27 research outputs found
Sphingosine-1-Phosphate Shapes Healthy Monocytes into An Immunosuppressive Phenotype
No full textBackground/Aims: The physiological phenotype of individuals can influence and shape reallife phenomena in that it can contribute to the development of specific characteristics that can affect the immune response to specific stimuli. In this study we aimed to understand whether the sphingosine/sphingosine-1-phoshate (S1P) axis can modulate the immunotype of circulating cells. Methods: To pursue this goal, we performed bioinformatic analyses of public datasets. Results: The transcriptomic profile of healthy subjects of GSE192829 dataset identified two clusters with different transcriptional repertoire. Cluster 1 expressed higher levels of enzymes for S1P formation than cluster 0 which was characterized by enzymes that lead to ceramide formation, which represent the opposite metabolic direction. Inference analysis showed that cluster 1 was higher populated by monocytes, CD4 + T and B cells than cluster 0. Of particular interest was the phenotype of the monocytes in cluster 1 which showed an immunosuppressive nature compared to those in cluster 0. The role of S1P signature in healthy PBMCs was confirmed with other dataset analyses, supporting that circulating monocytes positive to the ceramidase, unlike the negative ones, had an immunosuppressive phenotype characterized by hub immunosuppressive markers (i.e. TYROBP, FCER1G, SYK, SIRPA, CSF1R, AIF1, FCGR2A, CLEC7A, LYN, PLCG2, LILRs, HCK, GAB2). This hub genes well discriminated the immunotype of healthy subjects. Conclusion: In conclusion this study highlights that S1P-associated hub markers can be useful to discriminate subjects with pronounced immunosuppression. (c) 2024 The Author(s). Published by Cell Physiol Biochem Press GmbH&Co. K
INFRARED EMISSION SPECTRUM OF DBO
No full textY. Kawashima et al., J. Molec. Spectrosc. \textbf{133}, 116-127 (1989) and {44th Symp. Molec. Spectrosc}., Columbus, (1989). P. Colarusso et al Sympos. on Molec. Spectrosc. Columbus, (1996).Author Institution: Department of Chemistry, University of Waterloo; Department of Chemical Technology, Kanagawa Institute of Technology; Department of Chemical Technology, The Graduate University for Advanced StudiesWe generated the transient molecule DBO by reading deuterium with the parent molecule, HBO. at temperatures above in a ceramic tube furnace. In fared emission spectra were recorded with a Fourier transform spectrometer at a resolution of from 350 to 3600 . We observed the three fundamental vibrational bands as well as various hot and combination bands. A strong Coriolis interaction was detected between the and energy levels. The high-resolution infrared data for DBO will be combined with previous to yield a thorough analysis of the ground electronic state
Identification of 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based small molecules as selective BRD9 binders
No full text: Targeting bromodomain-containing protein 9 (BRD9) represents a promising strategy for the development of new agents endowed with anticancer properties. With this aim, a set of 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based compounds was investigated following a combined approach that relied on in silico studies, chemical synthesis, biophysical and biological evaluation of the most promising items. The protocol was initially based on molecular docking experiments, accounting a library of 1896 potentially synthesizable items tested in silico against the bromodomain of BRD9. A first set of 21 compounds (1-21) was selected and the binding on BDR9 was assessed through AlphaScreen assays. The obtained results disclosed compounds 17 and 20 able to bind BRD9 in the submicromolar range (IC50 = 0.35 ± 0.18 μM and IC50 = 0.14 ± 0.03 μM, respectively) showing a promising selectivity profile when tested against further nine bromodomains. Taking advantage of 3D structure-based pharmacophore models, additional 10 derivatives were selected in silico for the synthetic step and binding assessment, highlighting seven compounds (22, 23, 25, 26, 28, 29, 31) able to selectively bind BRD9 among different bromodomains. The ability of the identified BRD9 binders to cross artificial membranes in vitro was also assessed, revealing a very good passive permeability profile. Preliminary studies were carried out on a panel of healthy and cancer human cell lines to explore the biological behavior of the selected compounds, disclosing a moderate activity and significant selectivity profile towards leukaemia cells. These results highlighted the applicability of the reported multidisciplinary approach for accelerating the selection of promising items and for driving the chemical synthesis of novel selective BRD9 binders. Moreover, the low molecular weight of the reported 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based BRD9 binders suggests the possibility for further exploring the chemical space in order to obtain new analogues with improved potency
2-Substituted 1,5-benzothiazepine-based HDAC inhibitors exert anticancer activities on human solid and acute myeloid leukemia cell lines
No full text: Herein, we report the development of a new series of histone deacetylase inhibitors (HDACi) containing a 2-substituted 1,5-benzothiazepine scaffold. First, a virtual combinatorial library (∼1.6 × 103 items) was built according to a convenient synthetic route, and then it was submitted to molecular docking experiments on seven HDACs isoforms belonging to classes I and II. Integrated computational filters were used to select the most promising ones that were synthesized through an optimized approach, also amenable to generating both racemic and enantioenriched benzothiazepine-based derivatives. The obtained compounds showed potent HDAC inhibitory activity, especially those containing the sulphone moiety, endowed with IC50 in the nanomolar range. In addition, in vitro outcomes of our synthesized compounds demonstrated a cytotoxic effect on U937 and HCT116 cell lines and an arrest in the G2/M phase (13 ≤ IC50 ≤ 18 μM). Finally, Western blot analyses outlined the modulation of the histone acetyl markers such as H3K9/14, acetyl-tubulin, and the apoptotic indicator p21 in both cancer cell lines, disclosing a good HDAC inhibitor activity exerted by the designed items. Given the key role of HDACs in many cellular pathways, which makes these enzymes appealing and "hot" drug targets, our findings highlighted the importance of these 2-substituted 1,5-benzothiazepine-based compounds (both in the reduced and oxidized version) for the development of novel epidrugs
Short-term Cardio-Vascular Risk Score Changes in Type 2 Diabetic Patients on Empaglifozin: A Real-Life Clinical Experience
No full textIs the inflammasome at the crosstalk between COPD and lung cancer?
No full text2018 - 2019Background. Chronic obstructive pulmonary disease (COPD) is considered as a risk factor for lung cancer establishment. Epidemiological evidence indicate that patients with COPD have a 6.35-fold higher risk to develop lung cancer compared to the normal population.
Aim. Based on the notion that chronic inflammation is common to both COPD and lung cancer and that in our laboratory we found that the inflammasome is involved in lung carcinogenesis, we focused our attention on this multimeric complex, which role in both pathologies still counts many controversies in literature.
Therefore, the main goal of this PhD project was to evaluate whether the inflammasome was at the crosstalk between COPD and lung cancer. In particular, we focused our attention on air pollution and smoking as inflammasome inducers.
1st year results. The exposure of peripheral blood mononuclear cells (PBMCs) isolated from smokers to ultrafine particles (UFPs), which mimic small size air pollutants, led to an inflammatory process that was responsible for IL-1-like cytokines release and was associated to the activation of the canonical, caspase-1-dependent, NLRP3 inflammasome. This effect was not observed in non-smoker subjects, who instead released higher levels immunesuppressive IL-10 (Chapter 1). Instead, UFPs induced the release of IL-18 and IL-33 from exacerbated COPD-derived circulating cells in a NLRP3-/caspase-1- and caspase-8-independent manner (Chapter 2)... [edited by Author]Background. La broncopneumopatia cronica ostruttiva (BPCO) è considerata un fattore di rischio per l'insorgenza del carcinoma polmonare. Evidenze epidemiologiche indicano che i pazienti con BPCO hanno un rischio 6.35 volte maggiore di sviluppare il cancro ai polmoni rispetto alla popolazione normale.
Scopo. Basandoci sul concetto che l'infiammazione cronica è comune sia alla BPCO che al cancro del polmone e che nel nostro laboratorio abbiamo scoperto che l'inflammosoma è coinvolto nella carcinogenesi polmonare, abbiamo concentrato la nostra attenzione su questo complesso multimerico, il cui ruolo in entrambe le patologie conta ancora molte controversie in letteratura.
Pertanto, l'obiettivo principale di questo progetto di Dottorato di Ricerca era valutare se l'inflammosoma fosse al crosstalk tra BPCO e tumore al polmone. In particolare, abbiamo focalizzato la nostra attenzione sull'inquinamento ambientale e sul fumo come induttori dell’inflammosoma.
Risultati del I anno. L'esposizione delle cellule mononucleate del sangue periferico (PBMC) isolate dai fumatori alle particelle ultrafini (UFP), che mimano gli inquinanti ambientali di piccole dimensioni, ha portato a un processo infiammatorio responsabile del rilascio di citochine della famiglia IL-1 ed è stato associato all'attivazione canonica, dipendente dalla caspasi-1, dell'inflammosoma NLRP3. Questo effetto non è stato osservato nei soggetti non fumatori, che invece hanno rilasciato livelli più elevati di IL-10 immunosoppressiva (Capitolo 1). Invece, le UFP hanno indotto il rilascio di IL-18 e IL-33 dalle cellule circolanti isolate da pazienti con BPCO esacerbata in modo indipendente da NLRP3-/caspase-1 e caspase-8 (Capitolo 2)... [a cura dell'Autore]XXXII cicl
Lipohypertrophy in Elderly Insulin-Treated Patients With Type 2 Diabetes
No full textBackground: The number of older adults with insulin-treated diabetes mellitus (DM) is steadily increasing worldwide. Errors in the insulin injection technique can lead to skin lipohypertrophy (LH), which is the accumulation of fat cells and fibrin in the subcutaneous tissue. While lipohypertrophic lesions/nodules (LHs) due to incorrect insulin injection techniques are very common, they are often flat and hardly visible and thus require thorough deep palpation examination and ultrasonography (US) for detection. Detection is crucial because such lesions may eventually result in poor diabetes control due to their association with unpredictable insulin release patterns. Skin undergoes fundamental structural changes with aging, possibly increasing the risk for LH. We have therefore investigated the effect of age on the prevalence of LHs and on factors potentially associated with such lesions. Methods: A total of 1227 insulin-treated outpatients with type 2 DM (T2DM) referred to our diabetes centers were consecutively enrolled in the study. These patients underwent a thorough clinical and US evaluation of the skin at injection sites, as previously described, with up to 95% concordance betweenthe clinical and US screening techniques. Of these 1227 patients, 718 (59%) had LH (LH+) and 509 (41%) were LH-free (LH−). These patients were then assigned to two age class groups (≤ 65 years and > 65 years), and several clinical features, diabetes complication rates, and injection habits were investigated. Results: Comparison of the two age subgroups revealed that 396 (48%) and 322 (79%) patients in the younger and older groups, respectively, had LHs (p < 0.001). Compared to the younger subgroup, the older subgroup displayed a higher LH rate in the abdomen (52.9 vs. 38.3%; p < 0.01) and a lower rate in the arms (25.4 vs. 35.8%; p < 0.05), thighs (26.7 vs. 33.4%; p < 0.05), and buttocks (4.9 vs. 26.2%; p < 0.01). In older subjects, the most relevant parameters were: habit of injecting insulin into LH nodules (56 vs. 47% [younger subjects]; p < 0.01), rate of post-injection leakage of insulin from injection site (drop-leaking rate; 47 vs. 39% [younger subjects]; p < 0.05), and rate of painful injections (5 vs. 16% [younger subjects]; p < 0.001). Multivariate analysis showed a stronger association between LH and poor habits, as well as between several clinical parameters, among which the most relevant were hypoglycemic events and glycemic variability. Discussion: The higher rate of post-injection drop-leaking and pain-free injections might find an explanation in skin changes typically observed in older adults, including lower thickness, vascularity and elasticity, and a more prominent fibrous texture, all of which negatively affect tissue distensibility. Consequently, in addition to the well-known association between aging skin impaired drug absorption rate, aging skin displays a progressively decreasing ability to accommodate large volumes of insulin-containing fluid. Conclusions: The strong association between LH rate and hypoglycemic events plus glycemic variability suggests the need (1) to take specific actions to prevent and control the high risk of acute cardiovascular events expected to occur in older subjects in the case of hypoglycemic events, and (2) to identify suitable strategies to fulfill the difficult task of performing effective educational programs specifically targeted to the elderly. Trial Registration: Trial registration number 172–11:12.2019, Scientific and Ethical Committee of Campania University “Luigi Vanvitelli”, Naples, Italy)
HIGH RESOLUTION INFRARED EMISSION SPECTROSCOPY OF DICHLOROBORANE
No full textAuthor Institution: Department of Chemistry, University of WaterlooThe absorption spectrum of dichloroborane was accidentally recorded during Fourier transform emission measurements of HBO. Gaseous dichloroborane was generated by the reaction of amorphous boron powder with at 1400 C. The bands centred near 2617, 1089 and were assigned as the (B-H stretch), the (HBCl bend), and the antisymmetric stretch) fundamental modes, respectively. Modular constants were determined from rotational analyses of these bands. This is a first analysis of the rotational structure of the and modes
Multiple ovarian cysts in a young girl with severe hypothyroidism.
No full textCase study of a young female patient with severe hypothyroidism due to autoimmune thyroiditis and multiple ovarian cysts is reported. A 14-year 7-month-old girl presented with pelvic and abdominal pain and severe asthenia. Her last menstrual period was 10 months before presentation. Physical examination showed obesity; apathetic and flat expression; periorbital puffiness; pale, cold, dry skin and slow sustained reflexes; swelling in the hands and feet; no galactorrhea; a hardly palpable thyroid gland; and ovaries with a palpable irregular surface. Her heart rate was 90 bpm with a blood pressure within the normal range (110/70 mmHg). Laboratory findings showed severe hypothyroidism (thyroid-stimulating hormone [TSH]: 960 mIU/L), gravis macrocytic anemia, hyperfibrinogenemia, and hyperprolactinemia. Imaging examinations revealed a normal-size thyroid with irregular echogenicity, strongly hypoechogenous area at the neck ultrasonography, bilateral multilocular ovarian masses with cystic components at pelvic ultrasound and computed tomography, and both anterior and posterior pericardial effusion at echocardiography. As soon as thyroid replacement therapy was initiated, all symptoms progressively disappeared and biochemical and hormonal values normalized, while the right ovary did not decrease in size during the follow-up period. For this reason, our patient underwent right ovarian wedge resection 14 months after the initiation of medication replacement. Ovarian histological examination showed a benign ovarian cyst with extensive hemorrhage and myxedematous infiltration. It is concluded that it is important to recognize early in young girls the association between large multiple ovarian cysts and high elevated levels of TSH in order to resolve this disorder with substitutive therapy
HIGH-RESOLUTION INFRARED SPECTROSCOPY OF SrF
No full textAuthor Institution: Department of Chemistry, University of Waterloo Centre for Molecular Beams and Laser ChemistryThe infrared spectrum of gaseous SrF was recorded using a Bruker Fourier transform spectrometer. The thermal emission spectrum of SrF was obtained at with Si;B detector at a resolution of . Vibrational-rotational bands of the ground state were observed in the region between . A rotational analysis of the spectrum will be presented
