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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 42129

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Prof. Dr. Vera Marisa Costa

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UCIBIO, REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Interests: Cardiotoxicity; cardio-oncology; chemobrain; clinical toxicology
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Félix Carvalho

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UCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira nº 228, 4050-313 Porto, Portugal
Interests: toxicology; Drugs of abuse; pesticides; antidotes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cardiovascular diseases are leading causes of death worldwide. Among them, heart failure (HF) has a 50% death rate at 5 years, with no foreseen curable approach. HF numbers are increasing due to population ageing, metabolic diseases (e.g., obesity and diabetes), and even as a result of drug adverse effects, which makes it a public health issue. In particular, the setting of the full picture of the underlying mechanisms of HF; the molecules and pathways involved; the finding of new reliable, accessible, and early detecting biomarkers of damage, where subclinical damage is prevailing; and new curable or life prolonging drugs or therapies that decrease the social and economic of this emergent disease are urgent and will have immediate impact.

Therefore, this Special Issue will accept original research articles and up-to-date reviews about all aspects of cardiovascular diseases, mainly focusing on heart failure, and that cover but are not restricted to molecules involved in

The pathophysiology of HF
Disrupted intracellular pathways
Early biomarkers of the disease that can have future clinical relevance
Treatment approaches for heart failure

Dr. Vera Marisa Costa
Prof. Dr. Félix Carvalho
Guest Editors

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Keywords

Intercellular communication
Metabolomics
Biomarkers of damage
Biomarkers of susceptibility
Intracellular pathways
Treatment

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Published Papers (9 papers)

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Research

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20 pages, 2953 KiB

Open AccessEditor’s ChoiceArticle

The Potential Mechanisms behind Loperamide-Induced Cardiac Arrhythmias Associated with Human Abuse and Extreme Overdose

by Hua Rong Lu, Bruce P. Damiano, Mohamed Kreir, Jutta Rohrbacher, Henk van der Linde, Tamerlan Saidov, Ard Teisman and David J. Gallacher

Biomolecules 2023, 13(9), 1355; https://doi.org/10.3390/biom13091355 - 6 Sep 2023

Cited by 1 | Viewed by 3259

Abstract

Loperamide has been a safe and effective treatment for diarrhea for many years. However, many cases of cardiotoxicity with intentional abuse of loperamide ingestion have recently been reported. We evaluated loperamide in in vitro and in vivo cardiac safety models to understand the mechanisms for this cardiotoxicity. Loperamide slowed conduction (QRS-duration) starting at 0.3 µM [~1200-fold (×) its human Free Therapeutic Plasma Concentration; FTPC] and reduced the QT-interval and caused cardiac arrhythmias starting at 3 µM (~12,000× FTPC) in an isolated rabbit ventricular-wedge model. Loperamide also slowed conduction and elicited Type II/III A-V block in anesthetized guinea pigs at overdose exposures of 879× and 3802× FTPC. In ion-channel studies, loperamide inhibited hERG (I_Kr)_, I_Na, and I_Ca currents with IC₅₀ values of 0.390 µM, 0.526 µM, and 4.091 µM, respectively (i.e., >1560× FTPC). Additionally, in silico trials in human ventricular action potential models based on these IC50s confirmed that loperamide has large safety margins at therapeutic exposures (≤600× FTPC) and confirmed repolarization abnormalities in the case of extreme doses of loperamide. The studies confirmed the large safety margin for the therapeutic use of loperamide but revealed that at the extreme exposure levels observed in human overdose, loperamide can cause a combination of conduction slowing and alterations in repolarization time, resulting in cardiac proarrhythmia. Loperamide’s inhibition of the I_Na channel and hERG-mediated IKr are the most likely basis for this cardiac electrophysiological toxicity at overdose exposures. The cardiac toxic effects of loperamide at the overdoses could be aggravated by co-medication with other drug(s) causing ion channel inhibition. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)

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22 pages, 6958 KiB

Open AccessArticle

Cardiac Molecular Remodeling by Anticancer Drugs: Doxorubicin Affects More Metabolism While Mitoxantrone Impacts More Autophagy in Adult CD-1 Male Mice

by Sofia Reis Brandão, Ana Reis-Mendes, Margarida Duarte-Araújo, Maria João Neuparth, Hugo Rocha, Félix Carvalho, Rita Ferreira and Vera Marisa Costa

Biomolecules 2023, 13(6), 921; https://doi.org/10.3390/biom13060921 - 31 May 2023

Cited by 3 | Viewed by 2375

Abstract

Doxorubicin (DOX) and mitoxantrone (MTX) are classical chemotherapeutic agents used in cancer that induce similar clinical cardiotoxic effects, although it is not clear if they share similar underlying molecular mechanisms. We aimed to assess the effects of DOX and MTX on the cardiac remodeling, focusing mainly on metabolism and autophagy. Adult male CD-1 mice received pharmacologically relevant cumulative doses of DOX (18 mg/kg) and MTX (6 mg/kg). Both DOX and MTX disturbed cardiac metabolism, decreasing glycolysis, and increasing the dependency on fatty acids (FA) oxidation, namely, through decreased AMP-activated protein kinase (AMPK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) content and decreased free carnitine (C0) and increased acetylcarnitine (C2) concentration. Additionally, DOX heavily influenced glycolysis, oxidative metabolism, and amino acids turnover by exclusively decreasing phosphofructokinase (PFKM) and electron transfer flavoprotein-ubiquinone oxidoreductase (ETFDH) content, and the concentration of several amino acids. Conversely, both drugs downregulated autophagy given by the decreased content of autophagy protein 5 (ATG5) and microtubule-associated protein light chain 3 (LC3B), with MTX having also an impact on Beclin1. These results emphasize that DOX and MTX modulate cardiac remodeling differently, despite their clinical similarities, which is of paramount importance for future treatments. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)

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12 pages, 529 KiB

Open AccessArticle

Predictive Value of Collagen Biomarkers in Advanced Chronic Kidney Disease Patients

by Carina Ureche, Gianina Dodi, Adela Mihaela Șerban, Andreea Simona Covic, Luminița Voroneanu, Simona Hogaș, Radu Andy Sascău, Cristian Stătescu and Adrian Covic

Biomolecules 2023, 13(2), 389; https://doi.org/10.3390/biom13020389 - 18 Feb 2023

Cited by 3 | Viewed by 1812

Abstract

Patients with chronic kidney disease have an increased risk of all-cause death. The value of collagen biomarkers such as procollagen type I carboxy-terminal propeptide (PICP) and procollagen type III N-terminal peptide (P3NP), in end-stage renal disease (ESRD), has not yet been defined (in the literature and in clinics). The purpose of this study was to determine the potential value of these new biomarkers in the prediction of mortality in this population. Plasma PICP and P3NP levels were determined in 140 patients with ESRD, not yet on dialysis, who were followed up for 36 ± 5.3 months. During follow-up, 58 deaths were recorded (41.4%), with the majority of them being cardiovascular deaths (43, 74.13%). Using the ROC curve, the cut-off value for the prediction of mortality for PICP was 297.31 µg/L, while for P3NP, the cut-off value was 126.67 µg/L. In univariate analysis, a value of PICP above the cut-off point was associated with a fivefold increased risk of mortality (hazard ratio (HR) 5.071, 95% confidence interval 1.935–13.29, p = 0.001) and a value of P3NP above the cut-off point was associated with a twofold increased risk of mortality (HR 2.089, 95% CI 1.044–4.178, p = 0.002). In a multivariable Cox proportional hazards model, PICP values remained independent predictors of mortality (HR 1.22, 95% CI 1.1–1.31, p < 0.0001). Our data suggest that the collagen biomarker PICP is an independent predictor of mortality in ESRD patients who are not yet on dialysis. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)

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11 pages, 1421 KiB

Open AccessArticle

Comparison of Antiplatelet Effects of Phenol Derivatives in Humans

by Marcel Hrubša, Raúl Alva, Mst Shamima Parvin, Kateřina Macáková, Jana Karlíčková, Jaka Fadraersada, Lukáš Konečný, Monika Moravcová, Alejandro Carazo and Přemysl Mladěnka

Biomolecules 2022, 12(1), 117; https://doi.org/10.3390/biom12010117 - 12 Jan 2022

Cited by 6 | Viewed by 2388

Abstract

Flavonoids are associated with positive cardiovascular effects. However, due to their low bioavailability, metabolites are likely responsible for these properties. Recently, one of these metabolites, 4-methylcatechol, was described to be a very potent antiplatelet compound. This study aimed to compare its activity with its 22 close derivatives both of natural or synthetic origin in order to elucidate a potential structure–antiplatelet activity relationship. Blood from human volunteers was induced to aggregate by arachidonic acid (AA), collagen or thrombin, and plasma coagulation was also studied. Potential toxicity was tested on human erythrocytes as well as on a cancer cell line. Our results indicated that 17 out of the 22 compounds were very active at a concentration of 40 μM and, importantly, seven of them had an IC₅₀ on AA-triggered aggregation below 3 μM. The effects of the most active compounds were confirmed on collagen-triggered aggregation too. None of the tested compounds was toxic toward erythrocytes at 50 μM and four compounds partly inhibited proliferation of breast cancer cell line at 100 μM but not at 10 μM. Additionally, none of the compounds had a significant effect on blood coagulation or thrombin-triggered aggregation. This study hence reports four phenol derivatives (4-ethylcatechol, 4-fluorocatechol, 2-methoxy-4-ethylphenol and 3-methylcatechol) suitable for future in vivo testing. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)

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21 pages, 7395 KiB

Open AccessArticle

Role of Inflammation and Redox Status on Doxorubicin-Induced Cardiotoxicity in Infant and Adult CD-1 Male Mice

by Ana Reis-Mendes, Ana Isabel Padrão, José Alberto Duarte, Salomé Gonçalves-Monteiro, Margarida Duarte-Araújo, Fernando Remião, Félix Carvalho, Emília Sousa, Maria Lourdes Bastos and Vera Marisa Costa

Biomolecules 2021, 11(11), 1725; https://doi.org/10.3390/biom11111725 - 19 Nov 2021

Cited by 24 | Viewed by 3916

Abstract

Doxorubicin (DOX) is a topoisomerase II inhibitor commonly used in the treatment of several types of cancer. Despite its efficacy, DOX can potentially cause fatal adverse effects, like cardiotoxicity. This work aimed to assess the role of inflammation in DOX-treated infant and adult mice and its possible link to underlying cardiotoxicity. Two groups of CD-1 male mice of different ages (infants or adults) were subjected to biweekly DOX administrations, to reach a cumulative dose of 18.0 mg/kg, which corresponds approximately in humans to 100.6 mg/m² for infants and 108.9 mg/m² for adults a clinically relevant dose in humans. The classic plasmatic markers of cardiotoxicity increased, and that damage was confirmed by histopathological findings in both groups, although it was higher in adults. Moreover, in DOX-treated adults, an increase of cardiac fibrosis was observed, which was accompanied by an increase in specific inflammatory parameters, namely, macrophage M1 and nuclear factor kappa B (NF-κB) p65 subunit, with a trend toward increased levels of the tumor necrosis factor receptor 2 (TNFR2). On the other hand, the levels of myeloperoxidase (MPO) and interleukin (IL)-6 significantly decreased in DOX-treated adult animals. In infants, a significant increase in cardiac protein carbonylation and in the levels of nuclear factor erythroid-2 related factor 2 (Nrf2) was observed. In both groups, no differences were found in the levels of tumor necrosis factor (TNF-α), IL-1β, p38 mitogen-activated protein kinase (p38 MAPK) or NF-κB p52 subunit. In conclusion, using a clinically relevant dose of DOX, our study demonstrated that cardiac effects are associated not only with the intensity of the inflammatory response but also with redox response. Adult mice seemed to be more prone to DOX-induced cardiotoxicity by mechanisms related to inflammation, while infant mice seem to be protected from the damage caused by DOX, possibly by activating such antioxidant defenses as Nrf2. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)

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Review

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10 pages, 448 KiB

Open AccessReview

Cardiac-Targeting Peptide: From Discovery to Applications

by Daniella Sahagun and Maliha Zahid

Biomolecules 2023, 13(12), 1690; https://doi.org/10.3390/biom13121690 - 23 Nov 2023

Cited by 4 | Viewed by 2065

Abstract

Despite significant strides in prevention, diagnosis, and treatment, cardiovascular diseases remain the number one cause of mortality in the United States, with rates climbing at an alarming rate in the developing world. Targeted delivery of therapeutics to the heart has been a lofty goal to achieve with strategies ranging from direct intra-cardiac or intra-pericardial delivery, intra-coronary infusion, to adenoviral, lentiviral, and adeno-associated viral vectors which have preference, if not complete cardio-selectivity, for cardiac tissue. Cell-penetrating peptides (CPP) are 5–30-amino-acid-long peptides that are able to breach cell membrane barriers while carrying cargoes up to several times their size, in an intact functional form. Identified nearly three decades ago, the first of these CPPs came from the HIV coat protein transactivator of transcription. Although a highly efficient CPP, its clinical utility is limited by its robust ability to cross any cell membrane barrier, including crossing the blood–brain barrier and transducing neuronal tissue non-specifically. Several strategies have been utilized to identify cell- or tissue-specific CPPs, one of which is phage display. Using this latter technique, we identified a cardiomyocyte-targeting peptide (CTP) more than a decade ago, a finding that has been corroborated by several independent labs across the world that have utilized CTP for a myriad of different purposes in pre-clinical animal models. The goal of this publication is to provide a comprehensive review of the identification, validation, and application of CTP, and outline its potential in diagnostic and therapeutic applications especially in the field of targeted RNA interference. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)

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34 pages, 2479 KiB

Open AccessFeature PaperReview

Natural Sympathomimetic Drugs: From Pharmacology to Toxicology

by Vera Marisa Costa, Luciana Grazziotin Rossato Grando, Elisa Milandri, Jessica Nardi, Patrícia Teixeira, Přemysl Mladěnka, Fernando Remião and on behalf of The OEMONOM

Biomolecules 2022, 12(12), 1793; https://doi.org/10.3390/biom12121793 - 30 Nov 2022

Cited by 10 | Viewed by 8786

Abstract

Sympathomimetic agents are a group of chemical compounds that are able to activate the sympathetic nervous system either directly via adrenergic receptors or indirectly by increasing endogenous catecholamine levels or mimicking their intracellular signaling pathways. Compounds from this group, both used therapeutically or abused, comprise endogenous catecholamines (such as adrenaline and noradrenaline), synthetic amines (e.g., isoproterenol and dobutamine), trace amines (e.g., tyramine, tryptamine, histamine and octopamine), illicit drugs (e.g., ephedrine, cathinone, and cocaine), or even caffeine and synephrine. In addition to the effects triggered by stimulation of the sympathetic system, the discovery of trace amine associated receptors (TAARs) in humans brought new insights about their sympathomimetic pharmacology and toxicology. Although synthetic sympathomimetic agents are mostly seen as toxic, natural sympathomimetic agents are considered more complacently in the terms of safety in the vision of the lay public. Here, we aim to discuss the pharmacological and mainly toxicological aspects related to sympathomimetic natural agents, in particular of trace amines, compounds derived from plants like ephedra and khat, and finally cocaine. The main purpose of this review is to give a scientific and updated view of those agents and serve as a reminder on the safety issues of natural sympathomimetic agents most used in the community. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)

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27 pages, 764 KiB

Open AccessEditor’s ChoiceReview

Dysregulated Epicardial Adipose Tissue as a Risk Factor and Potential Therapeutic Target of Heart Failure with Preserved Ejection Fraction in Diabetes

by Teresa Salvatore, Raffaele Galiero, Alfredo Caturano, Erica Vetrano, Luca Rinaldi, Francesca Coviello, Anna Di Martino, Gaetana Albanese, Sara Colantuoni, Giulia Medicamento, Raffaele Marfella, Celestino Sardu and Ferdinando Carlo Sasso

Biomolecules 2022, 12(2), 176; https://doi.org/10.3390/biom12020176 - 21 Jan 2022

Cited by 36 | Viewed by 6135

Abstract

Cardiovascular (CV) disease and heart failure (HF) are the leading cause of mortality in type 2 diabetes (T2DM), a metabolic disease which represents a fast-growing health challenge worldwide. Specifically, T2DM induces a cluster of systemic metabolic and non-metabolic signaling which may promote myocardium derangements such as inflammation, fibrosis, and myocyte stiffness, which represent the hallmarks of heart failure with preserved ejection fraction (HFpEF). On the other hand, several observational studies have reported that patients with T2DM have an abnormally enlarged and biologically transformed epicardial adipose tissue (EAT) compared with non-diabetic controls. This expanded EAT not only causes a mechanical constriction of the diastolic filling but is also a source of pro-inflammatory mediators capable of causing inflammation, microcirculatory dysfunction and fibrosis of the underlying myocardium, thus impairing the relaxability of the left ventricle and increasing its filling pressure. In addition to representing a potential CV risk factor, emerging evidence shows that EAT may guide the therapeutic decision in diabetic patients as drugs such as metformin, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 inhibitors (SGLT2-Is), have been associated with attenuation of EAT enlargement. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)

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23 pages, 1422 KiB

Open AccessEditor’s ChoiceReview

Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence

by Teresa Salvatore, Raffaele Galiero, Alfredo Caturano, Erica Vetrano, Luca Rinaldi, Francesca Coviello, Anna Di Martino, Gaetana Albanese, Raffaele Marfella, Celestino Sardu and Ferdinando Carlo Sasso

Biomolecules 2021, 11(12), 1834; https://doi.org/10.3390/biom11121834 - 4 Dec 2021

Cited by 58 | Viewed by 9566

Abstract

Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the prognosis of HF, represents a crucial issue. Currently, the choice is between the new drugs sodium/glucose co-transporter 2 inhibitors that have consistently shown in large CV outcome trials (CVOTs) to reduce the risk of HF-related outcomes in T2DM, and metformin, an old medicament that might end up relegated to the background while exerting interesting protective effects on multiple organs among which include heart failure. When compared with other antihyperglycemic medications, metformin has been demonstrated to be safe and to lower morbidity and mortality for HF, even if these results are difficult to interpret as they emerged mainly from observational studies. Meta-analyses of randomized controlled clinical trials have not produced positive results on the risk or clinical course of HF and sadly, large CV outcome trials are lacking. The point of force of metformin with respect to new diabetic drugs is the amount of data from experimental investigations that, for more than twenty years, still continues to provide mechanistic explanations of the several favorable actions in heart failure such as, the improvement of the myocardial energy metabolic status by modulation of glucose and lipid metabolism, the attenuation of oxidative stress and inflammation, and the inhibition of myocardial cell apoptosis, leading to reduced cardiac remodeling and preserved left ventricular function. In the hope that specific large-scale trials will be carried out to definitively establish the metformin benefit in terms of HF failure outcomes, we reviewed the literature in this field, summarizing the available evidence from experimental and clinical studies reporting on effects in heart metabolism, function, and structure, and the prominent pathophysiological mechanisms involved. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)

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