20 research outputs found
Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care
Melatonin, more commonly known as the sleep hormone, is mainly secreted by the pineal gland in dark conditions and regulates the circadian rhythm of the organism. Its intrinsic properties, including high cell permeability, the ability to easily cross both the bloodâbrain and placenta barriers, and its role as an endogenous reservoir of free radical scavengers (with indirect extra activities), confer it beneficial uses as an adjuvant in the biomedical field. Melatonin can exert its effects by acting through specific cellular receptors on the plasma membrane, similar to other hormones, or through receptor-independent mechanisms that involve complex molecular cross talk with other players. There is increasing evidence regarding the extraordinary beneficial effects of melatonin, also via exogenous administration. Here, we summarize molecular pathways in which melatonin is considered a master regulator, with attention to cell death and inflammation mechanisms from basic, translational and clinical points of view in the context of newborn care
Harmonization and standardization of data for a pan-European cohort on SARS- CoV-2 pandemic
The European project ORCHESTRA intends to create a new pan-European cohort to rapidly advance the knowledge of the effects and treatment of COVID-19. Establishing processes that facilitate the merging of heterogeneous clusters of retrospective data was an essential challenge. In addition, data from new ORCHESTRA prospective studies have to be compatible with earlier collected information to be efficiently combined. In this article, we describe how we utilized and contributed to existing standard terminologies to create consistent semantic representation of over 2500 COVID-19-related variables taken from three ORCHESTRA studies. The goal is to enable the semantic interoperability of data within the existing project studies and to create a common basis of standardized elements available for the design of new COVID-19 studies. We also identified 743 variables that were commonly used in two of the three prospective ORCHESTRA studies and can therefore be directly combined for analysis purposes. Additionally, we actively contributed to global interoperability by submitting new concept requests to the terminology Standards Development Organizations
Breakthrough invasive fungal infections in liver transplant recipients exposed to prophylaxis with echinocandins vs other antifungal agents: A systematic review and meta-analysis
Introduction: Although echinocandins are recommended as first-line prophylaxis for high-risk orthotopic liver transplant (OLT) recipients, occurrence of breakthrough-invasive fungal infections (IFIs) remains a serious concern. We aim to assess the risk of breakthrough IFIs among OLT recipients exposed to prophylaxis with echinocandins compared to other antifungals. Materials and methods: Two authors independently searched PubMed-MEDLINE, Embase, study registries and reference lists from inception to March 2021, to retrieve randomised controlled trials (RCTs) or observational studies comparing efficacy and safety of echinocandins vs other antifungals for prophylaxis in OLT recipients. Data were independently extracted from two authors, and the quality of included studies was independently assessed according to ROB 2.0 tool for RCTs and ROBINS-I tool for observational studies. The primary outcome was occurrence of breakthrough IFI at the end of prophylaxis (EOP). Results: 698 articles were screened, and ten studies (3 RCTs and 7 observational) were included. No difference between echinocandins and other antifungals in terms of breakthrough IFIs at the EOP emerged both from RCTs (odds ratio [OR] 0.85, 95% CI 0.24â2.99) and observational studies (OR 1.43, 95% CI 0.28â7.40). No difference emerged also for secondary outcomes. In the subgroup comparison between echinocandins and polyenes, a trend for higher risk of breakthrough IFI at the EOP (OR 4.82, 95% CI 0.97â24.03) was noted. Conclusions: Echinocandins do not seem to be associated with increased risk of breakthrough IFIs in OLT recipients. However, the large diversity in the comparator group hinders a definitive interpretation. Further studies exploring the relationship between echinocandin use and breakthrough IFIs according to specific comparators are warranted
Association of Patientsâ Epidemiological Characteristics and Comorbidities with Severity and Related Mortality Risk of SARS-CoV-2 Infection: Results of an Umbrella Systematic Review and Meta-Analysis
The objective of this study was to assess the association between patientsâ epidemiological characteristics and comorbidities with SARS-CoV-2 infection severity and related mortality risk. An umbrella systematic review, including a meta-analysis examining the association between patientsâ underlying conditions and severity (defined as need for hospitalization) and mortality of COVID-19, was performed. Studies were included if they reported pooled risk estimates of at least three underlying determinants for hospitalization, critical disease (ICU admission, mechanical ventilation), and hospital mortality in patients diagnosed with SARS-CoV-2 infection. Evidence was summarized as pooled odds ratios (pOR) for disease outcomes with 95% confidence intervals (95% CI). Sixteen systematic reviews investigating the possible associations of comorbidities with severity or death from COVID-19 disease were included. Hospitalization was associated with age > 60 years (pOR 3.50; 95% CI 2.97â4.36), smoking habit (pOR 3.50; 95% CI 2.97â4.36), and chronic pulmonary disease (pOR 2.94; 95% CI 2.14â4.04). Chronic pulmonary disease (pOR 2.82; 95% CI 1.92â4.14), cerebrovascular disease (pOR 2.74; 95% CI 1.59â4.74), and cardiovascular disease (pOR 2.44; 95% CI 1.97â3.01) were likely to be associated with increased risk of critical COVID-19. The highest risk of mortality was associated with cardiovascular disease (pOR 3.59; 95% CI 2.83â4.56), cerebrovascular disease (pOR 3.11; 95% CI 2.35â4.11), and chronic renal disease (pOR 3.02; 95% CI 2.61â3.49). In conclusion, this umbrella systematic review provides a comprehensive summary of meta-analyses examining the impact of patientsâ characteristics on COVID-19 outcomes. Elderly patients and those cardiovascular, cerebrovascular, and chronic renal disease should be prioritized for pre-exposure and post-exposure prophylaxis and early treatment
Effect of a Fourth Dose of mRNA Vaccine and of Immunosuppression in Preventing SARS-CoV-2 Breakthrough Infections in Heart Transplant Patients
Patients with heart transplantation (HT) have an increased risk of COVID-19 disease and the efficacy of vaccines on antibody induction is lower, even after three or four doses. The aim of our study was to assess the efficacy of four doses on infections and their interplay with immunosuppression. We included in this retrospective study all adult HT patients (12/21â11/22) without prior infection receiving a third or fourth dose of mRNA vaccine. The endpoints were infections and the combined incidence of ICU hospitalizations/death after the last dose (6-month survival rate). Among 268 patients, 62 had an infection, and 27.3% received four doses. Following multivariate analysis, three vs. four doses, mycophenolate (MMF) therapy, and HT < 5 years were associated with an increased risk of infection. MMF â„ 2000 mg/day independently predicted infection, together with the other variables, and was associated with ICU hospitalization/death. Patients on MMF had lower levels of anti-RBD antibodies, and a positive antibody response after the third dose was associated with a lower probability of infection. In HT patients, a fourth dose of vaccine against SARS-CoV-2 reduces the risk of infection at six months. Mycophenolate, particularly at high doses, reduces the clinical effectiveness of the fourth dose and the antibody response to the vaccine
Angiotensin II Promotes SARS-CoV-2 Infection via Upregulation of ACE2 in Human Bronchial Cells
Blockers of the reninâangiotensin system (RAS) have been reported to increase the angiotensin
converting enzyme (ACE)2, the cellular receptor of SARSâCoVâ2, and thus the risk and course
of COVIDâ19. Therefore, we investigated if angiotensin (Ang) II and RAS blockers affected ACE2
expression and SARSâCoVâ2 infectivity in human epithelial bronchial Caluâ3 cells. By infectivity
and spikeâmediated cellâcell fusion assays, we showed that Ang II acting on the angiotensin type 1
receptor markedly increased ACE2 at mRNA and protein levels, resulting in enhanced SARSâCoVâ
2 cell entry. These effects were abolished by irbesartan and not affected by the blockade of ACEâ1â
mediated Ang II formation with ramipril, and of ACE2â mediated Ang II conversion into Ang 1â7
with MLNâ4760. Thus, enhanced Ang II production in patients with an activated RAS might expose
to a greater spread of COVIDâ19 infection in lung cells. The protective action of Angiotensin type 1
receptor antagonists (ARBs) documented in these studies provides a mechanistic explanation for
the lack of worse outcomes in highârisk COVIDâ19 patients on RAS blockers
Serum levels of autoantibodies against the angiotensin II type I receptor are not associated with serum dicarbonyl or AGE levels in patients with an aldosterone-producing adenoma
Patients with an aldosterone-producing adenoma (APA) carry a higher risk of cardiovascular disease and commonly have high levels of autoantibodies (AT1AA) that may activate the angiotensin II type 1 receptor (AT1R). AT1R activation is linked to an increase of the glucose metabolite methylglyoxal (MGO), a potential precursor of advanced glycation endproducts (AGEs) and driver of vascular inflammation. We investigated whether serum AT1AA levels are associated with serum MGO and AGE levels in APA patients. In a case series of 26 patients with APA we measured levels of dicarbonyls MGO, glyoxal (GO) and 3-deoxyglucosone (3-DG), and dicarbonyl-derived AGEs 5-hydro-5-methylimidazolone (MG-H1), N-epsilon-(carboxyethyl)lysine (CEL) and N-epsilon-(carboxymethyl)lysine (CML) with UPLC-MS/MS. We also measured AT1AA by ELISA. These measurements were repeated 1-month after adrenalectomy in a subset of 14 patients. Panels of inflammation and endothelial function were also measured by immunoassays. Although baseline higher AT1AA levels tended to be correlated with higher baseline serum MGO, GO and 3-DG levels (r = 0.18, p = 0.38; r = 0.20, p = 0.33; r = 0.23, p = 0.26; respectively), these correlations were not statistically significant. We observed no obvious correlations between higher AT1AA levels and protein-bound and free MG-H1, CEL and CML levels, and markers of inflammation and endothelial function. No decrease was observed in any of the dicarbonyls, protein-bound AGE levels and markers of inflammation and endothelial function after adrenalectomy. In patients with APA the serum levels of AT1AA were not significantly correlated with serum dicarbonyls, protein-bound and free AGE levels. Increased signalling of the AT1AA receptor may therefore be unlikely to overtly increase systemic dicarbonyl levels
STAT3 localizes to the ER, acting as a gatekeeper for ER-mitochondrion Ca2+ fluxes and apoptotic responses
STAT3 is an oncogenic transcription factor exerting its functions both as a canonical transcriptional activator and as a non-canonical regulator of energy metabolism and mitochondrial functions. While both activities are required for cell transformation downstream of different oncogenic stimuli, they rely on different post-translational activating events, namely phosphorylation on either Y705 (nuclear activities) or S727 (mitochondrial functions). Here, we report the discovery of the unexpected STAT3 localization to the endoplasmic reticulum (ER), from where it modulates ER-mitochondria Ca2+ release by interacting with the Ca2+ channel IP3R3 and facilitating its degradation. The release of Ca2+ is of paramount importance for life/death cell decisions, as excessive Ca2+ causes mitochondrial Ca2+ overload, the opening of the mitochondrial permeability transition pore, and the initiation of the intrinsic apoptotic program. Indeed, STAT3 silencing enhances ER Ca2+ release and sensitivity to apoptosis following oxidative stress in STAT3-dependent mammary tumor cells, correlating with increased IP3R3 levels. Accordingly, basal-like mammary tumors, which frequently display constitutively active STAT3, show an inverse correlation between IP3R3 and STAT3 protein levels. These results suggest that STAT3-mediated IP3R3 downregulation in the ER crucially contributes to its anti-apoptotic functions via modulation of Ca2+ fluxes