Future Pharmacology最新文献

{"title":"Single Turnover of Transient of Reactants Supports a Complex Interplay of Conformational States in the Mode of Action of Mycobacterium tuberculosis Enoyl Reductase","authors":"Leonardo K. Martinelli, M. Rotta, C. V. Bizarro, Pablo Machado, L. A. Basso","doi":"10.3390/futurepharmacol3020023","DOIUrl":"https://doi.org/10.3390/futurepharmacol3020023","url":null,"abstract":"The enoyl reductase from Mycobacterium tuberculosis (MtInhA) was shown to be a major target for isoniazid, the most prescribed first-line anti-tuberculosis agent. The MtInhA (EC 1.3.1.9) protein catalyzes the hydride transfer from the 4S hydrogen of β-NADH to carbon-3 of long-chain 2-trans-enoyl thioester substrates (enoyl-ACP or enoyl-CoA) to yield NAD+ and acyl-ACP or acyl-CoA products. The latter are the long carbon chains of the meromycolate branch of mycolic acids, which are high-molecular-weight α-alkyl, β-hydroxy fatty acids of the mycobacterial cell wall. Here, stopped-flow measurements under single-turnover experimental conditions are presented for the study of the transient of reactants. Single-turnover experiments at various enzyme active sites were carried out. These studies suggested isomerization of the MtInhA:NADH binary complex in pre-incubation and positive cooperativity that depends on the number of enzyme active sites occupied by the 2-trans-dodecenoyl-CoA (DD-CoA) substrate. Stopped-flow results for burst analysis indicate that product release does not contribute to the rate-limiting step of the MtInhA-catalyzed chemical reaction. The bearings that the results presented herein have on function-based anti-tuberculosis drug design are discussed.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84430531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic Curcumin Analogues Present Antiflavivirus Activity In Vitro with Potential Multiflavivirus Activity from a Thiazolylhydrazone Moiety","authors":"M. Serafim, T. Kronenberger, R. B. de Oliveira, E. Kroon, J. Abrahão, B. E. Mota, V. Maltarollo","doi":"10.3390/futurepharmacol3020022","DOIUrl":"https://doi.org/10.3390/futurepharmacol3020022","url":null,"abstract":"Arboviral diseases caused by flaviviruses, such as dengue, are a continuing threat and major concern worldwide, with over three billion people estimated to be living with the risk of dengue virus (DENV) infections. There are thus far no antiviral drugs available for treatment, and limited or no vaccines are available. Curcumin and seven synthetic analogues were evaluated for their antiviral activity against dengue virus serotype 2, yellow fever virus and Zika virus, as well as for their cytotoxicity in Vero cells, both by employing MTT assays. Compounds 6 and 7, which present a thiazolylhydrazone moiety, showed moderate activity against all three flaviviruses, with selectivity index (SI) values up to 4.45. In addition, the envelope protein (E) was predicted as the potential target inhibited by both compounds, supported by molecular docking and dynamics simulation analysis. We hope that this data can contribute to the development of new curcumin antiviral analogues in the near future and can help in the search for new promising compounds as potential therapeutic agents to treat flaviviruses infections.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89700641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systems Pharmacology and Network Analysis to Advance Pharmacogenomics and Precision Medicine Decisions in Type-2 Diabetes Therapy","authors":"Aikaterini Saiti, Alexandros Giannopoulos-Dimitriou, Ioannis Kazakos, Eleftheria Galatou, I. Vizirianakis","doi":"10.3390/futurepharmacol3010021","DOIUrl":"https://doi.org/10.3390/futurepharmacol3010021","url":null,"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 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.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86231396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the Impact of Salbutamol Polytherapy: Clinically Relevant Drug Interactions","authors":"Lara Marques, N. Vale","doi":"10.3390/futurepharmacol3010019","DOIUrl":"https://doi.org/10.3390/futurepharmacol3010019","url":null,"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 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.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81449259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Roles of Vitamin D and Polyphenols in the Management of Age-Related Macular Degeneration: A Narrative Review","authors":"N. Fernandes, Marta Castro Araújo, C. Lança","doi":"10.3390/futurepharmacol3010020","DOIUrl":"https://doi.org/10.3390/futurepharmacol3010020","url":null,"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 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.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"184 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83040395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fatty Acid-Binding Protein 5 Gene Deletion Enhances Nicotine-Conditioned Place Preference: Illuminating the Putative Gateway Mechanisms.","authors":"Nicole Roeder, Brittany Richardson, Abrianna Mihalkovic, Samantha Penman, Olivia White, John Hamilton, Ashim Gupta, Kenneth Blum, Mark S Gold, Panayotis K Thanos","doi":"10.3390/futurepharmacol3010007","DOIUrl":"10.3390/futurepharmacol3010007","url":null,"abstract":"<p><p>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. <i>FABP5</i> ^+/+ and <i>FABP5</i> ^-/- 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 <i>FABP5</i> ^-/- mice displayed a higher place preference for 0.1 mg/kg nicotine than the <i>FABP5</i> ^+/+ mice, while no CPP difference was observed for 0.5 mg/kg nicotine between the genotypes. In conclusion, <i>FABP5</i> 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.</p>","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"3 1","pages":"108-116"},"PeriodicalIF":0.0,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9969817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10823357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plant-Derived Metal Nanoparticles (PDMNPs): Synthesis, Characterization, and Oxidative Stress-Mediated Therapeutic Actions","authors":"M. F. Khan, Mohd Aamish Khan","doi":"10.3390/futurepharmacol3010018","DOIUrl":"https://doi.org/10.3390/futurepharmacol3010018","url":null,"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 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.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"77 2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90586536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obeticholic Acid—A Pharmacological and Clinical Review","authors":"Caezaan Keshvani, J. Kopel, H. Goyal","doi":"10.3390/futurepharmacol3010017","DOIUrl":"https://doi.org/10.3390/futurepharmacol3010017","url":null,"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 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.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"92 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80975247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polyols Permeability on Caco-2 Cells and Their Effects on Transport of Low-Permeability Drugs","authors":"D. Truffin, O. Häusler, Mary Martin, S. Cotier, J. Laparre, Manilduth Ramnath","doi":"10.3390/futurepharmacol3010016","DOIUrl":"https://doi.org/10.3390/futurepharmacol3010016","url":null,"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, 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).","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84428723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Applications and Utility of Three-Dimensional In Vitro Cell Culture for Therapeutics","authors":"Suchitra Maheswari Ajjarapu, A. Tiwari, Sundip Kumar","doi":"10.3390/futurepharmacol3010015","DOIUrl":"https://doi.org/10.3390/futurepharmacol3010015","url":null,"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 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.","PeriodicalId":12592,"journal":{"name":"Future Pharmacology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73260045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}