scholarly journals Inherited and Acquired Rhythm Disturbances in Sick Sinus Syndrome, Brugada Syndrome, and Atrial Fibrillation: Lessons from Preclinical Modeling

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3175
Author(s):  
Laura Iop ◽  
Sabino Iliceto ◽  
Giovanni Civieri ◽  
Francesco Tona
Keyword(s):  
Atrial Fibrillation ◽  
Cardiovascular Diseases ◽  
Brugada Syndrome ◽  
In Silico ◽  
Cardiac Fibrosis ◽  
Sick Sinus Syndrome ◽  
In Vitro Models ◽  
Global Functioning

Rhythm disturbances are life-threatening cardiovascular diseases, accounting for many deaths annually worldwide. Abnormal electrical activity might arise in a structurally normal heart in response to specific triggers or as a consequence of cardiac tissue alterations, in both cases with catastrophic consequences on heart global functioning. Preclinical modeling by recapitulating human pathophysiology of rhythm disturbances is fundamental to increase the comprehension of these diseases and propose effective strategies for their prevention, diagnosis, and clinical management. In silico, in vivo, and in vitro models found variable application to dissect many congenital and acquired rhythm disturbances. In the copious list of rhythm disturbances, diseases of the conduction system, as sick sinus syndrome, Brugada syndrome, and atrial fibrillation, have found extensive preclinical modeling. In addition, the electrical remodeling as a result of other cardiovascular diseases has also been investigated in models of hypertrophic cardiomyopathy, cardiac fibrosis, as well as arrhythmias induced by other non-cardiac pathologies, stress, and drug cardiotoxicity. This review aims to offer a critical overview on the effective ability of in silico bioinformatic tools, in vivo animal studies, in vitro models to provide insights on human heart rhythm pathophysiology in case of sick sinus syndrome, Brugada syndrome, and atrial fibrillation and advance their safe and successful translation into the cardiology arena.

Vascularized Cardiac Spheroids as Novel 3D in vitro Models to Study Cardiac Fibrosis

2017 ◽  
Vol 204 (3-4) ◽  
pp. 191-198 ◽  
Author(s):  
Gemma A. Figtree ◽  
Kristen J. Bubb ◽  
Owen Tang ◽  
Eddy Kizana ◽  
Carmine Gentile
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Cardiac Fibrosis ◽  
Transforming Growth Factor ◽  
Three Dimensional ◽  
In Vitro Models ◽  
Tissue Growth ◽  
Cardiovascular Research

Spheroid cultures are among the most explored cellular biomaterials used in cardiovascular research, due to their improved integration of biochemical and physiological features of the heart in a defined architectural three-dimensional microenvironment when compared to monolayer cultures. To further explore the potential use of spheroid cultures for research, we engineered a novel in vitro model of the heart with vascularized cardiac spheroids (VCSs), by coculturing cardiac myocytes, endothelial cells, and fibroblasts isolated from dissociated rat neonatal hearts (aged 1-3 days) in hanging drop cultures. To evaluate the validity of VCSs in recapitulating pathophysiological processes typical of the in vivo heart, such as cardiac fibrosis, we then treated VCSs with transforming growth factor beta 1 (TGFβ1), a known profibrotic agent. Our mRNA analysis demonstrated that TGFβ1-treated VCSs present elevated levels of expression of connective tissue growth factor, fibronectin, and TGFβ1 when compared to control cultures. We demonstrated a dramatic increase in collagen deposition following TGFβ1 treatment in VCSs in the PicroSirius Red-stained sections. Doxorubicin, a renowned cardiotoxic and profibrotic agent, triggered apoptosis and disrupted vascular networks in VCSs. Taken together, our findings demonstrate that VCSs are a valid model for the study of the mechanisms involved in cardiac fibrosis, with the potential to be used to investigate novel mechanisms and therapeutics for treating and preventing cardiac fibrosis in vitro.

Analyses of Gingival Adhesion Molecules in Periodontitis: Theoretical In Silico, Comparative In Vivo, and Explanatory In Vitro Models

2016 ◽  
Vol 87 (2) ◽  
pp. 193-202 ◽  
Author(s):  
Ulvi K. Gürsoy ◽  
Fares Zeidán-Chuliá ◽  
Dogukan Yilmaz ◽  
Vural Özdemir ◽  
Juho Mäki-Petäys ◽  
...  
Keyword(s):  
Adhesion Molecules ◽  
In Silico ◽  
In Vitro Models

ADMET Profiling in Drug Discovery and Development: Perspectives of in silico, in vitro and integrated approaches

2021 ◽  
Vol 22 ◽  
Author(s):  
Nour El-Huda Daoud ◽  
Pobitra Borah ◽  
Pran Kishore Deb ◽  
Katharigatta N. Venugopala ◽  
Wafa Hourani ◽  
...  
Keyword(s):  
Drug Discovery ◽  
In Silico ◽  
Predictive Power ◽  
Early Stage ◽  
In Vitro Models ◽  
Prediction Ability ◽  
Drug Discovery And Development ◽  
In Silico Admet

: In the drug discovery setting, undesirable ADMET properties of a pharmacophore with good predictive power obtained after a tedious drug discovery and development process may lead to late-stage attrition. The early-stage ADMET profiling has introduced a new dimension to leading development. Although several high-throughput in vitro models are available for ADMET profiling, however, the in silico methods are gaining more importance because of their economic and faster prediction ability without the requirements of tedious and expensive laboratory resources. Nonetheless, in silico ADMET tools alone are not accurate and, therefore, ideally adopted along with in vitro and or in vivo methods in order to enhance predictability power. This review summarizes the significance and challenges associated with the application of in silico tools as well as the possible scope of in vitro models for integration to improve the ADMET predictability power of these tools.

scholarly journals The Combination of Cell Cultured Technology and In Silico Model to Inform the Drug Development

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 704
Author(s):  
Zhengying Zhou ◽  
Jinwei Zhu ◽  
Muhan Jiang ◽  
Lan Sang ◽  
Kun Hao ◽  
...  
Keyword(s):  
Drug Development ◽  
In Silico ◽  
In Vitro Models ◽  
Clinical Settings ◽  
Culture Methods ◽  
Physiologically Based Pharmacokinetic ◽  
Induced Pluripotent ◽  
In Silico Models

Human-derived in vitro models can provide high-throughput efficacy and toxicity data without a species gap in drug development. Challenges are still encountered regarding the full utilisation of massive data in clinical settings. The lack of translated methods hinders the reliable prediction of clinical outcomes. Therefore, in this study, in silico models were proposed to tackle these obstacles from in vitro to in vivo translation, and the current major cell culture methods were introduced, such as human-induced pluripotent stem cells (hiPSCs), 3D cells, organoids, and microphysiological systems (MPS). Furthermore, the role and applications of several in silico models were summarised, including the physiologically based pharmacokinetic model (PBPK), pharmacokinetic/pharmacodynamic model (PK/PD), quantitative systems pharmacology model (QSP), and virtual clinical trials. These credible translation cases will provide templates for subsequent in vitro to in vivo translation. We believe that synergising high-quality in vitro data with existing models can better guide drug development and clinical use.

Thioflavin-based molecular probes for application in Alzheimer's disease: from in silico to in vitro models

Metallomics ◽  
2015 ◽  
Vol 7 (1) ◽  
pp. 83-92 ◽  
Author(s):  
C. Rodríguez-Rodríguez ◽  
M. A. Telpoukhovskaia ◽  
J. Alí-Torres ◽  
L. Rodríguez-Santiago ◽  
Y. Manso ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Silico ◽  
In Vitro Models ◽  
Molecular Probes ◽  
Drug Candidate ◽  
Chemical Tools

The proposed ThT-based drug candidate series is validated as chemical tools for further in vivo development.

scholarly journals Models of Latent Tuberculosis: Their Salient Features, Limitations, and Development

2011 ◽  
Vol 3 (02) ◽  
pp. 075-079 ◽  
Author(s):  
Kamlesh Patel ◽  
Sarbjit Singh Jhamb ◽  
Prati Pal Singh
Keyword(s):  
In Silico ◽  
Latent Tuberculosis ◽  
Oxygen Depletion ◽  
In Vitro Models ◽  
Human Infection ◽  
Nutrient Starvation ◽  
Host Immune System ◽  
In Silico Models

ABSTRACTLatent tuberculosis is a subclinical condition caused by Mycobacterium tuberculosis, which affects about one-third of the population across the world. To abridge the chemotherapy of tuberculosis, it is necessary to have active drugs against latent form of M. tuberculosis. Therefore, it is imperative to devise in vitro and models of latent tuberculosis to explore potential drugs. In vitro models such as hypoxia, nutrient starvation, and multiple stresses are based on adverse conditions encountered by bacilli in granuloma. Bacilli experience oxygen depletion condition in hypoxia model, whereas the nutrient starvation model is based on deprivation of total nutrients from a culture medium. In the multiple stress model dormancy is induced by more than one type of stress. In silico mathematical models have also been developed to predict the interactions of bacilli with the host immune system and to propose structures for potential anti tuberculosis compounds. Besides these in vitro and in silico models, there are a number of in vivo animal models like mouse, guinea pig, rabbit, etc. Although they simulate human latent tuberculosis up to a certain extent but do not truly replicate human infection. All these models have their inherent merits and demerits. However, there is no perfect model for latent tuberculosis. Therefore, it is imperative to upgrade and refine existing models or develop a new model. However, battery of models will always be a better alternative to any single model as they will complement each other by overcoming their limitations.

Computational and bioengineered lungs as alternatives to whole animal, isolated organ, and cell-based lung models

2012 ◽  
Vol 303 (9) ◽  
pp. L733-L747 ◽  
Author(s):  
Brijeshkumar Patel ◽  
Robert Gauvin ◽  
Shahriar Absar ◽  
Vivek Gupta ◽  
Nilesh Gupta ◽  
...  
Keyword(s):  
In Silico ◽  
In Vitro Models ◽  
In Vivo Models ◽  
The Past ◽  
Complex Anatomy ◽  
Human Lungs ◽  
Conventional Cell ◽  
In Silico Models

Development of lung models for testing a drug substance or delivery system has been an intensive area of research. However, a model that mimics physiological and anatomical features of human lungs is yet to be established. Although in vitro lung models, developed and fine-tuned over the past few decades, were instrumental for the development of many commercially available drugs, they are suboptimal in reproducing the physiological microenvironment and complex anatomy of human lungs. Similarly, intersubject variability and high costs have been major limitations of using animals in the development and discovery of drugs used in the treatment of respiratory disorders. To address the complexity and limitations associated with in vivo and in vitro models, attempts have been made to develop in silico and tissue-engineered lung models that allow incorporation of various mechanical and biological factors that are otherwise difficult to reproduce in conventional cell or organ-based systems. The in silico models utilize the information obtained from in vitro and in vivo models and apply computational algorithms to incorporate multiple physiological parameters that can affect drug deposition, distribution, and disposition upon administration via the lungs. Bioengineered lungs, on the other hand, exhibit significant promise due to recent advances in stem or progenitor cell technologies. However, bioengineered approaches have met with limited success in terms of development of various components of the human respiratory system. In this review, we summarize the approaches used and advancements made toward the development of in silico and tissue-engineered lung models and discuss potential challenges associated with the development and efficacy of these models.

Nanodrugs as a new approach in therapy of cardiovascular diseases and cancer with tumor-associated angiogenesis

2020 ◽  
Vol 28 ◽  
Author(s):  
Justyna Hajtuch ◽  
Karolina Niska ◽  
Iwona Inkielewicz-Stepniak
Keyword(s):  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Controlled Drug Release ◽  
Biological Properties ◽  
Comprehensive Information ◽  
Conventional Drug ◽  
Key Factor ◽  
Functionalized Materials

Background: Cancer along with cardiovascular diseases are globally defined as leading causes of death. Importantly, some risk factors are common to these diseases. The process of angiogenesis and platelets aggregation are observed in cancer development and progression. In recent years, studies have been conducted on nanodrugs in these diseases that have provided important information on the biological and physicochemical properties of nanoparticles. Their attractive features are that they are made of biocompatible, well-characterized and easily functionalized materials. Unlike conventional drug delivery, sustained and controlled drug release can be obtained by using nanomaterials. Methods: In this article, we review the latest research to provide comprehensive information on nanoparticle-based drugs for the treatment of cancer, cardiovascular disease associated with abnormal haemostasis, and the inhibition of tumorassociated angiogenesis. Results: The results of the analysis of data based on nanoparticles with drugs confirm their improved pharmaceutical and biological properties, which gives promising antiplatelet, anticoagulant and antiangiogenic effects. Moreover, the review included in vitro, in vivo research and presented nanodrugs with chemotherapeutics approved by Food and Drug Administration. Conclusion: By the optimization of nanoparticles size and surface properties, nanotechnology are able to deliver drugs with enhanced bioavailability in treatment of cardiovascular disease, cancer and inhibition of cancer-related angiogenesis. Thus, nanotechnology can improve the therapeutic efficacy of the drug, but there is a need for a better understanding of the nanodrugs interaction in the human body, because this is a key factor in the success of potential nanotherapeutics.

Recent In Vitro and In Silico Advances in the Understanding of Intranasal Drug Delivery

2020 ◽  
Vol 26 ◽  
Author(s):  
John Chen ◽  
Andrew Martin ◽  
Warren H. Finlay
Keyword(s):  
Drug Delivery ◽  
In Silico ◽  
Local Drug Delivery ◽  
In Vivo Studies ◽  
Intranasal Drug Delivery ◽  
Nasal Sprays ◽  
In Silico Studies ◽  
Drug Delivery Devices

Background: Many drugs are delivered intranasally for local or systemic effect, typically in the form of droplets or aerosols. Because of the high cost of in vivo studies, drug developers and researchers often turn to in vitro or in silico testing when first evaluating the behavior and properties of intranasal drug delivery devices and formulations. Recent advances in manufacturing and computer technologies have allowed for increasingly realistic and sophisticated in vitro and in silico reconstructions of the human nasal airways. Objective: To perform a summary of advances in understanding of intranasal drug delivery based on recent in vitro and in silico studies. Conclusion: The turbinates are a common target for local drug delivery applications, and while nasal sprays are able to reach this region, there is currently no broad consensus across the in vitro and in silico literature concerning optimal parameters for device design, formulation properties and patient technique which would maximize turbinate deposition. Nebulizers are able to more easily target the turbinates, but come with the disadvantage of significant lung deposition. Targeting of the olfactory region of the nasal cavity has been explored for potential treatment of central nervous system conditions. Conventional intranasal devices, such as nasal sprays and nebulizers, deliver very little dose to the olfactory region. Recent progress in our understanding of intranasal delivery will be useful in the development of the next generation of intranasal drug delivery devices.

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