Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition

Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species and complement, inhibition of mast cell degranulation and leucocyte infiltration, blockade of inflammatory cytokines, and inhibition of adaptive B and T-lymphocytes. Herein, we provide a systematic review on post-MI immunomodulation trials and a meta-analysis of studies targeting the inflammatory cytokine Interleukin-1. Despite an enormous effort into a significant number of clinical trials on a variety of targets, a striking heterogeneity in study population, timing and type of treatment, and highly variable endpoints limits the possibility for meaningful meta-analyses. To conclude, we highlight critical considerations for future studies including (i) the therapeutic window of opportunity, (ii) immunological effects of routine post-MI medication, (iii) stratification of the highly diverse post-MI patient population, (iv) the potential benefits of combining immunomodulatory with regenerative therapies, and at last (v) the potential side effects of immunotherapies

Immunomodulatory interventions in myocardial infarction and heart failure: a systematic review of clinical trials and meta-analysis of IL-1 inhibition.

Following a myocardial infarction (MI), the immune system helps to repair ischaemic damage and restore tissue integrity, but excessive inflammation has been implicated in adverse cardiac remodelling and development towards heart failure (HF). Pre-clinical studies suggest that timely resolution of inflammation may help prevent HF development and progression. Therapeutic attempts to prevent excessive post-MI inflammation in patients have included pharmacological interventions ranging from broad immunosuppression to immunomodulatory approaches targeting specific cell types or factors with the aim to maintain beneficial aspects of the early post-MI immune response. These include the blockade of early initiators of inflammation including reactive oxygen species and complement, inhibition of mast cell degranulation and leucocyte infiltration, blockade of inflammatory cytokines, and inhibition of adaptive B and T-lymphocytes. Herein, we provide a systematic review on post-MI immunomodulation trials and a meta-analysis of studies targeting the inflammatory cytokine Interleukin-1. Despite an enormous effort into a significant number of clinical trials on a variety of targets, a striking heterogeneity in study population, timing and type of treatment, and highly variable endpoints limits the possibility for meaningful meta-analyses. To conclude, we highlight critical considerations for future studies including (i) the therapeutic window of opportunity, (ii) immunological effects of routine post-MI medication, (iii) stratification of the highly diverse post-MI patient population, (iv) the potential benefits of combining immunomodulatory with regenerative therapies, and at last (v) the potential side effects of immunotherapies

Design and modulation of selectivity toward vanadium(V) and uranium(VI) ions: coordination properties and affinity of hydroxylamino-triazine siderophores

Based on the strong binding and high selectivity properties of 2,6-bis[hydroxy(methyl)amino]-4-morpholino-1,3,5-triazine (H2bihyat) for [UVIO2]2+, novel binucleating ligands (BLs) N,N′,N″,N‴-((1,4-phenylenebis(oxy))bis(1,3,5-triazine-6,2,4-triyl))tetrakis(N-methylhydroxylamine) (H4qtn), N1,N4-bis(4,6-bis(hydroxy(methyl)amino)-1,3,5-triazin-2-yl)benzene-1,4-diamine (H4pdl), and N1,N2-bis(4,6-bis(hydroxy(methyl)amino)-1,3,5-triazin-2-yl)ethane-1,2-diamine (H4enl) were synthesized. Binuclear complexes formed by coordination of hard metal ions with H4qtn are thermodynamically more stable than their mononuclear analogues with H2bihyat due to the increase in entropy accompanying the formation of more chelate rings. Reaction of either H4qtn or H4pdl or H4enl with [UVIO2]2+ and [VVO2]+ resulted in the isolation of the binuclear complexes [(UVIO2)2(μ-qtn)(H2O)4] (1), [(VVO2)2(μ-qtn)][PPh4]2[PPh4] (2), [(UVIO2)2(μ-pdl)(H2O)2(MeOH)2] (3), [(VVO2)2(μ-pdl)][PPh4]2 (4), [(UVIO2)2(μ-enl)(H2O)4] (5), and [(VVO2)2(μ-enl)][PPh4]2 (6). The binuclear complexes 1–6 were characterized by single-crystal X-ray diffraction analysis in solid state and by NMR and ESI-MS in solution. The comparison of the coordination ability of the BLs with either pyridine-2,6-dicarboxylic acid (H2dipic) or H2bihyat or CO32– toward [UVIO2]2+ and [VVO2]+ was investigated by NMR and UV–vis spectroscopies and DFT theoretical calculations, revealing a superior performance of BLs. The selectivity of the BLs for [UVIO2]2+ over [VVO2]+ is decreased compared to that of H2bihyat but increases considerably at pH > 9 values. Formation of the mixed-metal binuclear species [UVIO2(μ-O)VVO2] influences the selectivity and dynamics of the reaction of H4qtn for [UVIO2]2+ and [VVO2]+ in aqueous solution. The results of this study provide crucial information for the ligand design and the development of stronger and more selective systems

Characterization of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by multiparametric quantitative cardiac magnetic resonance imaging.

Hemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Epicutaneous treatment of mice with the Toll-like receptor 7 (TLR-7) agonist Resiquimod induces auto-antibodies and systemic tissue damage, including in the heart, and is used as an inducible mouse model of systemic lupus erythematosus (SLE). Here, we show that overactivation of the TLR-7 pathway of viral recognition by Resiquimod treatment of CFN mice induces severe thrombocytopenia and internal bleeding, which manifests most prominently as hemorrhagic myocarditis. We optimized a cardiac magnetic resonance (CMR) tissue mapping approach for the in vivo detection of diffuse infiltration, fibrosis and hemorrhages using a combination of T1, T2 and T2 * relaxation times, and compared results with ex vivo histopathology of cardiac sections corresponding to CMR tissue maps. This allowed detailed correlation between in vivo CMR parameters and ex vivo histopathology, and confirmed the need to include T2 * measurements to detect tissue iron for accurate interpretation of pathology associated with CMR parameter changes. In summary, we provide detailed histological and in vivo imaging-based characterization of acute hemorrhagic myocarditis as an acute cardiac complication in the mouse model of Resiquimod-induced SLE, and a refined CMR protocol to allow non-invasive longitudinal in vivo studies of heart involvement in acute inflammation. We propose that adding T2 * mapping to CMR protocols for myocarditis diagnosis improves diagnostic sensitivity and interpretation of disease mechanisms.This article has an associated First Person interview with the first author of the paper

Towards elucidating carnosic acid biosynthesis in Lamiaceae: Functional characterization of the three first steps of the pathway in Salvia fruticosa and Rosmarinus officinalis

Carnosic acid (CA) is a phenolic diterpene with anti-tumour, anti-diabetic, antibacterial and neuroprotective properties that is produced by a number of species from several genera of the Lamiaceae family, including Salvia fruticosa (Cretan sage) and Rosmarinus officinalis (Rosemary). To elucidate CA biosynthesis, glandular trichome transcriptome data of S. fruticosa were mined for terpene synthase genes. Two putative diterpene synthase genes, namely SfCPSand SfKSL, showing similarities to copalyl diphosphate synthase and kaurene synthase-like genes, respectively, were isolated and functionally characterized. Recombinant expression in Escherichia coli followed by in vitro enzyme activity assays confirmed that SfCPS is a copalyl diphosphate synthase. Coupling of SfCPS with SfKSL, both in vitro and in yeast, resulted in the synthesis miltiradiene, as confirmed by 1D and 2D NMR analyses (1H, 13C, DEPT, COSY H-H, HMQC and HMBC). Coupled transient in vivo assays of SfCPS and SfKSL in Nicotiana benthamiana further confirmed production of miltiradiene in planta. To elucidate the subsequent biosynthetic step, RNA-Seq data of S. fruticosa and R. officinalis were searched for cytochrome P450 (CYP) encoding genes potentially involved in the synthesis of the first phenolic compound in the CA pathway, ferruginol. Three candidate genes were selected, SfFS, RoFS1 and RoFS2. Using yeast and N. benthamiana expression systems, all three where confirmed to be coding for ferruginol synthases, thus revealing the enzymatic activities responsible for the first three steps leading to CA in two Lamiaceae genera

Cross-Priming Dendritic Cells Exacerbate Immunopathology After Ischemic Tissue Damage in the Heart.

BACKGROUND: Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of heart failure. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells, and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4 METHODS: We induced type 2 myocardial infarction-like ischemic injury in the heart by treatment with a single high dose of the β-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long-term cardiac immunopathology and functional decline in wild type and RESULTS: A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. CONCLUSION: Activation of cytotoxic CD

Experimental and theoretical investigation of the mechanism of the reduction of O2 from air to O22– by VIVO2+–N,N,N-amidate compounds and their potential use in fuel cells

The two-electron reductive activation of O2 to O22– is of particular interest to the scientific community mainly due to the use of peroxides as green oxidants and in powerful fuel cells. Despite of the great importance of vanadium(IV) species to activate the two-electron reductive activation of O2, the mechanism is still unclear. Reaction of VIVO2+ species with the tridentate-planar N,N,N-carboxamide (ΗL) ligands in solution (CH3OH:H2O) under atmospheric O2, at room temperature, resulted in the quick formation of [VV(═O)(η2-O2)(κ3-L)(H2O)] and cis-[VV(═O)2(κ3-L)] compounds. Oxidation of the VIVO2+ complexes with the sterically hindered tridentate-planar N,N,N-carboxamide ligands by atmospheric O2 gave only cis-[VV(═O)2(κ3-L)] compounds. The mechanism of formation of [VV(═O)(η2-O2)(κ3-L)(H2O)] (I) and cis-[VV(═O)2(κ3-L)] (II) complexes vs time, from the interaction of [VIV(═O)(κ3-L)(Η2Ο)2]+ with atmospheric O2, was investigated with 51V, 1H NMR, UV–vis, cw-X-band EPR, and 18O2 labeling IR and resonance Raman spectroscopies revealing the formation of a stable intermediate (Id). EPR, MS, and theoretical calculations of the mechanism of the formation of I and II revealed a pathway, through a binuclear [VIV(═O)(κ3-L)(H2O)(η1,η1-O2)VIV(═O)(κ3-L)(H2O)]2+ intermediate. The results from cw-EPR, 1H NMR spectroscopies, cyclic voltammetry, and the reactivity of the complexes [VIV(═O)(κ3-L)(Η2Ο)2]+ toward O2 reduction fit better to an intermediate with a binuclear nature. Dynamic experiments in combination with computational calculations were undertaken to fully elucidate the mechanism of the O2 reduction to O22– by [VIV(═O)(κ3-L)(Η2Ο)2]+. The galvanic cell {Zn|VIII,VII||Id, [VIVO(κ3-L)(H2O)2]+|O2|C(s)} was manufactured, demonstrating the important applicability of this new chemistry to Zn|H2O2 fuel cells technology generating H2O2 in situ from the atmospheric O2

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe