scholarly journals Dysfunctional MnSOD leads to redox dysregulation and activation of prosurvival AKT signaling in uterine leiomyomas

2016 ◽  
Vol 2 (11) ◽  
pp. e1601132 ◽  
Author(s):  
Vania Vidimar ◽  
David Gius ◽  
Debabrata Chakravarti ◽  
Serdar E. Bulun ◽  
Jian-Jun Wei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Manganese Superoxide Dismutase ◽  
Akt Signaling ◽  
Uterine Leiomyomas ◽  
Public Health Issue ◽  
Causative Role ◽  
Ros Scavenging ◽  
Growth And Survival ◽  
Oxidative Inactivation ◽  
Mnsod Activity

AKT signaling promotes cell growth and survival and is often dysregulated via multiple mechanisms in different types of cancer, including uterine leiomyomas (ULMs). ULMs are highly prevalent fibrotic tumors that arise from the smooth muscular layer of the uterus, the myometrium (MM). ULMs pose a major public health issue because they can cause severe morbidity and poor pregnancy outcomes. ‬We investigate the mechanisms driving ULM growth and survival via aberrant activation of AKT. We demonstrate that an acetylation-mediated impairment of the manganese superoxide dismutase (MnSOD) activity is prevalent in ULM cells compared to the normal-matched MM from the same patients. This impairment increases the levels of superoxide and oxidative stress, which activate AKT via oxidative inactivation of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Redox activation of AKT promotes ULM cell survival under conditions of moderate but persistent oxidative stress that are compatible with ULM’s prooxidative microenvironment. Moreover, because of impaired MnSOD activity, ULM cells are sensitive to high levels of reactive oxygen species (ROS) and superoxide-generating compounds, resulting in decreased ULM cell viability. On the contrary, MM cells with functional MnSOD are more resistant to high levels of oxidants. This study demonstrates a causative role of acetylation-mediated MnSOD dysfunction in activating prosurvival AKT signaling in ULMs. The specific AKT and redox states of ULM cells provide a potential novel therapeutic rationale to selectively target ULM cells because of their defective ROS-scavenging system.‬‬‬‬‬‬‬‬

174 OXIDATIVE STRESS AND LIPID PEROXIDATION IN BOVINE IN VITRO-PRODUCED EMBRYOS WITH DIFFERENT DEVELOPMENTAL SPEEDS

2012 ◽  
Vol 24 (1) ◽  
pp. 199
Author(s):  
S. Di Francesco ◽  
M. Rubessa ◽  
L. Boccia ◽  
M. De Blasi ◽  
P. Stiuso ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Bovine Serum ◽  
Manganese Superoxide Dismutase ◽  
Embryo Viability ◽  
Sod Activity ◽  
Stage Of Development ◽  
Mnsod Activity

In vitro-produced embryos are less viable than their in vivo counterparts. It is known that the developmental speed is a reliable marker of embryo viability. One of the major factors impairing in vitro embryo development is oxidative stress. The aim of the study was to evaluate oxidative stress and lipid peroxidation in bovine in vitro-produced embryos that reached different developmental stages at the end of culture. Abattoir-derived oocytes were matured in vitro in TCM-199 with 15% bovine serum, 0.5 μg mL–1 of FSH, 5 μg mL–1 of LH, 0.8 mM L-glutamine and 50 mg mL–1 of gentamicin. Mature cumulus–oocyte complexes (COC) were fertilized in Tyrode's modified medium, supplemented by 5.3 SI mL–1 of heparin, 30 μM penicillamine, 15 μM hypotaurine, 1 μM epinephrine and 1% of bovine serum. Both in vitro maturation and IVF were carried out at 39°C and 5% CO2 in air. After 20 to 22 h of gamete co-incubation, presumptive zygotes were denuded and cultured in SOF for 7 days at 39°C under humidified air with 5% CO2, 7% O2 and 88% N2 in air. At the end of culture, embryos were assessed according to the stage of development as tight morulae (TM), early blastocysts (eBl), blastocysts (Bl), expanded blastocysts (XBl) and hatched blastocysts (HBl). For each stage of development, an average of 20 embryos were used to determine manganese superoxide dismutase (MnSOD) activity and levels of nitric oxide (NO2–) and thiobarbituric acid-reactive substances (TBARS). The SOD activity was determined by a colourimetric method (Caraglia M et al. 2011 Cell Death Dis. 2, 150, doi:10.1038/cddis.2011.34) whereas NO2– and TBARS were measured by a spectrophotometric method (Balestrieri et al. 2011 J. Cell. Physiol. doi:10.1002/jcp.22874). Data were analysed by t-test. Greater (P < 0.05) MnSOD activity was observed in faster developing embryos (i.e. XBl and HBl) compared with slower ones (i.e. TM, eBl and Bl; 0.46 ± 0.04, 0.46 ± 0.03, 0.14 ± 0.01, 1.66 ± 0.01 and 3.26 ± 0.3 U μg–1 of protein, in TM, eBl, Bl, XBl and HBl, respectively). At the same time, XBl and HBl showed the lowest NO2– levels. However, NO2– values were lower in TM compared with eBl and Bl (0.04 ± 0.002, 0.07 ± 0.005, 0.06 ± 0.003, 0.01 ± 0.002 and 0.01 ± 0.001 nM μg–1 of protein, in TM, eBl, Bl, XBl and HBl, respectively). Similarly to NO2–, TBARS levels were lower in XBl and HBl compared with the other stages (0.0059 ± 0.002, 0.009 ± 0.003, 0.006 ± 0.002, 0.001 ± 0.0001 and 0.0009 ± 0.0002 μM μg–1 of protein, in TM, eBl, Bl, XBl and HBl, respectively). In conclusion, these results clearly indicate developmental stage-dependent changes in MnSOD activity and levels of NO2– and TBARS, suggesting that oxidative stress and lipid peroxidation are reduced in faster developing embryos.

Foxo3 Transcription Factor Regulates Oxidative Stress in In Vivo Erythropoiesis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 468-468
Author(s):  
Dragan Marinkovic ◽  
Xin Zhang ◽  
Carlo Brugnara ◽  
Saghi Ghaffari
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Akt Signaling ◽  
Pi3 Kinase ◽  
Erythroid Cells ◽  
Akt Signaling Pathway ◽  
Ros Scavenging ◽  
Erythroid Progenitor ◽  
Scavenging Enzymes ◽  
Ros Scavenging Enzymes

Abstract Reactive oxygen species (ROS) such as superoxide anions and hydrogen peroxides are byproducts of normal oxidative metabolism that play an important role in regulating the proliferation of many cell types including hematopoietic cells. However, excess production of ROS induces damage to cellular components including DNA, maintains cellular transformation, apoptosis and senescence, and is associated with leukemias. Therefore highly regulated mechanisms are required for balancing ROS production during normal hematopoiesis. In particular, erythroid cells require an efficient scavenging mechanism for ROS because of high exposure to oxidative stress as a result of an abundance of heme iron. Specifically, deficiencies in erythroid ROS scavenging enzymes are associated with malignancies and other hematopoietic disorders such as sideroblastic anemia. We have recently shown that Erythropoietin (Epo)-induced activation of the PI3-kinase/AKT signaling pathway supports differentiation and maturation of primary erythroid progenitor cells (Zhao et al., Blood 2006; Ghaffari et al., Blood 2006). FOXO forkhead transcription factors constitute one of downstream targets of the PI3-kinase/AKT signaling pathway. In response to Epo, activation of PI3-kinase/AKT signaling pathway results in rapid phosphorylation of FOXO proteins triggering its translocation to the cytosol where, away from their transcriptional targets, FOXO are inhibited. FOXO proteins play many fundamental functions including protecting cells against oxidative insults by controlling the expression of ROS scavenging enzymes manganese superoxide dismutase and catalase. Here we show that Foxo3 is the most abundant FOXO protein in erythroid cells whose expression is upregulated several fold during maturation of mouse primary fetal liver erythroid progenitor cells. Using immunofluorescent staining and reporter gene assay, we show that Foxo3 enters the nucleus and becomes transcriptionally active as fetal liver erythroblasts mature. Notably, Foxo3 activation is concomitant with downregulation of Epo receptor (EpoR) on maturing erythroblasts. We further demonstrate that Foxo3 regulates levels of ROS in adult erythroid cells. In particular, eight to twelve week old Foxo3-deficient mice (kindly provided by Dr. Ron DePinho, Harvard Medical School) exhibit hemolysis that is responsive to in vivo therapy by N-Acetyl- l-Cysteine, a generic scavenger of ROS, suggesting that Foxo3−/ − hemolysis is induced by ROS. In addition, Foxo3−/ − hemolysis is characterized by enhanced concentration of erythroid ROS as determined by dichlorofluorescein assay and significantly decreased expression of ROS scavenging enzymes, leading to protein oxidation and shortened erythrocyte lifespan. In agreement with these results, Foxo3−/ − mice are highly sensitive to oxidative stress and, in contrast to their wild type counterparts, do not survive treatment with phenylhydrazine which reacts with hemoglobin to generate ROS. These results demonstrate that Foxo3 is required for protecting erythroid cells from oxidative stress. Finally, our data further support an important function for Foxo3 in coordinating cell cycle and differentiation of primary erythroblasts that is mediated by a ROS-regulated mechanism. Collectively, these findings establish Foxo3, a transcription factor targeted by EpoR signaling, as a regulator of oxidative stress in primary erythropoiesis.

scholarly journals Water restriction increases renal inner medullary manganese superoxide dismutase (MnSOD)

2012 ◽  
Vol 303 (5) ◽  
pp. F674-F680 ◽  
Author(s):  
Xiaoming Zhou ◽  
Maurice B. Burg ◽  
Joan D. Ferraris
Keyword(s):  
Oxidative Stress ◽  
Manganese Superoxide Dismutase ◽  
Mdck Cells ◽  
Mitochondrial Enzymes ◽  
Water Restriction ◽  
Manganese Superoxide ◽  
Tnf Α ◽  
Concentrate Urine ◽  
Important Regulator ◽  
Mnsod Activity

Oxidative stress damages cells. NaCl and urea are high in renal medullary interstitial fluid, which is necessary to concentrate urine, but which causes oxidative stress by elevating reactive oxygen species (ROS). Here, we measured the antioxidant enzyme superoxide dismutases (SODs, MnSOD, and Cu/ZnSOD) and catalase in mouse kidney that might mitigate the oxidative stress. MnSOD protein increases progressively from the cortex to the inner medulla, following the gradient of increasing NaCl and urea. MnSOD activity increases proportionately, but MnSOD mRNA does not. Water restriction, which elevates renal medullary NaCl and urea, increases MnSOD protein, accompanied by a proportionate increase in MnSOD enzymatic activity in the inner medulla, but not in the cortex or the outer medulla. In contrast, Cu/ZnSOD and TNF-α (an important regulator of MnSOD) do not vary between the regions of the kidney, and expression of catalase protein actually decreases from the cortex to the inner medulla. Water restriction increases activity of mitochondrial enzymes that catalyze production of ROS in the inner medulla, but reduces NADPH oxidase activity there. We also examined the effect of high NaCl and urea on MnSOD in Madin-Darby canine kidney (MDCK) cells. High NaCl and high urea both increase MnSOD in MDCK cells. This increase in MnSOD protein apparently depends on the elevation of ROS since it is eliminated by the antioxidant N-acetylcysteine, and it occurs without raising osmolality when ROS are elevated by antimycin A or xanthine oxidase plus xanthine. We conclude that ROS, induced by high NaCl and urea, increase MnSOD activity in the renal inner medulla, which moderates oxidative stress.

scholarly journals Maresin 1 protects the liver against ischemia/reperfusion injury via the ALXR/Akt signaling pathway

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Da Tang ◽  
Guang Fu ◽  
Wenbo Li ◽  
Ping Sun ◽  
Patricia A. Loughran ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Liver Injury ◽  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Serum Aminotransferase ◽  
Primary Mouse ◽  
Maresin 1

Abstract Background Hepatic ischemia/reperfusion (I/R) injury can be a major complication following liver surgery contributing to post-operative liver dysfunction. Maresin 1 (MaR1), a pro-resolving lipid mediator, has been shown to suppress I/R injury. However, the mechanisms that account for the protective effects of MaR1 in I/R injury remain unknown. Methods WT (C57BL/6J) mice were subjected to partial hepatic warm ischemia for 60mins followed by reperfusion. Mice were treated with MaR1 (5-20 ng/mouse), Boc2 (Lipoxin A4 receptor antagonist), LY294002 (Akt inhibitor) or corresponding controls just prior to liver I/R or at the beginning of reperfusion. Blood and liver samples were collected at 6 h post-reperfusion. Serum aminotransferase, histopathologic changes, inflammatory cytokines, and oxidative stress were analyzed to evaluate liver injury. Signaling pathways were also investigated in vitro using primary mouse hepatocyte (HC) cultures to identify underlying mechanisms for MaR1 in liver I/R injury. Results MaR1 treatment significantly reduced ALT and AST levels, diminished necrotic areas, suppressed inflammatory responses, attenuated oxidative stress and decreased hepatocyte apoptosis in liver after I/R. Akt signaling was significantly increased in the MaR1-treated liver I/R group compared with controls. The protective effect of MaR1 was abrogated by pretreatment with Boc2, which together with MaR1-induced Akt activation. MaR1-mediated liver protection was reversed by inhibition of Akt. Conclusions MaR1 protects the liver against hepatic I/R injury via an ALXR/Akt signaling pathway. MaR1 may represent a novel therapeutic agent to mitigate the detrimental effects of I/R-induced liver injury.

scholarly journals Protective Effects of Gintonin on Reactive Oxygen Species-Induced HT22 Cell Damages: Involvement of LPA1 Receptor-BDNF-AKT Signaling Pathway

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4138
Author(s):  
Yeon-Jin Cho ◽  
Sun-Hye Choi ◽  
Ra-Mi Lee ◽  
Han-Sung Cho ◽  
Hyewhon Rhim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Signaling Pathway ◽  
Reactive Oxygen ◽  
Akt Signaling ◽  
Atp Depletion ◽  
Oxygen Species ◽  
Akt Signaling Pathway ◽  
Neuroprotective Effects ◽  
Lpa1 Receptor

Gintonin is a kind of ginseng-derived glycolipoprotein that acts as an exogenous LPA receptor ligand. Gintonin has in vitro and in vivo neuroprotective effects; however, little is known about the cellular mechanisms underlying the neuroprotection. In the present study, we aimed to clarify how gintonin attenuates iodoacetic acid (IAA)-induced oxidative stress. The mouse hippocampal cell line HT22 was used. Gintonin treatment significantly attenuated IAA-induced reactive oxygen species (ROS) overproduction, ATP depletion, and cell death. However, treatment with Ki16425, an LPA1/3 receptor antagonist, suppressed the neuroprotective effects of gintonin. Gintonin elicited [Ca2⁺]i transients in HT22 cells. Gintonin-mediated [Ca2⁺]i transients through the LPA1 receptor-PLC-IP3 signaling pathway were coupled to increase both the expression and release of BDNF. The released BDNF activated the TrkB receptor. Induction of TrkB phosphorylation was further linked to Akt activation. Phosphorylated Akt reduced IAA-induced oxidative stress and increased cell survival. Our results indicate that gintonin attenuated IAA-induced oxidative stress in neuronal cells by activating the LPA1 receptor-BDNF-TrkB-Akt signaling pathway. One of the gintonin-mediated neuroprotective effects may be achieved via anti-oxidative stress in nervous systems.

scholarly journals Kahweol Ameliorates Cisplatin-Induced Acute Kidney Injury through Pleiotropic Effects in Mice

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 572
Author(s):  
Jung-Yeon Kim ◽  
Jungmin Jo ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Renal Injury ◽  
Manganese Superoxide Dismutase ◽  
Immune Cell ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Kidney Injury ◽  
Pleiotropic Effects ◽  
Induced Apoptosis ◽  
Vascular Adhesion

Cisplatin is an effective chemotherapeutic agent, but its clinical use is frequently limited by its nephrotoxicity. The pathogenesis of cisplatin-induced acute kidney injury (AKI) remains incompletely understood, but oxidative stress, tubular cell death, and inflammation are considered important contributors to cisplatin-induced renal injury. Kahweol is a natural diterpene extracted from coffee beans and has been shown to possess anti-oxidative and anti-inflammatory properties. However, its role in cisplatin-induced nephrotoxicity remains undetermined. Therefore, we investigated whether kahweol exerts a protective effect against cisplatin-induced renal injury. Additionally, its mechanisms were also examined. Administration of kahweol attenuated renal dysfunction and histopathological damage together with inhibition of oxidative stress in cisplatin-injected mice. Increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4 and decreased expression of manganese superoxide dismutase and catalase after cisplatin treatment were significantly reversed by kahweol. Moreover, kahweol inhibited cisplatin-induced apoptosis and necroptosis in the kidneys. Finally, kahweol reduced inflammatory cytokine production and immune cell accumulation together with suppression of nuclear factor kappa-B pathway and downregulation of vascular adhesion molecules. Together, these results suggest that kahweol ameliorates cisplatin-induced renal injury via its pleiotropic effects and might be a potential preventive option against cisplatin-induced nephrotoxicity.

scholarly journals The Remarkable Antioxidant and Anti-Inflammatory Potential of the Extracts of the Brown Alga Cystoseira amentacea var. stricta

Marine Drugs ◽  
2020 ◽  
Vol 19 (1) ◽  
pp. 2
Author(s):  
Gina De La Fuente ◽  
Marco Fontana ◽  
Valentina Asnaghi ◽  
Mariachiara Chiantore ◽  
Serena Mirata ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
No Production ◽  
Low Grade ◽  
Raw 264.7 ◽  
Ros Scavenging ◽  
Ligurian Sea ◽  
Raw 264.7 Macrophages ◽  
Pharmaceutical Industries ◽  
Anti Inflammatory ◽  
First Time

Inflammation and oxidative stress are part of the complex biological responses of body tissues to harmful stimuli. In recent years, due to the increased understanding that oxidative stress is implicated in several diseases, pharmaceutical industries have invested in the research and development of new antioxidant compounds, especially from marine environment sources. Marine seaweeds have shown the presence of many bioactive secondary metabolites, with great potentialities from both the nutraceutical and the biomedical point of view. In this study, 50%-ethanolic and DMSO extracts from the species C. amentacea var. stricta were obtained for the first time from seaweeds collected in the Ligurian Sea (north-western Mediterranean). The bioactive properties of these extracts were then investigated, in terms of quantification of specific antioxidant activities by relevant ROS scavenging spectrophotometric tests, and of anti-inflammatory properties in LPS-stimulated macrophages by evaluation of inhibition of inflammatory cytokines and mediators. The data obtained in this study demonstrate a strong anti-inflammatory effect of both C. amentacea extracts (DMSO and ethanolic). The extracts showed a very low grade of toxicity on RAW 264.7 macrophages and L929 fibroblasts and a plethora of antioxidant and anti-inflammatory effects that were for the first time thoroughly investigated. The two extracts were able to scavenge OH and NO radicals (OH EC50 between 392 and 454 μg/mL; NO EC50 between 546 and 1293 μg/mL), to partially rescue H2O2-induced RAW 264.7 macrophages cell death, to abate intracellular ROS production in H2O2-stimulated macrophages and fibroblasts and to strongly inhibit LPS-induced inflammatory mediators, such as NO production and IL-1α, IL-6, cyclooxygenase-2 and inducible NO synthase gene expression in RAW 264.7 macrophages. These results pave the way, for the future use of C. amentacea metabolites, as an example, as antioxidant food additives in antiaging formulations as well as in cosmetic lenitive lotions for inflamed and/or damaged skin.

scholarly journals Beneficial effect of 1,25 dihydroxyvitamin D3 on cytokine-treated human pancreatic islets

2001 ◽  
Vol 169 (1) ◽  
pp. 161-168 ◽  
Author(s):  
R Riachy ◽  
B Vandewalle ◽  
S Belaich ◽  
J Kerr-Conte ◽  
V Gmyr ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vitamin D ◽  
Cell Viability ◽  
Pancreatic Islets ◽  
Mhc Class I ◽  
Class I ◽  
Insulin Content ◽  
Hsp70 Expression ◽  
Human Pancreatic Islets ◽  
Mnsod Activity

We examined whether 1,25 dihydroxyvitamin D(3) (1,25 D(3)), the active form of vitamin D involved in the regulation of the immune system, may also protect human pancreatic islet cells from destruction induced by cytokines. In this study, we specifically investigated the effect of 1,25 D(3) on oxidative stress and major histocompatibility complex (MHC) induction, both implicated in cytokine-induced islet cell dysfunction and destruction. We also investigated the effects of 1,25 D(3) on interleukin (IL)-6, a pleiotropic cytokine implicated in the pathogenesis of immunoinflammatory disorders. Human pancreatic islets, isolated from heart-beating donors, were treated with a combination of three cytokines, IL-1beta+tumor necrosis factor alpha+interferon gamma, in the presence or absence of vitamin D, and compared with with untreated control cells. Metabolic activity was assessed by cell viability and insulin content. Oxidative stress was estimated by heat shock protein 70 (hsp70) expression, cell manganese superoxide dismutase (MnSOD) activity and nitrite release, a reflexion of nitric oxide (NO) synthesis. Variation of immunogenicity of islet preparations was determined by analysis of the MHC class I and class II transcripts. Inflammatory status was evaluated by IL-6 production. After 48 h of contact with cytokines, insulin content was significantly decreased by 40% but cell viability was not altered. MHC expression significantly increased six- to sevenfold as well as NO and IL-6 release (two- to threefold enhancement). MnSOD activity was not significantly induced and hsp70 expression was not affected by the combination of cytokines. The addition of 1,25 D(3) significantly reduced nitrite release, IL-6 production and MHC class I expression which then became not significantly different from controls. These results suggest that the effect of 1,25 D(3) in human pancreatic islets cells may be a reduction of the vulnerability of cells to cytotoxic T lymphocytes and a reduction of cytotoxic challenge. Hence, 1,25 D(3) might play a role in the prevention of type 1 diabetes and islet allograft rejection.

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