The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection is not limited to the respiratory tract as receptors, including the angiotensin-converting enzyme 2 (ACE2), are expressed across many tissues. This study employed a new conditional mouse model, Rosa26creERT2/chACE2, which expresses human ACE2 (hACE2) across multiple organs, to investigate the effects of SARS-CoV-2 infection beyond the respiratory system. This strain demonstrated susceptibility to SARS-CoV-2 infection in a dose and sex-dependent manner, showing that infected male mice exhibited more severe disease outcomes, including significant weight loss, pronounced lung pathology and dysfunction, and increased mortality, compared to females. In contrast to intratracheal infection, intranasal virus administration facilitated viral spread to the brain, thereby underscoring the nasal route's role in the pathogenesis of neurological manifestations. Intranasal infection also led to increased innate immune system activation as compared to intratracheal virus administration, even though both routes activated the adaptive immune response. This model provides a valuable tool to study SARS-CoV-2 in individual tissues or use a multisystemic approach, and it also advances possibilities for preclinical evaluation of antiviral therapies and vaccine strategies.
- MeSH
- Angiotensin-Converting Enzyme 2 * genetics metabolism MeSH
- COVID-19 * pathology virology immunology genetics MeSH
- Respiratory System virology pathology MeSH
- Humans MeSH
- Disease Models, Animal MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Lung virology pathology MeSH
- Immunity, Innate MeSH
- SARS-CoV-2 * pathogenicity MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The global COVID-19 pandemic, caused by SARS-CoV-2, has led to significant morbidity and mortality, with a profound impact on cardiovascular health. This review investigates the mechanisms of SARS-CoV-2's interaction with cardiac tissue, particularly emphasizing the role of the Spike protein and ACE2 receptor in facilitating viral entry and subsequent cardiac complications. We dissect the structural features of the virus, its interactions with host cell receptors, and the resulting pathophysiological changes in the heart. Highlighting SARS-CoV-2's broad organ tropism, especially its effects on cardiomyocytes via ACE2 and TMPRSS2, the review addresses how these interactions exacerbate cardiovascular issues in patients with pre-existing conditions such as diabetes and hypertension. Additionally, we assess both direct and indirect mechanisms of virus-induced cardiac damage, including myocarditis, arrhythmias, and long-term complications such as 'long COVID'. This review underscores the complexity of SARS-CoV-2's impact on the heart, emphasizing the need for ongoing research to fully understand its long-term effects on cardiovascular health. Key words: COVID-19, Heart, ACE2, Spike protein, Cardiomyocytes, Myocarditis, Long COVID.
- MeSH
- Angiotensin-Converting Enzyme 2 * metabolism MeSH
- COVID-19 * metabolism MeSH
- Spike Glycoprotein, Coronavirus * metabolism MeSH
- Virus Internalization MeSH
- Myocytes, Cardiac metabolism virology pathology MeSH
- Humans MeSH
- Myocardium metabolism pathology MeSH
- SARS-CoV-2 * pathogenicity MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a respiratory virus that emerged in late 2019 and rapidly spread worldwide, causing the COVID-19 pandemic. The spike glycoprotein (S protein) plays a crucial role in viral target recognition and entry by interacting with angiotensin, converting enzyme 2 (ACE2), the functional receptor for the virus, via its receptor binding domain (RBD). The RBD availability for this interaction can be influenced by external factors, such as fatty acids. Linoleic acid (LA), a free fatty acid, has been shown to bind the S protein, modulating the viral infection by reducing initial target recognition. LA interacts with the fatty acid binding pocket (FABP), a potential drug target against SARS-CoV-2. In this study, we aimed to exploit the FABP as a drug target by performing a docking-based virtual screening with a library of commercially available, drug-like compounds. The virtual hits identified were then assessed in in vitro assays for the inhibition of the virus-host interaction and cytotoxicity. Binding assays targeting the spike-ACE2 interaction identified multiple compounds with inhibitory activity and low cytotoxicity.
- MeSH
- Angiotensin-Converting Enzyme 2 * metabolism chemistry MeSH
- Antiviral Agents pharmacology chemistry metabolism MeSH
- COVID-19 virology metabolism MeSH
- COVID-19 Drug Treatment MeSH
- Spike Glycoprotein, Coronavirus * metabolism chemistry MeSH
- Linoleic Acid metabolism chemistry MeSH
- Humans MeSH
- Fatty Acid-Binding Proteins metabolism MeSH
- SARS-CoV-2 * metabolism drug effects MeSH
- Molecular Docking Simulation * MeSH
- Protein Binding * MeSH
- Binding Sites MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION AND OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the nasal cavity, penetrates the nasal epithelial cells through the interaction of its spike protein with the host cell receptor angiotensin-converting enzyme 2 (ACE2) and then triggers a cytokine storm. We aimed to assess the biocompatibility of fullerenol nanoparticles C60(OH)40 and ectoine, and to document their effect on the protection of primary human nasal epithelial cells (HNEpCs) against the effects of interaction with the fragment of virus - spike protein. This preliminary research is the first step towards the construction of a intranasal medical device with a protective, mechanical function against SARS-CoV-2 similar to that of personal protective equipment (eg masks). METHODS: We used HNEpCs and the full-length spike protein from SARS-CoV-2 to mimic the first stage of virus infection. We assessed cell viability with the XTT assay and a spectrophotometer. May-Grünwald Giemsa and periodic acid-Schiff staining served to evaluate HNEpC morphology. We assessed reactive oxygen species (ROS) production by using 2',7'-dichlorofluorescin diacetate and commercial kit. Finally, we employed reverse transcription polymerase chain reaction, Western blotting and confocal microscopy to determine the expression of angiotensin-converting enzyme 2 (ACE2) and inflammatory cytokines. RESULTS: There was normal morphology and unchanged viability of HNEpCs after incubation with 10 mg/L C60(OH)40, 0.2% ectoine or their composite for 24 h. The spike protein exerted cytotoxicity via ROS production. Preincubation with the composite protected HNEpCs against the interaction between the spike protein and the host membrane and prevented the production of key cytokines characteristic of severe coronavirus disease 2019, including interleukin 6 and 8, monocyte chemotactic protein 1 and 2, tissue inhibitor of metalloproteinases 2 and macrophage colony-stimulating factor. CONCLUSION: In the future, the combination of fullerenol and ectoine may be used to prevent viral infections as an intranasal medical device for people with reduced immunity and damaged mucous membrane.
- MeSH
- Amino Acids, Diamino MeSH
- Angiotensin-Converting Enzyme 2 metabolism MeSH
- COVID-19 * prevention & control MeSH
- Cytokines metabolism MeSH
- Epithelial Cells * drug effects virology MeSH
- Fullerenes * pharmacology chemistry MeSH
- Spike Glycoprotein, Coronavirus * metabolism MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Nanoparticles * chemistry MeSH
- Nasal Mucosa drug effects cytology MeSH
- Reactive Oxygen Species metabolism MeSH
- SARS-CoV-2 * drug effects MeSH
- Cytokine Release Syndrome * prevention & control MeSH
- Cell Survival * drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
The novel coronavirus disease 2019 (COVID-19) pandemic outbreak caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has garnered unprecedented global attention. It caused over 2.47 million deaths through various syndromes such as acute respiratory distress, hypercoagulability, and multiple organ failure. The viral invasion proceeds through the ACE2 receptor, expressed in multiple cell types, and in some patients caused serious damage to tissues, organs, immune cells, and the microbes that colonize the gastrointestinal tract (GIT). Some patients who survived the SARS-CoV-2 infection have developed months of persistent long-COVID-19 symptoms or post-acute sequelae of COVID-19 (PASC). Diagnosis of these patients has revealed multiple biological effects, none of which are mutually exclusive. However, the severity of COVID-19 also depends on numerous comorbidities such as obesity, age, diabetes, and hypertension and care must be taken with respect to other multiple morbidities, such as host immunity. Gut microbiota in relation to SARS-CoV-2 immunopathology is considered to evolve COVID-19 progression via mechanisms of biochemical metabolism, exacerbation of inflammation, intestinal mucosal secretion, cytokine storm, and immunity regulation. Therefore, modulation of gut microbiome equilibrium through food supplements and probiotics remains a hot topic of current research and debate. In this review, we discuss the biological complications of the physio-pathological effects of COVID-19 infection, GIT immune response, and therapeutic pharmacological strategies. We also summarize the therapeutic targets of probiotics, their limitations, and the efficacy of preclinical and clinical drugs to effectively inhibit the spread of SARS-CoV-2.
- MeSH
- COVID-19 * immunology complications therapy MeSH
- Dysbiosis * MeSH
- COVID-19 Drug Treatment MeSH
- Gastrointestinal Tract microbiology MeSH
- Humans MeSH
- Post-Acute COVID-19 Syndrome MeSH
- Probiotics therapeutic use MeSH
- SARS-CoV-2 * immunology MeSH
- Gastrointestinal Microbiome * MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.
- MeSH
- Acute Kidney Injury * chemically induced pathology metabolism prevention & control drug therapy MeSH
- Cisplatin * toxicity MeSH
- Diminazene * analogs & derivatives pharmacology therapeutic use MeSH
- Angiotensin-Converting Enzyme Inhibitors pharmacology MeSH
- Rats MeSH
- Kidney drug effects pathology metabolism MeSH
- Lisinopril * pharmacology MeSH
- Rats, Wistar * MeSH
- Antineoplastic Agents toxicity MeSH
- Valsartan * pharmacology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
Angiotensin-converting enzyme 2 (ACE2), one of the key enzymes of the renin-angiotensin system (RAS), plays an important role in SARS-CoV-2 infection by functioning as a virus receptor. Angiotensin peptides Ang I and Ang II, the substrates of ACE2, can modulate the binding of SARS-CoV-2 Spike protein to the ACE2 receptor. In the present work, we found that co incubation of HEK-ACE2 and Vero E6 cells with the SARS-CoV-2 Spike pseudovirus (PVP) resulted in stimulation of the virus entry at low and high micromolar concentrations of Ang I and Ang II, respectively. The potency of Ang I and Ang II stimulation of virus entry corresponds to their binding affinity to ACE2 catalytic pocket with 10 times higher efficiency of Ang II. The Ang II induced mild increase of PVP infectivity at 20 microM; while at 100 microM the increase (129.74+/-3.99 %) was highly significant (p<0.001). Since the angiotensin peptides act in HEK ACE2 cells without the involvement of angiotensin type I receptors, we hypothesize that there is a steric interaction between the catalytic pocket of the ACE2 enzyme and the SARS-CoV-2 S1 binding domain. Oversaturation of the ACE2 with their angiotensin substrate might result in increased binding and entry of the SARS-CoV-2. In addition, the analysis of angiotensin peptides metabolism showed decreased ACE2 and increased ACE activity upon SARS-CoV-2 action. These effects should be taken into consideration in COVID-19 patients suffering from comorbidities such as the over-activated renin-angiotensin system as a mechanism potentially influencing the SARS-CoV-2 invasion into recipient cells.
- MeSH
- Angiotensin I metabolism pharmacology MeSH
- Angiotensin II metabolism MeSH
- Peptidyl-Dipeptidase A metabolism MeSH
- Angiotensin-Converting Enzyme 2 metabolism MeSH
- COVID-19 * MeSH
- Spike Glycoprotein, Coronavirus * MeSH
- Angiotensin-Converting Enzyme Inhibitors MeSH
- Humans MeSH
- Renin-Angiotensin System * MeSH
- SARS-CoV-2 metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Activators of hypoxia inducible factors (HIFs), such as roxadustat, are promising agents for anemia treatment. However, since HIFs are also involved in the regulation of the pulmonary circulation, we hypothesized that roxadustat increases pulmonary vascular resistance and vasoconstrictor reactivity. Using isolated, cell-free solution perfused rat lungs, we found perfusion pressure-flow curves to be shifted to higher pressures by 2 weeks of roxadustat treatment (10 mg/kg every other day), although not as much as by chronic hypoxic exposure. Vasoconstrictor reactivity to angiotensin II and acute hypoxic challenges was not altered by roxadustat. Since roxadustat may inhibit angiotensin-converting enzyme 2 (ACE2), we also tested a purported ACE2 activator, diminazene aceturate (DIZE, 0.1 mM). It produced paradoxical, unexplained pulmonary vasoconstriction. We conclude that the risk of serious pulmonary hypertension is not high when roxadustat is given for 14 days, but monitoring is advisable.
- MeSH
- Angiotensin-Converting Enzyme 2 * MeSH
- Vascular Resistance MeSH
- Hypoxia chemically induced MeSH
- Rats MeSH
- Vasoconstrictor Agents * pharmacology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Covid-19 je virové onemocnění, během kterého se mohou různými mechanismy rozvinout stavy vedoucí ke vzniku trombóz v žilách i tepnách. Podobně i vakcinace proti covid-19 může spustit mechanismy vedoucí k tromboembolickým komplikacím. V předkládané kazuistice popisujeme případ 70letého jinak zdravého muže, u kterého se během onemocnění covid-19 a po aplikaci vakcinace proti covid-19 rozvinula progredující cyanóza na horních končetinách na podkladě trombózy tepen palmárních oblouků a aa. ulnares. Situaci se podařilo vyřešit kombinací antikoagulační a antitrombotické léčby.
COVID-19 represents an acute viral disease that may, by various mechanisms, lead to the development of coagulopathy, resulting in arterial or venous thrombotic events. Accordingly, vaccination against COVID-19 may lead to thromboembolic complications. In the presented case report we describe the case of a 70-year-old otherwise healthy male, who presented to our clinic with the progressive cyanosis of the fingers of the upper extremities initiated during COVID-19 and promoted after COVID-19 vaccination. Observed cyanosis was a result of the arterial thrombosis of the ulnar arteries and the arteries of the palmar arches. Progression of the disease was stopped and resolved using a combination of antithrombotic and anticoagulation therapy.
- MeSH
- Adenovirus Vaccines adverse effects MeSH
- Angiotensin-Converting Enzyme 2 biosynthesis deficiency MeSH
- COVID-19 complications blood MeSH
- Cyanosis * diagnosis etiology therapy MeSH
- Embolism and Thrombosis etiology MeSH
- Hematologic Agents administration & dosage pharmacology therapeutic use MeSH
- Upper Extremity blood supply MeSH
- Blood Coagulation Factor Inhibitors analysis MeSH
- Humans MeSH
- Blood Specimen Collection MeSH
- Rehabilitation MeSH
- Aged MeSH
- Thromboinflammation etiology physiopathology MeSH
- Ultrasonography, Doppler MeSH
- COVID-19 Vaccines blood adverse effects MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Aged MeSH
- Publication type
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
Článek pojednává o riziku přenosu infekce SARS-CoV-2 (Severe Acute Respiratory Syndrome-related coronavirus) pro plod v děloze. Transplacentární přenos viru je možný, ale je vzácný díky speciálnímu ochrannému vybavení placenty. Ve vlastním souboru rodiček, který autoři sestavili, bylo riziko nákazy plodu a novorozence nízké. U nemocných rodiček vyšetřovali histologické změny placenty a popsali obraz placentitidy způsobený infekcí SARS-CoV-2. Autoři přidali ilustrační kazuistiku nedonošeného dítěte s vrozenou infekcí SARS-CoV-2. V diskuzi pak autoři popisují možnosti a podrobnosti přenosu SARS-CoV-2 na plod a novorozence, onemocnění novorozenců a prognózu na základě literárních referencí.
This article discusses the risk of transmission of SARS-CoV-2 (Severe acute respiratory syndrome-related coronavirus) infection to the fetus in utero. Transplacental transmission of the virus is possible but is rare due to the special protective equipment of the placenta. In the authors' own cohort of parturients, the risk of fetal and neonatal infection was low. They examined histological changes in the placentas of the affected mothers and described a picture of placentitis caused by SARS-CoV-2 infection. The authors added an illustrative case report of a premature infant with congenital SARS-CoV-2 infection.In the discussion, the authors then describe the possibilities and details of SARS-CoV-2 transmission to the fetus and newborn, neonatal disease, and prognosis based on literature references.
- MeSH
- Angiotensin-Converting Enzyme 2 MeSH
- COVID-19 * transmission prevention & control MeSH
- Gravidity genetics MeSH
- Case Reports as Topic MeSH
- Humans MeSH
- Placenta Diseases etiology prevention & control virology MeSH
- Infant, Newborn MeSH
- Parturition MeSH
- SARS-CoV-2 pathogenicity MeSH
- Pregnant People MeSH
- Infectious Disease Transmission, Vertical MeSH
- Check Tag
- Humans MeSH
- Infant, Newborn MeSH
- Female MeSH
- Publication type
- Observational Study MeSH
