scholarly journals Nitrosative Redox Homeostasis and Antioxidant Response Defense in Disused Vastus lateralis Muscle in Long-Term Bedrest (Toulouse Cocktail Study)

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 378
Author(s):  
Dieter Blottner ◽  
Daniele Capitanio ◽  
Gabor Trautmann ◽  
Sandra Furlan ◽  
Guido Gambara ◽  
...  
Keyword(s):  
Defense Response ◽  
Antioxidant Defense ◽  
Vastus Lateralis ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Vastus Lateralis Muscle ◽  
Related Factor ◽  
Label Free ◽  
Positive Effects ◽  
Intervention Protocol

Increased oxidative stress by reactive oxygen species (ROS) and reactive nitrogen species (RNS) is a major determinant of disuse-induced muscle atrophy. Muscle biopsies (thigh vastus lateralis, VL) obtained from healthy male subjects enrolled in the Toulouse Cocktail bedrest (BR) study were used to assess efficacy of an antioxidant cocktail (polyphenols, omega-3, vitamin E, and selenium) to counteract the increased redox homeostasis and enhance the antioxidant defense response by using label-free LC–MS/MS and NITRO-DIGE (nitrosated proteins), qPCR, and laser confocal microscopy. Label-free LC–MS/MS indicated that treatment prevented the redox homeostasis dysregulation and promoted structural remodeling (TPM3, MYH7, MYBPC, MYH1, MYL1, HRC, and LUM), increment of RyR1, myogenesis (CSRP3), and skeletal muscle development (MUSTN1, LMNA, AHNAK). These changes were absent in the Placebo group. Glycolysis, tricarboxylic acid cycle (TCA), oxidative phosphorylation, fatty acid beta-oxidation, and mitochondrial transmembrane transport were normalized in treated subjects. Proteins involved in protein folding were also normalized, whereas protein entailed in ion homeostasis decreased. NITRO-DIGE analysis showed significant protein nitrosylation changes for CAT, CA3, SDHA, and VDAC2 in Treatment vs. Placebo. Similarly, the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response element (Nrf-2 ARE) signaling pathway showed an enhanced response in the Treatment group. Increased nitrosative redox homeostasis and decreased antioxidant defense response were found in post-BR control (Placebo, n = 10) vs. the antioxidant cocktail treated group (Treatment, n = 10). Taken together, increased nitrosative redox homeostasis and muscle deterioration during BR-driven physical inactivity were prevented, whereas decreased antioxidant nitrosative stress defense response was attenuated by Treatment suggesting positive effects of the nutritional intervention protocol in bedrest.

scholarly journals Clock Protein Bmal1 and Nrf2 Cooperatively Control Aging or Oxidative Response and Redox Homeostasis by Regulating Rhythmic Expression of Prdx6

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1861 ◽  
Author(s):  
Bhavana Chhunchha ◽  
Eri Kubo ◽  
Dhirendra P. Singh
Keyword(s):  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Related Factor ◽  
Antioxidant Genes ◽  
Rhythmic Expression ◽  
Circadian Control ◽  
Ros Accumulation ◽  
E Box ◽  
Direct Binding

Many disorders of aging, including blinding-diseases, are associated with deficiency of brain and muscle arnt-like protein 1 (Bmal1) and, thereby, dysregulation of antioxidant-defense pathway. However, knowledge is limited regarding the role of Bmal1 regulation of antioxidant-pathway in the eye lens/lens epithelial cells (LECs) at the molecular level. We found that, in aging human (h)LECs, a progressive decline of nuclear factor erythroid 2-related factor 2 (Nrf2)/ARE (antioxidant response element)-mediated antioxidant genes was connected to Bmal1-deficiency, leading to accumulation of reactive oxygen species (ROS) and cell-death. Bmal1-depletion disrupted Nrf2 and expression of its target antioxidant genes, like Peroxiredoxin 6 (Prdx6). DNA binding and transcription assays showed that Bmal1 controlled expression by direct binding to E-Box in Prdx6 promoter to regulate its transcription. Mutation at E-Box or ARE reduced promoter activity, while disruption of both sites diminished the activity, suggesting that both sites were required for peak Prdx6-transcription. As in aging hLECs, ROS accumulation was increased in Bmal1-deficient cells and the cells were vulnerable to death. Intriguingly, Bmal1/Nrf2/Prdx6 and PhaseII antioxidants showed rhythmic expression in mouse lenses in vivo and were reciprocally linked to ROS levels. We propose that Bmal1 is pivotal for regulating oxidative responses. Findings also reveal a circadian control of antioxidant-pathway, which is important in combating lens/LECs damage induced by aging or oxidative stress.

scholarly journals Sulforaphane-Induced Klf9/Prdx6 Axis Acts as a Molecular Switch to Control Redox Signaling and Determines Fate of Cells

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1159 ◽  
Author(s):  
Bhavana Chhunchha ◽  
Eri Kubo ◽  
Dhirendra P. Singh
Keyword(s):  
Cell Death ◽  
Antioxidant Defense ◽  
Antioxidant Response ◽  
Therapeutic Interventions ◽  
Related Factor ◽  
Antioxidant Genes ◽  
Peroxiredoxin 6 ◽  
Dose Levels ◽  
Dose Dependent ◽  
Higher Doses

Sulforaphane (SFN), an activator of transcription factor Nrf2 (NFE2-related factor), modulates antioxidant defense by Nrf2-mediated regulation of antioxidant genes like Peroxiredoxin 6 (Prdx6) and affects cellular homeostasis. We previously observed that dose levels of SFN are crucial in determining life or death of lens epithelial cells (LECs). Herein, we demonstrated that higher doses of SFN (>6 μM) activated death signaling by overstimulation of Nrf2/ARE (antioxidant response element)-mediated Kruppel-like factor (Klf9) repression of Prdx6 expression, which increased reactive oxygen species (ROS) load and cell death. Mechanistically, Klf9 bound to its repressive Klf9 binding elements (RKBE; 5-CA/GCCC-3) in the Prdx6 promoter, and repressed Prdx6 transcription. Under the condition of higher dose of SFN, excessive Nrf2 abundance caused death signaling by enforcing Klf9 activation through ARE (5-RTGAYnnnGC-3) in Klf9 promoter that suppress antioxidant genes such as Prdx6 via a Klf9-dependent fashion. Klf9-depletion showed that Klf9 independently caused ROS reduction and subsequent cell survival, demonstrating that Klf9 upregulation caused cell death. Our work revealed the molecular mechanism of dose-dependent altered activity of SFN in LECs, and demonstrated that SFN activity was linked to levels of Nrf2/Klf9/Prdx6 axis. We proposed that in the development of therapeutic interventions for aging/oxidative disorders, combinations of Klf9-ShRNA and Nrf2 inducers may prove to be a promising strategy.

scholarly journals Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches – Pulmonary Disease/Asthma

2021 ◽  
Vol 12 ◽  
Author(s):  
Camille Audousset ◽  
Toby McGovern ◽  
James G. Martin
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Protective Role ◽  
Experimental Models ◽  
Chronic Obstructive ◽  
Related Factor ◽  
Obstructive Pulmonary Disease

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major transcription factor involved in redox homeostasis and in the response induced by oxidative injury. Nrf2 is present in an inactive state in the cytoplasm of cells. Its activation by internal or external stimuli, such as infections or pollution, leads to the transcription of more than 500 elements through its binding to the antioxidant response element. The lungs are particularly susceptible to factors that generate oxidative stress such as infections, allergens and hyperoxia. Nrf2 has a crucial protective role against these ROS. Oxidative stress and subsequent activation of Nrf2 have been demonstrated in many human respiratory diseases affecting the airways, including asthma and chronic obstructive pulmonary disease (COPD), or the pulmonary parenchyma such as acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Several compounds, both naturally occurring and synthetic, have been identified as Nrf2 inducers and enhance the activation of Nrf2 and expression of Nrf2-dependent genes. These inducers have proven particularly effective at reducing the severity of the oxidative stress-driven lung injury in various animal models. In humans, these compounds offer promise as potential therapeutic strategies for the management of respiratory pathologies associated with oxidative stress but there is thus far little evidence of efficacy through human trials. The purpose of this review is to summarize the involvement of Nrf2 and its inducers in ARDS, COPD, asthma and lung fibrosis in both human and in experimental models.

scholarly journals Nuclear Factor-Erythroid 2-Related Factor 2 (Nrf2) and Mitochondrial Dynamics/Mitophagy in Neurological Diseases

Antioxidants ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 617 ◽  
Author(s):  
Tae-Cheon Kang
Keyword(s):  
Quality Control ◽  
Antioxidant Defense ◽  
Mitochondrial Dynamics ◽  
Neurological Diseases ◽  
Redox Homeostasis ◽  
Related Factor ◽  
Nuclear Factor ◽  
Antioxidant Defense Enzymes ◽  
Antioxidant Defense Systems ◽  
The Relationship

Mitochondria play an essential role in bioenergetics and respiratory functions for cell viability through numerous biochemical processes. To maintain mitochondria quality control and homeostasis, mitochondrial morphologies change rapidly in response to external insults and changes in metabolic status through fusion and fission (so called mitochondrial dynamics). Furthermore, damaged mitochondria are removed via a selective autophagosomal process, referred to as mitophagy. Although mitochondria are one of the sources of reactive oxygen species (ROS), they are themselves vulnerable to oxidative stress. Thus, endogenous antioxidant defense systems play an important role in cell survival under physiological and pathological conditions. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that maintains redox homeostasis by regulating antioxidant-response element (ARE)-dependent transcription and the expression of antioxidant defense enzymes. Although the Nrf2 system is positively associated with mitochondrial biogenesis and mitochondrial quality control, the relationship between Nrf2 signaling and mitochondrial dynamics/mitophagy has not been sufficiently addressed in the literature. This review article describes recent clinical and experimental observations on the relationship between Nrf2 and mitochondrial dynamics/mitophagy in various neurological diseases.

scholarly journals Activation of Nrf2 by Natural Bioactive Compounds: A Promising Approach for Stroke?

2020 ◽  
Vol 21 (14) ◽  
pp. 4875 ◽  
Author(s):  
Agnese Gugliandolo ◽  
Placido Bramanti ◽  
Emanuela Mazzon
Keyword(s):  
Bioactive Compounds ◽  
Hemorrhagic Stroke ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Natural Compounds ◽  
Therapeutic Strategies ◽  
Experimental Models ◽  
Beneficial Effects ◽  
Positive Effects ◽  
Pathological Subtypes

Stroke represents one of the main causes of disability and death worldwide. The pathological subtypes of stroke are ischemic stroke, the most frequent, and hemorrhagic stroke. Nrf2 is a transcription factor that regulates redox homeostasis. In stress conditions, Nrf2 translocates inside the nucleus and induces the transcription of enzymes involved in counteracting oxidative stress, endobiotic and xenobiotic metabolism, regulators of inflammation, and others. Different natural compounds, including food and plant-derived components, were shown to be able to activate Nrf2, mediating an antioxidant response. Some of these compounds were tested in stroke experimental models showing several beneficial actions. In this review, we focused on the studies that evidenced the positive effects of natural bioactive compounds in stroke experimental models through the activation of Nrf2 pathway. Interestingly, different natural compounds can activate Nrf2 through multiple pathways, inducing a strong antioxidant response associated with the beneficial effects against stroke. According to several studies, the combination of different bioactive compounds can lead to a better neuroprotection. In conclusion, natural bioactive compounds may represent new therapeutic strategies against stroke.

scholarly journals Triggers for the Nrf2/ARE Signaling Pathway and Its Nutritional Regulation: Potential Therapeutic Applications of Ulcerative Colitis

2021 ◽  
Vol 22 (21) ◽  
pp. 11411
Author(s):  
Hu Liu ◽  
Lee J. Johnston ◽  
Fenglai Wang ◽  
Xi Ma
Keyword(s):  
Ulcerative Colitis ◽  
Signaling Pathway ◽  
Tissue Injury ◽  
Critical Role ◽  
Antioxidant Response ◽  
Activation Process ◽  
Related Factor ◽  
Nutritional Regulation ◽  
Colonic Injury ◽  
Positive Effects

Ulcerative colitis (UC), which affects millions of people worldwide, is characterized by extensive colonic injury involving mucosal and submucosal layers of the colon. Nuclear factor E2-related factor 2 (Nrf2) plays a critical role in cellular protection against oxidant-induced stress. Antioxidant response element (ARE) is the binding site recognized by Nrf2 and leads to the expression of phase II detoxifying enzymes and antioxidant proteins. The Nrf2/ARE system is a key factor for preventing and resolving tissue injury and inflammation in disease conditions such as UC. Researchers have proposed that both Keap1-dependent and Keap1-independent cascades contribute positive effects on activation of the Nrf2/ARE pathway. In this review, we summarize the present knowledge on mechanisms controlling the activation process. We will further review nutritional compounds that can modulate activation of the Nrf2/ARE pathway and may be used as potential therapeutic application of UC. These comprehensive data will help us to better understand the Nrf2/ARE signaling pathway and promote its effective application in response to common diseases induced by oxidative stress and inflammation.

scholarly journals Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 481 ◽  
Author(s):  
Azhwar Raghunath ◽  
Kiruthika Sundarraj ◽  
Frank Arfuso ◽  
Gautam Sethi ◽  
Ekambaram Perumal
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcription Factor ◽  
Cancer Progression ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Related Factor ◽  
Liver Malignancy ◽  
Beneficial Effects ◽  
Nrf2 Activation ◽  
Key Factor

The liver executes versatile functions and is the chief organ for metabolism of toxicants/xenobiotics. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third foremost cause of cancer death worldwide. Oxidative stress is a key factor related with the development and progression of HCC. Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2) is a cytosolic transcription factor, which regulates redox homeostasis by activating the expression of an array of antioxidant response element-dependent genes. Nrf2 displays conflicting roles in normal, healthy liver and HCC; in the former, Nrf2 offers beneficial effects, whereas in the latter it causes detrimental effects favouring the proliferation and survival of HCC. Sustained Nrf2 activation has been observed in HCC and facilitates its progression and aggressiveness. This review summarizes the role and mechanism(s) of action of Nrf2 dysregulation in HCC and therapeutic options that can be employed to modulate this transcription factor.

scholarly journals Low-Dose Dose–Response for In Vitro Nrf2-ARE Activation in Human HepG2 Cells

Dose-Response ◽  
2017 ◽  
Vol 15 (2) ◽  
pp. 155932581769969 ◽  
Author(s):  
Kenneth T. Bogen
Keyword(s):  
Dose Response ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Study Data ◽  
Related Factor ◽  
Response Data ◽  
Linear Slope ◽  
And Shifts ◽  
Hepg2 Cell Lines

Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-like factor 2-related factor 2 (Nrf2), and the antioxidant response element (ARE) are interacting components of a master regulatory signaling pathway that coordinates redox homeostasis, cytoprotective responses, and shifts in stem cell state. This study reexamined detailed dose–response (DR) data reported for in vitro Nrf2-ARE activation in human hepatoblastoma HepG2 cell lines containing either a ARE- bla or ARE- luc reporter at 12 different concentrations of each of 15 chemicals. The normalized study data were combined among chemicals exhibiting a positive response, yielding n = 531 (179) DR data for 9 (7) chemicals using the ARE- bla (ARE- luc) assay. Three-parameter linear/ kth-power regression fits obtained to each combined set of ARE- bla- or ARE- luc-assay response data provided good fits ( R2 = .99 or .91, respectively, Pfit > .99) that each incorporate a highly significant negative initial linear slope ( P = 4 × 10−5 or .00025) and an overall J-shaped DR pattern. Results from this reanalysis of high-resolution ARE response data support the hypothesis that nonlinear ARE-mediated adaptive cellular responses to oxidative stress are governed by an ultrasensitive molecular switch.

Targeting PPARalpha in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 345-354 ◽  
Author(s):  
Barbara D'Orio ◽  
Anna Fracassi ◽  
Maria Paola Cerù ◽  
Sandra Moreno
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Redox Homeostasis ◽  
Antioxidant Response ◽  
Peroxisome Proliferator ◽  
Prevailing Paradigm

Background: The molecular mechanisms underlying Alzheimer's disease (AD) are yet to be fully elucidated. The so-called “amyloid cascade hypothesis” has long been the prevailing paradigm for causation of disease, and is today being revisited in relation to other pathogenic pathways, such as oxidative stress, neuroinflammation and energy dysmetabolism. The peroxisome proliferator-activated receptors (PPARs) are expressed in the central nervous system (CNS) and regulate many physiological processes, such as energy metabolism, neurotransmission, redox homeostasis, autophagy and cell cycle. Among the three isotypes (α, β/δ, γ), PPARγ role is the most extensively studied, while information on α and β/δ are still scanty. However, recent in vitro and in vivo evidence point to PPARα as a promising therapeutic target in AD. Conclusion: This review provides an update on this topic, focussing on the effects of natural or synthetic agonists in modulating pathogenetic mechanisms at AD onset and during its progression. Ligandactivated PPARα inihibits amyloidogenic pathway, Tau hyperphosphorylation and neuroinflammation. Concomitantly, the receptor elicits an enzymatic antioxidant response to oxidative stress, ameliorates glucose and lipid dysmetabolism, and stimulates autophagy.

Ayurvedic management of Myositis Ossificans of Vastus Lateralis Muscle (Urusthamba) - A Case Study

2017 ◽  
Vol 2 (1) ◽  
Author(s):  
Vishnu Mohan ◽  
Gopikrishna BJ ◽  
Avnish Pathak ◽  
Mahesh Kumar ES ◽  
Duradundi G
Keyword(s):  
Heterotopic Ossification ◽  
Myositis Ossificans ◽  
Vastus Lateralis ◽  
Treatment Protocol ◽  
Vastus Lateralis Muscle ◽  
Satisfactory Treatment ◽  
Lateralis Muscle ◽  
Ayurvedic Treatment

Myositis ossificansis characterized by heterotopic ossification (calcification) of muscle of various etiologies. It is most commonly affected in the quadriceps of the thighs. There are many tools available for diagnosis of Myositis ossificans, but lack of satisfactory treatment. So the development of a treatment protocol for Myositis ossificans is the need of today`s era. In Ayurveda, the same can be understood as Urusthamba. The present paper discusses a case of Myositis ossificans of right vastus lateralis muscle and its Ayurvedic treatment.

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