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1.
Bioorg Chem ; 151: 107663, 2024 Oct.
Article de Anglais | MEDLINE | ID: mdl-39088977

RÉSUMÉ

Intersite communication in dimeric enzymes, triggered by ligand binding, represents both a challenge and an opportunity in enzyme inhibition strategy. Though often understestimated, it can impact on the in vivo biological mechansim of an inhibitor and on its pharmacokinetics. Thymidylate synthase (TS) is a homodimeric enzyme present in almost all living organisms that plays a crucial role in DNA synthesis and cell replication. While its inhibition is a valid strategy in the therapy of several human cancers, designing specific inhibitors of bacterial TSs poses a challenge to the development of new anti-infective agents. N,O-didansyl-l-tyrosine (DDT) inhibits both Escherichia coli TS (EcTS) and Lactobacillus casei TS (LcTS). The available X-ray structure of the DDT:dUMP:EcTS ternary complex indicated an unexpected binding mode for DDT to EcTS, involving a rearrangement of the protein and addressing the matter of communication between the two active sites of an enzyme dimer. Combining molecular-level information on DDT binding to EcTS and LcTS extracted from structural and FRET-based fluorometric evidence with a thermodynamic characterization of these events obtained by fluorometric and calorimetric titrations, this study unveiled a negative cooperativity between the DDT bindings to the two monomers of each enzyme dimer. This result, complemented by the species-specific thermodynamic signatures of the binding events, implied that communication across the protein dimer was triggered by the first DDT binding. These findings could challenge the conventional understanding of TS inhibition and open the way for the development of novel TS inhibitors with a different mechanism of action and enhanced efficacy and specificity.


Sujet(s)
Escherichia coli , Thermodynamique , Thymidylate synthase , Tyrosine , Sites de fixation , Relation dose-effet des médicaments , Antienzymes/composition chimique , Antienzymes/pharmacologie , Antienzymes/synthèse chimique , Escherichia coli/enzymologie , Lacticaseibacillus casei/enzymologie , Modèles moléculaires , Structure moléculaire , Relation structure-activité , Thymidylate synthase/métabolisme , Thymidylate synthase/antagonistes et inhibiteurs , Thymidylate synthase/composition chimique , Tyrosine/composition chimique , Tyrosine/métabolisme
3.
J Appl Microbiol ; 135(3)2024 Mar 01.
Article de Anglais | MEDLINE | ID: mdl-38520154

RÉSUMÉ

AIMS: Our study evaluates the capacity of direct real-time PCR for detecting Mycobacterium tuberculosis complex (MTBC), with a focus on diagnostic performances and the feasibility of implementing this protocol in an eradication campaign. Specifically, we compare the effectiveness of the direct PCR method to various culture systems used by the Italian National Reference Laboratory over the last decade to detect MTBC. METHODS AND RESULTS: Bovine tissue samples were routinely tested and analyzed for bovine tuberculosis (bTB) confirmation using microbiological culture (solid and liquid media), histopathological analysis, and a direct PCR assay targeting IS6110, an insertion sequence specific to the MTBC that is widely used for tuberculosis diagnosis. The direct real-time PCR demonstrated a high concordance (K = 0.871) with microbiological culture, as well as good sensitivity (91.84%) and specificity (95.24%). In contrast, histopathology demonstrated lower concordance (K = 0.746) and performance levels (sensitivity 91.41%, specificity 82.88%). Liquid media promoted faster and more efficient growth of MTBC than solid media. M. bovis and M. caprae had the comparable ability to respond to the direct real-time PCR test and grow on the microbiological medium. CONCLUSIONS: This study confirms that direct real-time PCR can detect MTBC with high diagnostic accuracy within a few days. This study found no significant differences in performance between culture media and direct PCR for M. bovis and M. caprae.


Sujet(s)
Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculose bovine , Tuberculose , Animaux , Bovins , Humains , Mycobacterium tuberculosis/génétique , Tuberculose/diagnostic , Tuberculose/médecine vétérinaire , Tuberculose/microbiologie , Tuberculose bovine/diagnostic , Réaction de polymérisation en chaine en temps réel/méthodes , Italie , Sensibilité et spécificité
4.
Fertil Steril ; 122(1): 106-113, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38342371

RÉSUMÉ

OBJECTIVE: To evaluate whether laser-mediated assisted hatching (AH) performed on vitrified/warmed blastocysts before embryo transfer can improve live birth rate. DESIGN: The "pArtiaL zonA pelluciDa removal by assisteD hatchINg of blastocysts (ALADDIN)" is a 2-center comparative study with a parallel randomized controlled design. SETTING: University hospital. PATIENTS: Participants were recruited between September 2018 and November 2021. They were aged 18-39 years, underwent nondonor in vitro fertilization cycles, and were scheduled for elective single embryo transfer with vitrified/warmed blastocysts. Those with uterine abnormalities, body mass index of >35 kg/m2, severe male factor infertility, or performing preimplantation genetic testing were excluded. INTERVENTION: Assisted hatching was performed using a 1,480 nm diode laser, removing approximately one-third of the zona pellucida with continuous 0.2 ms pulses applied from the 1-5 o'clock positions. MAIN OUTCOME MEASURES: The primary outcome was the live birth rate. Secondary end points included clinical pregnancy, miscarriage, multiple pregnancies, preterm births, obstetric and neonatal complications, and congenital anomalies. RESULTS: Overall, 698 participants met the inclusion criteria and were randomized: 352 patients were assigned to the AH arm and 346 to the control arm. Of the participants, 105 (29.8%) and 101 (29.2%), respectively, achieved a live birth after treatment. The relative risk of live birth in patients with vitrified/warmed blastocysts treated with AH was 1.02 (95% confidence interval, 0.86-1.19). Exploratory subgroup analyses for women's age, recruiting centers, indications for in vitro fertilization, method of insemination, blastocyst quality, and days of blastocyst development failed to highlight any clinical situation that could benefit from AH in thawed blastocysts. CONCLUSION: In patients undergoing frozen embryo transfer with vitrified/warmed blastocysts, laser AH does not improve the live birth rate. Further studies are required to rule out milder but potentially interesting benefits in specific subgroups of patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03623659.


Sujet(s)
Blastocyste , Naissance vivante , Taux de grossesse , Vitrification , Humains , Femelle , Adulte , Grossesse , Cryoconservation/méthodes , Zone pellucide , Jeune adulte , Fécondation in vitro/méthodes , Infertilité/thérapie , Infertilité/physiopathologie , Infertilité/diagnostic , Adolescent , Transfert d'embryon/méthodes , Transfert d'embryon/effets indésirables , Résultat thérapeutique , Techniques de culture d'embryons , Transfert d'embryon unique/méthodes , Transfert d'embryon unique/effets indésirables , Lasers , Mâle
6.
Eur J Med Chem ; 264: 115946, 2024 Jan 15.
Article de Anglais | MEDLINE | ID: mdl-38043491

RÉSUMÉ

Pteridine reductase 1 (PTR1) is a catalytic protein belonging to the folate metabolic pathway in Trypanosmatidic parasites. PTR1 is a known target for the medicinal chemistry development of antiparasitic agents against Trypanosomiasis and Leishmaniasis. In previous studies, new nitro derivatives were elaborated as PTR1 inhibitors. The compounds showing a diamino-pyrimidine core structure were previously developed but they showed limited efficacy. Therefore, a new class of phenyl-, heteroaryl- and benzyloxy-nitro derivatives based on the 2-nitroethyl-2,4,6-triaminopyrimidine scaffold were designed and tested. The compounds were assayed for their ability to inhibit T. brucei and L. major PTR1 enzymes and for their antiparasitic activity towards T. brucei and L. infantum parasites. To understand the structure-activity relationships of the compounds against TbPTR1, the X-ray crystallographic structure of the 2,4,6-triaminopyrimidine (TAP) was obtained and molecular modelling studies were performed. As a next step, only the most effective compounds against T. brucei were then tested against the amastigote cellular stage of T. cruzi, searching for a broad-spectrum antiprotozoal agent. An early ADME-Tox profile evaluation was performed. The early toxicity profile of this class of compounds was investigated by measuring their inhibition of hERG and five cytochrome P450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4), cytotoxicity towards A549 cells and mitochondrial toxicity. Pharmacokinetic studies (SNAP-PK) were performed on selected compounds using hydroxypropyl-ß-cyclodextrins (50 % w/v) to preliminarily study their plasma concentration when administered per os at a dose of 20 mg/kg. Compound 1p, showed the best pharmacodynamic and pharmacokinetic properties, can be considered a good candidate for further bioavailability and efficacy studies.


Sujet(s)
Antiprotozoaires , Maladie de Chagas , Trypanosoma brucei brucei , Trypanosoma cruzi , Humains , Relation structure-activité , Antiprotozoaires/composition chimique , Modèles moléculaires , Antiparasitaires/pharmacologie , Maladie de Chagas/traitement médicamenteux
7.
Int J Infect Dis ; 140: 17-24, 2024 Mar.
Article de Anglais | MEDLINE | ID: mdl-38157929

RÉSUMÉ

OBJECTIVES: To describe how SARS-CoV-2 infection at the time of delivery affected maternal and neonatal outcomes across four major waves of the COVID-19 pandemic in Italy. METHODS: This is a large, prospective, nationwide cohort study collecting maternal and neonatal data in case of maternal peripartum SARS-CoV-2 infection between February 2020 and March 2022. Data were stratified across the four observed pandemic waves. RESULTS: Among 5201 COVID-19-positive mothers, the risk of being symptomatic at delivery was significantly higher in the first and third waves (20.8-20.8%) than in the second and fourth (13.2-12.2%). Among their 5284 neonates, the risk of prematurity (gestational age <37 weeks) was significantly higher in the first and third waves (15.6-12.5%). The risk of intrauterine transmission was always very low, while the risk of postnatal transmission during rooming-in was higher and peaked at 4.5% during the fourth wave. A total of 80% of positive neonates were asymptomatic. CONCLUSION: The risk of adverse maternal and neonatal outcomes was significantly higher during the first and third waves, dominated by unsequenced variants and the Delta variant, respectively. Postnatal transmission accounted for most neonatal infections and was more frequent during the Omicron period. However, the paucity of symptoms in infected neonates should lead us not to separate the dyad.


Sujet(s)
COVID-19 , Néonatologie , Complications infectieuses de la grossesse , Nouveau-né , Femelle , Grossesse , Humains , Nourrisson , SARS-CoV-2 , COVID-19/épidémiologie , Pandémies , Études prospectives , Études de cohortes , Transmission verticale de maladie infectieuse , Italie/épidémiologie , Mères , Complications infectieuses de la grossesse/épidémiologie
8.
ACS Mater Au ; 3(5): 528-539, 2023 Sep 13.
Article de Anglais | MEDLINE | ID: mdl-38089092

RÉSUMÉ

Hybrid solid polymer electrolytes (HSPE) comprising poly(ethylene oxide) (PEO), LiTFSI, barium titanate (BaTiO3), and viologen are prepared by a facile hot press. The physical properties of the HSPE membranes are studied by using small-angle and wide-angle X-ray scattering, thermogravimetric analysis, differential scanning calorimetry, and tensile strength. The prepared hybrid solid polymer electrolytes are also investigated by means of ionic conductivity and transport number measurements. The employed analyses collectively reveal that each additive in the PEO host contributes to a specific property: LiTFSI is essential in providing ionic species, while BaTiO3 and viologen enhance the thermal stability, ionic conductivity, and transport number. The enhanced value in the Li+-transport number of HSPE are presumably attributed to the electrostatic attraction of TFSI anions and the positive charges of viologen. Synergistically, the added BaTiO3 and viologen improve the electrochemical properties of HSPE for the applications in all-solid-state-lithium polymer batteries.

9.
J Med Chem ; 66(22): 15230-15255, 2023 11 23.
Article de Anglais | MEDLINE | ID: mdl-37921561

RÉSUMÉ

Broad-spectrum anti-infective chemotherapy agents with activity against Trypanosomes, Leishmania, and Mycobacterium tuberculosis species were identified from a high-throughput phenotypic screening program of the 456 compounds belonging to the Ty-Box, an in-house industry database. Compound characterization using machine learning approaches enabled the identification and synthesis of 44 compounds with broad-spectrum antiparasitic activity and minimal toxicity against Trypanosoma brucei, Leishmania Infantum, and Trypanosoma cruzi. In vitro studies confirmed the predictive models identified in compound 40 which emerged as a new lead, featured by an innovative N-(5-pyrimidinyl)benzenesulfonamide scaffold and promising low micromolar activity against two parasites and low toxicity. Given the volume and complexity of data generated by the diverse high-throughput screening assays performed on the compounds of the Ty-Box library, the chemoinformatic and machine learning tools enabled the selection of compounds eligible for further evaluation of their biological and toxicological activities and aided in the decision-making process toward the design and optimization of the identified lead.


Sujet(s)
Leishmania infantum , Trypanosoma brucei brucei , Trypanosoma cruzi , Tests de criblage à haut débit , Antiparasitaires
10.
Pediatrics ; 152(5)2023 11 01.
Article de Anglais | MEDLINE | ID: mdl-37830167

RÉSUMÉ

OBJECTIVES: To evaluate the rate of postnatal infection during the first month of life in neonates born to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive mothers during the predominant circulation of the omicron (B.1.1.529) variant. METHODS: This prospective, 10-center study enrolled mothers infected by SARS-CoV-2 at delivery and their infants, if both were eligible for rooming-in, between December 2021 and March 2022. Neonates were screened for SARS-CoV-2 RNA at 1 day of life (DOL), 2 to 3 DOL, before discharge, and twice after hospital discharge. Mother-infant dyads were managed under a standardized protocol to minimize the risk of viral transmission. Sequencing data in the study area were obtained from the Italian Coronavirus Disease 2019 Genomic platform. Neonates were included in the final analysis if they were born when the omicron variant represented >90% of isolates. RESULTS: Eighty-two percent (302/366) of mothers had an asymptomatic SARS-CoV-2 infection. Among 368 neonates, 1 was considered infected in utero (0.3%), whereas the postnatal infection rate during virtually exclusive circulation of the omicron variant was 12.1%. Among neonates infected after birth, 48.6% became positive during the follow-up period. Most positive cases at follow-up were detected concurrently with the peak of coronavirus disease 2019 cases in Italy. Ninety-seven percent of the infected neonates were asymptomatic. CONCLUSIONS: The risk of early postnatal infection by the SARS-CoV-2 omicron variant is higher than that reported for previously circulating variants. However, protected rooming-in practice should still be encouraged given the paucity of symptoms in infected neonates.


Sujet(s)
COVID-19 , Complications infectieuses de la grossesse , Nourrisson , Nouveau-né , Femelle , Humains , Grossesse , Mères , Études prospectives , ARN viral , SARS-CoV-2/génétique , Complications infectieuses de la grossesse/diagnostic , Complications infectieuses de la grossesse/épidémiologie , Transmission verticale de maladie infectieuse
11.
Reprod Biomed Online ; 47(1): 77-83, 2023 07.
Article de Anglais | MEDLINE | ID: mdl-37150703

RÉSUMÉ

RESEARCH QUESTION: Can preconception adherence to a Mediterranean diet influence the rate of poor response to ovarian stimulation in IVF cycles? DESIGN: The impact of dietary habits on the success of IVF is controversial. Inconsistencies may be explained by confounders associated with the use of pregnancy as an outcome as well as by a reductionist view of diet that focuses on single components rather than on food patterns. This cross-sectional study analysed adherence to a Mediterranean diet in women with unexpected poor response to ovarian stimulation. Main inclusion criteria were: age 18-39 years, normal weight, preserved ovarian reserve and starting dose of gonadotrophins of 150-225 IU/day. Adherence to the Mediterranean diet was assessed through a Mediterranean diet score (MDS). Unexpected poor ovarian response was defined as the retrieval of ≤3 suitable oocytes. RESULTS: A total of 296 women were included, of whom 47 (15.9%) showed an unexpected poor response. A clear dose-related association with tertiles of MDS was not observed in the univariate analysis. However, in the multivariate analysis, the risk of unexpected poor response was significantly lower for women in the second tertile of MDS compared with the first tertile (adjusted odds ratio [OR] 0.29, 95% confidence interval [CI] 0.11-0.76) and for women in the second and third tertiles, grouped together, compared with the first tertile (adjusted OR 0.34, 95% CI 0.14-0.82). CONCLUSIONS: Low adherence to a Mediterranean diet could be a risk factor for unexpected poor ovarian response.


Sujet(s)
Régime méditerranéen , Fécondation in vitro , Grossesse , Femelle , Humains , Taux de grossesse , Études transversales , Induction d'ovulation
12.
Cancers (Basel) ; 15(2)2023 Jan 08.
Article de Anglais | MEDLINE | ID: mdl-36672361

RÉSUMÉ

Ovarian cancer is a highly lethal gynecological malignancy. Drug resistance rapidly occurs, and different therapeutic approaches are needed. So far, no biomarkers have been discovered to predict early response to therapies in the case of multi-treated ovarian cancer patients. The aim of our investigation was to identify a protein panel and the molecular pathways involved in chemotherapy response through a combination of studying proteomics and network enrichment analysis by considering a subset of samples from a clinical setting. Differential mass spectrometry studies were performed on 14 serum samples from patients with heavily pretreated platinum-resistant ovarian cancer who received the FOLFOX-4 regimen as a salvage therapy. The serum was analyzed at baseline time (T0) before FOLFOX-4 treatment, and before the second cycle of treatment (T1), with the aim of understanding if it was possible, after a first treatment cycle, to detect significant proteome changes that could be associated with patients responses to therapy. A total of 291 shared expressed proteins was identified and 12 proteins were finally selected between patients who attained partial response or no-response to chemotherapy when both response to therapy and time dependence (T0, T1) were considered in the statistical analysis. The protein panel included APOL1, GSN, GFI1, LCATL, MNA, LYVE1, ROR1, SHBG, SOD3, TEC, VPS18, and ZNF573. Using a bioinformatics network enrichment approach and metanalysis study, relationships between serum and cellular proteins were identified. An analysis of protein networks was conducted and identified at least three biological processes with functional and therapeutic significance in ovarian cancer, including lipoproteins metabolic process, structural component modulation in relation to cellular apoptosis and autophagy, and cellular oxidative stress response. Five proteins were almost independent from the network (LYVE1, ROR1, TEC, GFI1, and ZNF573). All proteins were associated with response to drug-resistant ovarian cancer resistant and were mechanistically connected to the pathways associated with cancer arrest. These results can be the basis for extending a biomarker discovery process to a clinical trial, as an early predictive tool of chemo-response to FOLFOX-4 of heavily treated ovarian cancer patients and for supporting the oncologist to continue or to interrupt the therapy.

13.
Cancers (Basel) ; 15(2)2023 Jan 11.
Article de Anglais | MEDLINE | ID: mdl-36672414

RÉSUMÉ

Local Excision (LE) or Watch and Wait (WW) for patients with complete clinical response or near-complete clinical response after neoadjuvant chemoradiotherapy (nCRT) were proposed to avoid morbidity and impairment of quality of life after rectal resection. The aim of this study is to perform a systematic review of the literature, and to compare rectal-sparing approaches, in terms of rectum-preservation rate, local control, and distant recurrences. A systematic review and meta-analysis were performed of studies published until July 2022 (PROSPERO, registration CRD42022341480), and the quality of evidence was assessed using a GRADE approach. Seven retrospective studies and one prospective trial were included. In six studies, patients were treated with standard long-course nCRT, and in two with Total Neoadjuvant Therapy (TNT). Overall, there were 213 and 188 patients in WW and LE group, respectively, and no difference was found between WW and LE when considering rectum-preservation rate (OR 0.80 95%CI 0.31-2.01, p = 0.63), local disease (OR 1.60 95%CI 0.75-3.42, p = 0.22), locoregional failure (OR 0.85 95%CI 0.20-3.66, p = 0.83) and distant recurrence (OR 0.76 95%CI 0.37-1.55, p = 0.45). Studies directly comparing WW and LE are still lacking, even though no differences between WW and LE in terms of rectum-preservation, local control, and distant recurrences have been found.

14.
Elife ; 112022 12 07.
Article de Anglais | MEDLINE | ID: mdl-36475542

RÉSUMÉ

Drugs that target human thymidylate synthase (hTS), a dimeric enzyme, are widely used in anticancer therapy. However, treatment with classical substrate-site-directed TS inhibitors induces over-expression of this protein and development of drug resistance. We thus pursued an alternative strategy that led us to the discovery of TS-dimer destabilizers. These compounds bind at the monomer-monomer interface and shift the dimerization equilibrium of both the recombinant and the intracellular protein toward the inactive monomers. A structural, spectroscopic, and kinetic investigation has provided evidence and quantitative information on the effects of the interaction of these small molecules with hTS. Focusing on the best among them, E7, we have shown that it inhibits hTS in cancer cells and accelerates its proteasomal degradation, thus causing a decrease in the enzyme intracellular level. E7 also showed a superior anticancer profile to fluorouracil in a mouse model of human pancreatic and ovarian cancer. Thus, over sixty years after the discovery of the first TS prodrug inhibitor, fluorouracil, E7 breaks the link between TS inhibition and enhanced expression in response, providing a strategy to fight drug-resistant cancers.


Sujet(s)
Tumeurs de l'ovaire , Thymidylate synthase , Femelle , Animaux , Souris , Humains , Sites de fixation , Thymidylate synthase/composition chimique , Thymidylate synthase/métabolisme , Fluorouracil/pharmacologie , Tumeurs de l'ovaire/traitement médicamenteux , Antienzymes/pharmacologie
16.
Sci Rep ; 12(1): 8467, 2022 05 19.
Article de Anglais | MEDLINE | ID: mdl-35589752

RÉSUMÉ

There is growing interest on the potential clinical relevance of the endometrial microbiome. However, insufficient attention has been given to the methodology of sampling. To minimize contamination, we advocate the use of the double-lumen catheters commonly employed for the embryo transfer. Endometrial fluid samples obtained from 53 women scheduled for IVF were studied for microbiome characterization. Control samples from the vagina of these same women were concomitantly obtained. Samples were analysed by V3-V4-V6 regions of 16S rRNA gene sequencing with Next Generation Sequencing technique. Endometrial Lactobacillus-dominant cases were uncommon compared to previous evidence, being observed in only 4 (8%) women. Taxonomy markedly differed between the endometrial and vaginal microbiomes composition. The most common bacterial genera coincided in only 4 (8%) women. The comparison between women who did and did not subsequently become pregnant failed to identify any microorganism associated with the success of the procedure. However, the endometrial biodiversity resulted higher among pregnant women. Shannon's Equitability index in pregnant and non pregnant women was 0.76 [0.57-0.87] and 0.55 [0.51-0.64], respectively (p = 0.002). In conclusion, the use of embryo transfer catheters for testing the endometrial microbiome is promising. The scant concordance with vaginal samples supports the validity of this approach. Moreover, our study highlighted a possible beneficial role of a higher biodiversity on endometrial receptivity.


Sujet(s)
Implantation embryonnaire , Microbiote , Transfert d'embryon , Endomètre/microbiologie , Femelle , Humains , Mâle , Microbiote/génétique , Grossesse , ARN ribosomique 16S/génétique , Vagin/microbiologie
17.
Materials (Basel) ; 15(3)2022 Jan 25.
Article de Anglais | MEDLINE | ID: mdl-35160864

RÉSUMÉ

Low-cost and simple methods are constantly chased in order to produce less expensive lithium-ion batteries (LIBs) while possibly increasing the energy and power density as well as the volumetric capacity in order to boost a rapid decarbonization of the transport sector. Li alloys and tin-carbon composites are promising candidates as anode materials for LIBs both in terms of capacity and cycle life. In the present paper, electrospinning was employed in the preparation of Sn/SnOx@C composites, where tin and tin oxides were homogeneously dispersed in a carbonaceous matrix of carbon nanofibers. The resulting self-standing and light electrode showed a greatly enhanced performance compared to a conventional electrode based on the same starting materials that are simply mixed to obtain a slurry then deposited on a Cu foil. Fast kinetics were achieved with more than 90% of the reaction that resulted being surface-controlled, and stable capacities of about 300 mAh/g over 500 cycles were obtained at a current density of 0.5 A/g.

18.
Pharmaceutics ; 14(2)2022 Feb 10.
Article de Anglais | MEDLINE | ID: mdl-35214125

RÉSUMÉ

The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. To exploit the advantages of drug repurposing in the search of new drugs, we developed a similar approach for the identification of new hits interfering with TEAD target gene expression. In our study, a 27-member in-house library was assembled, characterized, and screened for its cancer cell growth inhibition effect. In a secondary luciferase-based assay, only seven compounds confirmed their specific involvement in TEAD activity. IA5 bearing a p-quinoid structure reduced the cytoplasmic level of phosphorylated YAP and the YAP-TEAD complex transcriptional activity and reduced cancer cell growth. IA5 is a promising hit compound for TEAD activity modulator development.

19.
PLoS One ; 17(1): e0261591, 2022.
Article de Anglais | MEDLINE | ID: mdl-35073322

RÉSUMÉ

OBJECTIVE: To evaluate whether telomere length (TL), mitochondrial-DNA (mt-DNA) or epigenetic age estimators based on DNA methylation (DNAm) pattern could be considered reliable predictors of in-vitro-fertilization (IVF) success in terms of live birth rate. DESIGN: Prospective cohort study. SETTING: Infertility Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. PATIENTS: 181 women aged 37-39 years who underwent IVF at a single-centre between January 2017 and December 2018. INTERVENTIONS: On the day of recruitment, blood samples were collected, and genomic DNA was isolated from white blood cells. TL, mt-DNA and DNAm assessment was performed using quantitative real-time polymerase chain reaction (qPCR). Biological age (DNAm age) was computed as the algorithm based on methylation pattern of five genes. Epigenetic age acceleration was estimated from the residuals of the linear model of epigenetic age regressed on chronological age. Long Interspersed Nuclear Elements (LINE)-1 methylation pattern was used as a surrogate for global DNA methylation. MAIN OUTCOME MEASURES: This study investigated whether peripheral TL, mt-DNA and DNAm could predict live birth in IVF cycles. RESULTS: TL, mt-DNA and LINE-1 methylation were not associated with IVF success. Conversely, DNAm age resulted significantly lower in women who had a live birth compared to women who did not (36.1 ± 4.2 and 37.3 ± 3.3 years, respectively, p = 0.04). For DNAm age, odds ratio (OR) for live birth per year of age was 0.90 (95%CI: 0.82-0.99, p = 0.036) after adjusting for FSH and antral follicle count (AFC) and 0.90 (95%CI: 0.82-0.99, p = 0.028) after adjusting also for number of oocytes retrieved. A significant association also emerged for epigenetic age acceleration after adjustments (OR = 0.91, 95%CI: 0.83-1.00, p = 0.048). CONCLUSION: DNAm age is associated with IVF success but the magnitude of this association is insufficient to claim a clinical use. However, our findings are promising and warrant further investigation. Assessment of biological age using different epigenetic clocks or focusing on different tissues may reveal new predictors of IVF success.


Sujet(s)
Méthylation de l'ADN , ADN mitochondrial/génétique , Mitochondries/génétique , Homéostasie des télomères , Adulte , Taux de natalité , Épigenèse génétique , Femelle , Fécondation in vitro , Humains , Italie , Éléments LINE , Âge maternel , Grossesse , Taux de grossesse , Études prospectives
20.
Polymers (Basel) ; 13(23)2021 Nov 30.
Article de Anglais | MEDLINE | ID: mdl-34883700

RÉSUMÉ

Carbon capture is amongst the key emerging technologies for the mitigation of greenhouse gases (GHG) pollution. Several materials as adsorbents for CO2 and other gases are being developed, which often involve using complex and expensive fabrication techniques. In this work, we suggest a sound, easy and cheap route for the production of nitrogen-doped carbon materials for CO2 capture by pyrolysis of electrospun poly(acrylonitrile) (PAN) fibers. PAN fibers are generally processed following specific heat treatments involving up to three steps (to get complete graphitization), one of these being stabilization, during which PAN fibers are oxidized and stretched in the 200-300 °C temperature range. The effect of stabilization temperature on the chemical structure of the carbon nanofibers is investigated herein to ascertain the possible implication of incomplete conversion/condensation of nitrile groups to form pyridine moieties on the CO2 adsorption capacity. The materials were tested in the pure CO2 atmosphere at 20 °C achieving 18.3% of maximum weight increase (equivalent to an uptake of 4.16 mmol g-1), proving the effectiveness of a high stabilization temperature as route for the improvement of CO2 uptake.

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