scholarly journals Ferric Carboxymaltose-Mediated Attenuation of Doxorubicin-Induced Cardiotoxicity in an Iron Deficiency Rat Model

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Jorge Eduardo Toblli ◽  
Carlos Rivas ◽  
Gabriel Cao ◽  
Jorge Fernando Giani ◽  
Felix Funk ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Nitrosative Stress ◽  
Ferric Carboxymaltose ◽  
Necrosis Factor Alpha ◽  
Spontaneously Hypertensive ◽  
Caveolin 1 ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Stress Markers ◽  
Neutrophil Gelatinase ◽  
Oxide Synthase

Since anthracycline-induced cardiotoxicity (AIC), a complication of anthracycline-based chemotherapies, is thought to involve iron, concerns exist about using iron for anaemia treatment in anthracycline-receiving cancer patients. This study evaluated how intravenous ferric carboxymaltose (FCM) modulates the influence of iron deficiency anaemia (IDA) and doxorubicin (3–5 mg per kg body weight [BW]) on oxidative/nitrosative stress, inflammation, and cardiorenal function in spontaneously hypertensive stroke-prone (SHR-SP) rats. FCM was given as repeated small or single total dose (15 mg iron per kg BW), either concurrent with or three days after doxorubicin. IDA (after dietary iron restriction) induced cardiac and renal oxidative stress (markers included malondialdehyde, catalase, Cu,Zn-superoxide dismutase, and glutathione peroxidase), nitrosative stress (inducible nitric oxide synthase and nitrotyrosine), inflammation (tumour necrosis factor-alpha and interleukin-6), and functional/morphological abnormalities (left ventricle end-diastolic and end-systolic diameter, fractional shortening, density of cardiomyocytes and capillaries, caveolin-1 expression, creatinine clearance, and urine neutrophil gelatinase-associated lipocalin) that were aggravated by doxorubicin. Notably, iron treatment with FCM did not exacerbate but attenuated the cardiorenal effects of IDA and doxorubicin independent of the iron dosing regimen. The results of this model suggest that intravenous FCM can be used concomitantly with an anthracycline-based chemotherapy without increasing signs of AIC.

Iron-deficiency anemia and cardio-renal toxicity of doxorubicin in hypertensive rats.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19569-e19569
Author(s):  
Jorge E Toblli ◽  
Carlos Rivas ◽  
Gabriel Cao ◽  
Jorge Giani ◽  
Fernando Dominici
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Nitrosative Stress ◽  
Renal Toxicity ◽  
Transferrin Saturation ◽  
Normal Diet ◽  
Deficiency Anemia ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Tissue Sections

e19569 Background: Hypertension and anemia are common in patients with neoplasm and may increase the toxicity of anti-cancer drugs. This study evaluated cardio-renaltoxicity of doxorubicin (DOX) in combination with iron deficiency anemia (IDA) in Spontaneously Hypertensive Stroke Prone (SHRSP) rats. Methods: SHRSP rats were randomized into six groups (A-F; n=8 each). IDA was induced in groups A-D by 12 weeks low iron diet; groups E and F had normal diet. After 6 weekly DOX or control treatments (0.9% saline), echocardiography was performed and blood analyzed for hemoglobin (Hb) and transferrin saturation (% TSAT). Tissue sections and homogenates from heart and kidney samples were analyzed for markers of oxidative-nitrosative stress and inflammation. Results: IDA plus DOX was associated with significantly lower cardiac performance (% FS) and kidney function (CrCl) and a higher degree of cardio-renal oxidative-nitrosative stress and inflammation (Table). Conclusions: The results show that IDA can aggravate dose dependent DOX-induced cardio-renal toxicity in hypertensive rats and confirm that IDA significantly induces oxidative-nitrosative stress and inflammation. [Table: see text]

scholarly journals Low-Dose Ribavirin Treatments Attenuate Neuroinflammatory Activation of BV-2 Cells by Interfering with Inducible Nitric Oxide Synthase

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Iva Bozic ◽  
Danijela Savic ◽  
Marija Jovanovic ◽  
Ivana Bjelobaba ◽  
Danijela Laketa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Low Dose ◽  
Nitrosative Stress ◽  
Morphological Changes ◽  
Necrosis Factor Alpha ◽  
External Threats ◽  
Cytokine Tumor Necrosis Factor ◽  
Induced Apoptosis ◽  
Oxide Synthase

Microglia play a key role in defending central nervous system from various internal and external threats. However, their excessive and/or chronic activation is associated with deleterious effects in a variety of neurodegenerative diseases. Previously, we have shown that ribavirin when applied in clinically relevant dosage (10 μM) modulates activated microglia in complex fashion inducing both anti- and proinflammatory effects, simultaneously causing cytotoxicity. Here, we examined potential of low-dose ribavirin (0.1 and 1 μM) to modulate activated BV-2 microglia. Morphological and functional activation of BV-2 cells was achieved with lipopolysaccharide (LPS) stimulation. Our results demonstrated that low-dose ribavirin did not induce cell death, while 10 μM ribavirin promoted LPS induced apoptosis. We determined that 1 μM ribavirin was equally efficient in deactivation of LPS induced morphological changes as 10 μM ribavirin treatment. Ribavirin showed halfway success in reducing markers of functional activation of microglia. Namely, none of the doses had effect on LPS triggered production of proinflammatory cytokine tumor necrosis factor alpha. On the other hand, low-dose ribavirin proved its effectiveness in reduction of another inflammatory mediator, nitric oxide, by inhibiting inducible form of nitric oxide synthase. Our results imply that low-dose ribavirin may alleviate nitrosative stress during neuroinflammation.

scholarly journals Caveolin-1/Endothelial Nitric Oxide Synthase Interaction Is Reduced in Arteries From Pregnant Spontaneously Hypertensive Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Jéssica A. Troiano ◽  
Simone R. Potje ◽  
Murilo E. Graton ◽  
Emily T. Gonçalves ◽  
Rita C. Tostes ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Wistar Rats ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Caveolin 1 ◽  
Vascular Bed ◽  
Hsp90 Expression ◽  
Mesenteric Vascular Bed ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

We have investigated the role caveolae/caveolin-1 (Cav-1) plays in endothelial nitric oxide synthase (eNOS) activation and how it impacts pregnancy-induced decreased vascular reactivity in normotensive (Wistar rats) and spontaneously hypertensive rats (SHR). Wistar rats and SHR were divided into non-pregnant (NP) and pregnant (P). Nitrite levels were assessed by the Griess method in the aorta and mesenteric vascular bed. In functional studies, arteries were incubated with methyl-β-cyclodextrin (dextrin, 10mmol/L), which disrupts caveolae by depleting cholesterol, and concentration-response curves to phenylephrine (PE) and acetylcholine (ACh) were constructed. Electronic microscopy was used to determine endothelial caveolae density in the aorta and resistance mesenteric artery in the presence of vehicle or dextrin (10mmol/L). Western blot was performed to evaluate Cav-1, p-Cav-1, calmodulin (CaM), and heat shock protein 90 (Hsp90) expression. Cav-1/eNOS interaction in the aorta and mesenteric vascular bed was assessed by co-immunoprecipitation. Nitric oxide (NO) generation was greater in arteries from P groups compared to NP groups. Dextrin did not change vascular responses in the aorta from P groups or the number of caveolae in P groups compared to NP groups. Compared to NP Wistar rats, NP SHR showed smaller number of caveolae and reduced Cav-1 expression. Pregnancy did not alter Cav-1, CaM, or Hsp90 expression in the aorta or mesenteric vascular bed from Wistar rats or SHR. These results suggest that pregnancy does not alter expression of the main eNOS regulatory proteins, but it decreases Cav-1/eNOS interaction. Reduced Cav-1/eNOS interaction in the aorta and mesenteric vascular bed seems to be an important mechanism to increase eNOS activity and nitric oxide production in pregnant normotensive and hypertensive rats.

Neutrophil gelatinase-associated lipocalin (NGAL) role in diagnosis of complications of liver cirrhosis

2021 ◽  
Vol 30 (2) ◽  
pp. 21-25
Author(s):  
Dalia K. Nassar ◽  
Mohamed F. Elkenawy ◽  
Mohammed M. El-Naggar ◽  
El-Sayed A. Khali ◽  
Ghada I. Barakat
Keyword(s):  
Acute Phase Protein ◽  
Kidney Injury ◽  
Necrosis Factor Alpha ◽  
Bacterial Peritonitis ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Tnf Α ◽  
Factor Alpha ◽  
Low Levels ◽  
Neutrophil Gelatinase ◽  
Necrosis Factor

Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa glycoprotein that is normally expressed at very low levels in several human tissues. NGAL comprises a critical component of innate immunity to bacterial infection acting as an acute phase protein. Also, it is one of the most promising markers for diagnosis of kidney injury. Abbreviations: NGAL: Neutrophil gelatinase-associated lipocalin, AKI: acute kidney injury, kDa: Kilo Dalton, ACLF: acute on chronic liver failure, LPS: lipopolysaccharides, TNF α: tumor necrosis factor alpha, SBP: spontaneous bacterial peritonitis.

Dietary iron deficiency induces ventricular dilation, mitochondrial ultrastructural aberrations and cytochrome c release: involvement of nitric oxide synthase and protein tyrosine nitration

2005 ◽  
Vol 109 (3) ◽  
pp. 277-286 ◽  
Author(s):  
Feng Dong ◽  
Xiaochun Zhang ◽  
Bruce Culver ◽  
Herbert G. Chew ◽  
Robert O. Kelley ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Cytochrome C ◽  
Nadph Oxidase ◽  
Dietary Iron ◽  
Cytochrome C Release ◽  
Caveolin 1 ◽  
Iron Deficient ◽  
Oxide Synthase ◽  
Cardiac Ultrastructure ◽  
Deficient Group

Iron deficiency is associated with multiple health problems, including the cardiovascular system. However, the mechanism of action of iron-deficiency-induced cardiovascular damage is unclear. The aim of the present study was to examine the effect of dietary iron deficiency on cardiac ultrastructure, mitochondrial cytochrome c release, NOS (nitric oxide synthase) and several stress-related protein molecules, including protein nitrotyrosine, the p47phox subunit of NADPH oxidase, caveolin-1 and RhoA. Male weanling rats were fed with either control or iron-deficient diets for 12 weeks. Cardiac ultrastructure was examined by transmission electron microscopy. Western blot analysis was used to evaluate cytochrome c, endothelial and inducible NOS, NADPH oxidase, caveolin-1 and RhoA. Protein nitrotyrosine formation was measured by ELISA. Rats fed an iron-deficient diet exhibited increased heart weight and size compared with the control group. Heart width, length and ventricular free wall thickness were similar between the two groups. However, the left ventricular dimension and chamber volume were significantly enhanced in the iron-deficient group compared with controls. Ultrastructural examination revealed mitochondrial swelling and abnormal sarcomere structure in iron-deficient ventricular tissues. Cytochrome c release was significantly enhanced in iron-deficient rats. Protein expression of eNOS (endothelial NOS) and iNOS (inducible NOS), and protein nitrotyrosine formation were significantly elevated in cardiac tissue or mitochondrial extraction from the iron-deficient group. Significantly up-regulated NADPH oxidase, caveolin-1 and RhoA expression were also detected in ventricular tissue of the iron-deficient group. Taken together, these results suggest that dietary iron deficiency may have induced cardiac hypertrophy characterized by aberrant mitochondrial and irregular sarcomere organization, which was accompanied by increased reactive nitrogen species and RhoA expression.

Genetic locus on MWF rat chromosome 6 affects kidney damage in response to l-NAME treatment in spontaneously hypertensive rats

2010 ◽  
Vol 42 (1) ◽  
pp. 126-133 ◽  
Author(s):  
Angela Schulz ◽  
Sabrina Schütten ◽  
Leonard Schulte ◽  
Peter Kossmehl ◽  
Jens R. Nyengaard ◽  
...  
Keyword(s):  
Spontaneously Hypertensive Rats ◽  
Genetic Locus ◽  
Premature Mortality ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Arterial Blood ◽  
Trait Locus ◽  
Neutrophil Gelatinase ◽  
Structural Injury

A major quantitative trait locus (QTL) on rat chromosome (RNO)6 was linked to albuminuria in Munich Wistar Frömter rats (MWF). We tested whether transfer of MWF RNO6 into the background of albuminuria-resistant spontaneously hypertensive rats (SHR) induces albuminuria in consomic SHR-6MWF animals. Male MWF, SHR, and SHR-6MWF were sham operated and treated between 6 and 24 wk of age with normal water (Sham) or with water containing 20 mg/l NG-nitro-l-arginine methyl ester (l-NAME) or unilaterally nephrectomized (Nx). Compared with SHR albuminuria was not increased in SHR-6MWF in both Sham and Nx groups. All animals survived the observation period in Sham and Nx groups, while premature mortality occurred from 12–14 wk on in l-NAME-treated SHR and SHR-6MWF compared with MWF l-NAME animals, in which survival was not affected ( P < 0.005, respectively). Subsequent further analysis of l-NAME-treated animals at 12 wk of age showed significantly increased arterial blood pressures in both SHR and SHR-6MWF compared with control ( P < 0.05), with higher levels in SHR compared with consomics ( P < 0.05). However, l-NAME-treated consomic animals demonstrated increased albuminuria compared with SHR (12.7 ± 3.5 vs. 0.8 ± 0.2 mg/24 h; P < 0.05) and an induction of tubulointerstitial structural injury and expression of neutrophil gelatinase-associated lipocalin mRNA ( P < 0.05 vs. other strains). Our study demonstrates that isolation of the RNO6 albuminuria QTL from the MWF background and transfer into SHR fails to induce an albuminuria phenotype during normal conditions or after nephron reduction. Moreover, our data indicate that genes on RNO6 contribute to the development of l-NAME-induced renal damage in the SHR strain.

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