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Future Pharmacol., Volume 3, Issue 1 (March 2023) – 21 articles

Cover Story (view full-size image): Ezrin (EZR), a member of the ERM (ezrin, radixin, moesin) protein family, is essential for linking the actin cytoskeleton to the cell membrane and participates in multiple key signal transduction pathways. Several clinical and preclinical studies on a wide variety of solid and hematological tumors indicate that EZR is highly expressed and predicts an unfavorable clinical outcome. Additionally, EZR inhibition reduces proliferation, migration, and invasion in experimental cancer models. The development of pharmacological inhibitors for EZR or the signaling pathways it mediates has sparked a new round of investigation. In this review, studies on EZR in cancer are compiled, providing proof of concept that targeting EZR has antineoplastic potential and could pave the way for therapeutic developments. View this paper
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35 pages, 10078 KiB  
Article
Systems Pharmacology and Network Analysis to Advance Pharmacogenomics and Precision Medicine Decisions in Type-2 Diabetes Therapy
by Aikaterini Saiti, Alexandros Giannopoulos-Dimitriou, Ioannis Kazakos, Eleftheria Galatou and Ioannis S. Vizirianakis
Future Pharmacol. 2023, 3(1), 329-363; https://doi.org/10.3390/futurepharmacol3010021 - 17 Mar 2023
Viewed by 2422
Abstract
Diabetes mellitus type-2 (DMT2) molecular pathophysiology is still challenging since the disease represents a complex, multifactorial metabolic disease caused by polygenic defects and environmental factors. In addition, the resulting secondary organ complications can be affected by various environmental and life-style factors over the [...] Read more.
Diabetes mellitus type-2 (DMT2) molecular pathophysiology is still challenging since the disease represents a complex, multifactorial metabolic disease caused by polygenic defects and environmental factors. In addition, the resulting secondary organ complications can be affected by various environmental and life-style factors over the years. The metabolic imbalance in DMT2 is manifested by the dysfunction of pancreatic β-cells in secreting insulin and the inability of other tissue cells to respond to insulin and utilize blood glucose. However, over recent years, through the advances in genomics and molecular analysis, several genes and microRNAs have been shown to be correlated as potential biomarkers with DMT2 prognosis, diagnosis, and therapy. Furthermore, drug therapy and clinical pharmacology have benefited from pharmacogenomics in a manner where the molecular knowledge can be translated into clinical information aiming to improve precision and personalized medicine therapeutic methodologies in healthcare. In this work, using systems pharmacology and network analysis approaches, we comprehensively assessed the molecular and genomics data associated with DMT2 to: (a) Better understand miRNA, gene, and drug associations; (b) Create connectivity and interaction maps of practical clinical utility; and (c) Facilitate the application of precision medicine therapeutic decisions in group and individual patients. Moreover, in order for the clinical pharmacology guidelines to be implemented in parallel with the generated molecular data, we also carried out an assessment of drug interactions in specific pharmacological classes that affect DMT2 pharmacotherapy outcomes. Overall, the proposed methodology and the results obtained: (a) Enrich our understanding of DMT2 molecular pathophysiology; (b) Unveil important biomarker and drug-gene pharmacogenomics associations; (c) Help the use of personalized therapy options; and (d) Allow precision medicine concepts to be broadly exploited in new therapeutic developments and within the clinical setting. Full article
(This article belongs to the Special Issue Feature Papers in Future Pharmacology)
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12 pages, 2544 KiB  
Review
The Roles of Vitamin D and Polyphenols in the Management of Age-Related Macular Degeneration: A Narrative Review
by Nádia Fernandes, Marta Castro Araújo and Carla Lança
Future Pharmacol. 2023, 3(1), 317-328; https://doi.org/10.3390/futurepharmacol3010020 - 10 Mar 2023
Viewed by 2441
Abstract
Age-related macular degeneration (AMD) is a chronic progressive ocular disease and the main cause of severe visual impairment in the elderly. Vitamin D deficiency may be a risk factor for AMD. Additionally, current evidence suggests dietary advice of increasing consumption of polyphenols, which [...] Read more.
Age-related macular degeneration (AMD) is a chronic progressive ocular disease and the main cause of severe visual impairment in the elderly. Vitamin D deficiency may be a risk factor for AMD. Additionally, current evidence suggests dietary advice of increasing consumption of polyphenols, which may have antioxidant and anti-inflammatory properties. The aim of this review was to describe the roles of vitamin D levels and polyphenols in the management of AMD. The results of this review showed mixed evidence regarding the protective effect of vitamin D against AMD. Polyphenols (flavonoids group, curcumin and resveratrol) seem to play an important role as angiogenesis inhibitors, but their effect on AMD is still unclear. Vitamin D and polyphenols may both play an important role as nutritional modifiable protective factors that reduce the risk of AMD progression. However, more research is necessary to better understand the roles of vitamin D and polyphenols in different stages of the disease. Full article
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21 pages, 1292 KiB  
Review
Unraveling the Impact of Salbutamol Polytherapy: Clinically Relevant Drug Interactions
by Lara Marques and Nuno Vale
Future Pharmacol. 2023, 3(1), 296-316; https://doi.org/10.3390/futurepharmacol3010019 - 10 Mar 2023
Cited by 2 | Viewed by 7023
Abstract
The proper drug choice determines the treatment quality for a disease. The pharmacotherapeutic strategy for respiratory diseases often involves the combination of different drugs with different mechanisms of action. Salbutamol is a short-acting β2-agonist (SABA) used as a reliever in the treatment of [...] Read more.
The proper drug choice determines the treatment quality for a disease. The pharmacotherapeutic strategy for respiratory diseases often involves the combination of different drugs with different mechanisms of action. Salbutamol is a short-acting β2-agonist (SABA) used as a reliever in the treatment of asthma and is frequently paired with inhaled corticosteroids (ICS). Indeed, drug–drug interactions (DDI) receive special attention as they are some of the most common causes of adverse effects and can lead to increased morbidity and mortality. DDIs can occur in patients undergoing polytherapy at the pharmacokinetic (PK) or pharmacodynamic (PD) level. Given this, the interaction of salbutamol with other drugs has been extensively explored in terms of PD and PK since its introduction into the pharmaceutical market. To date, more than a thousand salbutamol interactions have been reported. Here, we propose to review some interactions of salbutamol with other drugs such as beta-blockers, anticholinergics, other classes of bronchodilators, corticosteroids, and others, and point out significant gaps in the knowledge of DDI. Full article
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44 pages, 1763 KiB  
Review
Plant-Derived Metal Nanoparticles (PDMNPs): Synthesis, Characterization, and Oxidative Stress-Mediated Therapeutic Actions
by Mohammad Faheem Khan and Mohd Aamish Khan
Future Pharmacol. 2023, 3(1), 252-295; https://doi.org/10.3390/futurepharmacol3010018 - 01 Mar 2023
Cited by 6 | Viewed by 3515
Abstract
In the 21st century, plant-derived metal nanoparticles (PDMNPs) have gained considerable interest because of their tremendous and remarkable potential as therapeutic agents as well as development of less expensive, safer, and easier biomedical equipment. PDMNPs are synthesized from metal salts or oxides by [...] Read more.
In the 21st century, plant-derived metal nanoparticles (PDMNPs) have gained considerable interest because of their tremendous and remarkable potential as therapeutic agents as well as development of less expensive, safer, and easier biomedical equipment. PDMNPs are synthesized from metal salts or oxides by using plant extracts because plants have diversified bioactive compounds that can act as reducing and stabilizing agents at the time of nanoparticle synthesis. Besides, PDMNPs take advantages over the nanoparticles synthesized by other methods because of their low cost, environmental friendliness, and sustainability. The present review explains the synthesis of PDMNPs, their characterization techniques, and oxidative stress-mediated pharmacological effects. The mode of actions for antioxidant, antimicrobial, and anticancer properties has also been critically explored. Due to the plethora of data on plant-derived nanoparticles and their pharmacological properties, we have highlighted PDMNPs’ shape, size, metals of use, and experimental findings regarding their antioxidant, anti-microbial, and anticancer properties in a tabulated form for studies conducted in the last five years, from 2018 to 2022. Because of our review study, we, herein, contemplate that the scientific community as a whole will get a greater comprehension of PDMNPs and their numerous therapeutic applications in a single window. Full article
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14 pages, 791 KiB  
Review
Obeticholic Acid—A Pharmacological and Clinical Review
by Caezaan Keshvani, Jonathan Kopel and Hemant Goyal
Future Pharmacol. 2023, 3(1), 238-251; https://doi.org/10.3390/futurepharmacol3010017 - 28 Feb 2023
Cited by 3 | Viewed by 3252
Abstract
Obeticholic acid (OCA) or 6-alpha-ethyl-chenodeoxycholic acid is a semisynthetic modified bile acid derivative that acts on the farnesoid X receptor (FXR) as an agonist with a higher potency than bile acid. The FXR is a nuclear receptor highly expressed in the liver and [...] Read more.
Obeticholic acid (OCA) or 6-alpha-ethyl-chenodeoxycholic acid is a semisynthetic modified bile acid derivative that acts on the farnesoid X receptor (FXR) as an agonist with a higher potency than bile acid. The FXR is a nuclear receptor highly expressed in the liver and small intestine and regulates bile acid, cholesterol, glucose metabolism, inflammation, and apoptosis. The FXR group of bile acid receptors is currently under investigation for their potential role in the treatment of primary biliary cirrhosis (PBC), non-alcoholic steatohepatitis (NASH), and primary sclerosing cholangitis (PSC). Recent clinical studies suggest OCA may work synergistically with lipid modifying medications to further improve long-term outcomes with primary sclerosing cholangitis. Specifically, OCA can improve clinical outcomes in NASH patients with their different histological, metabolic, and biochemical issues as well as improve morbidity and mortality in patients suffering from PBC, PSC, or liver disease. This improvement is noted in both improved histological examination and reduced need for transplantation. In this review, we examine the pharmacology of OCA towards the treatment of PBC refractory and steatohepatitis (NASH). In addition, we examine future directions and applications of OCA for PBC, PSC, NASH, and NAFLD. Full article
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9 pages, 588 KiB  
Communication
Polyols Permeability on Caco-2 Cells and Their Effects on Transport of Low-Permeability Drugs
by Damien Truffin, Olaf Häusler, Maryse Martin, Sandrine Cotier, Jerôme Laparre and Manilduth Ramnath
Future Pharmacol. 2023, 3(1), 229-237; https://doi.org/10.3390/futurepharmacol3010016 - 11 Feb 2023
Viewed by 2472
Abstract
Some pharmaceutical excipients are able to modify intestinal permeability, thus influencing drug absorption and bioavailability. The effect of four polyols (mannitol, maltitol, sorbitol and xylitol) on the permeability of seven active pharmaceutical ingredients (API), representing different BCS classes (furosemide, amiloride, atenolol, ranitidine, nadolol, [...] Read more.
Some pharmaceutical excipients are able to modify intestinal permeability, thus influencing drug absorption and bioavailability. The effect of four polyols (mannitol, maltitol, sorbitol and xylitol) on the permeability of seven active pharmaceutical ingredients (API), representing different BCS classes (furosemide, amiloride, atenolol, ranitidine, nadolol, L-thyroxine and acyclovir), was investigated using the Caco-2 cell permeability model. Analytical methods for the sensitive polyol and API quantification were developed using Ultra High Performance Liquid Chromatography coupled to triple-quadrupole Mass Spectrometry (UHPLC-QqQ). Apparent permeability coefficients (Papp) were calculated from the measured concentrations in the apical and basolateral compartments. The cell monolayer remained intact throughout the experiment in all trials, neither significant Lucifer Yellow (LY) passage, nor modification of the electrical resistance was detected, demonstrating that no active principle or excipient (or combinations thereof) modulated the paracellular transport. The Papp values for apical to basolateral and basolateral to apical directions of drug + excipient combinations were compared with the Papp values for the drug substance alone. Our results show that mannitol, maltitol, sorbitol and xylitol did not modify the permeability of furosemide, amiloride, atenolol, ranitidine, nadolol, acyclovir and L-thyroxine APIs. Moreover, the presence of polyols did not alter the efflux of the active principle (basolateral to apical). Full article
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16 pages, 1466 KiB  
Review
Applications and Utility of Three-Dimensional In Vitro Cell Culture for Therapeutics
by Suchitra Maheswari Ajjarapu, Apoorv Tiwari and Sundip Kumar
Future Pharmacol. 2023, 3(1), 213-228; https://doi.org/10.3390/futurepharmacol3010015 - 10 Feb 2023
Cited by 7 | Viewed by 3134
Abstract
The field of 3D cell culture and its applications is rooted in the understanding of cell biology, tissue engineering, tissue morphology, disease mechanisms, and drug action. For many years, traditional 2D cell culture systems have been widely used but have proven to be [...] Read more.
The field of 3D cell culture and its applications is rooted in the understanding of cell biology, tissue engineering, tissue morphology, disease mechanisms, and drug action. For many years, traditional 2D cell culture systems have been widely used but have proven to be limited in their ability to accurately replicate the complex microenvironment of tissues. This often results in issues with cell proliferation, aggregation, and differentiation. 3D cell culture systems have emerged as a solution to this problem and have demonstrated a more accurate simulation of in vivo physiology. This has had a major impact on drug discovery and includes the use of spheroids, organoids, scaffolds, hydrogels, and organs. This review has addressed fundamental questions and exploited utility in 3D in vitro mode of cell culture in view of therapeutics. Full article
(This article belongs to the Special Issue Three-Dimensional In Vitro Cell Culture Models in Drug Discovery)
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15 pages, 8675 KiB  
Article
Role of Senescence-Resumed Proliferation in Keloid Pathogenesis
by Ching-Yun Wang, Chieh-Wen Wu and Ting-Yi Lin
Future Pharmacol. 2023, 3(1), 198-212; https://doi.org/10.3390/futurepharmacol3010014 - 07 Feb 2023
Cited by 1 | Viewed by 1290
Abstract
Senescence-resumed proliferation (SRP) is proposed to be a mechanism associated with the escape of p21-mediated senescence and the activation of Wnt/β-catenin pathways that enhance malignancy. The keloid genomic landscape shows heavy intersections between TP53 and TGF-β signaling. The machinery to maintain cellular integrity [...] Read more.
Senescence-resumed proliferation (SRP) is proposed to be a mechanism associated with the escape of p21-mediated senescence and the activation of Wnt/β-catenin pathways that enhance malignancy. The keloid genomic landscape shows heavy intersections between TP53 and TGF-β signaling. The machinery to maintain cellular integrity through senescence, apoptosis, and autophagy is co-regulated with stemness, hedgehog, and immunomodulation. Our study demonstrated the presence of SRP and how, on the transcriptome level, TP53 and Wnt/β-catenin pathways are regulated to deliver the same cellular fate. Our study proves that SRP co-regulated with senescence-associated reprogramming (Wnt/β-catenin pathways) and TP53-p21 dysregulations originate from a common etiology and present a novel therapeutic target opportunity. Full article
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18 pages, 3890 KiB  
Article
A Synergistic Antibacterial Platform Combining Low–Temperature Photothermal Therapy and Antibiotic Therapy
by Qiming Zhang, Lei Chang, Caixia Sun, Wanchao Zuo, Shibo Zhang, Cong Liu, Shuyue Deng, Pengcheng Wu, Panpan Dai, Jianjun Dai and Yanmin Ju
Future Pharmacol. 2023, 3(1), 180-197; https://doi.org/10.3390/futurepharmacol3010013 - 07 Feb 2023
Viewed by 1271
Abstract
Antimicrobial resistance has brought great burden to global public health. Alternative strategies are needed to reduce the development of drug resistance. Herein, we have developed an effective synergistic antibacterial strategy combining low–temperature photothermal therapy (LT–PTT) with antibiotic therapy, improving the bactericidal efficiency to [...] Read more.
Antimicrobial resistance has brought great burden to global public health. Alternative strategies are needed to reduce the development of drug resistance. Herein, we have developed an effective synergistic antibacterial strategy combining low–temperature photothermal therapy (LT–PTT) with antibiotic therapy, improving the bactericidal efficiency to avoid antimicrobial resistance. Copper sulfide templated with bovine serum albumin (CuS–BSA) nanoparticles were selected as the photothermal agent, and co–loaded into the hydrogel (Gel) with mupirocin. The Gel could slow down the release rate of CuS–BSA and mupirocin, thereby prolonging the effective drug reaction time. More importantly, when applying near–infrared laser irradiation, the antibacterial activity of the platform could be enhanced greatly by LT–PTT effect of CuS–BSA nanoparticles. In vitro and in vivo results both confirmed that the antibacterial efficacy of the synergistic therapeutic strategy was improved greatly with complete bacterial removal. Overall, this platform has posed a potential strategy to reduce the development of drug resistance and improve patient compliance. Full article
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18 pages, 3267 KiB  
Review
Acute Promyelocytic Leukemia (APL): A Review of the Classic and Emerging Target Therapies towards Molecular Heterogeneity
by Tâmara Dauare de Almeida, Fernanda Cristina Gontijo Evangelista and Adriano de Paula Sabino
Future Pharmacol. 2023, 3(1), 162-179; https://doi.org/10.3390/futurepharmacol3010012 - 01 Feb 2023
Cited by 3 | Viewed by 5570 | Correction
Abstract
The occurrence of severe bleeding syndrome because of the PML-RARα fusion protein is a life-threatening event in APL. This protein destabilizes homeostasis, maturation, remodeling, and tissue regeneration in addition to hampering the maintenance and differentiation of hematopoietic cells into different lineages, fixing cells [...] Read more.
The occurrence of severe bleeding syndrome because of the PML-RARα fusion protein is a life-threatening event in APL. This protein destabilizes homeostasis, maturation, remodeling, and tissue regeneration in addition to hampering the maintenance and differentiation of hematopoietic cells into different lineages, fixing cells in the promyelocyte stage. APL is a classic example of how effective targeted therapy is and, therefore, how important the use of such therapy is to the overall survival of patients, which in this case is represented by the use of ATRA/ATO. Despite that, about 10% of cases of APL patients demonstrate resistance to treatment. Facing this scenario, we point out promising target therapies such as those recommended by the NCCN and Leukemia Net. Since this is such a heterogeneous molecular disease, it is of great importance to understand how important combined chemotherapy, target therapy, immune-based therapy, and combined therapies are in the survival of these APL patients. Full article
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18 pages, 700 KiB  
Review
Aspirin Therapy, Cognitive Impairment, and Dementia—A Review
by Elizabeth H. Thong, Edward C. Y. Lee, Choi-Ying Yun, Tony Y. W. Li and Ching-Hui Sia
Future Pharmacol. 2023, 3(1), 144-161; https://doi.org/10.3390/futurepharmacol3010011 - 01 Feb 2023
Cited by 2 | Viewed by 5404
Abstract
Background: Dementia is associated with a greater burden of cardiovascular risk factors. There is a significant vascular contribution to dementia, and aspirin may play a role in targeting this vascular dysregulation via its anti-inflammatory and antiplatelet effects. We provide an overview of the [...] Read more.
Background: Dementia is associated with a greater burden of cardiovascular risk factors. There is a significant vascular contribution to dementia, and aspirin may play a role in targeting this vascular dysregulation via its anti-inflammatory and antiplatelet effects. We provide an overview of the effects of aspirin therapy on the prevention of dementia and cognitive decline in patients with or without dementia and/or cognitive impairment. Methods: We performed a search for studies enrolling adults with or without dementia or MCI and comparing aspirin with placebo, usual care, or active control with respect to cognitive outcomes. Results: We describe aspirin’s effects on the primary prevention of cognitive impairment and various subtypes of dementia, as well as its role in cognitive decline in certain subsets of patients, including those with cerebral small vessel disease (CVSD), coronary heart disease (CHD), and gender differences. Overall, the benefits of aspirin in preventing dementia and cognitive decline remain inconclusive. The majority of cohort studies investigating aspirin’s role in preventing cognitive decline or dementia looked promising, but this was not supported in most randomised controlled trials. However, aspirin may still be beneficial in certain subgroups of patients (such as CHD, VD, and CSVD) and warrants further investigation. Full article
(This article belongs to the Special Issue Feature Papers in Future Pharmacology)
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2 pages, 246 KiB  
Editorial
Acknowledgment to the Reviewers of Future Pharmacology in 2022
by Future Pharmacology Editorial Office
Future Pharmacol. 2023, 3(1), 142-143; https://doi.org/10.3390/futurepharmacol3010010 - 17 Jan 2023
Viewed by 920
Abstract
High-quality academic publishing is built on rigorous peer review [...] Full article
10 pages, 1958 KiB  
Article
Anxiolytic/Sedative Effect of Monoterpene (–)-Borneol in Mice and In Silico Molecular Interaction with GABAA Receptor
by Maurício Pires de Moura do Amaral, Marcelo Pereira da Silva Junior, Francisco das Chagas Alves Lima, Stanley Juan Chavez Gutierrez, Daniel Dias Rufino Arcanjo and Rita de Cássia Meneses Oliveira
Future Pharmacol. 2023, 3(1), 132-141; https://doi.org/10.3390/futurepharmacol3010009 - 13 Jan 2023
Cited by 3 | Viewed by 1994
Abstract
Anxiety is a normal behavioral component. When it is too frequent or appears in inappropriate contexts, it can be considered pathological. Benzodiazepines (BDZs) are drugs with clinical success in anxiety treatment. BDZs act as allosteric modulators of the γ- aminobutyric acid A receptor [...] Read more.
Anxiety is a normal behavioral component. When it is too frequent or appears in inappropriate contexts, it can be considered pathological. Benzodiazepines (BDZs) are drugs with clinical success in anxiety treatment. BDZs act as allosteric modulators of the γ- aminobutyric acid A receptor (GABAAR). However, these drugs cause adverse effects. Despite the therapeutic advances obtained with BDZs, the search for anxiolytics with fewer adverse effects is ongoing. Studies with monoterpene (–)-borneol [(–)-BOR] demonstrated pharmacological properties such as a partial agonist effect of GABAAR and an anticonvulsive effect. On the other hand, no work has been developed evaluating the anxiolytic/sedative potential. The objective of this study was to investigate the anxiolytic/sedative effects of (–)-BOR in animal models at doses of 25, 50, and 100 mg/kg (i.p.) and whether there was a molecular interaction with GABAAR. The anxiolytic effect of monoterpene (–)-BOR was tested on Swiss mice (25–30 g) in three anxiety models: the elevated plus maze test, the open field test, and the light-dark box test. The thiopental-induced sleep time model was a drug screen for the sedative and hypnotic activity related to GABAARs. In the molecular docking, the interaction between the GABAAR molecule and (–)-BOR was performed using the AutoDock 4.2.6 program. The results demonstrated that (–)-BOR has sedative and anxiolytic activity. The molecular docking study revealed that (–)-BOR can interact with GABAARs through hydrogen bonds. Full article
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15 pages, 929 KiB  
Review
Calcitonin Gene-Related Peptide (CGRP)-Targeted Treatments—New Therapeutic Technologies for Migraine
by Linda Sangalli and Stefania Brazzoli
Future Pharmacol. 2023, 3(1), 117-131; https://doi.org/10.3390/futurepharmacol3010008 - 12 Jan 2023
Cited by 1 | Viewed by 3411
Abstract
Migraine is ranked as the third most common disorder worldwide and is considered one of the most disabling neurological conditions. Its treatment has mostly relied on medications that were non-specifically developed for migraine, thus accompanied by low adherence, inadequate effectiveness and intolerable side [...] Read more.
Migraine is ranked as the third most common disorder worldwide and is considered one of the most disabling neurological conditions. Its treatment has mostly relied on medications that were non-specifically developed for migraine, thus accompanied by low adherence, inadequate effectiveness and intolerable side effects. These recent years have seen the development of new migraine-specific therapies targeting the calcitonin gene-related peptide (CGRP) and its receptor. These newly developed therapies, the small molecule gepants targeting the CGRP receptor and the anti-CGRP monoclonal antibodies (mAbs), are currently available in the market and FDA-approved for migraine treatment. As they are migraine-specific therapies, they largely expand their use to patients that could not tolerate previous treatments, either for systemic contraindications or drug-to-drug interactions, or where any other available option was not efficacious. Randomized controlled trials have demonstrated the efficacy of these new medications, with minor adverse effects reported (most commonly nausea and constipation). This article will review the mechanism of action, indications, contraindications, and tolerability profile of gepants and anti-CGRP mAbs, by summarizing the available literature. Finally, avenues for future research will be identified, so that upcoming controlled studies may be designed to fill such gaps. Full article
(This article belongs to the Special Issue Feature Papers in Future Pharmacology)
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9 pages, 841 KiB  
Article
Fatty Acid-Binding Protein 5 Gene Deletion Enhances Nicotine-Conditioned Place Preference: Illuminating the Putative Gateway Mechanisms
by Nicole Roeder, Brittany Richardson, Abrianna Mihalkovic, Samantha Penman, Olivia White, John Hamilton, Ashim Gupta, Kenneth Blum, Mark S. Gold and Panayotis K. Thanos
Future Pharmacol. 2023, 3(1), 108-116; https://doi.org/10.3390/futurepharmacol3010007 - 09 Jan 2023
Cited by 2 | Viewed by 1575
Abstract
Emerging evidence indicates that the endogenous cannabinoid system modulates the behavioral and physiological effects of nicotine. Fatty acid-binding proteins (FABPs) are among the primary intracellular trafficking mechanisms of endogenous cannabinoids, such as anandamide. To this end, changes in FABP expression may similarly impact [...] Read more.
Emerging evidence indicates that the endogenous cannabinoid system modulates the behavioral and physiological effects of nicotine. Fatty acid-binding proteins (FABPs) are among the primary intracellular trafficking mechanisms of endogenous cannabinoids, such as anandamide. To this end, changes in FABP expression may similarly impact the behavioral manifestations associated with nicotine, particularly its addictive properties. FABP5+/+ and FABP5−/− mice were tested for nicotine-conditioned place preference (CPP) at two different doses (0.1 or 0.5 mg/kg). The nicotine-paired chamber was assigned as their least preferred chamber during preconditioning. Following 8 days of conditioning, the mice were injected with either nicotine or saline. The mice were allowed to access to all the chambers on the test day, and their times spent in the drug chamber on the preconditioning versus the test days were used to examine the drug preference score. The CPP results showed that the FABP5−/− mice displayed a higher place preference for 0.1 mg/kg nicotine than the FABP5+/+ mice, while no CPP difference was observed for 0.5 mg/kg nicotine between the genotypes. In conclusion, FABP5 plays an important role in regulating nicotine place preference. Further research is warranted to identify the precise mechanisms. The results suggest that dysregulated cannabinoid signaling may impact nicotine-seeking behavior. Full article
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28 pages, 7533 KiB  
Review
SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies
by Conrad Fischer and Jenson R. Feys
Future Pharmacol. 2023, 3(1), 80-107; https://doi.org/10.3390/futurepharmacol3010006 - 09 Jan 2023
Cited by 9 | Viewed by 3440
Abstract
While the COVID-19 pandemic seems to be on its decline, the unclear impacts of long-COVID cases, breakthrough infections in immunocompromised individuals, vaccine hesitancy, and inhomogeneous health-care accessibility constitute a not to be underestimated threat. These cases, along with pandemic preparedness, ask for an [...] Read more.
While the COVID-19 pandemic seems to be on its decline, the unclear impacts of long-COVID cases, breakthrough infections in immunocompromised individuals, vaccine hesitancy, and inhomogeneous health-care accessibility constitute a not to be underestimated threat. These cases, along with pandemic preparedness, ask for an alert identification of new drugs and the optimization of existing drugs as therapeutic treatment options for this and potential future diseases. Mpro inhibitors were identified early on as potent drug candidates against coronaviruses, since they target viable processing machinery within the virus, i.e., the main protease that cleaves the polyproteins encoded by the viral RNA into functional proteins. Different strategies, including reversible and irreversible inhibition as well as allosteric inhibitors, mostly from drug repurposing endeavors, have been explored in the design of potent SARS-CoV-2 Mpro antivirals. Ambitious screening efforts have uttered an outstanding chemical and structural diversity, which has led to half a dozen lead compounds being currently in clinical trials and the emergency FDA approval of ritonavir-boosted nirmatrelvir as a COVID-19 therapeutic. This comprehensive analysis of the achieved inhibitor diversity sorted into irreversible, reversible, and allosteric Mpro binders, along with a discussion of emerging resistance reports and possible evasion strategies, is aimed at stimulating continuing Mpro drug design efforts. Full article
(This article belongs to the Special Issue Feature Papers in Future Pharmacology)
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19 pages, 2890 KiB  
Review
Perspectives for Targeting Ezrin in Cancer Development and Progression
by Jean Carlos Lipreri da Silva, Hugo Passos Vicari and João Agostinho Machado-Neto
Future Pharmacol. 2023, 3(1), 61-79; https://doi.org/10.3390/futurepharmacol3010005 - 09 Jan 2023
Cited by 1 | Viewed by 1971
Abstract
Recent advances have been made in understanding molecular markers involved in cancer malignancy, resulting in better tumor staging and identifying new potential therapeutic targets. Ezrin (EZR), a member of the ezrin, radixin, moesin (ERM) protein family, is essential for linking the actin cytoskeleton [...] Read more.
Recent advances have been made in understanding molecular markers involved in cancer malignancy, resulting in better tumor staging and identifying new potential therapeutic targets. Ezrin (EZR), a member of the ezrin, radixin, moesin (ERM) protein family, is essential for linking the actin cytoskeleton to the cell membrane and participates in the signal transduction of key signaling pathways such as Rho GTPases and PI3K/AKT/mTOR. Clinical and preclinical studies in a wide variety of solid and hematological tumors indicate that (i) EZR is highly expressed and predicts an unfavorable clinical outcome, and (ii) EZR inhibition reduces proliferation, migration, and invasion in experimental models. The development of pharmacological inhibitors for EZR (or the signaling mediated by it) has opened a new round of investigation, but studies are still limited. The scope of the present review is to survey studies on the expression and clinical impact of EZR in cancer, as well as studies that perform interventions on the function of this gene/protein in cancer cells, providing proof-of-concept of its antineoplastic potential. Full article
(This article belongs to the Special Issue Feature Papers in Future Pharmacology)
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13 pages, 1232 KiB  
Review
Three-Dimensional Cell Culture Methods in Infectious Diseases and Vaccine Research
by Gamze Varan and Serhat Unal
Future Pharmacol. 2023, 3(1), 48-60; https://doi.org/10.3390/futurepharmacol3010004 - 06 Jan 2023
Cited by 3 | Viewed by 2605
Abstract
Cells, the basic structures of all living organisms, reside in an extracellular matrix consisting of a complex three-dimensional architecture and interact with neighboring cells both mechanically and biochemically. Cell–cell and cell–extracellular matrix interactions form a three-dimensional network that maintains tissue specificity and homeostasis. [...] Read more.
Cells, the basic structures of all living organisms, reside in an extracellular matrix consisting of a complex three-dimensional architecture and interact with neighboring cells both mechanically and biochemically. Cell–cell and cell–extracellular matrix interactions form a three-dimensional network that maintains tissue specificity and homeostasis. Important biological processes in a cell cycle are regulated by principles organized by the microenvironment surrounding the cell. The conventional cell culture methods failed to mimic in vivo-like structural organization and are insufficient to examine features such as connectivity of cells, cellular morphology, viability, proliferation, differentiation, gene and protein expression, response to stimuli, and drug/vaccine metabolism. Three-dimensional cell culture studies are very important in terms of reducing the need for in vivo studies and creating an intermediate step. Three-dimensional cell culture methods have attracted attention in the literature in recent years, especially in examining the cellular distribution of organs in the presence of infectious diseases, elucidating the pathogenic mechanism of action of viruses, and examining virus–host interactions. This review highlights the use and importance of three-dimensional cell culture methods in the design and characterization of novel vaccine formulations and the pathogenesis of infectious diseases. Full article
(This article belongs to the Special Issue Three-Dimensional In Vitro Cell Culture Models in Drug Discovery)
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10 pages, 2020 KiB  
Communication
Flustramine Q, a Novel Marine Origin Acetylcholinesterase Inhibitor from Flustra foliacea
by Natalia M. Kowal, Xiaxia Di, Sesselja Omarsdottir and Elin S. Olafsdottir
Future Pharmacol. 2023, 3(1), 38-47; https://doi.org/10.3390/futurepharmacol3010003 - 06 Jan 2023
Cited by 1 | Viewed by 1680
Abstract
The bryozoan Flustra foliacea produces a range of indole alkaloids, and some have shown weak antibiotic, muscle-relaxant and cytotoxic properties; however, most of them have not been tested for bioactivity. Many of these alkaloids possess a physostigmine scaffold, and physostigmine is a well-known [...] Read more.
The bryozoan Flustra foliacea produces a range of indole alkaloids, and some have shown weak antibiotic, muscle-relaxant and cytotoxic properties; however, most of them have not been tested for bioactivity. Many of these alkaloids possess a physostigmine scaffold, and physostigmine is a well-known acetylcholinesterase (AChE) inhibitor. AChE inhibitors are of interest as drug leads in neurodegenerative diseases and are currently used in symptomatic treatment of Alzheimer’s disease (AD). In this study, the AChE inhibitory activity of Flustra alkaloids was studied in vitro using the colorimetric method of Ellman and AChE from Electrophorus electricus. Twenty-five compounds isolated from the Icelandic bryozoan F. foliacea were screened at a 100 µM concentration. Two of them, flustramine E and flustramine I, showed inhibition of 48%, and flustramine Q showed 82% inhibition. For flustramine Q, the IC50 was 9.6 µM. Molecular modelling and docking studies indicated that simple in silico designed derivatives of flustramine Q could have potential for increased potency. Marine natural products including brominated indole alkaloids from Flustra foliacea are an interesting new source of AChE inhibitors with potential towards central nervous system disorders, e.g., Alzheimer’s disease. Full article
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24 pages, 3977 KiB  
Review
Therapeutic Potential of Bioactive Flavonoids from Citrus Fruit Peels toward Obesity and Diabetes Mellitus
by Kaihui Lu and Yew Mun Yip
Future Pharmacol. 2023, 3(1), 14-37; https://doi.org/10.3390/futurepharmacol3010002 - 04 Jan 2023
Cited by 9 | Viewed by 3193
Abstract
Obesity is associated with a significantly increased risk of cardiovascular and metabolic diseases such as diabetes mellitus. Recently, a growing body of evidence shows that phytochemicals, especially many flavonoids, place an inhibitory regulatory effect on adipogenesis, obesity and diabetes. With computer-aided drug discovery, [...] Read more.
Obesity is associated with a significantly increased risk of cardiovascular and metabolic diseases such as diabetes mellitus. Recently, a growing body of evidence shows that phytochemicals, especially many flavonoids, place an inhibitory regulatory effect on adipogenesis, obesity and diabetes. With computer-aided drug discovery, the action modes of more and more bioactive flavonoids are being identified and confirmed at the molecular level. Citrus fruit peels are particularly rich in bioactive flavonoids which have demonstrated strong therapeutic potentials in regulating lipid metabolisms. However, they are usually thrown away after consuming the flesh, sometimes even causing environmental problems. Thus, extraction of useful flavonoids from citrus fruit waste for pharmaceutical industry could be a profitable and environmentally friendly solution in the future, advocating the concepts of circular economy and sustainable society. The aim of this review is to summarize current evidence on the antiobesity and antidiabetic potentials of identified bioactive flavonoids extracted from the peels of citrus fruits. Our results suggest that various citrus fruit peels could be potential sources for novel drugs and nutraceuticals. Combining experimental data and artificial intelligence methods to study citrus flavonoids would facilitate the discovery of novel drugs against obesity and obesity-related metabolic diseases. Full article
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13 pages, 5925 KiB  
Article
Topical Application of ASPP 092, a Diarylheptanoid Isolated from Curcuma comosa Roxb, Accelerates Wound Healing
by Waratta Hemtong, Aporn Chuncharunee and Gopinathan Pillai Sreekanth
Future Pharmacol. 2023, 3(1), 1-13; https://doi.org/10.3390/futurepharmacol3010001 - 21 Dec 2022
Cited by 1 | Viewed by 1927
Abstract
Wound healing is the restorative process of skin or tissue injury, composed of the inflammatory, proliferative, maturation, and remodeling phases. The current study aimed to examine the efficacy of ASPP 092 (a well-characterized diarylheptanoid from Curcuma comosa Roxb) in modulating wound healing. Full-thickness [...] Read more.
Wound healing is the restorative process of skin or tissue injury, composed of the inflammatory, proliferative, maturation, and remodeling phases. The current study aimed to examine the efficacy of ASPP 092 (a well-characterized diarylheptanoid from Curcuma comosa Roxb) in modulating wound healing. Full-thickness excision wounds were made in rats and treated with either ASPP 092 (dose: 1 mg/mL and 2 mg/mL) or mupirocin (bioequivalent formulation). A control group treated with the vehicle (gel base) was also maintained. The healing efficacy of ASPP 092 was evaluated based on gross appearance, wound closure, and histopathology on days 3, 7, and 12 post-wounding. The expression of cyclooxygenase-2 (COX-2) among the groups was also determined on day 3 post-wounding. Our results suggest that ASPP 092 treatment accelerated wound healing, as evidenced by rapid wound closure, re-epithelialization, and granulation of tissue formation with fewer inflammatory cells. More fibroblasts, collagen fibers, and blood vessels originated with reduced COX-2 expression in the wounds, demonstrating the anti-inflammatory potential of ASPP 092 in experimental wounds. In conclusion, our findings, for the first time, preliminarily identified the potential of ASPP 092 in accelerating wound healing; however, more detailed studies on its mechanism of action in wound healing are required. Full article
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