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991.
Andrea Mammoli Elisa Bianconi Luana Ruta Alessandra Riccio Carlo Bigiotti Maria Souma Andrea Carotti Sofia Rossini Chiara Suvieri Maria Teresa Pallotta Ursula Grohmann Emidio Camaioni Antonio Macchiarulo 《International journal of molecular sciences》2022,23(7)
Over the last two decades, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted wide interest as a key player in immune regulation, fostering the design and development of small molecule inhibitors to restore immune response in tumor immunity. In this framework, biochemical, structural, and pharmacological studies have unveiled peculiar structural plasticity of IDO1, with different conformations and functional states that are coupled to fine regulation of its catalytic activity and non-enzymic functions. The large plasticity of IDO1 may affect its ligand recognition process, generating bias in structure-based drug design campaigns. In this work, we report a screening campaign of a fragment library of compounds, grounding on the use of three distinct conformations of IDO1 that recapitulate its structural plasticity to some extent. Results are instrumental to discuss tips and pitfalls that, due to the large plasticity of the enzyme, may influence the identification of novel and differentiated chemical scaffolds of IDO1 ligands in structure-based screening campaigns. 相似文献
992.
Federica Tonolo Alessandra Folda Valeria Scalcon Oriano Marin Alberto Bindoli Maria Pia Rigobello 《International journal of molecular sciences》2022,23(8)
Redox status and inflammation are related to the pathogenesis of the majority of diseases. Therefore, understanding the role of specific food-derived molecules in the regulation of their specific pathways is a relevant issue. Our previous studies indicated that K-8-K and S-10-S, milk and soy-derived bioactive peptides, respectively, exert antioxidant effects through activation of the Keap1/Nrf2 pathway. A crosstalk between Nrf2 and NF-κB, mediated by the action of heme oxygenase (HO-1), is well known. On this basis, we studied if these peptides, in addition to their antioxidant activity, could exert anti-inflammatory effects in human cells. First, we observed an increase of HO-1 expression in Caco-2 cells treated with K-8-K and S-10-S, following the activation of the Keap1/Nrf2 pathway. Moreover, when cells are treated with the two peptides and stimulated by TNF-α, the levels of NF-κB in the nucleus decreased in comparison with TNF-α alone. In the same conditions, we observed the downregulation of the gene expression of proinflammatory cytokines (IL1B, IL6, and TNF), while the anti-inflammatory cytokine gene, IL1RN, was upregulated in Caco-2 cells processed as reported above. Then, when the cells were pretreated with the two peptides and stimulated with LPS, a different proinflammatory factor, (TNF-α) was estimated to have a lower secretion in the supernatant of cells. In conclusion, these observations confirmed that Nrf2-activating bioactive peptides, K-8-K and S-10-S, exerted anti-inflammatory effects by inhibiting the NF-κB pathway. 相似文献
993.
Guillaume P. Grolez Giorgia Chinig Alexandre Barras Mehdi Hammadi Lucile Noyer Kateryna Kondratska Etmar Bulk Thibauld Oullier Sverine Marionneau-Lambot Marilyne Le Me Stphanie Rtif Stphanie Lerondel Antonino Bongiovanni Tullio Genova Sbastien Roger Rabah Boukherroub Albrecht Schwab Alessandra Fiorio Pla Dimitra Gkika 《International journal of molecular sciences》2022,23(12)
In the fight against prostate cancer (PCa), TRPM8 is one of the most promising clinical targets. Indeed, several studies have highlighted that TRPM8 involvement is key in PCa progression because of its impact on cell proliferation, viability, and migration. However, data from the literature are somewhat contradictory regarding the precise role of TRPM8 in prostatic carcinogenesis and are mostly based on in vitro studies. The purpose of this study was to clarify the role played by TRPM8 in PCa progression. We used a prostate orthotopic xenograft mouse model to show that TRPM8 overexpression dramatically limited tumor growth and metastasis dissemination in vivo. Mechanistically, our in vitro data revealed that TRPM8 inhibited tumor growth by affecting the cell proliferation and clonogenic properties of PCa cells. Moreover, TRPM8 impacted metastatic dissemination mainly by impairing cytoskeleton dynamics and focal adhesion formation through the inhibition of the Cdc42, Rac1, ERK, and FAK pathways. Lastly, we proved the in vivo efficiency of a new tool based on lipid nanocapsules containing WS12 in limiting the TRPM8–positive cells’ dissemination at metastatic sites. Our work strongly supports the protective role of TRPM8 on PCa progression, providing new insights into the potential application of TRPM8 as a therapeutic target in PCa treatment. 相似文献
994.
Alessandro Del Conte Elisa De Carlo Elisa Bertoli Brigida Stanzione Alberto Revelant Manuela Bertola Michele Spina Alessandra Bearz 《International journal of molecular sciences》2022,23(12)
Patients with non-small cell lung cancer (NSCLC) develop bone metastasis (BoM) in more than 50% of cases during the course of the disease. This metastatic site can lead to the development of skeletal related events (SREs), such as severe pain, pathological fractures, spinal compression, and hypercalcemia, which reduce the patient’s quality of life. Recently, the treatment of advanced NSCLC has radically changed due to the advent of immunotherapy. Immune checkpoint inhibitors (ICI) alone or in combination with chemotherapy have become the main therapeutic strategy for advanced or metastatic NSCLC without driver gene mutations. Since survival has increased, it has become even more important to treat bone metastasis to prevent SRE. We know that the presence of bone metastasis is a negative prognostic factor. The lower efficacy of immunotherapy treatments in BoM+ patients could be induced by the presence of a particular immunosuppressive tumor and bone microenvironment. This article reviews the most important pre-clinical and clinical scientific evidence on the reasons for this lower sensitivity to immunotherapy and the need to combine bone target therapies (BTT) with immunotherapy to improve patient outcome. 相似文献
995.
Elisa De Carlo Elisa Bertoli Alessandro Del Conte Brigida Stanzione Eleonora Berto Alberto Revelant Michele Spina Alessandra Bearz 《International journal of molecular sciences》2022,23(12)
The therapeutic landscape in patients with advanced non-small-cell lung cancer harboring oncogenic biomarkers has radically changed with the development of targeted therapies. Although lung cancers are known to frequently metastasize to the brain, oncogene-driven non-small-cell lung cancer patients show a higher incidence of both brain metastases at baseline and a further risk of central nervous system progression/relapse. Recently, a new generation of targeted agents, highly active in the central nervous system, has improved the control of intracranial disease. The intracranial activity of these drugs poses a crucial issue in determining the optimal management sequence in oncogene-addicted non-small-cell lung cancer patients with brain metastases, with a potential change of paradigm from primary brain irradiation to central nervous system penetrating targeted inhibitors. 相似文献
996.
Gabriele A. Trombetti Alessandra Mezzelani Alessandro Orro 《International journal of molecular sciences》2022,23(12)
Chronic pain is a widespread disorder affecting millions of people and is insufficiently addressed by current classes of analgesics due to significant long-term or high dosage side effects. A promising approach that was recently proposed involves the systemic inhibition of the voltage-gated sodium channel Nav1.7, capable of cancelling pain perception completely. Notwithstanding numerous attempts, currently no drugs have been approved for the inhibition of Nav1.7. The task is complicated by the difficulty of creating a selective drug for Nav1.7, and avoiding binding to the many human paralogs performing fundamental physiological functions. In our work, we obtained a promising set of ligands with up to 5–40-fold selectivity and reaching 5.2 nanomolar binding affinity by employing a proper treatment of the problem and an innovative differential in silico screening procedure to discriminate for affinity and selectivity against the Nav paralogs. The absorption, distribution, metabolism, and excretion (ADME) properties of our top-scoring ligands were also evaluated, with good to excellent results. Additionally, our study revealed that the top-scoring ligand is a stereoisomer of an already-approved drug. These facts could reduce the time required to bring a new effective and selective Nav1.7 inhibitor to the market. 相似文献
997.
Maurizio Benaglia Giuseppe Celentano Mauro Cinquini Alessandra Puglisi Franco Cozzi 《Advanced Synthesis \u0026amp; Catalysis》2002,344(2):149-152
A tyrosine‐derived imidazolidin‐4‐one was immobilized on a modified poly(ethylene glycol) and converted in situ into a soluble polymer‐supported catalyst for the enantioselective Diels–Alder cycloaddition of acrolein to 1,3‐cyclohexadiene (up to 92% ee) and 2,3‐dimethyl‐1,3‐butadiene (73% ee). Catalyst recycling (up to four cycles) was accompanied by some loss of the chemical efficiency and marginal erosion of the enantioselectivity. 相似文献
998.
Maurizio Benaglia Mauro Cinquini Franco Cozzi Alessandra Puglisi Giuseppe Celentano 《Advanced Synthesis \u0026amp; Catalysis》2002,344(5):533-542
(2S,4R)‐4‐Hydroxyproline has been anchored to the monomethyl ether of poly(ethylene glycol), MW 5000, by means of a succinate spacer to afford a soluble, polymer‐supported catalyst (PEG‐Pro) for enantioselective aldol and iminoaldol condensation reactions. This organic catalyst can be considered as a minimalistic version of a type I aldolase enzyme, with the polymer chain replacing the enzyme's peptide backbone, and the proline residue acting as the enzyme's active site. In the presence of PEG‐Pro (0.25–0.35 mol equiv.), acetone reacted with enolizable and non‐enolizable aldehydes and imines to afford β‐ketols and β‐aminoketones in good yield and high enantiomeric excess (ee), comparable to those obtained using non‐supported proline derivatives as the catalysts. Extension of the PEG‐Pro‐promoted condensation to hydroxyacetone as the aldol donor opened an access to synthetically relevant anti‐α,β‐dihydroxyketones and syn‐α‐hydroxy‐β‐aminoketones, that were obtained in moderate to good yields, and good to high diastereo‐ and enantioselectivity. Exploiting its solubility properties, the PEG‐Pro catalyst was easily recovered and recycled to promote all of the above‐mentioned reactions, that occurred in slowly diminishing yields but virtually unchanged ee's. 相似文献
999.
1000.