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Pharmaceuticals, Volume 17, Issue 3 (March 2024) – 138 articles

Cover Story (view full-size image): This review highlights the substantial benefit that peptide receptor radionuclide therapy (PRRT) with an α-emitting radionuclide may offer patients with neuroendocrine tumors (NETs). The radiobiological basis for using α-emitters, based on their high linear energy transfer and short range, was discussed. Candidate α-emitters were critically evaluated. The current published literature for targeted alpha therapy of NETs was reviewed, from in vitro to clinical experience, showing a response rate far exceeding that expected from β-PRRT. Despite promising results, studies are heterogeneous, and treatment is non-optimized. It is hoped that theragnostic imaging and dosimetry will aid in understanding the relationships between activity, absorbed dose, therapeutic response, and toxicity to facilitate this optimization for future patients. View this paper
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48 pages, 13165 KiB  
Review
A Review of Advances in Bioanalytical Methods for the Detection and Quantification of Olanzapine and Its Metabolites in Complex Biological Matrices
by Anna Czyż, Alicja Zakrzewska-Sito and Julita Kuczyńska
Pharmaceuticals 2024, 17(3), 403; https://doi.org/10.3390/ph17030403 - 21 Mar 2024
Viewed by 889
Abstract
Schizophrenia is a serious mental disorder that significantly affects the social and professional life of patients, causing distortion of reality and loss of identity and cognitive abilities. Psychopharmacological treatment is an integral part of modern psychiatry, and the introduction of new “atypical” antipsychotic [...] Read more.
Schizophrenia is a serious mental disorder that significantly affects the social and professional life of patients, causing distortion of reality and loss of identity and cognitive abilities. Psychopharmacological treatment is an integral part of modern psychiatry, and the introduction of new “atypical” antipsychotic drugs has brought significant progress in the treatment of this disorder. One of these drugs is olanzapine, which has an effective effect on the productive symptoms of schizophrenia while having an almost minimal potential to cause extrapyramidal syndrome. However, its effectiveness is confronted with frequent side effects, referred to as “metabolic disorders”. Therefore, to ensure the effectiveness of treatment and to minimize the side effects caused by olanzapine, it is recommended to monitor the drug level during therapy. This article reviews the bioanalytical methodologies that enable efficient extraction and sensitive analysis of olanzapine. We considered the advantages and disadvantages of different sample pretreatment methods, including traditional and novel strategies. The analytical conditions required for the separation and detection of olanzapine and its metabolites were analyzed using chromatographic methods combined with various detectors. Full article
(This article belongs to the Section Pharmacology)
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19 pages, 4876 KiB  
Article
Chlojaponilactone B Attenuates THP-1 Macrophage Pyroptosis by Inhibiting the TLR/MyD88/NF-κB Pathway
by Qiyin Wen, Bingjinfeng Zhan, Lu Jin, Zijing Peng, Ju Liu, Longping Zhu, Depo Yang, Xinjun Xu, Lixia Zhang, Ge Li and Zhimin Zhao
Pharmaceuticals 2024, 17(3), 402; https://doi.org/10.3390/ph17030402 - 21 Mar 2024
Viewed by 768
Abstract
Pyroptosis, an innate immune response, plays a crucial role in the pathological process of inflammatory diseases. Although pyroptosis blockade is considered a potential therapeutic strategy, no ideal candidate drug has been identified. The natural product Chojaponilactone B (CJB) has demonstrated anti-inflammatory effects, but [...] Read more.
Pyroptosis, an innate immune response, plays a crucial role in the pathological process of inflammatory diseases. Although pyroptosis blockade is considered a potential therapeutic strategy, no ideal candidate drug has been identified. The natural product Chojaponilactone B (CJB) has demonstrated anti-inflammatory effects, but its role in macrophage pyroptosis has not been studied. This study aimed to investigate the effect and mechanism of CJB in inhibiting macrophage pyroptosis. Using an LPS/ATP-induced THP-1 macrophage pyroptosis model, we found that CJB significantly inhibited pyroptosis and reduced the levels of NLRP3, caspase 1, N-GSDMD, and inflammatory cytokines IL-1β and IL-18. RNA sequencing analysis revealed that CJB interfered with LPS/ATP-induced THP-1 macrophage gene expression, suggesting involvement in anti-inflammatory and anti-pyroptotic signaling pathways. Additionally, CJB suppressed LPS/ATP-induced elevations in TLRs, MyD88, pro-IL-1β, and NF-κB and blocked NF-κB p65 nuclear translocation. In summary, CJB inhibits NLRP3 activation and macrophage pyroptosis through the TLR/MyD88/NF-κB pathway, providing important evidence for its development as a potential drug for treating pyroptosis-related inflammatory diseases. Full article
(This article belongs to the Section Natural Products)
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15 pages, 1602 KiB  
Article
The Potential Role of the Extracellular Matrix Glycoprotein Reelin in Glioblastoma Biology
by Erika Ongemach, Daniela Zerrinius, Philipp Heimann, Christian Rainer Wirtz, Klaus-Michael Debatin, Mike-Andrew Westhoff and Aurelia Peraud
Pharmaceuticals 2024, 17(3), 401; https://doi.org/10.3390/ph17030401 - 21 Mar 2024
Viewed by 721
Abstract
Glioblastoma, the most common and lethal primary adult brain tumor, cannot be successfully removed surgically due to its highly invasive nature. Therapeutically, approaches must be aimed at a systemic brain disease and not merely at a tumor located within the brain, unless a [...] Read more.
Glioblastoma, the most common and lethal primary adult brain tumor, cannot be successfully removed surgically due to its highly invasive nature. Therapeutically, approaches must be aimed at a systemic brain disease and not merely at a tumor located within the brain, unless a successful containment strategy can be found. Reelin, an extracellular matrix glycoprotein, plays an important role in neuronal migration and serves here as a natural stop signal. Interestingly, the expression of reelin is negatively associated with tumor grade and, within glioblastoma, correlates with increased overall survival. To further elucidate a potential biological reason for these findings, we looked at the cellular behavior of glioblastoma cell lines grown on a pure fibronectin matrix or a matrix with reelin inserts. While reelin had no significant effects on cellular metabolism, proliferation, or resistance to chemotherapeutic agents, it did significantly affect the cells’ interaction with fibronectin. Both matrix attachment and detachment were modulated by reelin, and thus, the invasion and motility of cells interacting with a reelin-containing matrix were altered. The data presented in this work strongly suggest that reelin might be a potential modulator of underlying molecular mechanisms that contribute to glioblastoma invasion. Full article
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21 pages, 3217 KiB  
Article
Solubility of Poorly Soluble Drugs in Phosphatidylcholine-Based Drug Delivery Systems: Comparison of the Loading Capacity in the Bulk Formulation and Its Dispersed State
by Linda Grüne and Heike Bunjes
Pharmaceuticals 2024, 17(3), 400; https://doi.org/10.3390/ph17030400 - 21 Mar 2024
Viewed by 850
Abstract
The aim of this study was to determine the drug loading capacity of phosphatidylcholine-based formulations for four poorly water-soluble drug substances (clofazimine, fenofibrate, artemether, cannabidiol). Two self-dispersing lipid formulations were investigated, which consisted of soybean phospholipids, medium-chain triglycerides and ethanol with a different [...] Read more.
The aim of this study was to determine the drug loading capacity of phosphatidylcholine-based formulations for four poorly water-soluble drug substances (clofazimine, fenofibrate, artemether, cannabidiol). Two self-dispersing lipid formulations were investigated, which consisted of soybean phospholipids, medium-chain triglycerides and ethanol with a different phospholipid–oil ratio. The direct loading of the bulk formulation was conducted with dual centrifugation, which proved to be a suitable method for screening experiments with the highly viscous formulations. To estimate possible precipitation after dispersion in the gastrointestinal fluids, the solubility of the drugs was investigated in the dispersed formulations. For this purpose, nanodispersions were prepared from the bulk formulations via high pressure homogenization and subsequently subjected to passive loading. A newly developed HPLC method with Charged Aerosol Detection allowed a simultaneous evaluation of the content of soybean lecithin and medium-chain triglycerides in the nanodispersions. When comparing the two phosphatidylcholine-based formulations, a high content of oil was advantageous with regard to a high loading capacity. Drug substances with melting points below 150 °C exhibited a high solubility in the phospholipid-based formulations. A surprisingly high solubility was observed for artemether and cannabidiol with up to 13.0% and 33.3% drug loaded to the formulations, respectively. In the dispersions, a similar solubility as in the bulk formulations was obtained for fenofibrate and cannabidiol. Clofazimine yielded a higher loading result in the nanodispersions than in the bulk formulation. Full article
(This article belongs to the Special Issue Applications of Dual Centrifugation Technology in Pharmaceutics)
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11 pages, 1007 KiB  
Review
Terpenes from Cecropia Species and Their Pharmacological Potential
by Preslav Enchev, Yancho Zarev, Anzhelica Dakovska, Andrés Rivera-Mondragón, Ekaterina Kozuharova and Iliana Ionkova
Pharmaceuticals 2024, 17(3), 399; https://doi.org/10.3390/ph17030399 - 20 Mar 2024
Viewed by 673
Abstract
Cecropia is a genus of neotropical trees mainly distributed in Mexico and Central and South America. Currently, 63 species have been described, some of which have been used for centuries in traditional medicine to treat conditions such as diabetes, high blood pressure, and [...] Read more.
Cecropia is a genus of neotropical trees mainly distributed in Mexico and Central and South America. Currently, 63 species have been described, some of which have been used for centuries in traditional medicine to treat conditions such as diabetes, high blood pressure, and wound healing, among others. In recent times, modern phytochemical studies have succeeded in isolating individual compounds with potential specific medicinal applications. This review aims to examine the literature data regarding isolated terpenes and their correlation with pharmacological activities, with the goal of unveiling the future potential of the genus. Full article
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31 pages, 3020 KiB  
Review
Lactoferrins in Their Interactions with Molecular Targets: A Structure-Based Overview
by Roberta Piacentini, Alberto Boffi and Edoardo Milanetti
Pharmaceuticals 2024, 17(3), 398; https://doi.org/10.3390/ph17030398 - 20 Mar 2024
Viewed by 924
Abstract
Lactoferrins and lactoferrin-derived peptides display numerous functions linked to innate immunity in mammalians, spanning from antimicrobial to anti-inflammatory and immunomodulatory actions, and even demonstrate antitumor properties. To date, the proposed mechanisms for their biological actions are varied, although the molecular basis that governs [...] Read more.
Lactoferrins and lactoferrin-derived peptides display numerous functions linked to innate immunity in mammalians, spanning from antimicrobial to anti-inflammatory and immunomodulatory actions, and even demonstrate antitumor properties. To date, the proposed mechanisms for their biological actions are varied, although the molecular basis that governs lactoferrin interactions with molecular targets has been clarified only in a limited number of specific cases. However, key in silico methods have recently moved the topic to the fore, thus greatly expanding the possibilities of large-scale investigations on macromolecular interactions involving lactoferrins and their molecular targets. This review aims to summarize the current knowledge on the structural determinants that drive lactoferrin recognition of molecular targets, with primary focus on the mechanisms of activity against bacteria and viruses. The understanding of the structural details of lactoferrins’ interaction with their molecular partners is in fact a crucial goal for the development of novel pharmaceutical products. Full article
(This article belongs to the Special Issue Pharmaceutical Applications of Lactoferrin)
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18 pages, 2513 KiB  
Article
Adenosine Increases the Immunosuppressive Capacity of Cervical Cancer Cells by Increasing PD-L1 Expression and TGF-β Production through Its Interaction with A2AR/A2BR
by Rosario García-Rocha, Alberto Monroy-García, Ana Luisa Vázquez-Cruz, Luis Antonio Marín-Aquino, Benny Weiss-Steider, Jorge Hernández-Montes, Christian Azucena Don-López, Gabriela Molina-Castillo and María de Lourdes Mora-García
Pharmaceuticals 2024, 17(3), 397; https://doi.org/10.3390/ph17030397 - 19 Mar 2024
Viewed by 854
Abstract
The present study provides evidence showing that adenosine (Ado) increases the expression of programmed death ligand 1 (PD-L1) in cervical cancer (CeCa) cells by interacting with A2AR/A2BR and that TGF-β1 acts in an autocrine manner to induce PD-L1 expression, [...] Read more.
The present study provides evidence showing that adenosine (Ado) increases the expression of programmed death ligand 1 (PD-L1) in cervical cancer (CeCa) cells by interacting with A2AR/A2BR and that TGF-β1 acts in an autocrine manner to induce PD-L1 expression, enhancing the immunosuppressive effects of CeCa cells on activated T lymphocytes (ATLs) and CD8+ cytotoxic T lymphocytes (CTLs) specific for antigenic peptides derived from E6 and E7 proteins of HPV-16. Interestingly, the addition of the antagonists ZM241385 and MRS1754, which are specific for A2AR and A2BR, respectively, or SB-505124, which is a selective TGF-β1 receptor inhibitor, to CeCa cell cultures significantly inhibited PD-L1 expression. In addition, supernatants from CeCa cells that were treated with Ado (CeCa-Ado Sup) increased the expression of PD-1, TGF-β1, and IL-10 and decreased the expression of IFN-γ in ATLs. Interestingly, the addition of an anti-TGF-β neutralizing antibody strongly reversed the effect of CeCa-Ado Sup on PD-1 expression in ATLs. These results strongly suggest the presence of a feedback mechanism that involves the adenosinergic pathway, the production of TGF-β1, and the upregulation of PD-L1 expression in CeCa cells that suppresses the antitumor response of CTLs. The findings of this study suggest that this pathway may be clinically important and may be a therapeutic target. Full article
(This article belongs to the Special Issue Small Molecules in Cancer Immunotherapy)
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36 pages, 1970 KiB  
Review
Metformin and Breast Cancer: Current Findings and Future Perspectives from Preclinical and Clinical Studies
by Karen A. Corleto, Jenna L. Strandmo and Erin D. Giles
Pharmaceuticals 2024, 17(3), 396; https://doi.org/10.3390/ph17030396 - 19 Mar 2024
Viewed by 1317
Abstract
Over the last several decades, a growing body of research has investigated the potential to repurpose the anti-diabetic drug metformin for breast cancer prevention and/or treatment. Observational studies in the early 2000s demonstrated that patients with diabetes taking metformin had decreased cancer risk, [...] Read more.
Over the last several decades, a growing body of research has investigated the potential to repurpose the anti-diabetic drug metformin for breast cancer prevention and/or treatment. Observational studies in the early 2000s demonstrated that patients with diabetes taking metformin had decreased cancer risk, providing the first evidence supporting the potential role of metformin as an anti-cancer agent. Despite substantial efforts, two decades later, the exact mechanisms and clinical efficacy of metformin for breast cancer remain ambiguous. Here, we have summarized key findings from studies examining the effect of metformin on breast cancer across the translational spectrum including in vitro, in vivo, and human studies. Importantly, we discuss critical factors that may help explain the significant heterogeneity in study outcomes, highlighting how metformin dose, underlying metabolic health, menopausal status, tumor subtype, membrane transporter expression, diet, and other factors may play a role in modulating metformin’s anti-cancer effects. We hope that these insights will help with interpreting data from completed studies, improve the design of future studies, and aid in the identification of patient subsets with breast cancer or at high risk for the disease who are most likely to benefit from metformin treatment. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)
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17 pages, 1882 KiB  
Article
Digital Technology Applications in the Management of Adverse Drug Reactions: Bibliometric Analysis
by Olena Litvinova, Andy Wai Kan Yeung, Fabian Peter Hammerle, Michel-Edwar Mickael, Maima Matin, Maria Kletecka-Pulker, Atanas G. Atanasov and Harald Willschke
Pharmaceuticals 2024, 17(3), 395; https://doi.org/10.3390/ph17030395 - 19 Mar 2024
Viewed by 873
Abstract
Adverse drug reactions continue to be not only one of the most urgent problems in clinical medicine, but also a social problem. The aim of this study was a bibliometric analysis of the use of digital technologies to prevent adverse drug reactions and [...] Read more.
Adverse drug reactions continue to be not only one of the most urgent problems in clinical medicine, but also a social problem. The aim of this study was a bibliometric analysis of the use of digital technologies to prevent adverse drug reactions and an overview of their main applications to improve the safety of pharmacotherapy. The search was conducted using the Web of Science database for the period 1991–2023. A positive trend in publications in the field of using digital technologies in the management of adverse drug reactions was revealed. A total of 72% of all relevant publications come from the following countries: the USA, China, England, India, and Germany. Among the organizations most active in the field of drug side effect management using digital technologies, American and Chinese universities dominate. Visualization of publication keywords using VOSviewer software 1.6.18 revealed four clusters: “preclinical studies”, “clinical trials”, “pharmacovigilance”, and “reduction of adverse drug reactions in order to improve the patient’s quality of life”. Molecular design technologies, virtual models for toxicity modeling, data integration, and drug repurposing are among the key digital tools used in the preclinical research phase. Integrating the application of machine learning algorithms for data analysis, monitoring of electronic databases of spontaneous messages, electronic medical records, scientific databases, social networks, and analysis of digital device data into clinical trials and pharmacovigilance systems, can significantly improve the efficiency and safety of drug development, implementation, and monitoring processes. The result of combining all these technologies is a huge synergistic provision of up-to-date and valuable information to healthcare professionals, patients, and health authorities. Full article
(This article belongs to the Special Issue Drug Safety and Relevant Issues in the Real-World 2024)
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13 pages, 805 KiB  
Article
Real-World Safety Data of the Orphan Drug Onasemnogene Abeparvovec (Zolgensma®) for the SMA Rare Disease: A Pharmacovigilance Study Based on the EMA Adverse Event Reporting System
by Rosanna Ruggiero, Nunzia Balzano, Maria Maddalena Nicoletti, Gabriella di Mauro, Federica Fraenza, Maria Rosaria Campitiello, Francesco Rossi and Annalisa Capuano
Pharmaceuticals 2024, 17(3), 394; https://doi.org/10.3390/ph17030394 - 19 Mar 2024
Viewed by 1431
Abstract
The recent introduction of the innovative therapy, onasemnogene abeparvovec (Zolgensma®), has revolutionized the spinal muscular atrophy (SMA) therapeutic landscape. Although Zolgensma® therapy has proven to lead to functional improvements in SMA children, some gaps in its safety profile still need [...] Read more.
The recent introduction of the innovative therapy, onasemnogene abeparvovec (Zolgensma®), has revolutionized the spinal muscular atrophy (SMA) therapeutic landscape. Although Zolgensma® therapy has proven to lead to functional improvements in SMA children, some gaps in its safety profile still need to be investigated. To better characterize the Zolgensma® safety profile, we conducted a retrospective observational study, analyzing all the Individual Case Safety Reports (ICSRs) referred to it and collected in the European pharmacovigilance database between 1 January 2019 and 22 September 2023. We found 661 ICSRs related to Zolgensma®, with a growing trend in the annual reporting. The majority of the reports were sent by healthcare professionals and referred to infant females. In more than 90% of the cases, Zolgensma® was the only reported suspected drug. Out of a total of 2744 reported ADRs, increased hepatic enzymes, pyrexia, vomiting, and thrombocytopenia were the most commonly reported adverse reactions. Of these adverse reactions (ADRs), 56.9% were serious, causing or prolonging the patient’s hospitalization. A total of 39 ICSRs related to cases with a fatal outcome. Alterations in the heart rhythm, acute hepatic failure, and hepatic cytolysis emerged among the cardiac and hepatic disorders, respectively. Full article
(This article belongs to the Section Pharmacology)
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21 pages, 3217 KiB  
Article
Investigation of the Effects of a Novel NOX2 Inhibitor, GLX7013170, against Glutamate Excitotoxicity and Diabetes Insults in the Retina
by Stavroula Dionysopoulou, Per Wikstrom, Erik Walum, Spiros Georgakis and Kyriaki Thermos
Pharmaceuticals 2024, 17(3), 393; https://doi.org/10.3390/ph17030393 - 19 Mar 2024
Viewed by 690
Abstract
Glutamate excitotoxicity and oxidative stress represent two major pathological mechanisms implicated in retinal disorders. In Diabetic Retinopathy (DR), oxidative stress is correlated to NADPH oxidase (NOX), a major source of Reactive Oxygen Species (ROS), and glutamate metabolism impairments. This study investigated the role [...] Read more.
Glutamate excitotoxicity and oxidative stress represent two major pathological mechanisms implicated in retinal disorders. In Diabetic Retinopathy (DR), oxidative stress is correlated to NADPH oxidase (NOX), a major source of Reactive Oxygen Species (ROS), and glutamate metabolism impairments. This study investigated the role of NOX2 and the novel NOX2 inhibitor, GLX7013170, in two models of a) retinal AMPA excitotoxicity [AMPA+GLX7013170 (10−4 M, intravitreally)] and b) early-stage DR paradigm (ESDR), GLX7013170: 14-day therapeutic treatment (topically, 20 μL/eye, 10 mg/mL (300 × 10−4 M), once daily) post-streptozotocin (STZ)-induced DR. Immunohistochemical studies for neuronal markers, nitrotyrosine, micro/macroglia, and real-time PCR, Western blot, and glutamate colorimetric assays were conducted. Diabetes increased NOX2 expression in the retina. NOX2 inhibition limited the loss of NOS-positive amacrine cells and the overactivation of micro/macroglia in both models. In the diabetic retina, GLX7013170 had no effect on retinal ganglion cell axons, but reduced oxidative damage, increased Bcl-2, reduced glutamate levels, and partially restored excitatory amino acid transporter (EAAT1) expression. These results suggest that NOX2 in diabetes is part of the triad, oxidative stress, NOX, and glutamate excitotoxicity, key players in the induction of DR. GLX7013170 is efficacious as a neuroprotective/anti-inflammatory agent and a potential therapeutic in retinal diseases, including ESDR. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)
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31 pages, 5627 KiB  
Review
Identification and Development of BRD9 Chemical Probes
by Ester Colarusso, Maria Giovanna Chini, Giuseppe Bifulco, Gianluigi Lauro and Assunta Giordano
Pharmaceuticals 2024, 17(3), 392; https://doi.org/10.3390/ph17030392 - 19 Mar 2024
Viewed by 722
Abstract
The development of BRD9 inhibitors involves the design and synthesis of molecules that can specifically bind the BRD9 protein, interfering with the function of the chromatin-remodeling complex ncBAF, with the main advantage of modulating gene expression and controlling cellular processes. Here, we summarize [...] Read more.
The development of BRD9 inhibitors involves the design and synthesis of molecules that can specifically bind the BRD9 protein, interfering with the function of the chromatin-remodeling complex ncBAF, with the main advantage of modulating gene expression and controlling cellular processes. Here, we summarize the work conducted over the past 10 years to find new BRD9 binders, with an emphasis on their structure–activity relationships, efficacies, and selectivities in preliminary studies. BRD9 is expressed in a variety of cancer forms, hence, its inhibition holds particular significance in cancer research. However, it is crucial to note that the expanding research in the field, particularly in the development of new degraders, may uncover new therapeutic potentials. Full article
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13 pages, 2588 KiB  
Article
Medical Ozone: A Redox Regulator with Selectivity for Rheumatoid Arthritis Patients
by Olga Sonia León Fernández, Gabriel Takon Oru, Renate Viebahn-Haensler, Gilberto López Cabreja, Irainis Serrano Espinosa and María Elena Corrales Vázquez
Pharmaceuticals 2024, 17(3), 391; https://doi.org/10.3390/ph17030391 - 19 Mar 2024
Viewed by 756
Abstract
Rheumatoid arthritis (RA) and osteoarthritis (OA) are the most common arthritic diseases. Medical ozone has demonstrated its effectiveness in combination therapy with methotrexate or non-steroidal anti-inflammatory drugs for RA and OA, respectively. Although RA and OA have been compared from different points of [...] Read more.
Rheumatoid arthritis (RA) and osteoarthritis (OA) are the most common arthritic diseases. Medical ozone has demonstrated its effectiveness in combination therapy with methotrexate or non-steroidal anti-inflammatory drugs for RA and OA, respectively. Although RA and OA have been compared from different points of view, few studies have considered their redox status in spite of the oxidative processes that are involved in both diseases. The aim of this study was to compare RA with OA, evaluating their redox status and the effects of ozone on their clinical response to combined therapy with ozone. The redox status of 80 patients was determined: antioxidant defenses, injury markers, two subjective variables (pain and disability), and levels of antibodies against cyclic citrullinated peptides were evaluated. Oxidative stress and clinical response to combined therapy with ozone was higher than in the case of RA. After medical ozone treatment, there was an increase in antioxidant defense and a decrease in injury markers as well as pain, disability, and autoantibody concentrations. Redox biomarkers were able to differentiate between both arthritic diseases and combined therapy with ozone (methotrexate + ozone), showing a therapeutic selectivity for RA in comparison with OA. Full article
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28 pages, 32029 KiB  
Article
Target Development towards First Production of High-Molar- Activity 44gSc and 47Sc by Mass Separation at CERN-MEDICIS
by Edgars Mamis, Charlotte Duchemin, Valentina Berlin, Cyril Bernerd, Mathieu Bovigny, Eric Chevallay, Bernard Crepieux, Vadim Maratovich Gadelshin, Reinhard Heinke, Ronaldo Mendez Hernandez, Jake David Johnson, Patrīcija Kalniņa, Alexandros Koliatos, Laura Lambert, Ralf Erik Rossel, Sebastian Rothe, Julien Thiboud, Felix Weber, Klaus Wendt, Rudolfs Jānis Zabolockis, Elīna Pajuste and Thierry Storaadd Show full author list remove Hide full author list
Pharmaceuticals 2024, 17(3), 390; https://doi.org/10.3390/ph17030390 - 18 Mar 2024
Viewed by 937
Abstract
The radionuclides 43Sc,  44g/mSc, and 47Sc can be produced cost-effectively in sufficient yield for medical research and applications by irradiating  natTi and  natV target materials with protons. Maximizing [...] Read more.
The radionuclides 43Sc,  44g/mSc, and 47Sc can be produced cost-effectively in sufficient yield for medical research and applications by irradiating  natTi and  natV target materials with protons. Maximizing the production yield of the therapeutic 47Sc in the highest cross section energy range of 24–70 MeV results in the co-production of long-lived, high-γ-ray-energy 46Sc and 48Sc contaminants if one does not use enriched target materials. Mass separation can be used to obtain high molar activity and isotopically pure Sc radionuclides from natural target materials; however, suitable operational conditions to obtain relevant activity released from irradiated  natTi and  natV have not yet been established at CERN-MEDICIS and ISOLDE. The objective of this work was to develop target units for the production, release, and purification of Sc radionuclides by mass separation as well as to investigate target materials for the mass separation that are compatible with high-yield Sc radionuclide production in the 9–70 MeV proton energy range. In this study, the in-target production yield obtained at MEDICIS with 1.4 GeV protons is compared with the production yield that can be reached with commercially available cyclotrons. The thick-target materials were irradiated at MEDICIS and comprised of metallic  natTi,  natV metallic foils, and  natTiC pellets. The produced radionuclides were subsequently released, ionized, and extracted from various target and ion source units and mass separated. Mono-atomic Sc laser and molecule ionization with forced-electron-beam-induced arc-discharge ion sources were investigated. Sc radionuclide production in thick  natTi and  natV targets at MEDICIS is equivalent to low- to medium-energy cyclotron-irradiated targets at medically relevant yields, furthermore benefiting from the mass separation possibility. A two-step laser resonance ionization scheme was used to obtain mono-atomic Sc ion beams. Sc radionuclide release from irradiated target units most effectively could be promoted by volatile scandium fluoride formation. Thus, isotopically pure  44g/mSc, 46Sc, and 47Sc were obtained as mono-atomic and molecular ScF 2+ ion beams and collected for the first time at CERN-MEDICIS. Among all the investigated target materials,  natTiC is the most suitable target material for Sc mass separation as molecular halide beams, due to high possible operating temperatures and sustained release. Full article
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16 pages, 473 KiB  
Article
Cytotoxic and Antiproliferative Activity of LASSBio-2208 and the Attempts to Determine Its Drug Metabolism and Pharmacokinetics In Vitro Profile
by Raysa Magali Pillpe-Meza, Wesley Leandro Gouveia, Gisele Barbosa, Carlos A. M. Fraga, Eliezer J. Barreiro and Lidia Moreira Lima
Pharmaceuticals 2024, 17(3), 389; https://doi.org/10.3390/ph17030389 - 18 Mar 2024
Viewed by 800
Abstract
Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed in cancers. LASSBio-2208, has been previously described as a dual inhibitor in the nanomolar range of HDAC-6 and PI3Kα and is three times more [...] Read more.
Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed in cancers. LASSBio-2208, has been previously described as a dual inhibitor in the nanomolar range of HDAC-6 and PI3Kα and is three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its drug metabolism and pharmacokinetics (DMPK) in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on breast cancer cell line MCF-7 (IC50 = 23 µM), human leukaemia cell line CCRF-CEM (IC50 = 8.54 µM) and T lymphoblast cell line MOLT-4 (IC50 = 7.15 µM), with no cytotoxic effect on human peripheral blood mononuclear cells (hPBMC). In addition, it has a good antiproliferative effect on MCF-7 cells (IC50 = 5.44 µM), low absorption by parallel artificial membrane permeability—gastrointestinal tract (PAMPA—GIT) and low permeation by parallel artificial membrane permeability—blood–brain barrier (BBB) (PAMPA—BBB), exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentrations corresponding to their CC50 values on MOLT-4 and CCRF-CEM cells. Full article
(This article belongs to the Section Pharmacology)
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17 pages, 3737 KiB  
Article
Synthesis of a [18F]F Estradiol Derivative via Click Chemistry Using an Automated Synthesis Module: In Vitro Evaluation as Potential Radiopharmaceutical for Breast Cancer Imaging
by María Emilia Tejería, María Pía Pereira, Juan Pablo Gambini, Pablo Duarte, Javier Gabriel Giglio and Ana María Rey
Pharmaceuticals 2024, 17(3), 388; https://doi.org/10.3390/ph17030388 - 18 Mar 2024
Viewed by 648
Abstract
“Click reactions” are a very useful tool for the selective conjugation of different molecular subunits to produce complex structures in a simple way. In this paper, we present the application of Cu(I)-catalyzed biorthogonal reactions between alkynes and azides to the indirect radiofluorination of [...] Read more.
“Click reactions” are a very useful tool for the selective conjugation of different molecular subunits to produce complex structures in a simple way. In this paper, we present the application of Cu(I)-catalyzed biorthogonal reactions between alkynes and azides to the indirect radiofluorination of an estradiol derivative with potential applications in estrogen receptor imaging. The procedure was fully developed on an automated synthesis platform, and conditions were optimized to achieve the desired product with a reasonable yield without precipitation. Although the biological results were not adequate for a potential radiopharmaceutical, the outcome of this work is valuable since the use of automated platforms is required for the reliable and reproducible preparation of PET radiopharmaceuticals in GMP conditions while limiting the radiation dose rates to the personnel. Full article
(This article belongs to the Special Issue Click Reactions in Medicinal Chemistry II)
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14 pages, 2662 KiB  
Article
Sulfarotene Inhibits Colorectal Cancer via Mitigating Natural-Killer-Cell-Induced Stemness
by Keshu Hu, Yu Dong, Jiayu Zhang, Mengling Liu, Xun Sun, Xin Cao, Pengfei Zhang and Tianshu Liu
Pharmaceuticals 2024, 17(3), 387; https://doi.org/10.3390/ph17030387 - 18 Mar 2024
Viewed by 696
Abstract
Tumor cell stemness stands out as a pivotal factor driving tumor recurrence or metastasis and significantly contributes to the mortality of patients with colorectal cancer (CRC). Recent research has unveiled a link between immune-active cells and the induction of tumor cell stemness, ultimately [...] Read more.
Tumor cell stemness stands out as a pivotal factor driving tumor recurrence or metastasis and significantly contributes to the mortality of patients with colorectal cancer (CRC). Recent research has unveiled a link between immune-active cells and the induction of tumor cell stemness, ultimately leading to heightened resistance to treatment. In this study, stemness in CRC cell lines was assessed after co-culture with natural killer (NK) cells, both with and without sulfarotene administration. Furthermore, a CRC xenograft model was utilized to scrutinize the in vivo efficacy of sulfarotene in overcoming stemness induced by NK cell activation. As a result, CRC cells exhibited significant stemness after NK cell co-culture, as evidenced by the upregulation of several stemness markers associated with cancer stem cells. Moreover, these cells demonstrated remarkable resistance to commonly used chemotherapy agents for CRC, such as oxaliplatin and irinotecan. Importantly, sulfarotene effectively reversed the altered stemness of CRC cells in both in vitro and in vivo assays. In conclusion, sulfarotene emerges as a promising therapeutic strategy for overcoming colorectal cancer resistance to NK cells by effectively inhibiting stemness remodeling. This study underscores the potential of sulfarotene in augmenting NK-cell-mediated immune surveillance, proposing a novel immunotherapeutic approach against colorectal cancer. Full article
(This article belongs to the Special Issue Pharmacological Treatment of Colorectal Cancer)
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22 pages, 3573 KiB  
Article
Effect of Matricaria aurea Essential Oils on Biofilm Development, Virulence Factors and Quorum Sensing-Dependent Genes of Pseudomonas aeruginosa
by Haitham Qaralleh, Sultan Ayesh Mohammed Saghir, Muhamad O. Al-limoun, Saif M. Dmor, Khaled Khleifat, Basma Ezzat Mustafa Al-Ahmad, Laila Al-Omari, Yasser Tabana, Ramzi A. Mothana, Hanan M. Al-Yousef and Abdulaziz M. Alqahtani
Pharmaceuticals 2024, 17(3), 386; https://doi.org/10.3390/ph17030386 - 18 Mar 2024
Viewed by 924
Abstract
The emergence of drug-resistant microorganisms presents a substantial global public health threat. The increase in pathogens resistant to commonly prescribed antibiotics underscores the urgent requirement to explore alternative treatment strategies. This study adopts a novel approach by harnessing natural resources, specifically essential oils [...] Read more.
The emergence of drug-resistant microorganisms presents a substantial global public health threat. The increase in pathogens resistant to commonly prescribed antibiotics underscores the urgent requirement to explore alternative treatment strategies. This study adopts a novel approach by harnessing natural resources, specifically essential oils (EO), to combat bacterial pathogenicity. The primary aim of this research was to analyze the chemical composition of the aerial part of the Matricaria aurea (M. aureas) EO and evaluate its potential for inhibiting quorum sensing (QS) and disrupting biofilm formation in Pseudomonas aeruginosa (P. aeruginosa). The gas chromatography-mass spectrometry (GCMS) analysis unveiled that α-bisabolol oxide A constituted the predominant portion, comprising 64.8% of the total, with β-bisabolene at 6.3% and α-farnesene at 4.8% following closely behind. The antibiofilm efficacy was observed at concentrations of 0.3, 0.15, and 0.08 mg/mL, demonstrating negligible effects on cell viability. Furthermore, the EO from M. aurea effectively inhibited the formation of P. aeruginosa biofilms by diminishing aggregation, hydrophobicity, and swarming motility. Significantly, the EO treatment resulted in a conspicuous decrease in the production of pyocyanin, rhamnolipid, and extracellular polymeric substances (EPS), along with a reduction in the enzymatic activity of protease and chitinase. The EO effectively hindered QS by disrupting QS mechanisms, resulting in a marked decline in the secretion of N-Acyl homoserine lactone (AHL) molecules and the expression of phazA1 and aprA genes. This investigation offers compelling evidence supporting the potential of M. aurea EO as a promising therapeutic candidate for addressing infectious diseases induced by biofilm formation. Full article
(This article belongs to the Special Issue Natural Anti-Biofilm Agents)
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20 pages, 3189 KiB  
Article
Exploring the Therapeutic Potential of Ammodaucus leucotrichus Seed Extracts: A Multi-Faceted Analysis of Phytochemical Composition, Anti-Inflammatory Efficacy, Predictive Anti-Arthritic Properties, and Molecular Docking Insights
by Cheima Djehiche, Nadia Benzidane, Hanene Djeghim, Mehdi Tebboub, El Hassen Mokrani, Saad Mebrek, Mohammed Messaoudi, Chawki Bensouici, Ali Alsalme, David Cornu, Mikhael Bechelany, Lekhmici Arrar and Ahmed Barhoum
Pharmaceuticals 2024, 17(3), 385; https://doi.org/10.3390/ph17030385 - 18 Mar 2024
Viewed by 1045
Abstract
Ammodaucus leucotrichus exhibits promising pharmacological activity, hinting at anti-inflammatory and anti-arthritic effects. This study investigated seed extracts from Ammodaucus leucotrichus using methanol and n-hexane, focusing on anti-inflammatory and anti-arthritic properties. The methanol extract outperformed the n-hexane extract and diclofenac, a reference anti-inflammatory drug, [...] Read more.
Ammodaucus leucotrichus exhibits promising pharmacological activity, hinting at anti-inflammatory and anti-arthritic effects. This study investigated seed extracts from Ammodaucus leucotrichus using methanol and n-hexane, focusing on anti-inflammatory and anti-arthritic properties. The methanol extract outperformed the n-hexane extract and diclofenac, a reference anti-inflammatory drug, in trypsin inhibition (85% vs. 30% and 64.67% at 125 μg/mL). For trypsin inhibition, the IC50 values were 82.97 μg/mL (methanol), 202.70 μg/mL (n-hexane), and 97.04 μg/mL (diclofenac). Additionally, the n-hexane extract surpassed the methanol extract and diclofenac in BSA (bovine serum albumin) denaturation inhibition (90.4% vs. 22.0% and 51.4% at 62.5 μg/mL). The BSA denaturation IC50 values were 14.30 μg/mL (n-hexane), 5408 μg/mL (methanol), and 42.30 μg/mL (diclofenac). Gas chromatography–mass spectrometry (GC–MS) revealed 59 and 58 secondary metabolites in the methanol and n-hexane extracts, respectively. The higher therapeutic activity of the methanol extract was attributed to hydroxyacetic acid hydrazide, absent in the n-hexane extract. In silico docking studies identified 28 compounds with negative binding energies, indicating potential trypsin inhibition. The 2-hydroxyacetohydrazide displayed superior inhibitory effects compared to diclofenac. Further mechanistic studies are crucial to validate 2-hydroxyacetohydrazide as a potential drug candidate for rheumatoid arthritis treatment. Full article
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16 pages, 3457 KiB  
Article
Transcriptome-Wide 5-Methylcytosine Profiling of lncRNAs in the Mouse Cerebral Ischemia Model
by Chao Zhang, Junpeng Gao, Dan Xiong and Yan Zhao
Pharmaceuticals 2024, 17(3), 384; https://doi.org/10.3390/ph17030384 - 18 Mar 2024
Viewed by 713
Abstract
An increasing body of research has demonstrated the significant role of long non-coding RNAs (lncRNAs) in the pathogenesis of stroke. They can actively contribute to the disease’s progression either by directly participating in its pathogenesis or by acting as mediators through competing endogenous [...] Read more.
An increasing body of research has demonstrated the significant role of long non-coding RNAs (lncRNAs) in the pathogenesis of stroke. They can actively contribute to the disease’s progression either by directly participating in its pathogenesis or by acting as mediators through competing endogenous RNA (ceRNA) mechanisms. Concurrently, epigenetics plays a pivotal role in the pathological mechanisms underlying stroke. Epigenetic factors serve as valuable markers for disease progression, diagnostic biomarkers, and novel therapeutic targets. One of the most prevalent epigenetic modifications is 5-methylcytosine (m5C). However, the specific profiles of 5-methylcytosine in lncRNAs associated with stroke remain to be solved. Within the scope of this research, we performed a thorough transcriptome-wide analysis of m5C methylation within lncRNAs by methylated RNA immunoprecipitation sequencing (MeRIP-Seq), within a mouse stroke model induced by middle cerebral artery occlusion. Our findings reveal substantial disparities in both the quantity and distribution of m5C within the mouse stroke model compared to normal mice. This suggests a potential linkage between stroke and lncRNA m5C modifications, offering valuable insights into the mechanisms of stroke pathogenesis and the development of new drug targets. Full article
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6 pages, 230 KiB  
Communication
Aztreonam Combinations with Avibactam, Relebactam, and Vaborbactam as Treatment for New Delhi Metallo-β-Lactamase-Producing Enterobacterales Infections—In Vitro Susceptibility Testing
by Małgorzata Brauncajs, Filip Bielec, Marlena Malinowska and Dorota Pastuszak-Lewandoska
Pharmaceuticals 2024, 17(3), 383; https://doi.org/10.3390/ph17030383 - 17 Mar 2024
Viewed by 837
Abstract
Antimicrobial resistance is a major global health issue. Metallo-β-lactamases (MBL), in particular, are problematic because they can inactivate all classes of β-lactams except aztreonam. Unfortunately, the latter may be simultaneously inactivated by serine β-lactamases. The most dangerous known MBL is New Delhi Metallo-β-lactamase [...] Read more.
Antimicrobial resistance is a major global health issue. Metallo-β-lactamases (MBL), in particular, are problematic because they can inactivate all classes of β-lactams except aztreonam. Unfortunately, the latter may be simultaneously inactivated by serine β-lactamases. The most dangerous known MBL is New Delhi Metallo-β-lactamase (NDM). This study aimed to test the in vitro susceptibility to aztreonam in combination with novel β-lactamase inhibitors (avibactam, relebactam, and vaborbactam) in clinical strains of Enterobacterales NDM which is resistant to aztreonam. We investigated 21 NDM isolates—including Klebsiella pneumoniae, Escherichia coli, and Citrobacter freundii—which are simultaneously resistant to aztreonam, ceftazidime/avibactam, imipenem/relebactam, and meropenem/vaborbactam. MICs for aztreonam combinations with novel inhibitors were determined using the gradient strip superposition method. The most effective combination was aztreonam/avibactam, active in 80.95% strains, while combinations with relebactam and vaborbactam were effective in 61.90% and 47.62%, respectively. In three studied strains, none of the studied inhibitors restored aztreonam susceptibility. Aztreonam/avibactam has the most significant antimicrobial potential for NDM isolates. However, combinations with other inhibitors should not be rejected in advance because we identified strain susceptible only to tested combinations with inhibitors other than avibactam. Standardization committees should, as soon as possible, develop official methodology for antimicrobial susceptibility testing for aztreonam with β-lactamase inhibitors. Full article
16 pages, 1257 KiB  
Article
Absorption Distribution Metabolism Excretion and Toxicity Property Prediction Utilizing a Pre-Trained Natural Language Processing Model and Its Applications in Early-Stage Drug Development
by Woojin Jung, Sungwoo Goo, Taewook Hwang, Hyunjung Lee, Young-Kuk Kim, Jung-woo Chae, Hwi-yeol Yun and Sangkeun Jung
Pharmaceuticals 2024, 17(3), 382; https://doi.org/10.3390/ph17030382 - 17 Mar 2024
Viewed by 805
Abstract
Machine learning techniques are extensively employed in drug discovery, with a significant focus on developing QSAR models that interpret the structural information of potential drugs. In this study, the pre-trained natural language processing (NLP) model, ChemBERTa, was utilized in the drug discovery process. [...] Read more.
Machine learning techniques are extensively employed in drug discovery, with a significant focus on developing QSAR models that interpret the structural information of potential drugs. In this study, the pre-trained natural language processing (NLP) model, ChemBERTa, was utilized in the drug discovery process. We proposed and evaluated four core model architectures as follows: deep neural network (DNN), encoder, concatenation (concat), and pipe. The DNN model processes physicochemical properties as input, while the encoder model leverages the simplified molecular input line entry system (SMILES) along with NLP techniques. The latter two models, concat and pipe, incorporate both SMILES and physicochemical properties, operating in parallel and with sequential manners, respectively. We collected 5238 entries from DrugBank, including their physicochemical properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) features. The models’ performance was assessed by the area under the receiver operating characteristic curve (AUROC), with the DNN, encoder, concat, and pipe models achieved 62.4%, 76.0%, 74.9%, and 68.2%, respectively. In a separate test with 84 experimental microsomal stability datasets, the AUROC scores for external data were 78% for DNN, 44% for the encoder, and 50% for concat, indicating that the DNN model had superior predictive capabilities for new data. This suggests that models based on structural information may require further optimization or alternative tokenization strategies. The application of natural language processing techniques to pharmaceutical challenges has demonstrated promising results, highlighting the need for more extensive data to enhance model generalization. Full article
(This article belongs to the Special Issue Machine Learning Methods for Medicinal Chemistry)
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22 pages, 16782 KiB  
Article
Comparison of Glutathione Nanoparticles, CoEnzyme Q10, and Fish Oil for Prevention of Oxygen-Induced Retinopathy in Neonatal Rats
by Sidra Bashir, Charles L. Cai, Matthew Marcelino, Jacob V. Aranda and Kay D. Beharry
Pharmaceuticals 2024, 17(3), 381; https://doi.org/10.3390/ph17030381 - 17 Mar 2024
Viewed by 1029
Abstract
Notch ligands and receptors are important for cell specification and angiogenesis, but their role in oxygen-induced retinopathy (OIR) is not well studied. Delta-like ligand (DLL)-4/Notch inhibits angiogenesis, while Jagged-1/Notch promotes angiogenesis. We tested the hypothesis that early supplementation with antioxidants and/or fish oil [...] Read more.
Notch ligands and receptors are important for cell specification and angiogenesis, but their role in oxygen-induced retinopathy (OIR) is not well studied. Delta-like ligand (DLL)-4/Notch inhibits angiogenesis, while Jagged-1/Notch promotes angiogenesis. We tested the hypothesis that early supplementation with antioxidants and/or fish oil curtails severe OIR by inducing DLL-4/Notch and reducing Jagged-1/Notch. Newborn rats were exposed to brief intermittent hypoxia (IH) during hyperoxia, during which they received daily oral supplements of (1) fish oil, (2) coenzyme Q10 (CoQ10) in olive oil (OO), (3) glutathione nanoparticles (nGSH), (4) fish oil + CoQ10, or (5) OO (controls) from birth (P0) to P14. At P14, the pups were placed in room air (RA) until P21, with no further treatment. Oxidative stress, apoptosis, ocular histopathology, and Notch signaling were assessed. Neonatal IH resulted in severe retinal damage consistent with retinopathy of prematurity (ROP). Retinal damage was associated with induced oxidative stress and Jagged-1/Notch signaling, as well as reduced DLL-4/Notch signaling. All treatments reversed these outcomes, but nGSH produced the most beneficial outcomes. Severe OIR promoted the induction of Jagged-1/Notch and curtailed DLL-4/Notch, which was an effect that could be reversed with nGSH supplementation. These findings may indicate a potential alternate pathway for ROP treatment and/or prevention. Full article
(This article belongs to the Special Issue Pharmacotherapy for Retinopathy)
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16 pages, 2857 KiB  
Article
Cassia alata L.: A Study of Antifungal Activity against Malassezia furfur, Identification of Major Compounds, and Molecular Docking to Lanosterol 14-Alpha Demethylase
by Nyi Mekar Saptarini, Resmi Mustarichie, Silviana Hasanuddin and Mary Jho-Anne Tolentino Corpuz
Pharmaceuticals 2024, 17(3), 380; https://doi.org/10.3390/ph17030380 - 16 Mar 2024
Viewed by 837
Abstract
Empirically, in Indonesia, the leaves of Cassia alata L. (candle bush or ketepeng cina) have been used as a topical antifungal agent. Malassezia furfur is a natural microorganism found in the human body. It is among the factors contributing to conditions such as [...] Read more.
Empirically, in Indonesia, the leaves of Cassia alata L. (candle bush or ketepeng cina) have been used as a topical antifungal agent. Malassezia furfur is a natural microorganism found in the human body. It is among the factors contributing to conditions such as pityriasis versicolor, a common, benign, superficial fungal infection of the skin that is closely associated with seborrheic dermatitis and dandruff. This study aimed to explore C. alata leaves, starting from determining antifungal activity against M. furfur and the identification of major compounds in the ethyl acetate and n-hexane fractions, and then we carried out molecular docking of the major compounds in the n-hexane fraction to lanosterol 14-alpha demethylase. The method was the disc diffusion technique to test antifungal activity, LC-MS/MS for major compound identification, and homology modeling through Swiss Models for molecular docking. The fractions of ethyl acetate and n-hexane extract showed concentration-dependent antifungal activity against M. furfur. The LCMS/MS analysis revealed five major compounds in the ethyl acetate and n-hexane fractions. The molecular docking demonstrated the highest binding affinity with stearidonic acid at −7.2 kcal/mol. It can be concluded that the compounds in the n-hexane fraction have antifungal activity against M. furfur, as supported by both in vitro and in silico studies. Full article
(This article belongs to the Section Medicinal Chemistry)
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15 pages, 2088 KiB  
Article
The Association between Molecular Initiating Events and Drug-Induced Hiccups
by Ryuichiro Hosoya, Reiko Ishii-Nozawa, Tomoko Terajima, Hajime Kagaya and Yoshihiro Uesawa
Pharmaceuticals 2024, 17(3), 379; https://doi.org/10.3390/ph17030379 - 16 Mar 2024
Viewed by 891
Abstract
Hiccups can significantly reduce the quality of life of patients and can occur as a drug side effect. Previous reports have revealed sex-specific differences in the incidence of drug-induced hiccups. However, the pathogenesis of drug-induced hiccups remains unknown, and there is limited evidence [...] Read more.
Hiccups can significantly reduce the quality of life of patients and can occur as a drug side effect. Previous reports have revealed sex-specific differences in the incidence of drug-induced hiccups. However, the pathogenesis of drug-induced hiccups remains unknown, and there is limited evidence on its treatment or prevention. This study examined molecular initiating events (MIEs), which are the starting point of adverse events, to investigate the drug-induced pathways of hiccups. We extracted drugs suspected to cause hiccups using the FDA Adverse Event Reporting System, a large database on adverse drug reactions. Information on drugs suspected to be associated with hiccups was extracted from the overall population and sex-specific subgroups were divided. In each data table, the predicted activity values of nuclear receptors and stress response pathways for each drug were calculated using the Toxicity Predictor, a machine-learning model. Transforming growth factor-beta and antioxidant response elements were considered an independent factor for hiccups in the male and female subgroups, respectively. This report first examined one of the mechanisms of drug-induced hiccups and identified MIEs associated with drug-induced hiccups. The use of an adverse event database and the machine-learning model, Toxicity Predictor, may be useful for generating hypotheses for other adverse effects with unknown mechanisms. Full article
(This article belongs to the Section Pharmacology)
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14 pages, 2895 KiB  
Article
Anti-Inflammatory Effect of Columbianadin against D-Galactose-Induced Liver Injury In Vivo via the JAK2/STAT3 and JAK2/p38/NF-κB Pathways
by Zhe Ma, Lin Peng, Yaoyao Sheng, Wenhui Chu and Yongqian Fu
Pharmaceuticals 2024, 17(3), 378; https://doi.org/10.3390/ph17030378 - 15 Mar 2024
Viewed by 734
Abstract
Angelicae pubescentis radix (APR) has been traditionally used for thousands of years in China to treat rheumatoid arthritis (RA), an autoimmune disorder. As the main active coumarin of APR, columbianadin (CBN) exhibits a significant anti-inflammatory effect in vitro. However, the anti-inflammatory activity and [...] Read more.
Angelicae pubescentis radix (APR) has been traditionally used for thousands of years in China to treat rheumatoid arthritis (RA), an autoimmune disorder. As the main active coumarin of APR, columbianadin (CBN) exhibits a significant anti-inflammatory effect in vitro. However, the anti-inflammatory activity and underlying mechanism of CBN in vivo remain unclear. This work aimed to elucidate the anti-inflammatory activity of CBN in vivo and its related signaling pathways in a D-Gal-induced liver injury mouse model. Analysis of biochemical indices (ALT and AST) and pro-inflammatory cytokines (IL-1β and IL-6) in serum indicated that CBN significantly ameliorated D-Gal-induced liver injury. CBN treatment also significantly increased the activities of antioxidant enzymes (SOD, CAT, GPx), and decreased the levels of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in liver tissue. Liver histology revealed that CBN treatment reduced hepatic inflammation. Western blot analysis indicated that CBN down-regulates the expression of phosphorylated JAK2, STAT3, MAPK, and NF-κB in the related signaling pathways. These findings support the traditional use of APR as a remedy for the immune system, and indicate that the JAK2/STAT3 and JAK2/p38/NF-κB signaling pathways may be important mechanisms for the anti-inflammatory activity of CBN in vivo. Full article
(This article belongs to the Section Pharmaceutical Technology)
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15 pages, 5552 KiB  
Article
Synthesis, Computational Study, and In Vitro α-Glucosidase Inhibitory Action of 1,3,4-Thiadiazole Derivatives of 3-Aminopyridin-2(1H)-ones
by Zarina Shulgau, Irina V. Palamarchuk, Shynggys Sergazy, Assel Urazbayeva, Yerlan Ramankulov and Ivan V. Kulakov
Pharmaceuticals 2024, 17(3), 377; https://doi.org/10.3390/ph17030377 - 15 Mar 2024
Viewed by 733
Abstract
This article reports on the synthesis of nine promising new 1,3,4-thiadiazole derivatives based on 3-aminopyridones, containing various acidic linkers. The synthesis was carried out by cyclizing the corresponding thiohydrazides 4ac and anhydrides of glutaric, maleic, and phthalic acids upon heating in [...] Read more.
This article reports on the synthesis of nine promising new 1,3,4-thiadiazole derivatives based on 3-aminopyridones, containing various acidic linkers. The synthesis was carried out by cyclizing the corresponding thiohydrazides 4ac and anhydrides of glutaric, maleic, and phthalic acids upon heating in acetic acid solution. The conducted bio-screening of the synthesized new 1,3,4-thiadiazole derivatives containing different acidic linkers (butanoic, acrylic, and benzoic acids) showed that they have significant inhibitory activity against α-glucosidase (up to 95.0%), which is 1.9 times higher than the value for the reference drug acarbose (49.5%). Moreover, one of the 1,3,4-thiadiazole derivatives with a benzoic acid linker—2-(5-((6-Methyl-2-oxo-4-(thiophen-2-yl)-1,2-dihydropyridin-3-yl)carbamoyl)-1,3,4-thiadiazol-2-yl)benzoic acid (9′b)—showed an IC50 value of 3.66 mM, nearly 3.7 times lower than that of acarbose (IC50 = 13.88 mM). High inhibitory activity was also shown by 1,3,4-thiadiazole derivatives with a butanoic acid linker (compounds 7b, 7c)—with IC50 values of 6.70 and 8.42 mM, respectively. A correlation between the structure of the compounds and their activity was also established. The results of molecular docking correlated well with the bioanalytical data. In particular, the presence of a butanoic acid linker and a benzoic fragment in compounds 7b, 7c, and 9b increased their binding affinity with selected target proteins compared to other derivatives 36 (ac). Calculations according to Lipinski’s rule of five also showed that the synthesized compounds 7b, 7c, and 9b fully comply with Ro5 and meet all criteria for good permeability and acceptable oral bioavailability of potential drugs. These positive bioanalytical results will stimulate further in-depth studies, including in vivo models. Full article
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16 pages, 1728 KiB  
Article
New Pyrazolyl Thioureas Active against the Staphylococcus Genus
by Anna Maria Schito, Debora Caviglia, Susanna Penco, Andrea Spallarossa, Elena Cichero, Bruno Tasso and Chiara Brullo
Pharmaceuticals 2024, 17(3), 376; https://doi.org/10.3390/ph17030376 - 15 Mar 2024
Viewed by 635
Abstract
To meet the urgent need for new antibacterial molecules, a small library of pyrazolyl thioureas (PTUs) was designed, synthesized and tested against difficult-to-treat human pathogens. The prepared derivatives are characterized by a carboxyethyl functionality on C4 and different hydroxyalkyl chains on N1. Compounds [...] Read more.
To meet the urgent need for new antibacterial molecules, a small library of pyrazolyl thioureas (PTUs) was designed, synthesized and tested against difficult-to-treat human pathogens. The prepared derivatives are characterized by a carboxyethyl functionality on C4 and different hydroxyalkyl chains on N1. Compounds 1ao were first evaluated against a large panel of Gram-positive and Gram-negative pathogens. In particular, the majority of PTUs proved to be active against different species of the Staphylococcus genus, with MIC values ranging from 32 to 128 µg/mL on methicillin-resistant Staphylococcus strains, often responsible for severe pulmonary disease in cystic fibrosis patients. Time-killing experiments were also performed for the most active compounds, evidencing a bacteriostatic mechanism of action. For most active derivatives, cytotoxicity was evaluated in Vero cells, and at the tested concentrations and at the experimental exposure time of 24 h, none of the compounds analysed showed significant toxicity. In addition, favourable drug-like, pharmacokinetic and toxicity properties were predicted for all new synthesized derivatives. Overall, the collected data confirmed the PTU scaffold as a promising chemotype for the development of novel antibacterial agents active against Gram-positive multi-resistant strains frequently isolated from cystic fibrosis patients. Full article
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14 pages, 2503 KiB  
Article
Small-Angle X-ray Scattering (SAXS) Used for the Identification of Nicomorphine Polymorphic Changes at the Early Stage to Avoid Varied Stability and Possible Side Effects
by Nermina Malanovic, Giovanni Birarda, Simone Eder, Heidrun Gruber-Woelfler, Franz Reiter, Krunoslav Juraic and Aden Hodzic
Pharmaceuticals 2024, 17(3), 375; https://doi.org/10.3390/ph17030375 - 15 Mar 2024
Viewed by 749
Abstract
In this paper, we present the identification of polymorphisms at an early stage, identified by applying non-standard methods such as SAXS. We provide an analytical approach to polymorphism in the quality/purity of an active pharmaceutical ingredient (API), supplied to a generic company by [...] Read more.
In this paper, we present the identification of polymorphisms at an early stage, identified by applying non-standard methods such as SAXS. We provide an analytical approach to polymorphism in the quality/purity of an active pharmaceutical ingredient (API), supplied to a generic company by two different suppliers (i.e., manufacturers). Changes in thermodynamic polymorphism firstly become visible in traces in the larger crystal lattices, which are visible on the SAXS spectrum only using the logarithmic scale, as shown in the result figures. Hence, we are here on the trail of the beginning of a new polymorph in nicomorphine, whose crystal waviness at the early stage is visible only in the additional symmetrical peaks identified and calculated using SAXS, while the chemical analyses excluded all kinds of chemical impurities. The chemical and structural properties were studied using the following techniques: SAXS, WAXS, DSC, dissolution, Raman spectroscopy, and FTIR. Only the SAXS technique could identify crucial differences and calculate the additional signals related to giant crystals, whilst a standard method such as WAXS showed none, and nor did the chemical analyses, such as Raman spectroscopy and FT-IR. This means that due to water in crystallization (known in nicomorphine) or thermodynamic waviness, the formation of the new polymorph starts first in traces, which become visible at larger distances from the crystal lattice, detectible only in the SAXS range. This is a very important premise and hypothesis for further research, and we believe that this work lays a new stone in understanding the origin of new unknown polymorphs and their mixtures. Therefore, the aim of this work is to show that the use of non-standard methods (i.e., SAXS) can be of great benefit to API analysis and the identification of polymorphic changes in the early phase, which can cause varied stability, solubility and bioavailability and thus different therapeutic effects or side effects. Full article
(This article belongs to the Section Pharmaceutical Technology)
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18 pages, 4715 KiB  
Article
Liraglutide Attenuates Diabetic Cardiomyopathy via the ILK/PI3K/AKT/PTEN Signaling Pathway in Rats with Streptozotocin-Induced Type 2 Diabetes Mellitus
by Shatha M. Alobaid, Rahaf M. Alshahrani, Asma S. Alonazi, Nawal M. Alrasheed, Maha A. Alamin, Tahani K. Alshammari, Anfal F. Bin Dayel, Doaa M. Elnagar, Rana R. Alotaibi, Lama A. Almuthnabi, Dalia H. Almasud, Shahad E. Al-Ammar, Shahad O. Almadhi, Reema A. Almalke, Nouf T. Aldamri, Hanan K. Alghibiwi, Dalal A. Alkhelb and Nouf M. Alrasheed
Pharmaceuticals 2024, 17(3), 374; https://doi.org/10.3390/ph17030374 - 15 Mar 2024
Viewed by 997
Abstract
One of the possible candidates for the treatment of diabetic cardiomyopathy is liraglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist. In this study, the impacts of liraglutide on the integrin-linked kinase (ILK)-related PI3K/AKT axis in rats with type 2 diabetes induced via streptozotocin were [...] Read more.
One of the possible candidates for the treatment of diabetic cardiomyopathy is liraglutide, a glucagon-like peptide-1 receptor (GLP1R) agonist. In this study, the impacts of liraglutide on the integrin-linked kinase (ILK)-related PI3K/AKT axis in rats with type 2 diabetes induced via streptozotocin were examined. Twenty-four Wistar albino rats were distributed in four different groups, and a high-fat diet and streptozotocin were used to induce type 2 in two groups. Rats in the untreated control groups were administered 0.9% NaCl solution over a 6-week period, and those in the treatment groups were administered 0.9% NaCl for 3 weeks, followed by subcutaneous injection of liraglutide (150 μg/kg) for an additional 3 weeks. In the liraglutide-treated diabetic group, the heart-to-body weight ratio was significantly reduced, levels of cardiac biomarkers, troponin I and creatine-kinase-MB, were improved; activities of antioxidant enzymes, glutathione peroxidase and superoxide dismutase, were increased; and levels of malondialdehyde were decreased. Western blotting and immunohistochemical studies revealed increased levels of ILK, P-PI3K, P-AKT, and BCL2, as well as those of caspase 3, BAX, and P-PTEN, indicating mitigation of cardiomyocyte apoptosis. Our results show that liraglutide, by targeting GLP1Rs, enhances the expression of proteins in the ILK/PI3K/AKT/PTEN pathway and thereby exerts its cardioprotective effects in rats with DCM. Full article
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