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Aims Human epicardial adipose tissue (EAT) plays a crucial role in the development and progression of coronary artery disease, atrial fibrillation, and heart failure. Microscopically, EAT is composed of adipocytes, nerve tissues, inflammatory, stromovascular, and immune cells. Epicardial adipose tissue is a white adipose tissue, albeit it also has brown fat-like or beige fat-like features. No muscle fascia divides EAT and myocardium; this allows a direct interaction and crosstalk between the epicardial fat and the myocardium. Thus, it might be a therapeutic target for pharmaceutical compounds acting on G-protein–coupled receptors, such as those for glucose-dependent insulinotropic polypeptide (GIP), glucagon (GCG), and glucagon-like peptide-1 (GLP-1), whose selective stimulation with innovative drugs has demonstrated beneficial cardiovascular effects. The precise mechanism of these novel drugs and their tissue and cellular target(s) need to be better understood. We evaluate whether human EAT expresses GIP, GCG, and GLP-1 receptors and whether their presence is related to EAT transcriptome. We also investigated protein expression and cell-type localization specifically for GIP receptor (GIPR) and glucagon receptor (GCGR). Methods and results Epicardial adipose tissue samples were collected from 33 patients affected by cardiovascular diseases undergoing open heart surgery (90.9% males, age 67.2 ± 10.5 years mean ± SD). Microarray and immunohistochemistry analyses were performed. Microarray analysis showed that GIPR and GCGR messenger ribonucleic acids (mRNAs) are expressed in EAT, beyond confirming the previously found GLP-1 [3776 ± 1377 arbitrary unit (A.U.), 17.77 ± 14.91 A.U., and 3.41 ± 2.27 A.U., respectively]. The immunohistochemical analysis consistently indicates that GIPR and GCGR are expressed in EAT, mainly in macrophages, isolated, and in crown-like structures. In contrast, only some mature adipocytes of different sizes showed cytoplasmic immunostaining, similar to endothelial cells and pericytes in the capillaries and pre-capillary vascular structures. Notably, EAT GIPR is statistically associated with the low expression of genes involved in free fatty acid (FFA) oxidation and transport and those promoting FFA biosynthesis and adipogenesis (P < 0.01). Epicardial adipose tissue GCGR, in turn, is related to genes involved in FFA transport, mitochondrial fatty acid oxidation, and white-to-brown adipocyte differentiation, in addition to genes involved in the reduction of fatty acid biosynthesis and adipogenesis (P < 0.01). Conclusions Having reported the expression of the GLP-1 receptor previously, here, we showed that GIPR and GCGR similarly present at mRNA and protein levels in human EAT, particularly in macrophages and partially adipocytes, suggesting these G-protein–coupled receptors as pharmacological targets on the ongoing innovative drugs, which seem cardiometabolically healthy well beyond their effects on glucose and body weight.

OBJECTIVE The excess of visceral adipose tissue might hinder and delay immune response. How people with abdominal obesity (AO) will respond to mRNA vaccines against SARS-CoV-2 is yet to be established. We evaluated SARS-CoV-2 specific antibody responses after the first and second dose of the BNT162b2 mRNA vaccine comparing the response of individuals with AO to those without, discerning between individuals with or without prior infection. METHODS IgG neutralizing antibodies against the Trimeric-complex (IgG-TrimericS) were measured at four time points: at baseline, at day 21 after vaccine dose 1, at one and three months after dose 2. Nucleocapsid antibodies were assessed to detect prior SARS-CoV-2 infection. Waist circumference was measured to determine AO. RESULTS Between the first and third month after vaccine dose 2, the drop in IgG-TrimericS levels was more remarkable in individuals with AO compared to those without AO (2.44 fold [95%CI: 2.22-2.63] vs 1.82 fold [95%CI: 1.69-1.92], respectively, p

Obesity is an epidemic condition linked to cardiovascular disease severity and mortality. Fat localization and type represent cardiovascular risk estimators. Importantly, visceral fat secretes adipokines known to promote low-grade inflammation that, in turn, modulate its secretome and cardiac metabolism. In this regard, IL-33 regulates the functions of various immune cells through ST2 binding and—following its role as an immune sensor to infection and stress—is involved in the pro-fibrotic remodeling of the myocardium. Here we further investigated the IL-33/ST2 effects on cardiac remodeling in obesity, focusing on molecular pathways linking adipose-derived IL-33 to the development of fibrosis or hypertrophy. We analyzed the Zucker Fatty rat model, and we developed in vitro models to mimic the adipose and myocardial relationship. We demonstrated a dysregulation of IL-33/ST2 signaling in both adipose and cardiac tissue, where they affected Epac proteins and myocardial gene expression, linked to pro-fibrotic signatures. In Zucker rats, pro-fibrotic effects were counteracted by ghrelin-induced IL-33 secretion, whose release influenced transcription factor expression and ST2 isoforms balance regulation. Finally, the effect of IL-33 signaling is dependent on several factors, such as cell types’ origin and the balancing of ST2 isoforms. Noteworthy, it is reasonable to state that considering IL-33 to have a unique protective role should be considered over-simplistic.

The success of implant performance and arthroplasty is based on several factors, including oxidative stress-induced osteolysis. Oxidative stress is a key factor of the inflammatory response. Implant biomaterials can release wear particles which may elicit adverse reactions in patients, such as local inflammatory response leading to tissue damage, which eventually results in loosening of the implant. Wear debris undergo phagocytosis by macrophages, inducing a low-grade chronic inflammation and reactive oxygen species (ROS) production. In addition, ROS can also be directly produced by prosthetic biomaterial oxidation. Overall, ROS amplify the inflammatory response and stimulate both RANKL-induced osteoclastogenesis and osteoblast apoptosis, resulting in bone resorption, leading to periprosthetic osteolysis. Therefore, a growing understanding of the mechanism of oxidative stress-induced periprosthetic osteolysis and anti-oxidant strategies of implant design as well as the addition of anti-oxidant agents will help to improve implants’ performances and therapeutic approaches.

Purpose Chest X-ray (CXR) severity score and BMI-based obesity are predictive risk factors for COVID-19 hospital admission. However, the relationship between abdominal obesity and CXR severity score has not yet been fully explored. Methods This retrospective cohort study analyzed the association of different adiposity indexes, including waist circumference and body mass index (BMI), with CXR severity score in 215 hospitalized patients with COVID-19. Results Patients with abdominal obesity showed significantly higher CXR severity scores and had higher rates of CXR severity scores ≥ 8 compared to those without abdominal obesity (P

Background and aims Magnesium is a fundamental cation that regulates neuronal transmission, protein synthesis, energy metabolism. Magnesium deficiency mostly affects nervous and cardiovascular systems determining weakness, tremors, seizure and arrhythmias. This condition retains also a role in memory function and neuronal plasticity. Importantly magnesium deficiency could remain latent and asymptomatic resulting a risk factor for cardiovascular disease. In this sense we aim to determine magnesium status in patient presenting cognitive impairment of vascular origin. Methods 21 healthy subjects and 27 patients presenting vascular cognitive impairment were included in this study. Both plasma and intraerythrocitary magnesium level were measured to detect magnesium deficiency and cognitive performance was evaluated trough Mini Mental State Evaluation (MMSE). Results Here we showed that patients presenting vascular cognitive impairment present intraerythrocitary magnesium level lower than age-matched healthy subjects. To note their plasma magnesium resulted within reference limit. Conclusion We suggest that intracellular magnesium laboratory measurement is needed to detect occult magnesium deficiency in population at risk. Magnesium supplementation could represent an adjuvant for healthy aging in high risk population.

Glycation and glycosylation are non-enzymatic and enzymatic reactions, respectively, of glucose, glucose metabolites, and other reducing sugars with different substrates, such as proteins, lipids, and nucleic acids. Increased availability of glucose is a recognized risk factor for the onset and progression of diabetes-mellitus-associated disorders, among which cardiovascular diseases have a great impact on patient mortality. Both advanced glycation end products, the result of non-enzymatic glycation of substrates, and O-linked-N-Acetylglucosaminylation, a glycosylation reaction that is controlled by O-N-AcetylGlucosamine (GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), have been shown to play a role in cardiovascular remodeling. In this review, we aim (1) to summarize the most recent data regarding the role of glycation and O-linked-N-Acetylglucosaminylation as glucose-related pathogenetic factors and disease markers in cardiovascular remodeling, and (2) to discuss potential common mechanisms linking these pathways to the dysregulation and/or loss of function of different biomolecules involved in this field.

ObjectiveThe excess of visceral adipose tissue might hinder and delay the immune response. How people with abdominal obesity will respond to mRNA vaccines against SARS-CoV-2 is yet to be established. We evaluated SARS-CoV-2-specific antibody responses after the first and second dose of the BNT162b2 mRNA vaccine comparing the response of individuals affected by abdominal obesity (AO) to those without, discerning between individuals with or without prior infection.MethodsIgG neutralizing antibodies against the Trimeric complex (IgG-TrimericS) were measured at four time points: at baseline, at day 21 after vaccine dose-1, at one month and three months after dose-2. Nucleocapsid antibodies were assessed to detect prior SARS-CoV-2 infection. Waist circumference was measured to determine abdominal obesity.ResultsBetween the first and third month after vaccine dose-2, the drop in IgG-TrimericS levels was more remarkable in individuals with AO compared to those without AO (2.44 fold [95%CI: 2.22-2.63] vs 1.82 fold [95%CI: 1.69-1.92], respectively, pConclusionsOur findings highlight the need to extend the duration of serological monitoring of antibody levels in infection-naive individuals with abdominal obesity, a higher-risk population category in terms of possible weaker antibody response.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

In the brain, Oxidative Stress (OS) contribute to structural and functional changes associated with vascular aging, such as endothelial dysfunction, extracellular matrix degradation, resulting in age-related reduced vasodilatation in response to agonists. For this reason, OS is considered a key factor in Alzheimer’s Disease (AD) development and recent evidence correlated oxidative stress with vascular lesion in the pathogenesis of AD, but the mechanism still need to be fully clarified. The etiology of AD is still not completely understood and is influenced by several factors including Apolipoprotein E (ApoE) genotype. In particular, the Apo ε4 isoform is considered a risk factor for AD development. This study was aimed to evaluate the possible relationship between three plasmatic OS marker and Apo ε4 carrier status. Plasmatic soluble receptor for advanced glycation end products (sRAGE) levels, plasma antioxidant total defenses (by lag-time method) and plasmatic Reactive Oxygen species (ROS) levels were evaluated in 25 AD patients and in 30 matched controls. ROS were significantly higher while plasma antioxidant total defenses and sRAGE levels were significantly lower in AD patients compared to controls. In AD patients lag-time values show a significant positive linear correlation with sRAGE levels and a (even not significant) negative correlation with ROS levels. Lag-time is significantly lower in ε4 carrier (N = 13) than in ε4 non-carrier (N = 12). Our result confirms the substantial OS in AD. Lag-time levels showed a significant positive correlation with sRAGE levels and a significant association with ε4 carrier status suggesting that plasmatic lag-time evaluation can be considered as a potential useful OS risk marker in AD.

Sarcopenia is common in chronic kidney disease (CKD), and it is independently associated with morbidity and mortality. Advanced glycation end products (AGE) are mainly known as aging products. In CKD, AGE accumulate due to increased production and reduced kidney excretion. The imbalance between oxidant/antioxidant capacities in CKD patients is one of the main factors leading to AGE synthesis. AGE can, in turn, promote CKD progression and CKD-related complications by increasing reactive oxygen species generation, inducing inflammation, and promoting fibrosis. All these derangements can further increase AGE and uremic toxin accumulation and promote loss of muscle mass and function. Since the link between AGE and sarcopenia in CKD is far from being fully understood, we revised hereby the data supporting the potential contribution of AGE as mediators of oxidative stress in the pathogenesis of sarcopenia. Understanding how AGE and oxidative stress impact the onset of sarcopenia in CKD may help to identify new potential markers of disease progression and/or therapeutic targets.

Lucrezia Ferrario,1 Fabrizio Schettini,1 Angelo Avogaro,2 Chiara Bellia,3 Federico Bertuzzi,4 Graziella Bonetti,5 Antonio Ceriello,6 Marcello Ciaccio,3,7 Massimiliano Corsi Romanelli,8,9 Elena Dozio,9 Luca Falqui,10 Angela Girelli,11 Antonio Nicolucci,12 Gianluca Perseghin,13,14 Mario Plebani,15 Umberto Valentini,11 Martina Zaninotto,15 Silvana Castaldi,9,16 Emanuela Foglia1 1Centre for Health Economics, Social and Health Care Management, Università Carlo Cattaneo - LIUC, Castellanza, Italy; 2Department of Medicine, University-Hospital of Padova, Padova, Italy; 3Section of Clinical Biochemistry and Clinical Molecular Medicine, Department of Biopathology and Medical Biotechnologies, University of Palermo, Palermo, Italy; 4Diabetology Unit, Grande Ospedale Metropolitano Niguarda Hospital, Milan, Italy; 5Department of Medicine Services, Valcamonica Hospital, Esine, Italy; 6Department of Cardiovascular and Metabolic Diseases, Multimedica Research Institute, Milan, Italy; 7Department of Laboratory Medicine, University-Hospital of Palermo, Palermo, Italy; 8Service of Laboratory Medicine 1-Clinical Pathology, Policlinico San Donato, Milan, Italy; 9Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy; 10Department of Medicine, Diabetes and Endocrinology, Multimedica Research Institute, Milan, Italy; 11Diabetes Care Unit, Spedali Civili Hospital, Brescia, Italy; 12Center for Outcomes Research and Clinical Epidemiology, Pescara, Italy; 13Department of Medicine and Surgery, Università degli Studi di Milano Bicocca, Milan, Italy; 14Department of Medicine and Rehabilitation, Unit of Metabolic Medicine, Policlinico di Monza, Monza, Italy; 15Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy; 16Fondazione Ca’ Granda Ospedale Maggiore Policlinico Research Institute of Milano, Milano, ItalyCorrespondence: Lucrezia FerrarioCentre for Health Economics, Social and Health Care Management, Università Carlo Cattaneo – LIUC, Corso Matteotti 22, Castellanza, 21053, VA, ItalyTel +39 033 1572504Fax +39 033 1572513Email lferrario@liuc.itPurpose: To investigate the glycated albumin (GA) introduction implications, as an add-on strategy to traditional glycemic control (Hb1Ac and fasting plasma glucose – FPG) instruments, considering insulin-naïve individuals with type 2 diabetes mellitus (T2DM), treated with oral therapies.Methods: A Health Technology Assessment was conducted in Italy, as a multi-dimensional approach useful to validate any innovative technology. The HTA dimensions, derived from the EUnetHTA Core Model, were deployed by means of literature evidence, health economics tools and qualitative questionnaires, filled-in by 15 professionals.Results: Literature stated that the GA introduction could lead to a higher number of individuals achieving therapeutic success after 3 months of therapy (97.0% vs 71.6% without GA). From an economic point of view, considering a projection of 1,955,447 T2DM insulin-naïve individuals, potentially treated with oral therapy, GA introduction would imply fewer individuals requiring a therapy switch (− 89.44%), with a 1.06% in costs reduction, on annual basis, thus being also the preferable solution from a cost-effectiveness perspective (cost-effectiveness value: 237.74 vs 325.53). According to experts opinions, lower perceptions on GA emerged with regard to equity aspects (0.13 vs 0.72, p-value> 0.05), whereas it would improve both individuals (2.17 vs 1.33, p-value=0.000) and caregivers quality of life (1.50 vs 0.83, p-value=0.000). Even if in the short term, GA required additional investments in training courses (− 0.80 vs 0.10, p-value = 0.036), in the long run, GA could become the preferable technology (0.30 vs 0.01, p-value=0.018) from an organisational perspective.Conclusion: Adding GA to traditional glycaemic control instruments could improve the clinical pathway of individuals with T2DM, leading to economic and organisational advantages for both hospitals and National Healthcare Systems.Keywords: glycated albumin, type 2 diabetes mellitus, T2DM, Health Technology Assessment, economic evaluation, multidimensional approach

PurposeChest x-ray (CXR) severity score and general obesity are predictive risk factors for COVID-19 hospital admission. However, the relationship between abdominal obesity and CXR severity score has not yet been fully explored.MethodsThis retrospective cohort study analyzed the association of different adiposity indexes, including waist circumference and body mass index (BMI), with CXR severity score in 215 hospitalized patients with COVID-19.ResultsPatients with abdominal obesity had significantly higher CXR severity scores and higher rates of these scores than those without abdominal obesity (P

The receptor for advanced glycation end products (RAGE), a well-known player of diabetes mellitus (DM)-related morbidities, was supposed to be involved in coronavirus disease-19 (COVID-19), but no data exist about COVID-19, DM, and the soluble RAGE (sRAGE) forms. We quantified total sRAGE and its forms, the endogenously secretory esRAGE and the membrane-cleaved cRAGE, in COVID-19 patients with and without DM and in healthy individuals to explore how COVID-19 may affect these molecules and their potential role as biomarkers. Circulating sRAGE and esRAGE were quantified by enzyme-linked-immunosorbent assays. cRAGE was obtained by subtracting esRAGE from total sRAGE. sRAGE, esRAGE, cRAGE, and the cRAGE/esRAGE ratio did not differ between DM and non-DM patients and had the same trend when compared to healthy individuals. Levels of total sRAGE, cRAGE, and cRAGE/esRAGE ratio were upregulated, while esRAGE was downregulated. The lack of difference between DM and non-DM COVID-19 patients in the levels of sRAGE and its forms supports the hypothesis that in COVID-19 the RAGE system is modulated regardless of glycemic control. Identifying how sRAGE and its forms associate to COVID-19 prognosis and the potential of RAGE as a therapeutic target to control inflammatory burden seem of relevance to help treatment of COVID-19.

Background: COVID-19 associated coagulopathy is characterized by a pro-thrombotic state. However, the nature of this pattern has not been comprehensively studied. We investigated the coagulation pattern of patients with COVID-19 acute respiratory distress syndrome (ARDS) comparing survivors to not survivors. Methods: Prospective cohort study conducted in the Intensive Care Unit (ICU) of a University Hospital . Twenty COVID-19 ARDS patients received measurements of markers of thrombin generation (prothrombin fragment 1+2, PF 1+2); fibrinolysis activation (tissue plasminogen activator, tPA) and inhibition (plasminogen activator inhibitor-2, PAI-2); fibrin synthesis (fibrinopeptide A) and fibrinolysis magnitude (plasmin-antiplasmin complex, PAP, and D-dimers). Measurements were done at the ICU admission and after 10-14 days. Results: The general pattern showed an increased thrombin generation, modest or null release of t-PA, and increased levels of PAI-2, Fibrinopeptide A, PAP and D-dimers. At baseline, non survivors had a significantly (P=0.014) higher PAI-2/PAP ratio than survivors (109, interquartile range [IQR] 18.1-216, vs. 8.7, IQR 2.9-12.6). At follow-up, thrombin generation was significantly (P=0.025) reduced in survivors (PF 1+2 from 396 pg/mL, IQR 185-585 to 237 pg/mL, IQR 120-393), whereas it increased in non-survivors. Fibrinolysis inhibition at follow-up remained stable in survivors, and increased in non-survivors, leading to a significant (P=0.026) difference in PAI-2 levels (161 pg/mL, IQR 50-334, vs. 1,088 pg/mL, IQR 177-1,565). Conclusions: Severe patterns of COVID-19 infection (ARDS) are characterized by a thrombin burst, triggered by the release of IL-6 and other cytokines, and the consequent release of Tissue Factor. Mechanisms of fibrinolysis regulation appear unbalanced toward fibrinolysis inhibition. In survivors, this pattern ameliorates, whereas in non-survivors it worsens, leading to the environment for clinically relevant thrombi generation, that was found in 58% of non-surviving patients. Trial registration: clinicaltrials.gov (NCT04441502).

BACKGROUND AND AIMS Recently, it has been hypothesized that Tri-Ponderal Mass Index (TMI) may be a valid alternative to Body Mass Index (BMI) when measuring body fat in adolescents. We aimed to verify whether TMI has better accuracy than BMI in discriminating central obesity and hypertension in adolescents with overweight. METHODS AND RESULTS This monocentric and retrospective cross-sectional study included 3749 pupils, 1889 males and 1860 females, aged 12-13. BMI (kg/m2) was calculated and expressed as percentiles and as z-scores. TMI (kg/m3) was calculated, and we used pre-defined cut-off previously proposed by Peterson et al.. For central obesity we adopted the Waist-to-Height Ratio (WHtR) discriminatory value of 0.5. Hypertension was defined as blood pressure ≥95th percentile of age- sex-, and height-specific references recommended by NHBPEP Working Group. The discriminant ability of TMI, BMI and BMI z-score, with respect to central obesity and hypertension, was investigated using non-parametric receiver operating characteristic analysis. The overall misclassification rate for central obesity was 8.88% for TMI vs 14.10% for BMI percentiles and vs 14.92% for BMI z-scores (P

Erythrocytes are deeply sensitive cells and important health indicators. During inflammatory response RBC, as a part of haematological system, are exposed to circulating inflammatory mediators and related oxidative stress. They present a highly specialized and organized cell membrane that interacts with inflammatory mediators and oxidative agents, leading to a variety of structural changes that promptly signal an abnormal situation. This review is aimed to provide an overview on erythrocyte involvement in physiological and pathological processes related to oxidative stress, such as aging, Down syndrome, neurodegenerative diseases, for instance Alzheimer Disease, erectile dysfunction and cardiovascular diseases. In particular this review will focus on the effects of oxidative stress on structural changes in the cell membrane and also on in the activity of erythrocyte enzymes such as membrane-bound, cytosolic glycohydrolases and RBC-eNOS. This review also underlines the potential clinical application of erythrocyte specific related parameters, which can be important tools not only for the study but also for the monitoring of several oxidative stress related diseases.

A decline in metabolic health may take place before observing any alteration in the levels of the traditional metabolic markers. New indicators of metabolic derangement are therefore compelling. Irisin is a myokine with important metabolic functions. The role of irisin as a metabolic biomarker in humans has not been fully established yet. We quantified plasma irisin and esRAGE in 106 apparently healthy individuals and we performed a cluster analysis to evaluate their associations with metabolic profile. Plasma levels of various traditional markers of metabolic risk (i.e., glucose and lipid levels) were all within the ranges of normality. We identified two clusters of individuals. Compared to cluster 2, individuals in cluster 1 had higher irisin levels, a metabolic profile shifted toward the limits of the reference ranges and lower esRAGE levels. The traditional metabolic blood tests seem not to be enough to identify a metabolic decline early. Irisin increase and esRAGE decrease may reflect a metabolic derangement at the beginning of its development. The role of these molecules as early biomarkers of decline of metabolic health seems an interesting topic to be further explored.

Bone and the immune system are closely linked: bone regulates the hematopoietic stem cells, which are precursors of immune cells, and several immunoregulatory cytokines influence the differentiation of bone cells, thus defining the osteoimmunological system. Cytokines and growth factors produced by immune and bone cells promote tumors in bone, supporting the vicious cycle of bone metastasis. Therefore osteoimmunological molecules linking the immune and bone systems could have diagnostic and prognostic potential for bone metastases. The osteoimmunologic Wnt pathway has been recently described as an important pathway with a vital role in bone carcinogenesis and metastatic progression. We examined the Wnt inhibitor DKK-1, sclerostin and several other osteoimmunological biomarkers involved in bone metastatic progression: RANKL, OPG, OPN, matrix metalloproteinase MMP-3 and the Receptor of Advanced Glycosylated End-products sRAGE. OPN and sclerostin proved good biomarkers of metastatic bone progression; the RANKL/OPG ratio was a good indicator of bone erosion in the metastatic process, while sRAGE had a protective role against metastatic progression in bone. These results serve to define a panel of new osteoimmunological biomarkers that could be useful in assessing the progress of osteolytic bone metastases.

Epicardial adipose tissue (EAT) has the unique property to release mediators that nourish the heart in healthy conditions, an effect that becomes detrimental when volume expands and proinflammatory cytokines start to be produced. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a proinflammatory mediator involved in atherosclerosis, is also produced by visceral fat. Due to the correlation of inflammation with PCSK9 and EAT enlargement, we evaluated whether PCSK9 was expressed in EAT and associated with EAT inflammation and volume. EAT samples were isolated during surgery. EAT thickness was measured by echocardiography. A microarray was used to explore EAT transcriptoma. The PCSK9 protein levels were measured by Western Blot in EAT and ELISA in plasma. PCSK9 was expressed at both the gene and protein levels in EAT. We found a positive association with EAT thickness and local proinflammatory mediators, in particular, chemokines for monocytes and lymphocytes. No association was found with the circulating PCSK9 level. The expression of PCSK9 in EAT argues that PCSK9 is part of the EAT secretome and EAT inflammation is associated with local PCSK9 expression, regardless of circulating PCSK9 levels. Whether reducing EAT inflammation or PCSK9 local levels may have beneficial effects on EAT metabolism and cardiovascular risk needs further investigations.

Bone is not an inert structure but a living and metabolic active tissue, which undergoes continuous remodeling throughout life, to allow bone architecture to respond to mechanical stress, consisting in bone tissue renewal to replace old bone tissue with new bone matrix. The equilibrium between osteoblasts and osteoclasts activity is the key of bone homeostasis, and any perturbation of this balance leads to the development of skeletal pathological condition characterized by decrease or an excess of bone mass. Bone is a living tissue undergoing a continuous remodeling, in order to respond to a variety of different stimuli, ranging from mechanical loading, to hormonal factors and calcium homeostasis. For this reason, bone is a metabolically active tissue, and bone metabolism is a complex series of event under the control of different genetic, hormonal, and biochemical factors. This chapter will describe the molecular basis of the main bone disease characterized by or an excess of bone mass, as well as metabolic bone disease. In addition, due to its structure, bone is usually protected from infections, but it can undergo infection. Moreover, bone can also be affected by primary tumor or metastatic invasion. This chapter also provides the most recent insight concerning bone infections and bone tumors and metastases.

UHMWPE doped with vitamin E was introduced to provide oxidation resistance upon sterilization, without affecting UHMWPE's mechanical properties. Particle-induced macrophage activation leads to periprosthetic bone resorption, requiring total joint replacements. During osteolysis, osteoblasts produce osteoimmunological factors such as RANKL and OPG, and the inhibitors of the Wnt pathway DKK-1 and Sclerostin. This study investigated in vitro how vitamin E-blended-UHMWPE wear debris might affect osteoblast-mediated osteolysis and the production of RANKL, OPG, Sclerostin and DKK-1, compared to conventional UHMWPE wear debris. Human osteoblastic SaOS2 cells were incubated with wear particles from Vitamin E doped and conventional UHMWPE and the gene expression and protein production of IL-6, RANKL, OPG, DKK-1, and Sclerostin was evaluated, RANKL, a bone erosion marker, was reduced, while OPG, a bone protective marker, were increased by the vitamin E-blended UHMWPE compared to conventional UHMWPE. Vitamin E doped UHMWPE reduced Sclerostin level, and partially affected DKK-1 production, thereby protecting against bone erosion. In conclusion, Vitamin E-blended UHMWPE induced an osteoimmunological response in bone cells that had positive effects on the osteolysis induced by wear debris, reducing aseptic loosening of the implants. In conclusion, this is the first study showing that Vitamin E-blended UHMWPE induced an osteoimmunological response in bone cells that positively affect the osteolysis induced by wear debris, thereby reducing the aseptic loosening of the implants.

In chronic kidney disease patients on dialysis (CKD-G5D) accurate assessment of glycemic control is vital to improve their outcome and survival. The best glycemic marker for glucose control in these patients is still debated because several clinical and pharmacological factors may affect the ability of the available biomarkers to reflect the patient's glycemic status properly. This review discusses the role of glycated albumin (GA) both as a biomarker for glucose control and as a prognostic factor in CKD-G5D; it also looks at the pros and cons of GA in comparison to the other markers and its usefulness in hemodialysis and peritoneal dialysis.

In recent years, a new method for the evaluation of total plasma antioxidant defenses, known as lag time,3 has proved to be a valid marker of oxidative stress (OS) in different diseases.4 In this study we collected plasma samples from 13 COVID-19 patients and 52 non-COVID-19 patients presenting with COVID-19-like symptoms at the emergency room of Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Donato, San Donato Milanese, Milano, Italy. In the COVID19-positive group, lag-time values showed a significant negative linear correlation with GCR level, suggesting that this parameter could be a good indicator of OS in COVID-19 patients (Figure). [...]there has been little information on the involvement of plasma glycohydrolases in infectious diseases, such as HIV infection.5 In this regard, to our knowledge, our data highlight for the first time an activation of the lysosomal apparatus in SARS-CoV-2 infection. In particular, our results indicate a negative correlation between total plasma antioxidant defenses and GCR, suggesting a link between OS and lysosomal apparatus activation. [...]because of the clinical relevance of OS in COVID-19, the evaluation of both glycohydrolase levels and plasmatic antioxidant defenses could be suggested as a new possible tool for future studies characterizing the role of OS in COVID-19 infection. 1Department of Biomedical Sciences for Health (SCIBIS), Universita degli Studi di Milano, Milan, Italy;2Department of Cardiovascular Anesthesia and Intensive Care, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy;3IRCCS Orthopedic Institute, Galeazzi, Milan, Italy;4O.U. of Clinical Pathology, Department of Pathology and Laboratory Medicine, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy We acknowledge Camilla Mocchi, BSci, for her precious help in the enzymatic assay realization and Judy Baggott, PhD, for English editing.

Background Osteoporosis is a systemic metabolic disease based on age-dependent imbalance between the rates of bone formation and bone resorption. Recent studies on the pathogenesis of this disease identified that bone remodelling impairment, at the base of osteoporotic bone fragility, could be related to protein glycation, in association to oxidative stress. The glycation reactions lead to the generation of glycation end products (AGEs) which, in turn, accumulates into bone, where they binds to the receptor for AGE (RAGE). The aim of this study is to investigate the potential role of circulating sRAGE in osteoporosis, in particular evaluating the correlation of sRAGE with the fracture risk, in association with bone mineral density, the fracture risk marker FGF23, and lipid metabolism. Results Circulating level of soluble RAGE correlate with osteopenia and osteoporosis level. Serum sRAGE resulted clearly associated on the one hand to bone fragility and, on the other hand, with BMI and leptin. sRAGE is particularly informative because serum sRAGE is able to provide, as a single marker, information about both the aspects of osteoporotic disease, represented by bone fragility and lipid metabolism. Conclusions The measure serum level of sRAGE could have a potential diagnostic role in the monitoring of osteoporosis progression, in particular in the evaluation of fracture risk, starting from the prevention and screening stage, to the osteopenic level to osteoporosis.

C-peptide has been shown to exert several, previously unknown, biological effects. A recent cross-sectional study demonstrated an association between low C-peptide serum levels and low lumbar bone density of postmenopausal women not affected by diabetes. To date, very little research attention has been directed toward the association between C-peptide and osteoporotic fractures. To contribute toward filling this gap, we investigated the association between C-peptide and fractures in postmenopausal women. A cohort of 133 non-diabetic postmenopausal women with and without a history of fractures was evaluated in this cross-sectional investigation. Standardized interviews were performed to gather information on the patients’ fracture history. All of the participants underwent a bone mineral density assessment by DXA, radiographs, and a serum C-peptide measurement. Thirty-four women presented fractures. Bivariate analysis revealed an inverse correlation between C-peptide and fractures (r = −0.27, p = 0.002). A significant difference in mean C-peptide levels was also found between women with vs. without fractures (p = 0.01, adjusted for age, BMI and glucose). Logistic regression analysis showed that C-peptide levels, femoral and vertebral BMD were all negatively associated with fracture status (B = −1.097, ES = 0.401, p = 0.006, 95% CI 0.15–0.73; B = −15.6, SE = 4.17, p

The appropriate identification of bacterial infection is the basis for effective treatment and control of infective disease. Among this context, an emerging biomarker of infection is presepsin (PSP), recently described as early marker of different infections. PSP secretion has been shown to be associated with monocyte phagocytosis and plasmatic levels of PSP increase in response to bacterial infection and decrease after antibiotic treatment, therefore it can be considered a marker of activation of immune cell response towards an invading pathogen. Different methods have been developed to measure PSP and this review will briefly describe the different clinical fields of application of PSP, ranging from intensive care to neonatal infection, to orthopedic and pulmonary infection as well as fungal infections and cardiovascular infections.

Cardiac fibrosis is a significant global health problem associated with nearly all forms of heart disease. In the heart interstitial fibrosis may be reparative, replacing areas damaged by myocyte loss after acute infarction, or compensative, responding to cardiac overload. However, after injury in chronic cases activated myofibroblasts contribute to the tissue imbalance of the newer molecules associated with cardiac fibrosis, interleukin (IL-33), and suppression of tumorigenicity 2 (ST2). Physiological stretching causes myofibroblasts to release IL-33 which binds the ST2 receptor (ST2L) on the cardiomyocyte membrane, promoting cell survival and integrity. But in chronic conditions, local and neighboring cells can increase the release of IL-33's decoy, soluble ST2 (sST2), which blocks IL-33/ST2L binding, promoting tissue fibrosis. We review recent studies that have illustrated novel aspects of ST2/IL-33 signaling mediating cardiac fibrosis, and some newer biomolecular targets for the prevention and treatment of maladaptive remodeling.