scholarly journals Rho-Family Small GTPases: From Highly Polarized Sensory Neurons to Cancer Cells

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 92 ◽  
Author(s):  
Takehiko Ueyama
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Small Gtpases ◽  
In Vivo Studies ◽  
Signal Pathways ◽  
Ros Production ◽  
Oxygen Species ◽  
Rho Family Gtpases ◽  
Rho Family

The small GTPases of the Rho-family (Rho-family GTPases) have various physiological functions, including cytoskeletal regulation, cell polarity establishment, cell proliferation and motility, transcription, reactive oxygen species (ROS) production, and tumorigenesis. A relatively large number of downstream targets of Rho-family GTPases have been reported for in vitro studies. However, only a small number of signal pathways have been established at the in vivo level. Cumulative evidence for the functions of Rho-family GTPases has been reported for in vivo studies using genetically engineered mouse models. It was based on different cell- and tissue-specific conditional genes targeting mice. In this review, we introduce recent advances in in vivo studies, including human patient trials on Rho-family GTPases, focusing on highly polarized sensory organs, such as the cochlea, which is the primary hearing organ, host defenses involving reactive oxygen species (ROS) production, and tumorigenesis (especially associated with RAC, novel RAC1-GSPT1 signaling, RHOA, and RHOBTB2).

Scavenging of Reactive Oxygen Species and Inhibition of the Oxidation of Low Density Lipoprotein by the Aqueous Extraction ofAnoectochilus formosanus

2003 ◽  
Vol 31 (01) ◽  
pp. 25-36 ◽  
Author(s):  
Chun-Ching Shih ◽  
Yueh-Wern Wu ◽  
Wen-Chuan Lin
Keyword(s):  
Reactive Oxygen Species ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Reactive Oxygen ◽  
In Vivo Studies ◽  
Ldl Oxidation ◽  
Low Density ◽  
Dependent Manner ◽  
Oxygen Species

The ability of Anoectochilus formosanus extract (AFE) to react with relevant biological oxidants was evaluated in this study. In addition, its effect on oxidation of low density lipoprotein (LDL) was investigated in vitro and in vivo. AFE could scavenge reactive oxygen species, such as superoxide anion and hydroxyl radical. The study of human LDL oxidation showed that AFE delayed oxidation in a concentration-dependent manner. In vivo studies also showed that oral administration of AFE delayed the oxidation of LDL from hyperlipidemic hamsters. The ability of AFE to scavenge free radicals suggests that it may be a promising anti-atherogenic agent.

scholarly journals In Vivo Imaging of Reactive Oxygen Species in Mouse Brain by using [3H]Hydromethidine as a Potential Radical Trapping Radiotracer

2014 ◽  
Vol 34 (12) ◽  
pp. 1907-1913 ◽  
Author(s):  
Kohji Abe ◽  
Nozomi Takai ◽  
Kazumi Fukumoto ◽  
Natsumi Imamoto ◽  
Misato Tonomura ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Production Model ◽  
Whole Body ◽  
Ros Production ◽  
Oxygen Species ◽  
Radical Trapping ◽  
The Brain

To assess reactive oxygen species (ROS) production by detecting the fluorescent oxidation product, hydroethidine has been used extensively. The present study was undertaken to evaluate the potential of the hydroethidine derivative as a radiotracer to measure in vivo brain ROS production. [3H]-labeled N-methyl-2,3-diamino-6-phenyl-dihydrophenanthridine ([3H]Hydromethidine) was synthesized, and evaluated using in vitro radical-induced oxidization and in vivo brain ROS production model. In vitro studies have indicated that [3H]Hydromethidine is converted to oxidized products by a superoxide radical (O2• -) and a hydroxyl radical (OH• -) but not hydrogen peroxide (H2O2). In vivo whole-body distribution study showed that [3H]Hydromethidine rapidly penetrated the brain and then was washed out in normal mice. Microinjection of sodium nitroprusside (SNP) into the brain was performed to produce ROS such as OH• - via Fenton reaction. A significant accumulation of radioactivity immediately after [3H]Hydromethidine injection was seen in the side of the brain treated with SNP (5 and 20 nmol) compared with that in the contralateral side. These results indicated that [3H]Hydromethidine freely penetrated into the brain where it was rapidly converted to oxidized forms, which were trapped there in response to the production of ROS. Thus, [3H]Hydromethidine should be useful as a radical trapping radiotracer in the brain.

scholarly journals Mutant Kras as a Biomarker Plays a Favorable Role in FL118-Induced Apoptosis, Reactive Oxygen Species (ROS) Production and Modulation of Survivin, Mcl-1 and XIAP in Human Bladder Cancer

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3413
Author(s):  
Sreevidya Santha ◽  
Xiang Ling ◽  
Ieman A. M. Aljahdali ◽  
Sailee S. Rasam ◽  
Xue Wang ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Bladder Cancer ◽  
Reactive Oxygen ◽  
In Vivo Studies ◽  
Parp Cleavage ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Wild Type ◽  
Kras Mutations

Tumor heterogeneity in key gene mutations in bladder cancer (BC) is a major hurdle for the development of effective treatments. Using molecular, cellular, proteomics and animal models, we demonstrated that FL118, an innovative small molecule, is highly effective at killing T24 and UMUC3 high-grade BC cells, which have Hras and Kras mutations, respectively. In contrast, HT1376 BC cells with wild-type Ras are insensitive to FL118. This concept was further demonstrated in additional BC and colorectal cancer cells with mutant Kras versus those with wild-type Kras. FL118 strongly induced PARP cleavage (apoptosis hallmark) and inhibited survivin, XIAP and/or Mcl-1 in both T24 and UMUC3 cells, but not in the HT1376 cells. Silencing mutant Kras reduced both FL118-induced PARP cleavage and downregulation of survivin, XIAP and Mcl-1 in UMUC3 cells, suggesting mutant Kras is required for FL118 to exhibit higher anticancer efficacy. FL118 increased reactive oxygen species (ROS) production in T24 and UMUC3 cells, but not in HT1376 cells. Silencing mutant Kras in UMUC3 cells reduced FL118-mediated ROS generation. Proteomics analysis revealed that a profound and opposing Kras-relevant signaling protein is changed in UMUC3 cells and not in HT1376 cells. Consistently, in vivo studies indicated that UMUC3 tumors are highly sensitive to FL118 treatment, while HT1376 tumors are highly resistant to this agent. Silencing mutant Kras in UMUC3 cell-derived tumors decreases UMUC3 tumor sensitivity to FL118 treatment. Together, our studies revealed that mutant Kras is a favorable biomarker for FL118 targeted treatment.

scholarly journals Dual Regulation of Tank Binding Kinase 1 by BRG1 in Hepatocytes Contributes to Reactive Oxygen Species Production

2021 ◽  
Vol 9 ◽  
Author(s):  
Fangqiao Lv ◽  
Tinghui Shao ◽  
Yujia Xue ◽  
Xiulian Miao ◽  
Yan Guo ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Transcriptional Level ◽  
Ros Production ◽  
Oxygen Species ◽  
Alcoholic Fatty Liver ◽  
The One ◽  
Species Production

Excessive accumulation of reactive oxygen species (ROS) is considered a major culprit for the pathogenesis of non-alcoholic fatty liver disease (NAFLD). We have previously shown that deletion of Brahma related gene 1 (BRG1) mitigated NAFLD in mice in part by attenuating ROS production in hepatocyte. Here we report that BRG1 deletion led to simultaneous down-regulation in expression and phosphorylation of tank binding kinase 1 (TBK1) in vivo and in vitro. On the one hand, BRG1 interacted with AP-1 to bind to the TBK1 promoter and directly activated TBK1 transcription in hepatocytes. On the other hand, BRG1 interacted with Sp1 to activate the transcription of c-SRC, a tyrosine kinase essential for TBK1 phosphorylation. Over-expression of c-SRC and TBK1 corrected the deficiency in ROS production in BRG1-null hepatocytes whereas depletion of TBK1 or c-SRC attenuated ROS production. In conclusion, our data suggest that dual regulation of TBK1 activity, at the transcription level and the post-transcriptional level, by BRG1 may constitute an important mechanism underlying excessive ROS production in hepatocytes.

scholarly journals ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity

2015 ◽  
Vol 309 (8) ◽  
pp. H1271-H1280 ◽  
Author(s):  
Frances Belmonte ◽  
Samarjit Das ◽  
Polina Sysa-Shah ◽  
Vidhya Sivakumaran ◽  
Brian Stanley ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Antioxidant Defenses ◽  
In Vivo Studies ◽  
Oxygen Species ◽  
Doxorubicin Treatment ◽  
Neonatal Cardiomyocytes ◽  
Erbb2 Protein ◽  
The Status

Levels of the HER2/ErbB2 protein in the heart are upregulated in some women during breast cancer therapy, and these women are at high risk for developing heart dysfunction after sequential treatment with anti-ErbB2/trastuzumab or doxorubicin. Doxorubicin is known to increase oxidative stress in the heart, and thus we considered the possibility that ErbB2 protein influences the status of cardiac antioxidant defenses in cardiomyocytes. In this study, we measured reactive oxygen species (ROS) in cardiac mitochondria and whole hearts from mice with cardiac-specific overexpression of ErbB2 (ErbB2 tg) and found that, compared with control mice, high levels of ErbB2 in myocardium result in lower levels of ROS in mitochondria ( P = 0.0075) and whole hearts ( P = 0.0381). Neonatal cardiomyocytes isolated from ErbB2 tg hearts have lower ROS levels and less cellular death ( P < 0.0001) following doxorubicin treatment. Analyzing antioxidant enzyme levels and activities, we found that ErbB2 tg hearts have increased levels of glutathione peroxidase 1 (GPx1) protein ( P < 0.0001) and GPx activity ( P = 0.0031) in addition to increased levels of two known GPx activators, c-Abl ( P = 0.0284) and Arg ( P < 0.0001). Interestingly, although mitochondrial ROS emission is reduced in the ErbB2 tg hearts, oxygen consumption rates and complex I activity are similar to control littermates. Compared with these in vivo studies, H9c2 cells transfected with ErbB2 showed less cellular toxicity and produced less ROS ( P < 0.0001) after doxorubicin treatment but upregulated GR activity ( P = 0.0237) instead of GPx. Our study shows that ErbB2-dependent signaling contributes to antioxidant defenses and suggests a novel mechanism by which anticancer therapies involving ErbB2 antagonists can harm myocardial structure and function.

scholarly journals The Insert Region of Rac1 Is Essential for Membrane Ruffling but Not Cellular Transformation

2001 ◽  
Vol 21 (8) ◽  
pp. 2847-2857 ◽  
Author(s):  
Antoine E. Karnoub ◽  
Channing J. Der ◽  
Sharon L. Campbell
Keyword(s):  
Reactive Oxygen Species ◽  
Serum Response Factor ◽  
Reactive Oxygen ◽  
Cellular Transformation ◽  
Small Gtpases ◽  
Oxygen Species ◽  
Membrane Ruffling ◽  
Actin Organization ◽  
Insert Region

ABSTRACT The Rho family of Ras-related proteins, which includes Rac1, RhoA, and Cdc42, is distinguished from other members of the Ras superfamily of small GTPases in that its members possess additional sequences positioned between β-strand 5 and α-helix 4, designated the insert region. Previous studies have established the importance of an intact insert region for the transforming, but not actin cytoskeletal reorganization, activities of Cdc42 and RhoA. Similarly, the insert region was determined to be essential for Rac1-mediated mitogenesis. Additionally, an intact insert region was also determined to be required for the antiapoptotic activity of Rac1 as well as for Rac1 activation of reactive oxygen species and the NF-κB transcription factor. However, it has not been determined whether the insert region is important for Rac1-mediated growth transformation. In this study, we assessed the requirement for the insert region in Rac1 transformation and signaling in NIH 3T3 cells. Unexpectedly, we found that a mutant of constitutively activated Rac1 that lacked the insert region retained potent transforming activity. The insert region of Rac1 was dispensable for Rac1 stimulation of transcription from the cyclin D1 promoter and for activation of the c-Jun, NF-κB, and E2F-1 transcription factors but was essential for Rac1 induction of serum response factor activity. While an intact insert region was dispensable for inducing reactive oxygen species production in vivo, it was required for Rac1 induction of lamellipodia. When taken together, these results show that the insert region of Rac1 serves roles in regulating actin organization and cell growth that are distinct from those of the analogous regions of Cdc42 and RhoA and support its involvement in regulating specific downstream effector interactions.

scholarly journals Green Tea Suppresses the Radiation-Induced Increase of the AngiotensinConverting Enzyme & Reactive Oxygen Species in the Aorta of Rats

2021 ◽  
pp. 1-5
Author(s):  
Yuri. N. Korystov ◽  
Antonina Korystova ◽  
Ludmila Kublik ◽  
Maria Levitman ◽  
Tamara Samochvalova ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Green Tea ◽  
Control Level ◽  
Reactive Oxygen ◽  
Peroral Administration ◽  
Ros Production ◽  
Oxygen Species ◽  
Radiation Induced ◽  
Ace Activity

The consumption of green tea reduces the risk of cardiovascular diseases and suppresses the development of atherosclerosis. The main factor for the initiation and progression of atherosclerosis is an increase in the production of reactive oxygen species (ROS) in vessels. A significant contribution to the increase in ROS production is made by increased concentration of angiotensin II, a product of the angiotensin-converting enzyme (ACE). The effect of green tea on the level of ROS and ACE activity in blood vessels in vivo has not yet been studied. The activity of ACE in aorta sections of rat was determined by measuring the hydrolysis of hippuryl-L-histidyl-L-leucine, and the production of ROS was estimated from the oxidation of dichlorodihydrofluorescein. Green tea inhibited the radiation-induced activation of the ACE in the aorta of rats on intraperitoneal (i.p.) and peroral administration. Six hours after the administration of tea, the activity of ACE in irradiated rats decreased to the control level, and by 24 h after administration, the tea did not almost affect the ACE activity. On i.p. administration, effective doses were lower than on peroral administration. The concentration of orally administered tea that inhibited the ACE activation in irradiated rats by 50% (IC50) was 1 ml of an extract of 2.1 g of tea brewed per 100 ml of water. One milliliter of i.p. administered green tea (1 g per 100 ml of water) completely suppressed the increased ROS production in the aorta of irradiated rats.

scholarly journals DNA origami as a nanomedicine for targeted rheumatoid arthritis therapy through reactive oxygen species and nitric oxide scavenging

2022 ◽  
Author(s):  
Yuxuan Ma ◽  
Zhangwei Lu ◽  
Ye Shi ◽  
Zhe Li
Keyword(s):  
Rheumatoid Arthritis ◽  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Dna Origami ◽  
In Vivo Studies ◽  
Oxygen Species ◽  
Collagen Induced Arthritis ◽  
M1 Macrophages

High levels of reactive oxygen species (ROS) and nitric oxide (NO) generated by M1 macrophages induce inflammation in the development of rheumatoid arthritis (RA). The eliminating of ROS and NO therefore represents an alternative strategy for RA treatment. Because DNA molecules possess ROS- and endogenous NO-scavenging capability, herein, we develop a nanomedicine based on triangular DNA origami nanostructures for targeted RA treatment. We showed that folic acid-modified triangular DNA origami nanostructures (FA-tDONs) could reduce ROS and NO simultaneously inside proinflammatory M1 macrophages, leading to their polarization into anti-inflammatory M2 subtype. Further in vivo studies confirmed that FA-tDONs could actively target inflamed joints in collagen-induced arthritis (CIA) mice, attenuate inflammatory cytokines and alleviate disease progression. This work demonstrated that DNA origami itself could act as a potential nanomedicine for targeted RA treatment.

scholarly journals Acid Sphingomyelinase Contributes to the Control of Mycobacterial Infection via a Signaling Cascade Leading from Reactive Oxygen Species to Cathepsin D

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2406
Author(s):  
Yuqing Wu ◽  
Cao Li ◽  
Huiming Peng ◽  
Ashraf Swaidan ◽  
Andrea Riehle ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cathepsin D ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Reactive Oxygen ◽  
Systemic Infection ◽  
Acid Sphingomyelinase ◽  
In Vivo Studies ◽  
Oxygen Species

Tuberculosis, caused by Mycobacterium tuberculosis, is one of the most severe diseases worldwide. The initial pulmonary localization of the pathogen often develops into systemic infection with high lethality. The present work investigated the role of sphingolipids, specifically the function of acid sphingomyelinase (Asm) and ceramide, in infection of murine macrophages in vitro and mice in vivo with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). In vitro, we investigated macrophages from wild-type (wt) and Asm deficient (Asm−/−) mice to define signaling events induced by BCG infection and mediated by Asm. We demonstrate that infection of wt macrophages results in activation of Asm, which increases reactive oxygen species (ROS) via stimulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. ROS promote BCG degradation by cathepsin D. Asm deficiency in macrophages abrogates these effects. In vivo studies reveal that wt mice rapidly control BCG infection, while Asm−/− mice fail to control the infection and kill the bacteria. Transplantation of wt macrophages into Asm−/− mice reversed their susceptibility to BCG, demonstrating the importance of Asm in macrophages for defense against BCG. These findings indicate that Asm is important for the control of BCG infection.

scholarly journals Notch1 Pathway Protects against Burn-Induced Myocardial Injury by Repressing Reactive Oxygen Species Production through JAK2/STAT3 Signaling

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Weixia Cai ◽  
Xuekang Yang ◽  
Shichao Han ◽  
Haitao Guo ◽  
Zhao Zheng ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Notch Signaling ◽  
Myocardial Injury ◽  
Reactive Oxygen ◽  
Ros Production ◽  
Oxygen Species ◽  
Cellular Mechanisms ◽  
Stat3 Signaling

Oxidative stress plays an important role in burn-induced myocardial injury, but the cellular mechanisms that control reactive oxygen species (ROS) production and scavenging are not fully understood. This study demonstrated that blockade of Notch signaling via knockout of the transcription factor RBP-J or a pharmacological inhibitor aggravated postburn myocardial injury, which manifested as deteriorated serum CK, CK-MB, and LDH levels and increased apoptosisin vitroandin vivo. Interruption of Notch signaling increased intracellular ROS production, and a ROS scavenger reversed the exacerbated myocardial injury after Notch signaling blockade. These results suggest that Notch signaling deficiency aggravated postburn myocardial injury through increased ROS levels. Notch signaling blockade also decreased MnSOD expressionin vitroandin vivo. Notably, Notch signaling blockade downregulated p-JAK2 and p-STAT3 expression. Inhibition of JAK2/STAT3 signaling with AG490 markedly decreased MnSOD expression, increased ROS production, and aggravated myocardial injury. AG490 plus GSI exerted no additional effects. These results demonstrate that Notch signaling protects against burn-induced myocardial injury through JAK2/STAT3 signaling, which activates the expression of MnSOD and leads to decreased ROS levels.

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