Synthesis and Biological Evaluation of Dantrolene-Like Hydrazide and Hydrazone Analogues as Multitarget Agents for Neurodegenerative Diseases

Dantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newly synthesized compounds exhibited selectivity toward MAO B over either MAO A or AChE, with the secondary aldimine 9 and phenylhydrazone 20 attaining IC50 values of 0.68 and 0.81 μM, respectively. While no general SAR trend was observed with lipophilicity descriptors, a molecular simplification strategy allowed the main pharmacophore features to be identified, which are responsible for the inhibitory activity toward MAO B. Finally, further in vitro investigations revealed cell protection from oxidative insult and activation of carnitine/acylcarnitine carrier as concomitant biological activities responsible for neuroprotection by hits 9 and 20 and other promising compounds in the examined series

Is the first of the two born saved? A rare and dramatic case of double placental damage from SARS-CoV-2

The current coronavirus pandemic has affected, in a short time, various and different areas of medicine. Among these, the obstetric field has certainly been touched in full, and the knowledge of the mechanisms potentially responsible for placental damage from SARS-CoV-2 occupy a certain importance. Here we present here a rare case of dichorionic twins born at 30 weeks and 4 days of amenorrhea, one of whom died in the first few hours of life after placental damages potentially related to SARS-CoV-2. We also propose a brief review of the current literature giving ample emphasis to similar cases described

Purpuric skin rash in a patient undergoing pfizer-biontech covid-19 vaccination: Histological evaluation and perspectives

The COVID-19 pandemic has affected the entire planet, and within about a year and a half, has led to 174,502,686 confirmed cases of COVID-19 worldwide, with 3,770,361 deaths. Although it is now clear that SARS-CoV-2 can affect various different organs, including the lungs, brain, skin, vessels, placenta and others, less is yet known about adverse reactions from vaccines, although more and more reports are starting to emerge. Among the adverse events, we focused particularly on skin rashes. In this short report, we describe the case of a patient vaccinated with Comirnaty, who developed a purpuric rash resistant to oral steroid therapy after 2 weeks. To date, this is one of the very few cases in which skin biopsy was performed to better characterize the histopathological picture of this rash. Finally, we conduct a literature review of the cases of rashes from SARS-CoV-2 vaccines described in the literature, with the aim of laying foundations for future, larger case studies

Sars-cov-2 and skin: The pathologist’s point of view

The SARS-CoV-2 pandemic has dramatically changed our lives and habits. In just a few months, the most advanced and efficient health systems in the world have been overwhelmed by an infectious disease that has caused 3.26 million deaths and more than 156 million cases worldwide. Although the lung is the most frequently affected organ, the skin has also resulted in being a target body district, so much so as to suggest it may be a real “sentinel” of COVID-19 disease. Here we present 17 cases of skin manifestations studied and analyzed in recent months in our Department; immunohistochemical investigations were carried out on samples for the S1 spike-protein of SARS-CoV-2, as well as electron microscopy investigations showing evidence of virions within the constituent cells of the eccrine sweat glands and the endothelium of small blood vessels. Finally, we conduct a brief review of the COVID-related skin manifestations, confirmed by immunohistochemistry and/or electron microscopy, described in the literature

Glut1, glut3 expression and 18fdg-pet/ct in human malignant melanoma: What relationship exists? new insights and perspectives

Background: Malignant melanoma is the most aggressive of skin cancers and the 19th most common cancer worldwide, with an estimated age-standardized incidence rate of 2.8–3.1 per 100,000; although there have been clear advances in therapeutic treatment, the prognosis of MM patients with Breslow thickness greater than 1 mm is still quite poor today. The study of how melanoma cells manage to survive and proliferate by consuming glucose has been partially addressed in the literature, but some rather interesting results are starting to be present. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a search of PubMed and Web of Sciences (WoS) databases was performed until 27 September 2021 using the terms: glucose transporter 1 and 3 and GLUT1/3 in combination with each of the following: melanoma, neoplasm and immunohistochemistry. Results: In total, 46 records were initially identified in the literature search, of which six were duplicates. After screening for eligibility and inclusion criteria, 16 publications were ultimately included. Conclusions: the results discussed regarding the role and expression of GLUT are still far from definitive, but further steps toward understanding and stopping this mechanism have, at least in part, been taken. New studies and new discoveries should lead to further clarification of some aspects since the various mechanisms of glucose uptake by neoplastic cells are not limited to the transporters of the GLUT family alone

Results from the first use of low radioactivity argon in a dark matter search

Liquid argon is a bright scintillator with potent particle identification properties, making it an attractive target for direct-detection dark matter searches. The DarkSide-50 dark matter search here reports the first WIMP search results obtained using a target of low-radioactivity argon. DarkSide-50 is a dark matter detector, using two-phase liquid argon time projection chamber, located at the Laboratori Nazionali del Gran Sasso. The underground argon is shown to contain Ar-39 at a level reduced by a factor (1.4 +- 0.2) x 10^3 relative to atmospheric argon. We report a background-free null result from (2616 +- 43) kg d of data, accumulated over 70.9 live-days. When combined with our previous search using an atmospheric argon, the 90 % C.L. upper limit on the WIMP-nucleon spin-independent cross section based on zero events found in the WIMP search regions, is 2.0 x 10^-44 cm^2 (8.6 x 10^-44 cm^2, 8.0 x 10^-43 cm^2) for a WIMP mass of 100 GeV/c^2 (1 TeV/c^2 , 10 TeV/c^2).Comment: Accepted by Phys. Rev.

Search for dark matter-nucleon interactions via Migdal effect with DarkSide-50

Dark matter elastic scattering off nuclei can result in the excitation and ionization of the recoiling atom through the so-called Migdal effect. The energy deposition from the ionization electron adds to the energy deposited by the recoiling nuclear system and allows for the detection of interactions of sub-GeV/c$^2$ mass dark matter. We present new constraints for sub-GeV/c$^2$ dark matter using the dual-phase liquid argon time projection chamber of the DarkSide-50 experiment with an exposure of (12306 $\pm$ 184) kg d. The analysis is based on the ionization signal alone and significantly enhances the sensitivity of DarkSide-50, enabling sensitivity to dark matter with masses down to 40 MeV/c$^2$. Furthermore, it sets the most stringent upper limit on the spin independent dark matter nucleon cross section for masses below $3.6$ GeV/c$^2$.Comment: 7 pages, 3 figure

Search for dark matter particle interactions with electron final states with DarkSide-50

We present a search for dark matter particles with sub-GeV/$c^2$ masses whose interactions have final state electrons using the DarkSide-50 experiment's (12306 $\pm$ 184) kg d low-radioactivity liquid argon exposure. By analyzing the ionization signals, we exclude new parameter space for the dark matter-electron cross section $\bar{\sigma}_e$, the axioelectric coupling constant $g_{Ae}$, and the dark photon kinetic mixing parameter $\kappa$. We also set the first dark matter direct-detection constraints on the mixing angle $\left|U_{e4}\right|^2$ for keV sterile neutrinos.Comment: 6 pages, 2 figure

Search for dark matter annual modulation with DarkSide-50

Dark matter induced event rate in an Earth-based detector is predicted to show an annual modulation as a result of the Earth's orbital motion around the Sun. We searched for this modulation signature using the ionization signal of the DarkSide-50 liquid argon time projection chamber. No significant signature compatible with dark matter is observed in the electron recoil equivalent energy range above $40~{\rm eV_{ee}}$, the lowest threshold ever achieved in such a search.Comment: 8 pages, 4 figure

DarkSide status and prospects

Sem informaçãoDarkSide uses a dual-phase Liquid Argon Time Projection Chamber to search for WIMP dark matter. The current detector, DarkSide-50, is running since mid 2015 with a target of 50 kg of Argon from an underground source. Here it is presented the latest results of searches of WIMP-nucleus interactions, with WIMP masses in the GeV-TeV range, and of WIMP-electron interactions, in the sub-GeV mass range. The future of DarkSide with a new generation experiment, involving a global collaboration from all the current Argon based experiments, is presented.422-315Sem informaçãoSem informaçãoSem informaçã