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Fahmy UA, Ahmed OAA, Badr-Eldin SM, et al. Int J Nanomedicine. 2020;15:5253-5264. The Editor and Publisher of International Journal of Nanomedicine are retracting the above published article. An investigation by the Publisher, found overlap in images from Figure 6 of the published article above and the images from Figure 6 of the following published article: Ahmed OAA, Fahmy UA, Badr-Eldin SM, et al. Application of Nanopharmaceutics for Flibanserin Brain Delivery Augmentation Via the Nasal Route. Nanomaterials. 2020; 10(7):1270 (https://doi.org/10.3390/nano10071270). Specifically, this included: From the published article above, Figure 6B, plain in situ gel group, and 6D, optimized FLB-NLC in situ gel group, are the same images as Figure 6D, rats treated with optimized FLB-TRF hydrogel (gp4) and 6C, rats treated with raw FLB loaded in hydrogel (gp3), respectively, from Ahmed et al, 2020. Furthermore, the images in Figure 6 of the published article above are derived from the same image but used to describe different results. Specifically, this included: From the published article above, Figure 6A, Control untreated group; 6B, plain in situ gel group; 6C, raw FLB loaded in situ gel group and 6D, optimized FLB-NLC in situ gel group, are all derived from the same image but used to describe different results. The authors cooperated with the investigation and provided data and associated documents concerning the histopathological experiments from the reported study. However, the Editor and Publisher determined that the evidence provided did not establish sufficient justification for the duplication. Therefore, the Editor and Publisher are retracting the article. The authors have agreed to retract the article and have informed the Publisher that the first author, Usama A Fahmy, takes responsibility for the error which occurred. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”.

Usama A Fahmy,1 Osama AA Ahmed,1 Shaimaa M Badr-Eldin,1,2 Hibah M Aldawsari,1 Solomon Z Okbazghi,3 Zuhier A Awan,4 Muhammed A Bakhrebah,5 Mohammad N Alomary,5 Wesam H Abdulaal,6 Carlos Medina,7 Nabil A Alhakamy1 1Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 3Global Analytical and Pharmaceutical Development, Alexion Pharmaceuticals, New Haven, Connecticut, NE 06510, USA; 4Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 5Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh 11442, Kingdom of Saudi Arabia; 6Department of Biochemistry, Cancer Metabolism and Epigenetic Unit, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia; 7School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin IrelandCorrespondence: Shaimaa M Badr-Eldin Email sbadr5@hotmail.comBackground and Aim: Flibanserin (FLB) is a multifunctional serotonergic agent used for treating hypoactive sexual desire disorder in premenopausal women via oral administration. FLB has a reported limited oral bioavailability of 33% that could be attributed to the drug’s first-pass metabolism. In addition, FLB has a pH-dependent solubility that could be a challenging factor for drug dissolution in the body neutral fluid, and consequently, absorption via mucosal barriers. Thus, this work aims at investigating the potential of utilizing nanostructured lipid carriers (NLCs) to overcome the aforementioned drawbacks and to enhance nose-to-brain drug delivery.Methods: Box-Behnken design was applied to explore the impact of solid lipid % (SL%, X1), liquid lipid % (LL%, X2), and sonication time (ST, X3) on particle size. The optimized NLC formulation was characterized and incorporated into gellan gum in situ gel. The prepared gel was subjected to in vitro drug release, in vivo pharmacokinetic performance, and histopathological assessment in rats.Results: Statistical analysis revealed a significant negative effect for both SL% and ST on NLCs size. In contrast, a significant positive effect was observed for the LL%. The optimized formulation showed spherical shape with vesicular size of 114.63 nm. The optimized FLB-NLC in situ gel exhibited adequate stability and enhanced in vitro release compared to raw FLB control gel. The plasma and brain concentrations of the drug after nasal administration in rats increased by more than 3– 6-fold, respectively, compared to raw FLB in situ gel. In addition, the histopathological studies revealed the absence of any pathological signs.Conclusion: The aforementioned results highlight the safety of FLB-NLC in situ nasal gel and its potential to improve the drug bioavailability and brain delivery.Keywords: flibanserin, nanostructured lipid carrier, Compritol® 888 ATO, almond oil, gellan gum, pharmacokinetics

Maria J Santos-Martinez,1,2,* Krzysztof A Tomaszewski,1,3,* Carlos Medina,1 Despina Bazou,4 John F Gilmer,1 Marek W Radomski1,5,6 1School of Pharmacy and Pharma­ceutical Sciences and Trinity Biomedical Sciences Institute, 2School of Medicine, Trinity College Dublin, University of Dublin, Dublin, Ireland; 3Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland; 4Edwin L Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 5Kardio-Med Silesia, Zabrze, 6Medical University of Silesia, Katowice, Poland *These authors contributed equally to this paper Background: Engineered nanoparticles (NPs) can induce platelet activation and aggregation, but the mechanisms underlying these interactions are not well understood. This could be due in part to use of devices that study platelet function under quasi-static conditions with low sensitivity to measure platelet microaggregation. Therefore, in this study we investigated the pharmacological pathways and regulators of NP-induced platelet microaggregation under flow conditions at nanoscale using quartz crystal microbalance with dissipation (QCM-D) and compared the data thus obtained with those generated by light aggregometry. Methods: Blood was collected from healthy volunteers, and platelet-rich plasma was obtained. Thrombin receptor-activating peptide, a potent stimulator of platelet function, and pharmacological inhibitors were used to modulate platelet microaggregation in the presence/absence of silica (10 nm and 50 nm) and polystyrene (23 nm) NPs. Light aggregometry was used to study platelet aggregation in macroscale. Optical, immunofluorescence, and scanning electron microscopy were also used to visualize platelet aggregates. Results: Platelet microaggregation was enhanced by thrombin receptor-activating peptide, whereas prostacyclin, nitric oxide donors, acetylsalicylic acid, and phenanthroline, but not adenosine diphosphate (ADP) blockers, were able to inhibit platelet microaggregation. NPs caused platelet microaggregation, an effect not detectable by light aggregometry. NP-induced microaggregation was attenuated by platelet inhibitors. Conclusion: NP-induced platelet microaggregation appears to involve classical proaggregatory pathways (thromboxane A2-mediated and matrix metalloproteinase-2-mediated) and can be regulated by endogenous (prostacyclin) and pharmacological (acetylsalicylic acid, phenanthroline, and nitric oxide donors) inhibitors of platelet function. Quartz crystal microbalance with dissipation, but not light aggregometry, is an appropriate method for studying NP-induced microaggregation. Keywords: platelet microaggregation, quartz crystal microbalance with dissipation, pharmacology, nanoparticles

Stephen P Samuel,1 Maria J Santos-Martinez,2–4 Carlos Medina,2,3 Namrata Jain,1 Marek W Radomski,2,3 Adriele Prina-Mello,1,5 Yuri Volkov1,5 1Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland; 2School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland; 3Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland; 4School of Medicine, Trinity College Dublin, Dublin, Ireland; 5AMBER and CRANN, Trinity College Dublin, Dublin, Ireland Abstract: New nanomaterials intended for systemic administration have raised concerns regarding their biocompatibility and hemocompatibility. Quantum dots (QD) nanoparticles have been used for diagnostics, and recent work suggests their use for in vivo molecular and cellular imaging. However, the hemocompatibility of QDs and their constituent components has not been fully elucidated. In the present study, comprehensive investigation of QD–platelet interactions is presented. These interactions were shown using transmission electron microscopy. The effects of QDs on platelet function were investigated using light aggregometry, quartz crystal microbalance with dissipation, flow cytometry, and gelatin zymography. Platelet morphology was also analyzed by phase-contrast, immunofluorescence, atomic-force and transmission electron microscopy. We show that the QDs bind to platelet plasma membrane with the resultant upregulation of glycoprotein IIb/IIIa and P-selectin receptors, and release of matrix metalloproteinase-2. These findings unravel for the first time the mechanism of functional response of platelets to ultrasmall QDs in vitro. Keywords: platelets, quantum dots, aggregometry, flow cytometry, zymography, quartz crystal microbalance, transmission electron microscopy

Iwona Inkielewicz-Stepniak,1,* Maria Jose Santos-Martinez,2–4,* Carlos Medina,2,4 Marek W Radomski2,41Department of Medicinal Chemistry, Medical University Gdansk, Debinki, Poland; 2The School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College Dublin, Dublin, Ireland; 3School of Medicine, Trinity College Dublin, Dublin, Ireland; 4Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland*These authors contributed equally to this workBackground: Silver nanoparticles (AgNPs) and fluoride (F) are pharmacological agents widely used in oral medicine and dental practice due to their anti-microbial/anti-cavity properties. However, risks associated with the co-exposure of local cells and tissues to these xenobiotics are not clear. Therefore, we have evaluated the effects of AgNPs and F co-exposure on human gingival fibroblast cells.Methods: Human gingival fibroblast cells (CRL-2014) were exposed to AgNPs and/or F at different concentrations for up to 24 hours. Cellular uptake of AgNPs was examined by transmission electron microscopy. Downstream inflammatory effects and oxidative stress were measured by real-time quantitative polymerase chain reaction (PCR) and reactive oxygen species (ROS) generation. Cytotoxicity and apoptosis were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and real-time quantitative PCR and flow cytometry, respectively. Finally, the involvement of mitogen-activated protein kinases (MAPK) was studied using Western blot.Results: We found that AgNPs penetrated the cell membrane and localized inside the mitochondria. Co-incubation experiments resulted in increased oxidative stress, inflammation, and apoptosis. In addition, we found that co-exposure to both xenobiotics phosphorylated MAPK, particularly p42/44 MAPK.Conclusion: A combined exposure of human fibroblasts to AgNPs and F results in increased cellular damage. Further studies are needed in order to evaluate pharmacological and potentially toxicological effects of AgNPs and F on oral health.Keywords: nanoparticles, oxidative stress, apoptosis, inflammation, mitogen-activated protein kinases, matrix, metalloproteinases

J Jose Corbalan1,2, Carlos Medina1, Adam Jacoby2, Tadeusz Malinski2, Marek W Radomski11School of Pharmacy and Pharmaceutical Sciences, Faculty of Health Sciences, Panoz Institute, Trinity College Dublin, Ireland; 2Department of Chemistry and Biochemistry, Ohio University, Athens, OH, USABackground: Amorphous silica nanoparticles (SiNP) can be used in medical technologies and other industries leading to human exposure. However, an increased number of studies indicate that this exposure may result in cardiovascular inflammation and damage. A high ratio of nitric oxide to peroxynitrite concentrations ([NO]/[ONOO-]) is crucial for cardiovascular homeostasis and platelet hemostasis. Therefore, we studied the influence of SiNP on the platelet [NO]/[ONOO-] balance and platelet aggregation.Methods: Nanoparticle–platelet interaction was examined using transmission electron microscopy. Electrochemical nanosensors were used to measure the levels of NO and ONOO- released by platelets upon nanoparticle stimulation. Platelet aggregation was studied using light aggregometry, flow cytometry, and phase contrast microscopy.Results: Amorphous SiNP induced NO release from platelets followed by a massive stimulation of ONOO- leading to an unfavorably low [NO]/[ONOO-] ratio. In addition, SiNP induced an upregulation of selectin P expression and glycoprotein IIb/IIIa activation on the platelet surface membrane, and led to platelet aggregation via adenosine diphosphate and matrix metalloproteinase 2-dependent mechanisms. Importantly, all the effects on platelet aggregation were inversely proportional to nanoparticle size.Conclusions: The exposure of platelets to amorphous SiNP induces a critically low [NO]/[ONOO-] ratio leading to platelet aggregation. These findings provide new insights into the pharmacological profile of SiNP in platelets.Keywords: amorphous silica nanoparticles, nanotoxicology, nitric oxide, peroxynitrite, platelet aggregation

Maria Jose Santos-Martinez1–3, Iwona Inkielewicz-Stepniak1,4, Carlos Medina1, Kamil Rahme5,6, Deirdre M D'Arcy1, Daniel Fox3, Justin D Holmes3,5, Hongzhou Zhang3, Marek Witold Radomski3,51School of Pharmacy and Pharmaceutical Sciences, 2School of Medicine, 3Center for Research on Adaptive Nanostructures and Nanodevices, Trinity College Dublin, Dublin, Ireland; 4Department of Medicinal Chemistry, Medical University of Gdansk, Gdansk, Poland; 5Materials and Supercritical Fluids Group, Department of Chemistry and the Tyndall National Institute, University College Cork, Cork, Ireland; 6Department of Sciences, Faculty of Natural and Applied Science, Notre Dame University, Zouk Mosbeh, LebanonAbstract: Interactions between blood platelets and nanoparticles have both pharmacological and toxicological significance and may lead to platelet activation and aggregation. Platelet aggregation is usually studied using light aggregometer that neither mimics the conditions found in human microvasculature nor detects microaggregates. A new method for the measurement of platelet microaggregation under flow conditions using a commercially available quartz crystal microbalance with dissipation (QCM-D) has recently been developed. The aim of the current study was to investigate if QCM-D could be used for the measurement of nanoparticle-platelet interactions. Silica, polystyrene, and gold nanoparticles were tested. The interactions were also studied using light aggregometry and flow cytometry, which measured surface abundance of platelet receptors. Platelet activation was imaged using phase contrast and scanning helium ion microscopy. QCM-D was able to measure nanoparticle-induced platelet microaggregation for all nanoparticles tested at concentrations that were undetectable by light aggregometry and flow cytometry. Microaggregates were measured by changes in frequency and dissipation, and the presence of platelets on the sensor surface was confirmed and imaged by phase contrast and scanning helium ion microscopy.Keywords: platelet aggregation, nanoparticles, light aggregometer, quartz crystal microbalance with dissipation, scanning helium ion microscopy

J Jose Corbalan1,2, Carlos Medina1, Adam Jacoby2, Tadeusz Malinski2, Marek W Radomski11School of Pharmacy and Pharmaceutical Sciences, Faculty of Health Sciences, Panoz Institute, Trinity College Dublin, Dublin, Ireland; 2Department of Chemistry and Biochemistry, Ohio University, Athens, OH, USABackground: The purpose of this study was to investigate the mechanism of noxious effects of amorphous silica nanoparticles on human endothelial cells.Methods: Nanoparticle uptake was examined by transmission electron microscopy. Electrochemical nanosensors were used to measure the nitric oxide (NO) and peroxynitrite (ONOO-) released by a single cell upon nanoparticle stimulation. The downstream inflammatory effects were measured by an enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction, and flow cytometry, and cytotoxicity was measured by lactate dehydrogenase assay.Results: We found that the silica nanoparticles penetrated the plasma membrane and rapidly stimulated release of cytoprotective NO and, to a greater extent, production of cytotoxic ONOO-. The low [NO]/[ONOO-] ratio indicated increased nitroxidative/oxidative stress and correlated closely with endothelial inflammation and necrosis. This imbalance was associated with nuclear factor κB activation, upregulation of key inflammatory factors, and cell death. These effects were observed in a nanoparticle size-dependent and concentration-dependent manner.Conclusion: The [NO]/[ONOO-] imbalance induced by amorphous silica nanoparticles indicates a potentially deleterious effect of silica nanoparticles on vascular endothelium.Keywords: amorphous silica nanoparticles, nanotoxicology, nitric oxide, peroxynitrite, inflammation, risk factors

Se categorizaron la germinación y latencia de semillas de mortiño y se desarrolló un protocolo de remoción de esta última, aspectos que son básicos para procesos de conservación, siembra y fitomejoramiento de la especie. No se detectó latencia exógena, con imbibición de agua, por parte de las semillas en un sustrato húmedo. Las simientes exhibieron una respuesta fotoblástica positiva a la luz. Se determinó, mediante la aplicación de tetrazolio, que 15,8% de las semillas eran no viables, con 63,0% de semillas con germinación y 21,2% viables latentes. La germinación y remoción de la latencia fueron significativamente superiores a 20°C que a 25°C. La latencia de la semilla fue eliminada, casi por completo, bajo un régimen de luz blanca constante, a 20°C, con aplicación de GA3 en concentraciones de 500, 1.000 y 2.000 mg L-1. El bloqueo de la germinación se clasifcó como latencia fsiológica no profunda.

En el Centro de Investigación "La Selva", de la Corporación Colombiana de Investigación Agropecuaria (CORPOICA), localizado en Rionegro (Antioquia, Colombia),a 2120 msnm, se llevó a cabo una investigación, cuyo objetivo fue evaluar la resistencia de campo a la antracnosis de los frutos de tomate de árbol en la accesión 6975073 de especie C. uniloba, material que en observaciones previas no había presentado incidencia de la enfermedad. En el estudio se incluyeron igualmente 4 poblaciones de la especie cultivada C. betacea de diferentes tipos: rojo común, amarillo, partenocárpico y "mora" o "tamarillo" y una de la especie relacionada C. materna. El trabajo se llevó a cabo durante seis meses, cosechándose quincenalmente, en 5 árboles por accesión, los frutos sanos maduros y los enfermos, clasificados por grado de maduración. Todos los materiales recibieron control quí mico de la enfermedad, con excepción del tomate C. uniloba 6975073. Durante la evaluación se presentaron condiciones favorables para el desarrollo del patógeno, con una precipitación de 1361.1 mm y prevalencia de altas humedades relativas, con un promedio, al respecto, del 80.2%. Durante el período de desarrollo de la evaluación no se presentaron frutos con síntomas de antracnosis en la accesión 6975073, lo cual si ocurrió en los demás materiales, con un porcentaje de frutos enfermos que fluctuó entre el 57.64 y el 98.82%, encontrá ndose que los genotipos con mayor nivel de productividad, a su vez, presentaron la mayor suceptibilidad y pérdidas en rendimiento. Un estimado del valor de los frutos con antracnosis, proyectado a hectárea-año, señaló que las pérdidas de frutos en las diferentes accesiones de C. betacea fluctuaron entre 3006 y 11268 dólares. Complementariamente al estudio, se obtuvieron híbridos interespecí ficos entre el material resistente y una accesión de C. betacea.