Can Beta-2-Adrenergic Pathway Be a New Target to Combat SARS-CoV-2 Hyperinflammatory Syndrome?—Lessons Learned From Cancer

SARS-CoV-2 infection is a new threat to global public health in the 21st century (2020), which has now rapidly spread around the globe causing severe pneumonia often linked to Acute Respiratory Distress Syndrome (ARDS) and hyperinflammatory syndrome. SARS-CoV-2 is highly contagious through saliva droplets. The structural analysis suggests that the virus enters human cells through the ligation of the spike protein to angiotensin-converting enzyme 2 (ACE2). The progression of Covid-19 has been divided into three main stages: stage I—viral response, stage II—pulmonary phase, and stage III—hyperinflammation phase. Once the patients enter stage III, it will likely need ventilation and it becomes difficult to manage. Thus, it will be of paramount importance to find therapies to prevent or slow down the progression of the disease toward stage III. The key event leading to hyperinflammation seems to be the activation of Th-17 immunity response and Cytokine storm. B2-adrenergic receptors (B2ARs) are expressed on airways and on all the immune cells such as macrophages, dendritic cells, B and T lymphocytes. Blocking (B2AR) has been proven, also in clinical settings, to reduce Th-17 response and negatively modulate inflammatory cytokines including IL-6 while increasing IFNγ. Non-selective beta-blockers are currently used to treat several diseases and have been proven to reduce stress-induced inflammation and reduce anxiety. For these reasons, we speculate that targeting B2AR in the early phase of Covid-19 might be beneficial to prevent hyperinflammation

Cardiac and Vascular Microenvironment: Biological and Clinical Implications in Cardiology

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Addressing Post-Acute COVID-19 Syndrome in Cancer Patients, from Visceral Obesity and Myosteatosis to Systemic Inflammation: Implications in Cardio-Onco-Metabolism

Cardiovascular disease and cancer are the two leading causes of morbidity and mortality in the world. The emerging field of cardio-oncology described several shared risk factors that predispose patients to both cardiovascular disease and cancer. Post-acute COVID-19 syndrome is a chronic condition that occurs in many patients who have experienced a SARS-CoV-2 infection, mainly based on chronic fatigue, sedentary lifestyle, cramps, breathing difficulties, and reduced lung performance. Post-acute COVID-19 exposes patients to increased visceral adiposity, insulin resistance, myosteatosis, and white adipose tissue content (surrounded by M1 macrophages and characterized by a Th1/Th17 phenotype), which increases the risk of cardiovascular mortality and cancer recurrence. In this review, the main metabolic affections of post-acute COVID-19 syndrome in cancer patients at low and high risk of cardiomyopathies will be summarized. Furthermore, several non-pharmacological strategies aimed at reducing atherosclerotic and cardiac risk will be provided, especially through anti-inflammatory nutrition with a low insulin and glycemic index, appropriate physical activity, and immune-modulating bioactivities able to reduce visceral obesity and myosteatosis, improving insulin-related signaling and myocardial metabolism

Sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents ejection fraction reduction, reduces myocardial and renal NF-κB expression and systemic pro-inflammatory biomarkers in models of short-term doxorubicin cardiotoxicity

BackgroundAnthracycline-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in patients with cancer. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exert multiple cardiometabolic benefits in patients with/without type 2 diabetes, chronic kidney disease, and heart failure with reduced and preserved ejection fraction. We hypothesized that the SGLT2i dapagliflozin administered before and during doxorubicin (DOXO) therapy could prevent cardiac dysfunction and reduce pro-inflammatory pathways in preclinical models.MethodsCardiomyocytes were exposed to DOXO alone or combined with dapagliflozin (DAPA) at 10 and 100 nM for 24 h; cell viability, iATP, and Ca++ were quantified; lipid peroxidation products (malondialdehyde and 4-hydroxy 2-hexenal), NLRP3, MyD88, and cytokines were also analyzed through selective colorimetric and enzyme-linked immunosorbent assay (ELISA) methods. Female C57Bl/6 mice were treated for 10 days with a saline solution or DOXO (2.17 mg/kg), DAPA (10 mg/kg), or DOXO combined with DAPA. Systemic levels of ferroptosis-related biomarkers, galectin-3, high-sensitivity C-reactive protein (hs-CRP), and pro-inflammatory chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified. After treatments, immunohistochemical staining of myocardial and renal p65/NF-kB was performed.ResultsDAPA exerts cytoprotective, antioxidant, and anti-inflammatory properties in human cardiomyocytes exposed to DOXO by reducing iATP and iCa++ levels, lipid peroxidation, NLRP-3, and MyD88 expression. Pro-inflammatory intracellular cytokines were also reduced. In preclinical models, DAPA prevented the reduction of radial and longitudinal strain and ejection fraction after 10 days of treatment with DOXO. A reduced myocardial expression of NLRP-3 and MyD-88 was seen in the DOXO-DAPA group compared to DOXO mice. Systemic levels of IL-1β, IL-6, TNF-α, G-CSF, and GM-CSF were significantly reduced after treatment with DAPA. Serum levels of galectine-3 and hs-CRP were strongly enhanced in the DOXO group; on the other hand, their expression was reduced in the DAPA-DOXO group. Troponin-T, B-type natriuretic peptide (BNP), and N-Terminal Pro-BNP (NT-pro-BNP) were strongly reduced in the DOXO-DAPA group, revealing cardioprotective properties of SGLT2i. Mice treated with DOXO and DAPA exhibited reduced myocardial and renal NF-kB expression.ConclusionThe overall picture of the study encourages the use of DAPA in the primary prevention of cardiomyopathies induced by anthracyclines in patients with cancer

Prevalence of interstitial pneumonia suggestive of COVID-19 at 18F-FDG PET/CT in oncological asymptomatic patients in a high prevalence country during pandemic period: a national multi-centric retrospective study

Purpose: To assess the presence and pattern of incidental interstitial lung alterations suspicious of COVID-19 on fluorine-18-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) ([18F]FDG PET/CT) in asymptomatic oncological patients during the period of active COVID-19 in a country with high prevalence of the virus. Methods: This is a multi-center retrospective observational study involving 59 Italian centers. We retrospectively reviewed the prevalence of interstitial pneumonia detected during the COVID period (between March 16 and 27, 2020) and compared to a pre-COVID period (January\u2013February 2020) and a control time (in 2019). The diagnosis of interstitial pneumonia was done considering lung alterations of CT of PET. Results: Overall, [18F]FDG PET/CT was performed on 4008 patients in the COVID period, 19,267 in the pre-COVID period, and 5513 in the control period. The rate of interstitial pneumonia suspicious for COVID-19 was significantly higher during the COVID period (7.1%) compared with that found in the pre-COVID (5.35%) and control periods (5.15%) (p < 0.001). Instead, no significant difference among pre-COVID and control periods was present. The prevalence of interstitial pneumonia detected at PET/CT was directly associated with geographic virus diffusion, with the higher rate in Northern Italy. Among 284 interstitial pneumonia detected during COVID period, 169 (59%) were FDG-avid (average SUVmax of 4.1). Conclusions: A significant increase of interstitial pneumonia incidentally detected with [18F]FDG PET/CT has been demonstrated during the COVID-19 pandemic. A majority of interstitial pneumonia were FDG-avid. Our results underlined the importance of paying attention to incidental CT findings of pneumonia detected at PET/CT, and these reports might help to recognize early COVID-19 cases guiding the subsequent management

LCZ 696, administered during doxorubicin, trastuzumab or pertuzumab treatment, prevents cardiotoxicity in our in vitro model

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Trastuzumab and target-therapy side effects: Is still valid to differentiate anthracycline Type I from Type II cardiomyopathies?

The improvement in cancer therapy and the increasing number of long term survivors unearth the issue of cardiovascular side effects of anticancer treatments. As a paradox in cancer survivors, delayed cardiotoxicity has emerged as a significant problem. Two categories of cardiotoxic side effects of antineoplastic drugs have been previously proposed: Type I cardiotoxicity, defined as permanent cardiotoxicity, is usually caused by anthracyclines; Type II cardiotoxicity, considered as reversible cardiotoxicity, has been mainly related to monoclonal antibodies. The cardiotoxicity of antibodies has been associated to trastuzumab, a humanized anti-ErbB2 monoclonal antibody currently in clinical use for the therapy of breast carcinomas, which induces cardiac dysfunction when used in monotherapy, or in combination with anthracyclines. Furthermore, recent retrospective studies have shown an increased incidence of heart failure and/or cardiomyopathy in patients treated with trastuzumab, that can persist many years after the conclusion of the therapy, thus suggesting that the side toxic effects are not always reversible as it was initially proposed. On the other hand, early detection and prompt therapy of anthracycline associated cardiotoxicity can lead to substantial recovery of cardiac function. On the basis of these observations, we propose to find a new different classification for cardiotoxic side effects of drugs used in cancer therapy

Importance of the macrofauna for the feeding of young fish species from infralittoral of Arrozal - Cananeia lagoon estuarine region (25º02'S-47º56'W): Brazil

The aim of this study was to establish the importance of the macrofauna as food for young fish species that inhabit the infralittoral adjacent to the lower marsh. The sampling site is located at Arrozal, Cananéia lagoon estuarine region (25º02'S and 47º56'W) and the collectings were realized monthly, during a year. The results suggest that the studied area could be considered as a nursery ground for young fish species. The local macrofauna is composed mainly by several groups of crustaceans and has a marked temporal variation. Mysids were dominant in Spring, copepods in Summer, mysids and bivalves were co-dominants in the Autumn and amphipods in Winter. Mysids, copepods, ostracods, tan aids and other epifaunal crustaceans were more consumed than other items. According to the trophic habits, the twelve fish species could be divided into three groups: the first and the third as mysids and copepods eaters respectively, and the second group with a balanced diet reflecting more than the other groups the seasonal variation of the macrofauna collected by the dredge. Benthonic and benthopelagic organisms were considered the major food source, being consumed by 75% of the analysed fish species, in Cananéia infralittoral.<br>O objetivo do presente trabalho foi avaliar a importância da macrofauna do infralitoral, adjacente a marisma do Arrozal, região de Cananéia, na dieta alimentar de doze espécies de peixes jovens. De acordo com os resultados obtidos, a região pode ser considerada um berçário para muitas espécies de peixes. A macrofauna local é composta principalmente de crustáceos e apresenta uma acentuada variação temporal. Misidáceos foram dominantes na primavera, copépodes no verão, misidáceos e bivalves foram co-dominantes no outono e anfípodes no inverno. Misidáceos, copépodes, ostrácodes, tanaidáceos e outros crustáceos epifaunais foram mais consumidos pelos peixes macropredadores que outros itens. Os peixes capturados foram divididos em três grupos, de acordo com os hábitos tróficos: comedores de misidáceos, comedores de copépodes e "generalistas" que refletiu a variação sazonal da macrofauna. Setenta e cinco por cento das espécies de peixes predadores alimentaram-se de organismos bentônicos e bentopelágicos e vinte e cinco por cento de organismos pelágicos. Assim, no infralitoral de Cananéia - Arrozal os organismos bentônicos e bentopelágicos constituem a principal fonte alimentar de peixes jovens