Influenza A(H1N1)pdm09 Virus Aggravates Pathology of Blood Vessels in Wistar Rats with Premorbid Acute Cardiomyopathy.

Influenza virus can infect the vascular endothelium and cause endothelial dysfunction. Persons at higher risk for severe influenza are patients with acute and chronic cardiovascular disorders; however, the mechanism of influenza-induced cardiovascular system alteration remains not fully understood. The aim of the study was to assess the functional activity of mesenteric blood vessels of Wistar rats with premorbid acute cardiomyopathy infected with Influenza A(H1N1)pdm09 virus. For this, we determined (1) the vasomotor activity of mesenteric blood vessels of Wistar rats using wire myography, (2) the level of expression of three endothelial factors: endothelial nitric oxide synthase (eNOS), plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator (tPA) in the endothelium of mesenteric blood vessels using immunohistochemistry, and (3) the concentration of PAI-1 and tPA in the blood plasma using ELISA. Acute cardiomyopathy in animals was induced by doxorubicin (DOX) following infection with rat-adapted Influenza A(H1N1)pdm09 virus. The functional activity of mesenteric blood vessels was analyzed at 24 and 96 h post infection (hpi). Thus, the maximal response of mesenteric arteries to both vasoconstrictor and vasodilator at 24 and 96 hpi was significantly decreased compared with control. Expression of eNOS in the mesenteric vascular endothelium was modulated at 24 and 96 hpi. PAI-1 expression increased 3.47-fold at 96 hpi, while the concentration of PAI-1 in the blood plasma increased 6.43-fold at 24 hpi compared with control. The tPA concentration in plasma was also modulated at 24 hpi and 96 hpi. The obtained data indicate that influenza A(H1N1)pdm09 virus aggravates the course of premorbid acute cardiomyopathy in Wistar rats, causing pronounced dysregulation of endothelial factor expression and vasomotor activity impairment of mesenteric arteries.

The Role of NAD+, SIRTs Interactions in Stimulating and Counteracting Carcinogenesis.

The World Health Organization has identified oncological diseases as one of the most serious health concerns of the current century. Current research on oncogenesis is focused on the molecular mechanisms of energy-biochemical reprogramming in cancer cell metabolism, including processes contributing to the Warburg effect and the pro-oncogenic and anti-oncogenic roles of sirtuins (SIRTs) and poly-(ADP-ribose) polymerases (PARPs). However, a clear understanding of the interaction between NAD+, SIRTs in cancer development, as well as their effects on carcinogenesis, has not been established, and literature data vary greatly. This work aims to provide a summary and structure of the available information on NAD+, SIRTs interactions in both stimulating and countering carcinogenesis, and to discuss potential approaches for pharmacological modulation of these interactions to achieve an anticancer effect.

Molecular mechanisms of endothelial remodeling under doxorubicin treatment.

Doxorubicin (DOX) is an effective antineoplastic agent used to treat various types of cancers. However, its use is limited by the development of cardiotoxicity, which may result in heart failure. The exact mechanisms underlying DOX-induced cardiotoxicity are not fully understood, but recent studies have shown that endothelial-mesenchymal transition (EndMT) and endothelial damage play a crucial role in this process. EndMT is a biological process in which endothelial cells lose their characteristics and transform into mesenchymal cells, which have a fibroblast-like phenotype. This process has been shown to contribute to tissue fibrosis and remodeling in various diseases, including cancer and cardiovascular diseases. DOX-induced cardiotoxicity has been demonstrated to increase the expression of EndMT markers, suggesting that EndMT may play a critical role in the development of this condition. Furthermore, DOX-induced cardiotoxicity has been shown to cause endothelial damage, leading to the disruption of the endothelial barrier function and increased vascular permeability. This can result in the leakage of plasma proteins, leading to tissue edema and inflammation. Moreover, DOX can impair the production of nitric oxide, endothelin-1, neuregulin, thrombomodulin, thromboxane B2 etc. by endothelial cells, leading to vasoconstriction, thrombosis and further impairing cardiac function. In this regard, this review is devoted to the generalization and structuring of information about the known molecular mechanisms of endothelial remodeling under the action of DOX.

SIRT1 activation and its effect on intercalated disc proteins as a way to reduce doxorubicin cardiotoxicity.

According to the World Health Organization, the neoplasm is one of the main reasons for morbidity and mortality worldwide. At the same time, application of cytostatic drugs like an independent type of cancer treatment and in combination with surgical methods, is often associated with the development of cardiovascular complications both in the early and in the delayed period of treatment. Doxorubicin (DOX) is the most commonly used cytotoxic anthracycline antibiotic. DOX can cause both acute and delayed side effects. The problem is still not solved, as evidenced by the continued activity of researchers in terms of developing approaches for the prevention and treatment of cardiovascular complications. It is known, the heart muscle consists of cardiomyocytes connected by intercalated discs (ID), which ensure the structural, electrical, metabolic unity of the heart. Various defects in the ID proteins can lead to the development of cardiovascular diseases of various etiologies, including DOX-induced cardiomyopathy. The search for ways to influence the functioning of ID proteins of the cardiac muscle can become the basis for the creation of new therapeutic approaches to the treatment and prevention of cardiac pathologies. SIRT1 may be an interesting cardioprotective variant due to its wide functional significance. SIRT1 activation triggers nuclear transcription programs that increase the efficiency of cellular, mitochondrial metabolism, increases resistance to oxidative stress, and promotes cell survival. It can be assumed that SIRT1 can not only provide a protective effect at the cardiomyocytes level, leading to an improvement in mitochondrial and metabolic functions, reducing the effects of oxidative stress and inflammatory processes, but also have a protective effect on the functioning of IDs structures of the cardiac muscle.

Intravenous Nicotinamide Riboside Administration Has a Cardioprotective Effect in Chronic Doxorubicin-Induced Cardiomyopathy.

Doxorubicin, which is widely used to treat a broad spectrum of malignancies, has pronounced dose-dependent side effects leading to chronic heart failure development. Nicotinamide riboside (NR) is one of the promising candidates for leveling the cardiotoxic effect. In the present work, we performed a comparative study of the cardioprotective and therapeutic actions of various intravenous NR administration modes in chronic doxorubicin-induced cardiomyopathy in Wistar rats. The study used 60 mature male SPF Wistar rats. The animals were randomized into four groups (a control group and three experimental groups) which determined the doxorubicin (intraperitoneally) and NR (intravenous) doses as well as the specific modes of NR administration (combined, preventive). We demonstrated the protective effect of NR on the cardiovascular system both with combined and preventive intravenous drug administration, which was reflected in a fibrous tissue formation decrease, reduced fractional-shortening decrease, and better antioxidant system performance. At the same time, it is important to note that the preventive administration of NR had a more significant protective effect on the animal organism as a whole. This was confirmed by better physical activity parameters and vascular bed conditions. Thus, the data obtained during the study can be used for further investigation into chronic doxorubicin-induced cardiomyopathy prevention and treatment approaches.

Vascular Reactions of the Diving Reflex in Men and Women Carrying Different ADRA1A Genotypes.

The diving reflex is an oxygen-saving mechanism which is accompanied by apnea, reflex bradycardia development, peripheral vasoconstriction, spleen erythrocyte release, and selective redistribution of blood flow to the organs most vulnerable to lack of oxygen, such as the brain, heart, and lungs. However, this is a poorly studied form of hypoxia, with a knowledge gap on physiological and biochemical adaptation mechanisms. The reflective sympathetic constriction of the resistive vessels is realized via ADRA1A. It has been shown that ADRA1A SNP (p.Arg347Cys; rs1048101) is associated with changes in tonus in vessel walls. Moreover, the Cys347 allele has been shown to regulate systolic blood pressure. The aim of this work was to evaluate whether the ADRA1A polymorphism affected the pulmonary vascular reactions in men and women in response to the diving reflex. Men (n = 52) and women (n = 50) untrained in diving aged 18 to 25 were recruited into the study. The vascular reactions and blood flow were examined by integrated rheography and rheography of the pulmonary artery. Peripheral blood circulation was registered by plethysmography. The ADRA1A gene polymorphism (p.Arg347Cys; rs1048101) was determined by PCR-RFLP. In both men and women, reflective pulmonary vasodilation did occur in response to the diving reflex, but in women this vasodilation was more pronounced and was accompanied by a higher filling of the lungs with blood.. Additionally, ADRA1A SNP (p.Arg347Cys; rs1048101) is associated with sex. Interestingly, women with the Arg347 allele demonstrated the highest vasodilation of the lung vessels. Therefore, our data may help to indicate women with the most prominent adaptive reactions to the diving reflex. Our data also indicate that women and men with the Cys allele of the ADRA1A gene polymorphism have the highest risk of developing lung hypertension in response to the diving reflex. The diving reflex is an oxygen-saving mechanism which is accompanied by apnea, reflex bradycardia development, peripheral vasoconstriction, spleen erythrocyte release, and selective redistribution of blood flow to the organs most vulnerable to lack of oxygen, such as the brain, heart, and lungs. However, this is a poorly studied form of hypoxia, with a knowledge gap on physiological and biochemical adaptation mechanisms.

Influenza A Virus Causes Histopathological Changes and Impairment in Functional Activity of Blood Vessels in Different Vascular Beds.

It has been established that blood vessels are a target for influenza virus; however, the mechanism by which virus affects the cardiovascular system remains unknown. The aim of the study is the identification of histological changes and changes in the functional activity of the pulmonary and mesenteric blood vessels of Wistar rats. Wistar rats were intranasally infected with the influenza A(H1N1)pdm09 virus. At 24 and 96 h post infection (hpi), histopathological changes were observed in lung tissues with the absence of histological changes in mesenteric tissues. The functional activity of pulmonary and mesenteric arteries was determined using wire myography. In pulmonary arteries, there was a tendency towards an increase in integral response to the vasodilator and a decrease in the integral response to the vasoconstrictor at 24 hpi (compared with control). At 96 hpi, a tendency towards a decrease in the integral response to the vasoconstrictor persisted, while the response to acetylcholine was slightly increased. The functional activity of the mesenteric blood vessels was inverted: a significant decrease in the integral response to the vasodilator and an increase in the response to the vasoconstrictor at 24 hpi were observed; at 96 hpi, the integral response to the vasoconstrictor persisted, while the response to the vasodilator remained significantly reduced. Obtained data indicate the development of endothelial dysfunction in non-lethal and clinically non-severe experimental influenza virus infection.

Cardiac Involvement in Children Affected by COVID-19: Clinical Features and Diagnosis.

COVID-19 (Coronavirus disease 2019) in children is usually mild. However, multiple organ disorders associated with SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus 2) have been detected with poor respiratory symptoms. Cardiac changes are noted in 17% to 75% of cases, which are associated with diagnostic difficulties in high-risk groups for the development of complications that are associated with myocardial damage by the SARS-CoV-2 virus. The objective of this review is to identify the most significant symptoms of cardiac involvement affected by COVID-19, which require in-depth examination. The authors analyzed publications from December 2019 to the October 2022, which were published in accessible local and international databases. According to the analysis data, the main sign of myocardial involvement was increasing as cardiomarkers in the patient's blood, in particular troponin I or troponin T. Many authors noted that the increased level of CRP (C-reactive protein) and NT-proBNP, which are accompanied by changes in the ECG (electrocardiogram) and EchoCG (echocardiography), as a rule, were nonspecific. However, the identified cardiac functional dysfunctions affected by SARS-CoV-2, required an cardiac MRI. The lack of timely diagnosis of myocardial involvements, especially in children at high risk for the development of complications associated with SARS-CoV-2 myocardial injury, can lead to death. The direct damage of the structural elements of myocardial blood vessels in patients with severe hypoxic changes resulted from respiratory failure caused by SARS-CoV-2 lung damage, with the development of severe acute diffuse alveolar damage and cell-mediated immune response and myocardial involvement affected by SARS-CoV-2 damage. In this article, the authors introduce a clinical case of a child who dead from inflammatory myocardities with COVID-19 in a background of congenital heart disease and T-cell immunodeficiency.

Modeling Doxorubicin-Induced Cardiomyopathy With Fibrotic Myocardial Damage in Wistar Rats.

Background: Cardiovascular complications, arising after anthracycline chemotherapy, cause a significant deterioration in the life quality and expectancy of those patients who were previously successfully treated for malignant neoplasms. A number of clinical studies have demonstrated that patients with cardiotoxicity manifested during anthracyclines therapy also have extensive fibrotic changes in the cardiac muscle in the long term. Given the lack of an unambiguous understanding of the mechanisms of fibrotic changes formation under doxorubicin treatment in the myocardium, there is the obvious necessity to create a relevant experimental model of chronic doxorubicin-induced cardiomyopathy with fibrotic myocardial lesions and delayed development of diastolic dysfunction. Methods: The study was divided into two stages: first stage (creation of acute doxorubicin cardiomyopathy) - 35 male Wistar rats; second stage (creation of chronic doxorubicin cardiomyopathy) - 40 male Wistar rats. The animals were split into eight groups (two control ones and six experimental ones), which determined the doxorubicin dose (first stage: 25, 20.4, 15 mg/kg; second stage: 5, 10, 15 mg/kg, intraperitoneally) and the frequency of injection. Echocardiographic, hematological, histological, and molecular methods were used to confirm the successful modeling of acute and chronic doxorubicin-induced cardiomyopathy with fibrotic lesions. Results: A model of administration six times every other day with a cumulative dose of doxorubicin 20 mg/kg is suitable for evaluation of acute cardiotoxicity. The 15 mg/kg doxorubicin dose is highly cardiotoxic; what's more, it correlates with progressive deterioration of the clinical condition of the animals after 2 months. The optimal cumulative dose of doxorubicin leads to clinical manifestations confirmed by echocardiographic, histological, molecular changes associated with the development of chronic doxorubicin-induced cardiomyopathy with fibrotic lesions of the left ventricular of the cardiac muscle and ensure long-term survival of animals is 10 mg/kg doxorubicin. A dose of 5 mg/kg of the doxorubicin does not ensure the development of fibrous changes formation. Conclusion: We assume that cumulative dose of 10 mg/kg with a frequency of administration of six times in 2 days can be used to study the mechanisms of anthracycline cardiomyopathy development.

Nicotinamide Riboside for the Prevention and Treatment of Doxorubicin Cardiomyopathy. Opportunities and Prospects.

Despite the progress in the development of new anticancer strategies, cancer is rapidly spreading around the world and remains one of the most common diseases. For more than 40 years, doxorubicin has been widely used in the treatment of solid and hematological tumors. At the same time, the problem of its cardiotoxicity remains unresolved, despite the high efficiency of this drug. Symptomatic therapy is used as a treatment for side-effects of doxorubicin or pathological conditions that have already appeared in their background. To date, there are no treatment methods for doxorubicin cardiomyopathy as such. A drug such as nicotinamide riboside can play an important role in solving this problem. Nicotinamide riboside is a pyridine nucleoside similar to vitamin B3 that acts as a precursor to NAD+. There is no published research on nicotinamide riboside effects on cardiomyopathy, despite the abundance of works devoted to the mechanisms of its effects in various pathologies. The review analyzes information about the effects of nicotinamide riboside on various experimental models of pathologies, its role in the synthesis of NAD+, and also considers the possibility and prospects of its use for the prevention of doxorubicin cardiomyopathy.

Controlling the Movement of Magnetic Iron Oxide Nanoparticles Intended for Targeted Delivery of Cytostatics.

BACKGROUND: A promising approach to solve the problem of cytostatic toxicity is targeted drug transport using magnetic nanoparticles (MNPs). PURPOSE: To use calculation to determine the optimal characteristics of the magnetic field for controlling MNPs in the body, and to evaluate the efficiency of magnetically controlled delivery of MNPs in vitro and in vivo to a tumour site in mice. MATERIAL AND METHODS: For the in vitro study, reference MNPs were used, while for in vivo studies, MNPs coated in polylactide including fluorescent indocyanine (MNPs-ICG) were used. The in vivo luminescence intensity study was performed in mice with tumours, with and without of a magnetic field at the sites of interest. The studies were performed on a hydrodynamic stand developed at the Institute of Experimental Medicine of the Almazov National Medical Research Centre of the Ministry of Health of Russia. RESULTS: The use of neodymium magnets facilitated selective accumulation of MNPs. One minute after the administration of MNPs-ICG to mice with a tumour, MNPs-ICG predominantly accumulated in the liver, in the absence and presence of a magnetic field, which indicates its metabolic pathway. The intensity of the fluorescence in the animals' livers did not change over time, although an increase in fluorescence in the tumour was observed in the presence of a magnetic field. CONCLUSION: This type of MNP, used in combination with a magnetic field of calculated strength, can form the basis for the development of magnetically controlled transport of cytostatic drugs into tumour tissue.

Analysis of Models of Doxorubicin-Induced Cardiomyopathy in Rats and Mice. A Modern View From the Perspective of the Pathophysiologist and the Clinician.

Today the pharmacological possibilities of treating cancer are expanding and as a result, life expectancy is increasing against the background of chemotherapy and supportive treatment. In the conditions of successful antitumor treatment, complications associated with its toxic effect on healthy tissues and organs began to come to the fore. Anthracycline cardiomyopathy was the first serious cardiovascular complication to draw the attention of oncologists and cardiologists around the world. Anthracycline drugs such as doxorubicin, epirubicin, idarubicin are still widely used in oncological practice to treat a wide range of solid and hematological malignancies. Doxorubicin-induced cardiomyopathy is closely associated with an increase in oxidative stress, as evidenced by reactive oxygen species (ROS) nduced damage such as lipid peroxidation, and decreased levels of antioxidants. Myofibrillar destruction and dysregulation of intracellular calcium are also important mechanisms, usually associated with doxorubicin-induced cardiotoxicity. Despite the abundance of data on various mechanisms involved in the implementation of doxorubicin-induced cardiotoxicity, a final understanding of the mechanism of the development of doxorubicin cardiomyopathy has not yet been formed. It poses the most significant challenges to the development of new methods of prevention and treatment, as well as to the unambiguous choice of a specific treatment regimen using the existing pharmacological tools. In order to resolve these issues new models that could reflect the development of the chemotherapy drugs effects are needed. In this review we have summarized and analyzed information on the main existing models of doxorubicin cardiomyopathy using small laboratory animals. In addition, this paper discusses further areas of research devoted to the development and validation of new improved models of doxorubicin cardiomyopathy suitable both for studying the mechanisms of its implementation and for the preclinical drugs effectiveness assessment.