scholarly journals Upregulation of Mitochondrial Redox Sensitive Proteins in LPS-Treated Stefin B-Deficient Macrophages

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1476 ◽  
Author(s):  
Mojca Trstenjak Prebanda ◽  
Janja Završnik ◽  
Boris Turk ◽  
Nataša Kopitar Jerala
Keyword(s):  
Redox Homeostasis ◽  
Redox Status ◽  
Protective Role ◽  
Protein Levels ◽  
Lps Challenge ◽  
Pyrin Domain ◽  
Cysteine Cathepsins ◽  
Peroxiredoxin 3 ◽  
Superoxide Dismutase 2

Stefin B (cystatin B) is an intracellular inhibitor of cysteine cathepsins and mutations in the stefin B gene, resulting in the development of Unverricht–Lundborg disease, which is a form of myoclonic epilepsy. It was suggested that a key mechanism behind stefin B-mediated disease progression was impaired redox homeostasis. Stefin B-deficient mice were found more sensitive to lipopolysaccharide (LPS)-induced sepsis as a consequence of increased expression of caspase-11 and Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing (NLRP nflammasome activation and higher levels of mitochondrial reactive oxygen species (ROS). In the present study, we investigated if LPS-triggered oxidative stress affected the protein levels and redox status of redox sensitive proteins—thioredoxin, peroxiredoxins, and superoxide dismutases in macrophages and spleens of LPS-injected mice. LPS challenge was found to result in a marked elevation in mitochondrial peroxiredoxin 3 (Prx3), sulfiredoxin, and superoxide dismutase 2 (Sod2) in stefin B-deficient macrophages and spleens. We determined that sulfiredoxin is targeted to mitochondria after LPS challenge. In conclusion, the upregulation of mitochondrial redox-sensitive proteins Prx3 and Sod2 in stefin B-deficient cells implies a protective role of stefin B in mitochondrial function.

Protective role of interleukin-6 in coagulatory and hemostatic disturbance induced by lipopolysaccharide in mice

2004 ◽  
Vol 91 (06) ◽  
pp. 1194-1201 ◽  
Author(s):  
Ken-ichiro Inoue ◽  
Rie Yanagisawa ◽  
Miho Sakurai ◽  
Akinori Shimada ◽  
Takehito Morita ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Intraperitoneal Administration ◽  
Pulmonary Hemorrhage ◽  
Protective Role ◽  
Protein Levels ◽  
Proinflammatory Mediators ◽  
Lps Challenge ◽  
Inflammatory Protein ◽  
Significant Prolongation

SummaryAlthough the role of interleukin (IL)-6 in inflammatory diseases has been previously examined, its role in hemostasis, fibrinolysis, and coagulation during inflammation remains to be established. The present study elucidated the role of IL-6 in hemostatic and coagulatory changes during severe inflammation induced by intraperitoneal administration of lipopolysaccharide (LPS: 1 mg/kg) using IL-6 null (-/-) mice. After LPS challenge, IL-6 (-/-) mice revealed significant prolongation of prothrombin time and activated partial thromboplastin time and a significant decrease in platelet counts as compared with wild type mice. LPS treatment induced marked pulmonary hemorrhage with neutrophilic inflammation in IL-6 (-/-) mice, in contrast, only mild neutrophilic infiltration in WT mice confirmed by macroscopic and histological findings.The protein levels of proinflammatory mediators, such as IL-1?, macrophage inflammatory protein (MIP)-1a., MIP-2, macrophage chemoattractant protein1, granulocyte/macrophage-colony-stimulating factor, and keratinocyte chemoattractant in the lungs were significantly greater in IL-6 (-/-) mice than in WT mice after LPS challenge. These results directly indicate that IL-6 is protective against coagulatory and hemostatic disturbance and subsequent pulmonary hemorrhage induced by bacterial endotoxin, at least partly, via the modulation of proinflammatory processes.

scholarly journals Macrophage migration inhibitory factor may play a protective role in osteoarthritis

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Ming Liu ◽  
Zikun Xie ◽  
Guang Sun ◽  
Liujun Chen ◽  
Dake Qi ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Protective Role ◽  
Macrophage Migration ◽  
Chain Reaction ◽  
Protein Levels ◽  
Tnf Α ◽  
Polymerase Chain

Abstract Background Osteoarthritis (OA) is the most prevalent form of arthritis and the major cause of disability and overall diminution of quality of life in the elderly population. Currently there is no cure for OA, partly due to the large gaps in our understanding of its underlying molecular and cellular mechanisms. Macrophage migration inhibitory factor (MIF) is a procytokine that mediates pleiotropic inflammatory effects in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, data on the role of MIF in OA is limited with conflicting results. We undertook this study to investigate the role of MIF in OA by examining MIF genotype, mRNA expression, and protein levels in the Newfoundland Osteoarthritis Study. Methods One hundred nineteen end-stage knee/hip OA patients, 16 RA patients, and 113 healthy controls were included in the study. Two polymorphisms in the MIF gene, rs755622, and -794 CATT5-8, were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and PCR followed by automated capillary electrophoresis, respectively. MIF mRNA levels in articular cartilage and subchondral bone were measured by quantitative polymerase chain reaction. Plasma concentrations of MIF, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) were measured by enzyme-linked immunosorbent assay. Results rs755622 and -794 CATT5-8 genotypes were not associated with MIF mRNA or protein levels or OA (all p ≥ 0.19). MIF mRNA level in cartilage was lower in OA patients than in controls (p = 0.028) and RA patients (p = 0.004), while the levels in bone were comparable between OA patients and controls (p = 0.165). MIF protein level in plasma was lower in OA patients than in controls (p = 3.01 × 10−10), while the levels of TNF-α, IL-6 and IL-1β in plasma were all significantly higher in OA patients than in controls (all p ≤ 0.0007). Multivariable logistic regression showed lower MIF and higher IL-1β protein levels in plasma were independently associated with OA (OR per SD increase = 0.10 and 8.08; 95% CI = 0.04–0.19 and 4.42–16.82, respectively), but TNF-α and IL-6 became non-significant. Conclusions Reduced MIF mRNA and protein expression in OA patients suggested MIF might have a protective role in OA and could serve as a biomarker to differentiate OA from other joint disorders.

scholarly journals Differential regulation of Ca2+ influx by ORAI channels mediates enamel mineralization

2019 ◽  
Vol 12 (578) ◽  
pp. eaav4663 ◽  
Author(s):  
Miriam Eckstein ◽  
Martin Vaeth ◽  
Francisco J. Aulestia ◽  
Veronica Costiniti ◽  
Serena N. Kassam ◽  
...  
Keyword(s):  
Consumption Rate ◽  
Redox Homeostasis ◽  
Direct Interaction ◽  
Redox Status ◽  
Cellular Functions ◽  
Enamel Defects ◽  
Targeted Deletion ◽  
Anhidrotic Ectodermal Dysplasia ◽  
Enamel Mineralization

Store-operated Ca2+ entry (SOCE) channels are highly selective Ca2+ channels activated by the endoplasmic reticulum (ER) sensors STIM1 and STIM2. Their direct interaction with the pore-forming plasma membrane ORAI proteins (ORAI1, ORAI2, and ORAI3) leads to sustained Ca2+ fluxes that are critical for many cellular functions. Mutations in the human ORAI1 gene result in immunodeficiency, anhidrotic ectodermal dysplasia, and enamel defects. In our investigation of the role of ORAI proteins in enamel, we identified enamel defects in a patient with an ORAI1 null mutation. Targeted deletion of the Orai1 gene in mice showed enamel defects and reduced SOCE in isolated enamel cells. However, Orai2−/− mice showed normal enamel despite having increased SOCE in the enamel cells. Knockdown experiments in the enamel cell line LS8 suggested that ORAI2 and ORAI3 modulated ORAI1 function, with ORAI1 and ORAI2 being the main contributors to SOCE. ORAI1-deficient LS8 cells showed altered mitochondrial respiration with increased oxygen consumption rate and ATP, which was associated with altered redox status and enhanced ER Ca2+ uptake, likely due to S-glutathionylation of SERCA pumps. Our findings demonstrate an important role of ORAI1 in Ca2+ influx in enamel cells and establish a link between SOCE, mitochondrial function, and redox homeostasis.

scholarly journals Circadian Clock and OxInflammation: Functional Crosstalk in Cutaneous Homeostasis

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Elena Frigato ◽  
Mascia Benedusi ◽  
Anna Guiotto ◽  
Cristiano Bertolucci ◽  
Giuseppe Valacchi
Keyword(s):  
Circadian Clock ◽  
Redox Homeostasis ◽  
Physiological Role ◽  
Protective Role ◽  
Circadian System ◽  
Circadian Disruption ◽  
Cellular Damage ◽  
Lifestyle Risk Factors

Circadian rhythms are biological oscillations that occur with an approximately 24 h period and optimize cellular homeostasis and responses to environmental stimuli. A growing collection of data suggests that chronic circadian disruption caused by novel lifestyle risk factors such as shift work, travel across time zones, or irregular sleep-wake cycles has long-term consequences for human health. Among the multiplicity of physiological systems hypothesized to have a role in the onset of pathologies in case of circadian disruption, there are redox-sensitive defensive pathways and inflammatory machinery. Due to its location and barrier physiological role, the skin is a prototypical tissue to study the influence of environmental insults induced OxInflammation disturbance and circadian system alteration. To better investigate the link among outdoor stressors, OxInflammation, and circadian system, we tested the differential responses of keratinocytes clock synchronized or desynchronized, in an in vitro inflammatory model exposed to O3. Being both NRF2 and NF-κB two key redox-sensitive transcription factors involved in cellular redox homeostasis and inflammation, we analyzed their activation and expression in challenged keratinocytes by O3. Our results suggest that a synchronized circadian clock not only facilitates the protective role of NRF2 in terms of a faster and more efficient defensive response against environmental insults but also moderates the cellular damage resulting from a condition of chronic inflammation. Our results bring new insights on the role of circadian clock in regulating the redox-inflammatory crosstalk influenced by O3 and possibly can be extrapolated to other pollutants able to affect the oxinflammatory cellular processes.

Acetaminophen perturbed redox homeostasis in Wistar rat liver: protective role of aqueousPterocarpus osunleaf extract

2009 ◽  
Vol 33 (1) ◽  
pp. 77-87 ◽  
Author(s):  
Taofeek O. Ajiboye ◽  
Amadu K. Salau ◽  
Musa T. Yakubu ◽  
Adenike T. Oladiji ◽  
Musbau A. Akanji ◽  
...  
Keyword(s):  
Rat Liver ◽  
Redox Homeostasis ◽  
Wistar Rat ◽  
Protective Role

scholarly journals miR-135b Plays a Neuroprotective Role by Targeting GSK3β in MPP+-Intoxicated SH-SY5Y Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Jianlei Zhang ◽  
Wei Liu ◽  
Yabo Wang ◽  
Shengnan Zhao ◽  
Na Chang
Keyword(s):  
Cell Proliferation ◽  
Glycogen Synthase ◽  
Underlying Mechanism ◽  
Protective Role ◽  
Luciferase Reporter ◽  
Dependent Manner ◽  
Protective Effects ◽  
Inflammatory Cytokine Production ◽  
Protein Levels

miR-135a-5p was reported to play a crucial role in the protective effects of hydrogen sulfide against Parkinson’s disease (PD) by targeting rho-associated protein kinase 2 (ROCK2). However, the role of another member of miR-135 family (miR-135b) and the underlying mechanism in PD are still unclear. qRT-PCR and western blot showed that miR-135 was downregulated and glycogen synthase kinase 3β (GSK3β) was upregulated at mRNA and protein levels in MPP+-intoxicated SH-SY5Y cells in a dose- and time-dependent manner. MTT, TUNEL, and ELISA assays revealed that miR-135b overexpression significantly promoted cell proliferation and inhibited apoptosis and production of TNF-α and IL-1β in SH-SY5Y cells in the presence of MPP+. Luciferase reporter assay demonstrated that GSK3β was a direct target of miR-135b. Moreover, sodium nitroprusside (SNP), a GSK3β activator, dramatically reversed the effects of miR-135b upregulation on cell proliferation, apoptosis, and inflammatory cytokine production in MPP+-intoxicated SH-SY5Y cells. Taken together, miR-135b exerts a protective role via promotion of proliferation and suppression of apoptosis and neuroinflammation by targeting GSK3β in MPP+-intoxicated SH-SY5Y cells, providing a potential therapeutic target for the treatment of PD.

scholarly journals NQO1 binds and supports SIRT1 function

2017 ◽  
Author(s):  
Peter Tsvetkov ◽  
Julia Adler ◽  
Yaarit Adamovich ◽  
Gad Asher ◽  
Nina Reuven ◽  
...  
Keyword(s):  
Target Genes ◽  
Protective Role ◽  
Class Iii ◽  
Mitochondrial Stress ◽  
Protein Levels ◽  
Related Enzyme ◽  
Metabolic Sensing ◽  
Regulatory Loop ◽  
Nadh Oxidoreductase

AbstractSilent information regulator 2-related enzyme 1 (SIRT1) is an NAD+-dependent class III deacetylase and a key component of the cellular metabolic sensing pathway. The requirement of NAD+ for SIRT1 activity led us to assume that NQO1, an NADH oxidoreductase producing NAD+, regulates SIRT1 activity. We show here that SIRT1 is capable of increasing NQO1 (NAD(P)H Dehydrogenase Quinone 1) transcription and protein levels. NQO1 physically interacts with SIRT1 but not with an enzymatically dead SIRT1 H363Y mutant. The interaction of NQO1 with SIRT1 is markedly increased under mitochondrial inhibition. Interestingly, under this condition the nuclear pool of NQO1 is elevated. Depletion of NQO1 compromises the role of SIRT1 in inducing transcription of several target genes and eliminates the protective role of SIRT1 following mitochondrial inhibition. Our results suggest that SIRT1 and NQO1 form a regulatory loop where SIRT1 regulates NQO1 expression and NQO1 binds and mediates the protective role of SIRT1 during mitochondrial stress. The interplay between an NADH oxidoreductase enzyme and an NAD+ dependent deacetylase may act as a rheostat in sensing mitochondrial stress.

Acetaminophen perturbed redox homeostasis in Wistar rat liver: protective role of aqueousPterocarpus osunleaf extract

2009 ◽  
Vol 00 (00) ◽  
pp. 091009031943080-11 ◽  
Author(s):  
Taofeek O. Ajiboye ◽  
Amadu K. Salau ◽  
Musa T. Yakubu ◽  
Adenike T. Oladiji ◽  
Musbau A. Akanji ◽  
...  
Keyword(s):  
Rat Liver ◽  
Redox Homeostasis ◽  
Wistar Rat ◽  
Protective Role

New insight on the role of liraglutide in alleviating dexamethasone-induced pancreatic cytotoxicity via improving redox status, autophagy flux and PI3K/Akt/Nrf2 signaling

2021 ◽  
Author(s):  
Walaa Elseady ◽  
Rasha Abd Ellatif ◽  
Remon Estfanous ◽  
Marwa Emam ◽  
Walaa Arafa Keshk
Keyword(s):  
Cell Function ◽  
Pancreatic Injury ◽  
Redox Status ◽  
Protective Role ◽  
Caspase 9 ◽  
Β Cell ◽  
Autophagy Flux ◽  
Β Cell Function ◽  
Underlying Mechanisms

Chronic glucocorticoids therapy is commonly complicated by steroid diabetes, while the underlying mechanisms are still elusive. Liraglutide a glucagon like peptide -1 was initially found to induce glycemic control and recently it was found to have many pleotropic effects. However, its role in pancreas remains unknown. So, the present study aims to estimate the protective role of liraglutide on dexamethasone-induced pancreatic cytotoxicity, and hyperglycemia with highlighting the possible biochemical, molecular and cellular underlying mechanisms. Twenty-eight male Wistar rats were involved in this study and were randomly divided into four groups. Group III & IV were treated with 1mg/kg dexamethasone daily for 10 days. Group II & IV were treated with liraglutide in a dose of 0.8 mg/kg/day for 2 weeks. Pancreatic caspase-9, Nrf2, pAkt and sequestrome1 (p62) levels were assessed by immunoassay. Moreover, phosphoinositide 3-kinase (PI3K) expression by real time PCR, LC3B expression by immunohistochemistry, glycemic status, β-cell function by HOMA-β index, and pancreatic redox status were assessed. Liraglutide improved blood glucose level, β-cell function, pancreatic caspase 9 level, redox status, and autophagy. Additionally, it increased pancreatic PI3K, pAkt and Nrf2 levels. Moreover, preservation of pancreatic histological and the ultrastructural morphological features of β- and α-cell were observed. In conclusion: Liraglutide protected against dexamethasone-induced pancreatic injury, hyperglycemia and decelerated the progression towards steroid diabetes via activating PI3K/Akt/Nrf2 signaling and autophagy flux pathways

scholarly journals Oxidative Stress-Mediated Skeletal Muscle Degeneration: Molecules, Mechanisms, and Therapies

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Min Hee Choi ◽  
Jin Rong Ow ◽  
Nai-Di Yang ◽  
Reshma Taneja
Keyword(s):  
Oxidative Stress ◽  
Molecular Level ◽  
Redox Homeostasis ◽  
Redox Status ◽  
Muscle Degeneration ◽  
Dystrophic Muscle ◽  
Telomere Shortening ◽  
Cellular Redox ◽  
Pathological Conditions

Oxidative stress is a loss of balance between the production of reactive oxygen species during cellular metabolism and the mechanisms that clear these species to maintain cellular redox homeostasis. Increased oxidative stress has been associated with muscular dystrophy, and many studies have proposed mechanisms that bridge these two pathological conditions at the molecular level. In this review, the evidence indicating a causal role of oxidative stress in the pathogenesis of various muscular dystrophies is revisited. In particular, the mediation of cellular redox status in dystrophic muscle by NF-κB pathway, autophagy, telomere shortening, and epigenetic regulation are discussed. Lastly, the current stance of targeting these pathways using antioxidant therapies in preclinical and clinical trials is examined.

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