scholarly journals Proline metabolism and redox; maintaining a balance in health and disease

Amino Acids ◽  
2021 ◽  
Author(s):  
Lisa A. Vettore ◽  
Rebecca L. Westbrook ◽  
Daniel A. Tennant
Keyword(s):  
De Novo ◽  
Redox Homeostasis ◽  
Protein Structures ◽  
Treatment Strategies ◽  
Proline Metabolism ◽  
Cancer Proliferation ◽  
Cellular Redox ◽  
Proline Catabolism ◽  
Health And Disease ◽  
The Impact

AbstractProline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources, generated de novo within cells, and released from protein structures; a noteworthy source being collagen. Its catabolism within cells can generate ATP and reactive oxygen species (ROS). Recent findings suggest that proline biosynthesis and catabolism are essential processes in disease; not only due to the role in new protein synthesis as part of pathogenic processes but also due to the impact of proline metabolism on the wider metabolic network through its significant role in redox homeostasis. This is particularly clear in cancer proliferation and metastatic outgrowth. Nevertheless, the precise identity of the drivers of cellular proline catabolism and biosynthesis, and the overall cost of maintaining appropriate balance is not currently known. In this review, we explore the major drivers of proline availability and consumption at a local and systemic level with a focus on cancer. Unraveling the main factors influencing proline metabolism in normal physiology and disease will shed light on new effective treatment strategies.

scholarly journals Genomics of circadian rhythms in health and disease

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Filipa Rijo-Ferreira ◽  
Joseph S. Takahashi
Keyword(s):  
Genetic Regulation ◽  
Treatment Strategies ◽  
Circadian System ◽  
Chromosome Organization ◽  
Metabolic Function ◽  
Genome Wide ◽  
Circadian Control ◽  
Health And Disease ◽  
Genomic Regulation ◽  
The Impact

AbstractCircadian clocks are endogenous oscillators that control 24-h physiological and behavioral processes. The central circadian clock exerts control over myriad aspects of mammalian physiology, including the regulation of sleep, metabolism, and the immune system. Here, we review advances in understanding the genetic regulation of sleep through the circadian system, as well as the impact of dysregulated gene expression on metabolic function. We also review recent studies that have begun to unravel the circadian clock’s role in controlling the cardiovascular and nervous systems, gut microbiota, cancer, and aging. Such circadian control of these systems relies, in part, on transcriptional regulation, with recent evidence for genome-wide regulation of the clock through circadian chromosome organization. These novel insights into the genomic regulation of human physiology provide opportunities for the discovery of improved treatment strategies and new understanding of the biological underpinnings of human disease.

scholarly journals Loop size optimization: a new mechanism for protein stabilization

2016 ◽  
Author(s):  
Alessia Ruggiero ◽  
Nicole Balasco ◽  
Luciana Esposito ◽  
Luigi Vitagliano
Keyword(s):  
Secondary Structure ◽  
De Novo ◽  
Protein Structures ◽  
Protein Stabilization ◽  
Statistical Analyses ◽  
Fine Tuning ◽  
Marginal Stability ◽  
Loop Size ◽  
Thermophilic Organisms ◽  
The Impact

Motivation One of the fundamental issues in both chemistry and biology is the identification of the structural determinants that dictate protein folding and stability. The decoding of the folding code of protein structures would have a major impact on native structure prediction and on de novo design. This task is particularly difficult to achieve. Unlike synthetic polymers, protein structures combine complexity, fine-tuning and marginal stability. Despite these difficulties, in recent years major progresses have been made. A very recent breakthrough in the field is represented by the discovery of Baker and colleagues that the juxtaposition of basic secondary structure elements (α-helices and β-strands) follows well-defined rules ( Koga et al., 2012 ) . These investigations identified three fundamental rules for the preferences of βℓβ (strand-loop-strand), αℓβ (helix-loop-strand) and βℓα (strand-loop-helix) structural motifs. In particular, it was shown that the chirality of βℓβ and the orientation of βℓα/αℓβ strongly depend on the loop size. In this framework, we evaluated the impact of these rules on protein structures isolated from either (hyper)thermophilic or mesophilic organisms. We used the thioredoxin (Trx) system to experimentally validate the results emerged from the statistical analyses. Methods Statistical surveys Our statistical survey was based on the analyses of different structural databases made of proteins isolated from mesophilic or thermophilic organisms by assuming that the proteins of thermophilic species were on average more stable than those isolated from mesophilic ones. The adherence of these proteins to the rules identified by Baker and coworkers was evaluated. Experiments Wild-type E. coli Trx and a series of ad-hoc mutants were expressed and purified. The stability of these proteins was evaluated by CD spectroscopy. The structure of these variants was determined by X-ray crystallography. Results The statistical analyses indicate that in proteins isolated from thermophilic organisms better adhere to the Baker rules through the optimization of the size of the loop connecting secondary structure elements ( Balasco et al., 2013 ) . We then experimentally validated this mechanism using the thioredoxin isolated from E.coli (EcTrx), a widely characterized protein that has been used as a model in a large number of investigations ( Esposito et al., 2012 , Ruggiero et al., 2009 ) . Comparative analyses of loop sizes between EcTrx and Trx isolated from hyperthermophiles suggested that the size loop connecting helix 1 (α1) to strand 2 (β2) in EcTrx could be modified to better follow the rules. Chimeric variants were therefore prepared by replacing the loop of EcTrx with the corresponding ones present in the Trx isolated from Sulfolobus solfataricus and S. tokodaii. Abstract truncated at 3,000 characters - the full version is available in the pdf file

scholarly journals Loop size optimization: a new mechanism for protein stabilization

2016 ◽  
Author(s):  
Alessia Ruggiero ◽  
Nicole Balasco ◽  
Luciana Esposito ◽  
Luigi Vitagliano
Keyword(s):  
Secondary Structure ◽  
De Novo ◽  
Protein Structures ◽  
Protein Stabilization ◽  
Statistical Analyses ◽  
Fine Tuning ◽  
Marginal Stability ◽  
Loop Size ◽  
Thermophilic Organisms ◽  
The Impact

Motivation One of the fundamental issues in both chemistry and biology is the identification of the structural determinants that dictate protein folding and stability. The decoding of the folding code of protein structures would have a major impact on native structure prediction and on de novo design. This task is particularly difficult to achieve. Unlike synthetic polymers, protein structures combine complexity, fine-tuning and marginal stability. Despite these difficulties, in recent years major progresses have been made. A very recent breakthrough in the field is represented by the discovery of Baker and colleagues that the juxtaposition of basic secondary structure elements (α-helices and β-strands) follows well-defined rules ( Koga et al., 2012 ) . These investigations identified three fundamental rules for the preferences of βℓβ (strand-loop-strand), αℓβ (helix-loop-strand) and βℓα (strand-loop-helix) structural motifs. In particular, it was shown that the chirality of βℓβ and the orientation of βℓα/αℓβ strongly depend on the loop size. In this framework, we evaluated the impact of these rules on protein structures isolated from either (hyper)thermophilic or mesophilic organisms. We used the thioredoxin (Trx) system to experimentally validate the results emerged from the statistical analyses. Methods Statistical surveys Our statistical survey was based on the analyses of different structural databases made of proteins isolated from mesophilic or thermophilic organisms by assuming that the proteins of thermophilic species were on average more stable than those isolated from mesophilic ones. The adherence of these proteins to the rules identified by Baker and coworkers was evaluated. Experiments Wild-type E. coli Trx and a series of ad-hoc mutants were expressed and purified. The stability of these proteins was evaluated by CD spectroscopy. The structure of these variants was determined by X-ray crystallography. Results The statistical analyses indicate that in proteins isolated from thermophilic organisms better adhere to the Baker rules through the optimization of the size of the loop connecting secondary structure elements ( Balasco et al., 2013 ) . We then experimentally validated this mechanism using the thioredoxin isolated from E.coli (EcTrx), a widely characterized protein that has been used as a model in a large number of investigations ( Esposito et al., 2012 , Ruggiero et al., 2009 ) . Comparative analyses of loop sizes between EcTrx and Trx isolated from hyperthermophiles suggested that the size loop connecting helix 1 (α1) to strand 2 (β2) in EcTrx could be modified to better follow the rules. Chimeric variants were therefore prepared by replacing the loop of EcTrx with the corresponding ones present in the Trx isolated from Sulfolobus solfataricus and S. tokodaii. Abstract truncated at 3,000 characters - the full version is available in the pdf file

Long-term prognosis of de novo atrial fibrillation during acute myocardial infarction: the impact of anti-thrombotic treatment strategies

2020 ◽  
Author(s):  
Felix Hofer ◽  
Niema Kazem ◽  
Andreas Hammer ◽  
Feras El-Hamid ◽  
Lorenz Koller ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Atrial Fibrillation ◽  
Acute Myocardial Infarction ◽  
Cardiovascular Mortality ◽  
Patient Population ◽  
De Novo ◽  
Treatment Strategies ◽  
Increased Risk ◽  
The Impact

Abstract Aims While the prognosis of patients presenting with de novo atrial fibrillation (AF) during the acute phase of myocardial infarction has been controversially discussed, it seems intuitive that affected individuals have an increased risk for both thrombo-embolic events and mortality. However, profound data on long-term outcome of this highly vulnerable patient population are not available in current literature. Therefore, we aimed to investigate the impact of de novo AF and associated anti-thrombotic treatment strategies on the patient outcome from a long-term perspective. Methods and results Patients presenting with acute myocardial infarction, treated at the Medical University of Vienna, were enrolled within a clinical registry and screened for the development of de novo AF. After discharge, participants were followed prospectively over a median time of 8.6 years. Primary study endpoint was defined as cardiovascular mortality. Out of 1372 enrolled individuals 149 (10.9%) developed de novo AF during the acute phase of acute myocardial infarction. After a median follow-up time of 8.6 years, a total of 418 (30.5%) died due to cardiovascular causes, including 93 (62.4%) in the de novo AF subgroup. We found that de novo AF was significantly associated with long-term cardiovascular mortality with an adjusted HR of 1.45 (95% CI 1.19–2.57; P < 0.001). While patients with de novo AF were less likely to receive a triple anti-thrombotic therapy as compared to patients with pre-existing AF at time of discharge, this therapeutic approach showed a strong and inverse association with mortality in de novo AF, with an adj. HR of 0.86 (95% CI 0.45–0.92; P = 0.012). Conclusion De novo AF was independently associated with a poor prognosis with a 67% increased risk of long-term cardiovascular mortality. Intensified anti-thrombotic treatment in this high-risk patient population might be considered.

scholarly journals Leaf status and environmental signals jointly regulate proline metabolism in winter oilseed rape

2019 ◽  
Vol 71 (6) ◽  
pp. 2098-2111 ◽  
Author(s):  
Younes Dellero ◽  
Vanessa Clouet ◽  
Nathalie Marnet ◽  
Anthoni Pellizzaro ◽  
Sylvain Dechaumet ◽  
...  
Keyword(s):  
De Novo ◽  
Reproductive Organs ◽  
Vegetative Stage ◽  
Proline Metabolism ◽  
Proline Biosynthesis ◽  
Nitrogen Remobilization ◽  
Environmental Signals ◽  
Proline Catabolism ◽  
Multiple Processes ◽  
Developmental Phases

Abstract Proline metabolism is an essential component of plant adaptation to multiple environmental stress conditions that is also known to participate in specific developmental phases, particularly in reproductive organs. Recent evidence suggested a possible role for proline catabolism in Brassica napus for nitrogen remobilization processes from source leaves at the vegetative stage. Here, we investigate transcript levels of Δ1-PYRROLINE-5-CARBOXYLATE SYNTHASE (P5CS) and PROLINE DEHYDROGENASE (ProDH) genes at the vegetative stage with respect to net proline biosynthesis and degradation fluxes in leaves having a different sink/source balance. We showed that the underexpression of three P5CS1 genes in source leaves was accompanied by a reduced commitment of de novo assimilated 15N towards proline biosynthesis and an overall depletion of free proline content. We found that the expression of ProDH genes was strongly induced by carbon starvation conditions (dark-induced senescence) compared with early senescing leaves. Our results suggested a role for proline catabolism in B. napus, but acting only at a late stage of senescence. In addition, we also identified some P5CS and ProDH genes that were differentially expressed during multiple processes (leaf status, dark to light transition, and stress response).

scholarly journals Redox Systems in Botrytis cinerea: Impact on Development and Virulence

2014 ◽  
Vol 27 (8) ◽  
pp. 858-874 ◽  
Author(s):  
Anne Viefhues ◽  
Jens Heller ◽  
Nora Temme ◽  
Paul Tudzynski
Keyword(s):  
Botrytis Cinerea ◽  
Redox Homeostasis ◽  
Thioredoxin Reductase ◽  
Redox System ◽  
Redox Status ◽  
Redox Systems ◽  
Gene Encoding ◽  
Cellular Redox ◽  
Thioredoxin System ◽  
The Impact

The thioredoxin system is of great importance for maintenance of cellular redox homeostasis. Here, we show that it has a severe influence on virulence of Botrytis cinerea, demonstrating that redox processes are important for host-pathogen interactions in this necrotrophic plant pathogen. The thioredoxin system is composed of two enzymes, the thioredoxin and the thioredoxin reductase. We identified two genes encoding for thioredoxins (bctrx1, bctrx2) and one gene encoding for a thioredoxin reductase (bctrr1) in the genome of B. cinerea. Knockout mutants of bctrx1 and bctrr1 were severely impaired in virulence and more sensitive to oxidative stress. Additionally, Δbctrr1 showed enhanced H2O2 production and retarded growth. To investigate the impact of the second major cellular redox system, glutathione, we generated deletion mutants for two glutathione reductase genes. The effects were only marginal; deletion of bcglr1 resulted in reduced germination and, correspondingly, to retarded infection as well as reduced growth on minimal medium, whereas bcglr2 deletion had no distinctive phenotype. In summary, we showed that the balanced redox status maintained by the thioredoxin system is essential for development and pathogenesis of B. cinerea, whereas the second major cellular redox system, the glutathione system, seems to have only minor impact on these processes.

scholarly journals PsyMuKB: A De Novo Variant Knowledge Base Integrating Transcriptional and Translational Information to Identify Isoform-specific Mutations in Developmental Disorders

2019 ◽  
Author(s):  
Guan Ning Lin ◽  
Sijia Guo ◽  
Xian Tan ◽  
Weidi Wang ◽  
Wei Qian ◽  
...  
Keyword(s):  
Knowledge Base ◽  
Protein Interactions ◽  
Developmental Disorders ◽  
De Novo ◽  
Genetic Disorders ◽  
Expression Patterns ◽  
Protein Structures ◽  
Autism Spectrum ◽  
Functional Studies ◽  
The Impact

AbstractDe novo variants (DNVs) are one of the most significant contributors to severe early-onset genetic disorders such as autism spectrum disorder, intellectual disability, and other developmental and neuropsychiatric (DNP) disorders. Currently, a plethora of DNVs have being identified through the use of next-generation sequencing and much effort has been made to understand their impact at the gene level; however, there has been little exploration of the impact at the isoform level. The brain contains a high level of alternative splicing and regulation, and exhibits a more divergent splicing program than other tissues; therefore, it is crucial to explore variants at the transcriptional regulation level to better interpret the mechanisms underlying DNP disorders. To facilitate better usage and improve the isoform-level interpretation of variants, we developed the PsyMuKB (NeuroPsychiatric Mutation Knowledge Base), a knowledge base containing a comprehensive, carefully curated list of DNVs with transcriptional and translational annotations to enable identification of isoform-specific mutations. PsyMuKB allows a flexible search of genes or variants and provides both table-based descriptions and associated visualizations, such as expression, transcript genomic structures, protein interactions, and the mutation sites mapped on the protein structures. It also provides an easy-to-use web interface, allowing users to rapidly visualize the locations and characteristics of mutations and the expression patterns of the impacted genes and isoforms. PsyMuKB thus constitutes a valuable resource for identifying tissue-specific de novo mutations for further functional studies of related disorders. PsyMuKB is freely accessible at http://psymukb.net.

Drug Induced Changes in Cell Organelles

1968 ◽  
Vol 26 ◽  
pp. 110-111
Author(s):  
Sarah A. Luse
Keyword(s):  
Clinical Medicine ◽  
Cell Organelles ◽  
Riboflavin Deficiency ◽  
Drug Induced ◽  
New Era ◽  
Health And Disease ◽  
In The Beginning ◽  
Cellular Pathology ◽  
Induced Changes ◽  
The Impact

In the mid-nineteenth century Virchow revolutionized pathology by introduction of the concept of “cellular pathology”. Today, a century later, this term has increasing significance in health and disease. We now are in the beginning of a new era in pathology, one which might well be termed “organelle pathology” or “subcellular pathology”. The impact of lysosomal diseases on clinical medicine exemplifies this role of pathology of organelles in elucidation of disease today.Another aspect of cell organelles of prime importance is their pathologic alteration by drugs, toxins, hormones and malnutrition. The sensitivity of cell organelles to minute alterations in their environment offers an accurate evaluation of the site of action of drugs in the study of both function and toxicity. Examples of mitochondrial lesions include the effect of DDD on the adrenal cortex, riboflavin deficiency on liver cells, elevated blood ammonia on the neuron and some 8-aminoquinolines on myocardium.

The Laryngeal Epithelium in Reflux

2011 ◽  
Vol 21 (3) ◽  
pp. 112-117 ◽  
Author(s):  
Elizabeth Erickson-Levendoski ◽  
Mahalakshmi Sivasankar
Keyword(s):  
Laryngopharyngeal Reflux ◽  
Critical Role ◽  
Structure And Function ◽  
Laryngeal Disease ◽  
Health And Disease ◽  
And Function ◽  
The Impact

The epithelium plays a critical role in the maintenance of laryngeal health. This is evident in that laryngeal disease may result when the integrity of the epithelium is compromised by insults such as laryngopharyngeal reflux. In this article, we will review the structure and function of the laryngeal epithelium and summarize the impact of laryngopharyngeal reflux on the epithelium. Research investigating the ramifications of reflux on the epithelium has improved our understanding of laryngeal disease associated with laryngopharyngeal reflux. It further highlights the need for continued research on the laryngeal epithelium in health and disease.

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