scholarly journals The Cardioprotective Mechanism of Phenylaminoethyl Selenides (PAESe) Against Doxorubicin-Induced Cardiotoxicity Involves Frataxin

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoyu Fu ◽  
Mathew Eggert ◽  
Sieun Yoo ◽  
Nikhil Patel ◽  
Juming Zhong ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cumulative Dose ◽  
Myocardial Damage ◽  
Cellular Respiration ◽  
Protective Mechanism ◽  
Iron Sulfur Cluster ◽  
Free Iron ◽  
Ros Formation ◽  
H9c2 Cardiomyoblasts ◽  
The Stability

Doxorubicin (DOX) is an anthracycline cancer chemotherapeutic that exhibits cumulative dose-limiting cardiotoxicity and limits its clinical utility. DOX treatment results in the development of morbid cardiac hypertrophy that progresses to congestive heart failure and death. Recent evidence suggests that during the development of DOX mediated cardiac hypertrophy, mitochondrial energetics are severely compromised, thus priming the cardiomyocyte for failure. To mitigate cumulative dose (5 mg/kg, QIW x 4 weeks with 2 weeks recovery) dependent DOX, mediated cardiac hypertrophy, we applied an orally active selenium based compound termed phenylaminoethyl selenides (PAESe) (QIW 10 mg/kg x 5) to our animal model and observed that PAESe attenuates DOX-mediated cardiac hypertrophy in athymic mice, as observed by MRI analysis. Mechanistically, we demonstrated that DOX impedes the stability of the iron-sulfur cluster biogenesis protein Frataxin (FXN) (0.5 fold), resulting in enhanced mitochondrial free iron accumulation (2.5 fold) and reduced aconitase activity (0.4 fold). Our findings further indicate that PAESe prevented the reduction of FXN levels and the ensuing elevation of mitochondrial free iron levels. PAESe has been shown to have anti-oxidative properties in part, by regeneration of glutathione levels. Therefore, we observed that PAESe can mitigate DOX mediated cardiac hypertrophy by enhancing glutathione activity (0.4 fold) and inhibiting ROS formation (1.8 fold). Lastly, we observed that DOX significantly reduced cellular respiration (basal (5%) and uncoupled (10%)) in H9C2 cardiomyoblasts and that PAESe protects against the DOX-mediated attenuation of cellular respiration. In conclusion, the current study determined the protective mechanism of PAESe against DOX mediated myocardial damage and that FXN is implicitly involved in DOX-mediated cardiotoxicity.

Abstract 51: Thymosin β4 Targets Wisp1 to Protect Cardiomyocytes in AngII- induced Cardiac Hypertrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Sudhiranjan Gupta ◽  
Li Li ◽  
Rakesh Guleria ◽  
Kenneth M Baker
Keyword(s):  
Cardiac Hypertrophy ◽  
Fluorescent Microscopy ◽  
Marker Genes ◽  
Protective Mechanism ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Antiapoptotic Proteins ◽  
Neonatal Cardiomyocytes ◽  
Cell Proliferation And Differentiation ◽  
Pre Treatment

Background: Thymosin beta-4 (Tβ4) is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. However, the role of Tβ4 in cardiomyocytes hypertrophy is currently unknown. The purpose of this study is to dissect the cardio-protective mechanism of Tβ4 in Ang II induced cardiac hypertrophy. Methods: Rat neonatal cardiomyocytes with or without Tβ4 pretreatment were stimulated with Ang II and expression of cell sizes, hypertrophy marker genes and Wnt signaling components was evaluated by quantitative real-time PCR, western blotting and fluorescent microscopy. Selected target gene Wisp-1 was either overexpressed or silenced by siRNA transfections in neonatal cardiomyocytes and effect of Tβ4 in Ang II-induced cardiac hypertrophy was evaluated. Results: Pre-treatment of Tβ4 resulted in reduction of cell sizes, hypertrophy marker genes and WNT-associated gene expression and levels induced by Ang II in cardiomyocytes. Tβ4 pretreatment also resulted in an increase in the expression of antiapoptotic proteins and reduction of Bax/BCl 2 ratio in the cardiomyocytes. Wisp-1 overexpression promotes cardiac hypertrophy and was reversed by pretreatment with Tβ4. Knocking down of Wisp1 partly rescue the cells from hypertrophic response after Tβ4 treatment. Conclusion: This is the first report that demonstrates the effect of Tβ4 on cardiomyocytes hypertrophy and its capability to selectively target Wisp-1 in neonatal cardiomyocytes thus preventing cell death, thereby, protecting the myocardium. Wisp-1 promotes the cardiac hypertrophy which was prevented by Tβ4 treatment.

scholarly journals Evaluation of subclinical cardiotoxicity in patients with breast cancer and arterial hypertension in two regimens of anthracycline-containing chemotherapy

2018 ◽  
Vol 15 (4) ◽  
pp. 59-64 ◽  
Author(s):  
A A Avalyan ◽  
E V Oshchepkova ◽  
M A Saidova ◽  
V N Shitov ◽  
E V Glazkova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Arterial Hypertension ◽  
Cumulative Dose ◽  
Treatment Duration ◽  
Troponin T ◽  
Myocardial Damage ◽  
Breast Cancer Patients ◽  
Duration Of Treatment ◽  
Imaging Results ◽  
Group 2

Objective. To study of subclinical cardiotoxicity of two anthracycline-containing chemotherapy regimens in breast cancer patients with normotension and arterial hypertension. Materials and methods. 119 women (mean age 48,8±10,9 years) with triple negative breast cancer were enrolled. They are received one of two chemotherapy options that differed in the intensity and duration of treatment, including the total dose of anthracyclines. Depending on the chemotherapy option, the patients were divided into two groups: group 1 (n=54) - treatment duration ≤8 weeks, cumulative dose of doxorubicin was 200 mg/m2, group 2 (n=65) - treatment duration ≤16 weeks, the cumulative dose of doxorubicin was 320 mg/m2. Before and after chemotherapy completion of all patients, the level of troponin T (h.s.) and NT-proBNP was determined, and heart ultrasound was performed, 2D and 3D speckle tracking imaging. Results. In patients who received a higher cumulative dose of doxorubicin (group 2), a statistically significant increase in biomarkers of myocardial damage was observed (h.s. troponin T before chemotherapy was 7.8±0.5 pg/ml, after chemotherapy - 55.0±7.0 pg/ml, p

Effect of oxygen on the stability and inducibility of the biodegradative capability of benzoate

2003 ◽  
Vol 48 (8) ◽  
pp. 247-254 ◽  
Author(s):  
Ö Çinar ◽  
T. Deniz ◽  
C.P.L. Grady
Keyword(s):  
Oxygen Demand ◽  
Exposure Period ◽  
Protective Mechanism ◽  
Batch Reactors ◽  
Anoxic Conditions ◽  
Recirculation Flow ◽  
Anoxic Environments ◽  
The Stability ◽  
Effect Of Oxygen ◽  
Almost All

Anoxic zones in biological nitrogen removal systems are typically open to the atmosphere and receive oxygen from the atmosphere and the recirculation flow from the aerobic zone. This raises the question of how such oxygen input might influence the stability and inducibility of the enzyme systems involved in biodegradation of aromatic compounds. To investigate this, various amounts of oxygen were added to mixed culture denitrifying chemostats receiving benzoate at 667 mg/h as chemical oxygen demand (COD), and the stability and inducibility of the culture’s benzoate biodegradative capability (BBC) were tested in aerobic and anoxic fed-batch reactors (FBRs). Cultures from chemostats receiving oxygen at 0, 33, 133, 266, and 466 mg O2/h lost almost all of their anoxic BBC within one hour after being transferred to an aerobic FBR and the first three cultures did not recover it upon being returned to anoxic conditions. The last two cultures recovered their anoxic BBC between 9 and 16 h during the 16 h aerobic exposure period that preceded their return to anoxic conditions and continued to increase their anoxic BBC as they were retained under anoxic conditions. In contrast, the culture from a chemostat receiving oxygen at 67 mg O2/h retained its anoxic BBC longer, recovered it within 3 h after its return to anoxic conditions, and increased it linearly thereafter. None of the cultures developed any aerobic BBC during the 16 h aerobic exposure period in FBRs. The results suggest that higher oxygen inputs into anoxic reactors helped the mixed microbial cultures recover and/or induced anoxic BBC more easily when they were exposed to alternating aerobic/anoxic environments. The exceptional behavior of the culture from the chemostat receiving oxygen at a rate of 67 mg O2/h may have been caused by the presence of a protective mechanism against the toxic forms of oxygen.

Abstract 239: Selective Class I and II Histone Deacetylation Inhibitors Alter Stability of HDAC-Corepressor Complexes

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Hsiao C Wang ◽  
Lillianne G Harris ◽  
James C Chou ◽  
Santhosh Mani ◽  
Donald Menick
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Cardiac Hypertrophy ◽  
Critical Role ◽  
Hdac Inhibitors ◽  
Class I ◽  
Proximal Promoter ◽  
Repressor Complex ◽  
The Stability

Introduction: Alterations in expression and activity of different genes have been implicated in the pathogenesis of heart failure. Our lab has shown that HDAC-repressor complexes play a critical role in the upregulation Sodium Calcium Exchanger ( Ncx1) and HDAC inhibition causes changes that attenuated cardiac remodeling during cardiac hypertrophy and heart failure. Thus, treatment with HDAC inhibitors has been proposed as a potential strategy for treatment of cardiac hypertrophy and heart failure. HDAC inhibitors repress deacetylase activity but we propose that they also affect HDAC confirmation and interaction with other protein factors. We hypothesize that HDAC inhibitors affect the stability of the co-repressor complex with specific transcription factors and that this effect is dependent on the transcription factor. Results: Inhibition of HDACs in adult cardiomyocytes results in the greater stabilization of HDACs with co-repressor molecules that were recruited to the NCX1 promoter through Nkx2.5 transcription factor. HDAC class I specific inhibitor, MS 275 demonstrated stronger association between HDACs and co-repressors while other Class I inhibitors, PD106 and BML 210 failed on showing this phenomenal. The results suggested that class I HDACs inhibitors may affect formations of HDAC-complex via alternated active site interactions other than chelating with zinc binding domain. These results compliment ChIP experiments which also demonstrate the different recruitments of Sin3a at the proximal promoter of NCX1. In vivo analysis on HDAC5 knockout mice reveal that the Sin3a-HDAC1/2 repressor complex is not recruited to the Ncx1 promoter in the absence of HDAC5, indicating not only Class I HDAC but also Class II HDACs play an important role on HDAC-complex formation. Conclusions: This work gives insight into part of the molecular mechanism of how HDAC inhibitors can affect the stability of the HDAC co-repressor complex in cardiac hypertrophy and heart failure. In addition, we demonstrated the Class IIa HDACs are required for the recruitment of the Sin3a/HDAC1/2 co-repressor complex to specific transcription factors on the target promoter.

The synthesis and properties of iron, ruthenium, and osmium octabutoxynaphthalocyanine

2012 ◽  
Vol 16 (09) ◽  
pp. 1068-1071 ◽  
Author(s):  
Junhwan Kim ◽  
Malcolm E. Kenney
Keyword(s):  
Mass Spectrometry ◽  
Iron Complexes ◽  
Axial Ligand ◽  
Iron Complex ◽  
Free Iron ◽  
Metal Free ◽  
Ligand Free ◽  
The Stability

New series of iron, ruthenium, and osmium octabutoxynaphthalocyanines were synthesized by inserting corresponding metals into the metal-free octabutoxynaphthalocyanine. Although preparation of axial ligand-free iron octabutoxynaphthalocyanines was reported before, we could not reproduce the synthesis by following the reported method. We attributed the failure to the instability of the iron octabutoxynaphthalocyanines. Bis-ligation increased the stability of the iron complex but only sufficiently for characterization. The application of iron complexes will be limited by their instability. However, ruthenium and osmium formed stable complexes with this macrocycle ring but with significantly lower reaction yields. These new complexes were characterized by NMR, UV-vis, and mass spectrometry.

scholarly journals Myocardial Cell Death and Regeneration during Progression of Cardiac Hypertrophy to Heart Failure

2004 ◽  
Vol 279 (50) ◽  
pp. 52630-52642 ◽  
Author(s):  
Sagartirtha Sarkar ◽  
Mamta Chawla-Sarkar ◽  
David Young ◽  
Kazutoshi Nishiyama ◽  
Mary E. Rayborn ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cell Death ◽  
Cardiac Hypertrophy ◽  
Disease Process ◽  
Myocardial Damage ◽  
Myocardial Cell ◽  
Mouse Heart ◽  
Ki 67 ◽  
End Stage Heart Failure ◽  
End Stage

Cardiac hypertrophy and ensuing heart failure are among the most common causes of mortality worldwide, yet the triggering mechanisms for progression of hypertrophy to failure are not fully understood. Tissue homeostasis depends on proper relationships between cell proliferation, differentiation, and death and any imbalance between them results in compromised cardiac function. Recently, we developed a transgenic (Tg) mouse model that overexpress myotrophin (a 12-kDa protein that stimulates myocyte growth) in heart resulting in hypertrophy that progresses to heart failure. This provided us an appropriate model to study the disease process at any point from initiation of hypertrophy end-stage heart failure. We studied detailed apoptotic signaling and regenerative pathways and found that the Tg mouse heart undergoes myocyte loss and regeneration, but only at a late stage (during transition to heart failure). Several apoptotic genes were up-regulated in 9-month-old Tg hearts compared with age-matched wild type or 4-week-old Tg hearts. Cardiac cell death during heart failure involved activation of Fas, tumor necrosis factor-α, and caspases 9, 8, and 3 and poly(ADP-ribose) polymerase cleavage. Tg mice with hypertrophy associated with compromised functionshowedsignificantup-regulationofcyclins,cyclin-dependent kinases (Cdks), and cell regeneration markers in myocytes. Furthermore, in human failing and nonfailing hearts, similar observations were documented including induction of active caspase 3 and Ki-67 proteins in dilated cardiomyopathic myocytes. Taken together, our data suggest that the stress of extensive myocardial damage from longstanding hypertrophy may cause myocytes to reenter the cell cycle. We demonstrate, for the first time in an animal model, that cell death and regeneration occur simultaneously in myocytes during end-stage heart failure, a phenomenon not observed at the onset of the disease process.

scholarly journals MICOS and F1FO-ATP synthase crosstalk is a fundamental property of mitochondrial cristae

2021 ◽  
Author(s):  
Lawrence Rudy Cadena ◽  
Ondrej Gahura ◽  
Brian Panicucci ◽  
Alena Zíková ◽  
Hassan Hashimi
Keyword(s):  
Atp Synthase ◽  
Positive Curvature ◽  
Model Organism ◽  
Fundamental Property ◽  
Cellular Respiration ◽  
Contact Site ◽  
The Core ◽  
Subunit E ◽  
Membrane Bending ◽  
The Stability

Mitochondrial cristae are polymorphic invaginations of the inner membrane that are the fabric of cellular respiration. Both the Mitochondrial Contact Site and Cristae Organization System (MICOS) and the F1FO-ATP synthase are vital for sculpting cristae by opposing membrane bending forces. While MICOS promotes negative curvature at cristae junctions, dimeric F1FO-ATP synthase is crucial for positive curvature at cristae rims. Crosstalk between these two complexes has been observed in baker’s yeast, the model organism of the Opisthokonta supergroup. Here, we report that this property is conserved in Trypanosoma brucei, a member of the Discoba supergroup that separated from Opisthokonta ~2 billion years ago. Specifically, one of the paralogs of the core MICOS subunit Mic10 interacts with dimeric F1FO-ATP synthase, whereas the other core Mic60 subunit has a counteractive effect on F1FO-ATP synthase oligomerization. This is evocative of the nature of MICOS-F1FO-ATP synthase crosstalk in yeast, which is remarkable given the diversification these two complexes have undergone during almost 2 eons of independent evolution. Furthermore, we identified a highly diverged trypanosome homolog of subunit e, which is essential for the stability of F1FO-ATP synthase dimers in yeast. Just like subunit e, it is preferentially associated with dimers, interacts with Mic10 and its silencing results in severe defects to cristae and disintegration of F1FO-ATP synthase dimers. Our findings indicate that crosstalk between MICOS and dimeric F1FO-ATP synthase is a fundamental property impacting cristae shape throughout eukaryotes.

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