The search of antivirals against SARS‐CoV‐2 in available libraries of compounds was initiated as soon as WHO announced that the coronavirus outbreak became a pandemic. That pivotal task has been ...conducted by both experimental groups in wet‐labs as well as by theoretical chemists in supercomputing centers. The combination of biochemical and clinical intuitions yields first to remdesivir, a broad‐spectrum antiviral that remains as the standard solution for the treatment of severe cases, while paxlovid, molnupiravir and fluvoxamine have been recently proposed as oral alternatives. Unfortunately, the intensive publication of standard virtual screening (VS) simulations might be not the best strategy to increase that short list of antivirals. This contribution joins theory and biological assays to rescore massive VS. Our goal is to critically assess pros and cons of using molecular models for drug repurposing.
Massive virtual screenings with a focus on SARS‐CoV‐2 are now available in the literature. Unfortunately, standard implementations without further refinements and/or biological assays have shown a limited impact in real clinical applications. To guide next computational efforts, herein we combine theory and experiments to critically assess pros and cons of such methods.
NLRP3 (NOD-like receptor pyrin domain-containing protein 3) is an innate immune sensor that contributes to the development of different diseases, including monogenic autoinflammatory syndromes, gout, ...atherosclerosis, and Alzheimer's disease. The molecule sulfonylurea MCC950 is a NLRP3 inflammasome inhibitor with potential clinical utility. However, the mechanism of action of MCC950 remains unknown. Here, we characterize the mechanism of action of MCC950 in both wild-type and autoinflammatory-related NLRP3 mutants, and demonstrate that MCC950 closes the 'open' conformation of active NLRP3.
The monofunctional platinum drug phenanthriplatin (phenPt) blocks the replication of cancer cells even if it reacts with only one guanine base. However, there is still insufficient experimental data ...to improve its cytotoxicity and all previously proposed chemical modifications of the parent structure have resulted in a loss of activity. We use theoretical tools to illustrate the key steps in the biological mechanisms of phenPt; that is, its activation in water and the subsequent attack on DNA. Our simulations suggest that the measured kinetic parameters, which are based on free nucleobases in solution, need to be reinterpreted because the self-assembled stacked reactive adduct formed in the reaction is inaccessible in real DNA. The constants reported here will help guide future work in the synthesis of anticancer platinum drugs.
New heterometallic binuclear and trinuclear platinum(IV)-gold(I) compounds of the type Pt(L)
Cl
(OH){(OOC-4-C
H
-PPh
)AuCl}
(L=NH
, n=2; x=1, 2; L=diaminocyclohexane, DACH, n=1; x=2) are described. ...These compounds are cytotoxic and selective against a small panel of renal, bladder, ovarian, and breast cancer cell lines. We selected a trinuclear PtAu
compound containing the Pt
core based on oxaliplatin, to further investigate its cell-death pathway, cell and organelle uptake and anticancer effects against the triple-negative breast cancer (TNBC) MDA-MB-231 cell line. This compound induces apoptosis and accumulates mainly in the nucleus and mitochondria. It also exerts remarkable antimigratory and antiangiogenic properties, and has a potent cytotoxic effect against TNBC 3D spheroids. Trinuclear compounds do not seem to display relevant interactions with calf thymus (CT) DNA and plasmid (pBR322) even in the presence of reducing agents, but inhibit pro-angiogenic enzyme thioredoxin reductase (TrxR) in TNBC cells.
BACKGROUND:The outbreak of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), in December 2019 in Wuhan, People’s Republic of China, has ...developed into an unprecedented pandemic with enormous pressure on health-care providers around the world. A higher mortality rate has been described in older infected individuals. Patients with hip fracture are a particularly vulnerable population during this pandemic because older age is associated with a higher mortality rate. Our aim was to describe the early mortality rate and demographic variables in a hip fracture sample population in Spain during the coronavirus pandemic.
METHODS:This is a multicenter, observational, retrospective, descriptive study. We collected data from 13 major hospitals in Spain from the beginning of the national state of alarm (declared on March 14, 2020, by the Spanish government) until the end of our study period on April 4, 2020. All patients who were ≥65 years of age, presented to the Emergency Department of the participating hospitals during this period with a diagnosis of proximal femoral fracture, and had a minimum follow-up of 10 days were included in the cohort. In addition to mortality, demographic and other potential prognostic variables were also collected.
RESULTS:In this study, 136 patients with a hip fracture were included. Of these patients, 124 underwent a surgical procedure and 12 were managed nonoperatively. The total mortality rate was 9.6%. Sixty-two patients were tested for COVID-19, with 23 patients being positive. The mortality rate for these 23 patients was 30.4% (7 of 23 patients) at a mean follow-up of 14 days. The mortality rate was 10.3% (4 of 39) for patients who had been tested and had a negative result and 2.7% (2 of 74) for patients who had not been tested. Of the 12 patients who were managed nonoperatively, 8 (67%) died, whereas, of the 124 patients who were surgically treated, 5 (4%) died. Results differed among centers.
CONCLUSIONS:There is a higher mortality rate in patients with a hip fracture and an associated positive test for COVID-19.
LEVEL OF EVIDENCE:Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Phenanthriplatin (PtPPH) is a monovalent platinum(II)-based complex with a large cytotoxicity against cancer cells. Although the aqua-activated drug has been assumed to be the precursor for DNA ...damage, it is still under debate whether the way in which that metallodrug attacks to DNA is dominated by a direct binding to a guanine base or rather by an intercalated intermediate product. Aiming to capture the mechanism of action of PtPPH, the present contribution used theoretical tools to systematically assess the sequence of all possible mechanisms on drug activation and reactivity, for example, hydrolysis, intercalation, and covalent damage to DNA. Ab initio quantum mechanical (QM) methods, hybrid QM/QM′ schemes, and independent gradient model approaches are implemented in an unbiased protocol. The performed simulations show that the cascade of reactions is articulated in three well-defined stages: (i) an early and fast intercalation of the complex between the DNA bases, (ii) a subsequent hydrolysis reaction that leads to the aqua-activated form, and (iii) a final formation of the covalent bond between PtPPH and DNA at a guanine site. The permanent damage to DNA is consequently driven by that latter bond to DNA but with a simultaneous π–π intercalation of the phenanthridine into nucleobases. The impact of the DNA sequence and the lateral backbone was also discussed to provide a more complete picture of the forces that anchor the drug into the double helix.
Gut microorganisms metabolize azobenzene compounds (Ph1−N=N−Ph2) into free aniline products (Ph1−NH2+H2N−Ph2), a process that has been largely investigated to reduce dyes residues in the textile ...industry. However, the action of bacterial core enzymes such as azoreductases (AzoR) might also help to deliver prodrugs that become active when they reach the colonic region, a mechanism with potential applications for the treatment of inflammatory bowel disease (IBD) and colorectal cancer. So far, three azo‐bonded prodrugs of 5‐aminosalicylic acid (5‐ASA), for example, sulfasalazine, olsalazine and balsalazide, have been used for colon‐targeted delivery. The present contribution describes the first rational design of a novel azobenzene prodrug thanks to a computational approach, with a focus on linking 5‐ASA to another approved anti‐inflammatory drug. The resulting prodrugs were assessed for their degradation upon AzoR action. Replacing the original carriers by irsogladine is found to improve action.
Targeting colon tissue: Azo‐bonds could be exploited to assemble two drugs in one single molecule. The main advantage of such bifunctional agents is their ability to be degraded by colonic bacteria, which opens the door to a controlled release in that tissue. Here a computational chemistry approach was used to rationalise the synthesis of a new generation of azo‐prodrugs.
The outbreak of coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), in December 2019 in Wuhan, People's Republic of China, has developed into ...an unprecedented pandemic with enormous pressure on health-care providers around the world. A higher mortality rate has been described in older infected individuals. Patients with hip fracture are a particularly vulnerable population during this pandemic because older age is associated with a higher mortality rate. Our aim was to describe the early mortality rate and demographic variables in a hip fracture sample population in Spain during the coronavirus pandemic.
This is a multicenter, observational, retrospective, descriptive study. We collected data from 13 major hospitals in Spain from the beginning of the national state of alarm (declared on March 14, 2020, by the Spanish government) until the end of our study period on April 4, 2020. All patients who were ≥65 years of age, presented to the Emergency Department of the participating hospitals during this period with a diagnosis of proximal femoral fracture, and had a minimum follow-up of 10 days were included in the cohort. In addition to mortality, demographic and other potential prognostic variables were also collected.
In this study, 136 patients with a hip fracture were included. Of these patients, 124 underwent a surgical procedure and 12 were managed nonoperatively. The total mortality rate was 9.6%. Sixty-two patients were tested for COVID-19, with 23 patients being positive. The mortality rate for these 23 patients was 30.4% (7 of 23 patients) at a mean follow-up of 14 days. The mortality rate was 10.3% (4 of 39) for patients who had been tested and had a negative result and 2.7% (2 of 74) for patients who had not been tested. Of the 12 patients who were managed nonoperatively, 8 (67%) died, whereas, of the 124 patients who were surgically treated, 5 (4%) died. Results differed among centers.
There is a higher mortality rate in patients with a hip fracture and an associated positive test for COVID-19.
Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
IntroductionThe media portrayal of mental health is relevant in shaping the population’s attitudes towards mental disorders. However, there is little information about the representation of children ...and adolescent mental health in the Spanish press, especially in the context of the COVID-19 pandemic. The general objective of this study was to analyze the tone and content of Spanish newspaper articles about mental disorders in youth during the COVID-19 pandemic.MethodWe collected media articles from 10 news sources, comprising the digital editions of five online news websites and five printed newspapers over a 6 month period (January 2021-June 2021). These articles were coded for content using a standardized codebook, followed by a qualitative thematic analysis. A total of 205 news items were evaluated.ResultsResults showed that the majority of the news items had an overall positive tone (68.3%), only 5.4% were stigmatizing and only 7.3% were related to violence. However, few articles offered help seeking information (6%), adolescents were rarely quoted (14%) and children were never quoted. Substantial differences are described in terms of age, gender and disorder, with adolescents, males and patients with psychosis or behavioral disorders most associated with stigmatizing content or violence. The thematic analysis led to three emergent themes: (i) violence and victimization; (ii) the COVID-19 pandemic; and (iii) technology and social media. The number of articles that described young people with mental health problems as victims of violence was prominent.ConclusionsThe Spanish media generally does not stigmatize mental health problems in children and adolescents. Furthermore, the COVID-19 pandemic may have promoted more positive discussion about youth mental health. However, there remains some room for improvement, as patients are seldom quoted, very few articles offer help-seeking information, and a narrative of victimization without appropriate discussion of resilience regularly occurs.Disclosure of InterestNone Declared
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