45 research outputs found
Structure-Activity Relationships and Therapeutic Potentials of 5-HT7 Receptor Ligands: An Update
No full textSerotonin 5-HT7 receptor (5-HT7R) has been the subject of intense research efforts because of its presence in brain areas such as the hippocampus, hypothalamus, and cortex. Preclinical data link the 5-HT7R to a variety of central nervous system processes including the regulation of circadian rhythms, mood, cognition, pain processing, and mechanisms of addiction. 5-HT7R blockade has antidepressant effects and may ameliorate cognitive deficits associated with schizophrenia. 5-HT7R has been recently shown to modulate neuronal morphology, excitability, and plasticity, thus contributing to shape brain networks during development and to remodel neuronal wiring in the mature brain. Therefore, the activation of 5-HT7R has been proposed as a therapeutic approach for neurodevelopmental and neuropsychiatric disorders associated with abnormal neuronal connectivity. This Perspective celebrates the silver jubilee of the discovery of 5-HT7R by providing a survey of recent studies on the medicinal chemistry of 5-HT7R ligands and on the neuropharmacology of 5-HT7R
Combination of heme oxygenase-1 inhibitors and temozolomide to improve the anticancer effect in glioblastoma
No full textHeme oxygenase-1 (HO-1) is involved in the oncogenesis of glioblastoma (GBM). In this work, we investigated for the first time how the co-administration (combo) of the HO-1 inhibitors SI1/09 or LS6/42 with temozolomide (TMZ) or temozolomide acid (TMZ Ac) may influence the proliferation of U87MG GBM cell lines. Moreover, two novel TMZ/HO-1 inhibitors codrugs LS8/21 and LS8/24 were synthesised, characterised and tested. Results indicate that the combos TMZ or TMZ Ac with LS6/42, as well as the corresponding LS8/24, are more efficacious in reducing U87MG cell proliferation with respect to reference drugs, allowing a possible reduction of the TMZ dosage and related side effects in clinical practice. The chemical and enzymatic stability of the most potent codrug LS8/24 was evaluated. The observed high potency performed by both combos and LS8/24 in cells suggests that HO-1 inhibition may give additional contribution to the antiproliferative effect of TMZ
Combination of heme oxygenase-1 inhibition and sigma receptor modulation for anticancer activity
No full textCancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (σRs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and σR ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/σRs) 1–4 containing the chemical features needed for HO-1 inhibition and σR modulation. Herein, we report for the first time that targeting simultaneously HO-1 and σR proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/σRs hybrids to develop novel potential anticancer agents
Discovery of SI 1/20 and SI 1/22 as Mutual Prodrugs of 5-Fluorouracil and Imidazole-Based Heme Oxygenase 1 Inhibitor with Improved Cytotoxicity in DU145 Prostate Cancer Cells
No full textIn this work, we extend the concept of 5-fluorouracil/heme oxygenase 1 (5-FU/HO-1) inhibitor hybrid as an effective strategy for enhancing 5-FU-based anticancer therapies. For this purpose, we designed and synthesized new mutual prodrugs, named SI 1/20 and SI 1/22, in which the two active parent drugs (i. e., 5-FU and an imidazole-based HO-1 inhibitor) were connected through an easily cleavable succinic linker. Experimental hydrolysis rate, and in silico ADMET predictions were indicative of good drug-likeness and pharmacokinetic properties. Novel hybrids significantly reduced the viability of prostate DU145 cancer cells compared to the parent compounds 5-FU and HO-1 inhibitor administered alone or in combination. Interestingly, both compounds showed statistically significant lower toxicity, than 5-FU at the same dose, against non-tumorigenic human benign prostatic hyperplasia (BPH-1) cell line. Moreover, the newly synthesized mutual prodrugs inhibited the HO-1 activity both in a cell-free model and in vitro, as well as downregulated the HO-1 expression and increased the reactive oxygen species (ROS) levels
Lipid Nanoparticles Traverse Non-Corneal Path to Reach the Posterior Eye Segment: In Vivo Evidence
No full textLipid-based nanocarriers (LNs) have made it possible to prolong corneal residence time and improve the ocular bioavailability of ophthalmic drugs. In order to investigate how the LNs interact with the ocular mucosa and reach the posterior eye segment, we have formulated lipid nanocarriers that were designed to bear a traceable fluorescent probe in the present work. The chosen fluorescent probe was obtained by a conjugation reaction between fluoresceinamine and the solid lipid excipient stearic acid, forming a chemically synthesized adduct (ODAF, N-(3′,6′-dihydroxy-3-oxospiro [isobenzofuran-1(3H),9′-[9H] xanthen]-5-yl)-octadecanamide). The novel formulation (LN-ODAF) has been formulated and characterized in terms of its technological parameters (polydispersity index, mean particle size and zeta potential), while an in vivo study was carried out to assess the ability of LN-ODAF to diffuse through different ocular compartments. LN-ODAF were in nanometric range (112.7 nm ± 0.4), showing a good homogeneity and long-term stability. A TEM (transmission electron microscopy) study corroborated these results of characterization. In vivo results pointed out that after ocular instillation, LN ODAF were concentrated in the cornea (two hours), while at a longer time (from the second hour to the eighth hour), the fluorescent signals extended gradually towards the back of the eye. From the results obtained, LN-ODAF demonstrated a potential use of lipid-based nanoparticles as efficient carriers of an active pharmaceutical ingredient (API) involved in the management of retinal diseases
Danno tanatologico: il dibattito sulla risarcibilità del danno da perdita della vita
No full textL’Autore esamina e critica la sentenza delle SezioniUnite. n° 15350 del 22/7/2015 che, chiamata ad affrontare il quesito circa la risarcibilità o meno del danno da perdita della vita immediatamente conseguente alle lesioni derivanti da fatto illecito, ha optato in favore della tesi maggioritaria e prevalente di segno negativo spegnendo le speranze sorte dalla coraggiosa sentenza “Scarano” n°1361/2014.
Ritiene infatti che il mancato riconoscimento della risarcibilità del danno “tanatologico”, così come argomentato e motivato dalle S.U., non consente affatto di ritenere chiusa la questione dogmatica ed interpretativa controversa. Con appena dieci pagine di motivazione, le S.U. intenderebbero porre fine alla vexata quaestio lasciando tuttavia privo di tutela il diritto alla vita, il diritto principe della esistenza umana.
L’auteur examine et critique le jugement n°15350 du 22/7/2015 rendu par la Cour de Cassation italienne, Sections Unies. La Cour a dû s’exprimer sur la question liée à l’indemnisation du préjudice pour son propre décès à la suite des lésions corporelles provoquées par un crime. Elle a opté pour la thèse dominante et négative qui a éteint les espoirs nés après le courageux jugement n°1361/2014 « Scarano » .
L’auteur estime en effet que la non-reconnaissance de l’indemnisation du dommage « thanatologique », ainsi que l’expliquent les Sections Unies, ne permet pas de considérer comme terminé le débat controversé dogmatique et interprétatif. Avec dix pages de motifs seulement, les Sections Unies auraient l’intention de mettre fin à cette question ainsi ancienne que controversée, sans toutefois protéger le droit à la vie, le droit fondamental de l’existence humaine.
The author examines and criticizes the court judgment of Italian Court of Cassation, United Sections, n. 15350 of 22 July 2015 when having to deal with the issue about the compensation in the event of wrongful death as an immediate consequence of the injuries due to an illegal action, the option was for the prevailing thesis which was negative. In this way the hopes produced by the brave Scarano judgment n. 1361/2014 were cancelled.
The author underlines that the non-recognition of compensation for thanatological damage as explained by United Sections does not allow to consider the dogmatic contentious issue as concluded. With just ten written pages, they intend to explain and to finish such a vexata quaestio thus leaving the right to life without protection, that is to say the basic right of human existence
Correction to “Nitric Oxide Photo-Donor Hybrids of Ciprofloxacin and Norfloxacin: A Shift in Activity from Antimicrobial to Anticancer Agents”
No full textNo abstract availabl
Nitric Oxide Photo-Donor Hybrids of Ciprofloxacin and Norfloxacin: A Shift in Activity from Antimicrobial to Anticancer Agents
No full textThe potential anticancer effect of fluoroquinolone antibiotics has been recently unveiled and related to their ability to
interfere with DNA topoisomerase II. We herein envisioned the design and synthesis of novel Ciprofloxacin and Norfloxacin nitric oxide (NO) photo-donor hybrids to explore the potential synergistic antitumor effect exerted by the fluoroquinolone scaffold and NO eventually produced upon light irradiation. Anticancer activity, evaluated on a panel of tumor cell lines, showed encouraging results with IC50 values in the low micromolar range. Some compounds displayed intense antiproliferative activity on triple-negative and doxorubicin-resistant breast cancer cell lines, paving the way for their potential use to treat aggressive, refractory and multidrug-resistant breast cancer. No significant additive effect was observed on PC3 and DU145 cells following NO release.
Conversely, antimicrobial photodynamic experiments on both Gram-negative and Gram-positive microorganisms displayed a significant killing rate in Staphylococcus aureus, accounting for their potential effectiveness as selective antimicrobial photosensitizers
Targeting heme Oxygenase-1 with hybrid compounds to overcome Imatinib resistance in chronic myeloid leukemia cell lines
No full textHeme oxygenase-1 (HO-1) is a cytoprotective enzyme and a survival-enhancing factor in a number of cancers. Chronic myeloid leukemia (CML) is a blood cancer caused by pathological kinase activity of the BCR-ABL protein, currently treated with tyrosine kinase inhibitors (TKIs) such as Imatinib (IM). However, resistance to TKIs persists in a number of patients and HO-1 overexpression has been linked with the induction of chemoresistance in CML. With this in mind, in this study, we designed and synthesized the first series of hybrid compounds obtained by combining the structures of IM, as BCR-ABL inhibitor, with imidazole-based HO-1 inhibitors. We found that many hybrids were able to inhibit the enzymatic activity of both targets and to reduce the viability of CML-IM resistant cells, showing that a single molecular entity may reduce the resistance phenomenon
Strategies to Improve Resveratrol Systemic and Topical Bioavailability: An Update
No full textIn recent years, a great deal of attention has been paid to natural compounds due to their many biological effects. Polyphenols are a class of plant derivatives that have been widely investigated for preventing and treating many oxidative stress-related pathological conditions, such as neurodegenerative and cardiovascular diseases, cancer, diabetes mellitus and inflammation. Among these polyphenols, resveratrol (RSV) has attracted considerable interest owing to its high antioxidant and free radical scavenging activities. However, the poor water solubility and rapid metabolism of RSV lead to low bioavailability, thus limiting its clinical efficacy. After discussing the main biochemical mechanisms involved in RSV biological activities, this review will focus on the strategies attempted to improve RSV effectiveness, both for systemic and for topical administration. In particular, technological approaches involving RSV incorporation into different delivery systems such as liposomes, polymeric and lipid nanoparticles, microemulsions and cyclodextrins will be illustrated, highlighting their potential clinical applications. In addition, chemical modifications of this antioxidant aimed at improving its physicochemical properties will be described along with the results of in vitro and in vivo studies
