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Circulation Research May 2021Acute decompensated heart failure (ADHF) is one of the leading admission diagnoses worldwide, yet it is an entity with incompletely understood pathophysiology and... (Review)
Review
Acute decompensated heart failure (ADHF) is one of the leading admission diagnoses worldwide, yet it is an entity with incompletely understood pathophysiology and limited therapeutic options. Patients admitted for ADHF have high in-hospital morbidity and mortality, as well as frequent rehospitalizations and subsequent cardiovascular death. This devastating clinical course is partly due to suboptimal medical management of ADHF with persistent congestion upon hospital discharge and inadequate predischarge initiation of life-saving guideline-directed therapies. While new drugs for the treatment of chronic HF continue to be approved, there has been no new therapy approved for ADHF in decades. This review will focus on the current limited understanding of ADHF pathophysiology, possible therapeutic targets, and current limitations in expanding available therapies in light of the unmet need among these high-risk patients.
Topics: Acute Disease; Body Fluids; Cardio-Renal Syndrome; Cardiotoxins; Comorbidity; Heart Failure; Hospitalization; Humans; Inflammation Mediators; Myocardial Contraction; Natriuretic Peptide, Brain; Patient Discharge; Patient Readmission; Renin-Angiotensin System; Symptom Assessment; Vascular Resistance; Vasoconstriction; Vasodilator Agents
PubMed: 33983837
DOI: 10.1161/CIRCRESAHA.121.318186 -
International Journal of Molecular... Nov 2022Skeletal muscle injuries occur frequently in daily life and exercise. Understanding the mechanisms of regeneration is critical for accelerating the repair and... (Review)
Review
Skeletal muscle injuries occur frequently in daily life and exercise. Understanding the mechanisms of regeneration is critical for accelerating the repair and regeneration of muscle. Therefore, this article reviews knowledge on the mechanisms of skeletal muscle regeneration after cardiotoxin-induced injury. The process of regeneration is similar in different mouse strains and is inhibited by aging, obesity, and diabetes. Exercise, microcurrent electrical neuromuscular stimulation, and mechanical loading improve regeneration. The mechanisms of regeneration are complex and strain-dependent, and changes in functional proteins involved in the processes of necrotic fiber debris clearance, M1 to M2 macrophage conversion, SC activation, myoblast proliferation, differentiation and fusion, and fibrosis and calcification influence the final outcome of the regenerative activity.
Topics: Mice; Animals; Cardiotoxins; Muscular Diseases; Muscle, Skeletal; Macrophages; Aging
PubMed: 36362166
DOI: 10.3390/ijms232113380 -
Nature Cell Biology Aug 2018Fibro-adipogenic progenitors (FAPs) are typically activated in response to muscle injury, and establish functional interactions with inflammatory and muscle stem cells... (Comparative Study)
Comparative Study
Fibro-adipogenic progenitors (FAPs) are typically activated in response to muscle injury, and establish functional interactions with inflammatory and muscle stem cells (MuSCs) to promote muscle repair. We found that denervation causes progressive accumulation of FAPs, without concomitant infiltration of macrophages and MuSC-mediated regeneration. Denervation-activated FAPs exhibited persistent STAT3 activation and secreted elevated levels of IL-6, which promoted muscle atrophy and fibrosis. FAPs with aberrant activation of STAT3-IL-6 signalling were also found in mouse models of spinal cord injury, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS) and in muscles of ALS patients. Inactivation of STAT3-IL-6 signalling in FAPs effectively countered muscle atrophy and fibrosis in mouse models of acute denervation and ALS (SOD mice). Activation of pathogenic FAPs following loss of integrity of neuromuscular junctions further illustrates the functional versatility of FAPs in response to homeostatic perturbations and suggests their potential contribution to the pathogenesis of neuromuscular diseases.
Topics: Adipogenesis; Amyotrophic Lateral Sclerosis; Animals; Cardiotoxins; Cell Line; Coculture Techniques; Denervation; Disease Models, Animal; Fibrosis; Humans; Interleukin-6; Male; Mice, Inbred C57BL; Mice, Transgenic; Muscular Atrophy; Muscular Atrophy, Spinal; Mutation; Myoblasts, Skeletal; Neuromuscular Agents; Quadriceps Muscle; STAT3 Transcription Factor; Sciatic Nerve; Signal Transduction; Spinal Cord Injuries; Superoxide Dismutase-1
PubMed: 30050118
DOI: 10.1038/s41556-018-0151-y -
PloS One 2016A longstanding goal in regenerative medicine is to reconstitute functional tissues or organs after injury or disease. Attention has focused on the identification and... (Comparative Study)
Comparative Study
BACKGROUND
A longstanding goal in regenerative medicine is to reconstitute functional tissues or organs after injury or disease. Attention has focused on the identification and relative contribution of tissue specific stem cells to the regeneration process. Relatively little is known about how the physiological process is regulated by other tissue constituents. Numerous injury models are used to investigate tissue regeneration, however, these models are often poorly understood. Specifically, for skeletal muscle regeneration several models are reported in the literature, yet the relative impact on muscle physiology and the distinct cells types have not been extensively characterised.
METHODS
We have used transgenic Tg:Pax7nGFP and Flk1GFP/+ mouse models to respectively count the number of muscle stem (satellite) cells (SC) and number/shape of vessels by confocal microscopy. We performed histological and immunostainings to assess the differences in the key regeneration steps. Infiltration of immune cells, chemokines and cytokines production was assessed in vivo by Luminex®.
RESULTS
We compared the 4 most commonly used injury models i.e. freeze injury (FI), barium chloride (BaCl2), notexin (NTX) and cardiotoxin (CTX). The FI was the most damaging. In this model, up to 96% of the SCs are destroyed with their surrounding environment (basal lamina and vasculature) leaving a "dead zone" devoid of viable cells. The regeneration process itself is fulfilled in all 4 models with virtually no fibrosis 28 days post-injury, except in the FI model. Inflammatory cells return to basal levels in the CTX, BaCl2 but still significantly high 1-month post-injury in the FI and NTX models. Interestingly the number of SC returned to normal only in the FI, 1-month post-injury, with SCs that are still cycling up to 3-months after the induction of the injury in the other models.
CONCLUSIONS
Our studies show that the nature of the injury model should be chosen carefully depending on the experimental design and desired outcome. Although in all models the muscle regenerates completely, the trajectories of the regenerative process vary considerably. Furthermore, we show that histological parameters are not wholly sufficient to declare that regeneration is complete as molecular alterations (e.g. cycling SCs, cytokines) could have a major persistent impact.
Topics: Animals; Barium Compounds; Chlorides; Cobra Cardiotoxin Proteins; Cold Injury; Cytokines; Elapid Venoms; Fibrosis; Freezing; Green Fluorescent Proteins; Macrophages; Mice; Mice, Inbred C57BL; Mice, Transgenic; Models, Animal; Muscle Development; Muscle, Skeletal; Myoblasts; Necrosis; Neovascularization, Physiologic; Regeneration; Satellite Cells, Skeletal Muscle; Stem Cells; Vascular Endothelial Growth Factor Receptor-2
PubMed: 26807982
DOI: 10.1371/journal.pone.0147198 -
Archives of Toxicology Dec 2019High-content screening (HCS) technology combining automated microscopy and quantitative image analysis can address biological questions in academia and the... (Review)
Review
High-content screening (HCS) technology combining automated microscopy and quantitative image analysis can address biological questions in academia and the pharmaceutical industry. Various HCS experimental applications have been utilized in the research field of in vitro toxicology. In this review, we describe several HCS application approaches used for studying the mechanism of compound toxicity, highlight some challenges faced in the toxicological community, and discuss the future directions of HCS in regards to new models, new reagents, data management, and informatics. Many specialized areas of toxicology including developmental toxicity, genotoxicity, developmental neurotoxicity/neurotoxicity, hepatotoxicity, cardiotoxicity, and nephrotoxicity will be examined. In addition, several newly developed cellular assay models including induced pluripotent stem cells (iPSCs), three-dimensional (3D) cell models, and tissues-on-a-chip will be discussed. New genome-editing technologies (e.g., CRISPR/Cas9), data analyzing tools for imaging, and coupling with high-content assays will be reviewed. Finally, the applications of machine learning to image processing will be explored. These new HCS approaches offer a huge step forward in dissecting biological processes, developing drugs, and making toxicology studies easier.
Topics: Animals; Cardiotoxins; Chemical and Drug Induced Liver Injury; High-Throughput Screening Assays; Humans; Kidney Diseases; Mutagenicity Tests; Neurotoxicity Syndromes; Toxicology
PubMed: 31664499
DOI: 10.1007/s00204-019-02593-5 -
F1000Research 2018Recent advances in cancer prevention and management have led to an exponential increase of cancer survivors worldwide. Regrettably, cardiovascular disease has risen in... (Review)
Review
Recent advances in cancer prevention and management have led to an exponential increase of cancer survivors worldwide. Regrettably, cardiovascular disease has risen in the aftermath as one of the most devastating consequences of cancer therapies. In this work, we define cancer therapeutics-induced cardiotoxicity as the direct or indirect cardiovascular injury or injurious effect caused by cancer therapies. We describe four progressive stages of this condition and four corresponding levels of prevention, each having a specific goal, focus, and means of action. We subsequently unfold this didactic framework, surveying mechanisms of cardiotoxicity, risk factors, cardioprotectants, biomarkers, and diagnostic imaging modalities. Finally, we outline the most current evidence-based recommendations in this area according to multidisciplinary expert consensus guidelines.
Topics: Animals; Antineoplastic Agents; Cardiotonic Agents; Cardiotoxicity; Cardiotoxins; Cardiovascular Diseases; Humans; Neoplasms
PubMed: 30345014
DOI: 10.12688/f1000research.15190.1 -
Toxicon: X Mar 2022Toads of the genus are chemically defended by a unique combination of endogenously synthesized cardiotoxins (bufadienolides) and neurotoxins which may be sequestered... (Review)
Review
Toads of the genus are chemically defended by a unique combination of endogenously synthesized cardiotoxins (bufadienolides) and neurotoxins which may be sequestered (guanidinium alkaloids). Investigation into small-molecule chemical defenses has been primarily concerned with identifying and characterizing various forms of these toxins while largely overlooking their ecological roles and evolutionary implications. In addition to describing the extent of knowledge about toxin structures, pharmacology, and biological sources, we review the detection, identification, and quantification methods used in studies of toxins to date and conclude that many known toxin profiles are unlikely to be comprehensive because of methodological and sampling limitations. Patterns in existing data suggest that both environmental (toxin availability) and genetic (capacity to synthesize or sequester toxins) factors influence toxin profiles. From an ecological and evolutionary perspective, we summarize the possible selective pressures acting on toxicity and toxin profiles, including predation, intraspecies communication, disease, and reproductive status. Ultimately, we intend to provide a basis for future ecological, evolutionary, and biochemical research on .
PubMed: 35146414
DOI: 10.1016/j.toxcx.2022.100092 -
European Review For Medical and... Apr 2018Breast cancer is the most common cancer among women. In the last twenty years early diagnosis, neoadjuvant and adjuvant systemic treatment that targeted to specific... (Review)
Review
OBJECTIVE
Breast cancer is the most common cancer among women. In the last twenty years early diagnosis, neoadjuvant and adjuvant systemic treatment that targeted to specific molecular targets have significantly reduced the mortality from breast cancer. However, the increase in survival has allowed to observe the cardiotoxic effects of anticancer therapy and increased mortality from cardiovascular causes, resulting in a large literature where experts try to identify the correct management of this critical problem. Even thought the increased attention in this field, many questions have not yet answers and new studies are needed.
MATERIALS AND METHODS
We conducted a broad search of the English-language literature in Medline using the following search terms: cardiotoxicity, anthracyclines, trastuzumab, breast cancer, left ventricular dysfunction, heart failure. A manual examination of the articles found has been performed.
RESULTS
We provide a comprehensive assessment of the current knowledge about cardiotoxicity induced by anthracycline plus trastuzumab in women affected by breast cancer.
CONCLUSIONS
Early identification and prompt treatment of subclinical cardiotoxicity may improve cardiologic prognosis of these patients and may allow oncologists to avoid withdrawal of chemotherapy. That is why it becomes always more important the creation of multidisciplinary teams where cardiologists and oncologists work together to ensure optimal care to oncologic patients treated with cardiotoxic agents.
Topics: Animals; Anthracyclines; Antineoplastic Agents, Immunological; Breast Neoplasms; Cardiotoxicity; Cardiotoxins; Cell Transformation, Neoplastic; Female; Humans; Trastuzumab
PubMed: 29687878
DOI: 10.26355/eurrev_201804_14752 -
Scientific Reports Jun 2022Duchenne muscular dystrophy is a severe neuromuscular disease causing a progressive muscle wasting due to mutations in the DMD gene that lead to the absence of...
Duchenne muscular dystrophy is a severe neuromuscular disease causing a progressive muscle wasting due to mutations in the DMD gene that lead to the absence of dystrophin protein. Adeno-associated virus (AAV)-based therapies aiming to restore dystrophin in muscles, by either exon skipping or microdystrophin expression, are very promising. However, the absence of dystrophin induces cellular perturbations that hinder AAV therapy efficiency. We focused here on the impact of the necrosis-regeneration process leading to nuclear centralization in myofiber, a common feature of human myopathies, on AAV transduction efficiency. We generated centronucleated myofibers by cardiotoxin injection in wild-type muscles prior to AAV injection. Intramuscular injections of AAV1 vectors show that transgene expression was drastically reduced in regenerated muscles, even when the AAV injection occurred 10 months post-regeneration. We show also that AAV genomes were not lost from cardiotoxin regenerated muscle and were properly localised in the myofiber nuclei but were less transcribed leading to muscle transduction defect. A similar defect was observed in muscles of the DMD mouse model mdx. Therefore, the regeneration process per se could participate to the AAV-mediated transduction defect observed in dystrophic muscles which may limit AAV-based therapies.
Topics: Animals; Cardiotoxins; Dependovirus; Dystrophin; Genetic Therapy; Genetic Vectors; Mice; Mice, Inbred mdx; Muscle, Skeletal; Muscular Dystrophy, Animal; Muscular Dystrophy, Duchenne; Regeneration; Transgenes
PubMed: 35690627
DOI: 10.1038/s41598-022-13405-9 -
Journal of the American College of... Jan 2013Cancer genomics has focused on the discovery of mutations and chromosomal structural rearrangements that either increase susceptibility to cancer or support the cancer... (Review)
Review
Cancer genomics has focused on the discovery of mutations and chromosomal structural rearrangements that either increase susceptibility to cancer or support the cancer phenotype. Protein kinases are the most frequently mutated genes in the cancer genome, making them attractive therapeutic targets for drug design. However, the use of some of the kinase inhibitors (KIs) has been associated with toxicities to the heart and vasculature, including acute coronary syndromes and heart failure. Herein we discuss the genetic basis of cancer, focusing on mutations in the kinase genome (kinome) that lead to tumorigenesis. This will allow an understanding of the real and potential power of modern cancer therapeutics. The underlying mechanisms that drive the cardiotoxicity of the KIs are also examined. The preclinical models for predicting cardiotoxicity, including induced pluripotent stem cells and zebrafish, are reviewed, with the hope of eventually being able to identify problematic agents before their use in patients. Finally, the use of biomarkers in the clinic is discussed, and newer strategies (i.e., metabolomics and enhanced imaging strategies) that may allow earlier and more accurate detection of cardiotoxicity are reviewed.
Topics: Animals; Antineoplastic Agents; Cardiotoxins; DNA Mutational Analysis; DNA Repair; Drug Evaluation, Preclinical; Genome, Human; Heart; Humans; Metabolomics; Neoplasms; Practice Guidelines as Topic; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction
PubMed: 23328609
DOI: 10.1016/j.jacc.2012.05.066