Implications of plasma thiol redox in disease

2018 ◽  
Vol 132 (12) ◽  
pp. 1257-1280 ◽  
Author(s):  
Percíllia V.S. Oliveira ◽  
Francisco R.M. Laurindo
Keyword(s):  
Disease Risk ◽  
Relevant Information ◽  
Water Soluble ◽  
Clear Cut ◽  
Disease States ◽  
Oxidation Reduction ◽  
Age Related ◽  
Thiol Redox ◽  
Intrinsic Reactivity ◽  
Thiol Proteins

Thiol groups are crucially involved in signaling/homeostasis through oxidation, reduction, and disulphide exchange. The overall thiol pool is the resultant of several individual pools of small compounds (e.g. cysteine), peptides (e.g. glutathione), and thiol proteins (e.g. thioredoxin (Trx)), which are not in equilibrium and present specific oxidized/reduced ratios. This review addresses mechanisms and implications of circulating plasma thiol/disulphide redox pools, which are involved in several physiologic processes and explored as disease biomarkers. Thiol pools are regulated by mechanisms linked to their intrinsic reactivity against oxidants, concentration of antioxidants, thiol-disulphide exchange rates, and their dynamic release/removal from plasma. Major thiol couples determining plasma redox potential (Eh) are reduced cysteine (CyS)/cystine (the disulphide form of cysteine) (CySS), followed by GSH/disulphide-oxidized glutathione (GSSG). Hydrogen peroxide and hypohalous acids are the main plasma oxidants, while water-soluble and lipid-soluble small molecules are the main antioxidants. The thiol proteome and thiol-oxidoreductases are emerging investigative areas given their specific disease-related responses (e.g. protein disulphide isomerases (PDIs) in thrombosis). Plasma cysteine and glutathione redox couples exhibit pro-oxidant changes directly correlated with ageing/age-related diseases. We further discuss changes in thiol-disulphide redox state in specific groups of diseases: cardiovascular, cancer, and neurodegenerative. These results indicate association with the disease states, although not yet clear-cut to yield specific biomarkers. We also highlight mechanisms whereby thiol pools affect atherosclerosis pathophysiology. Overall, it is unlikely that a single measurement provides global assessment of plasma oxidative stress. Rather, assessment of individual thiol pools and thiol-proteins specific to any given condition has more solid and logical perspective to yield novel relevant information on disease risk and prognosis.

scholarly journals The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Megan C. Bakeberg ◽  
Madison E. Hoes ◽  
Anastazja M. Gorecki ◽  
Frances Theunissen ◽  
Abigail L. Pfaff ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Symptom Onset ◽  
Disease Risk ◽  
Age Of Onset ◽  
Sequencing Analysis ◽  
Age Related ◽  
Australian Cohort ◽  
Progression Markers ◽  
Age Related Cognitive Decline

AbstractAbnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant ‘523’ poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 ‘523’ allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 ‘523’ and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 ‘523’ allele groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not after correction for covariates, or in the Australian cohort. Whilst variation in the TOMM40 ‘523’ polymorphism was not associated with PD risk, the possibility that it may be a modifying factor for age of symptom onset warrants further investigation in other PD populations.

scholarly journals Dietary Fiber, Atherosclerosis, and Cardiovascular Disease

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 1155 ◽  
Author(s):  
Ghada A. Soliman
Keyword(s):  
Cardiovascular Disease ◽  
Dietary Fiber ◽  
Water Solubility ◽  
Disease Risk ◽  
Current Knowledge ◽  
Digestive Enzyme ◽  
Water Soluble ◽  
Blood Cholesterol ◽  
Fiber Intake ◽  
Intestinal Transit Time

Observational studies have shown that dietary fiber intake is associated with decreased risk of cardiovascular disease. Dietary fiber is a non-digestible form of carbohydrates, due to the lack of the digestive enzyme in humans required to digest fiber. Dietary fibers and lignin are intrinsic to plants and are classified according to their water solubility properties as either soluble or insoluble fibers. Water-soluble fibers include pectin, gums, mucilage, fructans, and some resistant starches. They are present in some fruits, vegetables, oats, and barley. Soluble fibers have been shown to lower blood cholesterol by several mechanisms. On the other hand, water-insoluble fibers mainly include lignin, cellulose, and hemicellulose; whole-grain foods, bran, nuts, and seeds are rich in these fibers. Water-insoluble fibers have rapid gastric emptying, and as such may decrease the intestinal transit time and increase fecal bulk, thus promoting digestive regularity. In addition to dietary fiber, isolated and extracted fibers are known as functional fiber and have been shown to induce beneficial health effects when added to food during processing. The recommended daily allowances (RDAs) for total fiber intake for men and women aged 19–50 are 38 gram/day and 25 gram/day, respectively. It is worth noting that the RDA recommendations are for healthy people and do not apply to individuals with some chronic diseases. Studies have shown that most Americans do not consume the recommended intake of fiber. This review will summarize the current knowledge regarding dietary fiber, sources of food containing fiber, atherosclerosis, and heart disease risk reduction.

Information overload in business organizations and entrepreneurship: An analytical review of the literature

2021 ◽  
pp. 026638212110549
Author(s):  
CA(Dr.) Gaurav Bhambri
Keyword(s):  
Intelligent Agents ◽  
Information Overload ◽  
Personal Information ◽  
Management Strategies ◽  
Value Added ◽  
Relevant Information ◽  
Business Organizations ◽  
Professional Literature ◽  
Clear Cut ◽  
Paradoxical Situation

In this paper I analytically review the literature on the information overload problem, with special reference to the business organizations and entrepreneurship and the study mainly reveals that the problem of the information overload has been existed for many years, whereas in current years the problem has become more clearly recognized and experienced. A concern stressed in the literature is the paradoxical situation that most probably there is an abundance of information available and it is often difficult to obtain useful, and relevant information when it may be needed. Both perceptions and the actual effects of information overload have exacerbated by rapid advances made in the information and communication technology, whereas it is not clear cut as to whether Internet has worsened/improved the situation. Some solutions have put forward to reduce the information overload are a reduction in duplication of the information found in professional literature; the adoption of the personal information management strategies, along with the integration of software solutions such as push technology and intelligent agents; and the provision of value-added information. Main emphasis is placed on the technology as a tool and not driver, while increased in information literacy may provide key to reducing the information overload in organisations.

scholarly journals Kidney aging.Geriatric view

2021 ◽  
pp. 76-81
Author(s):  
L. I. Merkusheva ◽  
N. K. Runikhina ◽  
O. N. Tkacheva
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Structural Changes ◽  
Water Soluble ◽  
Older Age ◽  
Sodium Reabsorption ◽  
Tubular Atrophy ◽  
Age Related ◽  
Population Demographic

Individuals age >65 years old are the fastest expanding population demographic throughout the developed world. Consequently, more aged patients than before are receiving diagnoses of impaired renal function and nephrosclerosis. In this review, we examine these features of the aged kidney and explore the various validated and putative pathways contributing to the changes observed with aging. Senescence or normal physiologic aging portrays the expected age-related changes in the kidney as compared to chronic kidney disease (CKD) in some individuals. The microanatomical structural changes of the kidney with older age include a decreased number of functional glomeruli from an increased prevalence of nephrosclerosis (arteriosclerosis, glomerulosclerosis, and tubular atrophy with interstitialfibrosis), and to some extent, compensatory hypertrophy of remaining nephrons. Among the macroanatomical structural changes, older age associates with smaller cortical volume. There is reason to be concerned that the elderly are being misdiagnosed with CKD. In addition to the structural changes in the kidney associated with aging, physiological changes in renal function are also found in older adults, such as decreased glomerular filtration rate, vascular dysautonomia, altered tubular handling of creatinine, reduction in sodium reabsorption and potassium secretion, and diminished renal reserve. These alterations make aged individuals susceptible to the development of clinical conditions in response to usual stimuli that would otherwise be compensated for in younger individuals, including acute kidney injury, volume depletion and overload, disorders of serum sodium and potassium concentration, and toxic reactions to water -soluble drugs excreted by the kidneys. Additionally, the preservation with aging of a normal urinalysis, normal serum urea and creatinine values, erythropoietin synthesis, and normal phosphorus, calcium and magnesium tubular handling distinguishes decreased GFR due to normal aging from that due to chronic kidney disease.

scholarly journals Predicting COVID-19 Severity with a Specific Nucleocapsid Antibody plus Disease Risk Factor Score

mSphere ◽  
2021 ◽  
Vol 6 (2) ◽  
Author(s):  
Sanjana R. Sen ◽  
Emily C. Sanders ◽  
Kristin N. Gabriel ◽  
Brian M. Miller ◽  
Hariny M. Isoda ◽  
...  
Keyword(s):  
Risk Factor ◽  
Factor Score ◽  
Disease Risk ◽  
Severe Disease ◽  
Enzyme Linked Immunosorbent Assay ◽  
Disease Risk Factor ◽  
Disease States ◽  
Wide Range ◽  
Risk Factor Score ◽  
Prognostic Prediction

ABSTRACT Effective methods for predicting COVID-19 disease trajectories are urgently needed. Here, enzyme-linked immunosorbent assay (ELISA) and coronavirus antigen microarray (COVAM) analysis mapped antibody epitopes in the plasma of COVID-19 patients (n = 86) experiencing a wide range of disease states. The experiments identified antibodies to a 21-residue epitope from nucleocapsid (termed Ep9) associated with severe disease, including admission to the intensive care unit (ICU), requirement for ventilators, or death. Importantly, anti-Ep9 antibodies can be detected within 6 days post-symptom onset and sometimes within 1 day. Furthermore, anti-Ep9 antibodies correlate with various comorbidities and hallmarks of immune hyperactivity. We introduce a simple-to-calculate, disease risk factor score to quantitate each patient’s comorbidities and age. For patients with anti-Ep9 antibodies, scores above 3.0 predict more severe disease outcomes with a 13.42 likelihood ratio (96.7% specificity). The results lay the groundwork for a new type of COVID-19 prognostic to allow early identification and triage of high-risk patients. Such information could guide more effective therapeutic intervention. IMPORTANCE The COVID-19 pandemic has resulted in over two million deaths worldwide. Despite efforts to fight the virus, the disease continues to overwhelm hospitals with severely ill patients. Diagnosis of COVID-19 is readily accomplished through a multitude of reliable testing platforms; however, prognostic prediction remains elusive. To this end, we identified a short epitope from the SARS-CoV-2 nucleocapsid protein and also a disease risk factor score based upon comorbidities and age. The presence of antibodies specifically binding to this epitope plus a score cutoff can predict severe COVID-19 outcomes with 96.7% specificity.

scholarly journals Sexual dimorphism in the progression of type 2 diabetic kidney disease in T2DN rats

2021 ◽  
Author(s):  
Denisha R Spires ◽  
Oleg Palygin ◽  
Vladislav Levchenko ◽  
Elena Isaeva ◽  
Christine A. Klemens ◽  
...  
Keyword(s):  
Sexual Dimorphism ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Disease Risk ◽  
Plasma Cholesterol ◽  
Cardiovascular Disease Risk ◽  
Glomerular Injury ◽  
Diabetic Kidney ◽  
Age Related

Diabetic kidney disease (DKD) is a common complication of diabetes, which frequently leads to end-stage renal failure and increases cardiovascular disease risk. Hyperglycemia promotes renal pathologies such as glomerulosclerosis, tubular hypertrophy, microalbuminuria, and a decline in glomerular filtration rate. Importantly, recent clinical data have demonstrated distinct sexual dimorphism in the pathogenesis of DKD in people with diabetes, which impacts both severity- and age-related risk factors. This study aimed to define sexual dimorphism and renal function in a non-obese type 2 diabetes model with the spontaneous development of advanced diabetic nephropathy (T2DN rats). T2DN rats at 12- and over 48-weeks old were used to define disease progression and kidney injury development. We found impaired glucose tolerance and glomerular hyperfiltration in T2DN rats to compare with non-diabetic Wistar control. The T2DN rat displays a significant sexual dimorphism in insulin resistance, plasma cholesterol, renal and glomerular injury, urinary nephrin shedding, and albumin handling. Our results indicate that both male and female T2DN rats developed non-obese type 2 DKD phenotype, where the females had significant protection from the development of severe forms of DKD. Our findings provide further evidence for the T2DN rat strain's effectiveness for studying the multiple facets of DKD.

scholarly journals Electrophysiological Evidence for Preserved Primacy of Lexical Prediction in Normative Aging

2017 ◽  
Author(s):  
Shruti Dave ◽  
Trevor A. Brothers ◽  
Matthew J. Traxler ◽  
Fernanda Ferreira ◽  
John M. Henderson ◽  
...  
Keyword(s):  
Older Adults ◽  
Young Adults ◽  
Prediction Accuracy ◽  
Predictive Accuracy ◽  
Accurate Prediction ◽  
Self Report ◽  
Clear Cut ◽  
Age Related ◽  
Contextual Support ◽  
Normative Aging

Young adults show consistent neural benefits of predictable contexts when processing upcoming words, but these benefits are less clear-cut in older adults. Here we conduct two ERP experiments to examine whether aging uniquely affects neural correlates of prediction accuracy, as compared to contextual support independent of accuracy. In Experiment 1, readers were asked to predict sentence-final words and self-report prediction accuracy, allowing for separation of ERP effects of accurate prediction and contextual support. While N250 and N400 effects of accurate prediction were reduced in older readers, both temporal primacy and relative amplitudes of predictive compared to contextual processing were similar across age. In Experiment 2, participants read for comprehension without an overt prediction task and showed similar age-related declines in N400 amplitude across experiments. In both studies, older adults showed relatively larger frontal post-N400 positivities (PNPs) than young adults, suggesting age-graded differences in revision following unexpected items. Previous research suggests the production system may be linked to lexical prediction, but here we found that verbal fluency modulated PNP effects of contextual support, but not predictive accuracy. Taken together, our findings suggest that normative aging does not result in specific declines or boosts of lexical prediction.

scholarly journals Recurrent structural variation, clustered sites of selection, and disease risk for the complement factor H (CFH) gene family

2018 ◽  
Vol 115 (19) ◽  
pp. E4433-E4442 ◽  
Author(s):  
Stuart Cantsilieris ◽  
Bradley J. Nelson ◽  
John Huddleston ◽  
Carl Baker ◽  
Lana Harshman ◽  
...  
Keyword(s):  
Gene Family ◽  
Structural Variation ◽  
Disease Risk ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Primate Evolution ◽  
Factor H ◽  
Age Related Macular Degeneration ◽  
Complement Factor H ◽  
Complement Factor ◽  
Age Related

Structural variation and single-nucleotide variation of the complement factor H (CFH) gene family underlie several complex genetic diseases, including age-related macular degeneration (AMD) and atypical hemolytic uremic syndrome (AHUS). To understand its diversity and evolution, we performed high-quality sequencing of this ∼360-kbp locus in six primate lineages, including multiple human haplotypes. Comparative sequence analyses reveal two distinct periods of gene duplication leading to the emergence of fourCFH-related (CFHR) gene paralogs (CFHR2andCFHR4∼25–35 Mya andCFHR1andCFHR3∼7–13 Mya). Remarkably, all evolutionary breakpoints share a common ∼4.8-kbp segment corresponding to an ancestralCFHRgene promoter that has expanded independently throughout primate evolution. This segment is recurrently reused and juxtaposed with a donor duplication containing exons 8 and 9 from ancestralCFH, creating fourCFHRfusion genes that include lineage-specific members of the gene family. Combined analysis of >5,000 AMD cases and controls identifies a significant burden of a rare missense mutation that clusters at the N terminus ofCFH[P= 5.81 × 10−8, odds ratio (OR) = 9.8 (3.67-Infinity)]. A bipolar clustering pattern of rare nonsynonymous mutations in patients with AMD (P< 10−3) and AHUS (P= 0.0079) maps to functional domains that show evidence of positive selection during primate evolution. Our structural variation analysis in >2,400 individuals reveals five recurrent rearrangement breakpoints that show variable frequency among AMD cases and controls. These data suggest a dynamic and recurrent pattern of mutation critical to the emergence of newCFHRgenes but also in the predisposition to complex human genetic disease phenotypes.

Progressive and predictive markers of disease evolution: platelet transcriptome in chronic myeloproliferative neoplasms

2021 ◽  
Author(s):  
Zhu Shen ◽  
Wenfei Du ◽  
Cecelia Perkins ◽  
Lenn Fechter ◽  
Vanita Natu ◽  
...  
Keyword(s):  
Machine Learning ◽  
Risk Stratification ◽  
Disease Risk ◽  
Myeloproliferative Neoplasms ◽  
Penalized Regression ◽  
Machine Learning Algorithms ◽  
Disease Evolution ◽  
Chronic Myeloproliferative Neoplasms ◽  
Age Related ◽  
Wide Range

Predicting disease natural history remains a particularly challenging endeavor in chronic degenerative disorders and cancer, thus limiting early detection, risk stratification, and preventive interventions. Here, profiling the spectrum of chronic myeloproliferative neoplasms (MPNs), as a model, we identify the blood platelet transcriptome as a generalizable strategy for highly sensitive progression biomarkers that also enable prediction via machine learning algorithms. Using RNA sequencing (RNA seq), we derive disease relevant gene expression and alternative splicing in purified platelets from 120 peripheral blood samples constituting two independently collected and mutually validating patient cohorts of the three MPN subtypes: essential thrombocythemia, ET (n=24), polycythemia vera, PV (n=33), and primary or post ET/PV secondary myelofibrosis, MF (n=42), as well as healthy donors (n=21). The MPN platelet transcriptome discriminates each clinical phenotype and reveals an incremental molecular reprogramming that is independent of patient driver mutation status or therapy. Leveraging this dataset, in particular the progressive expression gradient noted across MPN, we develop a machine learning model (Lasso-penalized regression) predictive of the advanced subtype MF at high accuracy (AUC-ROC of 0.95-0.96) with validation under two conditions: i) temporal, with training on the first cohort (n=71) and independent testing on the second (n=49) and ii) 10 fold cross validation on the entire dataset. Lasso-derived signatures offer a robust core set of < 10 MPN progression markers. Mechanistic insights from our data highlight impaired protein homeostasis as a prominent driver of MPN evolution, with persistent integrated stress response. We also identify JAK inhibitor-specific signatures and other interferon, proliferation, and proteostasis associated markers as putative targets for MPN-directed therapy. Our platelet transcriptome snapshot of chronic MPNs establishes a methodological foundation for deciphering disease risk stratification and progression beyond genetic data alone, thus presenting a promising avenue toward potential utility in a wide range of age-related disorders.

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