scholarly journals The role of Nrf2 in acute and chronic muscle injury

2020 ◽  
Author(s):  
Iwona Bronisz-Budzyńska ◽  
Magdalena Kozakowska ◽  
Agnieszka Łoboda ◽  
Józef Dulak
Keyword(s):  
Experimental Models ◽  
Skeletal Muscle Regeneration ◽  
Muscle Pathology ◽  
Related Factor ◽  
Chronic Injury ◽  
Expression Of Genes ◽  
Fibrotic Scar ◽  
Anti Oxidant ◽  
And Function

Abstract The nuclear factor erythroid 2-related factor (Nrf2) is considered as a master cytoprotective factor regulating the expression of genes coding for anti-oxidant, anti-inflammatory, and detoxifying proteins. The role of Nrf2 in the pathophysiology of skeletal muscles has been evaluated in different experimental models, however, due to inconsistent data, we aimed to investigate how Nrf2 transcriptional deficiency (Nrf2tKO) affects muscle functions both in acute and chronic injury. The acute muscle damage was induced in mice of two genotypes – WT and Nrf2tKO mice by cardiotoxin (CTX) injection. To investigate the role of Nrf2 in chronic muscle pathology, mdx mice that share genetic, biochemical, and histopathological features with Duchenne muscular dystrophy (DMD) were crossed with mice lacking transcriptionally active Nrf2 and double knockouts (mdx/Nrf2tKO) were generated. We have observed slightly increased muscle degeneration and delayed regeneration in Nrf2tKO mice after CTX treatment. Nevertheless, transcriptional ablation of Nrf2 in mdx mice did not significantly aggravate the most deleterious pathological hallmarks of DMD such as degeneration, inflammation, fibrotic scar formation, and decreased angiogenesis, as well as the number and proliferation of satellite cells. In conclusion, our analyses in both acute and chronic injury mouse models have revealed no significant influence of Nrf2 transcriptional deficiency on skeletal muscle regeneration and function.

scholarly journals The role of Nrf2 in acute and chronic muscle injury

2020 ◽  
Author(s):  
Iwona Bronisz-Budzyńska ◽  
Magdalena Kozakowska ◽  
Paulina Podkalicka ◽  
Neli Kachamakova-Trojanowska ◽  
Agnieszka Łoboda ◽  
...  
Keyword(s):  
Muscle Injury ◽  
Experimental Models ◽  
Muscle Pathology ◽  
Related Factor ◽  
Chronic Injury ◽  
Inflammatory Infiltration ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Fibrotic Scar

Abstract The nuclear factor erythroid 2-related factor 2 (Nrf2) is considered as a master cytoprotective factor regulating the expression of genes encoding anti-oxidant, anti-inflammatory, and detoxifying proteins. The role of Nrf2 in the pathophysiology of skeletal muscles has been evaluated in different experimental models, however, due to inconsistent data, we aimed to investigate how Nrf2 transcriptional deficiency (Nrf2tKO) affects muscle functions both in an acute and chronic injury. The acute muscle damage was induced in mice of two genotypes – WT and Nrf2tKO mice by cardiotoxin (CTX) injection. To investigate the role of Nrf2 in chronic muscle pathology, mdx mice that share genetic, biochemical, and histopathological features with Duchenne muscular dystrophy (DMD) were crossed with mice lacking transcriptionally active Nrf2 and double knockouts (mdx/Nrf2tKO) were generated. To worsen the dystrophic phenotype, the analysis of disease pathology was also performed in aggravated conditions, by applying a long-term treadmill test. We have observed slightly increased muscle degeneration in Nrf2tKO mice after CTX treatment. Nevertheless, transcriptional ablation of Nrf2 in mdx mice did not significantly aggravate the most deleterious, pathological hallmarks of DMD related to degeneration, inflammation, fibrotic scar formation, angiogenesis, and the number and proliferation of satellite cells in non-exercised conditions. On the other hand, upon chronic exercises, the degeneration and inflammatory infiltration of the gastrocnemius muscle, but not diaphragm, turned to be increased in Nrf2tKOmdx in comparison to mdx mice. In conclusion, the lack of transcriptionally active Nrf2 influences moderately muscle pathology in acute CTX-induced muscle injury and chronic DMD mouse model, without affecting muscle functionality. Hence, in general, we demonstrated that the deficiency of Nrf2 transcriptional activity has no profound impact on muscle pathology in various models of muscle injury.

scholarly journals The role of Nrf2 in acute and chronic muscle injury

2020 ◽  
Author(s):  
Iwona Bronisz-Budzyńska ◽  
Magdalena Kozakowska ◽  
Paulina Podkalicka ◽  
Neli Kachamakova-Trojanowska ◽  
Agnieszka Łoboda ◽  
...  
Keyword(s):  
Muscle Damage ◽  
Muscle Injury ◽  
Experimental Models ◽  
Muscle Pathology ◽  
Related Factor ◽  
Chronic Injury ◽  
Inflammatory Infiltration ◽  
Genes Encoding ◽  
Fibrotic Scar

Abstract The nuclear factor erythroid 2-related factor 2 (Nrf2) is considered as a master cytoprotective factor regulating the expression of genes encoding anti-oxidant, anti-inflammatory, and detoxifying proteins. The role of Nrf2 in the pathophysiology of skeletal muscles has been evaluated in different experimental models, however, due to inconsistent data, we aimed to investigate how Nrf2 transcriptional deficiency (Nrf2tKO) affects muscle functions both in an acute and chronic injury. The acute muscle damage was induced in mice of two genotypes – WT and Nrf2tKO mice by cardiotoxin (CTX) injection. To investigate the role of Nrf2 in chronic muscle pathology, mdx mice that share genetic, biochemical, and histopathological features with Duchenne muscular dystrophy (DMD) were crossed with mice lacking transcriptionally active Nrf2 and double knockouts (mdx/Nrf2tKO) were generated. To worsen the dystrophic phenotype, the analysis of disease pathology was also performed in aggravated conditions, by applying a long-term treadmill test.We have observed slightly increased muscle damage in Nrf2tKO mice after CTX injection. Nevertheless, transcriptional ablation of Nrf2 in mdx mice did not significantly aggravate the most deleterious, pathological hallmarks of DMD related to degeneration, inflammation, fibrotic scar formation, angiogenesis, and the number and proliferation of satellite cells in non-exercised conditions. On the other hand, upon chronic exercises, the degeneration and inflammatory infiltration of the gastrocnemius muscle, but not diaphragm, turned to be increased in Nrf2tKOmdx in comparison to mdx mice. In conclusion, the lack of transcriptionally active Nrf2 influences moderately muscle pathology in acute CTX-induced muscle injury and chronic DMD mouse model, without affecting muscle functionality. Hence, in general, we demonstrated that the deficiency of Nrf2 transcriptional activity has no profound impact on muscle pathology in various models of muscle injury.

scholarly journals The role of Nrf2 in acute and chronic muscle injury

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Iwona Bronisz-Budzyńska ◽  
Magdalena Kozakowska ◽  
Paulina Podkalicka ◽  
Neli Kachamakova-Trojanowska ◽  
Agnieszka Łoboda ◽  
...  
Keyword(s):  
Muscle Damage ◽  
Muscle Injury ◽  
Experimental Models ◽  
Muscle Pathology ◽  
Related Factor ◽  
Chronic Injury ◽  
Inflammatory Infiltration ◽  
Genes Encoding ◽  
Fibrotic Scar

AbstractThe nuclear factor erythroid 2-related factor 2 (Nrf2) is considered as a master cytoprotective factor regulating the expression of genes encoding anti-oxidant, anti-inflammatory, and detoxifying proteins. The role of Nrf2 in the pathophysiology of skeletal muscles has been evaluated in different experimental models, however, due to inconsistent data, we aimed to investigate how Nrf2 transcriptional deficiency (Nrf2tKO) affects muscle functions both in an acute and chronic injury. The acute muscle damage was induced in mice of two genotypes—WT and Nrf2tKO mice by cardiotoxin (CTX) injection. To investigate the role of Nrf2 in chronic muscle pathology, mdx mice that share genetic, biochemical, and histopathological features with Duchenne muscular dystrophy (DMD) were crossed with mice lacking transcriptionally active Nrf2 and double knockouts (mdx/Nrf2tKO) were generated. To worsen the dystrophic phenotype, the analysis of disease pathology was also performed in aggravated conditions, by applying a long-term treadmill test. We have observed slightly increased muscle damage in Nrf2tKO mice after CTX injection. Nevertheless, transcriptional ablation of Nrf2 in mdx mice did not significantly aggravate the most deleterious, pathological hallmarks of DMD related to degeneration, inflammation, fibrotic scar formation, angiogenesis, and the number and proliferation of satellite cells in non-exercised conditions. On the other hand, upon chronic exercises, the degeneration and inflammatory infiltration of the gastrocnemius muscle, but not the diaphragm, turned to be increased in Nrf2tKOmdx in comparison to mdx mice. In conclusion, the lack of transcriptionally active Nrf2 influences moderately muscle pathology in acute CTX-induced muscle injury and chronic DMD mouse model, without affecting muscle functionality. Hence, in general, we demonstrated that the deficiency of Nrf2 transcriptional activity has no profound impact on muscle pathology in various models of muscle injury.

scholarly journals α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

2021 ◽  
Author(s):  
Alberto Delaidelli ◽  
Mette Richner ◽  
Lixiang Jiang ◽  
Amelia van der Laan ◽  
Ida Bergholdt Jul Christiansen ◽  
...  
Keyword(s):  
Nervous System ◽  
Parkinson Disease ◽  
Redox Homeostasis ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Motor Nucleus ◽  
Related Factor ◽  
Dorsal Motor Nucleus ◽  
Anti Oxidant

Circumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleionpathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2) is recognized as the master regulator of cellular anti-oxidant response, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, Prnp-SNCA*Ala53Thr), which manifest widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

scholarly journals α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Alberto Delaidelli ◽  
Mette Richner ◽  
Lixiang Jiang ◽  
Amelia van der Laan ◽  
Ida Bergholdt Jul Christiansen ◽  
...  
Keyword(s):  
Nervous System ◽  
Parkinson Disease ◽  
Redox Homeostasis ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Motor Nucleus ◽  
Related Factor ◽  
Dorsal Motor Nucleus ◽  
Anti Oxidant

AbstractCircumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleinopathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2/Nrf2) is recognized as ‘the master regulator of cellular anti-oxidant response’, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on the serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, expressing the mutant human A53T aSyn), which manifests widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

Acute renal failure. III. The role of growth factors in the process of renal regeneration and repair

2000 ◽  
Vol 279 (1) ◽  
pp. F3-F11 ◽  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Growth Factors ◽  
Experimental Models ◽  
Future Research ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Renal Regeneration ◽  
General Studies

This review, which is the final installment in a series devoted to controversial issues in acute renal failure (ARF) (3, 47), will examine available information regarding the role of growth factors in ARF. In general, studies in this area have fallen into two broad categories: 1) those that have examined the renal expression of genes encoding growth factors or transcriptional factors associated with the growth response that is induced after ARF, and 2) those that have examined the efficacy of exogenously administered growth factors in accelerating recovery of renal function in experimental models of ARF. Despite the vast amount of information that has accumulated in these two areas of investigation, our understanding of the mechanisms involved in the process of regeneration and repair after ARF, and the role of growth factors in this response, remains rudimentary. This overview, contributed to by a number of experts in the field, is designed to summarize present knowledge and to highlight potentially fertile areas for future research in this area.

scholarly journals Novel Insights into Concepts and Directionality of Maternal–Fetal Cholesterol Transfer across the Human Placenta

2018 ◽  
Vol 19 (8) ◽  
pp. 2334 ◽  
Author(s):  
Sampada Kallol ◽  
Xiao Huang ◽  
Stefan Müller ◽  
Corneille Ontsouka ◽  
Christiane Albrecht
Keyword(s):  
Cholesterol Efflux ◽  
Cellular Membrane ◽  
Experimental Models ◽  
Cholesterol Transport ◽  
Membrane Composition ◽  
Conventional Culture ◽  
Atp Binding Cassette Transporter ◽  
And Function ◽  
Fetal Organs

Cholesterol is indispensable for cellular membrane composition and function. It is also a precursor for the synthesis of steroid hormones, which promote, among others, the maturation of fetal organs. A role of the ATP-binding-cassette-transporter-A1 (ABCA1) in the transport of maternal cholesterol to the fetus was suggested by transferring cholesterol to apolipoprotein-A-1 (apo-A1), but the directionality of the apoA-1/ABCA1-dependent cholesterol transport remains unclear. We isolated primary trophoblasts from term placentae to test the hypotheses that (1) apoA-1/ABCA1 dispatches cholesterol mainly towards the fetus to support fetal developmental maturation at term, and (2) differentiated syncytiotrophoblasts (STB) exert higher cholesterol transport activity than undifferentiated cytotrophoblasts (CTB). As experimental models, we used (1) trophoblast monolayers grown on Transwell® system consisting of apical (maternal-like) and basal (fetal-like) compartments, and (2) trophoblasts grown on conventional culture plates at CTB and STB stages. Surprisingly, apoA-1-mediated cholesterol efflux operated almost exclusively at the apical-maternal side, where ABCA1 was also localized by immunofluorescence. We found greater cholesterol efflux capacity in STB, which was increased by liver-X-receptor agonist treatment and decreased by ABCA1 inhibition. We conclude that at term the apoA-1/ABCA1 pathway is rather involved in cholesterol transport to the mother than in transfer to the fully developed fetus.

The impact of epigenetics on cardiovascular disease

2020 ◽  
Vol 98 (1) ◽  
pp. 12-22 ◽  
Author(s):  
Dimple Prasher ◽  
Steven C. Greenway ◽  
Raja B. Singh
Keyword(s):  
Cardiac Fibrosis ◽  
Mortality And Morbidity ◽  
Rna Molecules ◽  
Expression Of Genes ◽  
Non Coding Rna ◽  
Novel Biomarkers ◽  
External Risk ◽  
And Function ◽  
The Impact

Mortality and morbidity from cardiovascular diseases (CVDs) represents a huge burden to society. It is recognized that environmental factors and individual lifestyles play important roles in disease susceptibility, but the link between these external risk factors and our genetics has been unclear. However, the discovery of sequence-independent heritable DNA changes (epigenetics) have helped us to explain the link between genes and the environment. Multiple diverse epigenetic processes, including DNA methylation, histone modification, and the expression of non-coding RNA molecules affect the expression of genes that produce important changes in cellular differentiation and function, influencing the health and adaptability of the organism. CVDs such as congenital heart disease, cardiomyopathy, heart failure, cardiac fibrosis, hypertension, and atherosclerosis are now being viewed as much more complex and dynamic disorders. The role of epigenetics in these and other CVDs is currently under intense scrutiny, and we can expect important insights to emerge, including novel biomarkers and new approaches to enable precision medicine. This review summarizes the recent advances in our understanding of the role of epigenetics in CVD.

scholarly journals Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

2016 ◽  
Vol 397 (5) ◽  
pp. 383-400 ◽  
Author(s):  
Noemí Esteras ◽  
Albena T. Dinkova-Kostova ◽  
Andrey Y. Abramov
Keyword(s):  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Related Factor ◽  
Mitochondrial Bioenergetics ◽  
Cytoprotective Activity ◽  
Nrf2 Activation ◽  
Potential Therapeutic Role ◽  
And Function

Abstract The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor well-known for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich’s ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

scholarly journals Sexual dimorphism in cognition and behaviour: the role of X-linked genes

2006 ◽  
Vol 155 (suppl_1) ◽  
pp. S99-S106 ◽  
Author(s):  
David H Skuse
Keyword(s):  
Sexual Dimorphism ◽  
Neural Development ◽  
Species Differences ◽  
Common Ancestor ◽  
Evolutionary Constraints ◽  
Brain Functions ◽  
Expression Of Genes ◽  
And Function ◽  
Evolutionary Role

Chimpanzees and humans last shared a common ancestor between 5 and 7 million years ago; 99% of the two species’ DNA is identical. Yet, since the paths of primate evolution diverged, there have been remarkable developments in the behavioural and cognitive attainments of our species, which ultimately reflect subtle differences in gene structure and function. These modifications have occurred despite evolutionary constraints upon the diversity of genetic influences, on the development and function of neural tissue. Significant species differences can be observed both at the levels of function (gene expression) and structure (amino acid sequence). Protein evolution is driving an accelerating increase in brain complexity and size. Playing centre stage, in terms of the proportion of genes involved in brain development and cognitive function, is the X chromosome. Recently, it has become clear that a long-standing theory, implicating X-linked genes in a sexually antagonistic evolutionary role, is probably correct. Genes on the sex chromosomes can directly influence sexual dimorphism in cognition and behaviour, independent of the action of sex steroids. Mechanisms by which sex-chromosomal effects, due to X-linked genes, influence neural development or function are reviewed. These include the biased expression of genes subject to X-inactivation, haploinsufficiency (in males) for non-inactivated genes with no Y homology, sex-specific brain functions and genomic imprinting of X-linked loci. Evidence supporting each of these mechanisms is available from both human and animal models. Recently, the first candidate genes have been discovered.

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