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Volume 13
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Pharmaceuticals, Volume 13, Issue 1 (January 2020) – 18 articles

Cover Story (view full-size image): The xenograft of human cancer cells in model animals is a powerful tool for understanding tumor progression and metastatic potential. Zebrafish larvae represent a valuable alternative to mice hosts, with a lower cost and a higher throughput for drug discovery and screening. Their small size and transparency allow the tracking of transplanted cells, enabling the evaluation of early steps of metastasis. Our standardization, automation, and validation of the zebrafish larvae xenograft assay has led to increased translatability and higher drug screening throughput. The insights gained with the ZeOncoTest have brought zebrafish larvae xenografts a step closer to entering the regulated preclinical drug discovery path. View this paper
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13 pages, 2933 KiB  
Communication
Electron Microscopy of In-Plaque Phage T3 Assembly: Proposed Analogs of Neurodegenerative Disease Triggers
by Philip Serwer, Barbara Hunter and Elena T. Wright
Pharmaceuticals 2020, 13(1), 18; https://doi.org/10.3390/ph13010018 - 18 Jan 2020
Cited by 13 | Viewed by 6648
Abstract
Increased knowledge of virus assembly-generated particles is needed for understanding both virus assembly and host responses to virus infection. Here, we use a phage T3 model and perform electron microscopy (EM) of thin sections (EM-TS) of gel-supported T3 plaques formed at 30 °C. [...] Read more.
Increased knowledge of virus assembly-generated particles is needed for understanding both virus assembly and host responses to virus infection. Here, we use a phage T3 model and perform electron microscopy (EM) of thin sections (EM-TS) of gel-supported T3 plaques formed at 30 °C. After uranyl acetate/lead staining, we observe intracellular black particles, some with a difficult-to-see capsid. Some black particles (called LBPs) are larger than phage particles. The LBP frequency is increased by including proflavine, a DNA packaging inhibitor, in the growth medium and increasing plaque-forming temperature to 37 °C. Acidic phosphotungstate-precipitate (A-PTA) staining causes LBP substitution by black rings (BRs) that have the size and shape expected of hyper-expanded capsid containers for LBP DNA. BRs are less frequent in liquid cultures, suggesting that hyper-expanded capsids evolved primarily for in-gel (e.g., in-biofilm) propagation. BR-specific A-PTA staining and other observations are explained by α-sheet intense structure of the major subunit of hyper-expanded capsids. We hypothesize that herpes virus triggering of neurodegenerative disease occurs via in-gel propagation-promoted (1) generation of α-sheet intense viral capsids and, in response, (2) host production of α-sheet intense, capsid-interactive, innate immunity amyloid protein that becomes toxic. We propose developing viruses that are therapeutic via detoxifying interaction with this innate immunity protein. Full article
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27 pages, 4543 KiB  
Article
Biopolymer Extracted from Anadenanthera colubrina (Red Angico Gum) Exerts Therapeutic Potential in Mice: Antidiarrheal Activity and Safety Assessment
by Thiago S. L. Araújo, Taiane M. de Oliveira, Nayara A. de Sousa, Luan K.M. Souza, Francisca B. M. Sousa, Ana P. de Oliveira, Lucas A. D. Nicolau, Alfredo A. V. da Silva, Alyne R. Araújo, Pedro J. C. Magalhães, Daniel F. P. Vasconcelos, Hugo R. de Jonge, Marcellus H. L. P. Souza, Durcilene A. Silva, Regina C. M. Paula and Jand Venes R. Medeiros
Pharmaceuticals 2020, 13(1), 17; https://doi.org/10.3390/ph13010017 - 18 Jan 2020
Cited by 19 | Viewed by 5243
Abstract
Anadenanthera colubrina var. cebil (Griseb.) Altschul (Fabaceae family), commonly known as the red angico tree, is a medicinal plant found throughout Brazil’s semi-arid area. In this study, a chemical analysis was performed to investigate the antidiarrheal activity and safety profile of red angico [...] Read more.
Anadenanthera colubrina var. cebil (Griseb.) Altschul (Fabaceae family), commonly known as the red angico tree, is a medicinal plant found throughout Brazil’s semi-arid area. In this study, a chemical analysis was performed to investigate the antidiarrheal activity and safety profile of red angico gum (RAG), a biopolymer extracted from the trunk exudate of A. colubrina. Upon FT-IR spectroscopy, RAG showed bands in the regions of 1608 cm−1, 1368 cm−1, and 1029 cm−1, which relate to the vibration of O–H water molecules, deformation vibration of C-O bands, and vibration of the polysaccharide C-O band, respectively, all of which are relevant to glycosidic bonds. The peak molar mass of RAG was 1.89 × 105 g/mol, with the zeta potential indicating electronegativity. RAG demonstrated high yield and solubility with a low degree of impurity. Pre-treatment with RAG reduced the total diarrheal stool and enteropooling. RAG also enhanced Na+/K+-ATPase activity and reduced gastrointestinal transit, and thereby inhibited intestinal smooth muscle contractions. Enzyme-Linked Immunosorbent Assay (ELISA) demonstrated that RAG can interact with GM1 receptors and can also reduce E. coli-induced diarrhea in vivo. Moreover, RAG did not induce any signs of toxicity in mice. These results suggest that RAG is a possible candidate for the treatment of diarrheal diseases. Full article
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58 pages, 10961 KiB  
Article
Design, Synthesis and Biochemical Evaluation of Novel Ethanoanthracenes and Related Compounds to Target Burkitt’s Lymphoma
by Andrew J. Byrne, Sandra A. Bright, James P. McKeown, John E. O’Brien, Brendan Twamley, Darren Fayne, D. Clive Williams and Mary J. Meegan
Pharmaceuticals 2020, 13(1), 16; https://doi.org/10.3390/ph13010016 - 17 Jan 2020
Cited by 7 | Viewed by 5446
Abstract
Lymphomas (cancers of the lymphatic system) account for 12% of malignant diseases worldwide. Burkitt’s lymphoma (BL) is a rare form of non-Hodgkin’s lymphoma in which the cancer starts in the immune B-cells. We report the synthesis and preliminary studies on the antiproliferative activity [...] Read more.
Lymphomas (cancers of the lymphatic system) account for 12% of malignant diseases worldwide. Burkitt’s lymphoma (BL) is a rare form of non-Hodgkin’s lymphoma in which the cancer starts in the immune B-cells. We report the synthesis and preliminary studies on the antiproliferative activity of a library of 9,10-dihydro-9,10-ethanoanthracene based compounds structurally related to the antidepressant drug maprotiline against BL cell lines MUTU-1 and DG-75. Structural modifications were achieved by Diels-Alder reaction of the core 9-(2-nitrovinyl)anthracene with number of dienophiles including maleic anhydride, maleimides, acrylonitrile and benzyne. The antiproliferative activity of these compounds was evaluated in BL cell lines EBV− MUTU-1 and EBV+ DG-75 (chemoresistant). The most potent compounds 13j, 15, 16a, 16b, 16c, 16d and 19a displayed IC50 values in the range 0.17–0.38 μM against the BL cell line EBV− MUTU-1 and IC50 values in the range 0.45–0.78 μM against the chemoresistant BL cell line EBV+ DG-75. Compounds 15, 16b and 16c demonstrated potent ROS dependent apoptotic effects on the BL cell lines which were superior to the control drug taxol and showed minimal cytotoxicity to peripheral blood mononuclear cells (PBMCs). The results suggest that this class of compounds merits further investigation as antiproliferative agents for BL. Full article
(This article belongs to the Special Issue Selected Papers from the 4th International Electronic Conference on Medicinal Chemistry)
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41 pages, 3530 KiB  
Review
Current Trends in the Pharmacotherapy of Cataracts
by Segewkal H. Heruye, Leonce N. Maffofou Nkenyi, Neetu U. Singh, Dariush Yalzadeh, Kalu K. Ngele, Ya-Fatou Njie-Mbye, Sunny E. Ohia and Catherine A. Opere
Pharmaceuticals 2020, 13(1), 15; https://doi.org/10.3390/ph13010015 - 16 Jan 2020
Cited by 39 | Viewed by 18115 | Correction
Abstract
Cataracts, one of the leading causes of preventable blindness worldwide, refers to lens degradation that is characterized by clouding, with consequent blurry vision. As life expectancies improve, the number of people affected with cataracts is predicted to increase worldwide, especially in low-income nations [...] Read more.
Cataracts, one of the leading causes of preventable blindness worldwide, refers to lens degradation that is characterized by clouding, with consequent blurry vision. As life expectancies improve, the number of people affected with cataracts is predicted to increase worldwide, especially in low-income nations with limited access to surgery. Although cataract surgery is considered safe, it is associated with some complications such as retinal detachment, warranting a search for cheap, pharmacological alternatives to the management of this ocular disease. The lens is richly endowed with a complex system of non-enzymatic and enzymatic antioxidants which scavenge reactive oxygen species to preserve lens proteins. Depletion and/or failure in this primary antioxidant defense system contributes to the damage observed in lenticular molecules and their repair mechanisms, ultimately causing cataracts. Several attempts have been made to counteract experimentally induced cataract using in vitro, ex vivo, and in vivo techniques. The majority of the anti-cataract compounds tested, including plant extracts and naturally-occurring compounds, lies in their antioxidant and/or free radical scavenging and/or anti-inflammatory propensity. In addition to providing an overview of the pathophysiology of cataracts, this review focuses on the role of various categories of natural and synthetic compounds on experimentally-induced cataracts. Full article
(This article belongs to the Special Issue Choices of the Journal)
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6 pages, 199 KiB  
Editorial
Acknowledgement to Reviewers of Pharmaceuticals in 2019
by Pharmaceuticals Editorial Office
Pharmaceuticals 2020, 13(1), 14; https://doi.org/10.3390/ph13010014 - 14 Jan 2020
Viewed by 1858
Abstract
The editorial team greatly appreciates the reviewers who have dedicated their considerable time and expertise to the journal’s rigorous editorial process over the past 12 months, regardless of whether the papers are finally published or not [...] Full article
17 pages, 6907 KiB  
Article
RETRACTED: Sanguinarine Inhibits Mono- and Dual-Species Biofilm Formation by Candida albicans and Staphylococcus aureus and Induces Mature Hypha Transition of C. albicans
by Weidong Qian, Wenjing Wang, Jianing Zhang, Miao Liu, Yuting Fu, Xiang Li, Ting Wang and Yongdong Li
Pharmaceuticals 2020, 13(1), 13; https://doi.org/10.3390/ph13010013 - 13 Jan 2020
Cited by 11 | Viewed by 4609 | Retraction
Abstract
Previous studies have reported that sanguinarine possesses inhibitory activities against several microorganisms, but its effects on mono- and dual-species biofilms of C. albicans and S. aureus have not been fully elucidated. In this study, we aimed to evaluate the efficacy of sanguinarine for [...] Read more.
Previous studies have reported that sanguinarine possesses inhibitory activities against several microorganisms, but its effects on mono- and dual-species biofilms of C. albicans and S. aureus have not been fully elucidated. In this study, we aimed to evaluate the efficacy of sanguinarine for mono- and dual-species biofilms and explore its ability to induce the hypha-to-yeast transition of C. albicans. The results showed that the minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC90) of sanguinarine against C. albicans and S. aureus mono-species biofilms was 4, and 2 μg/mL, respectively, while the MIC and MBIC90 of sanguinarine against dual-species biofilms was 8, and 4 μg/mL, respectively. The decrease in the levels of matrix component and tolerance to antibiotics of sanguinarine-treated mono- and dual-species biofilms was revealed by confocal laser scanning microscopy combined with fluorescent dyes, and the gatifloxacin diffusion assay, respectively. Meanwhile, sanguinarine at 128 and 256 μg/mL could efficiently eradicate the preformed 24-h biofilms by mono- and dual-species, respectively. Moreover, sanguinarine at 8 μg/mL could result in the transition of C. albicans from the mature hypha form to the unicellular yeast form. Hence, this study provides useful information for the development of new agents to combat mono- and dual-species biofilm-associated infections, caused by C. albicans and S. aureus. Full article
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13 pages, 1287 KiB  
Article
Current Status of PSMA-Radiotracers for Prostate Cancer: Data Analysis of Prospective Trials Listed on ClinicalTrials.gov
by Claus Zippel, Sarah C. Ronski, Sabine Bohnet-Joschko, Frederik L. Giesel and Klaus Kopka
Pharmaceuticals 2020, 13(1), 12; https://doi.org/10.3390/ph13010012 - 13 Jan 2020
Cited by 34 | Viewed by 8967
Abstract
The recent development of dedicated prostate-specific membrane antigen (PSMA) targeted radioligands shows the potential to change and improve the diagnosis and therapy of prostate cancer. There is an increasing number of prospective trials to further establish these tracers in the clinical setting. We [...] Read more.
The recent development of dedicated prostate-specific membrane antigen (PSMA) targeted radioligands shows the potential to change and improve the diagnosis and therapy of prostate cancer. There is an increasing number of prospective trials to further establish these tracers in the clinical setting. We analyzed data from the ClinicalTrials.gov registry including all listed prospective trials with PSMA-ligands for prostate cancer as of October 2019 concerning the different tracers and study characteristics. We found n = 104 eligible studies with a total of n = 25 different tracers in use: most frequently [68Ga]Ga-PSMA-11 (32%), followed by [18F]DCFPyL (24%) and [177Lu]Lu-PSMA-617 (10%). 85% are single-center, 15% multi-center studies. 95% national and 5% international studies. 34% are phase-II, 24% phase-I, 13% phase-I/-II, 12% phase-II/-III and phase-III and 7% early-phase-I. The primary purpose was classified as diagnostic in 72% of cases and therapeutic in 23% of cases. Most studies were executed in the USA (70%), followed by Canada (13%) and France (6%). This quantitative descriptive registry analysis indicates the rapid and global clinical developments and current status of PSMA-radioligands with emphasis on radiopharmaceutical and organizational aspects. It will be very interesting to see which tracers will prevail in the clinical setting. Full article
(This article belongs to the Special Issue The Future Direction of Radiopharmaceutical Development for Cancer Theranostics)
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14 pages, 2228 KiB  
Article
Production and Characterization of Chitosan–Polyanion Nanoparticles by Polyelectrolyte Complexation Assisted by High-Intensity Sonication for the Modified Release of Methotrexate
by Yhors Ciro, John Rojas, Maria J. Alhajj, Gustavo A. Carabali and Constain H. Salamanca
Pharmaceuticals 2020, 13(1), 11; https://doi.org/10.3390/ph13010011 - 8 Jan 2020
Cited by 26 | Viewed by 3925
Abstract
A promising strategy to improve the effectivity of anticancer treatment and decrease its side effects is to modulate drug release by using nanoparticulates (NPs) as carriers. In this study, methotrexate-loaded chitosan–polyanion nanoparticles were produced by polyelectrolyte complexation assisted by high-intensity sonication, using several [...] Read more.
A promising strategy to improve the effectivity of anticancer treatment and decrease its side effects is to modulate drug release by using nanoparticulates (NPs) as carriers. In this study, methotrexate-loaded chitosan–polyanion nanoparticles were produced by polyelectrolyte complexation assisted by high-intensity sonication, using several anionic polymers, such as the sodium and potassium salts of poly(maleic acid-alt-ethylene) and poly(maleic acid-alt-octadecene), here named PAM-2 and PAM-18, respectively. Such NPs were analyzed and characterized according to particle size, polydispersity index, zeta potential and encapsulation efficiency. Likewise, their physical stability was tested at 4 °C and 40 °C in order to evaluate any change in the previously mentioned particle parameters. The in vitro methotrexate release was assessed at a pH of 7.4, which simulated physiological conditions, and the data were fitted to the heuristic models of order one, Higuchi, Peppas–Sahlin and Korsmeyer–Peppas. The results revealed that most of the MTX-chitosan–polyanion NPs have positive zeta potential values, sizes <280 nm and monodisperse populations, except for the NPs formed with PAM-18 polyanions. Further, the NPs showed adequate physical stability, preventing NP–NP aggregation. Likewise, these carriers modified the MTX release by an anomalous mechanism, where the NPs formed with PAM-2 polymer led to a release mechanism controlled by diffusion and relaxation, whereas the NPs formed with PAM-18 led to a mainly diffusion-controlled release mechanism. Full article
(This article belongs to the Special Issue New Tools for Medicinal Chemists)
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21 pages, 4526 KiB  
Article
Troxerutin Prevents 5-Fluorouracil Induced Morphological Changes in the Intestinal Mucosa: Role of Cyclooxygenase-2 Pathway
by João Antônio Leal de Miranda, Conceição da Silva Martins, Lázaro de Sousa Fideles, Maria Lucianny Lima Barbosa, João Erivan Façanha Barreto, Helder Bindá Pimenta, Francisco Orlando Rafael Freitas, Paulo Vitor de Souza Pimentel, Claudio Silva Teixeira, Ariel Gustavo Scafuri, Maria Claudia dos Santos Luciano, Joabe Lima Araújo, Jefferson Almeida Rocha, Icaro Gusmão Pinto Vieira, Nágila Maria Pontes Silva Ricardo, Matheus da Silva Campelo, Maria Elenir Nobre Pinho Ribeiro, Gerly Anne de Castro Brito and Gilberto Santos Cerqueira
Pharmaceuticals 2020, 13(1), 10; https://doi.org/10.3390/ph13010010 - 8 Jan 2020
Cited by 21 | Viewed by 5900
Abstract
Intestinal mucositis is a common complication associated with 5-fluorouracil (5-FU), a chemotherapeutic agent used for cancer treatment. Troxerutin (TRX), a semi-synthetic flavonoid extracted from Dimorphandra gardneriana, has been reported as a potent antioxidant and anti-inflammatory agent. In the present study, we aimed [...] Read more.
Intestinal mucositis is a common complication associated with 5-fluorouracil (5-FU), a chemotherapeutic agent used for cancer treatment. Troxerutin (TRX), a semi-synthetic flavonoid extracted from Dimorphandra gardneriana, has been reported as a potent antioxidant and anti-inflammatory agent. In the present study, we aimed to evaluate the effect of TRX on 5-FU-induced intestinal mucositis. Swiss mice were randomly divided into seven groups: Saline, 5-FU, TRX-50, TRX-100, TRX-150, Celecoxib (CLX), and CLX + TRX-100. The weight of mice was measured daily. After treatment, the animals were euthanized and segments of the small intestine were collected to evaluate histopathological alterations (morphometric analysis), levels of malondialdehyde (MDA), myeloperoxidase (MPO), glutathione (GSH), mast and goblet cell counts, immunohistochemical analysis, and cyclooxygenase-2 (COX-2) activity. Compared to the saline treatment, the 5-FU treatment induced intense weight loss and reduction in villus height. TRX treatment (100 mg/kg) prevented the 5-FU-induced histopathological changes and decreased oxidative stress by decreasing the MDA levels and increasing GSH concentration. TRX attenuated inflammatory process by decreasing MPO activity, intestinal mastocytosis, and COX-2 expression. TRX also reversed the depletion of goblet cells. Our findings suggest that TRX at a concentration of 100 mg/kg had chemopreventive effects on 5-FU-induced intestinal mucositis via COX-2 pathway. Full article
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11 pages, 2207 KiB  
Review
Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer
by Sandeep Kumar, Daniel R. Principe, Sunil Kumar Singh, Navin Viswakarma, Gautam Sondarva, Basabi Rana and Ajay Rana
Pharmaceuticals 2020, 13(1), 9; https://doi.org/10.3390/ph13010009 - 7 Jan 2020
Cited by 28 | Viewed by 6477
Abstract
Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several [...] Read more.
Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several components of the MAPK signaling network have been proposed as viable targets for cancer therapy. However, the contributions of MAPK signaling extend well beyond the tumor cells, and several MAPK effectors have been identified as key mediators of the tumor microenvironment (TME), particularly with respect to the local immune infiltrate. In fact, a blockade of various MAPK signals has been suggested to fundamentally alter the interaction between tumor cells and T lymphocytes and have been suggested a potential adjuvant to immune checkpoint inhibition in the clinic. Therefore, in this review article, we discuss the various mechanisms through which MAPK family members contribute to T-cell biology, as well as circumstances in which MAPK inhibition may potentiate or limit cancer immunotherapy. Full article
(This article belongs to the Special Issue Protein Kinases and Cancer)
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43 pages, 3965 KiB  
Review
Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review
by Eavan C. McLoughlin and Niamh M. O’Boyle
Pharmaceuticals 2020, 13(1), 8; https://doi.org/10.3390/ph13010008 - 3 Jan 2020
Cited by 213 | Viewed by 11358 | Correction
Abstract
It is over 50 years since the discovery of microtubules, and they have become one of the most important drug targets for anti-cancer therapies. Microtubules are predominantly composed of the protein tubulin, which contains a number of different binding sites for small-molecule drugs. [...] Read more.
It is over 50 years since the discovery of microtubules, and they have become one of the most important drug targets for anti-cancer therapies. Microtubules are predominantly composed of the protein tubulin, which contains a number of different binding sites for small-molecule drugs. There is continued interest in drug development for compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs). This review highlights CBSIs discovered through diverse sources: from natural compounds, rational design, serendipitously and via high-throughput screening. We provide an update on CBSIs reported in the past three years and discuss the clinical status of CBSIs. It is likely that efforts will continue to develop CBSIs for a diverse set of cancers, and this review provides a timely update on recent developments. Full article
(This article belongs to the Special Issue Recent Contributions in Medicinal Chemistry Within European GP2A Network)
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16 pages, 2706 KiB  
Article
ASA Suppresses PGE2 in Plasma and Melanocytic Nevi of Human Subjects at Increased Risk for Melanoma
by Amir Varedi, Hafeez Rahman, Dileep Kumar, Jonathan L. Catrow, James E. Cox, Tong Liu, Scott R. Florell, Kenneth M. Boucher, Nwanneka Okwundu, William J. Burnett, Matthew W. VanBrocklin and Douglas Grossman
Pharmaceuticals 2020, 13(1), 7; https://doi.org/10.3390/ph13010007 - 2 Jan 2020
Cited by 7 | Viewed by 3918
Abstract
Potential anti-inflammatory and anticarcinogenic effects of aspirin (ASA) may be suitable for melanoma chemoprevention, but defining biomarkers in relevant target tissues is prerequisite to performing randomized controlled chemoprevention trials. We conducted open-label studies with ASA in 53 human subjects with melanocytic nevi at [...] Read more.
Potential anti-inflammatory and anticarcinogenic effects of aspirin (ASA) may be suitable for melanoma chemoprevention, but defining biomarkers in relevant target tissues is prerequisite to performing randomized controlled chemoprevention trials. We conducted open-label studies with ASA in 53 human subjects with melanocytic nevi at increased risk for melanoma. In a pilot study, 12 subjects received a single dose (325 mg) of ASA; metabolites salicylate, salicylurate, and gentisic acid were detected in plasma after 4–8 h, and prostaglandin E2 (PGE2) was suppressed in both plasma and nevi for up to 24 h. Subsequently, 41 subjects received either 325 or 81 mg ASA (nonrandomized) daily for one week. ASA metabolites were consistently detected in plasma and nevi, and PGE2 levels were significantly reduced in both plasma and nevi. Subchronic ASA dosing did not affect 5” adenosine monophosphate-activated protein kinase (AMPK) activation in nevi or leukocyte subsets in peripheral blood, although metabolomic and cytokine profiling of plasma revealed significant decreases in various (non-ASA-derived) metabolites and inflammatory cytokines. In summary, short courses of daily ASA reduce plasma and nevus PGE2 and some metabolites and cytokines in plasma of human subjects at increased risk for melanoma. PGE2 may be a useful biomarker in blood and nevi for prospective melanoma chemoprevention studies with ASA. Full article
(This article belongs to the Special Issue Choices of the Journal)
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2 pages, 178 KiB  
Editorial
2019: An Awesome Year for Pharmaceuticals
by Jean Jacques Vanden Eynde
Pharmaceuticals 2020, 13(1), 6; https://doi.org/10.3390/ph13010006 - 1 Jan 2020
Cited by 1 | Viewed by 2678
Abstract
Ending the year is an opportunity to reflect on the past, in particular the past twelve months [...] Full article
2 pages, 197 KiB  
Editorial
Special Issue “Carbohydrates 2018”
by Amélia Pilar Rauter and Nuno Manuel Xavier
Pharmaceuticals 2020, 13(1), 5; https://doi.org/10.3390/ph13010005 - 29 Dec 2019
Cited by 2 | Viewed by 2586
Abstract
This special issue of Pharmaceuticals has been dedicated to Carbohydrates on the occasion of the 29th International Carbohydrate Symposium, held at the Universidade de Lisboa from 15–19 July 2018 [...] Full article
(This article belongs to the Special Issue Carbohydrates 2018)
19 pages, 1836 KiB  
Review
Biological Applications of Thiocarbohydrazones and Their Metal Complexes: A Perspective Review
by Carmela Bonaccorso, Tiziano Marzo and Diego La Mendola
Pharmaceuticals 2020, 13(1), 4; https://doi.org/10.3390/ph13010004 - 25 Dec 2019
Cited by 69 | Viewed by 6425
Abstract
Although organic compounds account for more than 99% of currently approved clinical drugs, the established clinical use of cisplatin in cancer or auranofin in rheumatoid arthritis have paved the way to several research initiatives to identify metal-based drugs for a wide range of [...] Read more.
Although organic compounds account for more than 99% of currently approved clinical drugs, the established clinical use of cisplatin in cancer or auranofin in rheumatoid arthritis have paved the way to several research initiatives to identify metal-based drugs for a wide range of human diseases. Nitrogen and sulfur donor ligands, characterized by different binding motifs, have been the subject in recent years of one of the main research areas in coordination chemistry. Among the nitrogen/sulfur compounds, very little is known about thiocarbohydrazones (TCH), the higher homologues of the well-known thiosemicarbazones (TSC), and their metal complexes. The extra hydrazine moiety provides the ligands of variable metal binding modes, structural diversity and promising biological implications. The interesting coordination chemistry of TCH has mainly been focused on symmetric derivatives, which are relatively simple to synthesize while few examples of asymmetric ligands have been reported. This informative review on TCHs and their metal complexes will be helpful for improving the design of metal-based pharmaceuticals for applications ranging from anticancer to antinfective therapy. Full article
(This article belongs to the Special Issue Metal-Based Drugs: Updates and Perspectives)
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17 pages, 3742 KiB  
Article
Bio- Fortification of Angelica gigas Nakai Nano-Powder Using Bio-Polymer by Hot Melt Extrusion to Enhance the Bioaccessibility and Functionality of Nutraceutical Compounds
by Md Obyedul Kalam Azad, Wie Soo Kang, Jung Dae Lim and Cheol Ho Park
Pharmaceuticals 2020, 13(1), 3; https://doi.org/10.3390/ph13010003 - 25 Dec 2019
Cited by 10 | Viewed by 4006
Abstract
Angelica gigas Nakai (AGN) is a popular traditional herbal medicine which has been used to alleviate various human diseases in Korea since ancient times. However, the low bioaccessibility of the nutraceutical compounds of AGN results in a poor water solubility, thereby limiting bioavailability. [...] Read more.
Angelica gigas Nakai (AGN) is a popular traditional herbal medicine which has been used to alleviate various human diseases in Korea since ancient times. However, the low bioaccessibility of the nutraceutical compounds of AGN results in a poor water solubility, thereby limiting bioavailability. In this regard, a ternary AGN–biopolymer–plasticizer composite (AGNC) was developed to enhance the bioaccessibility of nutraceutical compounds from extrudate AGN formulations manufactured by hot melt extrusion (HME). The AGNC was prepared with extrudate AGN (EAGN) using different hydroxypropyl methylcellulose (HPMC) biopolymers (5% w/w) viz.: hypromellose phthalate (HP), hypromellose (AN), and hypromellose (CN) along with acetic acid (AA) (0.1 M, 20% w/v) as a plasticizer. The non-extrudate fresh AGN (FAGN) powder was used as a control. The physicochemical properties of the extrudate formulations and control were characterized by differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR). DSC analysis showed a lower enthalpy (ΔH) (12.22 J/g) and lower glass transition temperature (Tg) (41 °C) in HP-AA-EAGN compared to the control. FTIR confirmed the physical crosslinking between AGN and biopolymer in the extrudate composite and demonstrated that some functional groups formed viz., -OH and -CH2. The obtained result also shows that the particle size was reduced by 341 nm, and solubility was increased by 65.5% in HP-AA-EAGN compared to the control (1499 nm, 29.4%, respectively). The bioaccessibility of the total phenolic content and the total flavonoids—including decursin (D) and decursinol angelate (DA)—were significantly higher in HP-AA-EAGN compared to the control. The 2,2-diphenyl-1 picryl hydrazyl (DPPH) free radical scavenging capacity and ferric reducing antioxidant power assay (FRAP) indicated that the HP-AA-EAGN formulation preserves a greater antioxidant profile than the other formulations. Finally, it is summarized that the addition of acidified HP biopolymer increased the bioaccessibility, functionality, and improved the physicochemical properties of nutraceutical compounds in the extrudate AGN formulation. Full article
(This article belongs to the Special Issue New Tools for Medicinal Chemists)
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13 pages, 3811 KiB  
Article
Dextran-Curcumin Nanoparticles as a Methotrexate Delivery Vehicle: A Step Forward in Breast Cancer Combination Therapy
by Manuela Curcio, Giuseppe Cirillo, Paola Tucci, Annafranca Farfalla, Emilia Bevacqua, Orazio Vittorio, Francesca Iemma and Fiore Pasquale Nicoletta
Pharmaceuticals 2020, 13(1), 2; https://doi.org/10.3390/ph13010002 - 25 Dec 2019
Cited by 37 | Viewed by 4711
Abstract
With the aim to effectively deliver methotrexate (MTX) to breast cancer cells, we designed a nanocarrier system (DC) derived from the self-assembly of a dextran-curcumin conjugate prepared via enzyme chemistry with immobilized laccase acting as a solid biocatalyst. Nanoparticles consisted of homogeneously dispersed [...] Read more.
With the aim to effectively deliver methotrexate (MTX) to breast cancer cells, we designed a nanocarrier system (DC) derived from the self-assembly of a dextran-curcumin conjugate prepared via enzyme chemistry with immobilized laccase acting as a solid biocatalyst. Nanoparticles consisted of homogeneously dispersed nanospheres with a mean diameter of 290 nm, as characterized by combined transmission electron microscopy and dynamic light scattering investigations. DC was able to control the MTX release overtime (t1/2 value of 310 min), with cell internalization studies proving its presence inside MCF-7 cytoplasm. Finally, improved MTX efficacy was obtained in viability assays, and attributed to the synergy of curcumin moieties and loaded MTX as underlined by a combination index (CI) < 1. Full article
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18 pages, 5085 KiB  
Article
ZeOncoTest: Refining and Automating the Zebrafish Xenograft Model for Drug Discovery in Cancer
by Carles Cornet, Sylvia Dyballa, Javier Terriente and Valeria Di Giacomo
Pharmaceuticals 2020, 13(1), 1; https://doi.org/10.3390/ph13010001 - 24 Dec 2019
Cited by 20 | Viewed by 6271
Abstract
The xenograft of human cancer cells in model animals is a powerful tool for understanding tumor progression and metastatic potential. Mice represent a validated host, but their use is limited by the elevated experimental costs and low throughput. To overcome these restrictions, zebrafish [...] Read more.
The xenograft of human cancer cells in model animals is a powerful tool for understanding tumor progression and metastatic potential. Mice represent a validated host, but their use is limited by the elevated experimental costs and low throughput. To overcome these restrictions, zebrafish larvae might represent a valuable alternative. Their small size and transparency allow the tracking of transplanted cells. Therefore, tumor growth and early steps of metastasis, which are difficult to evaluate in mice, can be addressed. In spite of its advantages, the use of this model has been hindered by lack of experimental homogeneity and validation. Considering these facts, the aim of our work was to standardize, automate, and validate a zebrafish larvae xenograft assay with increased translatability and higher drug screening throughput. The ZeOncoTest reliability is based on the optimization of different experimental parameters, such as cell labeling, injection site, automated individual sample image acquisition, and analysis. This workflow implementation finally allows a higher precision and experimental throughput increase, when compared to previous reports. The approach was validated with the breast cancer cell line MDA-MB-231, the colorectal cancer cells HCT116, and the prostate cancer cells PC3; and known drugs, respectively RKI-1447, Docetaxel, and Mitoxantrone. The results recapitulate growth and invasion for all tested tumor cells, along with expected efficacy of the compounds. Finally, the methodology has proven useful for understanding specific drugs mode of action. The insights gained bring a step further for zebrafish larvae xenografts to enter the regulated preclinical drug discovery path. Full article
(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery)
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