Evaluation of novel 4-(4-fluorobenzyl)piperazin-1-yl]-based compounds as competitive tyrosinase inhibitors endowed with anti-melanogenic effects

There is a considerable attention for the development of inhibitors of tyrosinase (TYR) as therapeutic strategy for the treatment of hyperpigmentation disorders in humans. Continuing in our efforts to identify TYR inhibitors, we describe the design, synthesis and pharmacophore exploration of new small molecules structurally characterized by the presence of the 4-fluorobenzylpiperazine moiety as key pharmacophoric feature for the inhibition of TYR from  Agaricus bisporus (AbTYR). Our investigations resulted in the discovery of the competitive inhibitor [4-(4-fluorobenzyl)piperazin-1-yl]-(3-chloro-2-nitro-phenyl)methanone 26 (IC 50  = 0.18 μM) that proved to be ∼100-fold more active than reference compound kojic acid (IC 50  = 17.76 μM). Notably, compound 26 exerted anti-melanogenic effect on B16F10 cells in absence of cytotoxicity. Docking analysis suggested its binding mode into AbTYR and into modelled human TYR

Design, Synthesis, and in Vitro Evaluation of 4-(4-Hydroxyphenyl)piperazine-Based Compounds Targeting Tyrosinase

Melanin biosynthesis is enzymatically regulated by tyrosinase (TYR, EC 1.14.18.1), which is efficiently inhibited by natural and synthetic phenols, demonstrating potential therapeutic application for the treatment of several human diseases. Herein we report the inhibitory effects of a series of (4-(4-hydroxyphenyl)piperazin-1-yl)arylmethanone derivatives, that were designed, synthesised and assayed against TYR from Agaricus bisporus (AbTYR). The best inhibitory activity was predominantly found for compounds bearing selected hydrophobic ortho-substituents on the aroyl moiety (IC50 values in the range of 1.5–4.6 μM). They proved to be more potent than the reference compound kojic acid (IC50=17.8 μM) and displayed competitive mechanism of inhibition of diphenolase activity of AbTYR. Docking simulation predicted their binding mode into the catalytic cavities of AbTYR and the modelled human TYR. In addition, these compounds displayed antioxidant activity combined with no cytotoxicity in MTT tests. Notably, the best inhibitor affected tyrosinase activity in α-MSH-stimulated B16F10 cells, thus demonstrating anti-melanogenic activity

Involvement of GTA protein NC2β in Neuroblastoma pathogenesis suggests that it physiologically participates in the regulation of cell proliferation

<p>Abstract</p> <p>Background</p> <p>The General Transcription Apparatus (GTA) comprises more than one hundred proteins, including RNA Polymerases, GTFs, TAFs, Mediator, and cofactors such as heterodimeric NC2. This complexity contrasts with the simple mechanical role that these proteins are believed to perform and suggests a still uncharacterized participation to important biological functions, such as the control of cell proliferation.</p> <p>Results</p> <p>To verify our hypothesis, we analyzed the involvement in Neuroblastoma (NB) pathogenesis of GTA genes localized at 1p, one of NB critical regions: through RT-PCR of fifty eight NB biopsies, we demonstrated the statistically significant reduction of the mRNA for NC2β (localized at 1p22.1) in 74% of samples (p = 0.0039). Transcripts from TAF13 and TAF12 (mapping at 1p13.3 and 1p35.3, respectively) were also reduced, whereas we didn't detect any quantitative alteration of the mRNAs from GTF2B and NC2α (localized at 1p22-p21 and 11q13.3, respectively). We confirmed these data by comparing tumour and constitutional DNA: most NB samples with diminished levels of NC2β mRNA had also genomic deletions at the corresponding locus.</p> <p>Conclusion</p> <p>Our data show that NC2β is specifically involved in NB pathogenesis and may be considered a new NB biomarker: accordingly, we suggest that NC2β, and possibly other GTA members, are physiologically involved in the control of cell proliferation. Finally, our studies unearth complex selective mechanisms within NB cells.</p

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6+/-9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; pPeer reviewe

Maternal and perinatal outcomes of pregnant women with SARS-CoV-2 infection

Objectives To evaluate the maternal and perinatal outcomes of pregnancies affected by SARS-CoV-2 infection. Methods This was a multinational retrospective cohort study including women with a singleton pregnancy and laboratory-confirmed SARS-CoV-2 infection, conducted in 72 centers in 22 different countries in Europe, the USA, South America, Asia and Australia, between 1 February 2020 and 30 April 2020. Confirmed SARS-CoV-2 infection was defined as a positive result on real-time reverse-transcription polymerase chain reaction (RT-PCR) assay of nasopharyngeal swab specimens. The primary outcome was a composite measure of maternal mortality and morbidity, including admission to the intensive care unit (ICU), use of mechanical ventilation and death. Results In total, 388 women with a singleton pregnancy tested positive for SARS-CoV-2 on RT-PCR of a nasopharyngeal swab and were included in the study. Composite adverse maternal outcome was observed in 47/388 (12.1%) women; 43 (11.1%) women were admitted to the ICU, 36 (9.3%) required mechanical ventilation and three (0.8%) died. Of the 388 women included in the study, 122 (31.4%) were still pregnant at the time of data analysis. Among the other 266 women, six (19.4% of the 31 women with first-trimester infection) had miscarriage, three (1.1%) had termination of pregnancy, six (2.3%) had stillbirth and 251 (94.4%) delivered a liveborn infant. The rate of preterm birth before 37 weeks' gestation was 26.3% (70/266). Of the 251 liveborn infants, 69/251(27.5%) were admitted to the neonatal ICU, and there were five (2.0%) neonatal deaths. The overall rate of perinatal death was 4.1% (11/266). Only one (1/251, 0.4%) infant, born to a mother who tested positive during the third trimester, was found to be positive for SARS-CoV-2 on RT-PCR. Conclusions SARS-CoV-2 infection in pregnant women is associated with a 0.8% rate of maternal mortality, but an 11.1% rate of admission to the ICU. The risk of vertical transmission seems to be negligible. (C) 2020 International Society of Ultrasound in Obstetrics and Gynecology.Peer reviewe

4-Fluorobenzylpiperazine-containing derivatives as efficient inhibitors of mushroom tyrosinase

Tyrosinase is a type 3 copper protein involved in the biosynthesis of melanin pigments, therefore the inhibition of its enzymatic activity represents a promising strategy for the treatment of hyperpigmentation-related disorders. To address this point at issue we have previously designed a class of 4-(4-fluorobenzyl)piperazin-1-yl-based compounds proving to be more active inhibitor against tyrosinase from mushroom Agaricus bisporus when compared to positive control kojic acid. Herein, we report the synthesis of further series of 4-(4-fluorobenzyl)piperazin-1-yl-analogs bearing a (hetero)aromatic fragment as key feature to improve protein affinity. The new synthesized compounds were in vitro assayed proving to be potent inhibitors in low micromolar range. Then, the active 2-thienyl and 2-furyl derivatives were selected for further modifications considering their binding mode analyzed by docking studies and their satisfactory safety profiles

4‐Fluorobenzylpiperazine‐Containing Derivatives as Efficient Inhibitors of Mushroom Tyrosinase

Tyrosinase is a type 3 copper protein involved in the biosynthesis of melanin pigments, therefore the inhibition of its enzymatic activity represents a promising strategy for the treatment of hyperpigmentation-related disorders. To address this point at issue we have previously designed a class of 4-(4-fluorobenzyl)piperazin-1-yl-based compounds proving to be more active inhibitor against tyrosinase from mushroom Agaricus bisporus when compared to positive control kojic acid. Herein, we report the synthesis of further series of 4-(4-fluorobenzyl)piperazin-1-yl-analogs bearing a (hetero)aromatic fragment as key feature to improve protein affinity. The new synthesized compounds were in vitro assayed proving to be potent inhibitors in low micromolar range. Then, the active 2-thienyl and 2-furyl derivatives were selected for further modifications considering their binding mode analyzed by docking studies and their satisfactory safety profiles

A Combined Multidisciplinary Intervention for Health Promotion in the Workplace: A Pilot Study

The aim of this study was to assess the effects of a joint health promotion intervention on a cohort of healthcare workers (HCWs) who had at least one cardiovascular risk factor. The HCWs were assessed at three different times, i.e., time zero (T0), after 6 months (T6), and after 12 months (T12). The following parameters were measured at a medical examination: physical activity, blood pressure, waist circumference, body mass index (BMI), routine laboratory tests, plicometric analysis, work ability index (WAI), and body image dissatisfaction (BID). Among the 447 HCWs, 38 HCWs were included in the study; 45% (n = 17) were male. At T12, the average blood pressure, waist/hip ratio (WHR) index, BMI, total cholesterol, triglyceride level, and blood glucose values were reduced. The levels of physical activity and adherence to the Mediterranean diet had progressively increased. The WAI showed a significant shift from low to good work performance at T12, as well as BID score. This is the first study that has analyzed work performance in relation to a workplace health promotion through a multidisciplinary approach. This health promotion intervention that combined diet and sport activity has led to a significant change in HCWs’ lifestyles and body perceptions, as well as their ability to work. This project highlights the importance of using a multidisciplinary approach and the workplace setting in health promotion programs

NOCTURNIN Gene Diurnal Variation in Healthy Volunteers and Expression Levels in Shift Workers

The NOCTURNIN gene links nutrient absorption and metabolism to the circadian clock. Shift workers are at a heightened risk of overweight and of developing obesity and metabolic syndrome. This study investigates the diurnal variation of NOCTURNIN in healthy volunteers and its expression levels in rotational shift and daytime workers