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141.
Identification and Structure–Activity Relationship Studies of Small‐Molecule Inhibitors of the Methyllysine Reader Protein Spindlin1
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Dr. Dina Robaa Dr. Tobias Wagner Chiara Luise Dr. Luca Carlino Joel McMillan Dr. Ralf Flaig Prof. Dr. Roland Schüle Prof. Dr. Manfred Jung Prof. Dr. Wolfgang Sippl 《ChemMedChem》2016,11(20):2327-2338
The methyllysine reader protein Spindlin1 has been implicated in the tumorigenesis of several types of cancer and may be an attractive novel therapeutic target. Small‐molecule inhibitors of Spindlin1 should be valuable as chemical probes as well as potential new therapeutics. We applied an iterative virtual screening campaign, encompassing structure‐ and ligand‐based approaches, to identify potential Spindlin1 inhibitors from databases of commercially available compounds. Our in silico studies coupled with in vitro testing were successful in identifying novel Spindlin1 inhibitors. Several 4‐aminoquinazoline and quinazolinethione derivatives were among the active hit compounds, which indicated that these scaffolds represent promising lead structures for the development of Spindlin1 inhibitors. Subsequent lead optimization studies were hence carried out, and numerous derivatives of both lead scaffolds were synthesized. This resulted in the discovery of novel inhibitors of Spindlin1 and helped explore the structure–activity relationships of these inhibitor series. 相似文献
142.
Shepheard C. J. Vardanega P. J. Holcombe E. A. Hen-Jones R. De Luca F. 《Bulletin of Engineering Geology and the Environment》2019,78(7):4851-4864
Bulletin of Engineering Geology and the Environment - Identification of failure thresholds and critical uncertainties associated with slope stability often requires the specification of... 相似文献
143.
Tiziana Di Chiara Alessandro Del Cuore Mario Daidone Stefania Scaglione Rosario Luca Norrito Maria Grazia Puleo Rosario Scaglione Antonio Pinto Antonino Tuttolomondo 《International journal of molecular sciences》2022,23(5)
There is growing evidence that hypertension is the most important vascular risk factor for the development and progression of cardiovascular and cerebrovascular diseases. The brain is an early target of hypertension-induced organ damage and may manifest as stroke, subclinical cerebrovascular abnormalities and cognitive decline. The pathophysiological mechanisms of these harmful effects remain to be completely clarified. Hypertension is well known to alter the structure and function of cerebral blood vessels not only through its haemodynamics effects but also for its relationships with endothelial dysfunction, oxidative stress and inflammation. In the last several years, new possible mechanisms have been suggested to recognize the molecular basis of these pathological events. Accordingly, this review summarizes the factors involved in hypertension-induced brain complications, such as haemodynamic factors, endothelial dysfunction and oxidative stress, inflammation and intervention of innate immune system, with particular regard to the role of Toll-like receptors that have to be considered dominant components of the innate immune system. The complete definition of their prognostic role in the development and progression of hypertensive brain damage will be of great help in the identification of new markers of vascular damage and the implementation of innovative targeted therapeutic strategies. 相似文献
144.
Eugenia Z. Poh Courtney Green Luca Agostinelli Marissa Penrose-Menz Ann-Kathrin Karl Alan R. Harvey Jennifer Rodger 《International journal of molecular sciences》2022,23(5)
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has the potential to treat a variety of neurologic and psychiatric disorders. The extent of rTMS-induced neuroplasticity may be dependent on a subject’s brain state at the time of stimulation. Chronic low intensity rTMS (LI-rTMS) has previously been shown to induce beneficial structural and functional reorganisation within the abnormal visual circuits of ephrin-A2A5-/- mice in ambient lighting. Here, we administered chronic LI-rTMS in adult ephrin-A2A5-/- mice either in a dark environment or concurrently with voluntary locomotion. One day after the last stimulation session, optokinetic responses were assessed and fluorescent tracers were injected to map corticotectal and geniculocortical projections. We found that LI-rTMS in either treatment condition refined the geniculocortical map. Corticotectal projections were improved in locomotion+LI-rTMS subjects, but not in dark + LI-rTMS and sham groups. Visuomotor behaviour was not improved in any condition. Our results suggest that the beneficial reorganisation of abnormal visual circuits by rTMS can be significantly influenced by simultaneous, ambient visual input and is enhanced by concomitant physical exercise. Furthermore, the observed pathway-specific effects suggest that regional molecular changes and/or the relative proximity of terminals to the induced electric fields influence the outcomes of LI-rTMS on abnormal circuitry. 相似文献
145.
Alessandro Marchioni Roberto Tonelli Alessandro Andreani Gaia Francesca Cappiello Matteo Fermi Fabiana Trentacosti Ivana Castaniere Riccardo Fantini Luca Tabbì Dario Andrisani Filippo Gozzi Giulia Bruzzi Linda Manicardi Antonio Moretti Serena Baroncini Anna Valeria Samarelli Massimo Pinelli Giorgio De Santis Alessandro Stefani Daniele Marchioni Francesco Mattioli Enrico Clini 《International journal of molecular sciences》2022,23(5)
Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different aetiology. Although iatrogenic aetiology is the main cause of subglottic or tracheal stenosis, also autoimmune and infectious diseases may be involved in causing LTS. Furthermore, fibrotic obstruction in the anatomic region under the glottis can also be diagnosed without apparent aetiology after a comprehensive workup; in this case, the pathological process is called idiopathic subglottic stenosis (iSGS). So far, the laryngotracheal scar resulting from airway injury due to different diseases was considered as inert tissue requiring surgical removal to restore airway patency. However, this assumption has recently been revised by regarding the tracheal scarring process as a fibroinflammatory event due to immunological alteration, similar to other fibrotic diseases. Recent acquisitions suggest that different factors, such as growth factors, cytokines, altered fibroblast function and genetic susceptibility, can all interact in a complex way leading to aberrant and fibrotic wound healing after an insult that acts as a trigger. However, also physiological derangement due to LTS could play a role in promoting dysregulated response to laryngo-tracheal mucosal injury, through biomechanical stress and mechanotransduction activation. The aim of this narrative review is to present the state-of-the-art knowledge regarding molecular mechanisms, as well as mechanical and physio-pathological features behind LTS. 相似文献
146.
Diana Valeria Rossetti Ilaria Inserra Alessia Nestic Federica Vincenzoni Federica Iavarone Irene Messana Massimo Castagnola Luca Massimi Gianpiero Tamburrini Massimo Caldarelli Claudia Desiderio 《International journal of molecular sciences》2022,23(6)
The present investigation aimed to explore the intact proteome of tissues of pediatric brain tumors of different WHO grades and localizations, including medulloblastoma, pilocytic astrocytoma, and glioblastoma, in comparison with the available data on ependymoma, to contribute to the understanding of the molecular mechanisms underlying the onset and progression of these pathologies. Tissues have been homogenized in acidic water–acetonitrile solutions containing proteases inhibitors and analyzed by LC–high resolution MS for proteomic characterization and label-free relative quantitation. Tandem MS spectra have been analyzed by either manual inspection or software elaboration, followed by experimental/theoretical MS fragmentation data comparison by bioinformatic tools. Statistically significant differences in protein/peptide levels between the different tumor histotypes have been evaluated by ANOVA test and Tukey’s post-hoc test, considering a p-value > 0.05 as significant. Together with intact protein and peptide chains, in the range of molecular mass of 1.3–22.8 kDa, several naturally occurring fragments from major proteins, peptides, and proteoforms have been also identified, some exhibiting proper biological activities. Protein and peptide sequencing allowed for the identification of different post-translational modifications, with acetylations, oxidations, citrullinations, deamidations, and C-terminal truncations being the most frequently characterized. C-terminal truncations, lacking from two to four amino acid residues, particularly characterizing the β-thymosin peptides and ubiquitin, showed a different modulation in the diverse tumors studied. With respect to the other tumors, medulloblastoma, the most frequent malignant brain tumor of the pediatric age, was characterized by higher levels of thymosin β4 and β10 peptides, the latter and its des-IS form particularly marking this histotype. The distribution pattern of the C-terminal truncated forms was also different in glioblastoma, particularly underlying gender differences, according to the definition of male and female glioblastoma as biologically distinct diseases. Glioblastoma was also distinguished for the peculiar identification of the truncated form of the α-hemoglobin chain, lacking the C-terminal arginine, and exhibiting oxygen-binding and vasoconstrictive properties different from the intact form. The proteomic characterization of the undigested proteome, following the top-down approach, was challenging to originally investigate the post-translational events that differently characterize pediatric brain tumors. This study provides a contribution to elucidate the molecular profiles of the solid tumors most frequently affecting the pediatric age, and which are characterized by different grades of aggressiveness and localization. 相似文献
147.
Wenjian Kang Shan Liu Jin Xu Anna Abrimian Ayma F. Malik Raymond Chien Adejuyigbe Adaralegbe Akwasi Amponsah Luca Cartegni John Pintar Ying-Xian Pan 《International journal of molecular sciences》2022,23(6)
The mu opioid receptor has a distinct place in the opioid receptor family, since it mediates the actions of most opioids used clinically (e.g., morphine and fentanyl), as well as drugs of abuse (e.g., heroin). The single-copy mu opioid receptor gene, OPRM1, goes through extensive alternative pre-mRNA splicing to generate numerous splice variants that are conserved from rodents to humans. These OPRM1 splice variants can be classified into three structurally distinct types: (1) full-length 7 transmembrane (TM) carboxyl (C)-terminal variants; (2) truncated 6TM variants; and (3) single TM variants. Distinct pharmacological functions of these splice variants have been demonstrated by both in vitro and in vivo studies, particularly by using several unique gene-targeted mouse models. These studies provide new insights into our understanding of the complex actions of mu opioids with regard to OPRM1 alternative splicing. This review provides an overview of the studies that used these gene-targeted mouse models for exploring the functional importance of Oprm1 splice variants. 相似文献
148.
Hiroki Iwamoto Alexey Stankovskiy Luca Fiorito Gert Van den Eynde 《Journal of Nuclear Science and Technology》2018,55(5):539-547
The applicability of Monte Carlo techniques, namely the Monte Carlo sensitivity method and the random-sampling method, for uncertainty quantification of the effective delayed neutron fraction βeff is investigated using the continuous-energy Monte Carlo transport code, MCNP, from the perspective of statistical convergence issues. This study focuses on the nuclear data as one of the major sources of βeff uncertainty. For validation of the calculated βeff, a critical configuration of the VENUS-F zero-power reactor was used. It is demonstrated that Chiba's modified k-ratio method is superior to Bretscher's prompt k-ratio method in terms of reducing the statistical uncertainty in calculating not only βeff but also its sensitivities and the uncertainty due to nuclear data. From this result and a comparison of uncertainties obtained by the Monte Carlo sensitivity method and the random-sampling method, it is shown that the Monte Carlo sensitivity method using Chiba's modified k-ratio method is the most practical for uncertainty quantification of βeff. Finally, total βeff uncertainty due to nuclear data for the VENUS-F critical configuration is determined to be approximately 2.7% with JENDL-4.0u, which is dominated by the delayed neutron yield of 235U. 相似文献
149.
Biagio Barone Luigi Napolitano Marco Abate Luigi Cirillo Pasquale Reccia Francesco Passaro Carmine Turco Simone Morra Francesco Mastrangelo Antonio Scarpato Ugo Amicuzi Vincenzo Morgera Lorenzo Romano Francesco Paolo Calace Savio Domenico Pandolfo Luigi De Luca Achille Aveta Enrico Sicignano Massimiliano Trivellato Gianluca Spena Carlo DAlterio Giovanni Maria Fusco Raffaele Vitale Davide Arcaniolo Felice Crocetto 《International journal of molecular sciences》2022,23(7)
Testosterone is the most important hormone in male health. Aging is characterized by testosterone deficiency due to decreasing testosterone levels associated with low testicular production, genetic factors, adiposity, and illness. Low testosterone levels in men are associated with sexual dysfunction (low sexual desire, erectile dysfunction), reduced skeletal muscle mass and strength, decreased bone mineral density, increased cardiovascular risk and alterations of the glycometabolic profile. Testosterone replacement therapy (TRT) shows several therapeutic effects while maintaining a good safety profile in hypogonadal men. TRT restores normal levels of serum testosterone in men, increasing libido and energy level and producing beneficial effects on bone density, strength and muscle as well as yielding cardioprotective effects. Nevertheless, TRT could be contraindicated in men with untreated prostate cancer, although poor findings are reported in the literature. In addition, different potential side effects, such as polycythemia, cardiac events and obstructive sleep apnea, should be monitored. The aim of our review is to provide an updated background regarding the pros and cons of TRT, evaluating its role and its clinical applicability in different domains. 相似文献