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The study describes the current state of knowledge on nanotechnology and its utilization in medicine. The focus in this manuscript was on the properties, usage safety, and potentially valuable applications of chitosan-based nanomaterials. Chitosan nanoparticles have high importance in nanomedicine, biomedical engineering, discovery and development of new drugs. The manuscript reviewed the new studies regarding the use of chitosan-based nanoparticles for creating new release systems with improved bioavailability, increased specificity and sensitivity, and reduced pharmacological toxicity of drugs. Nowadays, effective cancer treatment is a global problem, and recent advances in nanomedicine are of great importance. Special attention was put on the application of chitosan nanoparticles in developing new system for anticancer drug delivery. Pre-clinical and clinical studies support the use of chitosan-based nanoparticles in nanomedicine. This manuscript overviews the last progresses regarding the utilization, stability, and bioavailability of drug nanoencapsulation with chitosan and their safety.
Javad Sharifi-Rad; Cristina Quispe; Monica Butnariu; Lia Sanda Rotariu; Oksana Sytar; Simona Sestito; Simona Rapposelli; Muhammad Akram; Mehwish Iqbal; Akash Krishna; Nanjangud Venkatesh Anil Kumar; Susana S. Braga; Susana M. Cardoso; Karolina Jafernik; Halina Ekiert; Natália Cruz-Martins; Agnieszka Szopa; Marcelo Villagran; Lorena Mardones; Miquel Martorell; Anca Oana Docea; Daniela Calina. Chitosan nanoparticles as a promising tool in nanomedicine with particular emphasis on oncological treatment. Cancer Cell International 2021, 21, 1 -21.
AMA StyleJavad Sharifi-Rad, Cristina Quispe, Monica Butnariu, Lia Sanda Rotariu, Oksana Sytar, Simona Sestito, Simona Rapposelli, Muhammad Akram, Mehwish Iqbal, Akash Krishna, Nanjangud Venkatesh Anil Kumar, Susana S. Braga, Susana M. Cardoso, Karolina Jafernik, Halina Ekiert, Natália Cruz-Martins, Agnieszka Szopa, Marcelo Villagran, Lorena Mardones, Miquel Martorell, Anca Oana Docea, Daniela Calina. Chitosan nanoparticles as a promising tool in nanomedicine with particular emphasis on oncological treatment. Cancer Cell International. 2021; 21 (1):1-21.
Chicago/Turabian StyleJavad Sharifi-Rad; Cristina Quispe; Monica Butnariu; Lia Sanda Rotariu; Oksana Sytar; Simona Sestito; Simona Rapposelli; Muhammad Akram; Mehwish Iqbal; Akash Krishna; Nanjangud Venkatesh Anil Kumar; Susana S. Braga; Susana M. Cardoso; Karolina Jafernik; Halina Ekiert; Natália Cruz-Martins; Agnieszka Szopa; Marcelo Villagran; Lorena Mardones; Miquel Martorell; Anca Oana Docea; Daniela Calina. 2021. "Chitosan nanoparticles as a promising tool in nanomedicine with particular emphasis on oncological treatment." Cancer Cell International 21, no. 1: 1-21.
Recent reports highlighted the significant neuroprotective effects of thyronamines (TAMs), a class of endogenous thyroid hormone derivatives. In particular, 3-iodothyronamine (T1AM) has been shown to play a pleiotropic role in neurodegeneration by modulating energy metabolism and neurological functions in mice. However, the pharmacological response to T1AM might be influenced by tissue metabolism, which is known to convert T1AM into its catabolite 3-iodothyroacetic acid (TA1). Currently, several research groups are investigating the pharmacological effects of T1AM systemic administration in the search of novel therapeutic approaches for the treatment of interlinked pathologies, such as metabolic and neurodegenerative diseases (NDDs). A critical aspect in the development of new drugs for NDDs is to know their distribution in the brain, which is fundamentally related to their ability to cross the blood–brain barrier (BBB). To this end, in the present study we used the immortalized mouse brain endothelial cell line bEnd.3 to develop an in vitro model of BBB and evaluate T1AM and TA1 permeability. Both drugs, administered at 1 µM dose, were assayed by high-performance liquid chromatography coupled to mass spectrometry. Our results indicate that T1AM is able to efficiently cross the BBB, whereas TA1 is almost completely devoid of this property.
Nicoletta di Leo; Stefania Moscato; Marco Borso'; Simona Sestito; Beatrice Polini; Lavinia Bandini; Agostina Grillone; Matteo Battaglini; Alessandro Saba; Letizia Mattii; Gianni Ciofani; Grazia Chiellini. Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study. Molecules 2021, 26, 1616 .
AMA StyleNicoletta di Leo, Stefania Moscato, Marco Borso', Simona Sestito, Beatrice Polini, Lavinia Bandini, Agostina Grillone, Matteo Battaglini, Alessandro Saba, Letizia Mattii, Gianni Ciofani, Grazia Chiellini. Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study. Molecules. 2021; 26 (6):1616.
Chicago/Turabian StyleNicoletta di Leo; Stefania Moscato; Marco Borso'; Simona Sestito; Beatrice Polini; Lavinia Bandini; Agostina Grillone; Matteo Battaglini; Alessandro Saba; Letizia Mattii; Gianni Ciofani; Grazia Chiellini. 2021. "Delivery of Thyronamines (TAMs) to the Brain: A Preliminary Study." Molecules 26, no. 6: 1616.
The complex network of malfunctioning pathways occurring in the pathogenesis of neurodegenerative diseases (NDDs) represents a huge hurdle in the development of new effective drugs to be used in therapy. In this context, redox reactions act as crucial regulators in the maintenance of neuronal microenvironment homeostasis. Particularly, their imbalance results in the severe compromising of organism’s natural defense systems and subsequently, in the instauration of deleterious OS, that plays a fundamental role in the insurgence and progress of NDDs. Despite the huge efforts in drug discovery programs, the identification process of new therapeutic agents able to counteract the relentless progress of neurodegenerative processes has produced low or no effective therapies. Consequently, a paradigm-shift in the drug discovery approach for these diseases is gradually occurring, paving the way for innovative therapeutical approaches, such as polypharmacology. The aim of this review is to provide an overview of the main pharmacological features of most promising nature-based scaffolds for a possible application in drug discovery, especially for NDDs, highlighting their multifaceted effects against OS and neuronal disorders.
Andrea Bacci; Massimiliano Runfola; Simona Sestito; Simona Rapposelli. Beyond Antioxidant Effects: Nature-Based Templates Unveil New Strategies for Neurodegenerative Diseases. Antioxidants 2021, 10, 367 .
AMA StyleAndrea Bacci, Massimiliano Runfola, Simona Sestito, Simona Rapposelli. Beyond Antioxidant Effects: Nature-Based Templates Unveil New Strategies for Neurodegenerative Diseases. Antioxidants. 2021; 10 (3):367.
Chicago/Turabian StyleAndrea Bacci; Massimiliano Runfola; Simona Sestito; Simona Rapposelli. 2021. "Beyond Antioxidant Effects: Nature-Based Templates Unveil New Strategies for Neurodegenerative Diseases." Antioxidants 10, no. 3: 367.
Enterovirus A71 (EV-A71) infection has emerged as a significant public health concern atthe global level. Epidemic events of EV-A71 have been reported worldwide, and this succession of outbreaks has heightened concern that EV-A71 may become a public health threat. In recent years, widespread A71 enterovirus also occurred in European countries. EV-A71 infection causes hand-foot-mouth disease (HFMD), herpangina, and fever. However, it can sometimes induce a variety of neurological complications, including encephalitis, aseptic meningitis, pulmonary edema, and acute flaccid paralysis. We identified new benzimidazole derivatives and described their in vitro cytotoxicity and broad-spectrum anti-enterovirus activity. Among them, derivative 2b resulted in interesting activity against EV-A71, and therefore it was selected for further investigations. Compound 2b proved to be able to protect cell monolayers from EV-A71-induced cytopathogenicity, with an EC50 of 3 µM. Moreover, Vero-76 cells resulted in being significantly protected from necrosis and apoptosis when treated with 2b at 20 and 80 µM. Compound 2b reduced viral adsorption to Vero-76 cells, and when evaluated in a time-of-addition assay, the derivative had the highest effect when added during the infection period. Moreover, derivative 2b reduced viral penetration into host cells. Besides, 2b did not affect intestinal monolayers permeability, showing no toxic effects. A detailed insight into the efficacy of compound 2b against EV-A71 showed a dose-dependent reduction in the viral titer, also at low concentrations. Mechanism of action investigations suggested that our derivative can inhibit viral endocytosis by reducing viral attachment to and penetration into host cells. Pharmacokinetic and toxicity predictions validated compound 2b as a good candidate for further in vivo assays.
Roberta Ibba; Antonio Carta; Silvia Madeddu; Paola Caria; Gabriele Serreli; Sandra Piras; Simona Sestito; Roberta Loddo; Giuseppina Sanna. Inhibition of Enterovirus A71 by a Novel 2-Phenyl-Benzimidazole Derivative. Viruses 2021, 13, 58 .
AMA StyleRoberta Ibba, Antonio Carta, Silvia Madeddu, Paola Caria, Gabriele Serreli, Sandra Piras, Simona Sestito, Roberta Loddo, Giuseppina Sanna. Inhibition of Enterovirus A71 by a Novel 2-Phenyl-Benzimidazole Derivative. Viruses. 2021; 13 (1):58.
Chicago/Turabian StyleRoberta Ibba; Antonio Carta; Silvia Madeddu; Paola Caria; Gabriele Serreli; Sandra Piras; Simona Sestito; Roberta Loddo; Giuseppina Sanna. 2021. "Inhibition of Enterovirus A71 by a Novel 2-Phenyl-Benzimidazole Derivative." Viruses 13, no. 1: 58.
Objectives Although the hepatomitogenic activity of triiodothyronine (T3) is well established, the wide range of harmful effects exerted by this hormone precludes its use in liver regenerative therapy. Selective agonists of the beta isoform of thyroid hormone receptor (TRβ) do not exhibit T3‐induced cardiotoxicity and show a good safety profile in patients with NASH. The aim of this study was to investigate whether two novel TRβ agonists, the prodrug TG68 and the active compound IS25 could stimulate hepatocyte proliferation without T3/TRα‐dependent side effects. Methods Rats were treated with three different doses (12.5, 25 and 50 μg/100 g body weight) for one week. Hepatocyte proliferation, liver injury and serum biochemical parameters were measured by immunohistochemistry, qRT‐PCR and Western blot. Results Both drugs increased hepatocyte proliferation as assessed by bromodeoxyuridine incorporation (from 14% to 28% vs 5% of controls) and mitotic activity. Enhanced proliferation occurred in the absence of significant signs of liver injury as shown by lack of increased serum transaminase levels or of apoptosis. No cardiac or renal hypertrophy typically associated with treatment with T3 was observed. Importantly, no proliferation of pancreatic acinar cells, such as that seen after administration of T3 or the TRβ agonist GC1 was detected following either TG68 or IS25, demonstrating the hepato‐specificity of these novel TRβ agonists. Conclusions The present study shows that TG68 and IS25 induce massive hepatocyte proliferation without overt toxicity. Hence, these agents may have a significant clinical application for regenerative therapies in liver transplantation or other surgical settings.
Andrea Perra; Marta Anna Kowalik; Lavinia Cabras; Massimiliano Runfola; Simona Sestito; Cristina Migliore; Silvia Giordano; Grazia Chiellini; Simona Rapposelli; Amedeo Columbano. Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration. Cell Proliferation 2020, 53, e12808 .
AMA StyleAndrea Perra, Marta Anna Kowalik, Lavinia Cabras, Massimiliano Runfola, Simona Sestito, Cristina Migliore, Silvia Giordano, Grazia Chiellini, Simona Rapposelli, Amedeo Columbano. Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration. Cell Proliferation. 2020; 53 (5):e12808.
Chicago/Turabian StyleAndrea Perra; Marta Anna Kowalik; Lavinia Cabras; Massimiliano Runfola; Simona Sestito; Cristina Migliore; Silvia Giordano; Grazia Chiellini; Simona Rapposelli; Amedeo Columbano. 2020. "Potential role of two novel agonists of thyroid hormone receptor‐β on liver regeneration." Cell Proliferation 53, no. 5: e12808.
In the two decades since its discovery, a large body of evidence has amassed to highlight the potential of 3-iodothyronamine (T1AM) as an antiobesity drug, whose pleiotropic signaling actions profoundly impact energy metabolism. In the present review, we recapitulate the most relevant properties of T1AM, including its structural and functional relationship to thyroid hormone, its endogenous levels, molecular targets, as well as its genomic and non-genomic effects on metabolism elicited in experimental models after exogenous administration. The physiological and pathophysiological relevance of T1AM in the regulation of energy homeostasis and metabolism is also discussed, along with its potential therapeutic applications in metabolic disturbances. Finally, we examine a number of T1AM analogs that have been recently developed with the aim of designing novel pharmacological agents for the treatment of interlinked diseases, such as metabolic and neurodegenerative disorders, as well as additional synthetic tools that can be exploited to further explore T1AM-dependent mechanisms and the physiological roles of trace amine-associated receptor 1 (TAAR1)-mediated effects.
Grazia Rutigliano; Lavinia Bandini; Simona Sestito; Grazia Chiellini. 3-Iodothyronamine and Derivatives: New Allies Against Metabolic Syndrome? International Journal of Molecular Sciences 2020, 21, 2005 .
AMA StyleGrazia Rutigliano, Lavinia Bandini, Simona Sestito, Grazia Chiellini. 3-Iodothyronamine and Derivatives: New Allies Against Metabolic Syndrome? International Journal of Molecular Sciences. 2020; 21 (6):2005.
Chicago/Turabian StyleGrazia Rutigliano; Lavinia Bandini; Simona Sestito; Grazia Chiellini. 2020. "3-Iodothyronamine and Derivatives: New Allies Against Metabolic Syndrome?" International Journal of Molecular Sciences 21, no. 6: 2005.
The family Arecaceae includes 181 genera and 2,600 species with a high diversity in physical characteristics. Areca plants, commonly palms, which are able to grow in nearly every type of habitat, prefer tropical and subtropical climates. The most studied species Areca catechu L. contains phytochemicals as phenolics and alkaloids with biological properties. The phenolics are mainly distributed in roots followed by fresh unripe fruits, leaves, spikes, and veins, while the contents of alkaloids are in the order of roots, fresh unripe fruits, spikes, leaves, and veins. This species has been reputed to provide health effects on the cardiovascular, respiratory, nervous, metabolic, gastrointestinal, and reproductive systems. However, in many developing countries, quid from this species has been associated with side effects, which include the destruction of the teeth, impairment of oral hygiene, bronchial asthma, or oral cancer. Despite these side effects, which are also mentioned in this work, the present review collects the main results of biological properties of the phytochemicals in A. catechu. This study emphasizes the in vitro and in vivo antioxidant, antimicrobial, anticancer, and clinical effectiveness in humans. In this sense, A. catechu have demonstrated effectiveness in several reports through in vitro and in vivo experiments on disorders such as antimicrobial, antioxidant, or anticancer. Moreover, our findings demonstrate that this species presents clinical effectiveness on neurological disorders. Hence, A. catechu extracts could be used as a bioactive ingredient for functional food, nutraceuticals, or cosmeceuticals. However, further studies, especially extensive and comprehensive clinical trials, are recommended for the use of Areca in the treatment of diseases.
Bahare Salehi; Dmitry A. Konovalov; Pascaline Fru; Petrina Kapewangolo; Gregorio Peron; Mileski S. Ksenija; Susana M. Cardoso; Olivia R. Pereira; Manisha Nigam; Silvana Nicola; Giuseppe Pignata; Simona Rapposelli; Simona Sestito; Nanjangud V. Anil Kumar; María De La Luz Cádiz‐Gurrea; Antonio Segura‐Carretero; Abhay P. Mishra; Mehdi Sharifi‐Rad; William C. Cho; Yasaman Taheri; William N. Setzer; Javad Sharifi‐Rad. Areca catechu —From farm to food and biomedical applications. Phytotherapy Research 2020, 34, 2140 -2158.
AMA StyleBahare Salehi, Dmitry A. Konovalov, Pascaline Fru, Petrina Kapewangolo, Gregorio Peron, Mileski S. Ksenija, Susana M. Cardoso, Olivia R. Pereira, Manisha Nigam, Silvana Nicola, Giuseppe Pignata, Simona Rapposelli, Simona Sestito, Nanjangud V. Anil Kumar, María De La Luz Cádiz‐Gurrea, Antonio Segura‐Carretero, Abhay P. Mishra, Mehdi Sharifi‐Rad, William C. Cho, Yasaman Taheri, William N. Setzer, Javad Sharifi‐Rad. Areca catechu —From farm to food and biomedical applications. Phytotherapy Research. 2020; 34 (9):2140-2158.
Chicago/Turabian StyleBahare Salehi; Dmitry A. Konovalov; Pascaline Fru; Petrina Kapewangolo; Gregorio Peron; Mileski S. Ksenija; Susana M. Cardoso; Olivia R. Pereira; Manisha Nigam; Silvana Nicola; Giuseppe Pignata; Simona Rapposelli; Simona Sestito; Nanjangud V. Anil Kumar; María De La Luz Cádiz‐Gurrea; Antonio Segura‐Carretero; Abhay P. Mishra; Mehdi Sharifi‐Rad; William C. Cho; Yasaman Taheri; William N. Setzer; Javad Sharifi‐Rad. 2020. "Areca catechu —From farm to food and biomedical applications." Phytotherapy Research 34, no. 9: 2140-2158.
3-iodothyronamine (T1AM) and the recently developed analog SG-2 are rapidly emerging as promising multi-target neuroprotective ligands able to reprogram lipid metabolism and to produce memory enhancement in mice. To elucidate the molecular mechanisms underlying the multi-target effects of these novel drug candidates, here we investigated whether the modulation of SIRT6, known to play a key role in reprogramming energy metabolism, might also drive the activation of clearing pathways, such as autophagy and ubiquitine-proteasome (UP), as further mechanisms against neurodegeneration. We show that both T1AM and SG-2 increase autophagy in U87MG cells by inducing the expression of SIRT6, which suppresses Akt activity thus leading to mTOR inhibition. This effect was concomitant with down-regulation of autophagy-related genes, including Hif1α, p53 and mTOR. Remarkably, when mTOR was inhibited a concomitant activation of autophagy and UP took place in U87MG cells. Since both compounds activate autophagy, which is known to sustain long term potentiation (LTP) in the entorhinal cortex (EC) and counteracting AD pathology, further electrophysiological studies were carried out in a transgenic mouse model of AD. We found that SG-2 was able to rescue LTP with an efficacy comparable to T1AM, further underlying its potential as a novel pleiotropic agent for neurodegenerative disorders treatment.
Lorenza Bellusci; Massimiliano Runfola; Vittoria Carnicelli; Simona Sestito; Federica Fulceri; Filippo Santucci; Paola Lenzi; Francesco Fornai; Simona Rapposelli; Nicola Origlia; Riccardo Zucchi; Grazia Chiellini. Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6. Molecules 2020, 25, 1054 .
AMA StyleLorenza Bellusci, Massimiliano Runfola, Vittoria Carnicelli, Simona Sestito, Federica Fulceri, Filippo Santucci, Paola Lenzi, Francesco Fornai, Simona Rapposelli, Nicola Origlia, Riccardo Zucchi, Grazia Chiellini. Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6. Molecules. 2020; 25 (5):1054.
Chicago/Turabian StyleLorenza Bellusci; Massimiliano Runfola; Vittoria Carnicelli; Simona Sestito; Federica Fulceri; Filippo Santucci; Paola Lenzi; Francesco Fornai; Simona Rapposelli; Nicola Origlia; Riccardo Zucchi; Grazia Chiellini. 2020. "Endogenous 3-Iodothyronamine (T1AM) and Synthetic Thyronamine-Like Analog SG-2 Act as Novel Pleiotropic Neuroprotective Agents through the Modulation of SIRT6." Molecules 25, no. 5: 1054.
Although triiodothyronine (T3) induces several beneficial effects on lipid metabolism, its use is hampered by toxic side-effects, such as tachycardia, arrhythmia, heart failure, bone and muscle catabolism and mood disturbances. Since the α isoform of thyroid hormone receptors (TRs) is the main cause of T3-related harmful effects, several efforts have been made to develop selective agonists of the β isoform that could induce some beneficial effects (i.e. lowering triglyceride and cholesterol levels reducing obesity and improving metabolic syndrome), while overcoming most of the adverse T3-dependent side effects. Herein, we describe the drug discovery process sustained by ADME-Toxicity analysis that led us to identify novel agonists with selectivity for the isoform TRβ and an acceptable off-target and absorption, distribution metabolism, excretion and toxicity (ADME-Tox) profile. Within the small series of compounds synthesized, derivatives 1 and 3, emerge from this analysis as "potentially safe" to be engaged in preclinical studies. In in vitro investigation proved that both compounds were able to reduce lipid accumulation in HepG2 and promote lipolysis with comparable effects to those elicited by T3, used as reference drug. Moreover, a preliminary in vivo study confirmed the apparent lack of toxicity, thus suggesting compounds 1 and 3 as new potential TRβ-selective thyromimetics.
Massimiliano Runfola; Simona Sestito; Lorenza Bellusci; Valeria La Pietra; Vincenzo Maria D’Amore; Marta Anna Kowalik; Grazia Chiellini; Sheraz Gul; Andrea Perra; Amedeo Columbano; Luciana Marinelli; Ettore Novellino; Simona Rapposelli. Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-toxicity analysis. European Journal of Medicinal Chemistry 2020, 188, 112006 .
AMA StyleMassimiliano Runfola, Simona Sestito, Lorenza Bellusci, Valeria La Pietra, Vincenzo Maria D’Amore, Marta Anna Kowalik, Grazia Chiellini, Sheraz Gul, Andrea Perra, Amedeo Columbano, Luciana Marinelli, Ettore Novellino, Simona Rapposelli. Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-toxicity analysis. European Journal of Medicinal Chemistry. 2020; 188 ():112006.
Chicago/Turabian StyleMassimiliano Runfola; Simona Sestito; Lorenza Bellusci; Valeria La Pietra; Vincenzo Maria D’Amore; Marta Anna Kowalik; Grazia Chiellini; Sheraz Gul; Andrea Perra; Amedeo Columbano; Luciana Marinelli; Ettore Novellino; Simona Rapposelli. 2020. "Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-toxicity analysis." European Journal of Medicinal Chemistry 188, no. : 112006.
In order to rapidly identify the phenotypic profile and possible off-target liability effects of novel synthesized thyromimetics for selection of lead compounds for further optimization studies, we performed in vitro screening on a new small library of synthetic thyromimetics. A comprehensive panel of early toxicity assays comprising cytotoxicity on 4 different cell lines (osteosarcoma, U2OS; lung fibroblast, hTERT; human breast adenocarcinoma, MCF7; human embryonic kidney, HEK293), hERG liability, cytochrome P450 inhibition (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 isoforms), and off-target liability against selected proteins (Aurora B kinase and phosphodiesterase PDE4C1) and epigenetic enzymes (HDAC4, HDAC6, HDAC8, HDAC9 & SIRT7). All the compounds were screened at 10 μM in at least triplicate using well-established in vitro assays with readouts in luminescence or fluorescence polarization mode. The raw data were processed using Microsoft Excel and the Z′ for each assay was calculated (acceptable Z' >0.40). The processed and normalized data were organized in tables and visualized using spider plots. The results which are reported in the present manuscript can be used in prediction studies of early toxicity and off-target liabilities of other thyromimetics using in silico methods. The data reported herein support our research article entitled “Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-Toxicity analysis” by Runfola M., Sestito S., et al. [1]
Massimiliano Runfola; Simona Sestito; Sheraz Gul; Grazia Chiellini; Simona Rapposelli. Collecting data through high throughput in vitro early toxicity and off-target liability assays to rapidly identify limitations of novel thyromimetics. Data in Brief 2020, 29, 105206 .
AMA StyleMassimiliano Runfola, Simona Sestito, Sheraz Gul, Grazia Chiellini, Simona Rapposelli. Collecting data through high throughput in vitro early toxicity and off-target liability assays to rapidly identify limitations of novel thyromimetics. Data in Brief. 2020; 29 ():105206.
Chicago/Turabian StyleMassimiliano Runfola; Simona Sestito; Sheraz Gul; Grazia Chiellini; Simona Rapposelli. 2020. "Collecting data through high throughput in vitro early toxicity and off-target liability assays to rapidly identify limitations of novel thyromimetics." Data in Brief 29, no. : 105206.
Deregulation of different intracellular signaling pathways is a common feature in cancer. Numerous studies indicate that persistent activation of the phosphoinositide 3-kinase (PI3K) pathway is often observed in cancer cells. 3-phosphoinositide dependent protein kinase-1 (PDK1), a transducer protein that functions downstream of PI3K, is responsible for the regulation of cell proliferation and migration and it also has been found to play a key role in different cancers, pancreatic and breast cancer amongst others. As PI3K is being described to be aberrantly expressed in several cancer types, designing inhibitors targeting various downstream molecules of PI3K has been the focus of anticancer agent development for a long time. In particular, dual inhibitory drugs targeting key signaling molecules in the PI3K pathway have attracted the attention of scientists. Several drugs have progressed to clinical trials, with limited success due to toxicity and bioavailability concerns. Very few anticancer drugs targeting the PI3K pathway have been approved for clinical use and their efficacy is particularly limited towards certain tumors such as pancreatic cancer. Here, we tested two drugs displaying dual inhibitory activity towards PDK1 and Aurora kinase A in a panel of pancreatic cancer cell lines and in two in vivo models of pancreatic cancer. Our data show that both inhibitors are able to impair cell proliferation and clonogenic potential in pancreatic cancer cells. However, the limited activity of both compounds in vivo indicates that further optimization of the pharmacokinetics properties is required.
Ilaria Casari; Alice Domenichini; Simona Sestito; Emily Capone; Gianluca Sala; Simona Rapposelli; Marco Falasca. Dual PDK1/Aurora Kinase A Inhibitors Reduce Pancreatic Cancer Cell Proliferation and Colony Formation. Cancers 2019, 11, 1695 .
AMA StyleIlaria Casari, Alice Domenichini, Simona Sestito, Emily Capone, Gianluca Sala, Simona Rapposelli, Marco Falasca. Dual PDK1/Aurora Kinase A Inhibitors Reduce Pancreatic Cancer Cell Proliferation and Colony Formation. Cancers. 2019; 11 (11):1695.
Chicago/Turabian StyleIlaria Casari; Alice Domenichini; Simona Sestito; Emily Capone; Gianluca Sala; Simona Rapposelli; Marco Falasca. 2019. "Dual PDK1/Aurora Kinase A Inhibitors Reduce Pancreatic Cancer Cell Proliferation and Colony Formation." Cancers 11, no. 11: 1695.
Hydrogen sulphide (H2S) is an endogenous gasotransmitter, largely known as a pleiotropic mediator endowed with antioxidant, anti-inflammatory, pro-autophagic, and neuroprotective properties. Moreover, a strong relationship between H2S and aging has been recently identified and consistently, a significant decline of H2S levels has been observed in patients affected by Alzheimer's disease (AD). On this basis, the use of H2S-donors could represent an exciting and intriguing strategy to be pursued for the treatment of neurodegenerative diseases (NDDs). In this work, we designed a small series of multitarget molecules combining the rivastigmine-scaffold, a well-established drug already approved for AD, with sulforaphane (SFN) and erucin (ERN), two natural products deriving from the enzymatic hydrolysis of glucosinolates contained in broccoli and rocket, respectively, endowed both with antioxidant and neuroprotective effects. Notably, all new synthetized hybrids exhibit a H2S-donor profile in vitro and elicit protective effects in a model of LPS-induced microglia inflammation. Moreover, a decrease in NO production has been observed in LPS-stimulated cells pre-treated with the compounds. Finally, the compounds showed neuroprotective and antioxidant activities in human neuronal cells. The most interesting compounds have been further investigated to elucidate the possible mechanism of action.
Simona Sestito; Letizia Pruccoli; Massimiliano Runfola; Valentina Citi; Alma Martelli; Giuseppe Saccomanni; Vincenzo Calderone; Andrea Tarozzi; Simona Rapposelli. Design and synthesis of H2S-donor hybrids: A new treatment for Alzheimer's disease? European Journal of Medicinal Chemistry 2019, 184, 111745 .
AMA StyleSimona Sestito, Letizia Pruccoli, Massimiliano Runfola, Valentina Citi, Alma Martelli, Giuseppe Saccomanni, Vincenzo Calderone, Andrea Tarozzi, Simona Rapposelli. Design and synthesis of H2S-donor hybrids: A new treatment for Alzheimer's disease? European Journal of Medicinal Chemistry. 2019; 184 ():111745.
Chicago/Turabian StyleSimona Sestito; Letizia Pruccoli; Massimiliano Runfola; Valentina Citi; Alma Martelli; Giuseppe Saccomanni; Vincenzo Calderone; Andrea Tarozzi; Simona Rapposelli. 2019. "Design and synthesis of H2S-donor hybrids: A new treatment for Alzheimer's disease?" European Journal of Medicinal Chemistry 184, no. : 111745.
The very aggressive nature and low survival rate of pancreatic ductal adenocarcinoma (PDAC) dictates the necessity to find novel efficacious therapies. Recent evidence suggests that phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1) are key effectors of oncogenic KRAS in PDAC. Herein, we report the role and mechanism of action of PDK1, a protein kinase of the AGC family, in PDAC. PDAC cell lines were treated with selective PDK1 inhibitors or transfected with specific PDK1-targeting siRNAs. In vitro and in vivo assays were performed to investigate the functional role of PDK1 in PDAC. Specifically, anchorage-dependent and anchorage-independent growth was assessed in PDAC cells upon inhibition or downregulation of PDK1. Detailed investigation of the effect of PDK1 inhibition/downregulation on specific signalling pathways was also performed by Western blotting analysis. A xenograft tumour mouse model was used to determine the effect of pharmacological inhibition of PDK1 on PDAC cells growth in vivo. Treatment with specific inhibitors of PDK1 impaired anchorage-dependent and anchorage-independent growth of pancreatic cancer cell lines, as well as pancreatic tumour growth in a xenograft model. Mechanistically, inhibition or downregulation of PDK1 resulted in reduced activation of the serum/glucocorticoid regulated kinase family member 3 and subsequent reduced phosphorylation of its target N-Myc downstream regulated 1. Additionally, we found that combination of sub-optimal concentrations of inhibitors selective for PDK1 and the class IB PI3K isoform p110γ inhibits pancreatic cancer cell growth and colonies formation more potently than each single treatment. Our data indicate that PDK1 is a suitable target for therapeutic intervention in PDAC and support the clinical development of PDK1 inhibitors for PDAC.
Aikaterini Emmanouilidi; Chanse A. Fyffe; Riccardo Ferro; Charlotte E. Edling; Emily Capone; Simona Sestito; Simona Rapposelli; Rossano Lattanzio; Stefano Iacobelli; Gianluca Sala; Tania Maffucci; Marco Falasca. Preclinical validation of 3-phosphoinositide-dependent protein kinase 1 inhibition in pancreatic cancer. Journal of Experimental & Clinical Cancer Research 2019, 38, 1 -12.
AMA StyleAikaterini Emmanouilidi, Chanse A. Fyffe, Riccardo Ferro, Charlotte E. Edling, Emily Capone, Simona Sestito, Simona Rapposelli, Rossano Lattanzio, Stefano Iacobelli, Gianluca Sala, Tania Maffucci, Marco Falasca. Preclinical validation of 3-phosphoinositide-dependent protein kinase 1 inhibition in pancreatic cancer. Journal of Experimental & Clinical Cancer Research. 2019; 38 (1):1-12.
Chicago/Turabian StyleAikaterini Emmanouilidi; Chanse A. Fyffe; Riccardo Ferro; Charlotte E. Edling; Emily Capone; Simona Sestito; Simona Rapposelli; Rossano Lattanzio; Stefano Iacobelli; Gianluca Sala; Tania Maffucci; Marco Falasca. 2019. "Preclinical validation of 3-phosphoinositide-dependent protein kinase 1 inhibition in pancreatic cancer." Journal of Experimental & Clinical Cancer Research 38, no. 1: 1-12.
The identification of a valid therapeutic treatment for Alzheimer's disease (AD) represents nowadays an urgent and still unmet medical need, since currently available anti-AD drugs only relieve symptoms and show a modest efficacy. Recent evidence indicates that multi-target-directed ligands (MTDLs) can potentially provide an effective strategy to develop innovative therapies directed towards the onset and progression of this multifactorial neurodegenerative disorder. In this work we designed, synthesized and evaluated a new series of MTDLs bearing the rivastigmine skeleton (ChE-inhibitor) linked to known metal-chelating moieties with linkers of different length. For all the novel derivatives, AChE/BuChE inhibitory activity, ROS scavenging activity and potential cytotoxicity have been assessed. For the best compound (4), copper chelating properties and neuroprotective effects were also evaluated. Our data demonstrated that hybrid derivative 4 is able to effectively inhibit AChE and BuChE and to chelate copper, showing a protective action on neurons. These results, although preliminary, indicate that compound 4 can be considered as a possible hit molecule for the development of new anti-AD MTDLs.
Simona Sestito; Shengnan Wang; Qiuhe Chen; Junfeng Lu; Simone Bertini; Christian Pomelli; Grazia Chiellini; Xixin He; Rongbiao Pi; Simona Rapposelli. Multi-targeted ChEI-copper chelating molecules as neuroprotective agents. European Journal of Medicinal Chemistry 2019, 174, 216 -225.
AMA StyleSimona Sestito, Shengnan Wang, Qiuhe Chen, Junfeng Lu, Simone Bertini, Christian Pomelli, Grazia Chiellini, Xixin He, Rongbiao Pi, Simona Rapposelli. Multi-targeted ChEI-copper chelating molecules as neuroprotective agents. European Journal of Medicinal Chemistry. 2019; 174 ():216-225.
Chicago/Turabian StyleSimona Sestito; Shengnan Wang; Qiuhe Chen; Junfeng Lu; Simone Bertini; Christian Pomelli; Grazia Chiellini; Xixin He; Rongbiao Pi; Simona Rapposelli. 2019. "Multi-targeted ChEI-copper chelating molecules as neuroprotective agents." European Journal of Medicinal Chemistry 174, no. : 216-225.
Introduction: 3-Phosphoinositide-dependent kinase 1 (PDK1), the “master kinase of the AGC protein kinase family”, plays a key role in cancer development and progression. Although it has been rather overlooked, in the last decades a growing number of molecules have been developed to effectively modulate the PDK1 enzyme. Areas covered: This review collects different PDK1 inhibitors patented from October 2014 to December 2018. The molecules have been classified on the basis of the chemical structure/type of inhibition and for each general structure examples have been discussed in extenso. Expert opinion: The role of PDK1 in cancer development and progression as well as in metastasis formation and in chemoresistance has been confirmed by a large number of studies. Therefore, the pharmaceutical discovery in both public and private institutions is still ongoing despite the plentiful molecules already published. The majority of the new molecules synthetized interact with binding sites different from the ATP binding site (i.e. PIF pocket or DFG-out conformation). However, many researchers are still looking for innovative PDK1 modulation strategy such as combination of well-known inhibitory agents or multitarget ligands, aiming to block, together with PDK1, other different critical players in the wide panorama of proteins involved in tumor pathways.
Simona Sestito; Simona Rapposelli. A patent update on PDK1 inhibitors (2015-present). Expert Opinion on Therapeutic Patents 2019, 29, 271 -282.
AMA StyleSimona Sestito, Simona Rapposelli. A patent update on PDK1 inhibitors (2015-present). Expert Opinion on Therapeutic Patents. 2019; 29 (4):271-282.
Chicago/Turabian StyleSimona Sestito; Simona Rapposelli. 2019. "A patent update on PDK1 inhibitors (2015-present)." Expert Opinion on Therapeutic Patents 29, no. 4: 271-282.
Hydrogen sulphide has recently drawn much attention due to its potent anti-inflammatory and neuroprotective roles in brain functions. The purpose of the current study was to exploit these beneficial properties of H2S to design a new agent for the treatment of Alzheimer’s disease (AD). To pursue our aims, we replaced the free amine group of memantine with an isothiocyanate functionality as a putative H2S-donor moiety. The new chemical entity, named memit, was then tested in vitro to determine whether it retains the pharmacological profile of the “native drug”, while also providing a source of H2S in the CNS. Indeed, Memit showed the ability to release H2S through a cysteine-mediated mechanism, thus generating memantine. Moreover, the new hybrid molecule exerts protective effects against neuronal inflammation and induces a drastic fall in ROS production. In addition, memit was also able to reduce the Aβ(1-42) self-induced aggregation and exerted cytoprotective effect against Aβ oligomers-induced damage in both human neurons and rat microglia cells. Finally, similarly to memantine, the new compound promotes autophagy, a complex process required for cellular homeostasis in cell survival that results to be altered in neurodegenerative diseases. In conclusion, our study revealed that memit is a prodrug of memantine. Further in vivo studies will be necessary to fully investigate the synergic or cumulative effects due to the H2S-releasing moiety and the native drug.
Simona Sestito; Simona Daniele; Deborah Pietrobono; Valentina Citi; Lorenza Bellusci; Grazia Chiellini; Vincenzo Calderone; Claudia Martini; Simona Rapposelli. Memantine prodrug as a new agent for Alzheimer’s Disease. Scientific Reports 2019, 9, 1 -11.
AMA StyleSimona Sestito, Simona Daniele, Deborah Pietrobono, Valentina Citi, Lorenza Bellusci, Grazia Chiellini, Vincenzo Calderone, Claudia Martini, Simona Rapposelli. Memantine prodrug as a new agent for Alzheimer’s Disease. Scientific Reports. 2019; 9 (1):1-11.
Chicago/Turabian StyleSimona Sestito; Simona Daniele; Deborah Pietrobono; Valentina Citi; Lorenza Bellusci; Grazia Chiellini; Vincenzo Calderone; Claudia Martini; Simona Rapposelli. 2019. "Memantine prodrug as a new agent for Alzheimer’s Disease." Scientific Reports 9, no. 1: 1-11.
The struggle to find novel efficacious pharmacological approaches for cancer treatment has led to the identification of several kinases involved in neoplastic genesis and cell development.
Simona Sestito; Sara Chiarugi; Eleonora Margheritis; Massimiliano Runfola; Simone Bertini; Gianpiero Garau; Simona Rapposelli. Novel Dual PDK1/AurK-A Inhibitors for Cancer Therapy: Med Chem Evolution and Crystallographic Investigation. Proceedings 2019, 22, 45 .
AMA StyleSimona Sestito, Sara Chiarugi, Eleonora Margheritis, Massimiliano Runfola, Simone Bertini, Gianpiero Garau, Simona Rapposelli. Novel Dual PDK1/AurK-A Inhibitors for Cancer Therapy: Med Chem Evolution and Crystallographic Investigation. Proceedings. 2019; 22 (1):45.
Chicago/Turabian StyleSimona Sestito; Sara Chiarugi; Eleonora Margheritis; Massimiliano Runfola; Simone Bertini; Gianpiero Garau; Simona Rapposelli. 2019. "Novel Dual PDK1/AurK-A Inhibitors for Cancer Therapy: Med Chem Evolution and Crystallographic Investigation." Proceedings 22, no. 1: 45.
Epibatidine is a natural alkaloid that acts at nicotinic acetylcholine receptors (nAChRs). The present review aims to carefully discuss the affinity of epibatidine and its synthetic derivatives, analogues to nAChRs for α4β2 subtype, pharmacokinetic parameters, and its role in health. Published literature shows a low affinity and lack of binding of epibatidine and its synthetic analogues to plasma proteins, indicating their availability for metabolism. Because of its high toxicity, the therapeutic use of epibatidine is hampered. However, new synthetic analogs endowed from this molecule have been developed, with a better therapeutic window and improved selectivity. All these aspects are also discussed here. On the other hand, many reports are devoted to structure–activity relationships to obtain optically active epibatidine and its analogues, and to access its pharmacological effects. Although pharmacological results are obtained from experimental studies and only a few clinical trials, new perspectives are open for the discovery of new drug therapies.
Bahare Salehi; Simona Sestito; Simona Rapposelli; Gregorio Peron; Daniela Calina; Mehdi Sharifi-Rad; Farukh Sharopov; Natália Martins; Javad Sharifi-Rad. Epibatidine: A Promising Natural Alkaloid in Health. Biomolecules 2018, 9, 6 .
AMA StyleBahare Salehi, Simona Sestito, Simona Rapposelli, Gregorio Peron, Daniela Calina, Mehdi Sharifi-Rad, Farukh Sharopov, Natália Martins, Javad Sharifi-Rad. Epibatidine: A Promising Natural Alkaloid in Health. Biomolecules. 2018; 9 (1):6.
Chicago/Turabian StyleBahare Salehi; Simona Sestito; Simona Rapposelli; Gregorio Peron; Daniela Calina; Mehdi Sharifi-Rad; Farukh Sharopov; Natália Martins; Javad Sharifi-Rad. 2018. "Epibatidine: A Promising Natural Alkaloid in Health." Biomolecules 9, no. 1: 6.
Glioblastoma multiforme (GBM) is the most common tumor of the CNS, and the deadliest form of brain cancer. The rapid progression, the anatomic location in the brain and a deficient knowledge of the pathophysiology, often limit the effectiveness of therapeutic interventions. Current pillars of GBM therapies include surgical resection, radiotherapy and chemotherapy, but the low survival rate and the short life expectation following these treatments strongly underline the urgency to identify innovative and more effective therapeutic tools. Frequently, patients subjected to a mono-target therapy, such as Temozolomide (TMZ), develop drug resistance and undergo relapse, indicating that targeting a single cellular node is not sufficient for eradication of this disease. In this context, a multi-targeted therapeutic approach aimed at using compounds, alone or in combination, capable of inhibiting more than one specific molecular target, offers a promising alternative. Such strategies have already been well integrated into drug discovery campaigns, including in the field of anticancer drugs. In this miniperspective, we will discuss the recent progress in the treatment of GBM focusing on innovative and effective preclinical strategies, which are based on a multi-targeted approach.
Simona Sestito; Massimiliano Runfola; Marco Tonelli; Grazia Chiellini; Simona Rapposelli. New Multitarget Approaches in the War Against Glioblastoma: A Mini-Perspective. Frontiers in Pharmacology 2018, 9, 874 .
AMA StyleSimona Sestito, Massimiliano Runfola, Marco Tonelli, Grazia Chiellini, Simona Rapposelli. New Multitarget Approaches in the War Against Glioblastoma: A Mini-Perspective. Frontiers in Pharmacology. 2018; 9 ():874.
Chicago/Turabian StyleSimona Sestito; Massimiliano Runfola; Marco Tonelli; Grazia Chiellini; Simona Rapposelli. 2018. "New Multitarget Approaches in the War Against Glioblastoma: A Mini-Perspective." Frontiers in Pharmacology 9, no. : 874.
3-Iodothyronamine (T1AM) is an endogenous high-affinity ligand of the trace amine-associated receptor 1 (TAAR1), detected in mammals in many organs, including the brain. Recent evidence indicates that pharmacological TAAR1 activation may offer a novel therapeutic option for the treatment of a wide range of neuropsychiatric and metabolic disorders. To assess potential neuroprotection by TAAR1 agonists, in the present work, we initially investigated whether T1AM and its corresponding 3-methylbiaryl-methane analog SG-2 can improve learning and memory when systemically administered to mice at submicromolar doses, and whether these effects are modified under conditions of MAO inhibition by clorgyline. Our results revealed that when i.p. injected to mice, both T1AM and SG-2 produced memory-enhancing and hyperalgesic effects, while increasing ERK1/2 phosphorylation and expression of transcription factor c-fos. Notably, both compounds appeared to rely on the action of ubiquitous enzymes MAO to produce the corresponding oxidative metabolites that were then able to activate the histaminergic system. Since autophagy is key for neuronal plasticity, in a second line of experiments we explored whether T1AM and synthetic TAAR1 agonists SG1 and SG2 were able to induce autophagy in human glioblastoma cell lines (U-87MG). After treatment of U-87MG cells with 1 μM T1AM, SG-1, SG-2 transmission electron microscopy (TEM) and immunofluorescence (IF) showed a significant time-dependent increase of autophagy vacuoles and microtubule-associated protein 1 light chain 3 (LC3). Consistently, Western blot analysis revealed a significant increase of the LC3II/LC3I ratio, with T1AM and SG-1 being the most effective agents. A decreased level of the p62 protein was also observed after treatment with T1AM and SG-1, which confirms the efficacy of these compounds as autophagy inducers in U-87MG cells. In the process to dissect which pathway induces ATG, the effects of these compounds were evaluated on the PI3K-AKT-mTOR pathway. We found that 1 μM T1AM, SG-1 and SG-2 decreased pAKT/AKT ratio at 0.5 and 4 h after treatment, suggesting that autophagy is induced by inhibiting mTOR phosphorylation by PI3K-AKT-mTOR pathway. In conclusion, our study shows that T1AM and thyronamine-like derivatives SG-1 and SG-2 might represent valuable tools to therapeutically intervene with neurological disorders.
Lorenza Bellusci; Annunziatina Laurino; Martina Sabatini; Simona Sestito; Paola Lenzi; Laura Raimondi; Simona Rapposelli; Francesca Biagioni; Francesco Fornai; Alessandra Salvetti; Leonardo Rossi; Riccardo Zucchi; Grazia Chiellini. New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection. Frontiers in Pharmacology 2017, 8, 1 .
AMA StyleLorenza Bellusci, Annunziatina Laurino, Martina Sabatini, Simona Sestito, Paola Lenzi, Laura Raimondi, Simona Rapposelli, Francesca Biagioni, Francesco Fornai, Alessandra Salvetti, Leonardo Rossi, Riccardo Zucchi, Grazia Chiellini. New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection. Frontiers in Pharmacology. 2017; 8 ():1.
Chicago/Turabian StyleLorenza Bellusci; Annunziatina Laurino; Martina Sabatini; Simona Sestito; Paola Lenzi; Laura Raimondi; Simona Rapposelli; Francesca Biagioni; Francesco Fornai; Alessandra Salvetti; Leonardo Rossi; Riccardo Zucchi; Grazia Chiellini. 2017. "New Insights into the Potential Roles of 3-Iodothyronamine (T1AM) and Newly Developed Thyronamine-Like TAAR1 Agonists in Neuroprotection." Frontiers in Pharmacology 8, no. : 1.