Publications by authors named "Alessandro Pini"

133 Publications

Is SF-12 a valid and reliable measurement of health-related quality of life among adults with Marfan syndrome? A confirmatory study.

PLoS One 2021 9;16(6):e0252864. Epub 2021 Jun 9.

Cardiovascular-Genetic Center, IRCCS Policlinico San Donato, San Donato Milanese, Italy.

Introduction: The structural validity and reliability of the Short-Form Health Survey 12 (SF-12) has not yet been tested in adults with the Marfan syndrome (MFS). This gap could undermine an evidence-grounded practice and research, especially considering that the need to assess health-related quality of life in patients with MFS has increased due to the improved life expectancy of these patients and the need to identify their determinants of quality of life. For this reason, this study aimed to confirm the dimensionality (structural validity) of the SF-12, its concurrent validity, and its reliability (internal consistency).

Methods: We performed a cross-sectional study in a convenience sample of 111 Italian adults with MFS, collecting anamnestic and socio-demographic information, the SF-12, and short-form Health Survey 36 (SF-36). A confirmatory factor analysis was performed to verify whether the items of SF-12 related to physical restrictions, physical functioning, and bodily pain were retained by the physical summary component of the SF-12. The items referred to the role limitations due to emotional issues, social functioning, and mental health were retained by the mental summary component (MCS12). SF-36 was used to assess the concurrent validity of SF-12, hypothesizing positive correlations among the equivalent summary scores.

Results: The two-factor structural solution resulted in fitting the sample statistics adequately. The internal consistency was adequate for the two factors. Furthermore, the physical and mental summary scores of the SF-36 were positively correlated with their equivalent summary scores derived from the SF-12.

Conclusions: This study confirmed the factor structure of the SF-12. Therefore, the use of SF-12 in clinical practice and research for assessing the health-related quality of life among adults with MFS is evidence-grounded. Future research is recommended to determine whether the SF-12 shows measurement invariance in different national contexts and determine eventual demographic variation in the SF-12 scores among patients with MFS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252864PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189474PMC
June 2021

Effects of short-term exposure to particulate matter on emergency department admission and hospitalization for asthma exacerbations in Brescia district.

J Asthma 2021 Jun 14:1-8. Epub 2021 Jun 14.

Respiratory Medicine Unit, ASST - Spedali Civili di Brescia, Brescia, Italy.

Background: Rising pollution plays a crucial role in worsening several respiratory diseases. Particulate Matter (PM)-induced asthma exacerbations are one of the most dangerous events.

Objectives: To assess the correlation between progressive particulate matter short-term exposure and asthma exacerbations, we investigated the role of PM levels on Emergency Department (ED) admissions and hospitalizations for these events in Brescia, an important industrial city located in northern Italy with high yearly levels of air pollution.

Methods: We analyzed 1050 clinical records of ED admissions for suspected asthma exacerbation, starting from January 2014 to December 2017. Daily PM levels were collected from the Environmental Protection Regional Agency. We performed a time-series analysis using a Poisson regression model with single and multiple day-lag. Results were expressed as Relative Risk (RR) and Excess of Relative Risk (ERR) of severe asthma exacerbation over a 10 µg/m increase in PM10 and PM2.5 concentration.

Results: We selected and focused our analysis on 543 admissions for indisputable asthma exacerbation in ED and hospital. The time-series study showed an increase of the RR (CI95%) for asthma exacerbation-related ED admissions of 1.24 with an ERR of 24.2% for PM2.5 at lag0-1 ( < 0.05). We also estimated for PM2.5 a RR (CI95%) of 1.12 with an ERR of 12.5% at lag0-5 ( ≤ 0.05). Again, for PM2.5, an increase of the RR (CI95%) for asthma exacerbation-related hospitalizations of 1.31 with an ERR of 30.7% at lag0-1 ( < 0.05) has been documented. These findings were confirmed and even reinforced considering only the population living in the city.

Conclusions: Short-term PM exposure, especially for PM2.5, plays a critical role in inducing asthma exacerbation events leading to ED admission or hospitalization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/02770903.2021.1929310DOI Listing
June 2021

eHealth for patients with rare diseases: the eHealth Working Group of the European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN).

Orphanet J Rare Dis 2021 Apr 8;16(1):164. Epub 2021 Apr 8.

Cardiovascular-Genetic Center, IRCCS Policlinico San Donato, Via Morandi 30, 20097, San Donato Milanese, MI, Italy.

Background: The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) was launched in 2017 and involves, to date, 35 highly specialised multidisciplinary expert centres (from the 30 full Healthcare Provider members) coming from 11 countries and more than 70 patient organizations from 16 countries. The eHealth Working Group (WG) of VASCERN was set up to develop practical, patient-centred solutions and strategies for effective use of eHealth tools to answer the needs of patients with multisystemic vascular rare diseases.

The Ehealth Wg: Following the identified patients' needs and following the guiding principles of collaboration and patient-centredness, the eHealth WG was created with the following aims: to develop a mobile app to help patients find expert centres and patient organizations, and to develop resources (Pills of Knowledge, PoK) for training and education via digital platforms (eLearning). The mobile app includes, to date, functionalities that allow users to find expert centres and patient organizations across Europe in the area of rare multisystemic vascular diseases. Discussed app developments include personalized digital patient passports, educational material, emergency management guidelines and remote consultations. Regarding training and education, a variety of PoK have been developed. The PoK cover several topics, target several user groups, and are delivered in various formats so that they are easy-to-use, easy-to-understand, informative, and viable for delivery and sharing through digital platforms (eLearning) including, e.g., the VASCERN YouTube™ channel.

Conclusion: Overall, the work carried out by the eHealth WG of VASCERN can be seen as a pilot experience that may serve as a basis to for collaborative development of patient-centred eHealth tools that answer the needs of patients with various rare diseases, not limited to rare multisystemic vascular diseases. By expanding the multidisciplinary approach here described, clinical and research networks can take advantage of eHealth services and use them as strategic assets in achieving the ultimate goal of ensuring equity of access to prevention programs, timely and accurate diagnosis and specialized care for patients with rare diseases throughout Europe.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-01604-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034087PMC
April 2021

Infantile hemangiomas β-adrenoceptor overexpression is associated with nonresponse to propranolol.

Pediatr Res 2021 Mar 2. Epub 2021 Mar 2.

Department of Clinical and Experimental Medicine, Division of Neonatology and NICU, University of Pisa, Pisa, Italy.

Background: Propranolol (antagonist of β-/β-AR but minimally active against β-AR) is currently the first-line treatment for infantile hemangiomas (IH). Its efficacy is attributed to the blockade of β-AR. However, its success rate is ~60%. Considering the growing interest in the angiogenic role of β-ARs, we evaluated a possible relationship between β-AR expression and response to propranolol.

Methods: Fifteen samples of surgical biopsies were collected from patients with IH. Three were taken precociously from infants and then successfully treated with propranolol (responder group). Twelve were taken later, from residual lesions noncompletely responsive to propranolol (nonresponder group). A morphometrical analysis of the percentage of β-, β-, and β-ARs positively stained area was compared between the two groups.

Results: While no difference was found in both β- and β-AR expression level, a statistically significant increase of β-AR positively stained area was observed in the nonresponder group.

Conclusions: Although the number of biopsies is insufficient to draw definitive conclusions, and the different β-AR pattern may be theoretically explained by the different timing of samplings, this study suggests a possible correlation between β-AR expression and the reduced responsiveness to propranolol treatment. This study could pave the way for new therapeutic perspectives to manage IH.

Impact: Propranolol (unselective antagonist of β and β-ARs) is currently the first-line treatment for IHs, with a success rate of ~60%. Its effectiveness has been attributed to its ability to block β-ARs. However, β-ARs (on which propranolol is minimally active) were significantly more expressed in hemangioma biopsies taken from patients nonresponsive to propranolol. This study suggests a possible role of β-ARs in hemangioma pathogenesis and a possible new therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41390-021-01385-xDOI Listing
March 2021

Emergency department admission and hospitalization for COPD exacerbation and particulate matter short-term exposure in Brescia, a highly polluted town in northern Italy.

Respir Med 2021 04 16;179:106334. Epub 2021 Feb 16.

Respiratory Medicine Unit, Spedali Civili, Brescia, Italy; Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Background: Short-term exposure to high Particulate Matter (PM) concentrations worsens several respiratory conditions.

Objectives: We evaluated the relationship between short-term exposure to Particulate Matter and fine Particulate Matter (PM10 - PM2.5) and Emergency Department (ED) admissions and hospitalizations for COPD exacerbation observed at the University Hospital, Spedali Civili of Brescia, a city with some of the highest yearly levels of air pollution in Italy.

Methods: We collected data from patients admitted to the ED with a COPD exacerbation diagnosis, starting from January 2014 to January 2016. Daily PM levels were collected from the Environmental Protection Regional Agency (ARPA). We performed a time-series analysis using the Poisson regression model with single and multiple day-lag. Results were expressed as Relative Risk (RR) and Excess of Relative Risk (ER) for COPD exacerbation-related ED admissions and hospitalizations, over a 10μg/m3 increase in PM concentration.

Results: We collected data from 431 COPD patients. Both PM10 and PM2.5 were significantly associated with the risk of COPD exacerbation-related ED admission and hospitalization. Each increase of 10μg/m3 of PM10 and PM2.5 corresponded respectively to a RR for ED admissions of 1.06 and 1.08 at lag0-1; 1.06 and 1.09 at lag0-5 (p < 0.05). Similar results for COPD Exacerbation-related hospitalizations were found, with a RR of 1.07 and 1.10 at lag0-1 and 1.07 and 1.11 at lag0-5 for each increase of 10μg/m3 PM10 and PM2.5, respectively.

Conclusions: Our findings show that in a highly polluted city of Northern Italy, short-term increase in exposure to PM10-PM2.5 is associated with a higher risk of ED admission and hospitalization due to COPD exacerbation with a greater incidence during the winter season.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rmed.2021.106334DOI Listing
April 2021

Exposure to fine particulate matter (PM) hampers myelin repair in a mouse model of white matter demyelination.

Neurochem Int 2021 05 12;145:104991. Epub 2021 Feb 12.

Department of Neuroscience Rita Levi-Montalcini, University of Turin, Italy; Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Regione Gonzole, 10, 10043, Orbassano (Turin), Italy. Electronic address:

Epidemiological studies show a strong association between exposure to air pollution - and particularly to particulate matter (PM) -, increased prevalence of Multiple Sclerosis (MS) and higher rates of hospital admissions for MS and MS relapses. Besides having immunomodulatory effects and sustaining a systemic oxidative-inflammatory response, PM may participate in MS pathogenesis by targeting also Central Nervous System (CNS)-specific processes, such as myelin repair. Here we show that, in a mouse model of lysolecithin-induced demyelination of the subcortical white matter, post-injury exposure to fine PM hampers remyelination, disturbs oligodendroglia differentiation dynamics and promotes astroglia and microglia reactivity. These findings support the view that exposure to fine PM can contribute to demyelinating pathologies by targeting the endogenous regenerative capability of the CNS tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuint.2021.104991DOI Listing
May 2021

Effect of Beta 3 Adrenoreceptor Modulation on Patency of the Ductus Arteriosus.

Cells 2020 12 7;9(12). Epub 2020 Dec 7.

Division of Neonatology and NICU, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.

β3-adrenoreceptor (β3-AR), a G-protein coupled receptor, has peculiar regulatory properties in response to oxygen and widespread localization. β3-AR is expressed in the most frequent neoplasms, also occurring in pregnant women, and its blockade reduces tumor growth, indicating β3-AR-blockers as a promising alternative to antineoplastic drugs during pregnancy. However, β3-AR involvement in prenatal morphogenesis and the consequences of its blockade for the fetus remain unknown. In this study, after the demonstrated expression of β3-AR in endothelial and smooth muscle cells of ductus arteriosus (DA), C57BL/6 pregnant mice were acutely treated at 18.5 of gestational day (GD) with indomethacin or with the selective β3-AR antagonist SR59230A, or chronically exposed to SR59230A from 15.5 to 18.5 GD. Six hours after the last treatment, fetuses were collected. Furthermore, newborn mice were treated straight after birth with BRL37344, a β3-AR agonist, and sacrificed after 7 h. SR59230A, at the doses demonstrated effective in reducing cancer progression (10 and 20 mg/kg) in acute and chronic mode, did not induce fetal DA constriction and did not impair the DA ability to close after birth, whereas at the highest dose (40 mg/kg), it was shown to cause DA constriction and preterm-delivery. BRL37344 administered immediately after birth did not alter the physiological DA closure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9122625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762377PMC
December 2020

Heparan Sulfate Proteoglycans Can Promote Opposite Effects on Adhesion and Directional Migration of Different Cancer Cells.

J Med Chem 2020 12 7;63(24):15997-16011. Epub 2020 Dec 7.

Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.

Heparan sulfate proteoglycans take part in crucial events of cancer progression, such as epithelial-mesenchymal transition, cell migration, and cell invasion. Through sulfated groups on their glycosaminoglycan chains, heparan sulfate proteoglycans interact with growth factors, morphogens, chemokines, and extracellular matrix (ECM) proteins. The amount and position of sulfated groups are highly variable, thus allowing differentiated ligand binding and activity of heparan sulfate proteoglycans. This variability and the lack of specific ligands have delayed comprehension of the molecular basis of heparan sulfate proteoglycan functions. Exploiting a tumor-targeting peptide tool that specifically recognizes sulfated glycosaminoglycans, we analyzed the role of membrane heparan sulfate proteoglycans in the adhesion and migration of cancer cell lines. Starting from the observation that the sulfated glycosaminoglycan-specific peptide exerts a different effect on adhesion, migration, and invasiveness of different cancer cell lines, we identified and characterized three cell migration phenotypes, where different syndecans are associated with alternative signaling for directional cell migration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c01848DOI Listing
December 2020

Antibacterial and Anti-Inflammatory Activity of an Antimicrobial Peptide Synthesized with D Amino Acids.

Antibiotics (Basel) 2020 Nov 24;9(12). Epub 2020 Nov 24.

Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.

The peptide SET-M33 is a molecule synthesized in tetra-branched form which is being developed as a new antibiotic against Gram-negative bacteria. Its isomeric form with D amino acids instead of the L version (SET-M33D) is also able to kill Gram-positive bacteria because of its higher resistance to bacterial proteases (Falciani et al., , 2012, 7, e46259). Here we report the strong in vitro activity of SET-M33D (MIC range 0.7-6.0 µM) against multiresistant pathogens of clinical interest, including Gram-positives , , and , and various Gram-negative enterobacteriaceae. SET-M33D antibacterial activity is also confirmed in vivo against a MRSA strain of with doses perfectly compatible with clinical use (5 and 2.5 mg/Kg). Moreover, SET-M33D strongly neutralized lipopolysaccharide (LPS) and lipoteichoic acid (LTA), thus exerting a strong anti-inflammatory effect, reducing expression of cytokines, enzymes, and transcription factors (TNF-α, IL6, COX-2, KC, MIP-1, IP10, iNOS, NF-κB) involved in the onset and evolution of the inflammatory process. These results, along with in vitro and in vivo toxicity data and the low frequency of resistance selection reported here, make SET-M33D a strong candidate for the development of a new broad spectrum antibiotic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antibiotics9120840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760307PMC
November 2020

GLP-2 Prevents Neuronal and Glial Changes in the Distal Colon of Mice Chronically Treated with Cisplatin.

Int J Mol Sci 2020 Nov 23;21(22). Epub 2020 Nov 23.

Histology and Embryology Research Unit, Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy.

Cisplatin is a chemotherapeutic agent widely used for the treatment of solid cancers. Its administration is commonly associated with acute and chronic gastrointestinal dysfunctions, likely related to mucosal and enteric nervous system (ENS) injuries, respectively. Glucagon-like peptide-2 (GLP-2) is a pleiotropic hormone exerting trophic/reparative activities on the intestine, via antiapoptotic and pro-proliferating pathways, to guarantee mucosal integrity, energy absorption and motility. Further, it possesses anti-inflammatory properties. Presently, cisplatin acute and chronic damages and GLP-2 protective effects were investigated in the mouse distal colon using histological, immunohistochemical and biochemical techniques. The mice received cisplatin and the degradation-resistant GLP-2 analog ([Gly2]GLP-2) for 4 weeks. Cisplatin-treated mice showed mucosal damage, inflammation, IL-1β and IL-10 increase; decreased number of total neurons, ChAT- and nNOS-immunoreactive (IR) neurons; loss of SOX-10-IR cells and reduced expression of GFAP- and S100β-glial markers in the myenteric plexus. [Gly2]GLP-2 co-treatment partially prevented mucosal damage and counteracted the increase in cytokines and the loss of nNOS-IR and SOX-10-IR cells but not that of ChAT-IR neurons. Our data demonstrate that cisplatin causes mucosal injuries, neuropathy and gliopathy and that [Gly2]GLP-2 prevents these injuries, partially reducing mucosal inflammation and inducing ENS remodeling. Hence, this analog could represent an effective strategy to overcome colonic injures induced by cisplatin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21228875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700273PMC
November 2020

Endocytosis and Trafficking of Heparan Sulfate Proteoglycans in Triple-Negative Breast Cancer Cells Unraveled with a Polycationic Peptide.

Int J Mol Sci 2020 Nov 5;21(21). Epub 2020 Nov 5.

Department of Molecular Biotechnology, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy.

The process of heparan sulfate proteoglycan (HSPG) internalization has been described as following different pathways. The tumor-specific branched NT4 peptide has been demonstrated to bind HSPGs on the plasma membrane and to be internalized in tumor cell lines. The polycationic peptide has been also shown to impair migration of different cancer cell lines in 2D and 3D models. Our hypothesis was that HSPG endocytosis could affect two important phenomena of cancer development: cell migration and nourishment. Using NT4 as an experimental tool mimicking heparin-binding ligands, we studied endocytosis and trafficking of HSPGs in a triple-negative human breast cancer cell line, MDA-MB-231. The peptide entered cells employing caveolin- or clathrin-dependent endocytosis and macropinocytosis, in line with what is already known about HSPGs. NT4 then localized in early and late endosomes in a time-dependent manner. The peptide had a negative effect on CDC42-activation triggered by EGF. The effect can be explained if we consider NT4 a competitive inhibitor of EGF on HS that impairs the co-receptor activity of the proteoglycan, reducing EGFR activation. Reduction of the invasive migratory phenotype of MDA-MB-231 induced by NT4 can be ascribed to this effect. RhoA activation was damped by EGF in MDA-MB-231. Indeed, EGF reduced RhoA-GTP and NT4 did not interfere with this receptor-mediated signaling. On the other hand, the peptide alone determined a small but solid reduction in active RhoA in breast cancer cells. This result supports the observation of few other studies, showing direct activation of the GTPase through HSPG, not mediated by EGF/EGFR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21218282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663799PMC
November 2020

Abdominal Symptoms and Colonic Diverticula in Marfan's Syndrome: A Clinical and Ultrasonographic Case Control Study.

J Clin Med 2020 Sep 28;9(10). Epub 2020 Sep 28.

Gastroenterology & Hepatology Section, Department of Medicine, University of Perugia Medical School, 06122 Perugia, Italy.

Background: Marfan's syndrome (MFS) seems to be frequently associated with colonic diverticulosis, but the prevalence of diverticula and symptoms evocative of diverticular disease in this population are still unknown.

Methods: This prospective case control study included 90 consecutive patients with MFS, 90 unselected controls, and 90 asymptomatic subjects. The clinical characteristics, including lower gastrointestinal symptoms, and ultrasonographic features of the bowel, including diverticula and thickening of the muscularis propria of the sigmoid colon, were investigated. In addition, the genotype of MFS patients was assessed. The characteristics of patients and controls were compared using parametric tests.

Results: Complaints of abdominal symptoms were made by 23 (25.6%) patients with MFS and 48 (53%) control subjects ( < 0.01). Constipation and bloating were reported less frequently by MFS patients than controls (constipation: 13.3% vs. 26.6%, = 0.039; bloating: 3.3% vs. 41.1%, < 0.0001), while other symptoms were not significantly different. Sigmoid diverticulosis was detected in 12 (12.3%) patients with MFS, as well as in 3 (3.3%) asymptomatic healthy subjects and 4 (4.4%) random controls ( = 0.0310). The genetic variants of MFS were not correlated with symptoms or diverticula.

Conclusion: Patients with MFS have a greater prevalence of diverticula, although less abdominal symptoms, compared to the general population. Symptoms and diverticula in MFS are not correlated with any genetic variant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9103141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599469PMC
September 2020

β3-Adrenoceptors as Putative Regulator of Immune Tolerance in Cancer and Pregnancy.

Front Immunol 2020 2;11:2098. Epub 2020 Sep 2.

Neonatal Intensive Care Unit, Medical Surgical Feto-Neonatal Department, A. Meyer University Children's Hospital, Florence, Italy.

Understanding the mechanisms of immune tolerance is currently one of the most important challenges of scientific research. Pregnancy affects the immune system balance, leading the host to tolerate embryo alloantigens. Previous reports demonstrated that β-adrenergic receptor (β-AR) signaling promotes immune tolerance by modulation of NK and Treg, mainly through the activation of β2-ARs, but recently we have demonstrated that also β3-ARs induce an immune-tolerant phenotype in mice bearing melanoma. In this report, we demonstrate that β3-ARs support host immune tolerance in the maternal microenvironment by modulating the same immune cells populations as recently demonstrated in cancer. Considering that β3-ARs are modulated by oxygen levels, we hypothesize that hypoxia, through the upregulation of β3-AR, promotes the biological shift toward a tolerant immunophenotype and that this is the same trick that embryo and cancer use to create an aura of immune-tolerance in a competent immune environment. This study confirms the analogies between fetal development and tumor progression and suggests that the expression of β3-ARs represents one of the strategies to induce fetal and tumor immune tolerance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.02098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492666PMC
May 2021

Postoperative and mid-term hemodynamic changes after replacement of the ascending aorta.

J Thorac Cardiovasc Surg 2020 May 27. Epub 2020 May 27.

Istituto Auxologico Italiano, IRCCS, Cardiology Unit, Milan, Italy; Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.

Objectives: To evaluate aortic distensibility and pulse waveform patterns associated with the ascending aortic aneurysm, and to analyze the postoperative and mid-term hemodynamic changes induced by prosthetic replacement of the ascending aorta.

Methods: Central blood pressure waves were recorded at the carotid artery level by means of a validated transcutaneous arterial tonometer in 30 patients undergoing prosthetic replacement of ascending aortic aneurysm and in 30 control patients. Measurements were obtained the day before surgery and 5 to 7 days and 16 to 20 months after surgery.

Results: The ascending aortic aneurysm was associated with a less steep slope of early systolic phase of the pressure curve (pulsus tardus) compared with a control group (0.54 ± 0.18 mm Hg/ms vs 0.69 ± 0.26 mm Hg/ms; P = .011). Replacing the ascending aorta with a noncompliant vascular prosthesis steepened the pulse pressure slope during the early systolic phase in the postoperative period (0.77 ± .29 mm Hg/ms), providing values comparable with those of the control group in the mid-term (0.67 ± .20 mm Hg/ms). No change in aortic stiffness was found either postoperatively or in the mid-term after ascending aorta surgical replacement (carotid-femoral pulse wave velocity: preoperative, 9.0 ± 2.6 m/s; postoperative, 9.0 ± 2.9 m/s; mid-term postoperative, 9.3 ± 2.8 m/s).

Conclusions: This study does not confirm the assumption that substitution of the viscoelastic ascending aorta with a rigid prosthesis can cause serious hemodynamic alterations downstream, because we did not observe a worsening of global aortic distensibility after insertion of a rigid prosthetic aorta. The ascending aortic aneurysm is associated with a pulsus tardus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtcvs.2020.05.031DOI Listing
May 2020

Increased fracture rate in children and adolescents with Marfan syndrome.

Bone 2020 06 25;135:115333. Epub 2020 Mar 25.

Cardiovascular-Genetic Center, IRCCS Policlinico San Donato, Milan, Italy.

Marfan syndrome (MFS) is an autosomal genetic disorder of connective tissue, due to alterated fibrillin-1. The aim of our study was to verify the rate of fractures in children with MFS in correlation to bone mineral density and compare the prevalence to the general population in the same latitude. We enrolled 80 patients (37 girls and 43 boys) with the diagnosis of Marfan syndrome, median age 10 y (3 to 17 years). Fracture occurrence was inferred from medical records of patients with MFS. Bone mineral density (BMD) was measured at lumbar spine, femoral neck and total femur by dual-energy x-ray absorptiometry. BMD values were expressed as z-scores, and adjusted for height using height-for-age z-scores. Bone turnover markers and vitamin D were measured. We assessed incidence of fracture in general pediatric population of our geographic area (45°N latitude). A total of 24 fractures were recorded in 21 patients (15 boys and 6 girls), involving both short and long bones, due to mild or moderate trauma. An incidence estimate has been calculated for each year, and an average incidence of 29.2/1000 MFS patients was obtained, markedly higher (P=0.034) than the incidence of fracture calculated in the same geographical area in pediatric patients (15.8/1000). We did not detect differences in anthropometric measurements, BMD values and biochemical indices between patients who fractured and patients who did not. Similarly, no differences were found between patients on losartan therapy and patients not in treatment for the same variables. In conclusion, the incidence of fractures was higher in patients with MFS compared to general population of the same age and latitude. The management of MFS must account bone status health and start strategies of fracture prevention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2020.115333DOI Listing
June 2020

Association of the Somatostatin Analog Octreotide With Magnetic Nanoparticles for Intraocular Delivery: A Possible Approach for the Treatment of Diabetic Retinopathy.

Front Bioeng Biotechnol 2020 25;8:144. Epub 2020 Feb 25.

Department of Biology, University of Pisa, Pisa, Italy.

The somatostatin analog octreotide (OCT) displays important neuroprotective and anti-angiogenic properties that could make it an interesting candidate to treat diabetic retinopathy (DR). Unfortunately, systemic drug administration is hindered by severe side effects, therefore topical administration routes are preferable. However, drug delivery through eye drops may be difficult due to ocular barriers and, in the long term, could induce ocular damage. On the other hand, intraocular injections must be repeated to maintain drug concentration, and this may cause severe damage to the eye. To decrease injection frequency, long-term release and reduced biodegradation could be obtained by binding the drug to biodegradable polymeric nanoparticles. In the present study, we made a preparation of OCT bound to magnetic nanoparticles (MNP-OCT) and tested its possible use as an OCT delivery system to treat retinal pathologies such as DR. In particular, , , and experimental models of the mammalian retina were used to investigate the possible toxicity of MNPs, possible effects of the binding to MNPs on OCT bioactivity, and the localization of MNP-OCT in the retina after intraocular injection. The results showed that, both in human retinal endothelial cells (HRECs) and in mouse retinal explants, MNPs were not toxic and the binding with MNPs did not influence OCT antiangiogenic or antiapoptotic activity. Rather, effects of MNP-OCT were observed at concentrations up to 100-fold (in HRECs) or 10-fold (in mouse retinal explants) lower compared to OCT, indicating that OCT bioactivity was enhanced in MNP-OCT. MNP-OCT in mouse retinas after intraocular delivery were initially localized mainly to the outer retina, at the level of the retinal pigment epithelium, while after 5 days they were observed throughout the retinal thickness. These observations demonstrate that MNP-OCT may be used as an OCT intraocular delivery system that may ensure OCT localization to the retina and enhanced OCT bioactivity. Further studies will be necessary to determine the OCT release rate in the retina and the persistence of drug effects in the long period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fbioe.2020.00144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051943PMC
February 2020

A New NT4 Peptide-Based Drug Delivery System for Cancer Treatment.

Molecules 2020 Feb 28;25(5). Epub 2020 Feb 28.

Department of Medical Biotechnology, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

The development of selective tumor targeting agents to deliver multiple units of chemotherapy drugs to cancer tissue would improve treatment efficacy and greatly advance progress in cancer therapy. Here we report a new drug delivery system based on a tetrabranched peptide known as NT4, which is a promising cancer theranostic by virtue of its high cancer selectivity. We developed NT4 directly conjugated with one, two, or three units of paclitaxel and an NT4-based nanosystem, using NIR-emitting quantum dots, loaded with the NT4 tumor-targeting agent and conjugated with paclitaxel, to obtain a NT4-QD-PTX nanodevice designed to simultaneously detect and kill tumor cells. The selective binding and in vitro cytotoxicity of NT4-QD-PTX were higher than for unlabeled QD-PTX when tested on the human colon adenocarcinoma cell line HT-29. NT4-QD-PTX tumor-targeted nanoparticles can be considered promising for early tumor detection and for the development of effective treatments combining simultaneous therapy and diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules25051088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179244PMC
February 2020

Antimicrobial Peptide-Loaded Nanoparticles as Inhalation Therapy for Infections.

Int J Nanomedicine 2020 17;15:1117-1128. Epub 2020 Feb 17.

Department of Medical Biotechnologies, University of Siena, Siena, Italy.

Introduction: Antibiotic-resistant bacteria kill 25,000 people every year in the EU. Patients subject to recurrent lung infections are the most vulnerable to severe or even lethal infections. For these patients, pulmonary delivery of antibiotics would be advantageous, since inhalation can achieve higher concentration in the lungs than iv administration and can provide a faster onset of action. This would allow for the delivery of higher doses and hence reduce the number of treatments required. We report here about a new nanosystem (M33-NS) obtained by capturing SET-M33 peptide on single-chain dextran nanoparticles. SET-M33 is a non-natural antimicrobial peptide synthesized in branched form. This form gives the peptide resistance to degradation in biological fluids. SET-M33 has previously shown efficacy in vitro against about one hundred of Gram-negative multidrug and extensively drug-resistant clinical isolates and was also active in preclinical infection models of pneumonia, sepsis and skin infections.

Methods: The new nanosystem was evaluated for its efficacy in bacteria cells and in a mouse model of pneumonia. Toxicity and genotoxicity were also tested in vitro. Biodistribution and pharmacokinetic studies in healthy rats were carried out using a radiolabeled derivative of the nanosystem.

Results: The M33-nanosystem, studied here, showed to be effective against in time-kill kinetic experiments. Cytotoxicity towards different animal cell lines was acceptable. Lung residence time of the antimicrobial peptide, administered via aerosol in healthy rats, was markedly improved by capturing SET-M33 on dextran nanoparticles. M33-NS was also efficient in eradicating pulmonary infection in a BALB/c mouse model of pneumonia caused by

Discussion: This study revealed that the encapsulation of the antimicrobial peptide in dextran nanoparticles markedly improved lung residence time of the peptide administered via aerosol. The result has to be considered among the aims of the development of a new therapeutic option for patients suffering recurrent infections, that will benefit from high local doses of persistent antimicrobials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJN.S218966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034994PMC
June 2020

Cyclophilin A/EMMPRIN Axis Is Involved in Pro-Fibrotic Processes Associated with Thoracic Aortic Aneurysm of Marfan Syndrome Patients.

Cells 2020 01 8;9(1). Epub 2020 Jan 8.

Unità di Medicina Rigenerativa e Biologia Vascolare, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy.

Background: Marfan syndrome (MFS) is a genetic disease, characterized by thoracic aortic aneurysm (TAA), which treatment is to date purely surgical. Understanding of novel molecular targets is mandatory to unveil effective pharmacological approaches. Cyclophilin A (CyPA) and its receptor EMMPRIN are associated with several cardiovascular diseases, including abdominal aortic aneurysm. Here, we envisioned the contribution of CyPA/EMMPRIN axis in MFS-related TAA.

Methods: We obtained thoracic aortic samples from healthy controls (HC) and MFS patients' aortas and then isolated vascular smooth muscle cells (VSMC) from the aortic wall.

Results: our findings revealed that MFS aortic tissue samples isolated from the dilated zone of aorta showed higher expression levels of EMMPRIN vs. MFS non-dilated aorta and HC. Interestingly, angiotensin II significantly stimulated CyPA secretion in MFS-derived VSMC (MFS-VSMC). CyPA treatment on MFS-VSMC led to increased levels of EMMPRIN and other MFS-associated pro-fibrotic mediators, such as TGF-β1 and collagen I. These molecules were downregulated by in vitro treatment with CyPA inhibitor MM284. Our results suggest that CyPA/EMMPRIN axis is involved in MFS-related TAA development, since EMMPRIN is upregulated in the dilated zone of MFS patients' TAA and the inhibition of its ligand, CyPA, downregulated EMMPRIN and MFS-related markers in MFS-VSMC.

Conclusions: these insights suggest both a novel detrimental role for CyPA/EMMPRIN axis and its inhibition as a potential therapeutic strategy for MFS-related TAA treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9010154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016677PMC
January 2020

An antimicrobial molecule mitigates signs of sepsis in vivo and eradicates infections from lung tissue.

FASEB J 2020 01 20;34(1):192-207. Epub 2019 Nov 20.

Department of Medical Biotechnology, University of Siena, Siena, Italy.

The peptide sequence KKIRVRLSA was synthesized in a dimeric structure (SET-M33DIM) and evaluated as a candidate drug for infections due to multidrug-resistant (MDR) Gram-negative pathogens. SET-M33DIM showed significant antibacterial activity against MDR strains of Klebsiella pneumoniae, Acinetobacter baumannii, and Escherichia coli (Minimal Inhibitory Concentration [MICs], 1.5-11 µM), and less activity against Pseudomonas aeruginosa (MICs, 11-22 µM). It showed very low toxicity in vitro, ex vivo, and in vivo; in cytotoxicity tests, its EC was as much as 22 times better than that of SET-M33, a peptide with the same amino-acid sequence, but synthesized in tetra-branched form (638 vs 28 µM). In in vivo and ex vivo experiments, SET-M33DIM cleared P. aeruginosa infection, significantly reducing signs of sepsis in animals, and restoring cell viability in lung tissue after bacterial challenge. It also quelled inflammation triggered by LPS and live bacterial cells, inhibiting expression of inflammatory mediators in lung tissue, cultured macrophages, and bronchial cells from a cystic fibrosis patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201901896RRDOI Listing
January 2020

NMR Study of the Secondary Structure and Biopharmaceutical Formulation of an Active Branched Antimicrobial Peptide.

Molecules 2019 Nov 25;24(23). Epub 2019 Nov 25.

Department of Medical Biotechnology, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

The synthetic antimicrobial peptide SET-M33 is being developed as a possible new antibacterial candidate for the treatment of multi-drug resistant bacteria. SET-M33 is a branched peptide featuring higher resistance and bioavailability than its linear analogues. SET-M33 shows antimicrobial activity against different species of multi-resistant Gram-negative bacteria, including clinically isolated strains of , , and . The secondary structure of this 40 amino acid peptide was investigated by NMR to fully characterize the product in the framework of preclinical studies. The possible presence of helixes or β-sheets in the structure had to be explored to predict the behavior of the branched peptide in solution, with a view to designing a formulation for parenteral administration. Since the final formulation of SET-M33 will be strictly defined in terms of counter-ions and additives, we also report the studies on a new salt form, SET-M33 chloride, that retains its activity against Gram-negative bacteria and gains in solubility, with a possible improvement in the pharmacokinetic profile. The opportunity of using a chloride counter-ion is very convenient from a process development point of view and did not increase the toxicity of the antimicrobial drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules24234290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930567PMC
November 2019

European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants.

Orphanet J Rare Dis 2019 11 21;14(1):264. Epub 2019 Nov 21.

VASCERN HTAD European Reference Centre, Ghent, Belgium.

The ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2-related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits.Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2.The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2-related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-019-1186-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868850PMC
November 2019

In vitro inhalation cytotoxicity testing of therapeutic nanosystems for pulmonary infection.

Toxicol In Vitro 2020 Mar 6;63:104714. Epub 2019 Nov 6.

Preclinical Pharmacology and In-vitro Toxicology, Fraunhofer ITEM, Hannover, Germany.

Due to the increasing need of new treatment options against bacterial lung infections, novel antimicrobial peptides (AMPs) are under development. Local bioavailability and less systemic exposure lead to the inhalation route of administration. Combining AMPs with nanocarriers (NCs) into nanosystems (NSs) might be a technique for improved results. An air-liquid interface (ALI) in vitro inhalation model was set up including a human alveolar lung cell line (A549) and an optimized exposure system (P.R.I.T.® ExpoCube®) to predict acute local lung toxicity. The approach including aerosol controls (cupper-II-sulfate and lactose) delivered lowest observable adverse effect levels (LOAELs). Different combinations of AMPs (AA139, M33) and NCs (polymeric nanoparticles (PNPs), micelles and liposomes) were tested under ALI and submerged in vitro conditions. Depending on the nature of AMP and NCs, packing of AMPs into NSs reduced the AMP-related toxicity. Large differences were found between the LOAELs determined by submerged or ALI testing with the ALI approach indicating higher sensitivity of the ALI model. Since aerosol droplet exposure is in vivo relevant, it is assumed that ALI based results represents the more significant source than submerged testing for in vivo prediction of local acute lung toxicity. In accordance with the current state-of-the-art view, this study shows that ALI in vitro inhalation models are promising tools to further develop in vitro methods in the field of inhalation toxicology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tiv.2019.104714DOI Listing
March 2020

Unraveling Heparan Sulfate Proteoglycan Binding Motif for Cancer Cell Selectivity.

Front Oncol 2019 18;9:843. Epub 2019 Sep 18.

Department of Medical Biotechnologies, University of Siena, Siena, Italy.

Membrane heparan sulfate proteoglycans (HSPG) regulate cell proliferation, migration, and differentiation and are therefore considered key players in cancer cell development processes. Here, we used the NT4 peptide to investigate how the sulfation pattern of HSPG on cells drives binding specificity. NT4 is a branched peptide that binds the glycosaminoglycan (GAG) chains of HSPG. It has already been shown to inhibit growth factor-induced migration and invasiveness of cancer cells, implying antagonist binding of HSPG. The binding affinity of NT4 with recombinant HSPG showed that NT4 bound glypican-3 and -4 and, with lower affinity, syndecan-4. NT4 binding to the cancer cell membrane was inversely correlated with sulfatase expression. NT4 binding was higher in cell lines with lower expression of SULF-1 and SULF-2, which confirms the determinant role of sulfate groups for recognition by NT4. Using 8-mer and 9-mer heparan sulfate (HS) oligosaccharides with analog disaccharide composition and different sulfation sites, a possible recognition motif was identified that includes repeated 6-O-sulfates alternating with N- and/or 2-O-sulfates. Molecular modeling provided a fully descriptive picture of binding architecture, showing that sulfate groups on opposite sides of the oligosaccharide can interact with positive residues on two peptide sequences of the branched structure, thus favoring multivalent binding and explaining the high affinity and selectivity of NT4 for highly sulfated GAGs. NT4 and possibly newly selected branched peptides will be essential probes for reconstructing and unraveling binding sites for cancer-involved ligands on GAGs and will pave the way for new cancer detection and treatment options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.00843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759624PMC
September 2019

NGS analysis in Marfan syndrome spectrum: Combination of rare and common genetic variants to improve genotype-phenotype correlation analysis.

PLoS One 2019 19;14(9):e0222506. Epub 2019 Sep 19.

Istituto Auxologico Italiano IRCCS, Molecular Biology Laboratory, Cusano Milanino, Milano, Italy.

The diagnosis of Marfan spectrum includes a large number of clinical criteria. Although the identification of pathogenic variants contributes to the diagnostic process, its value to the prediction of clinical outcomes is still limited. An important novelty of the present study is represented by the statistical approach adopted to investigate genotype-phenotype correlation. The analysis has been improved considering the extended genetic information obtained by Next Generation Sequencing (NGS) and combining the effects of both rare and common genetic variants in an inclusive model. To this aim a cohort of 181 patients were analyzed with a NGS panel including 11 genes associated with Marfan spectrum. The genotype-phenotype correlation was also investigated considering the possibility to predict presence of a pathological mutation in Marfan syndrome (MFS) main genes based only on the analysis of phenotypic traits. Results obtained indicate that information about clinical traits can be summarized in a new variable that resulted significantly associated with the probability to find a pathological mutation in MFS main genes. This is important since the choice of the genetic test is often influenced by the phenotypic characterization of patients. Moreover, both rare and common variants were found to significantly contribute to clinical spectrum and their combination allowed to increase the percentage of phenotype variability that could be explained based on genetic factors. Results highlight the opportunity to take advantage of the overall genetic information obtained by NGS data to have a better clinical classification of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222506PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752800PMC
March 2020

β3-adrenoreceptor blockade reduces tumor growth and increases neuronal differentiation in neuroblastoma via SK2/S1P modulation.

Oncogene 2020 01 2;39(2):368-384. Epub 2019 Sep 2.

Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.

Neuroblastoma (NB) is the most frequently observed among extracranial pediatric solid tumors. It displays an extreme clinical heterogeneity, in particular for the presentation at diagnosis and response to treatment, often depending on cancer cell differentiation/stemness. The frequent presence of elevated hematic and urinary levels of catecholamines in patients affected by NB suggests that the dissection of adrenergic system is crucial for a better understanding of this cancer. β3-adrenoreceptor (β3-AR) is the last identified member of adrenergic receptors, involved in different tumor conditions, such as melanoma. Multiple studies have shown that the dysregulation of the bioactive lipid sphingosine 1-phosphate (S1P) metabolism and signaling is involved in many pathological diseases including cancer. However, whether S1P is crucial for NB progression and aggressiveness is still under investigation. Here we provide experimental evidence that β3-AR is expressed in NB, both human specimens and cell lines, where it is critically involved in the activation of proliferation and the regulation between stemness/differentiation, via its functional cross-talk with sphingosine kinase 2 (SK2)/S1P receptor 2 (S1P) axis. The specific antagonism of β3-AR by SR59230A inhibits NB growth and tumor progression, by switching from stemness to cell differentiation both in vivo and in vitro through the specific blockade of SK2/S1P signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-019-0993-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949192PMC
January 2020

Antimicrobial activity of two novel antimicrobial peptides AA139 and SET-M33 against clinically and genotypically diverse Klebsiella pneumoniae isolates with differing antibiotic resistance profiles.

Int J Antimicrob Agents 2019 Aug 5;54(2):159-166. Epub 2019 Jun 5.

Department of Medical Microbiology and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address:

Colistin is an antimicrobial peptide (AMP) used as a drug of last resort, although plasmid-mediated colistin resistance (MCR) has been reported. AA139 and SET-M33 are novel AMPs currently in development for the treatment of multidrug-resistant (MDR) Gram-negative bacterial infections. As many AMPs have a similar mode of action to colistin, potentially leading to cross-resistance, the antimicrobial activity of AA139 and SET-M33 was investigated against a collection of 50 clinically and genotypically diverse Klebsiella pneumoniae isolates with differing antibiotic resistance profiles, including colistin-resistant strains. The collection was genotypically characterised and susceptibility to clinically relevant antibiotics was determined. Susceptibility to AA139 and SET-M33 did not differ among the collection despite differences in underlying mechanisms of resistance or susceptibility to colistin. For three colistin-susceptible and three colistin-resistant strains with distinct MDR profiles as well as an additional MCR-producing strain, the bactericidal activity of AA139, SET-M33 and colistin during 24 h of exposure was examined. Following 24 h of exposure to AA139, SET-M33 or colistin, the seven strains were tested for changes in susceptibility to the respective AMPs. AA139 and SET-M33 showed a concentration-dependent bactericidal effect irrespective of bacterial susceptibility to colistin. Exposure to low colistin concentrations resulted in the development of colistin resistance in colistin-susceptible strains, whereas susceptibility to AA139 and SET-M33 following exposure to the respective AMPs was maintained. The two novel AMPs remained effective against colistin-resistant strains and may be promising novel drugs for the treatment of clinically and genotypically diverse MDR K. pneumoniae infections, including infections associated with colistin-resistant bacteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijantimicag.2019.05.019DOI Listing
August 2019

Effects of PARP-1 Deficiency and Histamine H Receptor Inhibition in an Inflammatory Model of Lung Fibrosis in Mice.

Front Pharmacol 2019 16;10:525. Epub 2019 May 16.

Section of Pharmacology, Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.

Pulmonary fibrosis is the most frequent form of interstitial lung disease. Effective therapies are not yet available; novel therapeutic approaches are needed for counteracting fibrosis. Poly(ADP-ribose) polymerases are enzymes, involved in DNA repair and cell apoptosis. PARP-1 deficient mice exhibited reduced lung fibrosis in response to bleomycin treatment compared to wild-type controls. Histamine H receptors (HRs) have been recognized as a new target for inflammatory and immune diseases, and HR ligands reduced inflammation and oxidative stress in lung tissue. The aim of the study was to evaluate the cross-talk between PARP-1 and HR in a model of bleomycin-induced lung fibrosis in PARP-1 and WT mice. Animals were treated with bleomycin or saline by intra-tracheal injection. JNJ7777120, an HR antagonist, or VUF8430, an HR agonist, were administered i.p for 21 days. Airway resistance to inflation was evaluated, and lung tissues were processed for PARylated protein content, oxidative stress evaluation, and histology of small bronchi. The levels of pro-inflammatory (IL-1β and TNF-α), regulatory (IL-10), and pro-fibrotic (TGF-β) cytokines were evaluated. The deposition of αSMA was determined by immunofluorescence analysis. The results indicate that JNJ7777120 reduces PARylated protein production, decreases oxidative stress damage, and MPO, a marker for leukocyte tissue infiltration, in PARP-1 mice. A significant decrease in the production of both IL-1β and TNF-α and a significant increase in IL-10 levels are observed in mice treated with HR antagonist, suggesting a crucial anti-inflammatory activity of JNJ7777120. The smooth muscle layer thickness, the goblet cell relative number, and collagen deposition decreased following JNJ7777120 administration. The HR antagonist treatment also reduces TGF-β production and αSMA deposition, suggesting an important role of JNJ7777120 in airway remodeling. Our results show that PARylation is essential for the pathogenesis of pulmonary fibrosis and propose that PARP-1 and HRs are both involved in inflammatory and fibrotic responses. JNJ7777120 treatment, in a condition of PARP-1 inhibition, exerts anti-inflammatory and anti-fibrotic effects, reducing airway remodeling and bronchoconstriction. Therefore, selective inhibition of HRs together with non-toxic doses of selective PARP-1 inhibitors could have clinical relevance for the treatment of idiopathic pulmonary fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2019.00525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535496PMC
May 2019

Soluble EMMPRIN levels discriminate aortic ectasia in Marfan syndrome patients.

Theranostics 2019 12;9(8):2224-2234. Epub 2019 Apr 12.

Vascular Biology and Regenerative Medicine Unit, Centro Cardiologico Monzino IRCCS, Milan, Italy.

Marfan syndrome (MFS) is a rare genetic disease characterized by a matrix metalloproteases (MMPs) dysregulation that leads to extracellular matrix degradation. Consequently, MFS patients are prone to develop progressive thoracic aortic enlargement and detrimental aneurysm. Since MMPs are activated by the extracellular MMP inducer (EMMPRIN) protein, we determined whether its plasmatic soluble form (sEMMPRIN) may be considered a marker of thoracic aortic ectasia (AE). : We compared plasma sEMMPRIN levels of 42 adult Caucasian MFS patients not previously subjected to aortic surgery with those of matched healthy controls (HC) by ELISA. In the MFS cohort we prospectively evaluated the relationship between plasma sEMMPRIN levels and the main MFS-related manifestations. : MFS patients had lower plasma sEMMPRIN levels (mean±SD: 2071±637 pg/ml) than HC (2441±642 pg/ml, =0.009). Amongst all considered MFS-related clinical features, we found that only aortic root dilatation associated with circulating sEMMPRIN levels. Specifically, plasma sEMMPRIN levels negatively correlated with aortic Z-score (r=-0.431, =0.004), and were significantly lower in patients with AE (Z-score≥2, 1788±510 pg/ml) compared to those without AE (Z-score<2, 2355±634 pg/ml; =0.003). ROC curve analysis revealed that plasma sEMMPRIN levels discriminated patients with AE (AUC [95%CI]: 0.763 [0.610-0.916], =0.003) with 85.7% sensitivity, 76.2% specificity, and 81% accuracy. We defined plasma sEMMPRIN levels ≤2246 pg/ml as the best threshold discriminating the presence of AE in MFS patients with an odds ratio [95%CI] of 19.2 [3.947-93.389] (<0.001). : MFS patients are characterized by lower sEMMPRIN levels than HC. Notably, plasma sEMMPRIN levels are strongly associated with thoracic AE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.30714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531292PMC
June 2020

Effect of Bilastine on Diabetic Nephropathy in DBA2/J Mice.

Int J Mol Sci 2019 May 24;20(10). Epub 2019 May 24.

Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy.

Diabetic nephropathy is an unmet therapeutic need, and the search for new therapeutic strategies is warranted. Previous data point to histamine H receptor as a possible target for glomerular dysfunction associated with long term hyperglycaemia. Therefore, this study investigated the effects of the H receptor antagonist bilastine on renal morphology and function in a murine model of streptozotocin-induced diabetes. Diabetes was induced in DBA2/J male mice and, from diabetes onset (glycaemia ≥200 mg/dL), mice received bilastine (1-30 mg/kg/day) by oral gavage for 14 consecutive weeks. At the end of the experimental protocol, diabetic mice showed polyuria (+195.5%), increase in Albumin-to-Creatine Ratio (ACR, +284.7%), and a significant drop in creatinine clearance ( < 0.05). Bilastine prevented ACR increase and restored creatinine clearance in a dose-dependent manner, suggesting a positive effect on glomerular filtration. The ultrastructural analysis showed a preserved junctional integrity. Preservation of the basal nephrin, P-cadherin, and synaptopodin expression could explain this effect. In conclusion, the H receptor could contribute to the glomerular damage occurring in diabetic nephropathy. Bilastine preserved the glomerular junctional integrity, leading to the hypothesis of anti-H antihistamines as a possible add-on therapy for diabetic nephropathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20102554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566437PMC
May 2019