scholarly journals The Effect of Impaired Polyamine Transport on Pneumococcal Transcriptome

Pathogens ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1322
Author(s):  
Mary F. Nakamya ◽  
Moses B. Ayoola ◽  
Leslie A. Shack ◽  
Edwin Swiatlo ◽  
Bindu Nanduri
Keyword(s):  
Stress Responses ◽  
Nitrosative Stress ◽  
Sugar Metabolism ◽  
Pentose Phosphate ◽  
Therapeutic Interventions ◽  
Expression Of Genes ◽  
Polyamine Transport ◽  
Novel Target ◽  
Pentose Phosphate Pathways

Infections due to Streptococcus pneumoniae, a commensal in the nasopharynx, still claim a significant number of lives worldwide. Genome plasticity, antibiotic resistance, and limited serotype coverage of the available polysaccharide-based conjugate vaccines confounds therapeutic interventions to limit the spread of this pathogen. Pathogenic mechanisms that allow successful adaption and persistence in the host could be potential innovative therapeutic targets. Polyamines are ubiquitous polycationic molecules that regulate many cellular processes. We previously reported that deletion of polyamine transport operon potABCD, which encodes a putrescine/spermidine transporter (∆potABCD), resulted in an unencapsulated attenuated phenotype. Here, we characterize the transcriptome, metabolome, and stress responses of polyamine transport-deficient S. pneumoniae. Compared with the wild-type strain, the expression of genes involved in oxidative stress responses and the nucleotide sugar metabolism was reduced, while expression of genes involved in the Leloir, tagatose, and pentose phosphate pathways was higher in ΔpotABCD. A metabolic shift towards the pentose phosphate pathway will limit the synthesis of precursors of capsule polysaccharides. Metabolomics results show reduced levels of glutathione and pyruvate in the mutant. Our results also show that the potABCD operon protects pneumococci against hydrogen peroxide and nitrosative stress. Our findings demonstrate the importance of polyamine transport in pneumococcal physiology that could impact in vivo fitness. Thus, polyamine transport in pneumococci represents a novel target for therapeutic interventions.

scholarly journals Polyamine Transport Is Required for Stress Responses and Capsule Production in Streptococcus Pneumoniae

2021 ◽  
Author(s):  
Mary F. Nakamya ◽  
Moses B. Ayoola ◽  
Leslie A. Shack ◽  
Edwin Swiatlo ◽  
Bindu Nanduri
Keyword(s):  
Streptococcus Pneumoniae ◽  
Stress Responses ◽  
Nitrosative Stress ◽  
Pentose Phosphate ◽  
Therapeutic Interventions ◽  
Central Metabolism ◽  
Expression Of Genes ◽  
Capsule Production ◽  
Polyamine Transport ◽  
Novel Target

Abstract Infections due to Streptococcus pneumoniae, a commensal in the nasopharynx, still claim a significant number of lives worldwide. Genetic plasticity, antibiotic resistance, limited serotype coverage of the available polysaccharide-based conjugate vaccines confounds therapeutic interventions. Pathogenic systems that allow successful adaption and persistence in the host could be potential innovative targets for mediations. Polyamines are ubiquitous polycationic molecules and regulate many cellular processes. We previously reported that deletion of potABCD, an operon that encodes a putrescine/spermidine transporter (∆potABCD), resulted in an un-encapsulated attenuated phenotype. Here we characterize the transcriptome, metabolome, and stress responses of S. pneumoniae that is dependent on the polyamine transporter. Expression of genes involved in oxidative stress responses and the central metabolism was reduced while that of genes involved in the Leloir, tagatose, and pentose phosphate pathways was increased in ΔpotABCD. Downregulation of genes of the central metabolism will reduce production of precursors of capsule polysaccharides. Metabolomics results show reduced glutathione and pyruvate levels in the mutant. We also show that the potABCD operon protects pneumococci against hydrogen peroxide and nitrosative stress. These results show the importance of the potABCD operon and polyamine transport in pneumococcal physiology and fitness that represents a novel target for therapeutic interventions.

scholarly journals Methane and Inflammation - A Review (Fight Fire with Fire)

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Marietta Zita Poles ◽  
László Juhász ◽  
Mihály Boros
Keyword(s):  
Stress Responses ◽  
Nitrosative Stress ◽  
Ischemia Reperfusion ◽  
Signalling Pathways ◽  
Experimental Conditions ◽  
Neuroprotective Effects ◽  
Oxidative And Nitrosative Stress ◽  
Carbohydrate Fermentation ◽  
Insight Into

AbstractMammalian methanogenesis is regarded as an indicator of carbohydrate fermentation by anaerobic gastrointestinal flora. Once generated by microbes or released by a non-bacterial process, methane is generally considered to be biologically inactive. However, recent studies have provided evidence for methane bioactivity in various in vivo settings. The administration of methane either in gas form or solutions has been shown to have anti-inflammatory and neuroprotective effects in an array of experimental conditions, such as ischemia/reperfusion, endotoxemia and sepsis. It has also been demonstrated that exogenous methane influences the key regulatory mechanisms and cellular signalling pathways involved in oxidative and nitrosative stress responses. This review offers an insight into the latest findings on the multi-faceted organ protective activity of exogenous methane treatments with special emphasis on its versatile effects demonstrated in sepsis models.

scholarly journals Bioactivity of Inhaled Methane and Interactions With Other Biological Gases

2022 ◽  
Vol 9 ◽  
Author(s):  
László Juhász ◽  
Szabolcs Péter Tallósy ◽  
Anna Nászai ◽  
Gabriella Varga ◽  
Dániel Érces ◽  
...  
Keyword(s):  
Stress Responses ◽  
Mitochondrial Respiration ◽  
Nitrosative Stress ◽  
Oxidative And Nitrosative Stress ◽  
Key Events

A number of studies have demonstrated explicit bioactivity for exogenous methane (CH4), even though it is conventionally considered as physiologically inert. Other reports cited in this review have demonstrated that inhaled, normoxic air-CH4 mixtures can modulate the in vivo pathways involved in oxidative and nitrosative stress responses and key events of mitochondrial respiration and apoptosis. The overview is divided into two parts, the first being devoted to a brief review of the effects of biologically important gases in the context of hypoxia, while the second part deals with CH4 bioactivity. Finally, the consequence of exogenous, normoxic CH4 administration is discussed under experimental hypoxia- or ischaemia-linked conditions and in interactions between CH4 and other biological gases, with a special emphasis on its versatile effects demonstrated in pulmonary pathologies.

scholarly journals Peripheral Insulin Regulates a Broad Network of Gene Expression in the Hypothalamus, Hippocampus and Nucleus Accumbens

2021 ◽  
Author(s):  
Weikang Cai ◽  
Xuemei Zhang ◽  
Thiago M. Batista ◽  
Rubén García-Martín ◽  
Samir Softic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nucleus Accumbens ◽  
Cholesterol Biosynthesis ◽  
Peripheral Circulation ◽  
Fatty Acyl ◽  
Pentose Phosphate ◽  
Gaba A ◽  
Expression Of Genes ◽  
Pentose Phosphate Pathways ◽  
The Brain

The brain is now recognized as an insulin sensitive tissue, however, the role of changing insulin concentrations in the peripheral circulation on gene expression in the brain is largely unknown. Here we perform hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 hours. We show that increases in peripheral insulin within the physiological range regulate expression of a broad network of gene expression in the brain compared with saline-infused controls. Insulin regulates distinct pathways in the hypothalamus, hippocampus and nucleus accumbens. Insulin shows its most robust effect in the hypothalamus and regulates multiple genes involved in neurotransmission, including up-regulating expression of multiple subunits of GABA-A receptors, Na<sup>+</sup> and K<sup>+</sup> channels, and SNARE proteins; differentially modulating glutamate receptors; and suppressing multiple neuropeptides. Insulin also strongly modulates metabolic genes in the hypothalamus, suppressing genes in the glycolysis and pentose phosphate pathways, while increasing expression of genes regulating pyruvate dehydrogenase and long-chain fatty acyl-CoA and cholesterol biosynthesis, thereby rerouting of carbon substrates from glucose metabolism to lipid metabolism required for the biogenesis of membranes for neuronal and glial function and synaptic remodeling. Furthermore, based on the transcriptional signatures, these changes in gene expression involve neurons, astrocytes, oligodendrocytes, microglia and endothelial cells. Thus, peripheral insulin acutely and potently regulates expression of a broad network of genes involved in neurotransmission and brain metabolism. Dysregulation of these pathways could have dramatic effects in normal physiology and diabetes.

scholarly journals The effects of fructose and metabolic inhibition on hepatocellular carcinoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Brittany Dewdney ◽  
Mohammed Alanazy ◽  
Rhys Gillman ◽  
Sarah Walker ◽  
Miriam Wankell ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Metabolism ◽  
Pentose Phosphate ◽  
Metabolic Effects ◽  
Alcoholic Fatty Liver ◽  
Highly Active ◽  
Pentose Phosphate Pathways ◽  
Glycine Synthesis

Abstract Hepatocellular carcinoma is rapidly becoming one of the leading causes of cancer-related deaths, largely due to the increasing incidence of non-alcoholic fatty liver disease. This in part may be attributed to Westernised diets high in fructose sugar. While many studies have shown the effects of fructose on inducing metabolic-related liver diseases, little research has investigated the effects of fructose sugar on liver cancer metabolism. The present study aimed to examine the metabolic effects of fructose on hepatocellular carcinoma growth in vitro and in vivo. Fructose sugar was found to reduce cell growth in vitro, and caused alterations in the expression of enzymes involved in the serine-glycine synthesis and pentose phosphate pathways. These biosynthesis pathways are highly active in cancer cells and they utilise glycolytic by-products to produce energy and nucleotides for growth. Hence, the study further investigated the efficacy of two novel drugs that inhibit these pathways, namely NCT-503 and Physcion. The study is the first to show that the combination treatment of NCT-503 and Physcion substantially inhibited hepatocellular carcinoma growth in vitro and in vivo. The combination of fructose diet and metabolism-inhibiting drugs may provide a unique metabolic environment that warrants further investigation in targeting hepatocellular carcinoma.

scholarly journals OsnR is an autoregulatory negative transcription factor controlling redox-dependent stress responses in Corynebacterium glutamicum

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Haeri Jeong ◽  
Younhee Kim ◽  
Heung-Shick Lee
Keyword(s):  
Oxidative Stress ◽  
Corynebacterium Glutamicum ◽  
Stress Responses ◽  
Promoter Region ◽  
Underlying Mechanism ◽  
In Vitro Assays ◽  
Expression Of Genes

Abstract Background Corynebacterium glutamicum is used in the industrial production of amino acids and nucleotides. During the course of fermentation, C. glutamicum cells face various stresses and employ multiple regulatory genes to cope with the oxidative stress. The osnR gene plays a negative regulatory role in redox-dependent oxidative-stress responses, but the underlying mechanism is not known yet. Results Overexpression of the osnR gene in C. glutamicum affected the expression of genes involved in the mycothiol metabolism. ChIP-seq analysis revealed that OsnR binds to the promoter region of multiple genes, including osnR and cg0026, which seems to function in the membrane-associated redox metabolism. Studies on the role of the osnR gene involving in vitro assays employing purified OsnR proteins and in vivo physiological analyses have identified that OsnR inhibits the transcription of its own gene. Further, oxidant diamide stimulates OsnR-binding to the promoter region of the osnR gene. The genes affected by the overexpression of osnR have been found to be under the control of σH. In the osnR-overexpressing strain, the transcription of sigH is significantly decreased and the stimulation of sigH transcription by external stress is lost, suggesting that osnR and sigH form an intimate regulatory network. Conclusions Our study suggests that OsnR not only functions as a transcriptional repressor of its own gene and of those involved in redox-dependent stress responses but also participates in the global transcriptional regulation by controlling the transcription of other master regulators, such as sigH.

scholarly journals Peroxynitrite is essential for the initiation of cytomegalovirus replication in vitro and in vivo

2020 ◽  
Vol 2 (7A) ◽  
Author(s):  
Pragati Sabberwal ◽  
Lucy Chapman ◽  
Mathew Clement ◽  
Ceri Fielding ◽  
David Thomas ◽  
...  
Keyword(s):  
Virus Replication ◽  
Stress Responses ◽  
Nitrosative Stress ◽  
Hcmv Infection ◽  
Antiviral Drug ◽  
Congenital Infection ◽  
Cmv Infection ◽  
Novel Approach

Human cytomegalovirus (HCMV) is a pathogenic beta-herpesvirus that establishes a lifelong infection in hosts. It causes significant morbidity and mortality in the immunocompromised and is associated with a range of birth defects following congenital infection. Current therapeutic approaches that target key viral proteins are toxic and antiviral drug resistance is common. Thus, targeting host genes and cellular pathways essential for HCMV infection offers an alternative strategy for the development of antivirals. Here we show that host oxidative/nitrosative stress responses to CMV are critical for virus replication. Oxidative/nitrosative stress occurs due to accumulation of reactive oxygen/nitrogen species (ROS/RNS). Using a range of ROS/RNS scavengers, we identified that peroxynitrite, a powerful oxidant and nitrating agent, dramatically promoted virus replication in both in vitro and in vivo models of CMV infection. HCMV rapidly induced production of intracellular peroxynitrite upon infection. Inhibition of peroxynitrite within the first 24 hours alleviates efficient HCMV infection in both cell-free and cell-associated infection systems, indicating that peroxynitrite may influence pathways necessary for HCMV entry and/or replication. Furthermore, peroxynitrite inhibition also inhibited HCMV reactivation from latency. Interestingly, the neurotransmitter and naturally-occurring peroxynitrite antagonist 5-hydroxytryptamine, commonly known as serotonin, also impinged on HCMV-induced peroxynitrite production and exhibited anti-HCMV activity. Thus, overall, our study demonstrates a novel role for intracellular peroxynitrite in CMV pathogenesis and implies that peroxynitrite could be targeted as a novel approach to inhibiting CMV infection.

scholarly journals Peripheral Insulin Regulates a Broad Network of Gene Expression in the Hypothalamus, Hippocampus and Nucleus Accumbens

2021 ◽  
Author(s):  
Weikang Cai ◽  
Xuemei Zhang ◽  
Thiago M. Batista ◽  
Rubén García-Martín ◽  
Samir Softic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nucleus Accumbens ◽  
Cholesterol Biosynthesis ◽  
Peripheral Circulation ◽  
Fatty Acyl ◽  
Pentose Phosphate ◽  
Gaba A ◽  
Expression Of Genes ◽  
Pentose Phosphate Pathways ◽  
The Brain

The brain is now recognized as an insulin sensitive tissue, however, the role of changing insulin concentrations in the peripheral circulation on gene expression in the brain is largely unknown. Here we perform hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 hours. We show that increases in peripheral insulin within the physiological range regulate expression of a broad network of gene expression in the brain compared with saline-infused controls. Insulin regulates distinct pathways in the hypothalamus, hippocampus and nucleus accumbens. Insulin shows its most robust effect in the hypothalamus and regulates multiple genes involved in neurotransmission, including up-regulating expression of multiple subunits of GABA-A receptors, Na<sup>+</sup> and K<sup>+</sup> channels, and SNARE proteins; differentially modulating glutamate receptors; and suppressing multiple neuropeptides. Insulin also strongly modulates metabolic genes in the hypothalamus, suppressing genes in the glycolysis and pentose phosphate pathways, while increasing expression of genes regulating pyruvate dehydrogenase and long-chain fatty acyl-CoA and cholesterol biosynthesis, thereby rerouting of carbon substrates from glucose metabolism to lipid metabolism required for the biogenesis of membranes for neuronal and glial function and synaptic remodeling. Furthermore, based on the transcriptional signatures, these changes in gene expression involve neurons, astrocytes, oligodendrocytes, microglia and endothelial cells. Thus, peripheral insulin acutely and potently regulates expression of a broad network of genes involved in neurotransmission and brain metabolism. Dysregulation of these pathways could have dramatic effects in normal physiology and diabetes.

scholarly journals Comprehensive metabolomic study of the response of HK-2 cells to hyperglycemic hypoxic diabetic-like milieu

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alberto Valdés ◽  
Francisco J. Lucio-Cazaña ◽  
María Castro-Puyana ◽  
Coral García-Pastor ◽  
Oliver Fiehn ◽  
...  
Keyword(s):  
High Glucose ◽  
Human Cell Line ◽  
Pentose Phosphate ◽  
Extracellular Medium ◽  
Relevant Role ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Pentose Phosphate Pathways ◽  
Metabolomic Study

AbstractDiabetic nephropathy (DN) is the leading cause of chronic kidney disease. Although hyperglycaemia has been determined as the most important risk factor, hypoxia also plays a relevant role in the development of this disease. In this work, a comprehensive metabolomic study of the response of HK-2 cells, a human cell line derived from normal proximal tubular epithelial cells, to hyperglycemic, hypoxic diabetic-like milieu has been performed. Cells simultaneously exposed to high glucose (25 mM) and hypoxia (1% O2) were compared to cells in control conditions (5.5 mM glucose/18.6% O2) at 48 h. The combination of advanced metabolomic platforms (GC-TOF MS, HILIC- and CSH-QExactive MS/MS), freely available metabolite annotation tools, novel databases and libraries, and stringent cut-off filters allowed the annotation of 733 metabolites intracellularly and 290 compounds in the extracellular medium. Advanced bioinformatics and statistical tools demonstrated that several pathways were significantly altered, including carbohydrate and pentose phosphate pathways, as well as arginine and proline metabolism. Other affected metabolites were found in purine and lipid metabolism, the protection against the osmotic stress and the prevention of the activation of the β-oxidation pathway. Overall, the effects of the combined exposure of HK-cells to high glucose and hypoxia are reasonably compatible with previous in vivo works.

Antioxidant and bioenergetic coupling between neurons and astrocytes

2012 ◽  
Vol 443 (1) ◽  
pp. 3-11 ◽  
Author(s):  
Seila Fernandez-Fernandez ◽  
Angeles Almeida ◽  
Juan P. Bolaños
Keyword(s):  
Nitrosative Stress ◽  
Pentose Phosphate ◽  
Therapeutic Interventions ◽  
Biochemical Mechanism ◽  
Intercellular Coupling ◽  
Antioxidant Defence ◽  
Oxidative And Nitrosative Stress ◽  
Novel Targets ◽  
The Brain ◽  
Reduced State

Oxidative and nitrosative stress underlie the pathogenesis of a broad range of human diseases, in particular neurodegenerative disorders. Within the brain, neurons are the cells most vulnerable to excess reactive oxygen and nitrogen species; their survival relies on the antioxidant protection promoted by neighbouring astrocytes. However, neurons are also intrinsically equipped with a biochemical mechanism that links glucose metabolism to antioxidant defence. Neurons actively metabolize glucose through the pentose phosphate pathway, which maintains the antioxidant glutathione in its reduced state, hence exerting neuroprotection. This process is tightly controlled by a key glycolysis-promoting enzyme and is dependent on an appropriate supply of energy substrates from astrocytes. Thus brain bioenergetic and antioxidant defence is coupled between neurons and astrocytes. A better understanding of the regulation of this intercellular coupling should be important for identifying novel targets for future therapeutic interventions.

Sign in / Sign up

Export Citation Format

Share Document