Phosphate and Ceramide-1-Phosphate in Inflammation and Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Nitai C. Hait ◽  
Aparna Maiti
Keyword(s):  
Cell Growth ◽  
Cell Fate ◽  
Cancer Progression ◽  
Tissue Injury ◽  
Cell Types ◽  
Cancer Cell Growth ◽  
Ceramide Level ◽  
Cytokines And Chemokines ◽  
Sphingosine 1 Phosphate ◽  
Ceramide 1

Inflammation is part of our body’s response to tissue injury and pathogens. It helps to recruit various immune cells to the site of inflammation and activates the production of mediators to mobilize systemic protective processes. However, chronic inflammation can increase the risk of diseases like cancer. Apart from cytokines and chemokines, lipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), contribute to inflammation and cancer. S1P is an important player in inflammation-associated colon cancer progression. On the other hand, C1P has been recognized to be involved in cancer cell growth, migration, survival, and inflammation. However, whether C1P is involved in inflammation-associated cancer is not yet established. In contrast, few studies have also suggested that S1P and C1P are involved in anti-inflammatory pathways regulated in certain cell types. Ceramide is the substrate for ceramide kinase (CERK) to yield C1P, and sphingosine is phosphorylated to S1P by sphingosine kinases (SphKs). Biological functions of sphingolipid metabolites have been studied extensively. Ceramide is associated with cell growth inhibition and enhancement of apoptosis while S1P and C1P are associated with enhancement of cell growth and survival. Altogether, S1P and C1P are important regulators of ceramide level and cell fate. This review focuses on S1P and C1P involvement in inflammation and cancer with emphasis on recent progress in the field.

scholarly journals Antizyme induction by polyamine analogues as a factor of cell growth inhibition

2002 ◽  
Vol 366 (2) ◽  
pp. 663-671 ◽  
Author(s):  
John L.A. MITCHELL ◽  
Aviva LEYSER ◽  
Michelle S. HOLTORFF ◽  
Jill S. BATES ◽  
Benjamin FRYDMAN ◽  
...  
Keyword(s):  
Cell Growth ◽  
Growth Inhibition ◽  
Feedback Inhibition ◽  
Conformationally Constrained ◽  
Polyamine Analogues ◽  
Polyamine Transport ◽  
Mammalian Cell Growth ◽  
Htc Cells ◽  
Cell Growth And Viability ◽  
Selection Of

The polyamines spermidine and spermine and their diamine precursor putrescine are essential for mammalian cell growth and viability, and strategies are sought for reducing polyamine levels in order to inhibit cancer growth. Several structural analogues of the polyamines have been found to decrease natural polyamine levels and inhibit cell growth, probably by stimulating normal feedback mechanisms. In the present study, a large selection of spermine analogues has been tested for their effectiveness in inducing the production of antizyme, a key protein in feedback inhibition of putrescine synthesis and cellular polyamine uptake. Bisethylnorspermine, bisethylhomospermine, 1,19-bis-(ethylamino)-5,10,15-triazanonadecane, longer oligoamine constructs and many conformationally constrained analogues of these compounds were found to stimulate antizyme synthesis to different levels in rat liver HTC cells, with some producing far more antizyme than the natural polyamine spermine. Uptake of the tested compounds was found to be dependent on, and limited by, the polyamine transport system, for which all these have approximately equal affinity. These analogues differed in their ability to inhibit HTC cell growth during 3days of exposure, and this ability correlated with their antizyme-inducing potential. This is the first direct evidence that antizyme is induced by several polyamine analogues. Selection of analogues with this potential may be an effective strategy for maximizing polyamine deprivation and growth inhibition.

scholarly journals Adipo-Myokines: Two Sides of the Same Coin—Mediators of Inflammation and Mediators of Exercise

2013 ◽  
Vol 2013 ◽  
pp. 1-16 ◽  
Author(s):  
Silja Raschke ◽  
Jürgen Eckel
Keyword(s):  
Skeletal Muscle ◽  
Mrna Level ◽  
Cell Types ◽  
The Other ◽  
Target Tissue ◽  
Beneficial Effects ◽  
Mediators Of Inflammation ◽  
The One ◽  
Two Sides ◽  
Kinetics Of

This review summarizes the current literature regarding the most discussed contraction-regulated moykines like IL-6, IL-15, irisin, BDNF, ANGPTL4, FGF21, myonectin and MCP-1. It is suggested that the term myokine is restricted to proteins secreted from skeletal muscle cells, excluding proteins that are secreted by other cell types in skeletal muscle tissue and excluding proteins which are only described on the mRNA level. Interestingly, many of the contraction-regulated myokines described in the literature are additionally known to be secreted by adipocytes. We termed these proteins adipo-myokines. Within this review, we try to elaborate on the question why pro-inflammatory adipokines on the one hand are upregulated in the obese state, and have beneficial effects after exercise on the other hand. Both, adipokines and myokines do have autocrine effects within their corresponding tissues. In addition, they are involved in an endocrine crosstalk with other tissues. Depending on the extent and the kinetics of adipo-myokines in serum, these molecules seem to have a beneficial or an adverse effect on the target tissue.

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