The Association between Single Nucleotide Polymorphisms, including miR-499a Genetic Variants, and Dyslipidemia in Subjects Treated with Pharmacological or Phytochemical Lipid-Lowering Agents

none12noDisorders of lipoprotein metabolism are among the major risk factors for cardiovascular disease (CVD) development. Single nucleotide polymorphisms (SNPs) have been associated with the individual variability in blood lipid profile and response to lipid-lowering treatments. Here, we genotyped 34 selected SNPs located in coding genes related to lipid metabolism, inflammation, coagulation, and a polymorphism in the MIR499 gene-a microRNA previously linked to CVD-to evaluate the association with lipid trait in subjects with moderate dyslipidemia not on lipid-lowering treatment (Treatment-naïve (TN) cohort, n = 125) and in patients treated with statins (STAT cohort, n = 302). We also explored the association between SNPs and the effect of a novel phytochemical lipid-lowering treatment in the TN cohort. We found that 6 SNPs (in the MIR499, TNFA, CETP, SOD2, and VEGFA genes) were associated with lipid traits in the TN cohort, while no association was found with the response to twelve-week phytochemical treatment. In the STAT cohort, nine SNPs (in the MIR499, CETP, CYP2C9, IL6, ABCC2, PON1, IL10, and VEGFA genes) were associated with lipid traits, three of which were in common with the TN cohort. Interestingly, in both cohorts, the presence of the rs3746444 MIR499 SNP was associated with a more favorable blood lipid profile. Our findings could add information to better understand the individual genetic variability in maintaining a low atherogenic lipid profile and the response to different lipid-lowering therapies.openGiuliani, Angelica; Montesanto, Alberto; Matacchione, Giulia; Graciotti, Laura; Ramini, Deborah; Protic, Olga; Galeazzi, Roberta; Antonicelli, Roberto; Tortato, Elena; Bonfigli, Anna Rita; Sabbatinelli, Jacopo; Olivieri, FabiolaGiuliani, Angelica; Montesanto, Alberto; Matacchione, Giulia; Graciotti, Laura; Ramini, Deborah; Protic, Olga; Galeazzi, Roberta; Antonicelli, Roberto; Tortato, Elena; Bonfigli, Anna Rita; Sabbatinelli, Jacopo; Olivieri, Fabiol

Randomized, Double-Blind, Placebo-Controlled Trial to Test the Effects of a Nutraceutical Combination Monacolin K-Free on the Lipid and Inflammatory Profile of Subjects with Hypercholesterolemia

Background: Nutraceutical combinations (NCs) against hypercholesterolemia are increasing in the marketplace. However, the availability of NCs without monacolin K is scarce even though the statin-intolerant population needs it. Methods: This study is a parallel-group, randomized, placebo-controlled, double-blind trial. We evaluated the effects of the NC containing phytosterols, bergamot, olive fruits, and vitamin K2 on lipid profile and inflammatory biomarkers in 118 subjects (mean age ± SD, 57.9 ± 8.8 years; 49 men and 69 women) with hypercholesterolemia (mean total cholesterol ± SD, 227.4 ± 20.8 mg/dL) without clinical history of cardiovascular diseases. At baseline and 6 and 12 weeks of treatment, we evaluated lipid profile (total, LDL and HDL cholesterol, and triglycerides), safety (liver, kidney, and muscle parameters), and inflammatory biomarkers such as hs-CRP, leukocytes, interleukin-32, and interleukin-38 and inflammatory-microRNAs (miRs) miR-21, miR-126, and miR-146a. Results: Compared to the placebo, at 6 and 12 weeks, NC did not significantly reduce total cholesterol (p = 0.083), LDL cholesterol (p = 0.150), and triglycerides (p = 0.822). No changes were found in hs-CRP (p = 0.179), interleukin-32 (p = 0.587), interleukin-38 (p = 0.930), miR-21 (p = 0.275), miR-126 (p = 0.718), miR-146a (p = 0.206), myoglobin (p = 0.164), and creatine kinase (p = 0.376). Among the two reported, only one adverse event was probably related to the nutraceutical treatment. Conclusions: The evaluated nutraceutical combination did not change serum lipid profile and inflammatory parameters, at least not with the daily dose applied in the present study

TGF beta family members function in uterine healthy and fibrotic smooth muscle cells

Uterine leiomyomas are the most common benign tumors of fertile women and the most common indication for hysterectomy. Despite the high prevalence, significant health problems, and huge economical impact on the healthcare system, relatively little is understood about the etiology and pathophysiology of uterine leiomyoma (1). Consequently, medical treatments are still limited (2). The role of the growth factors as ultimate mediators of the steroids hormone is evident in the modulation of the cell proliferation and the morphological cells appearance (3). Activin-A and myostatin are growth factors belonging to TGF-β super family expressed and acting in myometrial (4,5) and leiomyoma cells (6) We aimed to explore the functions of activin and myostatin in human myometrial and leiomyoma cells. First we tested both Smad and non-Smad signaling pathways by western blot. We found that activin-A and myostatin can activate only Smad signaling pathway in both myometrial and leiomyoma cells. Next we explored the effect on cell proliferation and on fibrotic phenotype. We found that activin-A and myostatin are able to suppress primary myometrial cell proliferation but they cannot alter the proliferation of leiomyoma cells. In the next step, we found that activin-A can significantly increase fibronectin expression in leiomyoma cells. Those above results suggest that activin-A and myostatin may express antiproliferative and/or fibrotic effects depending on the cell types by activating Smad signaling pathway

Seasonal and inter-seasonal RSV activity in the European Region during the COVID-19 pandemic from autumn 2020 to summer 2022

© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.Background: The emergence of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in early 2020 and subsequent implementation of public health and social measures (PHSM) disrupted the epidemiology of respiratory viruses. This work describes the epidemiology of respiratory syncytial virus (RSV) observed during two winter seasons (weeks 40–20) and inter-seasonal periods (weeks 21–39) during the pandemic between October 2020 and September 2022. Methods: Using data submitted to The European Surveillance System (TESSy) by countries or territories in the World Health Organization (WHO) European Region between weeks 40/2020 and 39/2022, we aggregated country-specific weekly RSV counts of sentinel, non-sentinel and Severe Acute Respiratory Infection (SARI) surveillance specimens and calculated percentage positivity. Results for both 2020/21 and 2021/22 seasons and inter-seasons were compared with pre-pandemic 2016/17 to 2019/20 seasons and inter-seasons. Results: Although more specimens were tested than in pre-COVID-19 pandemic seasons, very few RSV detections were reported during the 2020/21 season in all surveillance systems. During the 2021 inter-season, a gradual increase in detections was observed in all systems. In 2021/22, all systems saw early peaks of RSV infection, and during the 2022 inter-seasonal period, patterns of detections were closer to those seen before the COVID-19 pandemic. Conclusion: RSV surveillance continued throughout the COVID-19 pandemic, with an initial reduction in transmission, followed by very high and out-of-season RSV circulation (summer 2021) and then an early start of the 2021/22 season. As of the 2022/23 season, RSV circulation had not yet normalised.Peer reviewe

Nutraceutical Combinations in Hypercholesterolemia: Evidence from Randomized, Placebo-Controlled Clinical Trials

There is an increasing number of nutraceutical combinations (NCs) on the market for hypercholesterolemia, although clinical trials to verify their safety and efficacy are scarce. We selected fourteen randomized, placebo-controlled clinical trials (RCTs) on different lipid-lowering NCs in hypercholesterolemic subjects. We described each compound′s mechanism of action and efficacy in the mixtures and summarized the clinical trials settings and NCs safety and efficacy results. Almost all NCs resulted efficient against hypercholesterolemia; only one reported no changes. Interestingly, red yeast rice (RYR) was present in eleven mixtures. It is not clear whether the lipid-lowering efficacy of these combinations derives mainly from the RYR component monacolin K “natural statin” single effect. Up to now, few RCTs have verified the efficacy of every single compound vs. NCs to evaluate possible additive or synergistic effects, probably due to the complexity and the high resources request. In conclusion, to manage the arising nutraceutical tide against hypercholesterolemia, it could be helpful to increase the number and robustness of clinical studies to verify the efficacy and safety of the new NCs

Involvement of Inflammation and Activin A in Pathogenesis of Uterine Leiomyoma

I leiomiomi (fibromi) uterini sono neoplasie benigne estremamente comuni. L’incidenza è di oltre il 60% in donne in età fertile e pertanto, rappresentano uno dei maggiori problemi di sanità pubblica. I leiomiomi sono spesso multipli, originano nello strato muscolare dell’utero, e si ritiene che ogni fibroma origina da una singola cellula trasformata. Sebbene si sta iniziando a comprende la patofisiologia dei leiomioma, la loro origine resta sconosciuta. Negli ultimi anni, i ricercatori hanno considerato i leiomiomi come una patologia fibrotica. La fibrosi è un processo continuo ed esagerato di guarigione innescato da danno tissutale ed è caratterizzata da eccessiva produzione di proteine della matrice extracellulare (ECM), in particolare collagene. La fibrosi è un meccanismo che include due eventi principali: reclutamento di cellule infiammatorie nel sito di lesione e l'attivazione di cellule – miofibroblasti - che producono collagene. La prima parte del nostro studio è stato condotta con un approccio morfologico. I nostri obiettivi erano di capire: 1. Se lo stimolo infiammatorio cronico che agisce sul miometrio può innescare, in cellule riparative ancora non identificate, la proliferare e la sintesi di quantità esagerate di ECM; 2. Se i miofibroblasti del leiomioma possono avere origine dai fibroblasti stromali CD34-positivi. I risultati ottenuti hanno mostrato la presenza di un gran numero di cellule infiammatorie all'interno del leiomioma e nel tessuto circostante, rispetto al miometrio autologo lontano dal leiomioma. Un forte aumento è stato osservato nella quantità di macrofagi, individuati da un anticorpo specifico per il CD68. I macrofagi tissutali sono cellule chiave nel processo riparativo e di cicatrizzazione, e nel processo di reclutamento e attivazione dei miofibroblasti. Pertanto, un aumento del numero di cellule infiammatorie nei leiomiomi è a favore e supporta l'ipotesi di una loro patogenesi di tipo infiammatoria. Una seconda serie di risultati morfologici suggeriscono la presenza, nei leiomiomi, di miofibroblasti che producono ECM. Il ruolo dell’activina A nel pathway infiammatorio è stato ampiamente documentato in diversi sistemi biologici. I livelli di activina A sono elevati durante l'infiammazione e l’activina A aumenta la produzione di ECM in diverse condizioni patologiche. Pertanto uno dei nostri scopi è stato anche quello di testare se l’activina-A può avere un ruolo nel processo di fibrosi uterina e nello sviluppo e crescita dei leiomioma, effettuando degli studi in vitro. Abbiamo visto che l’activina-A aumenta significativamente i livelli di mRNA della fibronectina, del collagene 1A1 e del versican nelle colture primarie di cellule di leiomioma, e ha aumentato in maniera significativa i livelli di mRNA della fibronectina ma non del collagene 1A1 e del versican in colture cellule primarie di cellule del miometrio. L'aumento della fibronectina indotto dall’activina-A nelle cellule di leiomioma è stato visto anche a livello proteico, mediante western blot e immunocitochimica. Considerato che l’activina A ha ruolo pro-fibrotico nei leiomioma uterini, abbiamo anche valutato se e quali molecole infiammatorie sono in grado di stimolare l'espressione di questa citochina profibrotica in vitro nelle cellule di leiomioma e di miometrio. Abbiamo trovato sia nelle cellule primarie che nelle linee cellulari che il TNF-α aumenta sostanzialmente i livelli di espressione di mRNA dell’activina. A tutt’oggi, non esiste ancora una terapia medica efficace contro i leiomiomi uterini. L’isterectomia, soluzione definitiva contro i leiomiomi, è uno dei principali interventi chirurgici addominali che determina un aumento del rischio di morbilità postoperatoria e che portano all’infertilità. Tranilast è una farmaco sintetico che presenta molteplici effetti terapeutici per diverse condizioni patologiche. Siccome non ci sono studi sui fibromi uterini, ci siamo chiesti se il tranilast avesse effetti sulle proteine della ECM nei leiomiomi. Nel presente studio abbiamo dimostrato che il tranilast ha un effetto anti-fibrotico sulle cellule primarie di miometrio e di leiomioma. Nel complesso, la nostra ricerca presenta un nuovo approccio per lo studio della patogenesi del leiomioma. I dati presentati supportano la presenza di infiammazione all’interno del fibroma uterino, l'attivazione di cellule produttrici di collagene-miofibroblasti e l'eccessiva produzione di proteine della ECM, che conducono al rimodellamento tissutale e alla crescita del leiomioma.Uterine leiomyomas (fibroids) are extremely common benign neoplasms. The incidence is over 60% in women of reproductive age and therefore represents one of the major public health problems. Leiomyomas are often multiple, originate in the smooth muscle layer of the uterus, and it has been proposed that each fibroid originates from a single transformed cell. Although the pathophysiology of leiomyomas is beginning to be understood their etiology still remains unknown. Over the last years, researchers have considered leiomyoma as a fibrotic disorder. Fibrosis is an exaggerated and continuous wound healing process triggered by tissue injury and characterized by excessive production of extracellular matrix (ECM) proteins, in particular collagens. Fibrosis is a mechanism that includes two main happenings: recruitment of inflammatory cells to the site of injury and activation of collagen producing cells- myofibroblasts. Our first study was morphological. We aimed to research: 1. If chronic inflammatory stimulus acting on the myometrium may trigger yet unidentified reparative cells to proliferate and to synthesize exaggerated amounts of ECM; 2. If leiomyoma myofibroblasts may derive from CD34-positive stromal fibroblasts. Our results showed the presence of a large number of inflammatory cells inside leiomyomas and in the surrounding tissue, when compared to autologous myometrium far from the leiomyoma. A large increase was observed in the amount of macrophages, identified by an antibody against CD68. Tissue macrophages are key cells in the reparative and scarring process, and in myofibroblasts recruitment and activation. Therefore, an increased number of inflammatory cells inside the leiomyoma support and agree with the hypothesis of an inflammatory pathogenesis of uterine leiomyoma. A second set of morphological results suggest the presence of myofibroblasts producing ECM in leiomyomas. The role of activin A in inflammatory pathways of different biological systems has been well documented. Since the level of Activin A is elevated during inflammation and is responsible for increase production of ECM in different pathological conditions. Therefore our aim was also to investigate if activin-A may have role in fibrosis process in uterus and leiomyoma development and growth, using an in vitro approach. We found that activin-A significantly increased fibronectin, collagen1A1 and versican mRNA expressions in primary leiomyoma cells, and it significantly increased fibronectin mRNA expressions but not collagen1A1 and versican expression in primary myometrial cells. The increased fibronectin expression by activin-A in leiomyoma cells was seen also at the protein level, by western blot and immunocytochemistry. Based on the findings that activin A has a pro-fibrotic role in uterine leiomyoma, we also evaluated whether and which inflammatory molecules are able to stimulate the expression of this profibrotic cytokine in leiomyoma and myometrial cells in vitro. We found in both, primary and immortalized cells, thatTNF-α was able to substantially increase activin A mRNA expression. To date, there is still no effective medical therapy against uterine leiomyomas. Hysterectomy, a permanent solution against leiomyomas, is a major abdominal surgical procedures caring on an increased risk of postoperative morbidity and leading to the loss of female reproductive potential. Tranilast is a synthetic drug that exhibits multiple therapeutic effects in diverse pathologic conditions. Since limited work has been reported in uterine fibroid biology, we aimed to research tranilast effect on ECM in leiomyoma. In the present study we demonstrated that tranilast has anti-fibrotic effect on human primary myometrial and leiomyoma cells. Overall, our research presents novel approach to leiomyoma pathogenesis. The presented data support the presence of inflammation inside the human uterine leiomyoma tissue, activation of collagen producing cells-myofibroblasts and the excessive production of ECM proteins, leading to the tissue remodeling and leiomyoma growth

Biomarkers of oxidative damage in patients with colon cancer

Meeting on Free Radicals and Oxidative Stress, 2003, Loannina, Greec

Primary prevention of SCD with ICD in the elderly

Implantable cardioverter defibrillators (ICDs) are electronic devices that can prevent sudden cardiac death (SCD) caused by arrhythmic events in patients. The latest ESC/EAS and ACC/AHA Guidelines deem the placement of an ICDs appropriate in patients with heart failure class NYHA II and III in the presence of an ejection fraction less than or equal to 35% [1,2]. ICDs are usually not indicated in either class I or IV patients. The Guidelines recommendations for primary prevention of SCD with ICD implantation do not take into account the age of the patients but only their life expectancy which must be at least 1 year. Our patients usually are over eighty years old with heart failure and severely reduced ejection fraction. We must consequently decide if it is right to implant these patients with an ICD. Is the use of ICD in the patients over 80, in particular over 90 years old, really make sense becomes particularly important considering demographic changes that await us in the coming decades

Complex networks of multiple factors in the pathogenesis of uterine leiomyoma

Objective: To summarize the information regarding pathogenetic factors of leiomyoma formation and growth, and to make a simple integrated pathogenetic view of this tumor for further thinking to establish new therapeutic options. Design: PubMed and Google Scholar searches were conducted to identify the relevant studies on pathogenesis of uterine leiomyoma, which are hereby reviewed and discussed. Setting: Academic medical center. Patient(s): Not applicable. Intervention(s): Not applicable. Main Outcome Measure(s): Not applicable. Result(s): To date, the pathogenesis of uterine leiomyomas is not well understood. However, genetic alterations (especially MED12 and HMGA2) and involvement of epigenetic mechanisms (DNA methylation, histone modifications, and microRNA) in leiomyoma provide the clue of initiator of this tumor. Estrogens and P are considered as promoters of leiomyoma growth, and growth factors, cytokines, and chemokines are thought to be as potential effectors of estrogens and P. Extracellular matrix components are a major structural part of leiomyoma tissue that are abnormally orientated and can modify mechanical stress on cells, which leads to activation of internal mechanical signaling and may contribute to leiomyoma growth. Conclusion(s): Besides many genetics and epigenetic factors, the important link among the sex steroids, growth factors, cytokines, chemokines, and extracellular matrix and their involvement in cell proliferation, fibrotic processes, apoptosis, and angiogenesis are implicating a complex network in leiomyoma formation and growth. Those findings could provide information to establish future therapeutic options for the management of this tumor

Tranilast, an orally active antiallergic compound, inhibits extracellular matrix production in human uterine leiomyoma and myometrial cells

To determine the effect of tranilast (an antiallergic drug known to suppress fibrosis or to stabilize mast cells) on extracellular matrix production in human leiomyoma and myometrial cells