Anthracycline-induced cardiomyopathy: cellular and molecular mechanisms

2020 ◽  
Vol 134 (13) ◽  
pp. 1859-1885
Author(s):  
Keith Dadson ◽  
Oscar Calvillo-Argüelles ◽  
Paaladinesh Thavendiranathan ◽  
Filio Billia
Keyword(s):  
Molecular Mechanisms ◽  
Underlying Mechanism ◽  
Chemotherapeutic Agents ◽  
Oxygen Species ◽  
Proliferating Cells ◽  
Early Use ◽  
Cellular Apoptosis ◽  
Underlying Causes ◽  
Intracellular Activities ◽  
Insight Into

Abstract Despite the known risk of cardiotoxicity, anthracyclines are widely prescribed chemotherapeutic agents. They are broadly characterized as being a robust effector of cellular apoptosis in rapidly proliferating cells through its actions in the nucleus and formation of reactive oxygen species (ROS). And, despite the early use of dexrazoxane, no effective treatment strategy has emerged to prevent the development of cardiomyopathy, despite decades of study, suggesting that much more insight into the underlying mechanism of the development of cardiomyopathy is needed. In this review, we detail the specific intracellular activities of anthracyclines, from the cell membrane to the sarcoplasmic reticulum, and highlight potential therapeutic windows that represent the forefront of research into the underlying causes of anthracycline-induced cardiomyopathy.

scholarly journals Chemotherapy-Induced Cardiotoxicity: Overview of the Roles of Oxidative Stress

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Paweorn Angsutararux ◽  
Sudjit Luanpitpong ◽  
Surapol Issaragrisil
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Chemotherapy Regimen ◽  
Model Development ◽  
Preventive Treatment ◽  
Chemotherapeutic Agents ◽  
Oxygen Species ◽  
Preventive Strategies ◽  
Wide Range ◽  
Threat To Life

Chemotherapy-induced cardiotoxicity is a serious complication that poses a serious threat to life and limits the clinical use of various chemotherapeutic agents, particularly the anthracyclines. Understanding molecular mechanisms of chemotherapy-induced cardiotoxicity is a key to effective preventive strategies and improved chemotherapy regimen. Although no reliable and effective preventive treatment has become available, numerous evidence demonstrates that chemotherapy-induced cardiotoxicity involves the generation of reactive oxygen species (ROS). This review provides an overview of the roles of oxidative stress in chemotherapy-induced cardiotoxicity using doxorubicin, which is one of the most effective chemotherapeutic agents against a wide range of cancers, as an example. Current understanding in the molecular mechanisms of ROS-mediated cardiotoxicity will be explored and discussed, with emphasis on cardiomyocyte apoptosis leading to cardiomyopathy. The review will conclude with perspectives on model development needed to facilitate further progress and understanding on chemotherapy-induced cardiotoxicity.

scholarly journals Molecular Mechanisms and Therapeutic Effects of (−)-Epicatechin and Other Polyphenols in Cancer, Inflammation, Diabetes, and Neurodegeneration

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Joseph Shay ◽  
Hosam A. Elbaz ◽  
Icksoo Lee ◽  
Steven P. Zielske ◽  
Moh H. Malek ◽  
...  
Keyword(s):  
Natural Products ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Epigallocatechin Gallate ◽  
Therapeutic Effects ◽  
Oxygen Species ◽  
The World ◽  
Map Kinase Pathway ◽  
Kinase Pathway ◽  
Insight Into

With recent insight into the mechanisms involved in diseases, such as cardiovascular disease, cancer, stroke, neurodegenerative diseases, and diabetes, more efficient modes of treatment are now being assessed. Traditional medicine including the use of natural products is widely practiced around the world, assuming that certain natural products contain the healing properties that may in fact have a preventative role in many of the diseases plaguing the human population. This paper reviews the biological effects of a group of natural compounds called polyphenols, including apigenin, epigallocatechin gallate, genistein, and (−)-epicatechin, with a focus on the latter. (−)-Epicatechin has several unique features responsible for a variety of its effects. One of these is its ability to interact with and neutralize reactive oxygen species (ROS) in the cell. (−)-Epicatechin also modulates cell signaling including the MAP kinase pathway, which is involved in cell proliferation. Mutations in this pathway are often associated with malignancies, and the use of (−)-epicatechin holds promise as a preventative agent and as an adjunct for chemotherapy and radiation therapy to improve outcome. This paper discusses the potential of some phenolic compounds to maintain, protect, and possibly reinstate health.

scholarly journals Pathological and Pharmacological Roles of Mitochondrial Reactive Oxygen Species in Malignant Neoplasms: Therapies Involving Chemical Compounds, Natural Products, and Photosensitizers

Molecules ◽  
2020 ◽  
Vol 25 (22) ◽  
pp. 5252
Author(s):  
Yasuyoshi Miyata ◽  
Yuta Mukae ◽  
Junki Harada ◽  
Tsuyoshi Matsuda ◽  
Kensuke Mitsunari ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Reactive Oxygen ◽  
Chemotherapeutic Agents ◽  
Malignant Neoplasms ◽  
Oxygen Species ◽  
Efficient Treatment ◽  
Intracellular Ros

Oxidative stress plays an important role in cellular processes. Consequently, oxidative stress also affects etiology, progression, and response to therapeutics in various pathological conditions including malignant tumors. Oxidative stress and associated outcomes are often brought about by excessive generation of reactive oxygen species (ROS). Accumulation of ROS occurs due to dysregulation of homeostasis in an otherwise strictly controlled physiological condition. In fact, intracellular ROS levels are closely associated with the pathological status and outcome of numerous diseases. Notably, mitochondria are recognized as the critical regulator and primary source of ROS. Damage to mitochondria increases mitochondrial ROS (mROS) production, which leads to an increased level of total intracellular ROS. However, intracellular ROS level may not always reflect mROS levels, as ROS is not only produced by mitochondria but also by other organelles such as endoplasmic reticulum and peroxisomes. Thus, an evaluation of mROS would help us to recognize the biological and pathological characteristics and predictive markers of malignant tumors and develop efficient treatment strategies. In this review, we describe the pathological significance of mROS in malignant neoplasms. In particular, we show the association of mROS-related signaling in the molecular mechanisms of chemically synthesized and natural chemotherapeutic agents and photodynamic therapy.

scholarly journals Clinical Value and Underlying Mechanisms of Upregulated LINC00485 in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Xinyu Zhu ◽  
Yanlin Feng ◽  
Dingdong He ◽  
Zi Wang ◽  
Fangfang Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Operating Characteristic ◽  
Characteristic Curve ◽  
Underlying Mechanism ◽  
Clinical Value ◽  
Serum Samples ◽  
Underlying Mechanisms ◽  
Insight Into

AimsThis study aimed to reveal the functional role of LINC00485 in hepatocellular carcinoma (HCC).Materials & Methods210 serum samples from Zhongnan Hospital of Wuhan University were employed to evaluate clinical value of LINC00485. Bioinformatics analysis was adopted to explore its potential mechanisms.ResultsLINC00485 was confirmed to be upregulated in HCC tissues and serum samples. Survival analysis and receiver operating characteristic curve revealed its prognostic and diagnostic roles. The combination of serum LINC00485 with AFP can remarkably improve diagnostic ability of HCC. Exploration of the underlying mechanism demonstrated that LINC00485 might exert pro-oncogenic activity by LINC00485—three miRNAs—four mRNAs network.ConclusionsOur study unveiled that upregulated LINC00485 could act as a potential diagnostic and prognostic biomarker and provide a novel insight into the molecular mechanisms of LINC00485 in HCC pathogenesis.

Selection of m. tuberculosis clinically isolated sensitive & resistant to fluoroquinolones

2021 ◽  
pp. 15-23
Author(s):  
Sudhakar Kancharla ◽  
Prachetha Kolli ◽  
Dr.K.Venkata Gopaiah
Keyword(s):  
Underlying Mechanism ◽  
Therapeutic Agents ◽  
Chemotherapeutic Agents ◽  
Hypothetical Proteins ◽  
Conserved Residues ◽  
Docking Analysis ◽  
Adverse Conditions ◽  
Gene Level ◽  
Insight Into ◽  
Selection Of

In the present study we observed on performing docking analysis that OFX interacted with conserved residues of Usp, SDR, PspA and CoA transferease domain of Rv2140c, Rv0148, Rv2744c and Rv3551, respectively, which might alter this function. It is predicted that these proteins might be exhibiting increased intensities to inhibit/modulate/compensate the effect of drugs. Further, detailed study in this direction might help to search new targets for drug development. Besides known proteins, upregulation of hypothetical proteins strengthen the possibility of some unknown underlying mechanism responsible for resistance to OFX. This could be crucial for the initial survival of the cells before gene level changes could come into play to ensure survival under prolonged adverse conditions. These findings may be further exploited to develop newer therapeutic agents derived from OFX. Further detailed and in-depth investigations to explore these leads will give an insight into probable sites of drug action, other than established primary sites and hence may help in the search of novel chemotherapeutic agents at these new sites as inhibitors and could provide the mankind with some ultimate treatmentstrategies.

Copper–oxygen Dynamics in Tyrosinase

2019 ◽  
Author(s):  
Nobutaka Fujieda ◽  
Sachiko Yanagisawa ◽  
Minoru Kubo ◽  
Genji Kurisu ◽  
Shinobu Itoh
Keyword(s):  
Catalytic Mechanism ◽  
Substrate Binding ◽  
Active Form ◽  
Copper Ion ◽  
Atomic Resolution ◽  
Oxygen Species ◽  
X Ray ◽  
Oxygen Dynamics ◽  
Insight Into ◽  
Copper Centre

To unveil the activation of dioxygen on the copper centre (Cu<sub>2</sub>O<sub>2</sub>core) of tyrosinase, we performed X-ray crystallograpy with active-form tyrosinase at near atomic resolution. This study provided a novel insight into the catalytic mechanism of the tyrosinase, including the rearrangement of copper-oxygen species as well as the intramolecular migration of copper ion induced by substrate-binding.<br>

Trilobatin Protects Cardiomyocytes from Hypoxia/ Reperfusion Injury by Regulating the Nuclear Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 Pathway

2020 ◽  
Vol 19 (2) ◽  
pp. 133-138
Author(s):  
Wenyu Chen ◽  
Hui He
Keyword(s):  
Heme Oxygenase ◽  
Molecular Mechanisms ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Cellular Injury ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
H9c2 Cells ◽  
Natural Plant ◽  
Induced Changes

Trilobatin is a natural plant-derived glycosylated flavonoid that has been shown to exhibit multiple beneficial pharmacologic activities including protection of heart against H/R-induced cardiomyocyte injury. However, the molecular mechanisms underlying protection from H/R-induced cardiomyocyte injury remain unknown. Using H9C2 cells as a model, we examined the effect of trilobatin on H/R-induced cellular injury, apoptosis, and generation of reactive oxygen species. The results showed that trilobatin protected H9C2 cells not only from cell death and apoptosis, but also counteracted H/R-induced changes in malondialdehyde, superoxide dismutase, glutathione, and glutathione peroxidase. The evaluation of the mechanism underlying the effect of trilobatin on protection from H/R-induced cellular injury suggested changes in the regulation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway.

Nano-Curcumin Regulates p53 Phosphorylation and PAI-1 Expression during Bleomycin Induced Injury in Alveolar Basal Epithelial Cells

2020 ◽  
Vol 16 (1) ◽  
pp. 85-89
Author(s):  
Mahesh M. Gouda ◽  
Ashwini Prabhu ◽  
Varsha Reddy S.V. ◽  
Rafa Jahan ◽  
Yashodhar P. Bhandary
Keyword(s):  
Epithelial Cells ◽  
Lung Injury ◽  
Molecular Mechanisms ◽  
A549 Cells ◽  
Plasminogen Activator Inhibitor ◽  
Underlying Mechanism ◽  
Protective Role ◽  
Alveolar Epithelial Cells ◽  
Cellular Damage

Background: Bleomycin (BLM) is known to cause DNA damage in the Alveolar Epithelial Cells (AECs). It is reported that BLM is involved in the up-regulation of inflammatory molecules such as neutrophils, macrophages, chemokines and cytokines. The complex underlying mechanism for inflammation mediated progression of lung injury is still unclear. This investigation was designed to understand the molecular mechanisms associated with p53 mediated modulation of Plasminogen Activator Inhibitor-I (PAI-I) expression and its regulation by nano-curcumin formulation. Methods: A549 cells were treated with BLM to cause the cellular damage in vitro and commercially available nano-curcumin formulation was used as an intervention. Cytotoxic effect of nano-curcumin was analyzed using Methyl Thiazolyl Tetrazolium (MTT) assay. Protein expressions were analyzed using western blot to evaluate the p53 mediated changes in PAI-I expression. Results: Nano-curcumin showed cytotoxicity up to 88.5 % at a concentration of 20 μg/ml after 48 h of treatment. BLM exposure to the cells activated the phosphorylation of p53, which in turn increased PAII expression. Nano-curcumin treatment showed a protective role against phosphorylation of p53 and PAI-I expression, which in turn regulated the fibro-proliferative phase of injury induced by bleomycin. Conclusion: Nano-curcumin could be used as an effective intervention to regulate the severity of lung injury, apoptosis of AECs and fibro-proliferation during pulmonary injury.

scholarly journals Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 795
Author(s):  
Lukas Gorecki ◽  
Martin Andrs ◽  
Jan Korabecny
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Patient Survival ◽  
Current Status ◽  
Future Perspectives ◽  
Phase Ii Trials ◽  
Anticancer Treatment ◽  
Positive Outlook ◽  
Insight Into

Selective killing of cancer cells while sparing healthy ones is the principle of the perfect cancer treatment and the primary aim of many oncologists, molecular biologists, and medicinal chemists. To achieve this goal, it is crucial to understand the molecular mechanisms that distinguish cancer cells from healthy ones. Accordingly, several clinical candidates that use particular mutations in cell-cycle progressions have been developed to kill cancer cells. As the majority of cancer cells have defects in G1 control, targeting the subsequent intra‑S or G2/M checkpoints has also been extensively pursued. This review focuses on clinical candidates that target the kinases involved in intra‑S and G2/M checkpoints, namely, ATR, CHK1, and WEE1 inhibitors. It provides insight into their current status and future perspectives for anticancer treatment. Overall, even though CHK1 inhibitors are still far from clinical establishment, promising accomplishments with ATR and WEE1 inhibitors in phase II trials present a positive outlook for patient survival.

scholarly journals Molecular Pathways Involved in the Development of Congenital Erythrocytosis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1150
Author(s):  
Jana Tomc ◽  
Nataša Debeljak
Keyword(s):  
Signal Transduction ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Oxygen Affinity ◽  
Molecular Pathways ◽  
Disease Development ◽  
Post Translational Modifications ◽  
Hemoglobin Oxygen Affinity ◽  
Insight Into ◽  
Idiopathic Erythrocytosis

Patients with idiopathic erythrocytosis are directed to targeted genetic testing including nine genes involved in oxygen sensing pathway in kidneys, erythropoietin signal transduction in pre-erythrocytes and hemoglobin-oxygen affinity regulation in mature erythrocytes. However, in more than 60% of cases the genetic cause remains undiagnosed, suggesting that other genes and mechanisms must be involved in the disease development. This review aims to explore additional molecular mechanisms in recognized erythrocytosis pathways and propose new pathways associated with this rare hematological disorder. For this purpose, a comprehensive review of the literature was performed and different in silico tools were used. We identified genes involved in several mechanisms and molecular pathways, including mRNA transcriptional regulation, post-translational modifications, membrane transport, regulation of signal transduction, glucose metabolism and iron homeostasis, which have the potential to influence the main erythrocytosis-associated pathways. We provide valuable theoretical information for deeper insight into possible mechanisms of disease development. This information can be also helpful to improve the current diagnostic solutions for patients with idiopathic erythrocytosis.

Sign in / Sign up

Export Citation Format

Share Document