400 research outputs found
Natural compounds as therapeutic agents: The case of human topoisomerase ib
Natural products are widely used as source for drugs development. An interesting example is represented by natural drugs developed against human topoisomerase IB, a ubiquitous enzyme involved in many cellular processes where several topological problems occur due the formation of supercoiled DNA. Human topoisomerase IB, involved in the solution of such problems relaxing the DNA cleaving and religating a single DNA strand, represents an important target in anticancer therapy. Several natural compounds inhibiting or poisoning this enzyme are under investigation as possible new drugs. This review summarizes the natural products that target human topoisomerase IB that may be used as the lead compounds to develop new anticancer drugs. Moreover, the natural compounds and their derivatives that are in clinical trial are also commented on
Analysis of four new enterococcus faecalis phages and modeling of a hyaluronidase catalytic domain from saphexavirus
Background: Phage therapy (PT), as a method to treat bacterial infections, needs identification of bacteriophages targeting specific pathogenic host. Enterococcus faecalis, a Gram-positive coccus resident in the human gastrointestinal tract, may become pathogenic in hospitalized patients showing acquired resistance to vancomycin and thus representing a possible target for PT. Materials and Methods: We isolated four phages that infect E. faecalis and characterized them by host range screening, transmission electron microscopy, and genome sequencing. We also identified and three-dimensional modeled a new hyaluronidase enzyme. Results: The four phages belong to Siphoviridae family: three Efquatrovirus (namely vB_EfaS_TV51, vB_EfaS_TV54, and vB_EfaS_TV217) and one Saphexavirus (vB_EfaS_TV16). All of them are compatible with lytic cycle. vB_EfaS_TV16 moreover presents a gene encoding for a hyaluronidase enzyme. Conclusions: The identified phages show features suggesting their useful application in PT, particularly the Saphexavirus that may be of enhanced relevance in PT because of its potential biofilm-digestion capability
Searching for Primordial Black Holes with the Einstein Telescope: impact of design and systematics
Primordial Black Holes (PBHs) have recently attracted much attention as they
may explain some of the LIGO/Virgo/KAGRA observations and significantly
contribute to the dark matter in our universe. The next generation of
Gravitational Wave (GW) detectors will have the unique opportunity to set
stringent bounds on this putative population of objects. Focusing on the
Einstein Telescope (ET), in this paper we analyse in detail the impact of
systematics and different detector designs on our future capability of
observing key quantities that would allow us to discover and/or constrain a
population of PBH mergers. We also perform a population analysis, with a mass
and redshift distribution compatible with the current observational bounds. Our
results indicate that ET alone can reach an exquisite level of accuracy on the
key observables considered, as well as detect up to tens of thousands of PBH
binaries per year, but for some key signatures (in particular high--redshift
sources) the cryogenic instrument optimised for low frequencies turns out to be
crucial, both for the number of observations and the error on the parameters
reconstruction. As far as the detector geometry is concerned, we find that a
network consisting of two separated L--shaped interferometers of 15 (20)~km arm
length, oriented at with respect to each other performs better
than a single triangular shaped instrument of 10 (15)~km arm length, for all
the metrics considered.Comment: 24 pages, 13 figure
Topoisomerase IB: a relaxing enzyme for stressed DNA
DNA topoisomerase I enzymes relieve the torsional strain in DNA; they are essential for fundamental molecular processes such as DNA replication, transcription, recombination, and chromosome condensation; and act by cleaving and then religating DNA strands. Over the past few decades, scientists have focused on the DNA topoisomerases biological functions and established a unique role of Type I DNA topoisomerases in regulating gene expression and DNA chromosome condensation. Moreover, the human enzyme is being investigated as a target for cancer chemotherapy. The active site tyrosine is responsible for initiating two transesterification reactions to cleave and then religate the DNA backbone, allowing the release of superhelical tension. The different steps of the catalytic mechanism are affected by various inhibitors; some of them prevent the interaction between the enzyme and the DNA while others act as poisons, leading to TopI-D NA lesions, breakage of DNA, and eventually cellular death. In this review, our goal is to provide an overview of mechanism of human topoisomerase IB action together with the different types of inhibitors and their effect on the enzyme functionality
Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia
Several chemo-resistance mechanisms including the Bcl-2 protein family overexpression and constitutive activation of the PI3K/Akt/mTOR signaling have been documented in acute lymphoblastic leukemia (ALL), encouraging targeted approaches to circumvent this clinical problem. Here we analyzed the activity of the BH3 mimetic ABT-737 in ALL, exploring the synergistic effects with the mTOR inhibitor CCI-779 on ABT-737 resistant cells. We showed that a low Mcl-1/Bcl-2 plus Bcl-xL protein ratio determined ABT-737 responsiveness. ABT-737 exposure further decreased Mcl-1, inducing apoptosis on sensitive models and primary samples, while not affecting resistant cells. Co-inhibition of Bcl-2 and the mTOR pathway resulted cytotoxic on ABT-737 resistant models, by downregulating mTORC1 activity and Mcl-1 in a proteasome-independent manner. Although Mcl-1 seemed to be critical, ectopic modulation did not correlate with apoptosis changes. Importantly, dual targeting proved effective on ABT-737 resistant samples, showing additive/synergistic effects. Together, our results show the efficacy of BH3 mimetics as single agent in the majority of the ALL samples and demonstrate that resistance to ABT-737 mostly correlated with Mcl-1 overexpression. Co-targeting of the Bcl-2 protein family and mTOR pathway enhanced drug-induced cytotoxicity by suppressing Mcl-1, providing a novel therapeutic approach to overcome BH3 mimetics resistance in ALL
Exploring risk of falls and dynamic unbalance in cerebellar ataxia by inertial sensor assessment
Background. Patients suffering from cerebellar ataxia have extremely variable gait kinematic features. We investigated whether and how wearable inertial sensors can describe the gait kinematic features among ataxic patients. Methods. We enrolled 17 patients and 16 matched control subjects. We acquired data by means of an inertial sensor attached to an ergonomic belt around pelvis, which was connected to a portable computer via Bluetooth. Recordings of all the patients were obtained during overground walking. From the accelerometric data, we obtained the harmonic ratio (HR), i.e., a measure of the acceleration patterns, smoothness and rhythm, and the step length coefficient of variation (CV), which evaluates the variability of the gait cycle. Results. Compared to controls, patients had a lower HR, meaning a less harmonic and rhythmic acceleration pattern of the trunk, and a higher step length CV, indicating a more variable step length. Both HR and step length CV showed a high effect size in distinguishing patients and controls (p < 0.001 and p = 0.011, respectively). A positive correlation was found between the step length CV and both the number of falls (R = 0.672; p = 0.003) and the clinical severity (ICARS: R = 0.494; p = 0.044; SARA: R = 0.680; p = 0.003). Conclusion. These findings demonstrate that the use of inertial sensors is effective in evaluating gait and balance impairment among ataxic patients
A protective role for autophagy in vitiligo
A growing number of studies supports the existence of a dynamic interplay between energetic metabolism and autophagy, whose induction represents an adaptive response against several stress conditions. Autophagy is an evolutionarily conserved and a highly orchestrated catabolic recycling process that guarantees cellular homeostasis. To date, the exact role of autophagy in vitiligo pathogenesis is still not clear. Here, we provide the first evidence that autophagy occurs in melanocytes and fibroblasts from non-lesional skin of vitiligo patients, as a result of metabolic surveillance response. More precisely, this study is the first to reveal that induction of autophagy exerts a protective role against the intrinsic metabolic stress and attempts to antagonize degenerative processes in normal appearing vitiligo skin, where melanocytes and fibroblasts are already prone to premature senescence
False-negative RT-PCR in SARS-CoV-2 disease: experience from an Italian COVID-19 unit
False-negative cases of COVID19 are being increasingly reported. Laboratory diagnosis through RT-PCR testing alone lacks adequate sensitivity to be recommended as the only valid criterion to confirm COVID-19 diagnosis
Dimethylmyricacene: An In Vitro and In Silico Study of a Semisynthetic Non-Camptothecin Derivative Compound, Targeting Human DNA Topoisomerase 1B
Human topoisomerase 1B regulates the topological state of supercoiled DNA enabling all fundamental cell processes. This enzyme, which is the unique molecular target of the natural anticancer compound camptothecin, acts by nicking one DNA strand and forming a transient protein–DNA covalent complex. The interaction of human topoisomerase 1B and dimethylmyricacene, a compound prepared semisynthetically from myricanol extracted from Myrica cerifera root bark, was investigated using enzymatic activity assays and molecular docking procedures. Dimethylmyricacene was shown to inhibit both the cleavage and the religation steps of the enzymatic reaction, and cell viability of A-253, FaDu, MCF-7, HeLa and HCT-116 tumor cell lines
In vitro and in silico characterization of an antimalarial compound with antitumor activity targeting human DNA topoisomerase IB
Human DNA topoisomerase IB controls the topological state of supercoiled DNA through a complex catalytic cycle that consists of cleavage and religation reactions, allowing the progression of fundamental DNA metabolism. The catalytic steps of human DNA topoisomerase IB were analyzed in the presence of a drug, obtained by the open-access drug bank Medicines for Malaria Venture. The experiments indicate that the compound strongly and irreversibly inhibits the cleavage step of the enzyme reaction and reduces the cell viability of three different cancer cell lines. Molecular docking and molecular dynamics simulations suggest that the drug binds to the human DNA topoisomerase IB-DNA complex sitting inside the catalytic site of the enzyme, providing a molecular explanation for the cleavage-inhibition effect. For all these reasons, the aforementioned drug could be a possible lead compound for the development of an efficient anti-tumor molecule targeting human DNA topoisomerase IB
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